IBMS/ECTS 2001 - PROGRAM and ABSTRACTS
POSTER PRESENTATIONS
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Osteoporosis: Treatment
THE EFECT OF FLUORIDE ON MINERAL FORMATION IN NOVEL HYDROGEL MATRICES OF POLY (VINYLALCOHOL).
J. P. Cassella1*, I. Ahmed1, S. Elliott2
1Division of Biological Sciences
2Division of Environmental Sciences
Taguchi et al (1999) reported the use of a PVA gel as a model for forming hydroxyapatite on/in the three-dimensional structured organic matrix.
By alternating the 'cycling process' in their reported methodology, Taguchi et al found it was possible to control the amount (wt%) of hydroxyapatite and the crystallinity formed as the final product.
Using this novel alternative cycling process, apatite formation at 4°C and 37°Cwas investigated in the presence and absence of fluoride.
The mineral formed was analysed using scanning electron microscopy with energy dispersive X-ray microanalysis (SEM-EDS), infra red spectroscopy (IR), inductively coupled plasma atomic emission spectroscopy (ICP) and X-ray powder diffraction (XRPD).
Using a 'low-cycling' protocol the product formed on the PVA gel at higher calcium-phosphate concentrations was a mixture of at least two phases as determined using XRPD; the main component being brushite (DCPD). At higher cycling and using lower calcium-phosphate concentrations, the sample was 90wt% hydroxyapatite (HA) with the remainder consisting of DCPD and octacalcium phosphate (OCP), both at 2-5wt%. SEM-EDS and ICP demonstrated a mixture of mineral phases resulting in a low calcium-phosphorus ratio compared to a standard sample of HA.
SEM clearly demonstrated the effect of fluoride on crystal structure. There was a marked difference in crystallinity with a reduction in the specific surface area. Fluorapatite formed in subsequent studies demonstrated identical IR spectra to samples of geological fluorapatite from three distinct locations.
The use of a PVA gel matrix offers the opportunity to use this three dimensional model as a powerful tool in the study of time dependent effects of factors such as ion activity on/in hydroxyapatite and drug effects on subsequent matrix mineralisation. The action of these moieties on various mixtures of HA, DCPD and OCP may also be studied due to this unique and novel cycling process which affects the percentages of calcium phosphate mineral-types formed on/in the PVA gel.
Taguchi T, Kishida A, Akashi M. Apatite formation on/in hydrogel matrices using an alternate soaking process (III): Effect of physico-chemical factors on apatite formation on/in poly(vinyl alcohol) hydrogel matrices. J Biomater. Sci Polymer Edn.
10: 8 795-804 1999.
PRAVASTATIN THERAPY INCREASES PROCOLLAGEN I N-TERMINAL PROPEPTIDE, A MARKER OF BONE FORMATION, IN POSTMENOPAUSAL WOMAN
C. De la Piedra1*, J. M. Mostaza2, M. Díaz-Curiel3, R. Peña2, C. Lahoz2
1Fundación Jiménez Díaz, Biochemistry Laboratory, Madrid, Spain
2Hospital Carlos III, Atherosclerosis Unit, Madrid, Spain
3Fundación Jiménez Díaz, Internal Medicine, Madrid, Spain
Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors increase trabecular bone formation in animals and decrease the risk of bone fracture in humans. However, no studies evaluating bone remodeling after HMGCoA reductase therapy have been performed. The aim of our study was to evaluate whether pravastatin treatment affected biochemical markers of bone turnover. Thirty-six hypercholesterolemic, postmenopausal women not on hormonal replacement therapy, were selected from a population study evaluating factors affecting cholesterol response to pravastatin. After a 6 weeks period on a 30% fat diet, participants received treatment with 20 mg per day of pravastatin during a 16-week follow-up period. Pre and post-treatment samples were analyzed for: procollagen I aminoterminal peptide (PINP) and bone alkaline phosphatase (bAP) as markers of bone formation, carboxyterminal telopeptide of collagen I (CTX) as a marker of bone resorption, and procollagen III aminoterminal propeptide (PIIINP) as a marker of fibrogenesis. Total cholesterol decreased from 281±32 mg/dl to 236±30 mg/dl with pravastatin treatment. PINP levels significantly increased (from 33.6±13 to 37.4±16, p=0.03) without changes in bAP or CTX. Individual changes in PINP correlated with individual reduction in cholesterol levels (r=0.337, p=0.04). There was no significant change in PIIINP concentration. Moreover, individual variations in PIIINP did not correlate either with PINP changes or with cholesterol reduction. We conclude that pravastatin treatment increase PINP levels, a marker of bone formation, in hypercholesterolemic, postmenopausal women, without affecting bone resorption. PIIINP concentration, a marker of liver fibrogenesis, was not affected by treatment.
EFFECT OF ANTIHYPERTENSIVE TREATMENT WITH QUINAPRIL, QUINAPRIL-HYDROCHLOROTHIAZIDE AND ENALAPRIL ON MINERAL BONE DENSITY IN HYPERTENSIVE PATIENTSPRELIMINARY RESULTS
J. L. Perez-Castrillón1*, J. Silva1, P. Escudero1, R. Igea1, I. Justo1, M. Martín-Luquero1, C. Pueyo2, C. Diaz2, G. Hernandez2, A. Dueñas1
1Hospital Rio Hortega, Valladolid, Spain
2Pfizer, Spain
OBJECTIVES: Hypertension and osteoporosis are two prevalent diseases in the western world, with a high public health cost; an inverse relationship has been established between systolic blood pressure and bone density, the main determinant of osteoporotic fracture.
The aim of this study is to evaluate the effect of 3 therapeutic drugs, Quinapril, Quinapril-Hydrochlorothiazide and Enalapril on bone mineral density during a follow up period of one year.
METHODS: We present data corresponding to the first 38 patients with mild/ moderate essential hypertension who have completed the study. After 10 days without any treatment, patients were randomized into one of the following 3 groups: Quinapril (40 mg/day), Quinapril (40 mg/day)+Hydrochlorothiazide (12.5 mg/day), Enalapril (20 mg/day). The bone density was measured from the lumbar column (L2-L4) at the beginning of the study and one year after with a DEXA equipment. The results were processed in a SPS statistical program.
RESULTS: At the beginning of the study no differences were found between the 3 groups regarding age, sex, degree of osteoporosis, risk factors, remodelling bone indicators and densitometry. The whole bone mineral density increased 0.63% in the Quinapril treated group, 1.27% in the Quinapril+Hydrocholothiazide group whereas it diminished 0.97% in the Enalapril group, although the differences among the 3 groups were not statistically significant.
CONCLUSIONS: These preliminary results suggest a different effect of Angiotensin-Converting Enzyme Inhibitors (ACEI) on the bone mineral density in hypertensive patients, showing an increase with Quinapril and Quinapril+hydrochlorothiazide and a decrease with Enalapril. These data are still preliminary and non-statistical significant probably because only 38 of the 150 randomized patients have already completed the study. The complete results will allow us to evaluate which is the most suitable treatment in osteoporotic hypertensive patients and the effect of the angiotensin-converting enzyme inhibition on bone mineral density.
PRELIMINARY OUTCOMES OF THE FIRST 311 CONSECUTIVE KYPHOPLASTIES FOR THE FIXATION OF PAINFUL OSTEOPOROTIC VERTEBRAL COMPRESSION FRACTURES
J. M. Lane1, F. P. Girardi1*, S. N. Khan1, F. P. Cammisa1, P. Philips2, H. Yuan3, S. Garfin4, I. H. Lieberman5, H. K. Parvataneni1
1Hospital for Special Surgery, Weill Medical College of Cornell University
2University of Chicago
3SUNY
4UCSD
5Cleveland Clinic
A study was performed to determine the efficacy and safety of minimally invasive reduction and fixation of painful osteoporotic vertebral body compression fractures, utilizing percutaneous Inflatable Bone Tamps.
A multicenter investigation at eight medical centers.
The first 311 consecutive kyphoplasties (164 patients, 190 procedures) were evaluated. The average age was 72.8 years (range 19-93) with 71% female. 1.49 levels were performed per each procedure with an average of 1.06 procedures performed per patient. 1.94 vertebral fractures were treated per patient with a maximum of 7 levels in 1 patient. 46% of the fractures were thoracic and 76% were at T11 and below. Diagnosis included primary osteoporosis (79%) secondary osteoporosis (15%) and multiple myeloma (3%) and other (4%). All patients had failed conservative medical management.
Main Outcome Measurements: Pain relief and correction of deformity.
Results: For pain results, 182 of 190 patients (95.8%) improved within 24 hours; for the rest the pain remained unchanged. 68/75 patients reached by telephone reported that their back pain was improved (90.7%) at the time of follow-up (average time: 4 months). 6/75 were the same (8.0%). 1/75 was worse (1.3%). The mean pre- versus post- treatment results were: anterior 68±12% of predicted normal height versus 84±14% (p<0.004); midline, 66±16% versus 90±12% (p<0.001); posterior, 74±7% versus 88±10% (p<0.01). This represents an average of 50% (anterior), 67% (midline) and 53% (posterior) of the lost height measurements. There were three major complications caused by the procedure, two neurological and one pulmonary. These represent a 1.8% complication rate per patient and 1.0% complication rate per procedure.
Conclusion: Kyphoplasty offers a highly successful method to provide marked rapid pain relief in (96%) patients with compression fractures that have failed medical management. Kyphoplasty therefore offers a solution for pain and deformity and rapid rehabilitation of the patient while awaiting the later benefits of medical intervention.
EFFECTS OF LOW FREQUENCY MAGNETIC FIELDS (LFMF) ON BONE QUALITY AND BONE METABOLISM IN OVARIECTOMIZED RATS
X. Y. Zhang*, Y. Xue
Department of Biology Engineering, Shenzhen University, Shenzhen 518060, China
Objective: To investigate mechanisms of prevention and treatment of osteoporosis using low frequency magnetic fields.
Methods: Sixty female SD rats (body weight 260±14) were divided into six groups: (A) Sham group, (B) OVX group, (C) OVX + Calcium(Ca) supplementation group, (D) OVX + Ca supplementation + magnetic field 30'/day, (E) OVX + magnetic field 30'/day, (F) OVX + magnetic field 60'/day.
Results:
(1) Femoral bone mineral density
BMD in F group was higher than those in B group and E group respectively by 8% and 4% (P<0.05). However, there was no significant difference in BMD among C group, B group and E group.
(2) Maximum of Load in D group was higher than those in C group and E group respectively by 5% and 9% (P<0.05). Elastic of Modulus in D group and E group were higher than those in C group (respectively by 11% and 1%, P<0.05).
(3) Dry weight of femur ash weight of femur bone mineral content (BMC) in F group were much higher than those in B group (P<0.05). BMC of E group was much higher than those in B group by 13% (P<0.05). Dry weight of femur | ash weight of femur in D group were higher than those in B group by 9% and 26% (P<0.05). Ash weight of femur | BMC of C group was higher than that in B group by 21% and 15%, (P<0.05).
Conclusions Low frequency magnetic fields could significantly improve the BMD, BMC and bone strength, having better effects compared with only Ca supplementation.
STUDY ON CLINICAL EFFECT OF PULSE ELECTROMAGNETIC FIELD TREATMENT
Y. T. Zhao*, C. F. Chen
Bone mineral Unit, Jinan military, General Hospital, Jinan, Shangdong 250031, PR China
Aim: The osteoporosis treatment system (OTS) (the pulse electromagnetic field treatment apparatus produced by Jangsu Tianma High Tech Co. Ltd.) is the crystallization of international technologies. The characteristic of OTS is to improve the basic metabolism of human body by means of intelligent physical electromagnetic therapy. In order to verify the reliability of the OTS treatment, we choose invited thirty patients (15 men and 15 women), aged from 46 to 66 years old (average 60) for treatment. All the information, including body height, weight and bone mineral density (BMD) (SPA,BMD-400) was put into computers. One treatment lasted 30~45 minutes. One period of treatment was 20~30 times.
Results: After the 30 patients accepted 2 to 5 periods of treatment, the bone pain induced by lacking calcium was relieved in all patients obviously compared with some medication. Also all patients felt full of vim and vigour.
Conclusions: The effect of OTS treatment is definite. It can relieve pain in a short time, the patients can feel in high spirits. Whether OTS could increase BMD and regulate DNA duplication, and decorate cell action, needs further study.
EFFECTS OF HMG-COA REDUCTASE INHIBITORS, STATINS, ON BONE LOSS: A PROSPECTIVE POPULATION-BASED COHORT STUDY IN EARLY POSTMENOPAUSAL WOMEN
J. Sirola1,2*, R. Honkanen1, H. Kröger2, J. Jurvelin3, P. Mäenpää1, S. Saarikoski4
1University of Kuopio, Kuopio, Finland
2Kuopio University Hospital, Department of Surgery, Kuopio, Finland
3Kuopio University Hospital, Dpt Nuclear Medicine & Clinical Physiology, Kuopio, Finland
4Kuopio University Hospital, Department of Obstetrics and Gynaecology, Kuopio, Finland
Recent experimental and epidemiological studies have suggested that the lipid-lowering HMG-CoA reductase inhibiting drugs, statins, may have a bone protective effect. We studied the effects of statin use on bone mineral density (BMD) change among 620 women aged 53-64 years in a prospective 4.5-year cohort study based on subjects from Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study, Finland. Of these women, 58 had a history of more than 4 years and 60 women less than 4 years of statin use. 142 of the 502 non-users of statins reported hypercholesterolaemia whereas the rest of the non-users did not. Characteristics of the study population were obtained with postal inquiries in 1994 and 1999 and the BMDs were measured with DXA in 1995-1996 and 1999-2000 in Kuopio University Hospital. The mean annual spinal and femoral BMD changes (%) of study groups were 0.35 and -0.38 for the more than 4-year statin users, 0.46 and -0.33 for the less than 4-year statin users, 0.18 and -0.55 for the hypercholesterolaemic non-users of statins and 0.28 and -0.54 for the non-users without hypercholesterolaemia, (p=0.500 and p=0.525) respectively. The corresponding BMD changes adjusted for age, years since menopause, BMI, BMD at baseline, calcium intake, estrogen and corticosteroid use and duration of follow-up were 0.37 and -0.38, 0.45 and -0.37, 0.11 and -0.54, 0.29 and -0.44 (p=0.358 and p=0.783), respectively. The comparison between the five different statin groups (simva-, lova-, fluva-, prava- and atorvastatin) also showed no effect between the two statin user groups. Our results suggest that statins should not be considered, in doses used for hypercholesterolaemia, as bone preserving agents in humans. Randomised trials are needed to confirm these results.
POSITIVE EFFECTS ON BMC AFTER A HIP FRACTURE. A 12 WEEK DOUBLE-BLIND STUDY WITH GROWTH HORMONE TREATMENT
M. Hedström1*, E. Brosjö2, C. Hurtig2, K. Sjöberg3, N. Dalén1
1Div of Orthopedics, Karolinska Institute, Danderyd Hospital, Danderyd, Sweden
2Div of Radiology, Karolinska Institute, Danderyd Hospital, Danderyd, Sweden
3Div of Geriatrics, Karolinska Institute, Danderyd Hospital, Danderyd, Sweden
Patients operated on for a hip fracture lose muscle and bone mineral mass (BMC) postoperatively. The aim with the present study was to investigate if growth hormone (GH) given postoperatively could reduce the loss of lean body mass and BMC.
PATIENTS AND METHODS 17 patients operated on for a hip fracture were randomized to a double-blind randomised study with s.c. injections daily of recombinant human growth hormone (Genotropin) O.1 IU/kg or placebo for 21-28 days, depending on the length of the hospital stay. BMC and body composition were assessed by DXA, and BMC was also measured with QCT. Serum IGF-I concentrations were measured by specific radioimmunoassay technique.
RESULTS The mean S-IGF-I increased from 59 ng/mL to 206 after 1 week with GH treatment, while the placebo group initially had a mean IGF-I level of 63ng/mL and after a week 80ng/mL. Total body BMC (DXA) as well as BMC in the distal femur (QCT) increased in the GH group while it decreased in the placebo group. The GH group did not lose lean body mass during treatment as the placebo group did.
CONCLUSIONS Despite the short period with GH treatment we found a positive effect on BMC and it seemed to preserve lean body mass. The treatment was well tolerated with few adverse events. There could be a beneficial effect of GH on BMC and lean body mass postoperatively in patients with hip fractures.
LONG-TERM EXPOSURE TO STRONTIUM RANELATE DOSE-DEPENDENTLY INCREASES BONE STRENGTH IN INTACT FEMALE RATS
P. Ammann1*, B. Robin2, J. P. Bonjour1, I. Tupinon-Mathieu2, J. M. Meyer1, R. Rizzoli1
1Div. of Bone Diseases, Dpt. of Int. Med., and School of Dentistry, Univ. Hosp., Geneva, Switzerland
2Inst. Recherches Internationales Servier, Courbevoie, France
Earlier studies in intact or ovariectomized rats have suggested that Strontium Ranelate (SR) stimulated bone formation, inhibited bone resorption and increased trabecular bone volume without altering mineralization. In this study, we investigated the long-term effects of SR on bone mineral density (BMD; mg/cm2), bone strength and bone outer dimensions at the level of the lumbar spine (L4) and midshaft femur. Seven-week old intact female rats were allocated to 4 groups of 30 rats fed a diet (ad libitum) containing SR at a dose of 0 (control), 225, 450 or 900 mg/kg/d, for 104 weeks. BMD was not adjusted for bone strontium content. Ultimate strength (in Newton, N), stiffness and energy (in N.mm) were measured using a compression test of vertebral body and a three-point bending test of midshaft femur. Values are means±SEM; * indicates p<0.05 vs control by ANOVA.
The energy was significantly increased by +54% and +19% at 900 mg/kg/d for the vertebra and femur, respectively. The increase of ultimate strength and energy was dose-dependant and was correlated to BMD mainly at the femur level. There was no difference in stiffness, suggesting no alteration of the bone quality, thus indicating no mineralization defect. The volume of the vertebrae increased significantly at the highest dose level (+6.5%), as did the diameter of the midshaft femur (+4.3%).
A long term treatment with a high dose of Strontium Ranelate in rats dose-dependently increased the bone strength in association with an increase of BMD and dimensions, whilst maintaining bone quality.
MILK BASIC PROTEIN (MBP) PROMOTES BONE FORMATION AND SUPPRESSES BONE RESORPTION IN VIVO
A. Itabashi1*, Y. Takada2, Y. Toba2, Y. Matsuoka2, S. Aoe2, H. Kawakami2, K. Nemoto1, M. Kumegawa3
1Clin Lab Med, Saitama Medical School, Saitama, Japan
2Nutr Sci Lab, Snow Brand Milk Co,, Saitama, Japan
3Oral Anatomy, Meikai University of Dentistry, Saitama, Japan
[Purpose] Milk is an excellent source for calcium supplementation to preserve skeletal health. However, milk contains various proteins other than calcium that may be important for skeletal growth. We previously reported that milk whey protein (MWP) as well as milk basic protein (MBP), an active component of MWP, stimulated osteoblastic bone formation and suppressed osteoclastic bone resorption in vitro. Moreover, MBP directly decreased the number of pits, dose-dependently in the isolated rabbit osteoclasts. In this report, we will show the effect of MBP in vivo, on the growing rats as well as on the ovariectomized (OVX) rats.
[Methods] Growing rats: Five-week-old female SD rats were separated into four experimental groups. Control rats were fed with the AIN-76 diet ad libitum for 4 weeks. MBP was given by mouth at the dose of 20 mg/kg, 40 mg/kg and 80 mg/kg per day to the MBP group. OVX rats: Fifty one-week-old female SD rats were ovariectomized or sham-operated (Sham). The OVX rats were fed with the control diet containing 0%, 0.01% or 0.1% MBP for 17 weeks. Sham rats were fed with the control diet. Bone mineral density (BMD) of the femur was serially measured using dual-energy X-ray absorptiometry. The breaking strength and bone histology were also determined.
[Results] In growing rats, MBP increased BMD and bone strength of the femur dose-dependently. MBP also increased the serum bone specific alkaline phosphatase, a marker of bone formation. Moreover, the osteoblast number of tibia also increased in this study. In addition, MBP stimulated the growth in the cartilage growth plate of the rat and increased the number of chondroblasts. In OVX rats, MBP prevented bone loss of the femoral metaphysis induced by ovariectomy and the breaking energy in the 0.1% MBP group was higher than OVX control group. Urinary excretion of deoxypyridinoline was clearly suppressed by the addition of MBP.
[Conclusion] Since MBP was found to promote bone formation and to suppress bone resorption in vivo as well as in vitro, it may be a very useful substance in the milk other than calcium for skeletal health.
MUSCLE/BONE BIOMECHANICAL INTERACTIONS AS AFFECTED BY GROWTH HORMONE (GH) TREATMENT IN HYPOPHYSECTOMIZED (HX) RATS
S. Feldman*, G. R. Cointry, R. Gordon, J. L. Ferretti
Department of Immunology and Center for P-Ca Metabolism Studies, Rosario University School of Medicine, Rosario, Argentina
This study analyzes the effects of 0, 30 or 150 mUI/d of sc GH for 45 days on bone mass, material properties, architecture (pQCT) and mechanical properties (3-point bending tests) of femur diaphyses, and the gastrocnemius wet mass in adult, Hx Sprague-Dawley rats (n=5, 8, 8).
Treatment improved the architectural indicators (periosteal -not endosteal- perimeter, cortical thickness, cross-sectional area and moments of inertia, CSMIs), the "mass" and calcification indicators (BMC, volumetric BMD) of cortical bones, and the mechanical indicators (diaphyseal stiffness and strength -fracture load-). The elastic modulus (intrinsic stiffness) of cortical bone did not change but correlated linearly with the diaphyseal stiffness and strength, with similar slopes but different intercepts for each group of animals. This suggests the participation of other (geometric) variables in the pathogenesis of GH-induced changes. The cortical area and CSMIs correlated with the improvements in mechanical properties showing a single slope for all groups, suggesting that GH effects depended more upon changes in bone architrecture than in material quality. The hormone also induced an "anabolic" shift of the "Distribution / quality" curves (CSMI / volumetric BMD or elastic modulus) of the total bone to the upper-right side of the graphs, following a dose-response fashion. Gastrocnemius mass (y) was increased parallelly to the improvements in CSMIs and mechanical properties (x) but treated rats showed a shift to the right, suggesting a decreasing impact of muscular hypertrophy on the diaphyseal design as the GH dose increased.
No negative effects of the hormone were shown. Treatment seems to have added new, normal or slightly overmineralized material of normal intrinsic stiffness, chiefly on the periosteum, thus improving bone design and strength showing a dose-related pattern. The significant but decreasing influence of the dose-dependent, progressive gastrocnemius hypertrophy on bone changes may be explained because GH increased more muscle mass than muscle strength. If so, then, at progressively higher doses, the induced improvement in bone mass and design would have depended more upon metabolic effects (balance between bone formation and resorption) than on biomechanical interactions.
CYCLICAL ETIDRONATE THERAPY FOR PREVENTION OF BONE LOSS IN MEN WITH IDIOPATHIC OSTEOPOROSIS: A 1-YEAR STUDY
B. Gerbert*, H. Heinze, J. Schulze
Clinic of Internal Medicine III, University of Dresden, Germany
The objective of this prospective study was to assess the efficiency of a cyclical therapy with etidronate on bone mineral density in men suffering from idiopathic osteoporosis. Subjects consisted of 50 men (age 50.4±14.4 years) with idiopathic osteoporosis (T-score <-2.5 at lumbar spine or neck). The primary clinical symptom was back pain. At enrollment 4 of them had one or more vertebral fractures.
On baseline both serum levels of vitamin D3, testosterone, TSH, parathyroid hormone, osteocalcin, calcium, phosphate, alkaline phosphatase and 24h-urine levels of cross links, N-telopeptides, calcium, phosphate were normal. We repeated all measurements after 3, 6 and 12 months of therapy. X-ray films of thoracic and lumbar spine and dual-energy X-ray absorptiometry (DXA) at various skeletal sites (hip, spine) were performed at enrollment and after one year of the cyclic therapy with etidronate (400 mg about 2 weeks every 3 months). Additionally, subjects received 1000 mg calcium and 800 IE colecalciferol daily.
After one year of therapy we found serum level of parathyroid hormone as well as urine levels of deoxypyridinolin-crosslinks and N-telopeptides to have decreased significantly, whereas a significant increase of calcium in urine was measured. Serum level of pyridinolin-crosslinks diminished not significantly, and serum levels of alkaline phosphatase, bone specific alkaline phosphatase and osteocalcin increased not significantly during the period of observation. Serum levels of calcium and phosphate remained unchanged.
We measured a significant increase of bone mineral density in the lumbar spine (p<0.01) by +3.0% (L1 +1.8%, L2 +3.4%, L3 4.1%, L4 +3.2%) and by +2.3% in the neck (p< 0.05). The increase of BMD in Ward’s triangle (+1.2%) and in the trochanter (+1.5%) was not significant.
No new vertebral or hip fracture was recorded in the course of the study.
It is concluded that cyclical etidronate therapy is efficient for male patients suffering from idiopathic osteoporosis.
ALENDRONATE TREATMENT OF PATIENTS WITH POSTMENOPAUSAL OSTEOPOROSIS AND IMPAIRED FASTING GLUCOSE
M. Cokolic1*, R. Hren2
1Teaching Hospital Maribor, Maribor, Slovenia
2University of Ljubljana, Ljubljana, Slovenia
Impaired fasting glucose (IFG) designates a metabolic stage between normal glucose homeostasis and diabetes (serum levels of fasting glucose between 6.1 mmol/l and 7.0 mmol/l). The primary aim of this study was to monitor levels of blood glucose, HbA1c, and bone mineral density (BMD) in patients with IFG that are treated for postmenopausal osteoporosis.
Six women with IFG and postmenopausal osteoporosis (T-score < - 2.5 SD) were enrolled in a one-year prospective study. Patients were 62 to 71 years old (mean: 68 years) and 9 to 28 years (mean: 18 years) after the menopause. They were treated with alendronate sodium (10 mg/d) in combination with 500-mg elemental calcium. The BMD in the lumbar spine (L2 - L4) and left hip was measured in all patients using dual energy X-ray densitometry (Hologic QDR 2000 +) at the start of the treatment and at 6 and 12 months after initiation of the treatment. The serum levels of glucose, HbA1c, Ca, P, Mg, alkaline phosphatase (ALP) and creatinine were measured at the same time intervals. In all patients, IFG was treated only with diabetic diet.
Serum levels of fasting glucose showed minimal variation during the treatment, with an average value of 6.3 mmol/l (range 6.1 - 6.6 mmol/l) in the beginning of the treatment and 6.3 mmol/l (range 6.1 - 6.4 mmol/l) after 12 months of treatment. The average level of HbA1c was 6.5% (range 6.2 - 6.6%) at the start of treatment and 6.6% (range 6.1 - 6.7%) after 12 months of treatment. In 12 months, BMD increased on average by 2.4% (range 0.0 - 6.5%) in the lumbar spine (L2 - L4) and by 2.4% (range 0.5 - 4.6%) in the left hip. Levels of Ca, P, Mg, ALP, and creatinine were within normal limits during the treatment, and no clinical side effects were observed during the study.
Our results suggest that alendronate sodium administration can provide clinically relevant benefits in postmenopausal women with IFG and osteoporosis while increasing BMD and not affecting serum levels of Ca, P, Mg,, ALP, creatinine, glucose, and HbA1c. Alendronate sodium was well tolerated in all patients.
EFFECT ON BMD OF VARIOUS DOSES OF PAMIDRONATE WITH CONSTANT YEARLY DOSE: A 2 YEARS PILOT STUDY
S. A. Fatio*, L. Sandini, O. Lamy, P. Burckhardt
Lausanne University Hospital, Switzerland
Introduction: Bisphosphonates are potent drugs for osteoporosis, but tolerance to oral treatment is often limited. Pamidronate (APD) administred intravenously every three months is well tolerated. However the best regimen is still unknown. We tested various doses of pamidronate in post-menopausal women with osteoporosis, keeping the yearly dose constant.
Methods: 25 postmenopausal women (age 62.4±2.5) received 120 mg/year intraveinously APD in 4times30 mg (nequal17) or 3times40 mg (nequal8) for two years. The two groups did not differ in age, BMI, baseline BMD or bone markers. Osteocalcine (OC) and urinary C-telopeptides (UCTX) were measured at months 0, 12 and 24, DEXA at months 0 and 24.
Results: The decrease of OC and UCTX are expressed in table (percent±SEM). The observed decrease of bone turnover was of the same magnitude as those noticed with oral bisphosphonates. The increase of BMD from month 0 to month 24 (±SEM) was significant for both groups, it was respectively for group 30 and 40 mg: lumbar spine 10.9%±2.5%* versus 7.8%±0.8%*, femoral neck 2.9%±1.4%** versus 2.2%±1.1%, trochanter 2.2%±1.3% versus 5.2%±1.7%** (*p value less than 0.001, ** p value less than 0.05, student t-test). There was no statistical difference between both groups (bone markers and BMD). We noticed respectively 7/17 and 2/8 flu-like syndrom in group 30 and 40 mg. There were 3 fractures occured in group 30 mg.
Conclusions: The decrease of bone remodelling parameters and the increase of BMD were of same magnitude as those observed with oral bisphosphonates. There was no statistical difference between intravenously APD administered in 4 times 30 mg or 3 times 40 mg. The result of this pilot study open the possibility to treat osteoporosis with only three or less perfusions per year.
| Month 12 | Month 24 | |
| OC APD 30 | -44.9±6.2** | -37.2±5.6** |
| OC APD 40 | -48.1±5.4** | -55.8±3.8* |
| UCTX APD 30 | -55.6±8.7** | -55.6±7* |
| UCTX APD 40 | -29.3±36.7 | -57.2±9** |
ALENDRONATE VERSUS ETIDRONATE FOR OSTEOPENIC PATIENTS WITH PRIMARY BILIARY CIRRHOSIS
N. Guañabens1*, A. Parés2, I. Ros1, F. Pons1, L. Alvarez1, L. Caballería2, A. Monegal1, M. Roca3, P. Peris1, J.Rodés2
1Metabolic Bone Diseases Unit, Hospital Clínic, IDIBAPS, University of Barcelona, Spain
2Liver Unit, Hospital Clínic, IDIBAPS, University of Barcelona, Spain
3Department of Pharmacy, Hospital Clínic, University of Barcelona, Spain
Since in osteopenic patients with primary biliary cirrhosis (PBC) etidronate has not enough potential for increasing bone mass after two years of treatment we have compared the effects of alendronate versus etidronate in 32 women with PBC (age: 57±1.3 years) who were randomly assigned to receive alendronate (10 mg/d) or etidronate (400 m/d during 14 days every 3 months) for two years. Bone mineral density (BMD, g/cm2) of the lumbar spine (L), and proximal femur -neck (N), Ward's triangle (W) and trochanter (T)- were measured by dual X-ray absorptiometry initially and every 6 months. Bone fractures were evaluated initially and at the end of the study. Serum bone Gla-protein, aminoterminal propeptide of type I procollagen, urinary hydroxyproline, and cross-linked C and N telopeptides of type I collagen CTx were measured initially and every 6 months.
Sixteen patients were allocated into each group, which were comparable with respect to the severity of PBC and osteopenia. Two patients with etidronate and one patient with alendronate left the trial because of gastrointestinal symptoms. Thirteen patients in each groups completed two years of treatment. At the end of the trial the BMD increase from baseline at the lumbar spine and proximal femur was significantly higher in patients taking alendronate (L: 5.8±1.3%; N: 3.5±0.9%; W: 2.3±1%; T: 5.1±1.6%) than in those receiving etidronate (L: 1.9±1.1%; N: 0.4±1.3%; W: -4.2±2.3%; T: 4.1±1.4%) No patient developed new vertebral fractures, but new peripheral fractures were detected in 2 patients under alendronate and in 1 receiving etidronate. After two year of treatment markers of bone turnover declined more markedly in patients under alendronate than in those under etidronate. Neither treatment impaired liver function.
We conclude that alendronate is safe and more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis.
INTRAVENOUS PAMIDRONATE TREATMENT IN PATIENTS' HOMES
K. R. H. Adams*, K. Turner
Royal Bolton Hospital, UK
AIM
To report on the experience of using intravenous Pamidronate in patients' homes, for patients with Paget's Disease or osteoporosis.
BACKGROUND
Intravenous Pamidronate has been used for Paget's Disease for sometime, and although not licensed is also used for treating osteoporosis, particularly for patients with severe back pain related to osteoporotic vertebral collapse. Patients admitted because of severe back pain due to osteoporotic vertebral collapse had the first two infusions given in the hospital. Initially in those not admitted, Pamidronate was given as a day case in hospital. Due to increasing pressure on beds it was decided to administer the first dose in hospital and subsequent doses at home using a specialised team of nurses - Rapid Response Team, who have been trained to administer intravenous treatments. Thereafter because of increasing confidence with using the treatment, it was decided wherever possible to administer all intravenous Pamidronate treatments at home. Doses of Pamidronate given for osteoporosis were 30mg followed by 60mg after two weeks, and 30mg every three months thereafter. The 30mg infusion was given over 30 minutes and the 60mg over 60 minutes. Pamidronate made up by hospital pharmacy.
RESULTS OVER A TWO YEAR PERIOD
Thirty two patients have been treated, involving 117 intravenous Pamidronate treatments at home. Average age 81.4 years (age range 60-94). Twenty nine had severe osteoporosis with multiple vertebral collapse and severe back pain. Twelve of these patients were intolerant of Cyclical Etidronate or Alendronate, eight reporting no benefit with oral Bisphosphonate. Three patients had treatment stopped in the osteoporosis group, one after a cerebral vascular accident (previous history of cerebral vascular accident), one reporting slight hair loss after her first treatment and one patient felt generally unwell for a few days after second treatment. Seventeen patients reported very significant improvement in back pain. All patients expressed satisfaction with being treated at home.
Three had Paget's Disease. One of the Paget's patient developed vomiting four days after the third infusion. This did not settle and investigation showed hepatic metastasis. No other adverse effects were reported.
COMMENT
Intravenous Pamidronate treatment at home is acceptable to patients. It saves significant use of hospital beds, and appears safe and well tolerated.
INTRAVENOUS IBANDRONATE IN OSTEOPOROTIC MEN WITH KLINEFELTER´S SYNDROME: EFFECTS ON BONE MINERAL DENSITY AND BIOCHEMICAL MARKERS DURING 2-YEARS TREATMENT AND AFTER WITHDRAWAL
J. J. Stepan1*, P. Burckhardt2, V. Hána1
13rd Dept. of Internal Medicine, Charles University Faculty of Medicine, Prague, Czech Republic
2Département de médecine interne, University, Lausanne, Switzerland
Effects of treatment and withdrawal of ibandronate was studied in 13 patients with Klinefelter´s syndrome. The diagnosis of Klinefelter´s syndrome was confirmed by cytogenetical analysis. The average age of the patients was 55.8 yr. (50 - 64 yr.), height 178.2±5.3 cm, and weight 86.1±14.1 kg. The patients were followed when untreated for 70.6±2.9 months, than treated for 2 years and followed again when untreated for 1 year. Mean rate of bone loss before treatment (±SD) was 1.34±0.77% per year at the lumbar spine, 0.90±0.32% at the femoral neck and 0.64±0.32% at the total body (DPX-L bone densitometer, Lunar, WI). Before treatment, mean BMD T-score at the lumbar spine, femoral neck and total body was -2.60±1.08, -1.40±0.94, and -1.70±1.06. Median serum testosterone concentration (1.1; 0.6 - 3.2 ng/ml) was significantly (p<0.01) decreased compared to normal values. After 12 and 24 months of treatment with intravenous (IV) ibandronate (2 mg every three months), respectively, patients had gained 8.11±2.14% and 10.06±4.29%, at the lumbar spine; 3.39±3.94% and 6.71±5.46% at the femoral neck, and 4.58±2.29% and 5.00±2.35% at the total body; serum CTX (Osteometer, Denmark) decreased by 4% and 19% and serum PINP (Orion, Finland) by 41% and 47% (p<0.05). One year after withdrawal of the treatment, patients had lost 2.06±3.17% at the lumbar spine; 4.31±3.83% at the femoral neck, and 0.12±2.40% at the total body; serum CTX increased by 102% and serum PINP by 83% (p<0.05), as compared with values on the second year of treatment. Conclusion: In men with Klinefelter´s syndrome and osteoporosis, treatment for 2 years with IV ibandronate increased BMD at the spine, hip, and total body. The increases in BMD were relatively similar at all sites except for forearm. After withdrawal of ibandronate, bone loss resumed above the pretreatment rate. In this situation of hypogonadism, and probably unlike postmenopausal osteoporosis, suppression of synthesis of type I collagen, exceeding suppression of collagen degradation, as well as secondary hyperparathyroidism seem to interfere with the antiresorptive effects of ibandronate.
FOLLOW-UP ENDOSCOPY STUDY COMPARING RISEDRONATE AND ALENDRONATE IN POSTMENOPAUSAL WOMEN STRATIFIED BY H. PYLORI STATUS
A. B. R. Thomson1*, J. K. Marshall2, R. H. Hunt2, F. L. Lanza3, M. A. Blank4
1University of Alberta, Edmonton, AB, Canada
2McMaster University, Hamilton, ON, Canada
3Houston Institute for Clinical Research, Houston, TX, USA
4Procter & Gamble Pharmaceuticals, Mason, OH, USA
Bisphosphonates (BPs) are effective treatments for osteoporosis but have been associated with GI mucosal injury. This study compared gastric ulcer incidence after treatment with risedronate (RIS) or alendronate (ALN) at doses approved for treatment of osteoporosis in healthy postmenopausal women stratified by H. pylori (HP) status. Subjects were randomized to receive RIS 5 mg (n=318) or ALN 10 mg (n= 317) daily for 14 days. Evaluator-blind assessment of the esophageal, gastric, and duodenal mucosa was performed at baseline and on Days 8 and 15.
The overall incidence of gastric ulcers greater than or equal 3 mm was lower in the RIS group (6.0%) than in the ALN group (12.1%) (p<0.05). In HP+ subjects gastric ulcer incidence was 3.9% (RIS) versus 13.9% (ALN) (p<0.05). In HP- subjects gastric ulcer incidence was 6.7% (RIS) versus 11.5% (ALN) (p>0.05). Ulcers greater than or equal to 5 mm were noted in 3.3% of RIS subjects versus 7.7% of ALN subjects. Mean gastric endoscopy scores at Days 8 and 15 were lower in the RIS group than in the ALN group (p<0.001). Mean esophageal and duodenal endoscopy scores were similar in the 2 groups at Days 8 and 15. Three esophageal ulcers in 2 patients were noted in ALN subjects and 1 esophageal ulcer was noted in 1 RIS subject. Clinical upper GI adverse events (dyspepsia, abdominal pain, regurgitation, esophageal reflux) occurred in more subjects on ALN (8.8%, n=28) than RIS (5.7%, n=18).
When administered at doses for the treatment of osteoporosis, RIS was associated with a significantly lower incidence of gastric ulcers than ALN. These results are consistent with those of a previous similar study despite differences between the studies in the shape and polish of the ALN tablets used. HP did not increase the incidence of BP-related GI injury. These findings support the hypothesis that BPs differ in their potential to produce upper GI mucosal damage.
RAPID AND SUSTAINED HIP FRACTURE RISK REDUCTION WITH RISEDRONATE IN ELDERLY WOMEN WITH OSTEOPOROSIS
C. Cooper1*, J. Y. Reginster2, M. McClung3, N. L. Zorich4, Z. Li4
1University of Southampton, Southampton, UK
2University of Liege, Liege, Belgium
3Oregon Osteoporosis Center, Portland, OR, USA
4Procter & Gamble Pharmaceuticals, Mason, OH, USA
Hip Intervention Program (HIP) is the largest prospectively planned study of risedronate (RIS) with hip fracture efficacy as a primary endpoint. Previously we reported that risedronate is effective in significantly reducing hip fracture risk over 3 years by 39% in Group 1 patients. Group 1 patients were enrolled based on a femoral neck T-score less than -3, aged less than 80 years and at least one additional clinical risk factor for hip fracture. Patients were randomized to receive RIS or placebo daily for 3 years, 1g/d calcium, and vitamin D supplementation if baseline levels were less than 40 nmol/L. We conducted an analysis to determine the onset of the effect of hip fracture reduction in Group 1 patients.
RIS reduced the risk of hip fracture by 47% in Group 1 patients from months 6-18 (p=0.043). There was a sustained reduction in the risk of hip fracture for the remainder of the study period: 45% (p=0.045) in Group 1 patients (months 18-36).
To summarize, risedronate produced rapid and sustained risk reductions of hip fracture in patients with confirmed osteoporosis.
| Hip Fracture Risk Reduction with Risedronate | ||||
| Interval, months | Incidence* % | Risk Reduction | p | |
| Control | RIS | |||
| 0-36 | 3.30 | 1.95 | 39% | 0.015 |
| 6-18 | 1.60 | 0.85 | 47% | 0.043 |
| 18-36 | 2.03 | 1.12 | 45% | 0.045 |
| *Kaplan-Meier estimate | ||||
RISEDRONATE PREVENTS BONE LOSS IN MEN ON GLUCOCORTICOID THERAPY
D. J. Hosking1*, D. M. Reid2, J. P. Devogelaer3, A. A. Chines4, E. Sod4
1Nottingham City Hospital, Nottingham, UK
2Aberdeen Royal Infirmary, Aberdeen, UK
3Louvain Catholic University, Brussells, Belgium
4Procter & Gamble Pharmaceuticals, Mason, OH, USA
Of the 518 patients enrolled in studies of patients initiating or on maintenance of glucocorticoid (GC) therapy (Prevention: less than 3 months on GC therapy and Treatment: greater than 6 months GC therapy), 186 were men. There were 77 men in the Prevention study and 109 in the Treatment study. The mean ages and lumbar spine T-scores were 59.5, -0.38 for the Prevention study and 56.2 and –1.67 for the Treatment study respectively. Patients were randomized to receive placebo, or risedronate (RIS) 2.5 mg, or RIS 5 mg daily for 1 year in both studies. Patients were supplemented with elemental calcium 500 mg/day or elemental calcium 1 g/ day and vitamin D 400 IU/day. Most men in the studies were taking GC therapy for either rheumatoid arthritis (38%) or lung disease (22%).
RIS 5 mg significantly increased BMD or prevented bone loss at both the spine and the hip in men.
23% (9 out of 38) of placebo patients had a new vertebral fracture compared with 5% in the risedronate 2.5 and 5 mg/day treated group (3 out of 58). The vertebral fracture risk reduction was 82% (p=0.008) for pooled risedronate doses.
In summary, these studies demonstrate that risedronate is effective in preventing bone loss in men recently on glucocorticoids and can increase BMD in men on long term glucocorticoid therapy.
| 1 year BMD Mean (SE) % Change from Baseline in Men Taking Glucocorticoids | |||
| Treatment Group | |||
| Prevention Study | Control n | RIS 2.5 mg n | RIS 5 mg n |
| Lumbar spine | -3.4 (0.8)* 19 | 0.3 (1.3) 9 | 0.8 (0.6)# 24 |
| Femoral neck | -3.3 (1.1)* 20 | -0.7 (1.7) 9 | 1.5 (1.0)# 24 |
| Trochanter | -3.4 (0.9)* 20 | -0.3 (1.1) 9 | 1.5 (0.8)# 24 |
| Treatment study | |||
| Lumbar spine | 1.2 (0.8) 22 | 2.1 (0.8)* 25 | 4.8 (0.9)*# 25 |
| Femoral neck | -0.2 (1.0) 24 | -0.7 (0.8) 25 | 2.1 (0.7)* 25 |
| Trochanter | 0.5 (1.4) 24 | 0.4 (0.8) 25 | 2.6 (0.5)* 25 |
| * p less than or equal to 0.05 vs. baseline; # p less than or equal to 0.05 vs. control | |||
EFFECT OF ALENDRONATE (ALE) AFTER SUCCESSFUL CYCLICAL ETIDRONATE (ICE) THERAPY IN OSTEOPOROTIC WOMEN
D. S. Ooi*, A. B. Cranney, M. Murdock, J. D. Gay
Ottawa Hospital Civic Campus, Ottawa, Canada
Background: In a retrospective study (Bone 23:S404-5), we reported increases in bone density by dual x-ray absorptiometry (DXA) with ALE following successful ICE. Here is a preliminary report on a 2y prospective study.
Subjects: Women on ICE for >2y and shown increases in DXA of >2%. Period between ICE and ALE therapies ranged from 0-11 months. ALE was given as 10mg daily dosage.
Study design: DXA of lumbar spine (LS) and femoral neck (FN) were available at least 2y prior and within 6mo of recruitment, and at 1y and 2y on ALE. Broadband ultrasound attenuation (BUA) on the calcaneus was measured on a Hologic Sahara, and blood was drawn for serum bone-specific alkaline phosphatase (BSALP, OstaseTM using a Beckman Access) and c-telopeptides (CTX, CrossLapsTM using a Roche Elecsys 1010) at recruitment, 6mo, 1y and 2y.
Results: We have 12 patients followed for 6mo and 8 for 1y. Mean (range) age, years postmenopausal and duration on ICE were 68.8(58-82)y, 21.5(12-32)y and 3.3(2-8)y respectively. The duration off ICE did not appear to affect baseline BSALP or CTX. No subject had BSALP or CTX concentrations above 95% percentile cut-off as started by assay manufacturer. Mean (SD) values at baseline, 6mo and 1y are shown below. 89% of subjects showed a >40% drop in CTX, whereas only 20% subjects showed a similar decrease in BSALP at 6mo. DXA LS and BUA were not significantly increased at 12mo.
Conclusions: At 1y, we were able to demonstrate significant increase in DXA FN in patients treated with ALE following successful ICE. ALE was able to further suppress bone resorption as evidenced by the marked decrease in serum CTX at 6mo in patients previously treated with ICE.
| Test | Baseline | 6 months | 12 months |
| DXA LS g/cm2 | 0.946 (0.09) | 0.958 (0.09) | |
| DXA FN g/cm2 | 0.766 (0.07) | 0.794a (0.09) | |
| BUA db/mHz | 55.3 (11) | 55.8 (13) | 61.4 (16) |
| BSALP microg/l | 9.7 (3.2) 20%b | 8.8 (5.6) 32%b | 7.1a (1.1) 50%b |
| CTX microg/l | 0.172 (0.13) 20%c | 0.087a (0.09) 37%c | 0.052a (0.107) 88%c |
| a P<0.05 when compared with
baseline values. For the serum markers, the percent with low concentrations are included; b <6microg/l; c <0.05microg/l. |
|||
BONE MINERAL DENSITY CHANGES IN THE FIRST TWO YEARS FOLLOWING DISCONTINUATION OF ALENDRONATE
J. D. Gay*, D. S. Ooi
Ottawa Hospital Civic Campus, Ottawa, Canada
Background: The EPIC study showed decline in bone density on discontinuation of low-dose alendronate (ALE). We studied bone mineral density changes by dual x-ray absorptiometry (BMD) in lumbar spine (LS) and femoral neck (FN) following discontinuation of ALE 10mg.
Methods: Retrospective study on 70 patients from a specialist clinic; median (range) age was 63 (39-82)y, years post-menopausal 17 (0-36). 61% had ALE for >2y. Patients continued with calcium alone or in combination with vitamin D and/ or hormone replacement therapy (HRT). BMD was available at start and discontinuation of ALE, after 1y of discontinuation for all patients, and 2y for 21 patients.
Results: Mean, median percent change in BMD and percent patients showing greater than 3% fall for (i) period on ALE treatment, (ii) year prior to discontinuation, (iii) first and (iv) second after discontinuation are shown in the table. There was no significant difference in BMD change after discontinuation of ALE based on age (<, >/= 60y), years postmenopausal (<5, 6 to 15, >/=16y), duration of ALE treatment (<, >/=2y), total increase during ALE treatment or post-ALE regimen type. Patients who showed >3% increase in LS in the year prior to discontinuation had significantly less decrease in LS BMD during the first year after stopping ALE. At the FN, the increase with ALE was less, and 21% showed >3% decrease in the first year of discontinuation.
Conclusions: The mean percent change in LS, FN BMD at 1 year were -0.4%, -0.5% and at 2 years: -0.7%, -0.1%. Only 10% of patients showed decrease in LS BMD of >3% for the first year of discontinuation, and 5% at the subsequent year. Following ALE discontinuation, there appears to be a sustained effect, especially in the LS, in many patients. This finding is in contrast to the decline seen in patients stopping ALE 2.5mg or 5mg treatment.
ESOPHAGEAL TRANSIT OF OVAL WAX-POLISHED ALENDRONATE TABLETS
W. M. Drake1*, D. F. Worsley2, B. C. Lentle2, D. L. Kendler1
1Department of Medicine, Vancouver Hospital, BC, Canada
2Department of Medical Imaging, Vancouver Hospital, BC, Canada
BACKGROUND. Alendronate sodium (Fosamax(r), Merck Frosst) is an oral N-containing bisphosphonate proven effective for the prevention and treatment of osteoporosis. Although adverse events are no more common with alendronate than placebo in clinical trials, post-marketing surveillance has highlighted case reports of esophagitis and esophageal erosions in alendronate-treated patients. In most cases, patients had pre-existing esophageal dysmotility/stricture or were dosing incorrectly. We studied the esophageal transit of alendronate in thirty healthy, post-menopausal women (mean age 62 years±7 SD). METHODS. 2-3 mm deep holes were bored in the center of alendronate 10 mg oval, wax-polished tablets. 25 MBq 99Tc labeled pertechnetate was micropipetted into the hole which was sealed flush with sterile bone cement. Subjects held the labeled tablet in the mouth, a gamma camera was started and the pill was swallowed with 8oz water. A cobalt transmission source behind the patient provided an outline of the lungs and diaphragm. Images were acquired at 1 frame/second. Once the tablet had passed well below the diaphragm, the examination was terminated. RESULTS. Esophageal transit time was calculated from the images obtained, using two methods: time to pass below the diaphragm; and from time-activity curves in a region of interest (ROI) drawn over the esophagus. The latter also permitted separate calculation of the transit times for the upper, middle and lower thirds of the esophagus. Median transit time to below the diaphragm was 3 seconds (range 2-6). Using the ROI technique, median transit time for the whole esophagus was 5 seconds (range 2-17). In 25/30 subjects (83%) the transit time was 6 seconds or less. In the 5 subjects in whom the transit time was >6 seconds, virtually all of this time was in the distal third in each case. CONCLUSIONS. In this study we have shown that oval wax-polished alendronate tablets pass rapidly into the stomach, suggesting that contact between drug and esophageal mucosa is minimal when correct dosing instructions are followed. Choice of therapy for the treatment and prevention of osteoporosis should therefore be based on the available evidence of its efficacy in the prevention of fracture. Physicians should provide clear instructions about correct dosing of alendronate.
COMPARISON OF THE EFFECTIVENESS OF HORMONE REPLACEMENT THERAPY, BISPHOSPHONATE, CALCITONIN, VITAMIN D, AND VITAMIN K IN POSTMENOPAUSAL OSTEOPOROSIS: A ONE-YEAR PROSPECTIVE, RANDOMIZED, CONTROLLED TRIAL
Y. Ishida1,2*, H. Soh2, M. Tsuchida1,2, S. Kawahara2, H. Murata2
1Yamaguchi University School of Medicine, Yamaguchi, Japan
2Tsushimi Hospital, Yamaguchi, Japan
Currently, several pharmacologic agents exist that have more or less proven positive effects on osteoporosis. This study was conducted to assess the effectiveness of various pharmacologic therapies on bone mineral density (BMD), biochemical bone markers, and fracture incidence in postmenopausal women. One hundred eighty-three postmenopausal women with established osteoporosis were randomly allocated into six groups: control (no treatment); hormone replacement therapy (HRT, conjugated estrogen 0.625 mg/day plus medroxyprogesterone 2.5 mg/day); etidronate (200 mgx14d q3m); eel calcitonin (CT, 20 IU/week); vitamin D3 (alfacalcidol 1 microg/day); and vitamin K2 (45mg/day). BMD of distal 1/3 radius was measured by dual energy X-ray absorptiometry, along with markers of bone formation [serum bone specific alkaline phosphatase (B-AP), serum osteocalcin (OC)] and bone resorption [urinary N-telopeptide of type I collagen (NTX), urinary deoxypyridinoline (D-Pyr)] at baseline, 3, 6, 9, and 12 months of treatment. All new symptomatic non-vertebral, radiographically defined fractures were recorded, and thoracic and lumbar spine radiographs were taken every 3 months to assess fractures. The fracture incidence in the control group was 10%, whilst that in HRT, etidronate, CT, vitamin D3, and vitamin K2 groups was 0%, 3%, 3%, 0%, and 0%, respectively. In the control group, BMD decreased significantly from baseline after 1 year (-1.9%, p<0.05). HRT significantly increased BMD after 1 year of treatment by 2.6% (p<0.001). Other treatments, etidronate, CT, vitamin D3, and vitamin K2, induced -0.3%, +0.2%, -0.8%, and +0.2% changes in BMD after 1 year, respectively. Changes in the levels of B-AP, OC, NTX and D-Pyr after 3 months were respectively -28, -6.8, -31.5, and -19.5% in HRT; -13.4, -9.5, -16.0, and -8.6% in etidronate; +10.2, +30.4, -0.7, and -19.5% in CT; +12.6, -2.0, +42.8, and +2.6% in vitamin D3; and +15.6, +2.3, +31.6, and -15.8% in vitamin K2. Logistic regression analysis revealed that changes in NTX after 3 months predicted changes in BMD after 1 year in all treatment groups (odds ratio, 1.25; p=0.016). In conclusion, HRT significantly reduced bone turnover, increased BMD, and decreased new fracture incidence, in postmenopausal women. The data support the clinical utility of NTX to predict future changes in BMD in response to pharmacologic treatments in postmenopausal osteoporosis.
ZOLEDRONIC ACID, A POTENT NEW BISPHOSPHONATE, REVERSES MECHANICAL HYPERALGESIA IN TWO RAT MODELS OF CHRONIC INFLAMMATORY AND NEUROPATHIC PAIN
A. Fox1, S. Patel1, K. McNair1, A. Kesingland1, L. Urban1, J. R. Green2 *
1Novartis Institute for Medical Sciences, London, UK
2Novartis Pharma Research, Basel, Switzerland
Zoledronic acid (ZOL), a new bisphosphonate containing a heterocyclic imidazole substituent, is a highly potent inhibitor of osteoclastic activity. The compound is currently in phase 3 clinical development for the treatment of benign and malignant bone disease. In addition to potently inhibiting bone resorption and angiogenesis, ZOL has now been found to exert profound effects on pain in 2 in vivo models.
In a rat model of inflammatory hyperalgesia induced by unilateral hindpaw injection of complete Freund’s adjuvant, a single injection of ZOL (0.003 - 0.1 mg/ kg s.c.) produced a dose-dependant reversal of mechanical hyperalgesia. The effect was rapid in onset, with a maximal 100% efficacy within 30 min, and of short duration with no significant activity 3 h after administration. This relatively short duration of response parallels the known pharmacokinetic profile of ZOL in plasma. Pamidronate (0.03 - 1 mg/kg s.c.) and clodronate (0.3 - 10 mg/kg s.c.) were both ineffective in reversing inflammatory mechanical hyperalgesia, but rather produced slight reductions of paw withdrawal thresholds at the highest doses tested. In a rat model of chronic neuropathic pain induced by unilateral partial sciatic nerve ligation, a single injection of ZOL (0.003 - 0.1 mg/kg s.c.) produced a moderate 40% reversal of mechanical hyperalgesia which was maximal within 30 min of administration and had declined to baseline by 6 h. Pamidronate (0.03 - 1 mg/kg s.c.) was only weakly active in this model, producing a maximal 20% reversal of hyperalgesia, whilst clodronate (0.3 - 10 mg/kg s.c.) was inactive.
The reversal of mechanical hyperalgesia by ZOL is a novel finding for a member of the bisphosphonate class of compounds. Since pamidronate and clodronate lacked any comparable activity, this effect does not appear to be an inherent property of the geminal bisphosphonate moiety or directly associated with osteoclastic inhibition.
CHANGES AFTER COMPLETION OF THREE YEARS TREATMENT WITH ALENDRONATE FOR OSTEOPOROSIS
P. Kyd1*, A. Fairney1, E. Robinson1, E. Thomas2
1Imperial College School of Medicine, London, UK
2Department of Clinical Physics, St Mary's NHS Trust, London, UK
Bisphosphonates, such as Alendronate, are effective anti bone resorptive agents for the treatment of patients with osteoporosis. They produce increases in bone density, decreases in bone turnover and substantially reduce the frequency of fractures. However, it is not clear how long these drugs should be used for, nor what happens to bone density and bone turnover after completion of treatment.
We have conducted an open study on post-menopausal osteoporotic patients (n=19) mean age 65 years, who were treated for three years with Alendronate 10mg, and calcium (1000mg) and Vitamin D (10ug) daily; base line mean LS T score (Lunar DXA) -2.89, urine N telopeptide of collagen cross links NTX 65.3 (12.06) mean (SD) BCE/mmol Creatinine, (reference range pre menopausal females <65, post menopausal females <131), bone alkaline phosphatase (Alkphase B) 16.9 units/L, (reference range pre-menopausal females 10-26, post-menopausal females 14-50). There was a 6.5% gain in LS bone density over the three years of treatment and no change during the first year after completion of treatment.
At the end of treatment, the urine NTX was 27.8 BCE/mmol creatinine and the bALP 18.6 units/L (42.6% and 110% respectively of the base line value). Subsequently, the values at six months after completion of treatment rose to 48.75 BCE/mmol (NTX) and 23.84 units per liter (bALP), and after 9 months off treatment the mean NTX was 56 BCE/mmol and bALP 27.6u/L. This represents a rise of 101% (NTX) and 48% (bALP) compared to the end of treatment level.
After three years treatment with Alendronate, BMD did not decline in the first post treatment year, and the bone resorption marker rose to almost pre-treatment levels whilst the bone formation marker showed evidence of enhanced osteoblast activity.
EFFECT OF ENZYME THERAPY AND COMBINATION THERAPY WITH ALENDRONATE ON THE OVARIECTOMIZED RATS
K. Svik*, E. Rovenska, M. Stancikova, R. Istok, J. Rovensky, Z. Veselkova
Research Institute of Rheumatic Diseases, Piestany, Slovakia
Objective. Enzyme therapy is used in a wide range of inflammatory diseases (sport-related trauma, arthritis) and have shown it has significant effect upon several critical immune functions. In this study we investigated the effects of enzyme therapy and combination therapy with alendronate on OVX-induced bone loss in a long-term prophylactic treatment regime.
Methods. Adult female Sprague Dawley rats (250±10g) were subjected to bilateral ovariectomy (OVX) and sham operation (SHAM). Forty eight animals were divided into six groups: (1) sham; (2) OVX controls; OVX rats treated: (3) with alendronate 250 µg/kg (ALN-250); (4) with alendronate 500 µg/kg (ALN-500); (5) with Phlogenzym(r) 90 mg/kg (PHL); and (6) Phlogenzym(r) plus alendronate (PHL+ALN-250). The animals were maintained on a commercial diet and treated for a period of 9 weeks. The daily dose of PHL 90 mg/kg was divided into two administration occasions of 45 mg/kg and administered rectally twice a day. Alendronate was applied orally once a day 5 times a week. Bone mineral density (BMD) and bone mineral content (BMC) of the whole body and femur were detected using DEXA.
Results. We observed significant increase of the whole body and femur BMD and BMC in the groups of rats treated with ALN-250, ALN-500 and PHL+ALN-250 in comparison with OVX untreated controls after 9 weeks of ovariectomy. PHL alone did not change these parameters in OVX rats, but in combination with ALN-250 increased their values.
Conclusion. Our data shows the significant preventive effect of alendronate in the treatment of OVX rats and the beneficial effect of Phlogenzym(r) in combination with alendronate.
ONE YEAR STUDY OF ALENDRONATE EFFECTS ON VERTEBRAL MINERAL DENSITY AND BONE TURNOVER IN WOMEN WITH MILD TYPE I OSTEOGENESIS IMPERFECTA
D. Grigorie1*, C. Barbu1, E. Neacsu1, M. Dumitrache1, M. Grigorie2, C. Dumitrache1
1C. I. Parhon Institute of Endocrinology, Bucharest, Romania
2Ana Aslan Institute of Geriatrics and Gerontology, Bucharest, Romania
The aim of this study was to evaluate the bone mass and bone turnover changes in 8 (7 women and 1 men with ages between 13 and 50) patients with mild osteogenesis imperfecta (OI) after 12 month of alendronate treatment. All patients received 500 mg Ca++ supplements. 25 hydroxyvitamin D3 plasma level was normal in every patient. Bone mineral density measurements were obtained at the lumbar spine and total body regions (TB) by dual X-ray absorbtiometry (LUNAR-DPXL) and data are expressed as T and Z scores. Serum intact osteocalcin (IRMA) and urinary deoxypyridinoline (ELISA) measurements were performed. Mean percent changes in vertebral mineral density (expressed as Z score due to heterogenity of the group), was 7.16±3.1 after 12 months of treatment with alendronate, with a major increase during the first 6 months of treatment (p<0.01). Urinary excretion of free deoxypyridinoline (DPyr, mean value=12.16 nmol/mmol ur creat) decreased maximally (31%) after 12 month of treatment (P<0.05). Mean serum level of osteocalcin (50.89 ng/ml) decreased by 15% after 12 month of treatment (NS). In conclusion, alendronate administration was followed by a significant increase in the lumbar bone mineral density as early as 6 months since therapy was started. Bone resorbtion decreased significantly after 6 months of treatment, but the decrease in serum osteocalcin levels was not significant, suggesting a positive balance in the bone remodeling process. This preliminary data suggest that alendronate produces a significant increase in lumbar bone mass in the patients with mild OI, which seems to be related to the inhibition of the bone resorbtion.
TREATMENT OF OSTEOPOROSIS IN MEN USING ALENDRONATE
E. Thomas1*, A. Fairney2, P. Kyd2
1Department of Clinical Physics, St Mary's NHS Trust, London, UK
2Imperial College School of Medicine, London, UK
Osteoporosis is a well-established cause of disability in postmenopausal women giving rise to fractures. It is less common in men, but approximately 25-30% of all hip fractures occur in men [1]. Interest in male osteoporosis is increasing, although treatments for osteoporosis in patients of this gender are not well established.
Twenty-nine male patients with idiopathic osteoporosis, mean age 60 years (BMD, Lunar DXA, base-line T score LS -2.9) who were referred from the community to our Osteoporosis Clinic were treated with Alendronate, 10mg daily, together with calcium and Vitamin D supplements, for two years.
The results show a significant increase in LS BMD after two years of treatment, which is similar to that previously described in women [2].
1. Cooper C, Campion G, Melton LJ III. Osteoporosis International 1999. 2: 285-9
2. Fairney A, Kyd P, Thomas, E, Wilson J. Osteoporosis International 2000 11: 621-625
| BMD Results (g/cm2) | ||
| LS | FN | |
| Base line | 0.881 | 0.754 |
| 1 year (n=29) | 0.930 | 0.761 |
| 2 years (n=18) | 0.940* | 0.747** |
| * Increase 7% p<0.0001 ** NS |
||
RISEDRONATE REDUCES THE RISK OF CLINICAL VERTEBRAL FRACTURES BY 1 YEAR.
D. M. Reid1*, R. Eastell2, C. Roux3, C. Kasibhatla4
1Aberdeen Royal Infirmary, Aberdeen, UK
2University of Sheffield, Sheffield, UK
3Rene Descartes University, Paris, France
4Procter & Gamble Pharmaceuticals, Mason, OH, USA
Fracture prevention is the ultimate goal of all osteoporosis treatments. Risedronate has been demonstrated to rapidly reduce radiographically-confirmed vertebral fractures. In an effort to determine the efficacy of risedronate in reducing the risk of clinical (i.e., symptomatic) vertebral fractures, we have analyzed data from two large multi-center, randomized, placebo controlled 3-year studies in postmenopausal women (VERT-NA and VERT-MN).
VERT-NA was conducted in North America and enrolled 2458 women, less than or equal to 85 years of age, who were at least 5 years postmenopausal, and had two or more prevalent vertebral fractures, or one prevalent vertebral fracture and low lumbar spine BMD (T-score less than or equal to -2). The VERT-MN study conducted in Europe and Australia, enrolled 1226 postmenopausal women based on two or more prevalent vertebral fractures. All patients received either placebo or risedronate (2.5 or 5 mg/day) as well as 1000 mg/day of calcium and 500 IU of vitamin D if needed. Clinical vertebral fractures were diagnosed by a physician and recorded as adverse events. Radiographic confirmation of a clinical fracture was performed at the investigator’s discretion. Importantly, 26% of the morphometric vertebral fractures were also reported as clinical vertebral fractures. Vertebral fracture incidence was calculated based upon Kaplan-Meier estimates.
In the combined analysis, there was a statistically significant, 69% reduction in the risk of clinical vertebral fractures at 1 year for patients in the risedronate 5 mg group (p=0.009). The fracture incidence was 0.6% in the risedronate group, compared with 1.7% in the control group. A statistically significant risk reduction of clinical vertebral fractures was observed over 3 years in the risedronate (5 mg/ day) treated group.
These studies demonstrate that risedronate reduces the risk of clinical vertebral fractures within 1 year of initiating treatment.
RISEDRONATE SIGNIFICANTLY REDUCES THE RISK OF NEW VERTEBRAL FRACTURES, IN WOMEN IRRESPECTIVE OF THE NUMBER OF PREVALENT VERTEBRAL FRACTURES IN JUST ONE YEAR
R. Eastell1*, J. Compston2, C. Roux3, N. Alsayed4, I. Barton5
1University of Sheffield, Sheffield, UK
2University of Cambridge, Cambridge, UK
3Rene Descartes University, Paris, France
4Procter & Gamble Pharmaceuticals, Geneva, Switzerland
5Procter & Gamble Pharmaceuticals, Staines, UK
Data from two large, controlled, randomized 3-year studies were analyzed to determine the effect of risedronate on reducing the risk of new vertebral fractures, based on the number of pre-existing fractures. VERT-NA (n=2458) enrolled patients who were less than or equal to 85 years of age, and at least 5 years postmenopausal with two or more vertebral fractures or one vertebral fracture and low BMD. VERT-MN (n=1226) enrolled patients less than or equal to 85 years of age, who were at least 5 years postmenopausal and had two or more prevalent vertebral fractures. All patients received placebo or risedronate (2.5 or 5 mg/day), 1000 mg/day calcium and vitamin D, if needed. Statistical analysis was based on intent-to-treat populations with new vertebral fractures within the first year of the trials. Kaplan-Meier estimates were used to determine the percentage of patients with incident vertebral fractures. The following table illustrates the results from the two studies which demonstrate that risedronate reduces the risk of vertebral fractures in 1 year by up to 74% depending on the severity of the disease.
In summary, risedronate significantly reduces the risk of new vertebral fractures at 1-year in osteoporotic patients over a range of osteoporosis disease severity.
| Vertebral fracture risk reduction (%) at 1-year vs. control in VERT-NA and VERT-MN* | ||
| Treatment group | VERT-NA | VERT-MN |
| All patients | 65 | 61 |
| Greater than or equal to 2 prevalent fx | 74 | 65 |
| Greater than or equal to 3 prevalent fx | 74 | 69 |
| Greater than or equal to 4 prevalent fx | 73 | 66 |
| *All reductions significant vs. placebo (p less than 0.01) | ||
INTRAVENOUS PAMIDRONATE IN THE MANAGEMENT OF DIFFICULT OSTEOPOROSIS
P. L. Selby1*, S. Vasireddy2, S. Harrison1, D. R. Swinson2
1Department of Medicine, Manchester Royal Infirmary, Manchester, UK
2Wrightington Hospital, Wigan, UK
Bisphosphonates are the mainstay of treatment for osteoporosis. Oral treatment not always well tolerated and there has been a tendency to use intravenous pamidronate for such subjects and also for those subjects in which oral agents have proved ineffective. Such treatment has not been subject to formal evaluation and so we have reviewed our experience of this form of management.
The case notes of 30 patients who had been treated with intravenous pamidronate for at least one year were reviewed and the changes in bone density noted.
The patients comprised 23 women and 7 men. Mean age was 59 (SD 13)y at the start of pamidronate therapy. Fifteen of the patients had received previous treatment with oral bisphosphonates. Twenty of the subjects had suffered at least one osteoporotic fracture. Fifteen of the subjects had received systemic corticosteroid therapy. The mean dose of pamidronate per year was 110(SE 9)mg and the mean number of doses given annually was 3.3(SE 0.2).
Bone mass was measured by DXA before, after one year, and, in 5 subjects, after 2 year’s therapy.
Lumbar spine BMD increased from 0.702(SE 0.023)g/cm2 to 0.756(SE 0.026)g/ cm2; +7.9%, p<0.001. In the total hip the increase was from 0.617(SE 0.037)g/cm2 to 0.639(SE 0.043)g/cm2; +3.2%; p=0.33. In subjects followed for two years these increases appeared to be maintained.
We conclude that intermittent intravenous infusions of pamidronate are potentially useful in the management of difficult cases of osteoporosis. Further controlled studies are indicated.
RSAI POLIMORPHISM OF ER-BETA GENE AND ALENDRONATE TREATMENT OF OSTEOPORORSIS
J. Marc1*, B. Arko1, J. Prezelj2, A. Kocijanèiè2
1Faculty of Pharmacy, Univ. of Ljubljana, Ljubljana, Slovenia
2Dept. of Endocrinology and Metabolic Diseases, Clinical center, Ljubljana, Slovenia
Backgrounds: As defined by WHO, osteoporosis is a skeletal disease in which the bone mass has been reduced. The course of osteoporosis is influenced by numerous risk factors, which also include the genetics. Aditionally, there are many new data which show that the effectiveness of osteoporosis treatment is somehow associated with changes in genes involved in pathogenesis of osteoporosis. The aim of the present study was to find out whether response to bisphosphonate therapy is different in regard to newly discovered RsaI polymorphism of estrogen receptor beta (ER-beta) gene.
Methods: A study on 76 patients treated for osteoporosis was carried out. Patients received alendronate (Fosamax, MSD) according to the treatment protocol. Bone mineral density (BMD) and biochemical markers of bone metabolism (osteocalcin, deoxypyridinoline) were measured at the start and after one year of therapy. According to RsaI polymorphism the patients were separated into two subgroups: RR (n=72) and Rr (n=4). They did not differ in age (66.0, and 63.9 years, respectively) nor in years after menopause (18.7 and 18.4 years, respectively) or in body weight (64.9 and 63.8 kg, respectively), the variables known to be associated with BMD.
Results: Results indicate that response to the alendronate therapy does not differ with respect to RsaI genotype. BMD of the lumbar spine (LS) and femoral neck (FN), the indicators of treatment efficacy were increased by 6.6% at LS and 3,8% at FN in patients with RR genotype, while in those with Rr genotype they increased only by 2.6% at LS and 3.6% at FN. During the alendronate therapy, which slows down the whole remodeling process, the biochemical marker of bone resorption (deoxypyridinoline) as well as the bone formation marker (osteocalcin) decreased significantly in all patients. The osteocalcin levels lowered for 44.3% in RR and for 35.8% in Rr patients, respectively. Further, the significant decrease in deoxypyridinoline urinary excretion was observed in RR (31,6%) as well as in Rr (17,0%) patients.
Conclusion: On the basis of our results it could not be concluded that RsaI polymorphism of ER-beta gene is involved in an individual's response to alendonate treatment of osteoporosis.
ALENDRONATE VS. CALCITONIN: 2-YEAR TREATMENT OF OSTEOPOROSIS IN POSTMENOPAUSAL WOMEN
C. J. Rosen1*, T. J. Schnitzer2, M. McClung3, P. D. Miller4, L. Wang5, L. K. Vanaman5, J. Yates5, M. E. Melton5, J.Palmisano5
St. Joseph Hospital, Bangor, ME, USA
Northwestern University, Chicago, IL, USA
Oregon Osteoporosis Center, Portland, OR, USA
Colorado Center for Bone Research, Lakewood, CO, USA
Merck & Co., Inc., West Point, PA, USA
Alendronate (ALN) and intranasal calcitonin (CT) are commonly prescribed treatments for osteoporosis in postmenopausal women. This randomized study enrolled 275 postmenopausal women with osteoporosis to compare the efficacy of daily ALN to CT for a period of 2 years.
During year 1, patients received ALN 10 mg/d, CT 200 IU/d or ALN placebo (2:2:1). Year 2 treatments were open label, ALN and CT groups continued; PBO group switched to ALN.
Year 1 results showed that ALN produced significantly greater BMD increases than CT at hip trochanter (HT) and lumbar spine (LS) at 6 and 12 months (p<0.001) and femoral neck (FN) at 12 months (p=0.002). BMD changes with CT were not different from PBO at HT, LS, and FN. ALN produced significantly greater decreases than CT of Urinary N-telopeptide (NTx) and Serum Bone-Specific Alkaline Phosphatase (BSAP) at 6 and 12 months (p<0.001).
After 24 months of treatment, ALN produced significantly greater increases in BMD when compared to CT at HT, LS and FN (p<0.001) and greater decreases than CT, in Urinary (NTx) and Serum (BSAP) at 24 months (p<0.001).
After two years of treatment, alendronate produced significantly greater increases in BMD than intranasal calcitonin at LS and hip in postmenopausal women with osteoporosis.
| BMD Mean Percent Change from Baseline | ||||
| Lumbar Spine | Lumbar Spine | Femoral Neck | Femoral Neck | |
| Treatment | 12 months | 24 months | 12 months | 24 months |
| ALN | 4.59*** | 5.77*** | 2.33** | 2.50*** |
| CT | 0.79 | 1.00 | 0.49 | -0.13 |
| PBO/ALN | 0.48 | 4.29 | 0.73 | 1.60 |
| ***p<0.001 ALN vs CT;**p<0.01 ALN vs. CT | ||||
A RANDOMISED TRIAL OF INTRAVENOUS PAMIDRONATE AND CALCIUM & VITAMIN D IN THE TREATMENT OF LOW BONE MINERAL DENSITY ASSOCIATED WITH CROHN'S DISEASE
S. A. Bartram1*, N. P. Thompson2, R. M. Francis1
1Musculoskeletal Unit, Freeman Hospital, Newcastle-upon-Tyne, UK
2Department of Gastroenterology, Freeman Hospital, Newcastle-upon-Tyne, UK
Introduction: Osteoporosis is now recognised as a common complication of Crohn's disease, affecting 10-42% of patients. Several groups have reported increased levels of bone resorption markers in these patients making the use of bisphosphonates, inhibitors of bone resorption, a potentially useful intervention. Optimum absorption of oral bisphosphonates is only 1-2% and we therefore studied the effect of a bisphosphonate given intravenously (pamidronate) compared to calcium & vitamin D supplements.
Methods: Sixty patients, (30 M, 30 F), with a median age of 44.5 years (range 25-70), all with a T score of -1.5 or less at either the lumbar spine or hip (a value recently suggested as the threshold for intervention) were randomised to receive either a daily dose of 500 mg of calcium with 400 IU of vitamin D alone (Group A, n=28) or in combination with 4 three-monthly infusions of 30 mg of intravenous pamidronate (Group B, n=32) over the course of 12 months. Nine patients in Group A (32%) and 16 patients in Group B (50%) were taking corticosteroids throughout the study. Bone mineral density (BMD) at the lumbar spine and hip was measured by dual x-ray absorptiometry at baseline and after 12 months.
Results: There were significant gains in BMD at the lumbar spine in both treatment groups, Group A = +2.1%±0.9% (mean±SEM), p less than 0.05, Group B = +2.5%±0.6%, p<0.0001. At the hip there was a significant gain of +2.5%±1.1%, p<0.05 in Group B compared to a gain of +1.1%±0.7%, p=0.2 in Group A. Four patients were unable to complete all four pamidronate infusions, 3 because of side effects, and 1 because of difficulty gaining intravenous access. Three patients were intolerant of the calcium & vitamin D supplements.
Conclusion: Despite a proportion of our patients taking corticosteroids both pamidronate and calcium & vitamin D supplements were effective in increasing bone density at the lumbar spine, but pamidronate was more effective than calcium & vitamin D at the hip. Both treatments were well tolerated.
BISPHOSPHONATES AND UPPER GI PROBLEMS - WHAT IS THE EVIDENCE?
B. Cryer1*, D. C. Bauer2
1University of Texas Southwestern, Dallas, TX, USA
2University of California, San Francisco, CA, USA
Upper gastrointestinal (UGI) tract mucosal irritation has been reported for a variety of bisphosphonates, including pamidronate, etidronate, clodronate, alendronate (ALN), tiludronate, and risedronate (RIS). Although the clinical relevance of short-term, transient endoscopic findings is uncertain, one endoscopic study reported a higher incidence of gastric lesions for ALN vs RIS, and others reported no difference for ALN vs RIS or placebo [1-4]. These endoscopic studies differed in regard to blinding, duration, and control. Endoscopy trials that were appropriately blinded and of longer duration (4-10 wks) found no difference between ALN and RIS or placebo, even at the higher doses used for once-weekly dosing [4] or to treat Paget's disease [3]. Randomized, blinded, controlled trials (RCTs) with clinically relevant GI endpoints represent the highest level of evidence, and tens of thousands of patients have participated in RCTs of ALN and RIS for up to 7 years. UGI complaints were common in these studies (~30% in the first year), and were comparable to placebo. In particular, the incidence of more worrisome UGI events (including esophageal events, and gastroduodenal perforations, ulcers, and bleeds) was low and comparable to the placebo group, even in high risk subgroups, among 6459 women randomized to ALN or placebo for up to 4.5 years in the Fracture Intervention Trial [5]. Furthermore, two independent RCTs of patients who had previously reported intolerance to bisphosphonate reported that the large majority (~85%) were able to continue ALN or RIS when treatment was resumed, and the permanent discontinuation rates were no different from the placebo group [6,7]. Based on extensive data from large RCTs, we conclude that any increase above placebo in clinically relevant UGI problems related to bisphosphonate use is very low - too low to detect in trials involving thousands of participants during several years of follow-up.
1) Lowe C, et al. Am J Gastroenterol 95:634-40, 2000. 2) Lanza F, et al. Gastroenterol 119:631-8, 2000. 3) Lanza F, et al. Am J Gastroenterol 95:3112-7, 2000. 4) Lanza F, et al. Arthritis Rheum 43(Suppl 9):S198, 2000. 5) Bauer DC, et al, Arch Intern Med 160:517-525, 2000. 6) Ettinger MP, et al. Arthritis Rheum 43(Suppl 9):S202, 2000. 7) Adachi JD, et al. Arthritis Rheum 43(Suppl 9):S202, 2000.
ALENDRONATE IS MUCH MORE EFFECTIVE THAN CALCITONIN AND ALFACALCIDOL FOR PREVENTING NONVERTEBRAL FRACTURES
K. Aoyagi1*, M. Shiraki2, M. Ito3, T. Nakamura4
1Public Health, Nagasaki University
2Research Institute and Practice for Involutional Diseases
3Radiology, Nagasaki University
4Orthopedic Surgery, University of Occupational and Environmental Health
It is unlikely that trials of sufficient size will be conducted to compare the antifracture efficacy of various agents. We previously developed a method for estimating and comparing the antifracture efficacy of various antiresorptive agents, expressed as the relative risk reduction (RRR) and number needed to treat (NNT) to prevent one case of fracture. These predictions are based on the observed effects on BMD from head-to-head (HTH) trials, together with the relationship between changes in BMD and fracture risk reductions derived from meta-analyses of antifracture trials. This approach provides a more accurate estimate of each agent's efficacy than relying on the results from a single trial, especially when fracture trials of adequate size are not available (e.g., alphacalcidol). Using BMD results from HTH trials avoids the potential for bias related to differences in baseline characteristics or other factors between trials. We previously reported the results comparing alendronate to calcitonin and alfacalcidol with regard to the predicted effects on vertebral fractures; now we report similar analyses for nonvertebral fractures. The predicted nonvertebral fracture RRR was 28% for alendronate 5 mg/ day, based on BMD changes in a HTH trial; this is similar to the published value in large clinical trials, thus validating the method. Assuming a nonvertebral fracture incidence of 19% over 3 years in untreated women with prior vertebral fractures (based on a large epidemiological study), the number needed to treat (NNT) to prevent a new nonvertebral fracture was 19 for alendronate, and 84 for alphacalcidol; similar results were observed for calcitonin. We conclude that alendronate is 3 to 4 times more effective for reducing nonvertebral fracture risk than alphacalcidol or calcitonin.
EFFECT OF ALENDRONATE TREATMENT FOR THE CHINESE POSTMENOPAUSAL WOMEN WITH OSTEOPOROTIC VERTEBRAL FRACTURES
A. P. C. Or1*, W. S. Chan1, E. M. C. Lau2, P. C. Leung1
1Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China
2Department of Community and Family Medicine, The Chinese University of Hong Kong, Hong Kong, PR China
Osteoporosis is a worldwide problem. Asia will be particularly affected with this apparently normal degenerative process since the Asian population is exceeding the other regions and life expectancies are getting prolonged year by year. The efficacy of antiresorptive therapy on the Chinese women with vertebral fracture is still unclear.
120 postmenopausal Chinese women aged between 55 to 83 suffering from vertebral fracture were randomized to receive an oral administration of 10mg alendronate or placebo for one year. All patients received 1200mg per day of supplemental calcium. The main outcome measures included the change of BMD of lumbar spine and hip measured by dual-energy x-ray absorptiometry, and the change of BMD of the distal radius and tibia measured by peripheral quantitative computed tomography. Besides, the occurrence of new fractures, the change of bone turnover and quality of life after one year treatment were the endpoints in this study.
After one year, 10mg alendronate induced significant increase in BMD at lumbar spine (9.05%), tBMD50 and cBMD of distal radius (0.56% and 0.24% respectively), and iBMD and cBMD of the distal tibia (1.18% and 0.65% respectively) as compared with the BMD change of patients receiving placebo (all p-value less than 0.05).
One year alendronate treatment was associated with reduction of the occurrence of new vertebral fracture. Only 2.5% patients in the alendronate group suffered from new vertebral fracture during the treatment period. However, 9.76% patients who receiving placebo got new fracture in the same period.
Nevertheless, no obvious improvement in quality of life was found in the alendronate group after one year when compared with the placebo group. For the tolerance, five patients in the alendronate group and 1 patient in placebo group experienced gastrointestinal disturbance within the treatment period.
In conclusion, alendronate induced BMD increase in the Chinese postmenopausal women with vertebral fractures. As a potent inhibitor of bone resorption, it can reduce markers of bone remodeling significantly. Although no remarkable improvement of quality of life found among the patients receiving alendronate, alendronate still useful and safe in preventing new vertebral fractures to occur.
HRT AND VARIOUS DOSES OF PAMIDRONATE IN POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS: ADDITIVE EFFECT ON BONE RESORPTION, NOT ON BONE FORMATION
L. Sandini*, O. Lamy, S. Fatio, I. Pache, P. Burckhardt
Department of Internal Medicine, Lausanne University Hospital, Switzerland
Background: In a previous short report we have shown that, at 6 months, 1x60 or 2x30 mg iv pamidronate (APD) induced a deep and sustained inhibition of bone resorption, but not formation, in osteoporotic women on hormone replacement therapy (HRT). This study assesses this observation at 12 months with various doses of APD, in a larger prospective cohort.
Results: Results are given in mean±SEM. 37 osteoporotic menopausal women (63±12 years) were randomized to receive 120mg APD/year intravenously: 30mg/3 months (n=18), 40mg/4 months (n=12), or 60mg/6 months (n=7). HRT (13 patients) treatment had started 2 years or more before inclusion. All got calcium supplements at 1500mg/d and Vitamin D3 800 IU/d. Urinary C-Terminal Telopeptide (UCTX) and Osteocalcin (OC) were determined fasting before each injection. The 3 APD groups did not differ in age or the percentage of HRT users (HRT+). HRT+ were significantly younger than the HRT- (53±10 vs 69±8 years).
There was no difference in baseline UCTX or OC between the 3 APD groups. At 12 months, the % decrease in UCTX and OC were not significantly different between the 3 APD groups.
UCTX were significantly lower in HTR+ at baseline (186±52 vs 270±36 micromol/mmol) and at 12 months (132±5 vs 59±16). Despite that, the percentual decrease in UCTX at 12 months was not different in HRT+ (-59±21%) and HRT- (-34±19%) groups. OC values were similar in HRT+ and HRT-, at baseline, at follow-up, or expressed as percentual decrease at 12 months.
Conclusions: An annual dose of 120mg of APD had the same result on bone remodeling markers independently on the distribution of the 3 dose over the year. These results open the possibility to treat osteoporosis with only two perfusions per year. The addition of APD to HRT had a particular favorable effect. Although HRT users have lower bone resorption markers at base line than non users, they respond to APD as well as non users.
RISEDRONATE REDUCES THE RISK OF NEW VERTEBRAL FRACTURES IN 1 YEAR IN POSTMENOPAUSAL WOMEN ON CORTICOSTEROID THERAPY
J. P. Devogelaer1*, D. Hosking2, S. Wallach3, D. J. Valent4
1Louvain Catholic University, Brussels, Belgium
2Nottingham City Hospital, Nottingham, UK
3Hospital for Joint Diseases, New York, NY, USA
4Procter & Gamble Pharmaceuticals, Geneva, Switzerland
Five hundred and nine patients, receiving moderate to high doses of oral corticosteroids (equivalent to 7.5mg prednisone daily or greater), were enrolled in two studies to examine the effect of risedronate. We report here on the results of the subgroup of postmenopausal women in these studies (n=255).
Patients in these studies were randomized to receive placebo, or risedronate (RIS) 2.5 mg, or RIS 5 mg for 1 year. Patients were supplemented with daily elemental calcium (500-1000mg) and the majority also received supplemental vitamin D (400 IU). Spinal BMD was measured every 3 months; spinal radiographs were taken at baseline and 1 year.
In this group of postmenopausal women, RIS 5 mg significantly increased spinal BMD by 2.6% vs placebo (p less than 0.01). Nine out of 56 placebo patients had a new vertebral fracture compared with 3 out of 62 in the RIS 5mg treated group. This vertebral fracture risk reduction was 73% (p=0.050). Effects of 2.5 mg were consistent with these results.
In summary, this study demonstrates that risedronate is effective in maintaining or increasing bone mass and reducing the risk of new vertebral fractures in postmenopausal women on corticosteroid therapy. These findings are consistent with risedronate effects observed in large, 3 year studies in women with confirmed postmenopausal osteoporosis.
RISEDRONATE IS WELL-TOLERATED IN POSTMENOPAUSAL WOMEN WHO ARE GI-INTOLERANT TO ALENDRONATE
S. Adami1*, J. D. Adachi2, P. D. Miller3, S. Horlait4
1Clinicizzato di Valeggio, Valeggio, Italy
2McMaster University, Hamilton, ON, Canada
3Colorado Center for Bone Research, Lakewood, CO, USA
4Procter & Gamble Pharmaceuticals, Neuilly-sur-Seine, France
Postmenopausal women who had previously discontinued alendronate 10 mg/d (ALN) due to upper GI (UGI) adverse events (AEs) entered a randomized, double-blind study. The study was designed to assess risedronate (RIS) treatment discontinuation due to upper GI AEs. 66 patients were randomized to receive either risedronate (5 mg/day, n=35) or placebo (n=31) for 3 months. 20% of the risedronate group and 19% of the placebo group had a history of H2-blocker/proton pump inhibitor (PPI) use. 16.1% in the placebo group and 11.4% in the risedronate-treated group discontinued due to upper GI AEs. The percentage of patients reporting any upper GI AE was similar between the two groups (19.4% and 20% for placebo and risedronate respectively).
Of the patients who discontinued, half discontinued in the first 28 days in both groups. Discontinuation rates among women using H2-blockers/PPIs, with a history of GI disease, or concurrently using NSAIDs during the trial, were similar between RIS and placebo-treated patients.
In summary, these findings demonstrate that risedronate is as well-tolerated as placebo in patients who could not tolerate alendronate.
RISEDRONATE IS EFFECTIVE IN PREVENTING FIRST VERTEBRAL FRACTURE IN WOMEN
I. Fogelman1*, C. Ribot2, J. Glowinski3, R. Crozier4
1Guy's Hospital, London, UK
2Hopital Rangueil, Toulouse, France
3Centre Hostitalier, Gonesse, France
4Procter & Gamble Pharmaceuticals, Geneva, Switzerland
Risk for future fractures is increased by the presence of a vertebral fracture. Therefore the prevention of the first vertebral fracture is an important consideration in the management of osteoporosis. We report on the effectiveness of risedronate (RIS) in reducing the risk of a vertebral fracture in postmenopausal women at risk for fracture but without a prevalent fracture. Patients with low BMD without fractures from three risedronate studies were examined (BMD-NA, BMD-MN and VERT-NA). The studies ranged from 1.5-3 years in duration. Patients from these 3 studies received RIS or placebo daily, in addition to calcium (1000 mg/d), and 500 IU/d vitamin D as needed. A total of 383 patients were enrolled with no prevalent vertebral fracture, low spinal BMD (LS T-score less than -2.5), and a range of mean ages from 63-71 across the studies.
Risedronate significantly increased lumbar spine BMD by up to 5.8% from baseline and reduced the risk of the first vertebral fracture by 70%. The reduction in risk was unaffected after adjustment for age or baseline LS T-score.
In summary, risedronate demonstrated a significant reduction in the risk of a first vertebral fracture in postmenopausal osteoporotic women.
A ONE-YEAR RANDOMIZED TRIAL OF ETIDRONATE AND VITAMIN K IN COMBINATION WITH VITAMIN D IN POSTMENOPAUSAL PATIENTS WITH RHEUMATOID ARTHRITIS
J. H. Hashimoto1*, T. T. Tomita1, H. O. Owaki2, K. T. Tsuyama2, T. O. Ochi1, H. Y. Yoshikawa1
1Dept. of Orthopedic Surg., Osaka University Medical School, Osaka, Japan
2Dept. of Orthopedic Surg., Osaka Kousei-Nenkin Hospital, Osaka, Japan
The prevention and treatment of secondary osteoporosis due to rheumatoid arthritis is one of major problem especially for elderly-patients. We used a randomized design to compare the efficacy of the combined treatment with cyclical etidronate plus vitamin D and the combined treatment with vitamin K plus vitamin D, in preventing bone loss in 44 postmenopausal patients with rheumatoid arthritis (RA) aged from 46 to 65 (mean±SE ; 57.6±0.76). Mean RA duration was 11.5±1.6 (mean±SE).
Etidronate was given according to the standard cyclical schedule, i.e. 400 mg/ day for periods of 14 days separated by 76-day intervals (n=22). Vitamin K2 group (n=22) received 450mg per day orally. In both groups, patients took 0.5 microgram 1.25(OH)2 vitamin D3 per day concurrently. Bone mineral density (BMD) increased by 2.4±1.0% (mean±SE) and 0.4±0.9% in lumbar spine, in the etidronate group and vitamin K group, respectively. There is no significant difference between two groups. At the femoral neck and Ward's triangle, there was a smaller BMD decrease in the vitamin K (-0.8±0.8% and -2.2±2.8%) than in the etidronate group (0.7±0.7% and 1.3±2.6%), but the difference was not statistically significant. At the diaphysis of radius, BMD decreased by -2.2±1.0% and -1.4±1.7%, in the etidronate group and vitamin K group, respectively. There was no significant difference between two groups.
The bone metabolic marker was measured 90 and 180 days after commencement of medication. There was a urinary deoxy-pyridinoline increase in the vitamin K group (10.9±11.0% and 35.4±21.5%, day 90 and day 180, respectively) while there was a decrease in the etidronate group (-18.4±6.3% and -19.4±7.8%), yielding a significant between-group difference (P=0.031 and 0.013).
Etidronate plus vitamin D and vitamin K plus vitamin D prevent lumbar spine and femoral neck bone loss in postmenopausal patients with rheumatoid arthritis, although the change in bone metabolic marker was quite different.
THE USE OF PAMIDRONATE TO TREAT OSTEOPOROSIS IN CHILDREN WITH SPASTIC QUADRIPLEGIC CEREBRAL PALSY AND RECURRENT FRACTURES
S. J. Bachrach1,2*, H. H. Kecskemethy1, H. T. Harcke1,2, F. Miller1,2
1A.I. duPont Hospital for Children, Wilmington, DE, USA
2Jefferson Medical College, Philadelphia, PA, USA
PURPOSE: To determine whether treatment with intravenous (IV) Pamidronate, a bisphosphonate, would be safe and effective in preventing further decrease in bone mineral density (BMD) and thus more fractures in children with cerebral palsy and recurrent fractures.
METHODS AND MATERIALS: Four children with spastic quadriplegic cerebral palsy and history of frequent fracture were studied prospectively with at least seventeen month follow-up. These four patients were treated on compassionate clinical grounds. IV Pamidronate was given for three consecutive days, every three months for 12 months (5 cycles). A dose of 1mg/kg (up to a max of 35 mg) was given daily x3 per cycle. BMD and blood studies were obtained serially.
RESULTS: No patients receiving Pamidronate had fractures in the seventeen to thirty six months after initiation of treatment. Patients had between one and five fractures in the year preceding treatment. The pre-treatment BMD in all patients was significantly below normal for age. Repeat assessments showed improvement in regional bone density measurements. BMD tended to rise in the 6 months after treatment began, reach a peak, and then remain near the peak value. While improving, BMD did not reach the normal range. Radiographs of patients receiving Pamidronate showed dense parallel metaphyseal bands which correlated with treatment cycles. Patients had no adverse clinical effects during administration of Pamidronate. Most experienced transient decreases in serum calcium and phosphorus, which returned to normal within a week of treatment.
CONCLUSION: Pamidronate proved to be a safe and effective medication for children with spastic quadriplegic cerebral palsy and a history of recurrent fracture. Patients had no fractures in the 17-36 months after initiation of treatment.
TREATMENT OF GLUCOCORTICOSTEROID-INDUCED OSTEOPOROSIS IN MALE RATS: HISTOMORPHOMETRIC ANALYSIS BETWEEN ALENDRONATE AND FLUORIDE
E. B. Dourador1*, V. Falco1, R. A. Souza1, B. Luna Filho2, E. D. Bonfa1, V. Jorgetti1
1Faculty of Medicine - Sao Paulo University, Sao Paulo, Brazil
2Paulista Medical School - Federal University, Sao Paulo, Brazil
Background: Glucocorticosteroid-induced osteoporosis (GI-OP) is an important clinical problem. Few studies have addressed the quantitative and qualitative differences between the treatment of GI-OP with alendronate or fluoride.
Objective: Evaluate the efficacy of alendronate and fluoride in treatment of GI-OP.
Material and Methods: Thirty Wistar male rats, weighting around 300 g, were studied. Initially the animals received 10mg/kg prednisolone/daily during six weeks, intraperitonially (IP), then they were divided into three groups: saline (0.5 ml/daily, IP - Control): alendronate (0.4 mg/kg/daily subcutaneously - treat-AL), and fluoride (0.5 mg/kg/daily PO - Treat-F). All animals were evaluated densitometrically at the beginning of this trial, after six weeks with corticosteroid and at the end of treatment (Hologic QDR 2000W DEXA, high resolution, small animal mode). After 12 weeks they were sacrified and the left femurs were dissected, decalcified and submitted to histomorphometric analysis.
Results: After six weeks of corticosteroid regimen, the densitometric analysis did not show bone loss but it was identified by the histomorphometric analysis. See Table I.
Conclusion: The Treat-AL and Treat-F groups both reverted the GI-OP. The Treat-F group had a reversal process similar to the control. By the other side the alendronate group showed qualitative and quantitative differences in relation to the fluoride and control groups.
| Table I: Histomorphometric Results: Mean and SD Values. | |||||
| Groups | BV:TV% | TbN:mm | ES:BS% | OS:BS% | MAR |
| Control | 21(3.35) | 3.96(0.74) | 6.27(3.14) | 3.8(2.4) | 0.34(0.08) |
| Treat-F | 22.7(4.9) | 3.7(0.2) | 7.2(1.78) | 3.92(2.54) | 0.4(0.05) |
| Treat-AL | 37.3(6.1)* | 7.6(1.2)* | 10.8(6.8)* | 0.74(0.47)* | 0.26(0.05)* |
| BT:TV= % bone volume in total volume;TbN=
trabecular number; ES:BS=% eroded surface; OS:BS= % osteoide surface; MAR= mineralization rate; * = p<0.01 |
|||||
ALENDRONATE VS INTRANASAL CALCITONIN FOR TREATMENT OF OSTEOPOROSIS IN POSTMENOPAUSAL WOMEN: 2 YEAR RESULTS
R. W. Downs1*, N. H. Bell2, B. Walsh3, M. P. Ettinger4, B. Mako5, M. E. Smith5, L. Wang5, J. Yates5, M. E. Melton5, J. Palmisano5
1Medical College of Virginia, Richmond, VA, USA
2University of South Carolina Research Service VMAC, Chareston, SC, USA
3Brigham & Women's Hospital, Boston, MA, USA
4Radient Research, Stuart, FL, USA
5Merck & Co., Inc., West Point, PA, USA
Two commonly prescribed treatments for osteoporosis in postmenopausal women are alendronate (ALN) and intranasal calcitonin (CT). This randomized study enrolled 299 postmenopausal women with osteoporosis to compare the efficacy of daily ALN to CT for a period of 2 years.
During year 1, patients received ALN 10 mg/d, CT 200 IU/d or ALN placebo. Year-2 treatments were open label, ALN and CT groups continued; PBO group switched to ALN.
Year-1 treatment with ALN produced significantly greater increases in BMD than CT at the hip trochanter (HT) and lumbar spine (LS) (p<0.001) at 6 and 12 months, and at the femoral neck (FN) (p<0.001) at 12 months. BMD changes with CT were not different from PBO at hip or spine. During year-2, the upward trend for ALN continued, with significantly greater BMD than CT at HT, LS and FN (p<0.001) at 24 months. BMD changes with CT were not significant from baseline at 24 months for HT, LS or FN.
After two years of treatment, alendronate produced significantly greater increases in BMD than nasal calcitonin at lumbar spine and hip in postmenopausal women with osteoporosis.
| BMD Mean Percent Change from Baseline | ||||
| Lumbar Spine | Lumbar Spine | Femoral Neck | Femoral Neck | |
| Treatment | 12 months | 24 months | 12 months | 24 months |
| ALN | 5.16* | 7.02* | 2.79* | 3.60* |
| CT | 1.20 | 0.68 | 0.63 | 0.37 |
| PBO/ALN | 0.16 | 3.53* | -1.27 | 0.94 |
| *p<0.001 ALN vs CT | ||||
ALENDRONATE REDUCES THE RISK OF CLINICAL VERTEBRAL FRACTURE IN OSTEOPENIC WOMEN: DATA FROM FIT
S. A. Quandt1*, D. E. Thompson2, D. Schnieder3, M. Nevitt3, T. Musliner2
1Wake Forest University
2Merck & Co, USA
3University of California, San Francisco, USA
Objective: To determine the effectiveness of alendronate in reducing the risk of clinical vertebral fractures (CVFX) in women with osteopenia who do not meet the BMD criterion for osteoporosis.
Design: We studied 3740 women, age 55 to 80, from the Fracture Intervention Trial who had BMD T-score > -2.5 at the femoral neck: 942 with an existing morphometric vertebral fracture (MVFX) and 2799 without. 1859 were treated with PBO and 1881 were treated with ALN 5mg per day for the first two years and 10mg for the remaining period for up to 4.5 years. All CVFX were confirmed by a physician.
Results: The absolute risk of CFVX was about 4 to 5 fold greater in women with existing MVFX than in those without. Alendronate significantly (p=0.005) reduced the overall risk of CFVX by 60% (RR = 0.40 (0.19, 0.76)). The reductions were consistent among those with and without MVFX: 0.34 (0.12, 0.84) and 0.46(0.16, 1.17) respectively. The effect was observed very early. There were no CFVX in the first year among the alendronate patients.
Conclusion: Alendronate was equally effective in reducing the relative risk of painful clinical vertebral fractures in women with and without existing MVFX. The effect was seen early.
THE EFFECT OF ALENDRONATE ON AGE-SPECIFIC INCIDENCE OF KEY OSTEOPOROTIC FRACTURES
M. C. Hochberg1*, D. E. Thompson2, D. Black3
1University of Maryland, USA
2Merck & Co, USA
3University of California, San Francisco, USA
Objective: To describe the behavior of the relative risk (RR), absolute risk reduction (ARR), and number needed to treat (NNT) by attained age for the hip, spine or forearm for alendronate treatment in women with osteoporosis. Design: 3658 women with osteoporosis from the Fracture Intervention Trial were followed for 3 to 4.5 years and treated with alendronate (ALN) at 5 mg/day for 2 years followed by 10 mg/day for the remainder of the trial. The age groups used in the analysis were: 55 - 65, 65 - 70, 70 - 75 and 75 - 85. All fractures were confirmed by xrays. Results: Risk reduction of hip, spine and forearm fractures were 53% (RR = 0.47, p<0.01), 45% (RR = 0.55, P<0.01) and 30% (RR = 0.70, p=0.038) respectively. The reductions did not depend on age. The ARR increased with age for each of the fracture sites. For the hip, the ARR increased from 0.13 women per 100 patient-years at risk (PYR) for the 55 to 65 group to 0.53 women per 100 PYR for the 75 to 85 group. The corresponding increases in ARR for the spine were 0.14 and 0.86. The NNTs for 5 years for the hip were 157 for the 55 - 65 year old and 45 for the 75 to 85 year old women. The corresponding numbers for the spine were 140 and 23. For the composite endpoint, the NNTs (for 5 years) were 38, 25, 17 and 13 for the age groups 55 - 65, 65 - 70, 70 - 75 and 75 - 85 respectively. Conclusion: Alendronate is very effective in reducing the risk of osteoporotic fractures, regardless of age.
SUSTAINED FRACTURE BENEFIT WITH FIVE YEARS OF RISEDRONATE IN POSTMENOPAUSAL WOMEN
D. Hosking1*, O. D. Sorensen2, H. Mulder3, S. Adami4, S. Pack5, D. Wenderoth5, J. Y. Reginster6
1Nottingham City Hospital, Nottingham, UK
2Hvidovre Universitetshospital, Hvidovre, Denmark
3Research Center Good Clinical Practice, Rotterdam, The Netherlands
4Clinicizzato di Valeggio, Valeggio, Italy
5Procter & Gamble Pharmaceuticals, Staines, UK
6University of Liège, Liège, Belgium
Risedronate therapy significantly reduced the risk of vertebral fractures in postmenopausal osteoporotic women in a 3-year, placebo-controlled study (Reginster, 2000). A group of patients who completed this study participated in a double-blind, placebo-controlled, 2-year extension study. Patients in the extension study continued receiving oral risedronate (5 mg) or placebo daily, creating the longest placebo-controlled trial with a bisphosphonate reported to date. All patients also received calcium supplementation (1 g/day), and up to 500 IU of vitamin D/ day if baseline levels were low. Spinal radiographs were taken yearly during the first 3 years and at year 5. BMD measurements were performed at yearly intervals in the extension study.
In total, 265 patients entered the extension (135 on risedronate 5mg and 130 on placebo); 82% completed the 2-year extension study. In Years 4-5, risedronate significantly reduced the incidence of new vertebral fractures (risedronate, 11.1%; placebo, 22.3%; p=0.011). After 5 years, lumbar spine BMD increased significantly from baseline by 9.3% in risedronate-treated patients and by 2.1% in placebo-treated patients. The overall incidence of side effects during the extension was comparable between treatment groups. The proportion of patients with upper GI adverse events was similar between the two treatment groups, and fewer risedronate patients discontinued due to adverse events compared with placebo patients (7% vs 12%). In conclusion, this first long-term controlled study of a bisphosphonate demonstrates that risedronate provides a significant, sustained fracture benefit.
BONE MINERAL DENSITY OF ELDERLY HIP FRACTURE PATIENTS AND THE EFFECT OF CALCITONIN ON FRACTURE FUSION
T. M. Huusko1*, H. Kautiainen2, R. Sulkava1
1Department of Public Health and General Practice, Division of Geriatrics, University of Kuopio, Finland
2Rheumatism Foundation Hospital, Heinola, Finland
The objective of this study was to assess the bone mineral density (BMD) of independently living hip fracture patients, aged 65 years or older, during the first year after hip fracture, and to evaluate the effect of a three-month intranasal calcitonin treatment on fracture fusion.
After hip fracture operation in Jyväskylä Central Hospital, the patients were randomly assigned to daily 200 IU intranasal Calcitonin (n=121) and placebo (n=122) for three months. BMD of both calcanei was measured from 37 consecutive patients by single energy photon absorption and compared with the population of the same age in the town of Jyväskylä in the Evergreen project using the same method and the same apparatus.
The mean BMD of the hip fracture patients was 0.009 g/cm3 lower than the mean BMD of the general population among women (p=0.059) and 0.025 g/cm3 lower among men (p=0.025). There were no significant differences between the BMD of the fracture side and the non-fracture side. The mean loss of bone during the first year after the hip fracture was 14% (p<0.001). Severe or moderate dementia was associated with lower BMD values. Among patients with osteosynthesis (n=99), fusion of the fracture was observed in an x-ray three months after the operation in 84% in the calcitonin group and in 63% in the placebo group (p=0.029).
We conclude that the mean BMD values of the calcaneus of the hip fracture patients were lower than in the general population with the similar age group. The difference was statistically significant among men. The loss of bone during the first year was substantial. A three-month intranasal calcitonin 200 IU daily improved the fusion of hip fractures treated with osteosynthesis. The link between dementia and lower BMD values and risk of hip fractures needs to be studied.
EFFECT OF INTRANASAL SALMON CALCITONIN ON BONE MARKERS IN MEN WITH IDIOPATHIC OSTEOPOROSIS
G. Trovas1*, G. Lyritis1, E. Constantelou2, J. Koulouris1
1University of Athens, Laboratory for Research of Musculoskeletal System "Th.Garofalidis", Athens, Greece
2Hormonological Laboratory of Public Hospital, Saint Panteleimonas, Piraeus, Greece
Although treatment with intranasalsalmon calcitonin has been shown to effectively inhibit postmenopausal bone loss little is known about its action in men with Idiopathic Osteoporosis. In a randomized, double-blind, placebo-controlled we assessed the effect of 200UI of inranasal Salmon calcitonin (SCT) or placebo on bone markers over a period of 12 months in 28 with osteoporosis, 27-74yr old (mean age 52.4yr). All received 500 mg calcium daily. Treatment with nasal SCT was associated with a pronounced suppression of bone resorption markers (urinaryDPD,NTX,CTX) and to a lesser extent in bone formation markers (bALP,OC,PICP,PINP), whereas placebo did not. Therapy was well tolerated and there were no significant treatment-related adverse events.
We conclude that intranasal SCT 200UI daily effectively reduces bone turnover in men with Idiopathic Osteoporosis.
DEXA AND PQCT CHANGES AFTER A CONTINUOUS INTRANASAL CALCITONIN TREATMENT IN WOMEN WITH POST MENOPAUSAL OSTEOPOROSIS
E. Kataxaki*, G. Skarantavos, I. Koulouris, G. Trovas, G. Raptou, M. Katsiri, M. Tsipra, A. Galanos, G. P. Lyritis
Laboratory for the Research of the Musculoskeletal System
Aim: To study the effect of one year continuous intranasal salmon calcitonin administration (100 IU, 200 IU, placebo) in postmenopausal osteoporotic women.
Methods: 45 osteoporotic women (Z score greaterthan or equal -2.5), aged 55-70 were included in the study randomly allocated in three groups (group A 200 IU nasal SCT, group B 100 IU and group C placebo nasal spray daily for one year). All women received additionally 1000 mg Calcium daily. Bone mineral measurements of the spine and hip were performed at 0, 6, 12 months of treatment.
All women were also measured by pQCT (2000 Stratec Medizintechnic) in a same time schedule. Measurements were performed at 4%, 14%, and 38% of the tibia length from the distal end. Estimations concerning mass and geometry parameters were performed separately for the trabecular, subcortical and cortical bone. The results were analyzed by ANOVA. Biochemical markers of bone turnover in serum osteocalcin, bone specific alkaline phosphatase, NTX, CTX, D-Pyr were measured initially and at 6, 12 months after treatment.
Results: There was a significant reduction of NTX both in 100 IU (80.9 to 51.6 p=0,003) and in 200 IU sCT groups (99,1 to 53,9 p=0,002). Significant reduction of D-Pyr was found only in the 200 IU group (10,4 to 7,3) p=0,001). No significant differences were found in all DEXA measurements. There was a significant augmentation of Total Bone mass at the 4% slice of pQCT, in the 100 IU SCT. This was due both to a significant augmentation of trabecular bone mass (66.6 to 78.7 p=0.01) and subcortical bone mass (161.5 to 145.6 p=0.02). At the 14% slice, the placebo group presented a loss of total bone mass (181.6 to 179 p=0.001) maily due to loss of subcortical bone mass (194.4 to 193.9 p=0.02) both in 6 and 12 months.
Conclusions: In both groups of active treatment it was found:
a) Reduction of the rate of bone turnover b) Prevention of trabecular bone loss
c) Prevents cortical bone loss of the endocortical bone surface.
THE EFFICACY OF BIOCHEMICAL BONE MARKERS AND BONE ARCHITECTURES, STRENGTH WITH CONTINUOUS TREATMENT OF INTRANASAL ADMINISTRATION OF SALMON CALCITONIN 200IU ON EARLY POSTMENOPAUSAL WOMEN
I. Koulouris*, E. Kataxaki, G. Trovas, G. Skarantavos, G. Raptou, M. Katsiri, A. Galanos, G. P. Lyritis
Laboratory for the Research of the Musculoskeletal System, University of Athens Medical School, Athens, Greece
AIM This prospective study was to assess the influence of 200IU sCT therapy given the response on the biochemical bone markers, architecture and bone strength on early postmenopausal women.
METHOD 50 early postmenopausal women with mean age 50±5. Group A was treated with 200IU nasal sCT whereas group B was placebo treated daily for one year period. Both groups received 800 mg of calcium carbonate additionally (included women with T score less than or equal 2SD by DEXA) and were measured biochemical bone markers and by pQCT at 0, 6, 12 months of treatment) at 4% and 20% of the left radius. The results were analysed by student's t-test.
RESULTS Alkaline phosphate values demonstrated significant difference (p=0.024) at 6 months, urinary levels of OHP/Creatinine decreased significantly in the sCT group (p=0.004).
A) The changes in the 4% of pQCT scans were: I) We have increase of the trabecular content (p=0.023) in the sCT group and non significant changes in group B. II) We have decrease in the trabecular area of the placebo (group B) (p=0.004) and non significant changes in the sCT group. III) In the total area we have increase in the sCT group (p=0.036) and non significant changes in the placebo group.
B) In the 20% slice in pQCT: I) the cortical thickness in the sCT group is significant (p=0.000) and placebo group significant as well (p=0.001). I) The cortical perimeter in the sCT group increased (p=0.004) but in the placebo group is non significant. The changes on the BSI are: Increase in the sCT group in comparison to the placebo group but on both groups was non significant.
CONCLUSION Treatment with 200 IU continuous of nasal sCT given daily for one year:
1) Resulted in changes of biochemical bone markers that reflect its effect on bone metabolism, decrease the bone turnover rate.
2) Affects the trabecular bone. Increases the cortical content in dose 200IU sCT, but decrease the cortical area-volume in the placebo group and we have increase in the total area of the sCT group (p=0.036).
3) The effect on the pericortical perimeter in sCT group increased. This shows that the protection which is provided to the bone durational strength is increased. In general the decrease of the bone turnover rates, the improvement of sCT on the bone microarchitecture so that both improved the bone quality in 1 year period.
THE RELATIONSHIP OF HYPOVITAMINOSIS AND SECONDARY HYPERPARATHYROIDISM TO BONE MINERAL DENSITY AMONGST UK RESIDENT INDO-ASIANS
E. Serhan1*, M. R. Holland2, B. M. Singh3
1Department of Rheumatology, New Cross Hospital, Wolverhampton, UK
2Department of Clinical Chemistry, New Cross Hospital, Wolverhampton, UK
3Diabetes Centre, New Cross Hospital, Wolverhampton, UK
High prevalence of hypovitaminosis D with or without secondary hyperparathyroidism amongst UK resident Indo-Asians is well documented.
Objective: To investigate the relationship of these conditions to bone mineral density (BMD) in Indo-Asian Rheumatology patients.
Methods: 134 patients aged 51±13 years, 85% (n=114) females were recruited into the study. Only 11 of these had inflammatory arthritis, the rest complained of non-specific musculo-skeletal aches & pains. Subjects on vitamin D supplements, anti-convulsants, with impaired renal function, pregnant and lactating mothers were excluded from the study. Dietary scores were obtained by questionnaire concerning their meat consumption. Investigations included routine biochemistry, 25-OH-vitamin D (NR=8.0-60.0 ug/l), parathyroid hormone (NR=12.0-72.0 ng/l) assays. BMD measurements at the femoral neck (FN), lumbar spine (LS) and distal radius (DR) were done using DXA on Lunar XL scanner. ‘T’ scores were used in definition of BMD findings. Normal (T>-1.0), osteopaenia (-1.0>T>-2.5) and osteoporosis (T<-2.5). The Tukey, Chi-square and Student’s unpaired t-tests, including stepwise multivariate regression, were used in statistical analysis.
Results: The whole group were divided into 3 subgroups. 21 (16%) had normal vitamin D and parathyroid hormone (PTH) levels, 79 (59%) had low vitamin D but normal PTH (HD) and 34 (25%) had both low vitamin D with raised PTH (HD-SHPT). Apart from vitamin D levels no significant differences existed between patients with normal vitamin D & PTH and those with HD. Therefore these were amalgamated (n=100) and compared to HD-SHPT group (n=34). HD-SHPT patients were older and tended to vegetarianism. HD-SHPT group had significantly lower vitamin D (3.2±2.5 ug/l v 6.6±5.3 ug/l, p<0.001), by definition higher PTH (148±143 ng/l v 40±15 ng/l, p<0.001), and higher alkaline phosphatase levels (362±361 IU/l v 177±54 IU/l NR=80-330, p<0.05). HD-SHPT patients also had significantly lower scores at the FN (-1.00±1.48 v -0.31±1.25, p<0.01) and DR (-1.79±1.81 v -0.5±1.79, p<0.001).
Conclusion: Our data show that HD-SHPT is attended by significantly reduced bone mass. The natural history of hypovitaminosis D to the onset of secondary hyperparathyroidism is unknown. Therefore early detection of hypovitaminosis D in Indo-Asian population and its treatment with calcium and vitamin D supplements, before the onset of secondary hyperparathyroidism is long overdue.
P583 W
Withdrawn
THE RELATIONSHIP BETWEEN VITAMIN D AND PTH: CALCIUM HOMEOSTASIS, BONE TURNOVER & BMD IN WOMEN WITH ESTABLISHED OSTEOPOROSIS
O. Sahota*, P. San2, T. Masud3, D. J. Hosking2
ADRU, University Hospital, Nottingham, UK
Division of Mineral Metabolism, City Hospital, Nottingham, UK
Dept Geriatric Medicine, City Hospital, Nottingham, UK
Hypovitaminosis-D is common in the elderly and untreated leads to secondary hyperparathyroidism. This pathological mechanism is widely recognised; however, not all patients with hypovitaminosis-D develop secondary hyperparathyroidism and although acknowledged, few studies have evaluated this sub-group of the population.
The aim of this study was to evaluate patients with hypovitaminosis-D and a low PTH in comparison to patients with hypovitaminosis-D and secondary hyperparathyroidism by investigating the effects on calcium homeostasis, bone turnover and BMD. Vitamin-D replete subjects were used as controls
300 community dwelling women, aged >60 yrs, with established vertebral osteoporosis (WHO T score-2.5) were evaluated. The mean (SD) age was 67.9±5.1 yrs (range 60-84), yrs past menopause 22.1±6.9 and body mass index 24.4±4.1 kg/ m2. 39%(117/300) had hypovitaminosis-D [25 hydroxyvitamin-D <30 nanomol/l]. 64 of these subjects had secondary hyperparathyroidism [defined as a PTH above upper tertile normal range] and the remaining low PTH [PTH below lower tertile normal range]. The mean(SD) effects on calcium homeostasis and bone turnover are shown below. BMD was lower (p<0.01) in patients with hypovitaminosis-D and secondary hyperparathyroidism in comparison to the other groups.
There is a high prevalence of hypovitaminosis-D in patients presenting to clinical attention with vertebral osteoporosis. PTH maintains the homeostasis of calcium through increased bone turnover, mediated by secondary hyperparathyroidism, although occurs at the expense of increased bone loss. Secondary hyperparathyroidism however, only occurred in a sub-group of patients with hypovitaminosis-D and the remaining a low PTH level. This group clearly displays a distinct biochemical skeletal abnormality. Bone loss may be protected through decreased bone turnover; however, the effects on bone mineralisation may be detrimental long-term.
Clinically if combination calcium and vitamin are effective by reducing the secondary hyperparathyroidism, their role in patients with hypovitaminosis-D and a low PTH needs to be further evaluated.
| vitamin D replete | hypovitaminosis D | ||
| low PTH | secondary hyperpara-thyroidism | ||
| Corrected Ca (2.2-2.6mmol/l) | 2.48(0.01) | 2.33(0.01)*a | 2.44(0.01)*a |
| 25OHD (22-115nmol/l) | 57.5(20.6)**ab | 23.4(4.4)**a | 23.6(5.2)**b |
| 1,25(OH)2D (48-110pmol/l) | 87.2(19.4)**a*b | 33.2(16.1)**a | 54.7(17.8)*b |
| bone alk phos (<120IU/l) | 125.1(35.3)*a | 122.4(28.1)*b | 148.6(38.2)*ab |
| free D-pyd (2-11nmol/mmol/creat) | 5.7(2.4)*a | 5.5(2.5) | 7.5(2.1)*a |
| **p<0.01, *p<0.05 (ANOVA) | |||
COMPARISON OF THE EFFECT OF COMBINED CALCIUM-VITAMIN D OR CALCIUM ALONE ADMINISTRATION ON CIRCULATING LEVELS OF PARATHYROID HORMONE (PTH) AND 25-OH VITAMIN D (25-OHD) IN AMBULATORY VITAMIN D-DEPLETED POST-MENOPAUSAL WOMEN
R. Deroisy1,2*, J. Collette1,2, A. N. Taquet1,2, Fr Thines3, J. Y. Reginster1,2
1WHO Collaborating Center of Public Aspects of Rheumatic Disorders, including Osteoporosis, Liège, Belgium
2Bone and Cartilage Metabolism Unit, University of Liège, Liège, Belgium
3WILL-PHARMA, Belgium
The present study was designed to evaluate the effects of the administration of an associated calcium-vitamin D supplementation compared to a calcium supplementation alone, on the serum circulating levels of PTH and 25-OHD in 100 ambulatory vitamin D deficiency menopausal women.
The study enrolled 100 patients randomized in 2 groups receiving either the associated calcium-vitamin D preparation or the plain calcium preparation.
Each patient was asked to take either one sachet of 500 mg elemental calcium associated with 200 IU vitamin D or one effervescent tablet of 500 mg elemental calcium, each day.
The objective of the study is to demonstrate the superiority of the calcium-vitamin D association compared to the calcium administration without vitamin D, with reference to serum PTH and 25-OHD circulating levels respectively.
Compliance and digestibility of both preparations are also part of the evaluation. The study duration is 3 month and is still on going. Results will be discussed during the Congress.
SUBSTANTIAL BENEFICIAL EFFECTS OF CALCIUM SUPPLEMENTATION ON SERUM LIPIDS IN NORMAL POSTMENOPAUSAL WOMEN
I. R. R. Reid*, B. Mason, A. Horne, R. Ames, J. Clearwater, F. Wu, M. C. Evans, G. Gamble
University of Auckland, Auckland, New Zealand
A small number of studies in the past have suggested that calcium may have a beneficial effect on serum lipids, possibly through binding of lipids in the gut. With the increasing use of calcium supplements in postmenopausal women for the prevention of osteoporosis, the cost-effectiveness of this intervention could be substantially impacted on by its possible effects on lipids.
We report a randomised, controlled trial of 223 normal postmenopausal women, randomised to take 1g elemental calcium daily (as calcium citrate) or identical placebo over a 12 month period.
The groups were comparable at baseline in lipid and clinical characteristics. Mean (SD) age was 72 (4) years. Total cholesterol tended to decline in both groups, more so in those receiving calcium. HDL increased significantly in the calcium group (from mean (SE) 1.65 (0.04) mmol/L to 1.80 (0.06) mmol/L, P=0.01 vs placebo group). LDL declined significantly in the calcium group. The ratio of HDL to LDL increased from 0.42 (0.02) at baseline to 0.50 (0.03) at one year, but did not change in the placebo group (P=0.0018 between groups). This difference was significant at 2 months and tended to increase over time.
These changes in HDL are comparable to those seen with simvastatin in the 4S study, though the LDL changes are only one quarter those produced by statins. The changes in lipids observed in the present study are likely to be associated with a 20-30% decrease in cardiovascular disease risk. We conclude that calcium supplementation has substantial beneficial effects on circulating lipids in normal postmenopausal women, strengthening the case for its widespread use as a prophylactic agent in this group of patients.
HIGH PROTEIN INTAKE SEEMS TO DIMINISH POSTMENOPAUSAL BONELOSS. 5 YEARS OF FOLLOW-UP ON THE DANISH OSTEOPOROSIS PREVENTION STUDY
A. P. Hermann1, L. Stilgren1*, J. Thomsen2, P. Vestergaard2, C. Brot3, N. Kolthoff4, L. Mosekilde2, P. Charles2
1Dept of Endocrinology, Odense University Hospital, Denmark
2Dept of Endocrinology, Aarhus amtssygehus, Aarhus University Hospital, Denmark
3Copenhagen Municipal Hospital, Copenhagen, Denmark
4Hillerød Hospital, Hillerød, Denmark
Results on the role of dietary protein in calcium economy are conflicting.
In the Danish Osteoporosis Prevention Study (DOPS) a 7 day diet record was obtained in 1902 healthy early postmenopausal women 695 of whom were afterwards allocated to hormone replacement therapy (HRT). Bone Mineral Density was measured in the lumbar spine, hip region, and whole body at study start and in 1802 women after 5 years. Of these 977 had not been taking hormones at any time during follow up and 508 were still on HRT. Mean bone loss in the 977 not treated women were 0.07 g/cm2 (SD: 0.05) in the lumbar spine, 0.05 g/cm2 (SD: 0.05) in the femoral neck, and 0.03 g/cm2 (SD: 0.03) in the whole body. Mean intake of protein was was 66 g/day (SD 16). Weightchange during the follow up periode was the strongest determinant for bone loss in treated as well as not treated women. (R2= 0.4-7,5 and 0.7-10.4), respectively. Dietary protein expressed as the fraction of daily energy intake obtained from proteins was inversely correlated to loss of bone in the spine and whole body (R2 = 0.1 and 1.1, p<0.01) in the not treated group. The relation was not found in the women taking HRT. Daily energy intake was not per se related to bone loss or weight change.
We conclude that high protein intake seems to have a weak but statistically highly significant bone-sparing effect in early postmenopausal women.
THE MAGNITUDE OF THE PTH RESPONSE TO CALCIUM SUPPLEMENTATION
R. P. Heaney1, M. S. Dowell1, J. Bierman1, C. A. Hale2, A. Bendich2*
1Creighton University, Omaha, NB, USA
2SmithKline Beecham Consumer Healthcare, Parsippany, NJ, USA
It is well accepted that iPTH will decrease in response to calcium supplementation provided that vitamin D status is normal. We recently examined the 24 hr bioavailability of a single dose of 500 mg of elemental calcium (Ca) as either calcium carbonate or calcium citrate, and at the same time, determined the serum iPTH, ionized Ca and urine Ca levels in 24 post-menopausal women given vitamin D and a low intake of calcium (400 mg/d) for one week prior to testing. Blood was drawn at 1, 3, 5, 7, 9, 12, and 24 hr post-dosing. Serum total Ca increased equivalently for both salts to about 6% over baseline and ionized Ca increased about 5% within 5 hours. Concomitantly, iPTH dropped 40% during the same time and returned to baseline by 24 hr. Serum total and ionized Ca also returned to within 1% of baseline at 24 hr, however the % of serum Ca that was ionized remained stable throughout the 24 hr. Serum iPTH dropped more rapidly and sooner than the rise in serum Ca. These data indicate that serum iPTH is a very sensitive indicator of calcium supplementation especially when measured at the time of maximal increase in either serum total or ionized Ca. It would appear that serum iPTH could also be useful in determining compliance of test subjects who are supposed to be on low Ca intake regimens.
FERMENTED SOYBEANS MAY ACCELERATE PREMENOPAUSAL BONE GAIN AND DECELERATE POSTMENOPAUSAL BONE LOSS IN HEALTHY JAPANESE POPULATION - JPOS COHORT STUDY
M. Iki1*, A. Morita1, Y. Ikeda1, H. Aihara1, A. Yura1, S. Kagamimori2, Y. Kagawa3, T. Matsuzaki4, H. Yoneshima5, F.Marumo6 for JPOS Study Group
1Kinki University School of Medicine, Osaka-Sayama, Japan
2Toyama Medical and Pharmaceutical University, Toyama, Japan
3Kagawa Nutrition University, Tokyo, Japan
4Institute of Comprehensive Community Health Care, Tokyo, Japan
5Kasukabe-Shuuwa Hospital, Kasukabe, Japan
6Tokyo Medical and Dental University, Tokyo, Japan
Japanese Population-based Osteoporosis (JPOS) cohort study was conducted to determine the changes in bone mineral density (BMD) of several skeletal sites in healthy Japanese women of various ages and to clarify the determinants of these BMD changes. We report here a skeletal effect of a Japanese traditional fermented food, 'natto', made of soybeans which is rich in vitamin K2.
We randomly selected 50 women each from 5-year age stratified populations (15-79 year), 1985 in total, according to the resident registration in each of 3 municipalities located north, middle and south parts of Japan. The follow-up study was conducted 3 years after the baseline study. Both studies comprised DXA bone densitometry at the spine, hip (QDR4500A, Hologic) and distal forearm (pDXA, Norland/Stratec), and interviews on medical histories and various lifestyle factors including the consumption of 'natto'.
Among 1628 women who underwent the baseline study, 1285 (78.9%) completed the follow-up study. Significant bone losses in the spine and femoral neck were observed in the subjects aged 45-74 at baseline and in those under 25 or over 40 years, respectively. In addition, menopause, height and weight had significant effects on the change in BMD in every skeletal sites. The subjects with greater intake of milk and 'natto' or with more active lifestyle tended to have smaller loss of BMD. We divided the subjects into 3 groups according to the amount of 'natto' consumption, i. e., at least 1 package (35g of 'natto' containing 320 microg of vitamin K2) per day, seldom/none and in-between. Premenopausal women gained BMD at the forearm dose-dependently with the intake of 'natto' even after the effects of other variables were adjusted. Postmenopausal women showed reduced loss of BMD dose-dependently with the increase in intake of 'natto' at every skeletal sites. Such a relationship was not observed for the intake of boiled soybeans or other soybean products like bean curd, 'tofu' which do not contain vitamin K.
We suggest that the intake of fermented soybeans is beneficial for both premenopausal and postmenopausal women in the prevention of osteoporosis through stimulating bone formation by the increased intake of vitamin K2.
RALOXIFENE EFFECTS ON BONE COULD BE ASSOCIATED WITH NITRIC OXIDE-PATHWAY
M. Lefort1*, E. García-Colis2, C. Méndez-Dávila1, C. De la Piedra1, A. López-Farré2, M. Díaz-Curiel3
1Fundación Jiménez Díaz, Laboratorio de Bioquímica, Madrid, Spain
2Fundación Jiménez Díaz, Laboratorio de Investigación Cardiovascular e Hipertensión, Madrid, Spain
3Fundación Jiménez Díaz, Medicina Interna, Madrid, Spain
Estrogen depletion increase bone mineral loss. Raloxifene (RLX), a selective estrogen receptor modulator, is used in the prevention and treatment of postmenopausal osteoporosis because it presents the estrogen protective-like actions on bone, without some of undesirable collateral effects of estradiol. Recent works suggest that nitric oxide (NO) seems to have a relevant role in the regulation of bone remodeling, the fall in NO levels increasing bone resorption. The aim of this work was to study the effects produced by RLX on neutrophil-endotelial-type NO-synthase (eNOS) expression in oophorectomized rats, an experimental model of postmenopausal osteoporosis. The simultaneous administration of RLX and aminoguanidine (AG), an inhibitor of the inducible NO-synthase activity was also analysed. Results were related to the changes in bone mineral density (BMD).
Fifty 15 week-old female Wistar rats were oophorectomized (OVX). Thirteen age-and-sex-matched rats were sham operated (SHAM). OVX rats were divided in groups: 1) OVX+RLX: received orally 1 mg/kg/day of RLX analogue (LY139481.HCl, Lilly); 2) OVX+RLX+AG: received RLX and AG (4 g/L in drinking water); 3) OVX: received vehicle. Treatments were followed during 3 months. BMD was determined in the left femur by DEXA (Hologic QDR 100; eNOS expression was analysed by Western blot. Statistics: Mann-Whitney test.
OVX rats presented a significant decrease in BMD (OVX: 0.2870±0.0115 g/cm2 vs. SHAM: 0.3124±0.0130 g/cm2, p<0.0001). RLX administration prevented bone loss (OVX+RLX: 0.3043±0.0054 g/cm2 vs. SHAM, p<0.10). The administration of AG to RLX treated rats decreased the effect of RLX on bone mass (OVX+RLX+AG: 0.2965±0.0115 g/cm2 vs. SHAM, p<0.01). We found a significant increase in the eNOS protein expression of group OVX+RLX: 128.12%, taking as reference value 100%, that of OVX group. Percent of expression of eNOS protein in group OVX+RLX+AG decreased to 86.06%.
The above results suggest that the protective effect of RLX in bone mass could be at least partially associated to an increase in eNOS protein expression and, therefore, in NO availability.
BONE TURNOVER IN SMOKING AND NON-SMOKING POSTMENOPAUSAL FEMALES BEFORE AND DURING ESTROGEN REPLACEMENT THERAPY
R. K. Tahtela1*, S. Sairanen2, K. Laitinen2, E. Hirvonen3, J. Risteli4, M. J. Valimaki2
1Leiras Oy, Clinical Research, Helsinki, Finland
2Helsinki University Hospital, Division of Endocrinology, Helsinki, Finland
3Helsinki Medical Center, Helsinki, Finland
4Oulu University Hospital, Dpt of Clinical Chemistry, Oulu, Finland
Smoking is a risk factor for osteoporosis. The mechanisms by which it affects bone are not fully elucidated. Smoking has been shown to have an antiestrogenic effect on calcium absorption in the gut, and to enhance hepatic metabolism of estrogens. Smoking may modulate the activity of cytokines and their receptors, involved in bone remodelling, leading to increased resorption. It also may have a direct effect on osteoblasts, lowering bone formation. Smoking may thus abolish the beneficial effect of estrogen replacement therapy (ERT) on bone.
We evaluated bone turnover of early postmenopausal women, smokers and non-smokers, by the aminoterminal propeptide of type I procollagen (S-PINP), a marker of bone formation, and the excretion of aminoterminal telopeptide of type I collagen (U-NTx), a resorption marker, before and after 1 and 2 years treatment with ERT. Smokers were allocated to receive 1 mg (n=32) or 1.5 mg (n=31) of transcutaneous 17-beta-estradiol (E) daily, non-smokers received 1 mg of E daily (n=45). The baseline turnover markers were compared to those of non-smoking premenopausal females (n=36).
U-NTx was higher in post- than in premenopausal females (p<0.001), S-PINP was similar in the three groups. Markers correlated less well in smokers than non-smokers, in postmenopausal smokers r=0.35 and in non-smokers r=0.60, in premenopausal non-smokers r=0.71. In smokers the two doses of E decreased the markers to a similar extent; thus the groups were combined. ERT decreased U-NTx similarly in smokers and non-smokers, but S-PINP decreased less in non-smokers during the first study year (p<0.05). During the second year S-PINP did not further change in smokers, but it increased in non-smokers, leading to a significant difference in changes from baseline between the groups (p<0.001). In smokers the correlation of the markers improved from 0.35 to 0.62 during the first year, and remained stable thereafter.
In conclusion, smoking did not lessen the antiresorptive effect of ERT, assessed by U-NTx, but it seemed to aggravate the ERT-induced suppression of bone formation, assessed by S-PINP. Consequently, ERT may result in a less positive bone balance in smoking than in non-smoking females.
DOES HORMONE REPLACEMENT THERAPY PREVENT NON VERTEBRAL FRACTURES: A REVIEW OF RANDOMISED TRIALS AND META-ANALYSIS
D. J. Torgerson*, S. E. M. Bell-Syer
University of York, York, UK
Hormone Replacement Therapy (HRT) is widely considered to reduce fractures; this belief, however, is based on non randomised data. We performed a meta-analysis of all randomized controlled trials of HRT that have collected non-vertebral fracture data. Seventy one potentially eligible trials were identified, 12 had published fracture data in the original reports. We wrote to authors of 59 studies and identified a further 11 studies with unpublished fracture data, making 23 included trials in total, with > 8000 women randomised. Pooling the 23 trials gave an overall 21% reduction in non-vertebral fractures [Relative Risk reduction favouring HRT (RR) 0.79, 95% confidence interval (CI) 0.68 to 0.93, p=0.01]. There seemed to be a greater effect among women randomised to HRT when aged less than 60 years where HRT use was associated with a 36% reduction in fracture risk [RR = 0.64, 95% CI = 0.49 to 0.83, p=0.001]. For women aged above 60 years of age there was little evidence of an effect of HRT on fractures [RR = 0.91 95% CI 0.74 to 1.12, p=0.35].
Randomised controlled trials of HRT among women aged less than 60 years show that non vertebral fractures are reduced by about 40%. However, this effect may be attenuated in older women.
EFFECT OF RALOXIFENE, A SELECTIVE ESTROGEN RECEPTOR MODULATOR (SERM), ON BONE RESORPTION MARKERS AND SERUM LIPIDS IN POSTMENOPAUSAL WOMEN ON CHRONIC HEMODIALYSIS (HD)
E. Hernandez1*, R. Valera1, J. Teran1, M. Bajares-Lilue2, F. Capriles3, E. Alonzo1, K. de Elquezabal1, R. Carlini1,3, E. Bellorin-Font1,3, J. R.Weisinger1,3
1Division of Nephrology, Hospital Universitario de Caracas, Venezuela
2Department of Gynecology, Hospital Universitario de Caracas, Venzuela
3Fresenius Medical Care de Venezuela
Although uremic patients are at increased risk for early menopause, osteoporosis and cardiovascular disease, few postmenopausal women receive hormone replacement therapy. Since renal failure may alter the pharmacokinetics of exogenous estradiol increasing the risks of side effects, we designed a blind, controlled and randomized study to evaluate the long-term effects of raloxifene on bone and lipid metabolism in a group of postmenopausal women on HD. After an informed consent was signed, 50 patients were randomized into groups that received 60 mg/day of raloxifene or placebo. Both groups were similar in terms of age, time after menopause, and time on dialysis. Z-score lumbar spine BMD by dual x-ray bone densitometry was similar in both groups (-2.0±1.09 vs. -2.54±1.5, in the control and raloxifene groups, respectively). Serum calcium, phosphorus and intact PTH were also similar. After 6 months on raloxifene serum pyridinoline decreased significantly (40.16±5.3 vs 29.5±4.1, p<0.05). No changes were observed in similar women on placebo (54.3±8.2 vs 49.2±13.7, NS). LDL-cholesterol decreased significantly in the raloxifene group (98.4±5.8 vs 83.1±4.4, p< 0.05), with no changes in the placebo group (108.8±5.9 vs 99.5±7.7, NS). No changes in HDL-cholesterol or triglycerides were observed in both groups. In summary, after 6 months on raloxifene, postmenopausal women on HD showed a significant decrease in bone resorption markers and LDL-cholesterol values. The long-term effect of this drug upon bone and lipid metabolism in HD patients remains to be determined.
LASOFOXIFENE INHIBITS BONE TURNOVER AND MAINTAINS SPINE BMD AFTER OVARIECTOMY IN MONKEYS
R. Brommage*, C. E. Hotchkiss, M. W. Stancill, C. J. Lees
Wake Forest University, Winston-Salem, USA
Lasofoxifene is a new SERM that inhibits bone loss in ovariectomized (OVX) rats without inducing uterine hypertrophy. The goal of this study was to determine if lasofoxifene has similar actions in OVX monkeys.
Adult female cynomolgus monkeys were divided into Sham-Vehicle, OVX-Vehicle and OVX groups given daily oral doses of either Conjugated Equine Estrogens (CEE - Premarin) or lasofoxifene at 1 or 5 mg/kg. DXA spine BMD along with serum levels of total alkaline phosphatase activity (ALP) and bone collagen crosslinks (CTX) were measured at baseline and 3, 6, 12, 18 and 24 months. Uterine weight was determined at 24 months. There were no differences in baseline values among groups. All data are means±SEM with ‡ indicating P<0.05 compared to the OVX-Vehicle control group by ANCOVA.
OVX produced osteopenia and treatment with CEE or lasofoxifene prevented this bone loss (24 month data presented). Uterine weight was reduced by OVX and increased with CEE, but not lasofoxifene treatment.
Loss of spine BMD induced by OVX was accompanied by increased bone remodeling as indicated by elevated levels of ALP (36%) and CTX (45%) compared to Sham. CEE and both doses of lasofoxifene prevented (P<0.01) this OVX-induced stimulation in bone remodeling.
These data demonstrate that lasofoxifene effectively inhibits the increases in bone turnover and bone loss following OVX in adult monkeys without producing uterine hypertrophy.
| Group | N | Change in Spine BMD (%) |
Uterine Weight (g) |
| Sham-Vehicle | 24 | 2.5±0.6? | 10.1±1.2? |
| OVX-Vehicle | 22 | -1.0±0.5 | 3.0±0.4 |
| CEE (21 microg/kg) | 25 | 2.2±0.7? | 15.7±4.3? |
| Lasofoxifene (1 mg/kg) | 23 | 0.4±0.6? | 3.3±0.4 |
| Lasofoxifene (5 mg/kg) | 25 | 0.2±0.6? | 4.2±1.2 |
DOES SMOKING INFLUENCE THE EFFICACY OF RALOXIFENE IN POSTMENOPAUSAL OSTEOPOROTIC WOMEN? RESULTS FROM THE MORE TRIAL
R. D. Chapurlat*, D. C. Bauer, S. Ewing, S. R. Cummings
University of California, San Francisco, USA
The efficacy of raloxifene may be modified in smoking postmenopausal women because of increased catabolism of estrogen and interaction of tobacco products with the estradiol receptor. Smoking women also have lower bone mineral density (BMD) and altered bone turnover.
To test the influence of smoking on the antiosteoporotic efficacy of raloxifene, we examined women (mean age 65) from the MORE trial, who were randomized to either raloxifene (60 or 120 mg/day) or placebo, during 4 years. We tested the smoking-treatment interaction on the percent change in markers of bone turnover (2500 women with serum osteocalcin and 2385 with urinary CTX) using logistic regression, the percent change in BMD using linear regression (5347 women with spine and hip BMD measurements), and the reduction in vertebral fracture risk using logistic regression.
In the 16% of women who were current smokers, we found, compared to non-smokers, lowered baseline trochanteric BMD (0.540 vs 0.557 g/cm2, p<0.001), serum 25OHD (69 nmol/l vs 71, p=0.01), and serum osteocalcin (24.8 ng/l vs 26.6, p<0.001). Baseline urinary CTX was increased among smokers (291.8 micromol/l vs 276.9, p=0.04). Mean baseline serum estradiol did not differ between smokers (23 pmol/l) and non-smokers (26 pmol/l), p= 0.4. Body mass index (BMI) was also lesser in smokers (24 vs 25, p<0.001). After 6 months of treatment, smokers had slightly lesser reduction in osteocalcin (median change was -24% for smokers and –25% for non-smokers, p for smoking-treatment interaction =0.06) and urinary CTX (median change was –25.6% for smokers and –26% for non-smokers, p for smoking-treatment interaction =0.06). After 4 years of treatment, the smoking-treatment interaction was not significant for the percent increase in femoral neck BMD between smokers (-0.1%) and non-smokers (+0.2%), p=0.25; the smoking-treatment interaction for reduction in vertebral fracture risk was not significant either (odds-ratio for fracture was 0.67 for smokers and 0.56 for non-smokers, p=0.44). These results were not modified after stratification according to tertiles of BMI.
We conclude that smoking, which is associated with lowered BMD, lowered bone formation, and increased bone resorption, does not influence antiosteoporotic effect of raloxifene.
SKELETAL AND SOMATIC CHANGES INDUCED BY TESTOSTERONE THERAPY IN HYPOGONADAL MEN
S. V. Karlsbrum1*, G. Geloso1, S. Aszpis1, P. Otero1, L. Schurman2, O. Levalle1, H. Salerni1
1División Endocrinología, Htal Durand, Buenos Aires, Argentina
2TCBA, Buenos Aires, Argentina
Acquired hypogonadism is increasingly recognized in men. The effects of long term testosterone replacement on body composition, bone mineral density and total calcium content are still controversial.
The aim of this study was to quantify the effects of long term testosterone replacement on total calcium content and body composition changes and its correlation with the hormonal and bone mineral density changes.
We investigated 15 men, mean age 31.3 years (18-51):11 with primary hypogonadism and 4 with central hypogonadism (the latter with no other hormonal deficits). For inclusion, serum testosterone (T) <3 ng/ml was required.
Baseline evaluation included serum determinations of T, bioavailable T (BioT) and estradiol (E2). Total calcium content (TCC), bone mineral density in: spine (SBMD) and trochanter (TBMD) femoral neck (FNBMD) and whole body (WBBMD), percent of body fat: total (%TBF) and abdominal (%AF) and lean mass (LM) by DEXA.
Testosterone replacement was initiated at a dose of 250 mg testosterone enanthate IM, twice a month. This dose normalized biochemichal parameters. at 3 and 6 months. Dexa measurements were repeated at 6 and 12 months. Under treatment %TBF and %AF decreased: p=0.0006 and p=0.0013; lean/fat ratio (LFR) increased: 2.06±0.71 vs 2.85±0.88, p=0.0052. BMD increased: SBMD (p=0.0007), TBMD (p=0.0016), FNBMD (p=0.0003) and TCC (p=0.022).
TCC correlated with increments in SBMD (r: 0.76, p<0.05); T (r: 0.78, p<0.05); BioT (r: 0.78, p<0.05) and E2 (r: 0.62, p<0.05). The changes in SBMD and BioT also correlated (r: 0.76, p< 0.01). Finally the lean/fat ratio and FNBMD increments correlated significantly (r: 0.91, p<0.01).
We concluded that testosterone therapy given to hypogonadal men decreases total body and abdominal fat mass with maintenance of BMI and increment in lean (muscle) mass. The increment in FNBMD could be explained by changes in muscle mass.
Total calcium content increments could depend on improvement of Spine BMD and could be explained by increments of T, BioT and E2.
PROGRESSIVE RESPONSE OF SERUM BETA-CROSSLAPS TO SUBCUTANEOUS ESTRADIOL IMPLANT
A. C. Eagleton*, C. A. Pereda, R. A. Hannon, K. E. Naylor, A. Blumsohn, R. Eastell
Bone Metabolism Group, University of Sheffield, UK
The effect of oral and transdermal estradiol (E2) replacement on bone turnover is well known. Bone resorption typically reaches a new steady state within three months on therapy. The aim of this study was to investigate changes in serum beta-Crosslaps (bCTX) and other markers of bone turnover in response to low-dose subcutaneous E2 implant. 21 postmenopausal women (hysterectomy 2-38 yrs previously; age 65.5yrs, range 49-76) were randomly assigned to a treated group (T-group, n=10; 25mg subcutaneous E2 implant inserted at 0, 25, 53 and 78 wks) or sham implant followed by E2 implant (S/T-group, n=11; sham implant at 0 and 25 wks; 25mg E2 implant at 53 and 78 wks). Morning fasting blood and second morning void urine samples were collected at 12 time points up to 104 wks.
Following implant there was a progressive decrease in bCTX level throughout the study period (57.9% 5.3%SEM decrease at 24 wks; 83.7% 6.8%SEM decrease at 104 wks). The S/T-group showed no response to sham implant, but a similar decline in bCTX following E2 implant.
Within subject variability CV(a+i) for bCTX off treatment was 14.9% at a repeat-test interval of 1 wk and 29.8% at an interval of 52 wks. CV(a+i) at an interval of 1 wk in treated subjects (12.4%) was similar to that off treatment. Least significant change (P=0.05, one sided) at 24 wks was 47.9% (95% CI 19.6–71.1) and 69.5% (95%CI 38.3-93.6) at 52 wks. Using this threshold as an indicator of response, 13 of 17 subjects would be classified as ‘responders’ at 24 wks of therapy and 13 of 15 subjects at 52 wks.
A signal to noise ratio (SN; %change at 24wks/CVa+i) was calculated for bCTX and compared to SN for other markers measured. bCTX had the highest SN (4.3) compared to serum markers of bone formation (BAP,1.3; OC 1.4; PINP 3.8) or urinary markers of resorption (freeDpd, 1.9; NTX 2.3). The progressive response to E2 implant may be related to escalating serum E2. Reliable serum markers of bone resorption are likely to provide a better indication of therapeutic response than urinary markers.
DOSE-RELATED DECREASES IN BONE BIOMARKERS DUE TO NORETHINDRONE ACETATE IN POSTMENOPAUSAL WOMEN TREATED WITH ETHINYL ESTRADIOL
J. A. Simon1*, J. C. Gallagher2, B. Drinkwater3, J. P. Symons4
1George Washington University School of Medicine, Washington, DC, USA
2Creighton University Medical Center, Omaha, Nebraska, USA
3Pacific Medical Center, Seattle, Washington, USA
4Pfizer Global Research and Development, Ann Arbor, Michigan, USA
Significant increased bone mineral density (BMD) has been obtained when 1mg norethindrone acetate (NA) is combined with 5mcg ethinyl estradiol (EE) compared to 5mcg EE alone in postmenopausal women. Lower doses of NA may not have this additive effect on BMD and the present study was undertaken to investigate the dose-related effect of NA in prevention of osteoporosis as assessed by biochemical markers of bone turnover.
This was a one-year, double-blind, placebo-controlled, parallel-group, multicenter study. Female subjects with intact uteri and with onset of menopause within 5 years were eligible for enrollment. 945 subjects were randomized to one of eight treatment groups: placebo; 0 NA/5mcg EE; 0 NA/10mcg EE; 0.25mg NA/ 5mcg EE; 1mg NA/5mcg EE; 0.5mg NA/10mcg EE; 1mg NA/10mcg EE, and unmasked 0.625 conjugated equine estrogen/2.5mg medroxyprogesterone acetate. All subjects received a supplement of 1000mg of calcium carbonate daily. Changes from baseline at 12 months were assessed for the biochemical bone markers urinary deoxypyridinoline (DPD), N-telopeptide (NTx), serum osteocalcin (Osteo) and bone-specific alkaline phosphatase (BSAP). For purposes of this analysis, only results from the double-blind treatment groups are reported.
At month 12, all subjects treated with either EE alone or EE in combination with NA had significant (p<0.05) decreases from baseline in all markers compared to the placebo-treated subjects. The steepest decrease in marker concentrations occurred during the first 3 months of treatment.
For both doses of EE, the largest decrease in markers was obtained with the combination with 1mg NA. This additive effect of NA showed a trend toward a linear dose response between dose of NA and the adjusted mean decreases from baseline.
The additive effect of NA on calcium balance shows an additive effect with EE as assessed by bone turnover markers. This combination effect has not been reported previously and confirms an independent effect of NA on bone metabolism.
EFFECTS OF DAIDZEIN ON THE PROLIFERATION AND DIFFERENTIATION OF FEMALE PIG OSTEOBLASTS
A. De Wilde1*, C. Colin1, A. Pointillart1, M. Lieberherr2
1LNSA, INRA, Jouy-en-Josas, France
2CNRS UPR 1524, INRA, Jouy-en-Josas, France
Although phytoestrogens reduce bone loss in ovariectomized rats, the mechanisms by which they act on bone, particularly on bone formation, are still not understood. We have studied the effects of daidzein on the proliferation and differentiation of osteoblasts (OB) isolated from metatarsal bones of one-month-old female pigs. OB were cultured for 15 days in phenol red-free DMEM medium with or without 1 nM daidzein (Dz). Dz had no effect on OB proliferation whereas it stimulated alkaline phosphatase (ALP) activity. The increase in ALP started earlier in Dz-treated OB (7 days) than in controls (14 days). The basal concentration of osteocalcin (OC) was unchanged by Dz treatment, whereas the OC response to 1 nM calcitriol was higher Dz-treated OB than in controls. Although Dz had no direct effect on creatine kinase (CK) activity in controls, it stimulated the CK response in Dz-treated OB. Dz treatment increased the synthesis of both types of estrogen receptors (ER alpha and beta) and of progesterone and vitamin D receptors. The basal cAMP content was 2.4 fold decreased in Dz-treated OB, but the cAMP response to 1 nM PTH was 2.7 times higher in the Dz-treated OB than in the controls. Dz increased within 5 s the intracellular concentration of calcium in both cell types, but the calcium response to Dz was 2 times higher in Dz-treated OB.
In conclusion, these data show for the first time that daidzein at a physiological concentration of 1 nM may modulate the differentiatiation of female pig osteoblasts when chronically added. Moreover, daidzein-treated OB seem to be more responsive to calciotropic hormones such as PTH and calcitriol.
RALOXIFENE PREVENTS URINARY CALCIUM LOSS IN LATE POSTMENOPAUSAL WOMEN
J. R. Talbot1, A. Marino2, J. Zanchetta2, G. Martinez2, M. Moran2*, O. D. Messina3
1River Plate University, School of Medicine, Argentina
2Osteology Master Program. USAL School of Medicine, Argentina
3Rheumatology & Osteolgy Research Institute, Argentina
It has been suggested that raloxifene induce a significant positive calcium balance in early postmenopausal women mainly by a raloxifene-induced fall in urinary calcium excretion.
The objective of this study was to extend this observation in late postmenopausal women. Twenty women of 65±5 years of age, on menopause for 15±5 years and with a history of increased basal 24-hour calcium excretion, were evaluated before, during and after discontinuation of raloxifene therapy.
Four months after raloxifene therapy administration (60 mg/day) a significant - 42% reduction in urinary calcium excretion was observed (p<0.001). However, one month after raloxifene discontinuation this reduction was not different from the pre treatment value (-5%, p=NS).
In summary, this study confirms the positive effect of raloxifene in reducing urinary calcium loss in late postmenopausal women, but this positive effect was not maintained after raloxifene discontinuation.
In conclusion, continuous administration of 60 mg/day of raloxifene is also necessary to prevent urinary calcium loss in late postmenopausal women.
COMPARISON OF FC1271A, A NOVEL SERM, AND RALOXIFENE IN POSTMENOPAUSAL WOMEN: A 12-WEEK CLINICAL PHASE II STUDY
R. U. Erkkola1*, M. DeGregorio2, K. Halonen3, Kangas3, Lammintausta3, Vihko3, J. Heikkinen4, S. Kivinen5, S. Saarikoski3, R. Tuimala3, Vihtamäki3, M. Tuppurainen3, S. Voipio1, O.Ylikorkala3
1Turku University Central Hospital, FIN-20520 Turku
2University of California, Davis, Sacramento, CA, USA
3Hormos Medical Ltd, FIN-20520 Turku
4Oulu Deaconess Institute, FIN-90100 Oulu
5Kanta-Häme Central Hospital, FIN-13530 Hämeenlinna
The objective of this study was to compare the effects of FC1271a (FC), a novel selective estrogen receptor modulator (SERM) to those of raloxifene hydro-chloride (RAL; Evista) in healthy postmenopausal women suffering from climacteric symptoms. Earlier clinical phase I studies (Voipio et al; in preparation) have shown FC to be well tolerated in healthy postmenopausal female volunteers. Consenting patients (N =120) received either 30, 60, or 90 mg of FC or 60mg of RAL daily for a period of 12 weeks in a double-blind randomized setting. Analyses of serum and urinary levels of indicators of bone metabolism showed FC to exert sparing effects on bone turnover resembling closely those observed during RAL treatment. However, 30 mg of FC daily proved to be ineffective. A decrease in serum gonadotropin levels during treatment was observed both with FC and RAL. 30 mg of FC showed no effects. Treatment with either SERM resulted in induction of serum sex-hormone binding globulin levels. Neither the use of FC nor ral resulted in significant changes in serum levels of low-density lipoprotein or high-density lipoprotein. Both SERMs studied were unable to induce endometrial proliferation during the study as analysed from vacuum aspiration cytological specimens. Interestingly, FC treatment exerted a clear estrogenic effect on vaginal and ectocervical cells as indicated by increased maturation of these epithelial cells in PAP smear cytological samples. Menopausal symptoms were somewhat relieved in patients receiving FC, but not in patients receiving RAL, as shown by findings on Kupperman’s indices. FC tended to decrease the experience of vaginal dryness when compared to RAL as indicated by observations on visual analogue scale analyses on this symptom; this finding, did not, however, reach statistical significance. In summary, we suggest that FC1271a is a promising new SERM in the therapeutic area of osteoporosis of postmenopausal women showing an interesting profile for further clinical studies.
THE RELATIONSHIP OF STIFFNESS INDEX BY ULTRASOUND OF THE CALCANEUS WITH WALKING BY VITAMIN D RECEPTOR GENOTYPE IN POSTMENOPAUSAL JAPANESE WOMEN
F. Omasu*, J. Kitagawa, Y. Nakahara
Department of Human System Science, Graduate School of Decision Science and Technology, Tokyo Institute of Technology, Tokyo, Japan
The purpose of this longitudinal study was to clarify the influences of environmental and genetic factors on bone. Stiffness of the calcaneus was measured at baseline by using the ultrasound bone densitometer (Lunar A-1000 Achilles) in 278 postmenopausal healthy Japanese women (aged 70.6±6.3 years, mean±SD). There was a significant negative correlation between age and stiffness by the simple regression analysis (p<0.001). The genetic and environmental variables that may affect this decrease in stiffness were investigated in 48 among 278 subjects. These measurements were done at baseline and after 2 years. Daily walking in these subjects was measured using a pedometer (Omron HJ-003) for 7 days and calculated as walking steps per day. The vitamin D receptor (VDR) gene polymorphism was defined by PCR-RFLP using the endonuclease BsmI. No significant association between BsmI VDR gene polymorphism and stiffness was found in either year (p=0.48 at baseline, p=0.59 after 2 years). There was a significant difference in stiffness between the two years (p<0.001), but the result varied by VDR genotypes. There was a significant difference in stiffness in the subjects with Bb genotype between the two years (p<0.01), but there was no significant difference in the bb genotype subjects (p=0.06). There was no significant association between VDR genotype and the rate of stiffness changes in any of the subjects. In addition, daily walking as a physical activity, which influences bone, was evaluated and there was a significant difference in stiffness changes between the low walking steps group at baseline in the Bb genotype and that of the bb genotype subjects (p<0.01), even though the rate of the increase in walking steps during 2 years was similar between the two groups. From the results of this study, we speculated that a good response to physical activity on bone may depend on genotype.
BRIEF HOME ISOMETRIC RESISTIVE EXERCISE STRENGTHENS BACK EXTENSOR MUSCLES IN OSTEOPOROSIS PATIENTS
R. L. Swezey*, A. M. Swezey
Osteoporosis Prevention & Treatment Center, Santa Monica, USA
Resistive exercises (RE) have been shown to enhance bone formation, strengthen muscles, improve balance and thereby lessen the risk of falling and fractures. A previous study utilizing a compressible and expandable vinyl ball in a series of 10 brief (5-second) "progressive resistive" exercises 3 times per week for 2 months in postmenopausal osteoporotic subjects demonstrated significant increases (P<0.05) in muscle strength in the neck and back extensor muscles, the quadriceps, grip, elbow flexors, and an increase in serum bone alkaline phosphatase (bone formation). Because of the importance of back
extensor muscle strength in osteoporosis prevention and treatment, as well as the difficulty in
performing back extensor strengthening exercises on a home program, the following study was undertaken.
METHODS. In this Back Extensor Strength (BES) study, 57 postmenopausal females age 50-82, mean age 64, participated in a series of 3 small group [3-10 participants] exercise classes for instruction in the home isometric RE program. All subjects were tested for BES (utilizing a hand-held dynamometer BES test standardized in the previous study) both initially and after 1 month on the home isometric RE program.
RESULTS. The mean percent increase in BES for all 57 subjects was 16% [P<0.001]. Of the 41 (72%) who increased BES, the mean percent increase was 26% [P<0.001]. Of the 10 (18%) who maintained their BES, 6 were athletic exercisers, 3 had articular pains, and one was apprehensive when retested. Six (10%) showed a loss attributable to illness or discomfort when tested.
CONCLUSION. Brief isometric progressive resistive exercises produce significant increases in back extensor muscle strength in just 1 month in postmenopausal osteoporotic subjects.
TAI CHI EXERCISE RETARDS RATE OF BONE LOSS IN POSTMENOPAUSAL WOMEN
L. Qin1*, K. M. Chan1, S. K. Au1, W. Y. Choy1, M. C. Lau2, J. Woo3, K. M. Lee4, M. A. Dambacher5
1Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China
2Department of Community and Family Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
3Department of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
4LeeHysan Clinical Research Laboratory, The Chinese University of Hong Kong, Hong Kong SAR, PR China
5Orthopädische Universitäsklinik Balgrist, Zürich, Switzerland
We studied the beneficial effect of Tai Chi in retardation of bone loss in the postmenopausal women. 84 postmenopausal women aged of 47 to 65 were recruited into the present study. All subjects have no history of metabolic bone diseases, no medications affecting bone metabolism and no regular physical exercise. Subjects were randomly assigned into Tai Chi (TC) (n=43) and normal control (NC) (n=41) groups. TC subjects practiced Tai Chi 45 min/day, 5 days/ week under a supervision of TC instructor. NC subjects did not participate in any exercises. Measurements included: 1) volumetric BMD and bone strength index (BSI) of both cortical and trabecular bone in non-dominant weight-bearing distal tibia by a high precise multi-slice pQCT (Densiscan 2000); 2) Areal BMD of AP spine and non-dominant proximal femur by DEXA (Norland XR-36); 3) The body flexibility (bend reach) and 4) muscle strength (quadriceps strength). All measurements were repeated 12 months later. Our pQCT data showed that there is a significant deceleration of rate of bone loss in distal tibia of TC subjects compared with NC group (TC vs. NC: trabecular BMD -0.56±1.50% vs. -1.34±2.03%; integral BMD: -0.89±1.74% vs. -1.90±1.56%; and cortical BMD: -0.55±1.32% vs. -1.68±1.45%). Significant difference was also found in rate of bone loss in cortical bone of distal radius (TC vs. NC: -1.23±1.68 vs. -1.98±1.64). Significantly lower rate of decline of proximal cortical BSI were also observed in both tibia and radius (Radius TC vs. NC: -0.61±3.12 vs. -1.99±2.75; Tibia TC vs. NC: -0.83±2.11 vs. -1.88±1.57). Paired t-test showed a significant increased quadriceps muscle strength (p<0.05) in TC group compared with NC group. Significantly improved bend reach was also found in TC group (p<0.05) but not in NC group. The decreased rate of bone loss was associated with improved muscle strength. These data suggested that regular exercise might be beneficial for prevention of osteoporosis development and age-related muscle atrophy and joint stiffness. In addition, with comparison of other physical exercise program (brisk walking), TC exerciser shows higher compliance as reflected by lower drop out rate (30% in TC vs. 45% in brisk walking program).
A TWO-YEAR PHYSICAL REHABILITATION/EXERCISE PROGRAM DECREASES BONE LOSS AT THE HIP IN 85-YEAR OLD WOMEN
K. Kramme1*, L. Puggaard2, E. N. Ebbesen3, B. Abrahamsen1, K. Brixen1
1Department of Endocrinology, Odense University Hospital, Denmark
2Institute of Physical Education and Biomechanics, University of Southern Denmark
3Department of Endocrinology, Aarhus University Hospital, Denmark
Background: Advancing age is associated with profound changes in body composition such as decreased BMD. Physical exercise may attenuate the accelerated decline in bone mass, however, the usually recommended high strain exercise programs seems inappropriate for old people.
Purpose: We examined the effect of a low-strain physical rehabilitation training program on lumbar spine, hip and whole-body BMD and BMC in very old women.
Study population and methods: A population of 55 healthy single home-dwelling women aged 85 were recruited using the central personal register and an interview. The participants were randomised into a training group (n=22) and controls (n=14). The initial control group were supplemented (n=19) due to an unexpected high drop-out-rate (nT=5, nC=17) due to death (n=3) or intercurrent diseases (n=18). The training group participated in a supervised physical class once a week for 8 months, and performed a homebased program accordingly individual interests for 12 months. The physical classes consisted of walking, rhythm exercises, muscle strengthening, reaction-, balance- and flexibility-exercises. The home training included walking and light muscle- and balance-exercises. The training program primarly aimed at increasing functional capabilities in Activities of Daily Living (ADL). BMC and BMD of whole-body, lumbar spine and the hip was measured at inclusion, after 12 months, and after 24 months using a Hologic-2000 DEXA-scanner.
Results: The table shows the changes in BMD in the proximal femur at 12 and 24 months. No significant changes were seen in the lumbar spine or whole-body BMC or BMD.
Conclusion: In very old women, a low-strain physical rehabilitation-program may reduce bone loss in the hip and it seems appropiate to encourage exercise programs in this age group to reduce osteoporotic fractures. However, the high drop-out rate in the control group in this study may confound the results, and underscores the practical problems in studies including very old people.
| Changes in hip BMD (g/cm2) | |||
| After 12 months | After 24 months | ||
| BMDtotal-hip | trained | -0.007±0.003* | -0.043±0.005 |
| controls | - 0.022±0.005 | -0.048±0.020 | |
| BMDfemoral neck | trained | -0.001±0.006 | -0.014±0.007* |
| controls | -0.018±0.010 | - 0.042±0.004 | |
| *significant difference at p<0.05 | |||
PREVENTIVE EFFECTS OF CHINESE HERBAL PREPARATION ON DEVELOPMENT OF OSTEOPOROSIS INDUCED BY OVARIECTOMY IN RATS
P. C. Leung1,2, Y. Y. Shi3, H. B. Lu1, G. Zhang3, Y. W. Hung1, Y. F. Chao3, S. C. Fu1, L. Qin1*
1Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China
2Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
3Suguang Hospital, Shanghai University of Chinese Medicine, PR China
Preventive effects of Chinese Herbal Preparation, with Epimedium Leptorhizum (FEL) as main component of the herb Yinyanghuo, on the development of osteoporosis induced by ovariectomy (OVX) in rats was investigated for a period of 12 weeks. A total of 28 ten-months old female SD rats were used including sham-operated (Sham) (n=10) and ovariectomized for establishing OVX model (n=8) and treatment with FEL (n=10) according to a randomized block design using body weight as the selection parameter. Oral administration of FEL (0.2g/kg bodyweight/day) started immediately after OVX. The BMD of proximal tibia, femur and lumbar spine (vertebral body) was evaluated using DXA (Norland XR36) and multislice pQCT (Densiscan 2000) for separate measurements of cortical and metabolically more active trabecular bone compartments.
Results showed that there were 1.0%-6.9% but not statistically significant differences in BMD among three groups. pQCT measurements showed a significantly lower trabecular BMD in OVX group compared with Sham group, with -18.9%, -15.0% and -18.8%, respectively, in lumbar vertebral body, proximal tibia and femur (all, p<0.001). Compared with Sham, FEL group only showed 12.5% lower trabecular BMD in lumbar vertebral body (p<0.05) but no differences in proximal femur and tibia. Compared with OVX group, FEL group showed a significantly 13.3% and 17.8% higher trabecular BMD in proximal femur and tibia, respectively. These results suggested that the Chinese Herbal Preparation developed for this study was effective to prevent osteoporosis development in weight bearing proximal femur and tibia but not in lumbar spine in OVX rats.
COLCHICINE FOR THE PREVENTION AND TREATMENT OF OSTEOPOROSIS
D. Schapira1,2*, A. Kabala2, R. Coleman2
1Dept Rheumatology, Rambam Medical Center, Haifa, Israel
2Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Colchicine is an effective drug for the treatment of several inflammatory joint diseases and amyloidosis. In organ cultures and animal studies it has been shown to inhibit parathyroid-induced bone resorption and have a similar effect to calcitonin leading to decreased mobilization of skeletal calcium and may even promote osteogenesis. The aim of the study was to elucidate the effects of prolonged colchicine therapy on bone mass and various parameters of skeletal metabolism. Experimental female Wistar rats aged from 1.5 to 20 months received ip injections of colchicine (0.5mg/kg/body wt) and were compared to age-related controls. Animals were sacrificed at 1.5, 4, 8, 12, 16 and 20 months. Several parameters were determined including: body weight, L5 vertebral weight, vertebral bone histology and histomorphometry (L4), and serum biochemistry. No significant differences were found in animal body weights. The vertebral weights were higher (+21%) at the end of the study in colchicine-treated rats. Vertebral calcium values were higher after colchicine-treatment than in controls at most ages. Bone phosphorus levels were elevated in colchicine-treated rats at the end of the study. Vertebral magnesium values remained high in both groups without significant differences. Vertebral protein values were elevated in colchicine-treated rats. Both bone alkaline phosphatase and acid phosphatase enzymatic activities were elevated in colchicine-treated rats (+19%, +25% respectively) compared to controls. Trabecular bone volumes showed age-related declines in both groups, but were slightly higher in the experimental animals. Cortical bone volume values showed similar age-related declines. Our study indicates that prolonged colchicine treatment seems to affect favorably the skeletal metabolism of aging laboratory rats. It is possible that higher doses of colchicine may be even more effective in preventing age-related bone loss.
ADVANTAGES OF IMMUNOASSAYS FOR MARKERS FOR BONE RESORPTION IN PREDICTING TREATMENT EFFICACY IN OSTEOPOROSIS ON INTERMITTENT CYCLICAL ETIDRONATE
K. Kitatani1*, K. Nakatsuka1, H. Naka1, T. Miki1, Y. Nisizawa1, H. Morii2
1Osaka City University, Osaka, Japan
2Aino Gakuin College, Ibaraki, Japan
Urinary excretion of deoxypyridinoline (u-DPD: Pyrilinks-D) and crosslinked N-telopeptides of type I collagen (u-NTx: Osteomark) have been established as biochemical markers specific to bone resorption and recently approved for use in the management of osteoporosis in Japan. However, few data are available on adequate use of u-DPD and u-NTx to predict treatment efficacy of intermittent cyclical etidronate (ICE) in individual patients. We conducted an open clinical trial with ICE in osteoporosis to clarify advantage of u-DPD and u-NTx over the other and intervals of repeated measurements of these markers in the predicting ICE efficacy effectively. Enrolled in the present study were 64 postmenopausal women with osteoporosis, who were on ICE (200-400mg of etidronate: 2 weeks on, 10 weeks off). Fasting urine samples were obtained at the same morning hour before and 2, 4, 12, and 24 weeks after the start of ICE for u-DPD and u-NTx simultaneously measured by ELISA kits. Average changes of resorption markers are shown in Table. No significant differences in signal/noise ratios were found between DPD and NTx at any interval of measurements. Lumbar spine BMDs (LS-BMD) increased by 3.6±3.6 (SD) (-5 - +14) % from baseline values 24 weeks following the start of ICE and maintained thereafter. ROC analysis was employed to assess abilities of changes of resorption markers from initial values to predict LS-BMD changes at 24 Week. Areas under the ROC curves (AUC) were as follows: DPD4w (0.45) <DPD12w (0.56)=NTx4w (0.56) <NTx12w (0.62). In conclusion, repeated measurement of u-DPD and u-NTx have equivalent abilities in the prediction of efficacy of ICE in term of LS-BMD gain later than 24 Week. Intervals of 12 weeks or more and 4 weeks or more are recommended for u-DPD and u-NTx, respectively, as adequate timings of repeated measurements of these markers.
| Marker | CV%* | 2 Week | 4 Week | 12 Week | 24 Week |
| DPD (%) | 14.1 | 0.7±22 | -4.3±23 | -10±24 * | -7.4±28.4 * |
| NTx (%) | 21.7 | 6.1±106 | -23±48* | -21±55 | -32±64 * |
| CV%: short-term day to day variation, *: p<0.05 (vs. baseline values) | |||||
PREDICTORS OF BONE MASS VARIATION IN ALENDRONATE TREATMENT OF OSTEOPOROSIS IN YOUNG PATIENTS
M. L. Bianchi1*, R. Cimaz2, M. Gattorno3, A. Dubini1, M. Bardare2, F. Zulian4, F. Falcini5, L. Lepore6, A. Boncompagni3
1Istituto Auxologico Italiano, Milano
2Clinica Pediatrica Università di Milano
3Istituto Gaslini, Genova
4Clinica Pediatrica Università di Padova
5Clinica Pediatrica Università di Firenze
6Istituto Burlo Garofolo, Trieste
We demonstrated that alendronate increases bone mineral density (BMD) in pediatric patients with rheumatic diseases and low bone mass.
We have now evaluated the variations of bone metabolism and disease activity in 45 patients with rheumatic diseases (31 F, 14 M; mean age 152 months, range 60-224) treated with alendronate for 12 months. Patients were on corticosteroids for an average of 39 months (range, 6-106). The analyzed variables were demographic and anthropometric data, bone turnover parameters (serum Ca, P, bone-specific alkaline phosphatase (BSAP), serum pyridinolines (PYR), osteocalcin (OC), parathyroid hormone, urinary procollagen telopeptide (NTx)), disease activity (ESR, CRP, haemoglobin, platelet count, IL-6, matrix metalloproteinase (MMP), and SLEDAI), and BMD. For all variables, differences between baseline and 12-month levels, and the relationship between BMD variation over 12 months and baseline levels of different variables, were evaluated. Variables significantly correlated with BMD were included in a multivariate model, in order to identify possible predictors of response to treatment. The BMD variation over 12 months was also correlated to the variation of the disease activity indexes.
There was a statistically significant decrease of bone turnover parameters over the year. On the contrary, none of the disease activity indexes changed significantly. In multivariate analysis, the only parameters significantly associated with BMD increase were BSAP (P=0.001) and MMP (P=0.012). BMD Z-score variation did not correlate with ESR, MMP, IL-6, or CRP variation.
Moreover, in patients with the highest increase in BMD (mean +16.2%), bone markers decreased maximally (NTx - 36±13%; PYR -32±12%; BSAP -27±10%; OC -21±8%). In patients with the lowest increase in BMD (mean +3.7%) bone markers decreased less (NTx -21±10%; PYR -18±9%; BSAP -16±9%; OC -13±6%).
In conclusion: 1) alendronate treatment induces a reduction of bone resorption parameters also in pediatric age; 2) BMD increase is not secondary to a reduction of inflammatory activity; 3) patients with high baseline levels of BSAP and MMP respond best; low baseline BMD values do not predict a better response; 4) the highest decrease of bone markers is observed in children with the highest increase of bone mass.
COMPLIANCE IN ANTIOSTEOPOROTIC TREATMENTS
J. Blanch*, M. Coll, J. M. Pujol, M. Ciria, L. Perez-Edo, P. Benito, J. Carbonell
Rheumatology Division, Hospitals Universitaris del Mar i de l'Esperança, Barcelona, Spain
Aims: Therapeutic non-compliance is one of the most relevant problems that have the antiosteoporotic treatments in clinical practice. The aim of this study was to assess the compliance in the treatments of osteoporosis and the factors that could modulate them.
Subjects and Methods: We have carried out a prospective study in 100 randomly selected osteoporotic patients that attend an Osteoporosis Outpatients' Clinic. The patients had to met the following inclusion criteria: suffer from primary osteoporosis and a minimum follow-up of 1 year. A questionnaire was applied by trained interviewers to them and the following data were recorded: socio-economic status, previous osteoporotic fractures, functional status, alcohol intake, tobacco use, concurrent diseases (comorbidity index of Charlston), drugs different than antiosteoporotics used, level of knowledge of the disease and of the treatment, degree of confidence in the treatments and level of declared therapeutic compliance. An statistical analysis was performed through parametric and non-parametric tests.
Results: 69 of patients declared to follow the therapeutic advises more than 75% of the medical instructions. No significative differences were found between compliers and non-compliers with regard to: gender, age, civil status, socio-economic status, use of tobacco or alcohol, functional capacity, educational level, laboral status, presence of osteoporotic fractures, co-morbidity index of Charlston, use of drugs different than antiosteoporotics; type of antiosteoporotic treatments, degree of knowledge of the disease and of the attending physician. Patients that knew the drug posology were more compliers than patients than do not. Calcium supplementation compliance was better in patients with a major knowledge of the brand name of the calcium supplement. The level of declared confidence in the efficacy of the antiosteoporotic drug was the factor more related to a better compliance.
Conclusions: The degree of declared compliance in antiosteoporotic treatment was high. The degree of compliance was related with the confidence than the patient had in the possible therapeutic benefit of the drug prescribed. No association was found within compliance and gender, age, socio-economic status, educational level, co-morbidity, functional status, presence of osteoporotic fractures, use of other drugs different than antiosteoporotic ones or degree of knowledge of the disease.
ACCEPTABILITY AND COMPLIANCE WITH HIP PROTECTORS BY COMMUNITY DWELLING WOMEN AT HIGH RISK OF HIP FRACTURE
R. Wills1*, L. Ogunremi1, S. Patel1,2
1Osteoporosis Unit, St George's Hospital, London, UK
2Dept of Rheumatology, St Helier Hospital, Surrey, UK
Hip fractures are common and associated with increased morbidity and mortality. Studies of frail institutionalised women show that hip protectors can reduce the rate of hip fracture. However it remains unclear whether independent community dwelling women will find hip protectors acceptable and adhere to their use.
We asked all women aged over 70 yrs and referred for open access bone densitometry who were at high risk of hip fracture to participate in this study. High risk was defined as presence of femoral neck osteoporosis (according to WHO criteria) and presence of one or more fall related factors (inability to perform tandem gait or 5 standups without arm use or reduced visual acuity). Over a 8 month period 77 women (mean age 75 yrs) referred for bone densitometry were found to be at high risk. These women were shown the results of their DXA scans and their increased risk of falls discussed. Following this, they were shown hip protectors (SAFEHIP) and asked whether they would participate in this study. 28 women (36%) agreed to participate. 8 of these women either dropped out within the first week or did not return diary cards leaving 20 / 77 (25%) who are continuing to wear hip protectors and returning diary cards. To date the mean duration of hip protector use in these women is 13 weeks (range 1 to 26) and average daily wearing is over 10 hours per day.
This study demonstrates that a substantial minority of women will agree to wear hip protectors. Further follow-up is planned to assess long term adherence. We suggest that community dwelling older women at high risk of hip fracture should be offered hip protectors and further work should be carried out to encourage long term use to reduce hip fracture rates.
SEX-BIAS IN REFERRAL FOR BONE DENSITOMETRY
M. A. Kotowicz*, B. Sarah, J. A. Pasco, M. J. Henry, K. M. Sanders, S. Korn, G. C. Nicholson
University of Melbourne, Geelong, Victoria, Australia
Osteoporosis in men has been a neglected area and awareness of male osteoporosis lags behind recognition of osteoporosis in women. Male fracture incidence is approximately one third that of females but hip fractures in men are associated with increased morbidity and mortality. The aim of this study was to determine whether a sex-bias applied for referrals for bone densitometry.
All DXA scans performed by the sole provider for a population of 221,000 between 1991-8 were investigated, excluding follow-up and research examinations. Age, sex, weight, lumbar spine (LS) and femoral neck (FN) BMD and indications for DXA were determined. Expected proportions for male and female referrals for fracture indications were predicted using age- and sex-specific fracture data for this region from the Geelong Osteoporosis Study.
Of 4984 referrals, 4591 were for women (age, median [range]: 57 [6-92]yr) and 393 for men (65 [15-92]yr), yielding crude referral rates of 55.1 and 4.9 per 10,000 p-y, respectively. Female:male rate ratio was 11.2 (95%CI 10.1, 12.5) and 8.6 (95%CI 7.8, 9.6) after age-adjustment. Overall, men had larger deficits in BMD at LS (T-score [males vs females]: mean±SEM, -1.087±0.086 vs -0.901±0.026, P<0.05) and FN (T-score: -1.678±0.084 vs -1.035±0.023, P<0.001). In men, T-scores remained stable across age groups at LS whereas age-related decreases were observed at FN and at both sites in women. Age- and weight- adjusted deficits were greater among males at LS (Z-score -0.346±0.086 vs 0.221±0.022, P<0.001) and FN (Z-score -0.525±0.074 vs -0.015±0.018, P<0.001). Referrals for evaluation of low trauma fracture represented 2.6% and 12.1% of all fracture cases for men and women, respectively. There were 78 men and 620 women with the proportion of male fracture referrals being 70% fewer than expected (P<0.0001). T-scores at LS did not differ between male and female fracture cases (P=0.17) but were lower at FN (-2.026±0.149 vs -1.672±0.053, P<0.05), with Z-scores being lower among males at both sites (LS:-0.723±0.151 vs -0.082±0.0623; FN:-0.790±0.122 vs -0.239±0.044, both P<0.001).
Lack of awareness of osteoporosis in men may explain the greater deficit in BMD at diagnosis because of late referral. Men are under-represented in DXA referrals, consistent with a sex-bias in referral for DXA.
UTILITY OF MEASUREMENT OF URINARY PYRIDINOLINE AND DEOXYPYRIDINOLINE FOR MONITORING EFFECTS OF TREATMENT WITH ESTROGEN AND ALFACALCIDOL IN WOMEN WITH OSTEOPOROSIS
Z. Zhan1*, I. Yamanoto2, R. Morita2, H. Miura3
1Xiao Xi Tian No.262 Hospital Beijing, China
2Department of Radiology, Shiga University of Medical Science, Otsu 520-21, Japan.
3Hikone Research Laboratories, Maruho Co. Ltd., Shiga 522-02, Japan.
Clinical utilities of bone metabolic markers in predicting the responses to treatment were evaluated. We measured urinary excretion of pyridinoline (Pyr) and deoxypyridinoline (Dpyr), and determined bone mineral density (BMD) by dual energy x-ray absorptiometry in 48 women with osteoporosis (age: 55.9±8.4 yr, mean±SD). Patients were admitted to hormone replacement therapy group (HRT, n=13), 1alpha hydroxyvitamin D3 (1alphaD3)-treated group (n=20) and control group (calcium alone; n=15). Baseline mean levels of urinary Pyr and Dpyr were significantly higher in 48 patients compared to those in the age-matched postmenopausal women and the levels of urinary Pyr and Dpyr were negatively correlated with BMD. After treatment with HRT and 1alphaD3, significant suppression of Pyr and Dpyr was observed and in case of HRT, elevated values were suppressed to the range in pre-menopausal women. Significant negative correlations was found between percent change in Pyr and Dpyr at 6 months and percent change in L2-4 BMD after 24 months of treatment (r= -0.521 and -0.432, p<0.01).
We conclude that urinary Pyr and Dpyr are sensitive markers of bone turnover and that they have clinical utility for monitoring and predicting the response to therapy of osteoporosis.
CLINICAL USEFULNESS OF BIOCHEMICAL RESORPTION MARKERS DURING ALENDRONATE TREATMENT IN POSTMENOPAUSAL OSTEOPOROSIS
M. T. Del Campo1, M. L. González Casaus2, M. Bernad3, M. V. Garcés4, J. Fernández3, M. Pombo3, M. E. Martínez1*
1Clinical Biochemistry Division, la Paz Hospital, Madrid, Spain
2Biopathology Department, Gómez Ulla Central Military Hospital, Madrid, Spain
3Rheumatology Service, La Paz Hospital, Madrid, Spain
4Medicine and Experimental Surgery, La Paz Hospital, Madrid, Spain
The effects of alendronate treatment on biochemical resorption markers of bone remodelling and bone mineral density (BMD) were studied in 35 postmenopausal women with T-score < -2.5 in the lumbar spine. The patients received alendronate (10 mg/day) for 12 months. Serum C-telopeptides of type I collagen (CTx) and urine deoxypyridinoline (Dpd) were measured at baseline and 3, 6 and 12 months. BMD was measured at the lumbar spine and hip (femoral neck, trochanter, intertrochanter and total hip) at baseline and 12 months.
The treatment with alendronate resulted in a significant increase in BMD of the lumbar spine and hip (p< 0.001). Neither baseline resorption marker values correlated with BMD increase at either lumbar spine or hip after one year of treatment.
Dpd levels at 6 months correlated with BMD increase at lumbar spine, femoral neck and total hip (r= -0.386, -0.396 and -0.399 respectively, p< 0.05), and at 12 months correlated with BMD increase at all hip sites (femoral neck r= -0.371, trochanter r= -0.395, intertrochanter r= -0.404 and total hip r= -0.367, p< 0.05).
CTx levels only correlated with BMD increase at lumbar spine at 6 months (r= -0.471, p<0.01).
Different results were obtained taking into account the percent of change in Dpd and CTx. CTx decrease at 6 months correlated with BMD increase at intertrochanter (r= -0.515, p< 0.01), lumbar spine and total hip (r= -0.397, -0.484 respectively, p< 0.05), and at 12 months correlated with BMD increase at all hip sites except femoral neck (trochanter r= -0.497, intertrochanter r= -0.495 and total hip r= -0.453, p<0.05).
Dpd decrease at 6 months correlated with BMD increase at femoral neck (r= -0.470, p<0.01), and at 12 months correlated with BMD increase at trochanter (r= -0.491, p< 0.01).
In conclusion, 1) there were no associations between baseline Dpd and CTx values and BMD increase after one year of alendronate therapy; 2) at 6 and 12 months, Dpd values showed the greatest association with increase in BMD after one year of treatment. However, at 6 and 12 months, the percent of change in CTx had the greatest association with increase in BMD.
EFFECT ON BONE MARKERS OF THREE MONTHLY 2MG INTRAVENOUS IBANDRONATE: 2 YEARS OF TREATMENT AND ONE YEAR AFTER WITHDRAWAL
O. Lamy*, I. Pache, S. Fatio, A. F. Jaquet, P. Burckhardt
University Hospital, Lausanne, Switzerland
Background: The tolerance to oral bisphosphonates is often low. The high potency of Ibandronate (IB) allows iv bolus injections that usually are given every three months. However the best dose and time interval are not know. Efficacy of 3 monthly iv IB was tested during a 2 years, prospective, open study in men with osteoporosis.
Method: 14 men with primary osteoporosis, mean age 57±12 years, received IB 2 mg iv every 3 months during 2 years. All got calcium 1g/d and vitamin D 1000 UI/d for 3 years. Parameters of bone metabolism were assessed every three months during 2 years and one year after withdrawal of IB.
Results: BMD increased significantly after two years by 6.7±1.5% at lumbar spine, 3.2±0.8% at trochanter and 1.4±1.1% at femoral neck (ns), and remained stable after 3 years. Results of bone remodeling parameters are shown in table (%±SEM, P<0.05, *P<0.01, **P<0.001). Calcemia increased slightly during 3 years and significantly after 1 year. PTH, 25OH- and 1,25OH vitamin D did not change. The decrease of serum crosslaps (CL) and osteocalcine (OC) occurred after 3 months. The magnitude of decline was by 28-46% for CL and by 29-39% for OC. The decrease of CL stabilized after 6 months, the decrease of OC after 9 months.
Conclusion: The observed decrease of bone remodeling parameters is of the same pattern and magnitude as those described with oral bisphosphonates, as well as the increase of BMD. The increase of calcemia from the lower to the middle tertile of the normal range confirm the positive effect of supplementation with calcium and vitamin D. These results suggest that three months is a good interval between two doses of IB, when 2 mg are given.
| Months | 6 | 12 | 24 | 36 |
| Calcemia | 1.8±1.0% | 2.7±1.3% | 4.5±1.5%* | 8.3±1.2%** |
| CL | -3 7±7%** | -46±9%** | -30±8%* | 24±20% |
| OC | -18±7%* | -29±6%** | -31±5%** | -14±10% |
ANTI-RESORPTIVE TREATMENT - A MODEL TO GAIN INSIGHT AND PREDICT LONG TERM BONE GAIN.
J. C. van der Linden*, J. A. N. Verhaar, H. Weinans
Erasmus University Rotterdam, Rotterdam, The Netherlands
Antiresorptive treatment is widely used to prevent postmenopausal bone loss, in the first three years of treatment gains of 5-8% in bone mass are seen in clinical studies. Bisphophonates are assumed to decrease activation frequency, resorption cavity depth and formation deficit. The contributions of these effects to the bone gain are not known. A fit of a mathematical model of bisphosphonate treatment to clinically measured values of bone gain resulted in a decrease of activation frequency of approx. 40%, in combination with a positive bone balance of approx. 1.4% per year (Heaney et al, JBMR, 1997).
We developed a three dimensional simulation model of remodeling in trabecular bone to mimic changes in remodeling during bisphophonate treatment. The remodeling parameters were based on biological values. Resorption cavities were created in a computer model of human vertebral trabecular bone, made using micro-CT. Trabeculae that were cut through by a cavity were not repaired, all other cavities were refilled three months later. These were not refilled completely, to simulate the formation deficit. Bone matrix deposited during treatment was marked in the model as containing bisphosphonates. Cavities created in this marked bone matrix were 25% less deep. In addition, the formation deficit during treatment was smaller, or there was even more bone deposited than previously resorbed, leading to a formation surplus.
Using this simulation model, we evaluated the effect of a decrease in activation frequency or in resorption depth, and a formation surplus, and combinations of these effects. A decrease in resorption depth resulted in an almost stable bone mass. Decreasing activation frequency resulted in bone gain for half a year, followed by bone loss. Combining these effects resulted in bone gain of 3-7%, followed by very slow bone loss, of less than 0.5% in 3 years. Combining this with a formation surplus led to a continued bone gain up to three years, as seen in clinical studies.
RELATIONSHIP BETWEEN 1-YEAR CHANGE IN THE BONE TURNOVER MARKER P1NP AND 3-YEAR VERTEBRAL FRACTURE RISK REDUCTION WITH RALOXIFENE THERAPY IN POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS: RESULTS FROM THE MORE TRIAL
J. Y. Reginster1*, S. Sarkar2, J. Collette1, B. Zegels1, Y. Henrotin1, O. Bruyere1, M. Wong2, K. Harper2, D. Agnusdei3
1CHU Centre-Ville, Liege, Belgium
2Eli Lilly and Company, Indianapolis, USA
3Eli Lilly Italia, Florence, Italy
The Multiple Outcomes of Raloxifene Evaluation (MORE) trial studied the effects of raloxifene in 7705 postmenopausal women with osteoporosis defined by low bone mineral density (BMD) and/or prevalent vertebral fractures (VF) [JAMA 282 (1999): 637-645]. Women were randomized to placebo or raloxifene (60 or 120 mg/day). Our previous analyses found that changes in BMD and biochemical markers of bone turnover are poorly predictive of the reduction in VF risk observed with raloxifene. This present study evaluated the effects of raloxifene on type I procollagen N-terminal propeptide (P1NP), a new bone turnover marker. Logistic regression analysis models evaluated the relationships between 1-year changes in P1NP, serum osteocalcin (OC) and urinary excretion of type I collagen C-telopeptide fragment normalized to creatinine (TICF/Cr) and the decreased risk of new VF at 3 years for each treatment group (placebo and pooled raloxifene). A subset of 967 women (mean age = 68 years) from the MORE cohort had P1NP, OC and TICF measurements. Raloxifene significantly decreased all biochemical markers of bone turnover at 1 year compared with placebo (p<0.001). At 1 year, the placebo and pooled raloxifene groups decreased P1NP levels by medians of 11.0% and 40.8%, respectively, from baseline. The placebo and raloxifene groups decreased serum OC by medians of 8.5% and 31.8% from baseline, respectively, and urinary TICF/Cr excretion by medians of 5.6% and 46.5% from baseline, respectively, at 1 year. In the raloxifene group, the logistic regression relationship between 3-year VF and 1-year percentage change for each biochemical marker was stronger with P1NP (slope estimate = 0.008, p-value = 0.012) than with OC (slope estimate = 0.006, p-value = 0.044) or TICF/Cr (slope estimate = 0.002, p-value = 0.294). In conclusion, raloxifene treatment significantly decreased bone turnover markers P1NP, OC and TICF/Cr at 1 year. However, in this subset of women from the MORE cohort, the relationship between the 3-year reduction in VF risk and the 1-year decrease in P1NP was stronger than the relationships observed between 3-year VF risk and the 1-year changes in either OC or TICF/Cr.
ADHERENCE TO OSTEOPOROSIS THERAPIES
J. Finigan*, P. R. Bainbridge, R. Eastell
University of Sheffield Division of Clinical Sciences, Northern General Hospital, Sheffield, S5 7AU, UK
Non-adherence to osteoporosis therapies limits their effectiveness when used in clinical practice. We have carried out an audit of a consecutive series of 190 patients attending for bone turnover marker monitoring during their first year of treatment. Adherence to therapy was assessed at 4, 7 and 10 months on treatment, with questioning by an osteoporosis specialist nurse. The cause of failure to adhere was noted and the patient was advised appropriately. Overall, 40 patients (21%) were reported at one or more visits not to have adhered to the instructions to take the therapy. The non-adherence rates at successive visits were 13%, 8%, and 7%. The non-adherence rates for therapy with bisphosphonates (n=118), HRT (and related compounds) (n=55), and vitamin D and calcium (and related treatments) (n=17) were 25%, 16% and 6%. The most common reasons for patients not adhering to bisphosphonate therapy were side effects (12 events), taking the treatment incorrectly (12 events), and repeat prescription not renewed correctly (9 events). The reasons for patients not adhering to HRT therapy were side effects (7 events) and failure to begin treatment (6 events). We conclude that attendance at the nurse monitoring clinic improves adherence to therapy and that the reasons for non-adherence differ by treatment type.
IMPACT OF AN EDUCATIONAL PROGRAM CONSISTING OF PERIPHERAL DUAL X-RAY ABSORPTIOMETRY (PDXA) SCREENING FOLLOWED BY A LECTURE
S. Levis1*, P. Lassanske2, N. Dgetluck3
1University of Miami School of Medicine, GRECC/VA Medical Center, State of Florida Teaching Nursing Home at Miami Jewish Home & Hospital for the Aged, Miami, FL, USA
2Elder Floridians Foundation, Tallahassee, FL, USA
3Martin Memorial Health Systems, Stuart, FL, USA
A healthy life-style and early detection and treatment of osteoporosis are associated with a lower rate of bone loss and decreased risk of fracture. Project Osteoporosis* is a community educational program that targets free-living elderly in the state of Florida (US) in order to raise their awareness about osteoporosis, assuming that increased knowledge would lead to positive behavioral changes.
Methods: This voluntary program was offered to Florida senior citizen organizations during their regular meetings or scheduled as a special event. Participants completed a risk assessment survey and watched an educational slide presentation, followed by a question and answer period, and a pDXA (peripheral dual X-ray absorptiometry) was taken of their forearm. After March 1998 follow-up surveys were mailed to attendees to assess the impact of the program.
Results: From September 1997 through March 2000, 10,193 individuals participated in the program, and 9,813 had a pDXA. Mean age was 64.9 years (±11.74 SD), and 88.7% were female. Results of pDXA indicated that 38.0% of the participants had osteopenia and 12.8% osteoporosis. Of the 9,813 surveys mailed, 2,983 participants responded (30% response rate). The responders had a mean age of 66.0 years (±11.83 SD), and 84.1% were female. Of the responders, 30.5% had osteopenia and 13.0% had osteoporosis. The pDXA was considered the most useful part of the program (56%); for 33.5% it was the lecture, and for 4.1% the informational material. Of the responders, 46% discussed their pDXA results with their physician which resulted in at least one new recommendation from their physician: central DXA (19%), calcium supplements (42%), estrogen (19%), antiresorptive medication (18%), exercise (14%), nutrition information (9%), and 15% made no recommendations.
Conclusion: Our results indicate that in Florida’s elderly population, an intervention consisting of an educational lecture and a pDXA scan provides an incentive to the participants to address osteoporosis prevention/treatment with their physicians resulting in a positive change in the physician recommendations.
CASE FINDING STRATEGIES IN OSTEOPOROSIS; PERFORMANCE OF A COMBINATION OF RISK FACTOR ASSESSMENT AND BONE DENSITOMETRY IN THE OUT PATIENT CLINICAL DECISION-MAKING: A REPORT OF 1438 CASES
J. A. Guerrero-S1,2*, C. Wong1, J. A. Tamayo1,2
1Osteoporosis Centre, Sanatorio Español, Torreón, México
2Comité Mexicano para estudio de la Osteoporosis, México City, México
Case finding strategies oriented to Osteoporosis care are a big challenge for decision makers, and must serve to define cost efficient policies with high global benefits. They may allow handling decisions in evidence-based principles. Cummings et al. (NEJM1995) correlated risk factors (RF) and bone mass (BMD) to predict hip fractures, nine groups were defined. We used these criteria to know how they define groups requiring different interventions. Group one is defined by normal bone mass and no risk factors (very low fracture risk) and group nine by low bone mass (BMD T score >-1.8 SD) and more than five risk factors; the highest fracture risk group.
We included all consecutive cases studied in our Osteoporosis Outpatient Clinic from April 1998 to January 2000 (1438 patients). All of them answered a validated risk factor questionnaire to define both the risk of becoming osteoporotic and lifelong fracture risk. We obtained BMD values with a Lunar DPX-L instrument (lumbar spine and proximal femur). BMD was considered normal, if within 1SD of the young adult mean, medium if between -1 and -1.8 SD, and low if bellow -1.8 SD. The risk factors were correlated with BMD as follows: 0-2, 3-4, and more than 5. We do report only women results. Aged 40-70 years, 243 (21.1%) had BMD scores in the WHO range of Osteoporosis, 230 patients (15.9%) have had a previous osteoporotic fracture (POF). Our results clearly show different risk levels (see table). As expected more than 70% of POF corresponded to the high risk groups, 42.02% of our population without previous fractures were at high risk therefore requiring fracture prevention strategies, aprox 40% = 400 cases were at low risk therefore just got information to be surveyed later. In the remaining groups a policy of bone mass restoration and improvement of life styles will be the focus. Over 80% of the times, the practicing physician will be confronted with quite different decisions.
| Group | Number of cases | percent |
| 1 | 184 | 12.79 |
| 2 | 207 | 14.39 |
| 3 | 54 | 3.7 |
| 4 | 135 | 9.3 |
| 5 | 177 | 12.3 |
| 6 | 75 | 5.2 |
| 7 | 140 | 9.72 |
| 8 | 283 | 19.6 |
| 9 | 183 | 12. |
A CLINICAL PATHWAY FOR A TARGETED MEDICAL MANAGEMENT OF PATIENTS WITH A RECENT OSTEOPOROTIC FRACTURE
T. Chevalley1,2*, P. Hoffmeyer3, J. P. Bonjour1, R. Rizzoli1
1Division of Bone Diseases, Department of Internal Medicine, University Hospital, Geneva, Switzerland
2Unit of Geriatric Evaluation, Department of Geriatrics
3Orthopedic Clinic, Department of Surgery
Preventive strategies against osteoporosis may involve population-based measures or case-selected targeted diagnostic and preventive procedures. Patients with osteoporotic fracture have an at least 2-fold increase to experience another fracture. These patients would thus fulfill the requirements of high risk patients to be selected for targeted diagnostic and treatment procedures. We set up a clinical pathway for the medical management of patients with low trauma fracture. They were enrolled into the pathway after the acute management of the fracture by the orthopedic team. The first step of the pathway includes the collection of all available information (risk factors for osteoporosis, laboratory and others X-ray examinations). Additional examination, including osteodensitometry and/or biochemical markers of bone remodeling may be proposed to the primary care physician who is in the center of the whole process. Then, a treatment is suggested to the physician. A multidisciplinary interactive teaching program on physical therapy, daily living activities and nutrition is proposed to the patients and their relatives. During a 36-month period, 385 patients (311 women and 74 men, mean age±SD: 73.0±13.5 years, hip fracture 45%, ankle/tibia 24%, proximal humerus 8.6%, spine 5.5%, pelvis 3.9%, distal forearm 3.6% and other sites 17.4%) were enrolled. An osteoporosis awareness questionnaire showed that 73% of the patients thought that their fracture was not related to osteoporosis. A DXA measurement was performed in 63% of the patients. Low bone mass or osteoporosis were found in 86% of the DXA examinations. Specific antiosteoporotic therapy was proposed for 33% of the patients, in addition to calcium and vitamin D supplements, which was suggested for 93%. A survey performed in 216 patients 6 months later, indicated that only 49% of the suggested specific antiosteoporotic treatments have been prescribed. Among the latter patients, 80% were still on the medication at 6 months. These results indicate that such a clincal pathway for the medical management of osteoporotic fracture can identify patients with osteoporosis, provide support to the primary care physician for diagnostic and treatment procedures, and should significantly contribute to increase the disease awareness of the patients and their relatives.
DEVELOPMENT OF A PREDICTIVE MODEL AND A RISK ASSESSMENT INSTRUMENT TO FACILITATE DIAGNOSIS OF LOW BONE MASS IN POSTMENOPAUSAL WOMEN
W. Bensedrine1*, T. Chevallier2, M. C. Micheletti3, B. Gelas3, J. Y. Reginster4
1Department of Epidemiology and Public Health, University of Liège, Belgium
2Department of Biostatistic Epidemiology and Clinical Research, University of Montpellier, France
3Medical Department, Theramex Laboratory, Monaco
4Georgetown University Medical Center - Washington DC, USA
Background: Although mass screening for osteoporosis is not recommended among postmenopausal women, its seems necessary to detect post menopausal women at risk of low bone density. Two predictive scales have been developed: the SCORE1 (Simple Calculated Osteoporosis Risk Estimation) and the ORAI2 (Osteoporosis Risk Assessment Instrument). We propose in this study a new predictive model and a new risk assessment instrument to facilitate diagnosis of low bone mass in postmenopausal women.
Methods: Using a retrospective data base from the Department of Epidemiology and Public Health, University of Liège, Belgium, we identified post menopausal women by 65 dependants variables. All these women had a Bone Mineral Densitometry (BMD), by dual-energy x-ray absorptiometry (DXA) on 3 sites: hip, femoral neck and lumbar spine. The main outcome measure was low BMD (T score of 2.5 or more standard deviation below the mean for young Belgian women) at either one of the 3 sites measured. Logistic regression analysis and receiver operating characteristic (ROC) analysis were used to identify the simplest algorithm that would identify women with low bone mass and to build a risk assessment instrument.
Results: The study population comprised 1304 women (848 with a normal BMD, 456 with a low BMD). A simple algorithm based on age, weight, current Hormone Replacement Therapy (HRT) use, past medical history of minimal trauma fracture, was developed.
A risk assessment instrument was then developed from these 4 variables. This instrument, with a cut off point fixed at 1, showed a sensitivity at 84.6% (95% CI 80.9%-87.7%), and a specificity at 40.3% (95% CI 37.0% - 43.7%).
Conclusion: This instrument with 4 variables identifies the majority of women likely to have low bone mineral density at either one of the 3 following sites: hip, femoral neck and lumbar spine. These results have to be validated by a prospective study.
References
1 - Lydick E and al. - Am J Manag Care 1998 ; 4 : 37-48
2 -Cadarette SM and al. - CMAJ 2000 ; 2 : 162-9
THE COST OF OSTEOPOROSIS TREATMENT IN A DEVELOPING COUNTRY: THE ECUADORIAN MODEL
V. M. Pacheco*, M. Miranda
Universidad Central del Ecuador - Pontificia Universidad Catolica del Ecuador - Superintendencia de Bancos, PO Box 17-03-775, Quito, Ecuador
INTRODUCTION: In Ecuador only 12% of population has access to any social security plan; this means that the health expenditure has to be assumed directly by the majority of patients. We investigate cost of osteoporosis treatment and their relations with the country's general economic conditions. The objective was to establish the population with no access or limited access to osteoporosis treatment. MATERIAL AND METHODS: We accepted: 1) SIBOMM and AACE/FDA recommendations as minimal rules for osteoporosis diagnosis and treatment, and 2) Official reports about Poverty Index (PI) in relation with the access to Family's Basic Hamper (FBH) and legal dispositions for Vital Minimal Salary (VMS) and Monthly Minimal Income (MMI). A direct investigation established the average of 'direct medical cost' for patient in 25 private medical services and of 'direct non medical cost' in 200 patients. We obtained the economical index from UNICEF, Institute of Statistics and Census and, Institute of Economical Investigations reports. RESULTS: Direct medical costs was between 357 and 1257 USA dollars/ year (3-7% for physicians consults, 14-22% for laboratory and images, 70-83% in drugs) and direct non medical costs between 26 and 102 dollars/year. The VMS is 5.76, MMI 96.6 and FBH 240 dollars. Direct annual cost of osteoporosis treatment varies between 62-218 VMS and between 4-13 MMI. The economical condition of Ecuador, with 60% of population under absolute poverty limits would mean that a similar percentage of people could not have access to adequate osteoporosis treatment, or that they would receive unqualified medical attention in the next years. DISCUSSION: In Ecuador, considering these facts, it would be necessary a National Health Plan for subventioning part of the cost for treating osteoporosis, and it is imperative to make promotion of healthy styles of life, that permit correction of risk factors, and perform permanent programs for primary prevention of this and other chronic diseases, in order to get the best quality of life for the older population.
ANABOLIC EFFECTS OF H-PTH (1-34) ON CORTICAL BONE IN STREPTOZOTOCIN-INDUCED DIABETIC RATS
T. Tsuchida1,3*, N. Miyakoshi1, Y. Kasukawa1, Y. Tamura1, K. Suzuki1, A. Seki2, K. Sato1
1Dept. of Orthopedic Surgery, Akita University, Akita, Japan
2Mitsubishi Chemical Safety institute, LTD, Kashima, Japan
3Dept. of Orthopedic Surgery, Koto General Hospital, Akita, Japan
It is known that human parathyroid hormone (h-PTH) shows anabolic effect on cancellous bone in diabetic rats. However, little is known of its effect on cortical bone in diabetes mellitus. The purpose of this study was therefore to determine whether h-PTH enhances cortical bone mineral density and strength in streptozotocin (STZ)-induced diabetic rats. Seven-month old female Wistar rats were divided into 5 groups: DM-BL group (the baseline control for DM at 4 weeks after STZ injection), DM-PTH and DM-vehicle groups (h-PTH or its vehicle administration was started 4 weeks after STZ injection), CL-4 and CL-12 groups (normal control groups killed at 4 or 12 weeks after the STZ-vehicle injection). h-PTH (6.0 microg/kg) or its vehicle was injected subcutaneously six times a week for 8 weeks. After their right femora were removed, we measured the diaphyseal cortical bone mineral density (Ct-BMD) and the cortical thickness (Ct.Th) using p-QCT (XCT-960A, Norland Stratec). Mechanical strength of the femur was evaluated by a three-point bending test using a material testing machine (MZ-500D, Maluto, Tokyo, Japan). Ct-BMD in the DM-BL group and the DM-vehicle group were significantly lower than those in the CL groups (p<0.01). Ct-BMD in the DM-PTH group was significantly higher than that in the DM-vehicle group (p<0.05), while there was no significant difference between DM-PTH group and DM-BL group. Ct.Th showed no significant differences between the groups. Femoral diaphyseal bone strength in the DM-BL group and the DM-vehicle group were decreased compared to their controls (93% and 90% of their CL group, respectively, p<0.05), but it was increased by the PTH treatment: DM-PTH group showed 99% of CL-12 group. These results suggest that h-PTH has an anabolic effect on cortical bone in streptozotocin-induced diabetic rats.
HISTOMORPHOMETRY AND MICROSTRUCTURE OF ILIAC TRABECULAR BONE IN OSTEOPOROSIS ON INTERMITTENT SUBCUTANEOUS ADMINISTRATION OF HUMAN PTH (1-34)
K. Nakatsuka1*, H. Naka1, H. Kawakami1, K. Kitatani1, T. Miki1, Y. Nishizawa1, H. Morii2
1Osaka City University, Osaka, Japan
2Aino Gakuin College, Ibaraki, Japan
Recent studies demonstrated that human PTH(1-34) increase trabecular bone mineral density in patients with osteoporosis as far as administered intermittently. Little is known on the histological and metabolic changes of trabecular bone on long-term use of intermittent human PTH(1-34) injection. The aim of the present 1 year open clinical trial was to evaluate safety and action of this peptide on bone following the treatment protocol. Enrolled in the study were10 osteoporotic patients, who have undergone iliac bone biopsy before and the bone histology was confirmed as having no abnormal appearances other than decreased bone volume. Human PTH (1-34) were subcutaneously injected at a dose of 100 IU once a week for 48 weeks. Two patients dropped from the study because of adverse events. Two patients refused bone biopsy at the end of the treatment. Thus, 6 patients completed the study and underwent iliac crest bone biopsy following tetracycline labeling. Calcified and stained thin section and MMA-embedded bone specimens were prepared for histomophometry and node-strut analysis, respectively. Microscopic observation and histomophometry revealed no the abnormal bone quality such as ostitis fibrosa, woven bone/osteoid, and bone mineralization defect. Average changes in histomorphometic and microstructual parameters are shown in Table. Osteoblastic function and bone mineralization at tissue levels are increased, resulting in increased nunbers of bone remodeling units. Interestingly, bone resorption are found attenuated. Parameters associated with trabecular structure and node-strut analysis indicated that continuity of trabecular bone were also ameliorated 1 year following the initiation of intermittent administration of human PTH(1-34). In conclusion, the results obtained from the present study confirm the evidences shown by preclinical trials demonstrating that human PTH(1-34) stimulate bone formation and increase bone mass and strength in experimental osteoporosis when administered intermittently.
| BV/TV | OS/BS | Obs/BS | ES/BS | MS/BS | BFR/BS | NdNd | NdTm | TmTm | |
| PB | 20.0 | 12.1 | 1.21 | 4.89 | 6.19 | 13.7 | 20.4 | 50.4 | 29.1 |
| BE | 23.3 | 24.4 | 2.54 | 2.42 | 9.61 | 16.6 | 30.3 | 47.3 | 22.4 |
| PB: previous biopsy, BE: biopsy at the end of the treatment | |||||||||
EVALUATION OF THE DIFFERENTIAL SKELETAL EFFECTS OF RHPTH IN THE OVARIECTOMIZED RHESUS MONKEY BY BONE DENSITOMETRY
S. Y. Smith1*, C. Chevrier1, A. J. Metcalfe2, J. Fox2, M. A. Miller2, M. K. Newman2
1CTBR, Senneville, QC, Canada
2NPS Pharmaceuticals, UT, USA
Osteopenic aged female rhesus monkeys were treated daily with recombinant human parathyroid hormone rhPTH at 0, 5, 10 or 25 microg/kg/day by s.c. injection for 16 months. Bone densitometry was evaluated in vivo by DXA at the lumbar spine, distal radius, proximal femur and distal femur, and ex vivo by pQCT at these sites following euthanasia. Peripheral QCT was used to separately evaluate the effects of rhPTH on trabecular and cortical bone.
Treatment with rhPTH resulted in significant increases in DXA BMD of up to 13% at the lumbar spine, 14% at the distal femur and 5% at the proximal femur, and decreases of up to 11% at the distal radius. Compared to vehicle controls, increases in pQCT-derived trabecular BMD of up to 49% were observed at the spine, 103% at the distal femur, 64% at the distal radius and 36% at the proximal femur. Significant decreases in metaphyseal and diaphyseal cortical BMD of 11 to 16% compared to vehicle controls were observed at the long bone sites. Cortical area and cortical thickness was increased at the distal femur, distal radius and proximal femur. While the effect on cortical BMD was similar at each site, the effect on trabecular bone varied amongst sites with the greatest effect at the distal femur and the least effect at the proximal femur. At all sites evaluated, treatment with rhPTH caused a "shift" in the relative amounts of higher density cortical bone and lower density trabecular bone to a greater area of lower density cortical bone and an area of higher density trabecular bone. However, this "shift" did not adversely affect bone strength.
These data obtained in the rhesus monkey show that pQCT precisely measured the effects of rhPTH on trabecular and cortical bone and that the magnitude of the response was dependent on the site selected for measurement. These observations have important implications for the clinical monitoring of osteoporosis drug therapy traditionally performed by DXA since the relative amounts of trabecular and cortical bone at each site evaluated may affect the outcome.
LOW BONE MINERAL DENSITY AS AN INDEPENDENT DETERMINANT OF THE FUNCTIONAL RECOVERY IN ELDERLY HIP-FRACTURED WOMEN
M. Di Monaco1*, R. Di Monaco2, M. Manca1, A. Cavanna1
1Presidio Sanitario San Camillo, Torino, Italy
2IRES Lucia Morosini, Torino, Italy
Bone mineral density is the best single predictor of the hip-fracture risk due to osteoporosis, however its prognostic role in the functional recovery after fractures has not been elucidated yet. We studied 170 women consecutively admitted to a rehabilitation hospital after their first hip fracture. Of these, 144 women were selected according to the following inclusion criteria: white race, fracture either spontaneous or sustained as a result of minimal trauma, surgically treated fracture and absence of bone diseases apart from osteoporosis. The bone mineral density of the unfractured femur was evaluated by DXA (Hologic QDR 4500W) at the time of admission to the rehabilitation hospital, 20±5.5 days (mean±SD) after surgery. The functional evaluation was performed by Barthel index both on admission (44.5±20.4) and at the time of discharge (73.5±24). A positive correlation was found between Barthel index on admission and bone mineral density measured at four different sites: total proximal femur (r=0.27; p<0.01), Ward's triangle (r=0.37; p<0.001), trochanter (r=0.27; p<0.01) and intertrochanteric area (r=0.26; p<0.01). A similar correlation was observed when Barthel index on discharge was evaluated. 11 confounding factors were included together with bone mineral density in a linear stepwise multiple regression analysis model, having Barthel index as dependent variable. The confounding variables were: age, weight, height, BMI, total lymphocyte count as marker of protein nutrition, pressure sores, cognitive impairment (MMSE<24/30), term between surgery and bone density assessment, fracture type (cervical or trochanteric), neurological diseases and infections during the hospitalization. Barthel index on admission was independently associated with bone mineral density measured at each of the four sites: total proximal femur (p<0.01), Ward's triangle (p<0.001), trochanter (p<0.01) and intertrochanteric area (p<0.01).Similar results were obtained when Barthel index on discharge was studied.
Data show that femur bone mineral density is associated with the functional recovery after hip fracture in elderly women. The association is independent of 11 confounding variables. It is suggested that bone mineral density measurement provides information about the functional recovery after hip fracture, apart from the estimation of the fracture risk. Prospective studies are needed to confirm this finding.
THE EFFECTS OF TREATMENT INTERVENTIONS ON HEALTH RELATED QUALITY OF LIFE (HRQL) IN POST-MENOPAUSAL WOMEN REGISTERED IN THE CANADIAN DATABASE OF OSTEOPOROSIS AND OSTEOPENIA (CANDOO) PATIENTS
G. Ioannidis1*, J. D. Adachi1, A. Petrie1, R. J. Sebaldt1, A. Papaioannou1, W. P. Olszynski2, D. A. Hanley3, C. H. Goldsmith1
1McMaster University, Hamilton, Ontario, Canada
2University of Saskatchewan, Saskatoon, Saskatchewan, Canada
3University of Calgary, Calgary, Alberta, Canada
There is a great deal of data available on the effects of interventions in osteoporosis patients in terms of treatment-induced changes in bone mass and fracture risk. However, therapeutic regiments should also be evaluated in terms of their impact on HRQL.
HRQL was examined in 1860 postmenopausal women 50 years and older who were registered in CANDOO. This database is a prospective registry of patients designed to capture a comprehensive set of osteoporosis-related clinical data during the course of routine specialist care. The mini-Osteoporosis Quality of Life Questionnaire (mini-OQLQ) was used to measure HRQL. This instrument includes 10 items divided into 5 domains (physical functioning, emotional functioning, activities of daily living, symptoms and leisure). Each item is associated with a seven-point scale in which a rating of 1 represents the worst possible function and a rating of 7 represents the best possible function. The total score for the instrument can vary from 10 to 70, while the domain scores can vary from 2 to 14. We conducted multiple regression analyses using 20 patient variables. Medications included in the analyses were bisphosphonates (etidronate or alendronate), estrogen, and others (calcitonin or fluoride). Other patient factors used in the regression models were incident vertebral fracture status, prevalent vertebral and non-vertebral fracture status, co-morbid conditions, age, dietary calcium intake, hours spent exercising, and lumbar spine and femoral neck bone mineral density.
Adjusted results indicated that subjects who received bisphosphonate therapy had higher HRQL scores as compared with those who were not taking bisphosphonates in the total score (1.4; 95% confidence intervals (CI): 0.1, 2.8) and the symptoms (0.6; 95% CI: 0.3, 0.8), activities of daily living (0.4; 95% CI: 0.1, 0.7), and leisure (0.3; 95% CI: 0.01, 0.6) domains of the mini-OQLQ. No significant differences in HRQL were observed between patients treated with estrogen, or other medications versus those who were not on these medications.
In conclusion, quality of life was higher in post-menopausal women treated with bisphosphonates as compared with non-users. Further research will be needed to determine the clinical relevance of these HRQL changes.
ECONOMIC COMPARISON OF DIAGNOSTIC APPROACHES FOR EVALUATING OSTEOPOROSIS IN OLDER WOMEN
D. F. Kraemer1*, H. D. Nelson1,2, D. C. Bauer3, M. Helfand1,2
1Oregon Health Sciences University, Portland, Oregon, USA
2Portland Veterans Affairs Medical Center
3University of California San Francisco, San Francisco, California, USA
Objectives: Diagnosis of osteoporosis is often based on dual-energy x-ray absorptiometry of the femoral neck (DXA-FN). Newer diagnostic devices such as quantitative ultrasound (QUS) may reduce costs, but clinical and economic comparisons with DXA-FN are limited. Our objective is to estimate numbers of hip fractures prevented and direct medical costs for two years following diagnosis. We compare three diagnostic approaches involving DXA-FN and QUS.
Methods: A decision analytic model is developed. Hip fracture incidence rates (average two-year follow-up) are from the Study of Osteoporotic Fractures (SOF), a large cohort study of older US women (mean age 76). Broadband Ultrasound Attenuation (BUA) of the calcaneus (Walker-Sonix UBA 575 QUS) and femoral neck bone density (Hologic QDR 1000) measurements are used. Three diagnostic approaches, DXA-FN alone, QUS/BUA alone, and a sequential approach (QUS/ BUA followed by DXA-FN only for those with QUS/BUA values below specified cut points) are compared to no diagnosis. A T-score of -2.5 determines high risk with DXA-FN and a range of cut points (50 to 85 dB/MHz) determine high risk for BUA. Treatment (alendronate or hormone replacement) efficacy and cost are based on recent US National Osteoporosis Foundation guidelines.
Results: The sequential approach has the lowest cost per hip fracture prevented for treatment with alendronate (see Table). Hormone replacement therapy results are similar except incremental costs per hip fracture prevented are higher. The short time horizon and the omission of other risk factors likely inflate these incremental costs. In sensitivity analyses, if treatment efficacy were less following QUS diagnosis than DXA-FN diagnosis (by 5% to 15%), QUS alone would be less cost-effective than, or even dominated by, DXA-FN at cut points of 75 dB/MHz or less.
Conclusion: A sequential approach (screening with QUS followed by DXA-FN) may be cost-effective when diagnosing osteoporosis in older women.
| Table. Incremental cost per hip fracture prevented (number of hip fractures prevented) compared to no diagnosis or to alternative with next lowest cost. | |||
| BUA (dB/MHz) | Sequential | QUS/BUA alone | DXA-FN alone |
| 55 | $142,406 (1.75) | dominated* (2.25) | $241,449 (2.92) |
| 65 | $160,373 (2.34) | $2,949,734 (3.00) | $268,624 (2.92) |
| 75 | $164,470 (2.84) | $558,503 (4.00) | dominated (2.92) |
| 85 | $179,038 (2.92) | $531,074 (4.51) | dominated (2.92) |
| *Dominated means this alternative costs more but provides less benefit. | |||
A RANDOMISED TRIAL OF A MODIFIED VERSION OF THE SF12 FOR USE IN QUALITY OF LIFE MEASUREMENT IN OSTEOPOROSIS STUDIES
D. J. Torgerson*, C. P. Iglesias, Y. F. Birks
University of York, UK
The SF36 and SF12 quality of life questionnaires are widely used. However, the current format of the questionnaires may be confusing for older people. We modified the layout of the SF12 for use in a study of hip protectors and tested the new format in a randomised trial. Women aged 70+ were sent a composite questionnaire including either the new or modified SF12 and a fracture risk factor questionnaire The latest version of the SF-12 was at the back of the questionnaire in either its original layout (single and grouped horizontal closed questions) or an alternative design including the same items but presented as single horizontal closed questions. We sent out a total of 1500 questionnaires, 750 of each version. 418 questionnaires were returned, 221 and 201 with the old and new versions, respectively. We found no significant difference in the overall response rates, 29.5%, and 26.8%, respectively. An analysis of the difference in missing items per questionnaire revealed statistical significant differences not only in the overall rate of missing items (18.1% diff, P<0.001), but in all of those questions where the layout was changed. Factor analysis of the structure of the new questionnaire showed a two factor solution, which confirmed the reliability of the new layout (reliability factors were 0.945 and 0.9125, for the modified SF12). Our modified version of the SF-12 showed significant decrease in the number of missing items, whilst showing improved reliability. The York SF-12 is more appropriate for older people than the existing version and should be used in osteoporosis trials which recruit older people.
REDUCTION OF PAIN AND IMPROVEMENT OF QUALITY OF LIFE IN OSTEOPOROTIC PATIENTS UNDER TREATMENT WITH INTRANASALLY ADMINISTERED SALMON CALCITONIN
C. Ràfols1*, I. Serra1, R. DeCastellar2, Acknowledgements to dr. Díez Pérez3
1ICN Ibérica S.A., Corbera de LLobregat (Barcelona), Spain
2Biométrica (CRO), Barcelona, Spain
3Manager of Infectious and Medical Service, Hospital de Mar, Barcelona, Spain
The FARMACAL study is a prospective, observational and multicenter study to evaluate the relative efficacy (reduction of pain) and the effect on quality of life associated with intranasally administered salmon, 200 IU/day, monodose, sterile calcitonin (i.n. sCT).
Quality of life was mesured by Spanish validated version of the EuroQoL 5-D at the start and the end of follow-up, patients refered pain changes by a visual analogue scale (VAS) every control. Five-hundred-twenty osteoporotic patients (92% females, mean age: 62.4, and 28% showing vertebral osteoporotic fractures) who were prescribed 200 IU monodose i.n. sCT were included in this 6-month follow-up study. Evaluations were scheduled at 1, 3 and 6 months.
At the end of treatment a significant reduction of pain according to VAS score was found (ANOVA, p<0.0001) and the mean of analgesic intake was also significantly reduced (ANOVA, p<0.0001). The reduction of pain in the VAS was strongly correlated with an improvement in the quality of life as measured by the EuroQol and specially by the Pain/Discomfort domain.
Ordinal regression analysis was used to estimate the VAS score reduction necessary to detect quality of life improvement by EuroQol 5-D (independent variables: categorized EuroQoL domains, dependent variable: VAS)
FREQUENCY OF HYPERCALCEMIA IN PATIENTS TREATED WITH ALFACALCIDOL.
W. F. Lems1*, F. van Berkum2
1Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands
2Ziekenhuis Twente, Twente, The Netherlands
Background: although alfacalcidol is often used in patients with osteoporosis or (renal) bone disease, some physicians limit its prescription because of fear of inducing hypercalcemia.
Purpose: to estimate the frequency of hypercalcemia in daily practice during treatment with alfacalcidol.
Patients and methods: in patients in which physicians thought alfacalcidol treatment was indicated, the following treatment regimen was suggested: initial dose of 0.25 mcg once daily; increase to 0.50 mcg daily in case of normal serum calcium levels after 1-2 months; continuation of total daily dose of 0.50 mcg after 3-4 months if serum calcium levels remained normal. Serum calcium was measured at least at 3 visits. In total 34 physicians participated in the survey (internists, geriatricians, rheumatologists and nephrologists). Definite hypercalcemia was defined as serum calcium levels within reference range at baseline, an increase in serum calcium to > 2.60 mmol/l during treatment at 2 consecutive measurements and an increase in serum calcium of at least 0.05mmol/l. If elevated serum calcium was observed only transiently, this was considered as be possible hypercalcemia.
Results: 307 patients (mean age 66 years; sex: 80.8% female) were enrolled. Mean serum calcium at visit 1: 2.35 mmol/l; at visit 2: 2.36 mmol/l; at visit 3: 2.38. Definite hypercalcemia was observed in only 2 patients (0.7%, C.I. 0.1%-2.6%). Possible hypercalcemia was observed in 16 patients (5.7%, C.I. 3.3%-9.1%). No cases of clinically relevant hypercalcemia were reported. In none of the patients with renal failure was hypercalcemia observed during treatment with alfacalcidol.
Conclusion: In daily practice, hypercalcemia occurs infrequently during (alfacalcidol) treatment.
ALFACALCIDOL IMPROVES BONE STRENGTH BY STIMULATING BONE FORMATION AND SUPPRESSING RESORPTION: COMPARATIVE STUDIES WITH VITAMIN K2
A. Shiraishi1*, S. Higashi1, T. Masaki1, Y. Uchida1, M. Saito1, M. Ito2, S. Ikeda3, T. Nakamura3
1Chugai Pharmaceutical Co, Ltd., Tokyo, Japan
2Nagasaki University, Nagasaki, Japan
3University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan
Alfacalcidol (ALF), an active vitamin D3 analog, has been reported to prevent osteoporotic bone loss in clinical and animal studies. Vitamin K2 (menatetrenone: VK) has recently attracted attention as a potential drug for the treatment of osteoporosis. Both the active vitamin D3 and VK are well known to promote calcification through the activation of osteocalcin production in vitro. Although it is assumed that both agents play essential roles in bone homeostasis, the differences among their actions in vivo are not fully understood. The present study was undertaken to compare their effects on bone mass and strength in ovariectomized (OVX) rat and to clarify the mechanisms of their actions by using a histomorphometric analysis. Female Wistar-Imamichi rats (10 month-old) were sham-operated or OVX. To OVX rats, ALF (0.1, 0.2 microg/kg) was orally administered 5 times a week, and VK (3, 30 mg/kg) was given as a dietary supplement for 6 months. OVX caused a significant decrease in femoral strength 6 months after surgery (p<0.05 vs. sham group). Both ALF and VK inhibited those decreases without causing hypercalcemia. The mechanical strength at femoral midshaft in the ALF 0.2 microg/kg-treated group is significantly (p<0.05) higher than that in the OVX group, and moreover, is over the sham level after the three-month treatment, while VK required a six-month treatment period to prevent a decrease in the strength. Then, in order to investigate the mechanisms of their effects on the midfemoral cortex, the bone histomorphometry was performed. In endocortical perimeters, ALF caused a significant suppression of bone resorption and yet maintained formation, and in periosteal perimeters ALF dose-dependently stimulated bone formation. On the other hand, no apparent effect of VK on those parameters was observed, however, VK as well as ALF ameliorated the material strength in femoral midshaft. These results suggested that ALF improved the bone quality with stimulating bone formation and suppressing resorption, whereas VK ameliorated the bone quality with no significant effects on bone turnover. In conclusion, as ALF promptly exerts anti-resorptive effects on osteoporotic bone, it seemed to be useful in the clinical treatment of osteoporosis.
EFFECT OF ZONISAMIDE, AN ANTIEPILEPTIC AGENT, ALONE AND IN COMBINATION WITH ALFACALCIDOL ON THE CONCENTRATIONS OF VITAMIN K ANALOGUES IN THE BONE IN GROWING RATS
A. Takahashi1*, K. Onodera2, H. Wakabayashi3, T. Saito4, H. Shinoda5, H. Mayanagi1
1Division of Pediatric Dentistry, Department of Lifelong Oral Health Sciences, Tohoku University Graduate School of Dentistry, Sendai, Japan
2Department of Dental Pharmacology, Okayama University Dental School, Okayama, Japan
3Department of Biophysical Chemistry, Niigata College of Pharmacy, Niigata, Japan
4Clinic of Dentistry for the disabled, Tohoku University School of Dentistry, Sendai, Japan
5Division of Pharmacology, Department of Oral Biology, Tohoku University Graduate School of Dentistry, Sendai, Japan
We previously reported that long-term administration of zonisamide (ZNS) at large doses could induce osteopenia accompanied by a decrease in bone mineral density (BMD) in various bones, and that the combined administration of alfacalcidol with ZNS could prevent such decreases in BMD in growing rats. The present study was undertaken to investigate whether long-term administration of ZNS (80mg/kg/day, s.c., for 5 weeks) alone or in combination with alfacalcidol (0.1 microg/kg/day, s.c.) with ZNS would affect the contents of vitamin K1 and vitamin K2 analogues (MK-n) in bone in growing rats. The high-performance liquid chromatography method we previously described was used to determine vitamin K analogues in the bone (femoral metaphysis). Bone-histomorphometric evaluation of the tibial metaphysis was also conducted. The following results were obtained. (1) Administration of ZNS alone significantly decreased the concentrations of vitamin K1 and vitamin K2 (MK-4 and MK-5) in the femoral metaphysis, compared with those in the control group: 62% reduction for vitamin K1, 57% for MK-4 and 58% for MK-5. (2) Combined administration of alfacalcidol with ZNS did not prevent these decreases in the concentrations of vitamin K1 and vitamin K2 analogues (MK-4, MK-5 and MK-6). (3) Administration of alfacalcidol alone did not change the concentrations of vitamin K1 and vitamin K2 analogues (MK-4, MK-5 and MK-6), compared with those in the control group. (4) Bone-histomorphometric analysis revealed that the administration of ZNS alone decreased trabecular bone volume, trabecular thickness and trabecular number in the metaphysis of tibia, which led to a decrease in BMD, and that the combined administration of alfacalcidol with ZNS prevented the decrease in BMD.
The above results suggest that osteopenia induced by ZNS might be associated with a disturbance in vitamin K metabolism, and prevention of the osteopenia by alfacalcidol might not be due to the correction of vitamin K metabolism.
THE REDUCED BONE FORMATION AND STRENGTH IN CARBON TETRACHLORIDE INDUCED HEPATIC OSTEODYSTROPHY ARE PARTIALLY PRVENTED BY ADMINISTRATION OF 1.25(OH)2D
S. Tanaka*, A. Sakai, H. Tsurukami, N. Okimoto, H. Otomo, T. Nakamura
Department of Orthopaedic Surgery, University of Occupational and Environmental Health, Japan
To clearify the bone metabolism in hepatic osteodystrophy and the therapeutic effect of 1.25(OH)2D, we developed a laboratory model of rat induced by intraperitoneal injection of carbon tetrachloride (CCl4) and treated with oral administration of 1.25(OH)2D. Fifty 3-week-old male Wistar rats were assigned to five. One of 5 groups was treated as a start control and another group as a normal control (Group N). CCl4-induced liver cirrhosis was developed in 3 groups. Two of 3 groups were treated with 0.05 µg/kg and 0.1µg/kg 1.25(OH)2D once a day for 7 weeks (Group D0.05 and Group D0.1). Another one was treated with vehicle (Group LC). The serum 1.25(OH)2D level in Group LC was significantly reduced as compared to that in Group N. That in Group D0.1 was significantly higher than that in Group LC. Serum osteocalcin (OC) level in Group LC was significantly lower than that in Group N. Urinary deoxypyridinoline (D-pyr) in Group LC was significantly higher than that in Group N. There were no significant differences in the serum OC and the urinary D-pyr among Group LC, Group D0.05, and Group D0.1. The BMD values of the lumbar vertebra and the femoral diaphysis in Group LC were significantly lower than those in Group N. The values in Group D0.05 and Group D0.01 were significantly higher than that in Group LC at the vertebra but not at the femora. The ultimate load of the lumbar vertebra and the femoral diaphysis in Group LC was significantly smaller than that in Group N. There were no significant difference among Group LC, Group D0.05, and Group D0.1. The bone histomorphometry of the lumbar vertebra showed that the bone volume (BV/TV) in Group LC was significantly lower than that in Group N. BV/TV in Group D0.1 was significantly higher than that in Group LC. The bone formation rate (BFR/BS) in Group LC was significantly lower than that in Group N. There were no significant differences among Group LC, Group D0.05, and Group D0.1. There were no significant differences in the value of the osteoclast surface (Oc.S/BS) and the osteoclast number (Oc.N/BS) among all groups. This study clearly demonstrated that osteoporosis was the predominant form of CCl4-induced hepatic osteodystrophy. The oral administration of 1.25(OH)2D partially improved hepatic osteodystrophy.
INCREASE IN FEMORAL BONE STRENGTH BY THE TREATMENT WITH ALFACALCIDOL BUT NOT WITH PLAIN VITAMIN D
S. Higashi1*, T. Masaki1, A. Shiraishi1, Y. Uchida1, M. Saito1, E. Ogata2, T. Nakamura3
1Chugai Pharmaceutical Co. Ltd., Tokyo, Japan
2Cancer Institute Hospital, Tokyo, Japan
3University of Occupational and Environmental Health, Fukuoka, Japan
Although active vitamin D analogs are used in the treatment of osteoporotic patients, their mechanism of action is not fully understood. As it is generally accepted that active vitamin D exerts skeletal effects in vitamin D-deficient patients with low calcium intake, it is of particular interest to examine the pharmacological effects of active vitamin D in the vitamin D-repleted condition in comparison with those of plain vitamin D. So far, we have already revealed that alfacalcidol, one of active vitamin D3 analogs, improved both bone mineral density (BMD) and bone strength in dose-dependent fashion without hypercalcemia, while plain vitamin D3 increased serum calcium concentration and BMD but failed to increase femoral bone strength. In addition, no difference in histomorphometrical indices at the trabecular sites was detected between alfacalcidol and plain vitamin D3 treated groups. In this study, we aimed to clarify this discrepancy by conducting the histomorphometrical analysis at the cortical site. Alfacalcidol (0.025 - 0.1 microg/ kg) and plain vitamin D3 (50 - 400 microg/kg) were orally administered to 8-months-old ovariectomized (OVX) rats for 3 months, and then the femurs were dissected. The central part of the femur, which is rich in cortical bone, was analyzed. As a result, both alfacalcidol and plain vitamin D3 inhibited the increase in parameters for bone resorption dose-dependently and maintain bone formation at the endocortical perimeters, and therefore, suppressed the decrease in the cortical area caused by OVX to the same extent. But the remarkable finding is that the plain vitamin D3 (400 microg/kg)-treated group, which did not express sufficient bone strength corresponding to the increased BMD, caused significant porosity (p<0.001 vs. sham; p<0.001 vs. OVX). As serum PTH concentration in neither alfacalcidol- nor plain vitamin D3-treated group was elevated, the porosity was not caused by hyperparathyroidism. Therefore, some metabolites derived from plain vitamin D3 might stimulate cortical porosity. In conclusion, beneficial effect on osteoporotic fracture could be achieved by alfacalcidol treatment, which may be explained at least partly by the action of alfacalcidol in increasing BMD and bone strength at the cortical site without increasing intra-cortical porosity, unlike plain vitamin D3.
ALPHACALCIDOL IN OSTEOPOROSIS PREVENTION IN POSTMENOPAUSAL WOMEN
O. A. Nikitinskaya*, L. I. Benevolenskaya
Institute of Rheumatology, Moscow, Russia
Aim: To assess the efficacy of alphacalcidol (alpha D3) in postmenopausal women with osteopenia.
Material and methods: 40 women aged 55-77 with osteopenia, 28 out of whom had bone mineral density (BMD) indices from 2.0 to 2.5 SD were 2 groups. The 1st group (n=20): median age 67.0±6.16, postmenopausal duration 17.75±7.35 years, BMD indices L1-L4 0.809±0.030 g/cm2. The 2nd group (n=20): median age 67.85±4.08, postmenopausal period 19.94±8.04 years, BMD L1-L4 – 0.838±0.047 g/cm2. Women in 1st group had alpha D3 in dosage of 0.5 micrograms/day for two years, in the 2nd group they had no therapy. Measuring of BMD in low back (by Hologic 4500 A) in both groups were carried out at the beginning of observation, in 12 and 24 months. The level of bone alkaline phosphatase (BAP) in blood serum and level of deoxypyridinoline (Dpd) in the urine were determined before the therapy and after 2 years.
Results: BMD indices in a year were not substantially changed in both group; in 2 years BMD increased in both groups: in the 1st - L1-L4 0.837±0.049 (p<0.005), in the 2nd - L1-L4 0.849±0.051 (NS). BAP level before the therapy was normal in 85% of women, decreased in 15%, after 24 months of therapy BAP level was normal in 82.5% and decreased in 17.5%. Dpd level was within the norm in 70%, increased in 30%, after 24 months of therapy in 5% of women the indices below the norm, in 47.5% within the norm and in 47.5% above it.
Conclusion: Thus, alphacalcidol taking in dosage of 0.5 micrograms/day for 2 years has no considerable effect of bone turnover but reliably increases low back BMD.
EFFECT OF CALCITRIOL ON BONE METABOLISM IN INSTITUTIONALIZED EPILEPTIC PATIENTS
M. A. Krieg1*, J. Fritschi2, F. Baronti2, P. Burckhardt1
1University Hospital, Lausanne
2Bethesda Klinik, Tschugg, Switzerland
Background: Anticonvulsants can affect bone metabolism, with decrease of 25-hydroxyvitamin D (25OHD), hypocalcemia, increase of alkaline phosphatase (AP) and PTH, osteopenia or osteomalacia on bone biopsy. These disturbances are partially explained by enzymatic induction with an increased hepatic catabolism of vitamin D. 30 institutionalized epileptic patients, aged ±57, who received phenobarbital, phenytoin or carbamazepine, were randomized in 2 groups, a treated group (n=14) who received calcitriol 0.5 ug/d, and a control group (n=16). At baseline, all the patients were assessed with a bone ultrasound (BU) of the phalanxes (DBM sonic 1200) and a measurement of the serum level of calcium, 25OHD, AP, PTH, C Telopeptide (CT) and 1,25OHD2.
Results: At baseline, 16 patients (53%) had a positive fracture history (28 fractures). 48% had vitamin D insufficiency, i.e. 25OHD<12 mg/l. The mean BU values were low (mean Z-score -1.4 SD). Age, BMI and CT explained 54% of the variability of BU (multivariate analysis). Baseline values of PTH, AP and CT (mean±SEM) and changes from baseline (%±SEM) are presented in table (* p<0.05, ** p<0.01 compared to baseline, § p<0.05, §§ p<0.01 compared to treated group). The 1,25-dihydroxyvitamin D status will be presented.
Conclusion: Calcitriol led to a significant decrease of PTH and AP and a trend of decrease of CT. After 6 months, PTH and CT differed significantly between the 2 groups. Calcitriol prevented the increase of bone remodeling during winter.
| Parameter | Calcitriol | Baseline (SEM) | M6 (spring) | M12 (autumn) |
| PTH (ng/l) | yes | 63.1 (20.6) | -19.6% (6.4)** | -19.5% (7.9)* |
| PTH (ng/l) | no | 49.9 (30.5) | 36.4% (6.5)**§§ | 8.6% (9.7)§ |
| AP (IU/l) | yes | 98.6 (42.5) | -8.1% (3.6)* | -15.5% (2.7)** |
| AP (IU/l) | no | 118.3 (38.7) | 4.1% (4.8) | -9.3% (3.7)* |
| CT (microg/l) | yes | 0.46 (0.18) | -16.3% (9.4) | -11.2% (5.4) |
| CT (microg/l) | no | 0.53 (0.33) | 30.6% (10.7)**§§ | 17.4% (9.6)§ |
ALFACALCIDOL INHIBITS BONE RESORPTION, MODULATES CYTOKINES AND REDUCES PAIN IN PATIENTS WITH RHEUMATOID ARTHRITIS AND OSTEOPENIA
S. H. Scharla*, S. Bawey, D. Holle, J. Boensch, I. Kamilli, E. Quade, C. Loeffel, U. G. Lempert
Klinikum Berchtesgadener Land, Schoenau am Koenigssee, Germany
Rheumatoid arthritis (RA) is known to increase the risk for osteopenia. Since cytokines are supposed to play a role in the development of osteopenia in these patients, we chose an agent known to have immunomodulatory effects for therapy. Therefore, we compared the effects of vitamin D and alfacalcidol in patients with RA.
62 patients with RA and osteopenia (T-score<1; DXA Hologic QDR-4500 A), mean age 65.3 years (range 40-80 years) were included in our study. After randomisation, patients received either vitamin D (1000IU/day) or alfacalcidol (1microg/day). Additionally, all patients received calcium (500mg/day). Routine serum parameters as well as serum parathyroid hormone (PTH), Interleukin 6 and 12 (IL 6, IL 12), tumor necrosis factor alpha (TNFalpha), bone resorption marker NTX (in urine) and urinary calcium excretion were measured before, 2 and 4 weeks after treatment. A pain score was used to evaluate subjective pain. Muscle strength was determined by isokinetic test.
Serum calcium was increased (n.s.) within the normal range by alfacalcidol. There was a slight decrease in TNFalpha in patients receiving alfacalcidol (p<0.05), whereas IL 6 and IL 12 were not changed significantly by neither alfacalcidol nor vitamin D. After 4 weeks, calciuria was increased (mostly within the normal range) in patients receiving alfacalcidol and slightly in the vitamin D group. PTH was decreased in the alfacalcidol group (group difference p<0.009) as well as NTX (p<0.01). A significant decrease of pain score occurred only in the alfacalcidol group (p<0.0001). Evaluation of muscle strength was possible in 17 patients. In patients receiving alfacalcidol muscle strength increased by 60% compared to 18% in patients of the vitamin D group (p<0.05).
Alfacalcidol was more effective in inhibition of bone resorption and modulation of TNFalpha as well as in reducing pain and increasing muscle strength than vitamin D. We suppose this to be due to greater availability of active viatmin D metabolite in the respective tissues.
GP’S KNOWLEDGE OF CALCIUM AND VITAMIN D PREPARATIONS FOR FRACTURE PREVENTION: COMPARISON BETWEEN RESEARCH PARTICIPANTS AND CONTROLS
R. J. Barr1*, A. Stewart1, B. Mcdonagh2, D. M. Reid1
1Dept. Medicine & Therapeutics, University of Aberdeen, Aberdeen, UK
2Strakan Ltd, Galashiels, UK
Background: Calcium and vitamin D has been shown to reduce hip fractures in elderly institutionalised women. We wished to examine the value of giving information to general practitioners (GPs) on effective dose and costs on prescribing habits of GPs participating in a targeted screening study.
Methods: Women over 70 years from 10 GP practices in Aberdeen were screened to identify those at increased risk of hip fracture by ultrasound measurement and fracture risk analysis. GPs were advised to prescribe a calcium and vitamin D preparation to those found to be at increased risk of hip fracture and dose and price information was provided for the available calcium and vitamin D preparations. A questionnaire, designed to evaluate calcium and vitamin D prescribing and knowledge of its use in hip fracture prevention, was sent to 58 GPs whose patients had taken part in the study and to 50 GP controls whose patients were not involved. In total 31 active (53.4%) and 32 control (64.0%) GPs have returned completed questionnaires to date.
Results: No significant difference was found in knowledge of the role of calcium and vitamin D in hip fracture prevention in the two groups of GPs. A significant difference was found between the two groups in the choice of preparation (p=0.009). The primary reasons for choosing a specific preparation were significantly different (p=0.038). Control GPs were more likely to cite hospital recommendation, as their primary reason (control n=9, active n=1), whereas active GPs were more likely to cite price and evidence of effectiveness. Active and control GPs ranked price of 5 preparations differently (p=0.013), with the active group more likely to get the ranking correct or nearly correct.
Conclusions: Participation in the research study did not appear to increase the knowledge of the GPs on the effectiveness of calcium and vitamin D, but giving information to GPs alters their choice of preparation based on effective dose and price. Further work is required on how best to advise GPs on relative costs of medications, as most could not identify the least and most expensive calcium and vitamin D preparations.
THE INFLUENCE OF VITAMIN D3 AND CALCIUM ON OSTEOPOROTIC FRACTURE HEALING
A. M. Doetsch1*, N. Lynnerup2, J. Faber1, H. Bliddal1, P. Beck1, B. Danneskiold-Samsoe1
1Parker Institute, Frederiksberg Hospital, Denmark
2Panum Institute, University of Copenhagen, Denmark
The purpose of the study was to investigate the influence of Vitamin D3 and Calcium on callus formation during the healing process of the osteoporotic shoulder fracture.
30 osteoporotic women (defined by traditional hip scan), free of diseases affecting the joints and not in oestrogen therapy, mean age 77.7 (Range: 58-88) with conservative treated collum chirurgicum fractures were included in a double blind placebo controlled study. The fracture site was chosen to quantify changes in BMD/BMC during healing without interference from metallic implants or casts.
16 patients received daily dosages of 1g of Calcium + 800 IE Vitamin D3, with 14 receiving placebos over the duration of the study. All patients were monitored after fracture occurrence with effect parameters including Dexa-scan, X-ray, Biochemical, and clinical tests at weeks 0, 2, 6 and 12.
Dexa-scans were performed in the Anterior-Posterior (AP) position with a Norland Dexa XR-26 scanner with ROI over the fracture area. Scan images were scaled to confirm anatomical landmarks against equivalent AP X-ray images. In previous studies (to be published) we confirmed scanner precision over the shoulder region at (CV) of 1.3%.
Both groups experienced statistically significant trends (increase) in BMD levels from week 0 over the observation period, with peak levels in week 6. (Active: p=0.00001, Control: p=0.0145051). From week 0 to week 6, the active group experienced a significantly higher increase in BMD (16.79% compared to 9.96%) (p=0.0275).
Observed variation in hip and shoulder BMD levels within the active group was consistently higher than the control group. Factors influencing variation in the shoulder region may include compliance in the active group, and difference in blood supply to the fracture area. Both hip and shoulder variation may be influenced by relatively small sample size. No statistically significant changes in hip BMD levels were observed in either group between weeks 0 and 12.
Our findings indicate that Vitamin D3 and Calcium increases callus formation and density over the osteoporotic fracture during the healing process. Further investigation is planned to determine correlation between callus formation and differences in clinical healing time of the osteoporotic fracture.
EFFECT OF DAILY REGIMEN ADMINISTRATION OF CALCIUM-VITAMIN D SUPPLEMENTS ON DECREASE OF PARATHYROID HORMONE LEVELS.
J. Y. Reginster1,2*, B. Zegels1, E. Lejeune1, A. N. Taquet1, M. C. Micheletti3, A. Albert4
1Bone and Cartilage Research Unit, University of Liège, Liège, Belgium
2WHO Collaborating Center on Public Health Aspects of Rheumatic Disorders, Liège, Belgium
3Medical Department, Laboratoire Theramex, Monaco
4Department of Medical Informatics, University of Liège, Liège, Belgium
Calcium and vitamin D supplementation have been shown to reduce secondary hyperparathyroidism and play a role in senile osteoporosis. In order to define the optimal regimen of calcium and vitamin D supplementation to produce the maximal inhibition of parathyroid hormone (PTH) secretion, we have compared the administration of a similar amount of calcium and vitamin D either as a single morning shot or split in two intakes, occurring at six-hour intervals.
Twelve healthy volunteers were randomly assigned to three investigational procedures, at weekly intervals. After a ' blank ' control procedure, when they were not exposed to any drug intake, they received, two calcium-vitamin D supplements regimens including either two doses of Orocal D3 (500 mg calcium and 400 IU vitamin D) at six-hour intervals or one water soluble effervescent powder pack of Cacit vitamin D3, in one single morning intake (1000 mg calcium and 880 IU vitamin D).
During the three procedures veinous blood was drawn every sixty minutes for up to nine hours, for serum calcium (CA) and PTH measurements.
No significant changes in CA were observed during the study. During the first six hours, following calcium-vitamin D supplementation, a statistically significant decrease in PTH was observed with both regimens, compared to baseline and to the control procedure. On this entire period, no differences, were observed between the two treatment regimen. However, between the sixth and the ninth hour, PTH levels were still significantly decreased compared to baseline with the split Orocal D3 administration while they returned to baseline value with Cacit D3. During this period, the percentual decrease in PTH, compared to baseline, was significantly more pronounced with Orocal D3 than Cacit D3 (p=0.0021).
The administration of two times 500 mg of calcium and 400 IU of vitamin D3, at six-hour intervals provides a more prolonged decrease in PTH levels than the administration of the same total amount of calcium and vitamin D, as a single morning intake in young healthy volunteers. This might have implications in terms of protection of the skeleton against secondary hyperparathyroidism and increased bone resorption and turnover, in elderly subjects.
