ABSTRACTS P-236 to P-305

POSTER PRESENTATIONS

 

Posters will be on display throughout the symposium, but will be attended by their presenting authors as follows:

Odd numbers on Friday 11:00 - 12:00, Sunday 11:00 - 12:00 and Monday 10:00 - 11:00
Even numbers on Saturday 11:00 - 12:00, Sunday 11:00 - 12:00 and Monday 10:00 - 11:00

 

Osteoporosis: Evaluation and Treatment continued....

 

P-236

PERFORMANCE OF A REAL-TIME IMAGING QUS SYSTEM USING AN ENHANCED COUPLING AGENT

G. F. Mitchelmore, W. K. Wacker, R. F. Morris, K. L. Morris, K. G. Faulkner*

GE Medical Systems Lunar, Madison, WI, USA

Ultrasonometry of the os calcis is increasingly accepted as an effective low-cost method to assess osteoporotic fracture risk. The Lunar Achilles InSight (GE Medical Systems) is a fourth-generation system incorporating a 2-D solid-state receiving array. It eliminates 'blind' measurement by displaying a real-time heel image prior to and during measurement. A Region-of-Measurement circle on the image shows the measurement location. Historically, ultrasonometers have used water, ultrasound gel or mineral oil as the coupling medium to transfer the ultrasound signal from the transducers through the heel. Oil-based agents create difficulties in clean up and staining of clothes. Gel is water-soluble but must be cleaned from the transducers and heel. We evaluated a new coupling agent, isopropyl alcohol (70%) that was selected for its recognized safety in external application.

In vivo performance was compared between the Achilles InSight and the Achilles Express (GE Medical Systems), a previous generation ultrasonometer. Volunteers (n=29, including 22 older women) with a wide range of heel densities were measured on two days, using gel one day and alcohol the other. The combined data were subjected to regression (alcohol on gel values) and paired t-test analysis. Stiffness Index was highly correlated between alcohol and gel (r=0.983). Slope was almost identical to 1 while offset equaled 1.5, not significantly different from zero (alpha = 0.05).

Measurement convergence time of Stiffness Index was evaluated on 22 subjects who were measured with gel and isopropyl alcohol using a fixed acquisition time of 3 minutes. Alcohol-coupled signals converged more rapidly and BUA and SOS values stabilized faster as compared to gel.

Precision (%CV) was calculated for alcohol and gel measurements made on the same foot on separate days. Ten subjects were measured fifteen times in succession with repositioning between measurements. Alcohol had better repeat precision (lower variance). Results were highly significant (p<0.001) by F-test for Stiffness Index (CV of 1.95% Vs. 2.55%), BUA and SOS.

Isopropyl alcohol as a coupling agent gives Stiffness Index results nearly identical to coupling gel. Alcohol provides significantly shorter measurement time, superior stability and improved precision while eliminating the problems of messy oils or gels.

[Programme]

 
P-237

THE EFFECTS OF MENATETRENONE ON THE BONE AND SERUM LEVELS OF VITAMIN K2 (MENAQUINONE DERIVATIVES) IN OSTEOPENIA INDUCED BY PHENYTOIN IN GROWING RATS

K. Onodera1*, A. Takahashi2, H. Wakabayashi3, J. Kamei4, N. Sogawa1, C. Sogawa1, S. Kitayama1, H. Mayanagi2, H. Shinoda5

1Division of Dental Pharmacology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

2Clinics of Dentistry for the Disabled, Tohoku University Dental Hospital, Sendai, Japan

3Department of Clinical Pharmacotherapy, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan

4Department of Pathophysiology & Therapeutics, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan

5Division of Pharmacology, Tohoku University Graduate School of Dentistry, Sendai, Japan

We reported that long-term treatment of phenytoin induced osteopenia and co- administration of vitamin K2(menatetrenone) prevented such bone loss. In this study, we investigated the effect of phenytoin and/or vitamin K2(menatetrenone) on bone mineral density (BMD) and the changes in the levels of menaquinone derivatives (MK-n) in the serum. The levels of menaquinone derivatives in the femur were measured using high-performance liquid chromatography with an electrochemical detector. In this study, we found that he values of BMD were significantly decreased in all parts of the femoral bones measured in the phenytoin-treated group. When the bone and the serum levels of MK-6 were decreased by phenytoin administration, we could observed bone loss in rats. Conversely, when bone loss was prevented by combined administration of menatetrenone with phenytoin, the bone levels of MK-6 were increased up to the levels of vehicle-treated rats. Accordingly, in this study, we

suggest that long-termed phenytoin exposure may inhibit bone formation concomitantly with insufficient of vitamin K, which, at least in part, contributed to bone loss in rats.

[Programme]

 
P-238

EFFECTS OF MENATETRENONE AND/OR ALENDRONATE ON BONE MINERAL DENSITY OF TIBIAE IN PHENYTOIN TREATED RATS

A. Takahashi1*, K. Onodera2, T. Saito1, H. Shinoda3, H. Mayanagi1

1Clinics of Dentistry for the Disabled, Tohoku University Dental Hospital, Sendai, Japan

2Division of Dental Pharmacology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

3Division of Pharmacology, Tohoku University Graduate School of Dentistry, Sendai, Japan

Antiepileptic drugs have been shown to induce hypocalcemia that is associated with osteomalacia and osteoporosis in clinical practice. Among the antiepileptic drugs, diphenylhydantoine (phenytoin, 5,5-diphenyl-2,4-imidazolidinedione) is one of the most commonly used for the therapy of patients with various types of seizures. Recently, we reported that long-term administration of phenytoin induces osteopenia in growing rats, moreover, daily intake of menatetrenone showed preventive effects against such phenytoin-induced osteopenia. In this study, we investigated the effects of menatetrenone and/or alendronate on bone mineral density in phenytoin-treated rats. A long-termed administration of phenytoin (20 mg/kg per day for 5 weeks) produced bone loss in the tibiae of growing rats. The values of bone mineral density (BMD) were significantly decreased in the tibial diaphysis and metaphysis in the phenytoin-treated group. Combined administration of menatetrenone or alendronate with phenytoin did not decrease BMD in the tibiae. Treatment of menatetrenone with phenytoin maintained BMD as same as control, however, treatment of alendronate with phenytoin increased BMD more than control. Administration of menatetrenone and alendronate with phenytoin showed additional effect on BMD. Thus, we conclude that combined treatment with menatetrenone plus alendoronate was more effective than therapy with menatetrenone alone on antiepileptics-induced bone loss.

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P-239

INTRAVENOUS INTERMITTENT NERIDRONATE IN THE TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS

V. Braga*, D. Gatti, J. Bakri, F. Colapietro, E. Battaglia, R. Prizzi, M. Rossini, S. Adami

Rheumatological Rehabilitation, University Hospital Valeggio S/M, Italy

Bisphosphonates have been used with success in the treatment of osteoporosis, but oral therapy often lacks compliance. Here we report the results of a clinical trial with the aminobisphosphonate neridronate administered intravenously (IV).

The study included 78 postmenopausal women with spine bone mineral density (BMD) at least -2.5 SD below peak. Patients were randomized to receive for two years either 50 mg IV neridronate bimonthly and 500 mg calcium plus 400 U vitamin D supplements daily (n. 39) or calcium vitamin D supplements alone (control group, n. 39). Treatment was continued over 2 years with an additional 1 year follow-up of calcium-vitamin D supplements alone in both groups.

Neridronate was well tolerated with the appearance of typical clinical signs of an acute phase reaction in 5 of the patients and only after the first infusion.

In the control group no significant changes in BMD or bone markers were observed. In the neridronate group BMD rose progressively at the spine up to 7.4%, 6.1% (SD) and at the femoral neck up to 5.8%, 8.2% (SD) at the end of the second year. In the succeeding follow-up months these gains were maintained at both skeletal sites. Serum bone alkaline phosphatase (bone AP) and serum type I collagen C- telopeptide (CTX) significantly decreased within 2 months. The bone AP values reached a -30% plateau after 6 months, while CTX attained the lowest mean value (- 47%) only by the end of the treatment with neridronate. Both bone markers returned almost to baseline values 1 year after treatment discontinuation.

Treatment of postmenopausal osteoporosis with 50 mg IV neridronate bimonthly results in clinically relevant increases in BMD amongst the largest so far observed with any other bisphosphonate.

[Programme]

 
P-240

ESTIMATION OF GLUCOCORTICOID EFFECTS ON BONE METABOLISM MARKER AND BONE MINERAL DENSITY IN RATS

F. Moradi1*, A. Sobhani1, M. Naraghi1, M. Moghadsi2, M. Ansari3, A. Ghasemzadeh1

1Dept. Anatomy, Faculty of Med.,Tehran Univ. of Med. Sci. Tehran, Iran

2Dept. Rheumatology, Faculty of Med.Tehran Univ. of Med. Sci. Tehran, Iran

3Dept. Biochemistry, Faculty of Med.Tehran Univ. of Med. Sci. Tehran, Iran

Abstract:

Introduction: Glucocorticoid induced osteoporosis was characterized by decreased of osteoblast numbers and a marked impairment of new bone formation. The present study evaluated the effect of methylprednisolone Acetate on metabolism and bone mineral density of rats.

Methods and Material: Total duration of the experiment was four weeks. Eighteen male Sprague Dawley rats (8 week old and 180 gr weight) were randomly divided into three groups: Group A (n=6), was a base line control or normal animal. Group B (n=6), get only normal saline (0.9%) and group C (n=6), get methylprednisolne acetate (0.2 mg/kg) subcutaneously 3 times for 4 weeks. For evaluation on Biochemical agents changed in the serum calcium, Acid phosphatas and osteocalcine were measured before and after treatment. Also, bone mineral density (BMD) of lumber vertebrae was measured by dual energy x-ray absorptiometry (DEXA).

Results: The results showed that, the serum calcium level unaffected (p<0.05) by methylprednisolone acetate, but the serum Acid phosphatase level was significantly (p<0.05) increased after 4 weeks treatment. Also, the serum osteocalcine level and bone mineral density of lumbar vertebrae were significantly (p<0.05) decreased by methylprednisolone acetate treatment compared with the other groups.

Conclusions: The findings indicate that by administration of methylprednisolne actate bone formation lumber vertebrae was decreased and bone resorption in lumber vertebrae was increased.

Key words: Glucocorticoid, osteoporosis, Bone Markers Metabolism, BMD and rat.

[Programme]

 
P-241

BONE DENSITOMETRY AND OSTEOPOROSIS DIAGNOSTIC THRESHOLD

Z. Killinger*, J. Payer, P. Hrśzikovį, E. Stenovį

1st Internal Clinic,University Hospital, Bratislava, Slovakia

Dual-energy X-ray absorptiometry /DXA/ is regarded as the best method for use in clinical practice for the diagnosis of osteoporosis. It still remains debate on, how the results obtained should be used to make decision about treatment. In routine practice T score below -2,5 SD is the most important factor for initiating an antiresorptive treatment. In most centres only one region is routinely measured. Presence of osteophytes, calcifications, vertebral deformities and different speed of bone loss after the menopause in individual regions may cause a discrepancy in BMD results. The type of DXA and used normative data contribute to the discrepancies. The diagnosis of osteoporosis may be missed if only one site is measured. In our centre we have performed since 1993 more than 30 000 scans of lumbar spine and femoral neck in each patient using Norland XR 36. We found relative high discrepancies between both measured sites.

We present the results of a retrospective analysis of 1018 women divided in 5 age groups. We found in 38% the difference between femoral neck and lumbar spine T score more than 1 SD and in 7,5% of patients more than 2 SD. If screened only at femoral neck 13,5% (mean) patients with osteopenia and 6% (mean) of patients with osteoporosis would be misdiagnosed as normal. Relative high differences were found in all age groups. In contrast with published data we found higher sensitivity of lumbar spine measurement also in older patients over 70y. in spite of occurrence of osteoproductive changes in this region. Consistent exclusion of lumbar vertebrae with anatomical changes will still increase the sensitivity of spine measurement. Selection of measured region, type of DXA device and used normative data should be taken in account /except of quality of the scan due to anatomic changes/ if the diagnosis of osteoporosis is the endpoint. Precise diagnosis and extrapolation of diagnostic criteria to intervention thresholds is a key issue in clinical decision making about antiresorptive treatment.

[Programme]

 
P-242

DEVELOPMENT OF MUSCLE STRENGHT, BONE MINERAL DENSITY, PHYSICAL FUNCTION, JOINT DAMAGE AND CLINICAL DISEASE ACTIVITY IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS. IMPACT OF PHYSICAL TRAINING. A 5-YEAR PROSPECTIVE STUDY

A. Häkkinen1, T. Sokka2,3, H. Kautiainen4, A. Kotaniemi4, P. Hannonen2*

1Department of Physical Medicine and Rehabilitation, Central Hospital, Jyväskylä, Finland

2Department of Medicine, central Hospital, Jyväskylä, Finland

3Division of Rheumatology, Vanderbilt University, Nashville, US

4Rheumatism Foundation Hospital, Heinola, Finland

Objective: To investigate the long-term effects of a 2-year home-based strength training on muscle strenght, bone mineral density (BMD), joint damage, disease activity and physical function in patients with early rheumatoid arthritis (RA) after a subsequent 3-year follow-up.

Methods: Seventy patients with early RA were randomly assigned to perform either strength training (EG) or range of motion exercises (CG). Maximal strength of various muscle groups were recorded with dynamometers, BMD was measured at the femoral neck and at the lumbar spine by dual x-ray densitometry. Disease activity was assessed by disease activity score (DAS), the extent of joint damage by Larsen`s score and physical function by the self report Health Assessment Questionnaire (HAQ).

Results: The respective mean maximum muscle strength index increases during the 2-year training period were 32% and 18% in EG and in CG and they remained at the reached level throughout the subsequent 3-year follow-up period. The BMD values between the study groups at both measured sites were comparable at baseline and at all subsequent measurements. The EC patients remained better physical function in comparison to the CG cases, while the development of joint erosions and DAs indices were comparable between groups throughout the study.

Conclusion: Individually tailored and regularly conducted physical exercises including strength training improves muscle strength and physical function and maintains BMD in patients with early RA. Further, it does not accelerate the development of radiographic joint damage or increase clinical disease activity.

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P-243

ALENDRONATE (ALN) TAKING IN POSTMENOPAUSAL OSTEOPOROSIS (PMO) AT DIFFERENT TIMES IN THE COURSE OF THE DAY

B. H. Hoene*, H. J. H. Heberling, J. S. Steindorf, T. M. Mühlberg, A. S. Sawistowsky, S. N. Neumann, S. G. Gerstenberger

Community Hospital Leipzig, Germany

Bisphosphonates are world-wide accepted as one of the most important treatment schedules of PMO. They are associated with stringent dosing recommendations due to their poor gastrointestinal absorption and upper gastrointestinal side effects. This facts may cause problems of compliance.

The aim of our clinical trial was to investigate the effects of taking ALN in the morning on the empty stomach and on the other hand in the evening.

We studied the effects of the two treatment groups on bone mineral density and bone turnover in 36 postmenopausal women with diminished BMD (at least minus 2.5 SD of peak bone mass). All patients were supplemented with calcium and vitamin D. BMD of lumbar spine and femur was measured using DEXA at different time intervals. Bone turnover markers were assessed at baseline,3, 6 and 12 months.

Results: Morning and evening taking of 10 mg ALN increased lumbar spine BMD by 4.5% and respectively 3.5% in relation to baseline. BMD gains were also seen at the femoral neck (Ward triangle) by 5.3% in the morning group and 3.8% in evening taking group. Even so was seen a significant suppression of the bone resoption markers in both doses regimes. The same percentage of withdrawals following an adverse effect was observed for patients receiving 10 mg in the morning and for those receiving 10 mg in the evening.

Conclusion:This small clinical trial demonstrates that ALN (10 mg) is efficacious in different taking regimes. The evening taking is an effective alternative in patients with problems in taking ALN on empty stomach.

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P-244

EFFECT OF EGGSHELL CALCIUM AND COMBINATION THERAPY WITH ALENDRONATE ON THE OVARIECTOMIZED RATS

K. Svik*, M. Stancikova, R. Istok, R. Stancik

National Institute of Rheumatic Diseases, Piestany, Slovakia

Objective. The effects of eggshell calcium in the form of biopreparation Biomin H as a source of calcium and its combination with sodium alendronate on ovariectomy (OVX) induced bone loss were studied in a long-term prophylactic treatment regime in rats.

Methods. Adult female Sprague Dawley rats (250±10g) were subjected to bilateral ovariectomy and sham operation (SHAM). Forty nine animals were divided into 7 groups of seven: (1) sham; (2) OVX controls; OVX rats treated: (3) with alendronate 250 µg/kg (ALN-1); (4) with alendronate 500 µg/kg (ALN-2); (5) with Biomin H 8 mg/kg (BIO-1); (6) with Biomin H 16 mg/kg (BIO-2); and (7) Biomin H 8 mg/kg plus alendronate 250 µg/kg (ALN-1+BIO-1). For a period of 9 weeks the animals were on a calculated diet containing 7.5 g Ca/kg, 6.5 g P/kg and 1000 IU vitamin D3/kg diet. Sodium alendronate and Biomin H were applied orally daily. Both pyridinoline (Pyr) and deoxypyridinoline (Dpyr) were determined in the urine by HPLC method. Bone mineral density (BMD) and bone mineral content (BMC) of the whole body and femur were detected using DEXA.

Results. All densitometric parameters except BMC of the whole body were markedly decreased in OVX rats in comparison with SHAM controls. Both urinary Pyr and Dpyr were significantly lower in SHAM, ALN-1, ALN-2, BIO-2 and ALN- 1+BIO-1 groups compared to the OVX control. The beneficial protective effect of these agents were observed on BMD and BMC of the whole body and femur after 9 weeks of ovariectomy. BIO-1 alone did not change significantly these parameters in OVX rats, but its combination with ALN-1 had similar effect as ALN-2.

Conclusion. Our data show the significant preventive effect of alendronate and Biomin H 16 mg/kg in the treatment of OVX rats and the beneficial effect of the combination of low dose eggshell calcium (Biomin H) with low dose alendronate, which may be cost saving due to reduce dose of alendronate.

[Programme]

 
P-245

VALUE OF BONE SCINTIGRAPHY FOR THE DETECTION AND AGEING OF VERTEBRAL FRACTURES IN PATIENTS WITH SEVERE OSTEOPOROSIS

E. Kucukalic*, A. Begic, I. Gavrankapetanovic, F. Gavrankapetanovic, J. Dizdarevic, S. Sokolovic, B. Hadzihasanovic, D. Avdic, I. Hizar

Clinical Center, University of Sarajevo, Sarajevo, Bosnia and Herzegovina

Bone scintigraphy is used to detect sceletal lesions a the earliest possible time, to monitor the course of skeletal disease and evaluate the metabolic activity of skeletal lesions.In osteoporosis it is useful for detection of age of fractures, particularly of the vertebrae. Acute vertebral colapse is associated with a characteristic pattern of intensive linear uptake corresponding to the site of fracture. Activity fades over the ensuing 6-18 months, which allows intensity of uptake to enable assessment of the age of fracture.

Aim: The aim of this study was to determine, by using the bone scan, age of veretebral fractures in patients with severe osteoporosis.

Materials and Methods: 24 female patients were studied with bone scintigraphy after BMD and radiographic examination. BMD was measured with DEXA HologicQDR 4500 Elite system. BMD showed T-score under -2.5 SD. The patients were divided into two groups according to the clinical simptoms: groupI: Patients with acute low back pain (onset at last 1-2 months); groupII: Patients with chronical back pain.

Scintigraphy was performed using double-head camera equiped with low energy high resolotion collimator 3 hours after i.v. injection of 740 MBq Tc-99m MDP.

MDP uptake was assessed visually and graded as 1.miled; 2.moderate; 3.intensive.

Results:

Gruop I : Intensive linear uptake of MDP was confirmed in 12 patients (100%)

Group II: Intensive linear uptake of radiofarmaceutical was confirmed in 1 patient (8.3%)

Moderate linear uptake of MDP we have found in 3 patients (25%)

Miled uptake of MDP was confirmed in 8 (66.7%)

Intensive uptake of radiofarmaceutical we have found in patients with acute low back pain.

Conclusion: Intensity of uptake of Tc-99m MDP is good parametar for assesssment of the age of fracture.

The present study confirms that Tc-99m MDP scintigraphy is an accurate method for the

detection of the ageing of fractures cousing osteoporosis.

[Programme]

 
P-246

CORRELATION BETWEEN BONE SCINTIGRAPY AND MINERAL BONE DENSITY IN PATIENTS WITH OSTEOPOROSIS AND OSTEOPENIA

A. Begic*, E. Kucukalic, I. Gavrankapetanovic, F. Gavrankapetanovic, J. Dizdarevic, S. Sokolovic, B. Hadzihasanovic, D. Avdic, I. Hizar, S. N. Begovic S, Beslic N

Clinical Center, University of Sarajevo, Sarajevo, Bosnia and Herzegovina

Aim: The aim of this study was to evaluate the role of Tc-99m MDP bone scintigraphy and compare with MBD measurment.

Materials and methods: This study included two groups of female patients: 13 postmenopausal women with established osteoporosis, and 5 women with osteopenia. BMD was measured wit DEXA Hologic QDR 4500 Elite system.

Scintigraphic examination were performed according to standard protocol, 3 hours after i.v. injection of 740 MBq Tc-99m MDP. All images were visually analysed by three nuclear medicine physicians.

Results: In the first group, all 13 scans showed an intensive linear uptake of MDP in the lumbar spine. In the same group, asymptomatic sites of increased tracer uptake were identified in femur of 1 patient, in humerus of 1 patient, and 1 scan revealed focal increased uptake in the ribs. In the second group (patients with osteopenia) WBS were found normal in 4 patients, and 1 patients had mild increased uptake of radiotracer in the region of lumbar spine.

Conclusion: WBS is in positive correlation with MBD, and can revealed all fractures sites in patients with osteoporosis. In patients with osteopenia WBS is not diagnostic procedure of choice.

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P-247

MINIMIZING ADVERSE SIDE EFFECTS DURING OSTEOPOROSIS INDUCTION IN SHEEP BY MODULATION OF CORTICOSTEROID ADMINISTRATION

R. Holz1,2*, C. Eckhardt1, E. Schneider1, C. A. Lill1,3

1AO Research Institute Davos

2Department of Traumatology, University of Regensburg

3Department of Orthopaedic Surgery, University of Heidelberg

Recent studies developed a large animal model for osteoporosis to investigate new fixation devices and fracture healing in osteoporotic bone with a combination of ovariectomy (OVX), calcium and vitamin D3 restricted diet, and application of

Methylprednisolone (MP). Due to the immunodepression effect of MP 31 % of the animals developed abscesses of the skin and internal organs. The aim of this project was to reduce the adverse side effects due to corticosteroid administration without compromising the desired bone loss, with combined treatment of OVX, diet and i.m. administration of an uniform total dose of 1800 mg MP. Four groups with different administration schedules were compared during a follow up of 4 months.

Thirty-six female white alpine sheep (6.5 ±0.6 years) included in this study. Bone mineral density (BMD) measurements in the distal tibia and radius were performed before and monthly during induction by peripheral quantitative CT (pQCT). Bone structure from biopsies of the iliac crest taken before and after osteoporosis induction and from necropsies of the femoral head and lumbar vertebral body (L4, L5) was determined using Micro-CT. The Health condition of the animals was documented weekly and postmortem examination of abdominal organs and subcutaneous tissue from the injection areas was performed.

Cancellous BMD in the radius diminished 30 % in group 1, 30 % in group 2, 31 % in group 3 and 22 % in group 4. The BMD of the tibia decreased 37 % in group 1, 34 % in group 2, 43 % in group 3 and 34 % in group 4.

In the iliac crest trabecular number was reduced 18 % in group 1, 18 % in group 2, 14% in group 3 and 9 % in group 4. Trabecular separation increased 34 % in group 1, 31 % in group 2, 28 % in group 2 and 16 % in group 4.

Except in group 3 adverse side effects like disseminated alopecia, local or systemic infections due to drug administration were seen.

It seems to be possible to induce osteoporosis in sheep without causing severe adverse side effects by reducing the number of steroid injections and increasing the single dose simultaneously.

[Programme]

 
P-248

EACH HERBAL EXTRACT OF SOPHORAE FLAVESCENTIS RADIX AND SOPHORAE FLOS (LEGUMINOSAE) PREVENTS BONE LOSS IN OVARIECTOMIZED (OVX) RATS

H. Ha1, C. Kim1*, K. Y. Song2

1Drug Research and Development, Korea Institute of Oriental Medicine, Seoul, Korea

2College of Medicine, Chung-Ang University, Seoul, Korea

Aging and estrogen deficiency after menopause induces bone loss and results in osteoporosis. Estrogen replacement therapy is indeed effective in preventing bone loss caused by menopause, but it is also accompanied by some adverse effects, such as uterus bleeding and breast cancer. This study was focused on development of new drug from herbal extract of Sophorae Flavescentis Radix (SR) or Sophorae Flos (SF), to prevent and treat osteoporosis after menopause without any side effects. The proliferation of osteoblast like cell (Saos-2) induced by each herbal extract was analyzed using a tetrazolim salt (MTT) and alkaline phosphatase (ALP) activity. Adult OVX SD rats (10 weeks old) were divided into five groups; sham, control, 17beta-estradiol (E2; 1 microg/kg/day), SR (5 g/kg/day), and SF (5 g/kg/day). Animals in each group were administrated daily dosage for 9 weeks. After complete blood cells counts and bioche trabecular bone areas (TBAs) of tibia and lumbar were measured by bone histomorphometry. In results, both SR and SF extracts induced cell proliferation on Saos-2 mical analysis in plasma as biomarkers, tibia and lumbar were isolated and then (117% and 119% of control). The ALP activities of the extracts on Saos-2 were 257% and 189% of control. The TBAs of tibia in SR and SF groups were increased 169% and 163% of control (p<0.01), better than that in E2 group (147% of control, P<0.05). SR and SF increased TBA of lumbar 141% (P<0.01) and 127% (P<0.05) of control (P<0.01), better than or similar to that in E2 (124% of control, P<0.05). Each herbal extract of SR and SF did not induce estrogenic side effects in uterus. In conclusion, both SR and SF extracts prevent OVX-induced cancellous bone loss for 9 weeks in OVX rats. (Supported partially by a grant from KIOM, Korea)

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P-249

HIGH INCIDENCE OF BONE TURNOVER DISTURBANCES WITH INCREASING AGE

D. Ivan1,2*, I. Zosin1, D. David1, M. Vlad1, P. Bottermann2

1Clinic of Endocrinology, University of Medicine and Pharmacy, Timisoara, Romania

22nd Medical Clinic, Technical University Munich, Germany

Introduction: Biochemical and hormonal markers of bone metabolism can offer useful information about the dynamics of bone turnover and type of bone loss. The aim of this study was to evaluate this information in an homogenous group of elderly people.

Material and Methods: 74 clinically healthy residents of a senior's home (56 women, 18 men, aged 56-95). Venous serum samples were drawn (in the middle of June) for determination of serum calcium and phosphorus, alkaline bone phosphatase, creatinine, urea-N, PTH, 25-OH-D3 and 1,25-(OH)2-D3 and the morning spot-urine was collected for measurement of deoxypyridinoline(DPD)-excretion.

Results: Subjects were divided in four age subgroups: 56-65 years (18 cases), 66- 75 years (27 cases), 76-85 years (21 cases) and 86-95 years (8 cases). All of them had normal renal function (creatinine<1.2 milig/dl, urea-N<22 milig/dl). 25-OH-D3 levels (mean ± SEM) were below the normal range in all four groups; serum calcium levels (mean ± SEM) decreased gradually but remained within the normal range and PTH levels increased gradually with age (mean ±SEM: 40.97 ±18.23, 45.96 ±18.30, 69.75 ±40.59, 101.74 ±64.81pico/ml) as well as the DPD-excretion (mean ±SEM of DPD/Creatinine ratio: 3.90 ±1.31, 5.02 ±1.69, 6.55 ±2.93, 8.82 ±4.72). In spite of low 25-OH-D3 levels, the serum levels of 1,25-(OH)2-D3 remained within the normal range.

Conclusions: 1.) The incidence of vitamin D deficiency is also in younger age groups very high and reaches with increasing age even 100%. 2.) The progressive decrease of serum calcium levels, even within normal range, leads to a secondary hyperparathyroidism with increased bone degradation (elevated DPD-excretion). 3.) Assessment of bone turnover in elderly persons has to take into account all the parameters, biochemical as well as hormonal (PTH and vitamin D); the information offered needs to be judged for each person separately. 4.) There is evidence that even at advanced age the kidney preserves its ability to synthesize normal amounts of 1,25- (OH)2-D3.

[Programme]

 
P-250

ONE-MONTH SALMON CALCITONIN EFFECT ON FRACTURE HEALING IN NORMAL AND ORCHIDECTOMISED MALE RATS

I. C. Koulouris*, I. Paspati, I. Dontas, P. Raptou, E. Kataxaki, G. P. Lyritis

Laboratory for the Research of Musculoskeletal Interactions, KAT Hospital, Medical School, University of Athens, Greece

Aim: The aim of this study is to investigate the volumetric changes in the callus after experimental osteotomy of the femur in normal male Wistar rats, normal rats treated with sCalcitonin (sCT), orchidectomised rats and orchidectomised rats treated with sCT.

Material & Methods: We used 112 male Wistar rats divided into 8 groups of 14 each. The 56 rats were orchidectomised at the age of 2 months and all the animals were undertaken hemiosteotomy (OT) in the middle of their right femur at the age of 3 months. The animals were divided in 8 groups as follows:

Group a, sacrificed at 2 weeks,normal

Group b, sacrifised at 2 weeks,normal+sCT

Group c, sacrificed at 2 weeks, orchidectomised

Group d, sacrificed at 2 weeks, orchidectomised + sCT

Group A, sacrificed at 4 weeks, normal

Group B, sacrificed at 4 weeks, normal +sCT

Group C, sacrificed at 4 weeks, orchidectomised

Group D, sacrificed at 4 weeks, orchidectomised + sCT

The animals of b, B, d and D groups immediately after the OT were given 5 IU of sCT subcutaneous daily. After the sacrifice of the animals we studied the total bone content, the total bone density and the total bone area of the callus by pQCT (STRATEC XCT 960).

Results were as follows:

For Total BMC (mg/cm2):

A compared to a: increase of 0.91%, ns

C compared to c: increase of 3.97%, ns

B compared to b: increase of 6.60%, ns

D compared to D: increase of 7.08%, p<0.0005

For Total BMD (mg/cm2):

A compared to a: decrease of 1.26%, ns

C compared to c: decrease of 0.69%, ns

B compared to b: increase of 6.84%, P=0.02

D compared to d: increase of 5.69%, p=0.02

For Total area (cm2)

A compared to a:increase of 3.3%, ns

C compared to c:increase of 4.85% , p=0.02

B compared to b: no change

D compared to d: increase of 10.94%, p=0.01

Conclusion: The volumetric parameters of the callus studied by pQCT in normal rats without treatment and normal rats given sCT do not demonstrate statistically significant changes, with the exception of total BMD. In orchidectomised rats treated with sCT these parameters demonstrate statistically significant increase between two and four weeks, thus suggesting a possible positive effect on salmon calcitonin on modeling phase during fracture healing in the orchidectomised animals.

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P-251

EVALUATION OF BMD MEASUREMENTS ACCORDING TO THE LEAST DENSE VERTEBRA: IMPLICATIONS FOR CLINICAL DENSITOMETRY

D. Hadjidakis*, A. Mylonakis, P. Katsavochristos, S. A. Raptis

2nd Department of Internal Medicine-Propaedeutic, Research Institute and Diabetes Center, 'Evangelismos' and 'Evgenidion' Hospitals, Athens University, Greece

The evaluation of L2-L4 bone mineral density (BMD) measurements is sometimes hintered by existing lesions which may result in major variations between individual vertebrae's BMD values Aim: To investigate the diagnostic value of one individual vertebra among L2-L4 presenting a remarkable difference of BMD value. Methods: In 1327 women with natural menopause (NMP), 331 women with premature natural menopause (EMP) and 510 women with surgical menopause (SUMP), BMD measurements were performed at L2-L4 vertebrae and femoral neck (FN) by DEXA.

All women were less than 66 years old and didn't suffer from any disease or receive any medication affecting bone metabolism. Those with obvious degenerative lesions on x-rays were excluded. Women whose vertebral measurements detected one vertebra with a BMD value less than 90% from the immediate denser one (LDV), comprised 3 subgroups [269 NMP aged 56.1 ±4.3 years (mean ±1SD), 43 EMP aged 53.7 ±7.4 and 60 SUMP aged 52 ±7.7]. Percentages of osteopenic (OPE) and osteoporotic (OPO) women based on L2-L4, LDV or FN BMD values were estimated (WHO criteria). Results: A LDV was detected in 20.3% of total NMP, 13% of EMP and 11.8% of SUMP women (NMP vs EMP, SUMP: p<0.001). The distribution of LDV didn't differ significantly between the subgroups with the L4 vertebra accounting for 70-77% of total LDV, the L2 for 18-26% and the L3 for 3-7%. In all subgroups percentages of OPE, OPO based on LDV BMD values were significantly higher compared to L2-L4 or FN respective ones (p<0.001). Only in NMP subgroup there was a significant correlation between either L2-L4 or LDV and FN BMD values (r=0.38 and 0.58 respectively, p<0.001). In the other subgroups LDV was always stronger correlated to FN BMD value, though not significantly. Conclusions: NMP women present significantly greater proportion of LTV compared to either EMP or SUMP. Most frequently L4 appears as the LDV. This LDV seems to be stronger correlated to femoral neck BMD values compared to mean L2-L4. The evaluation of a detected LDV seems to be necessary since it can ameliorate factors which interfere to vertebral DEXA measurements.

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P-252

RISEDRONATE THERAPY FOR PREVENTION OF BONE LOSS IN MEN WITH IDIOPATHIC OSTEOPOROSIS: A 1-YEAR STUDY

B. Gerbert1*, H. Heinze1, A. Oehme1, U. Nawroth2, J. Schulze1

1Clinic of Internal Medicine, Technical University of Dresden, Dresden, Germany

2Practice of Orthopaedics, Radebeul, Germany

The objective of this prospective study was to assess the efficiency of a therapy with 5 mg risedronate daily on bone mineral density and vertebral and non-vertebral fractures in men suffering from idiopathic osteoporosis. Subjects consisted of 93 men (age 57,2 ± 11,5 years) with idiopathic osteoporosis (T-score <-2,5 at lumbar spine or neck). The primary clinical symptom was back pain. At enrollment 16 of them had one or more vertebral fracture and 16 a non-vertebral fracture, altogether 38 vertebral and 24 non-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 therapy with risedronate. Additionally, subjects received 1000 mg calcium and 800 IE colecalciferol daily.

After one year of therapy we found serum level of PTH, calcium, osteocalcin, bone specific and alkaline phosphatase as well as urine levels of pyridinolin-, deoxypyridinolin-crosslinks and N-telopeptides to have decreased significantly, whereas a significant increase of phosphate in urine was measured. Urine level of calcium diminished not significantly.

We measured a significant increase of bone mineral density in the lumbar spine (p<0,01) by +4,7% (L1 +4,0%, L2 +4,0%, L3 4,1%, L4 +5,6%) and by +1,3 % in the neck ( p< 0,05). In comparison 9 patients were treated only with calcium and vitamin D and in this patients an increase of bone mineral density of + 2,2 % in the lumbar spine and of + 1,9 % in the neck was measured.

5 new vertebral (3 patients) and no new non-vertebral fractures were recorded in the course of the study. That means 12 % of the patients suffering from a prevalent vertebral fracture get a new fracture within the first year of therapy.

Conclusion: Therapy with 5 mg risedronate is efficient for male patients suffering from idiopathic osteoporosis. The study will be continued.

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P-253

FEMORAL QCT, BUT NOT PERIPHERAL QCT AND QUANTITATIVE ULRASOUND, IMPROVE THE PREDICTION OF FEMORAL FAILURE VERSUS IN SITU DXA

E-M. Lochmüller1*, V. Kuhn1, F. Eckstein2

1Gynaecology Hospital I, LMU München, Germay

2Institute of Anatomy, LMU München, Germany

Femoral fractures have the most substantial personal and socioeconomic impact in osteoporosis, and bone densitometry is currently clinically used to predict mechanical strength for estimating fracture risk. In this study we test the hypothesis that femoral strength prediction with DXA (bone mass) can be improved a) by geometric parameters obtained at the proximal femur itself using femoral QCT, and b) by geometric and ultrasound parameters obtained in the peripheral skeleton (distal radius and calcaneus, respectively).

89 specimens were investigated at an age of 80 ± 10 years. In situ DXA was performed on the left femur, and ex situ QCT on the same femur after degassing. One set of slices (2 mm) was acquired in the axial plane, and one set perpendicular to the neck (1 mm), and proprietory software was used for digital postprocessing. In situ pQCT was applied to the distal radius, and ex situ quantitative ultrasound to the calcaneus. Pairs of femora were tested to failure, one in side impact and one in vertical loading.

With the side impact, in situ DXA displayed a correlation of r = 0.72 with failure laods, whereas femoral density from QCT showed a correlation of 0.77 and femoral bone content (QCT) of 0.80. In a multiple regression model, a correlation of 0.87 was achieved when using femoral content and trabecular cross sectional area of the neck. In vertical loading, DXA displayed a correlation of 0.69 with failure loads, femoral content (QCT) of 0.80, and a multiple regression model with femoral content and the section modulus of the neck 0.82. The multiple regression models provided signficantly higher correlations (p < 0.05) than femoral DXA for both side impact and vertical loading. pQCT and QUS only displayed moderate correlations (0.34 to 0.64) and did not add significant information to DXA in muliple regression models.

Prediction of femoral strength can be effectively improved versus in situ DXA when determining densitometric and geometric variables with QCT. Peripheral measurements with pQCT and QUS, in contrast, add no significant information to DXA. Analysis of geometric properties may improve the prediction of fracture risk but should be performed at the site of interest.

[Programme]

 
P-254

DIFFERENTIAL PREDICTION OF EARLY POSTMENOPAUSAL FRACTURES BY FRACTURE HISTORY

R. J. Honkanen1,4*, H. Kroger2,4, M. Tuppurainen3,4, E. Alhava2,4

1Research Institute of Public Health, University of Kuopio, Kuopioi, Finland

2Department of Surgery, Kuopio University Hospital, Kuopio, Finland

3Department of Gynecology, Kuopio University Hospital, Kuopio, Finland

4Bone and Cartilage Research Unit, University of Kuopio, Kuopio, Finland

We have shown retrospectively that former wrist fracture is strongly associated with later wrist fracture but not with later non-wrist fracture, whereas former non- wrist fracture is associated with both later wrist and non-wrist fracture (CTI 1997:60:327-31). Now we studied if the same pattern can be seen prospectively.

The study population consisted of those OSTPRE cohort (13100 women born in 1932-41) women who responded to postal enquiries in May 1989 (baseline), May 1994 and May 1999 (N=11074) and who had fracture history information at baseline (N=10277). At baseline 1865 of these women reported a fracture and 559 women a wrist fracture since the age of 15. During the 10-year follow-up1915 women reported a fracture and 736 women a wrist fracture. These follow-up fractures were validated by patient record perusal.

History of fracture predicted follow-up fracture with an odds ratio (OR) of 1.9 (95%CI 1.7-2.2). Old wrist fracture predicted new wrist fracture with an OR of 2.6 (2.1-3.4) and other fractures with an OR of 1.5 (1.2-1.9), whereas old non-wrist fracture predicted new wrist fracture with an OR of 1.3 (1.1-1.6) and new non-wrist fracture with an OR of 1.7 (1.4-2.0). After excluding women who had sustained more than one fracture before or after baseline, 9624 women with 1415 (393 wrist) old and 1370 (496 wrist) new fractures were left for sub-analyses with following ORs: wrist to wrist 3.0 (2.2-4.1), wrist to non-wrist 1.3 (0.95-1.8), non-wrist to wrist 1.1 (0.8-1.5) and non-wrist to non-wrist 1.6 (1.3-1.9).

The strong wrist to wrist fracture prediction may be due to low bone density and quite uniform trauma mechanism (fall), whereas the weaker non-wrist to non-wrist fracture prediction may reflect both the more diversified nature of fracture and trauma mechanism as well as weaker bone density dependency. Interestingly, no clear predictions crossing over the fracture categories were found.

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P-255

RISEDRONATE EFFECTS ON BONE LOSS AND ARCHITECTURAL DISTURBANCES IN A RAT MODEL WITH A MASSIVE BONE LOSS. A DENSITOMETRIC, HISTOMORPHOMETRIC AND MICROTOMOGRAPHIC STUDY

S. Blouin1, H. Libouban1, M. F. Moreau1, S. Horlait2, M. Audran1, D. Chappard1*

1GEROM-LHEA Faculty of Medicine, Angers, France

2Procter and Gamble Pharmaceuticals, France

Risk factors for osteoporosis include deficiency of sexual steroids and disuse. The orchidectomized (ORX) rat is a suitable model for hypogonadism-induced osteoporosis. An IM injection of botulinum (BTX) neurotoxin produces a paralysis and induces a localized bone loss. ORX and BTX models were combined to see if bone loss could be prevented by risedronate.

36 aged male rats were randomized into 3 groups. Animals were either SHAM operated; ORX and paralyzed with BTX (one hindlimb); ORX+BTX+risedronate (5µg/kg/d). ORX and BTX were done the same day; risedronate therapy began on the day of surgery. Animals were euthanazied after one month. DXA was used to measure total and regional BMC on both hindlimbs and on excised right vs. left tibia and femur. Histomorphometry was done on the tibia to measure BV/TV and trabecular characteristics (Tb.Th, Tb.N, Tb.Sp). Microarchitecture was analyzed by X-ray microtomography; volume fraction, 3D trabecular thickness and Structure Modeling Index (SMI) were measured.

Whole body BMC was decreased after ORX; this was abolished by risedronate. Effects of ORX and BTX on bone loss were cumulative: a -30% BMC was observed in the isolated tibia of ORX+BTX animals on the paralyzed side. BV/TV and Tb.N decreased significantly after ORX whereas Tb.Sp increased significantly. Tb.Th did not decrease significantly on the non-paralyzed side and was significantly lower on the paralyzed side. Effects of ORX+BTX on bone loss were cumulative because significant differences were observed for BV/TV, Tb.N, Tb.Sp between two side. After risedronate therapy, BV/TV and Tb.Sp remained at the SHAM levels and Tb.N became significantly higher than SHAM value. Microtomography results confirmed these observations: SMI increased significantly in ORX+BTX confirming increased conversion of plates into pillars. Risedronate limited the 3D alterations and appeared to have early effects on the massive and acute bone loss induced by the combination of factors.

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[Programme]

 
P-256

PREDICTORS OF EARLY FAILURE OF BISPHOSPHONATE THERAPY IN PATIENTS REGISTERED IN THE CANADIAN DATABASE OF OSTEOPOROSIS AND OSTEOPENIA (CANDOO)

R. G. Josse1*, A. M. Sawka2, G. Ioannidis2, T. M. Murray1, R. J. Sebaldt2, D. A. Hanley3, J. P. Brown4, C. H. Goldsmith2, A. Papaioannou2, W. P. Olszynski5, A. Petrie2, J. D. Adachi1

1University of Toronto, Toronto, Ontario, Canada

2McMaster University, Hamilton, Ontario, Canada

3University of Calgary, Calgary, Alberta, Canada

4Laval University, Ste-Foy, Quebec, Canada

5University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Factors predicting early failure of bisphosphonate therapy are not well- characterized. Thus, our aim was to determine predictive characteristics of patients who experienced early failure of bisphosphonate therapy as defined by incident clinical fracture within 2 years of starting therapy ('early fracture') or loss of 3% or more of hip or spine bone mineral density from baseline to months 13 to 24 of therapy ('early densitometric failure'), using data from CANDOO. We studied 1588 patients (163 men and 1425 women) over the age of 50 years who were started on cyclic etidronate (n=1119) or daily alendronate (n=469) therapy following enrollment in CANDOO. The alendronate treated patients were subdivided into those taking alendronate with no previous history of etidronate use (n=209), and those with previous history of etidronate use (n=260). Several baseline variables including anthropometric and life style factors were examined. Multivariable logistic regression analysis using a backwards conditional approach was utilized to determine the association between these variables with early treatment failure. Odds ratios (OD) and 95% confidence intervals (CI) were calculated. Results indicated that 31 patients experienced an incident fracture within 2 years of starting bisphosphonate therapy. Seven sustained a clinical vertebral fracture, 22 a non-vertebral fracture and 2 had both clinical vertebral and non-vertebral fractures. Incident fracture within 2 years of starting therapy was most strongly independently predicted by a previous history of non-vertebral fracture (2.98; 95% CI: 1.30, 6.83). Ninety-eight patients lost >3% bone mass at the hip or spine from baseline to 13-24 months with bisphosphonate treatment (early densitometric failure). Early densitometric failure was most strongly independently predicted by treatment group. Alendronate treatment with no previous etidronate use (0.23; 95% CI: 0.09, 0.59) and with previous etidronate use (0.24; CI: 0.11, 0.51) was protective compared with current etidronate therapy. In addition, increased femoral neck bone density was also protective (1.36; 95% CI: 1.10-1.68: for each 0.1 gm/cm2 increase). In conclusion, in patients treated with bisphosphonates, the strongest predictor of early incident fracture is previous history of fracture, whereas early bone loss is predicted by the potency of the prescribed bisphosphonate and the baseline femoral neck bone density.

[Programme]

 
P-257

PREDICTIVE VALUE OF WHOLE BODY BISPHOSPHONATE RETENTION ON LUMBAR BMD AFTER A TWO YEARS PERIOD OF BISPHOSPHONATE THERAPY

A. Nzeusseu1, G. Depresseux1, F. Jamar2, J. P. Devogelaer1*

1Department of Rheumatology, Saint-Luc University Hospital, Belgium

2Department of Nuclear Medicine

Rationale

Nowadays, it is well established that bone fragility depends on both bone mineral density (BMD) and bone remodelling. Higher bone remodelling and lower BMD lead to an increased propensity to fracture. Therefore, we assessed whether bone turnover as measured by the whole body bisphosphonate (BP) retention (WBR) could predict BMD response to bisphosphonate therapy in patients suffering from osteoporosis (OP).

Methods

Out of 173 patients referred for BP-WBR, 154 patients were followed during an average of 26.9 ± 12.6 (SD) months. 19 patients were excluded owing to impaired renal function. All 154 patients had undergone at least two BMD and BP-WBR measurements during the period of follow-up. The patients were divided in two groups according to their BP-WBR, with a cut-off for high level of remodelling settled at 34 %. 22 patients were in the normal or low-turnover (LT) group (BP-WBR < 34 %), while 132 patients with a WBR > 34 % were considered high-turnover (HT) group.

Results

There was a strong negative correlation between L-BMD and BP-WBR measurements in the whole group (r = - 0.28; p = 0.0006). The L-BMD after a mean period of 26.9 months slightly but not significantly increased in the whole LT group (0.761 ± 0.143 g/cm2) as compared to baseline (0.743 ± 0.147 g/cm2). During the same period, L-BMD of the HT group significantly increased from 0.770 ± 0.143 g/cm2 to 0.797 ± 0.149 g/cm2 (p < 0.0001). Moreover, in the LT group, the L-BMDs in the 11 patients on BP therapy increased from 0.749 ± 0.164 g/cm2 to 0.780 ± 0.158 g/cm2 (p< 0.032), whereas in the HT group, the L-BMDs of the 87 BP-treated patients significantly and dramatically increased from 0.768 ± 0.142 g/cm2 to 0.800 ± 0.148 g/cm2 (p < 0.0001).

At the total hip (TH-BMD), there was no statistically significant change during the follow-up in either groups.

Conclusion

First, higher the BP-WBR, lower the L-BMD; Second, bone turnover as assessed by BP-WBR has some predictive value for response to BP therapy after two years. This could help to encourage patients to improve their compliance to therapy.

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P-258

ADHERENCE TO BISPHOSPHONATES AND HORMONE REPLACEMENT THERAPY IN A TERTIARY CARE SETTING OF PATIENTS IN THE CANADIAN DATABASE OF OSTEOPOROSIS AND OSTEOPENIA (CANDOO)

A. Papaioannou1*, G. Ioannidis1, R. J. Sebaldt1, J. P. Brown2, C. H. Goldsmith1, D. A. Hanley3, W. P. Olszynski4, A. Petrie1, R. G. Josse5, T. M. Murray5, P. Boulos1, N. Ferko1, J. D. Adachi1

1McMaster University, Hamilton, Ontario, Canada

2Laval University, Ste-Foy, Quebec, Canada

3University of Calgary, Calgary, Alberta, Canada

4University of Saskatchewan, Saskatoon, Saskatchewan, Canada

5University of Toronto, Toronto, Ontario, Canada

There is a growing number of available therapies that may be used in the treatment and prevention of osteoporosis and fragility fractures. However, therapies for osteoporosis must be taken long-term to be effective. The purpose of this study was to determine the difference in adherence to etidronate, alendronate and hormone replacement therapy in a group of patients seen at our tertiary care centres. CANDOO, a prospective observational database designed to capture clinical data, was searched for patients who started therapy following entry into CANDOO. A total of 1967 individuals met the inclusion criteria. Of these individuals, 1196, 477, and 294 men and women with a mean age (standard deviation) of 67.0 (8.6), 66.3 (8.4), 60.1 (7.5) years initiated etidronate, alendronate, or hormone replacement therapy respectively. Of the total sample, 441 (22.4%) individuals had a prevalent vertebral fracture, and 877 (44.5%) had a prevalent non-vertebral fracture at baseline. At one year, 85.7% of patients were still taking any one of the three therapies. This value decreased to 77.2% at 2 years and to 69.6% at 3 years. A Cox proportional hazards regression model was used to assess differences between treatment groups in the time to discontinuation of therapy (days). Several potential covariates such as anthropometry, medications, illnesses, fractures and lifestyle factors were entered into the model. A forward selection technique was used to generate the final model. Hazard ratios and 95% confidence intervals (CI) were calculated. Adjusted results indicated that alendronate- treated patients were more likely to discontinue therapy as compared with etidronate- treated patients (1.404; 95% CI: 1.15, 1.714). No statistically significant differences were found between hormone replacement therapy and etidronate users (0.971; 95% CI: 0.862, 1.093) and hormone replacement therapy and alendronate users (0.824;

95% CI: 0.624, 1.088) after controlling for a number of variables. Increasing age and presence of incident non-vertebral fractures were found to be independent predictors of adherence. In conclusion, alendronate users were 40.4% more likely to discontinue therapy than etidronate users over the follow-up period. Potential barriers to long-term patient adherence to osteoporosis therapies need to be evaluated.

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P-259

RELATIONSHIP OF VARIOUS PARAMETERS OF BONE RESORPTION (TRAP, COLLAGEN CROSSLINKS) WITH SERUM MARKERS OF BONE FORMATION AND HISTOMORPHOMETRIC BONE PARAMETERS

T. Eidner*, G. Lehmann, A. Müller, G. Hein

Rheumatology & Osteology, Dpt. of Internal Medicine IV, Friedrich-Schiller- University of Jena, Germany

Introduction: Tartrat-resistant acid phosphatase and urinary excretion of collagen crosslinks are common markers of bone resorption. We investigated the relations between these parameters and typical biochemical serum markers of bone formation or osteoblast activity as well as histomorphometric bone parameters for a group of patients with osteoporosis.

Materials and Methods: In 51 patients (31 women, mean age 57,2 ± 14 y., 20 men, mean age 49,3 ± 12 y.) with osteoporosis, who had undergone an iliac crest biopsy, we determined the serum parameters osteocalcin (OC, ng/ml), bone alkaline phosphatase (BAP, microg/l), tartrat-resistant acid phosphatase (TRAP) as well as the urinary excretion of pyridinoline (PYD) and desoxypyridinoline (DPD) by HPLC (nmol/mmol crea). Included histomorphometric parameters were: osteoid surface (OS), osteoblast-covered surface (Ob.S), erosion surface (ES), osteoclast-covered surface (Oc.S), number of osteoclasts (N.Oc) as well as mineralizing (tetracycline- labeled) surface (MS), mineral apposition rate (MAR) und bone formation rate (BFR).

Results: Serum and urinary parameters of bone resorption (TRAP vs PYD and TRAP vs DPD) did not correlate with each other (Spearman correlation coefficient r=0,14, p>0,3). On the other hand, we found close correlations with biochemical parameters of bone formation: TRAP related to OC (r=0,42, p=0,002), less strong to BAP (r=0,34, p=0,03); collagen crosslinks related to BAP (r=0,48 for PYD, r=0,57 for DPD, p=0,001), DPD also to OC (r=0,38, p=0,06). Neither TRAP nor collagen crosslinks correlated with the above histomorphometric parameters. Likewise, there were no significant relations between serum parameters of formation and histomorphometry.

Conclusions: 1. The missing correlation between TRAP and collagen crosslinks was not expected. Obviously, the two parameters characterize different aspects of bone resorption. 2. The close correlations between the biochemical parameters of bone resorption on the one hand and the parameters of bone resorption on the other hand suggest a sustained coupling between bone formation and resorption in most cases. 3. Significant relations between histomorphometric parameters (of trabecular iliac crest) and biochemical markers of turnover (of complete skeleton) were not detectable. Therefore, systemic bone turnover cannot be inferred from the histomorphometric results and vice versa.

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P-260

THE DECREASE IN STRENGTH OF THE FEMUR AND TIBIA ASSOCIATED WITH OVARIECTOMY OF ADULT RATS, IS PREVENTED BY LOW INTENSITY, HIGH FREQUENCY VIBRATION.

B. S. Oxlund, G. Ųrtoft, T. T. Andreassen, H. Oxlund*

Dept of Connective Tissue Biology, Inst of Anatomy, University of Aarhus, Aarhus, Denmark

The effect of low intensity, high frequency vibration on bone mass, bone strength and skeletal muscle mass was studied in an adult ovariectomized (OVX) rat model. One-year-old female rats were allocated randomly to the following groups: start control, sham OVX, OVX without vibration, OVX with vibration at 17 Hz (0.5xg), OVX with vibration at 30 Hz (1.5xg), OVX with vibration at 45 Hz (3.0xg). Vibrations were given 30 min/day for 90 days. During vibration each group of rats was placed in a box on top of the vibration motor. The amplitude of the vibration motor was 1.0 mm. The animals were labeled with calcein at day 63 and with tetracycline at day 84. The tibia mid-diaphysis was studied by mechanical testing and dynamic histomorphometry, the femur distal metaphysis by mechanical compression. OVX without vibration increased the periosteal bone formation rate and increased the medullary cross-sectional area i.e. increased the endocortical resorption and outward antero-medial and lateral drifts of cortical bone at the tibia mid-diaphysis. OVX also resulted in a reduced maximum bending stress of the tibia diaphysis and a reduced compressive stress of the femur distal metaphysis. Vibration at the highest intensity i.e. 45 Hz of OVX rats induced a further increase in periosteal bone formation rate and inhibited the endocortical resorption seen in OVX rats. Furthermore, vibration at 45 Hz inhibited the decline in maximum bending stress and compressive stress induced by OVX. Neither OVX nor OVX with vibration influenced skeletal muscle mass significantly. In conclusion, the results support the idea of a possible beneficial effect of passive physical loading on the preservation of bone in OVX animals.

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P-261

ROCQ: RECOGNIZING OSTEOPOROSIS AND ITS CONSEQUENCES IN QUÉBEC (ROCQ), A PATIENT HEALTH MANAGEMENT PROGRAMME

J. P. Brown1*, L. Bessette1, M. Beaulieu2, L. Lafortune3, S. Jean1, E. Morarescu1, L- G. Ste-Marie4

1Laval University, Québec, Canada

2Merck Frosst Canada, Montréal, Canada

3Aventis Pharma, Montréal, Canada and Procter & Gamble Pharmaceuticals, Toronto, Canada

4University of Montreal, Montréal, Canada

Background: It has been estimated that only 20-25% of women presenting with fragility fractures are subsequently investigated for osteoporosis, and only half of these receive treatment (Hajcsar EE, et al. CMAJ 2000; 163:819-822).

Objective: To improve the use of evidence-based diagnostic and treatment strategies for women 50 years and over, who have suffered a fragility fracture.

Hypotheses: ROCQ's interventions would: 1) double the baseline number of patients investigated for osteoporosis; 2) initiate pharmacological treatment in 70% of those identified with osteoporosis; 3) aim to reduce fragility fractures incidence by 12.5%, if applied on a long-term basis.

Methods: The ROCQ programme is a prospective cohort study using a randomized control design. At phase 1, women will sign a consent form and complete a questionnaire regarding the circumstances of their fracture (traumatic or non- traumatic). At phase 2 (6-8 months later), patients will be contacted by a non-health professional interviewer to complete a telephone questionnaire on osteoporosis (demographics, risk factors, co-morbidities, status of diagnosis and treatment), health utility index and health care resources utilization. The study coordinator will inform the patients by mail one week later, about the results of their randomization to one of 3 interventions: 1) to participate in a 2-hour learning programme held by their local community health centre and to receive additional written educational material directed at the patient and their family physician 2) to only receive written educational material by mail or, 3) no specific intervention other than the interest raised by the questionnaires. The educational material is based on the 2002 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada (Brown JP, et al. CMAJ 2002; 167:S1-S36). At phase 3 (6 months +2 after phase 2), patients with fragility fractures will complete similar questionnaires. Responses to these two questionnaires (phase 2 and 3) will be compared and differences between the two, will measure the effectiveness of ROCQ's interventions in improving diagnosis and treatment of osteoporosis. To test and improve recruitment strategies as well as the feasibility of ROCQ's interventions, a pilot study will take place during the first 18 months of the programme.

[Programme]

 
P-262

EFFECTIVENESS OF ETIDRONATE AND ALENDRONATE IN THE TREATMENT OF OSTEOPOROSIS IN MEN REGISTERED IN THE CANADIAN DATABASE OF OSTEOPOROSIS AND OSTEOPENIA (CANDOO)

W. P. Olszynski1*, G. Ioannidis2, R. J. Sebaldt2, D. A. Hanley3, A. Petrie2, J. P. Brown4, R. G. Josse5, T. M. Murray5, C. H. Goldsmith2, A. Papaioannou2, J. D. Adachi2

1University of Saskatchewan, Saskatoon, Saskatchewan, Canada

2McMaster University, Hamilton, Ontario, Canada

3University of Calgary, Calgary, Alberta, Canada

4Laval University, Ste-Foy, Quebec, Canada

5University of Toronto, Toronto, Ontario, Canada

Although osteoporosis is regarded as a disease of women, this condition is associated with disability and death in men. Thus, the purpose of our prospective one year cohort study was to determine the effectiveness of etidronate and alendronate to increase bone mineral density in men who were registered in CANDOO, a multi- centre prospective clinical database of tertiary care of osteoporosis paitents. The database was searched for men receiving daily etidronate (ETD), alendronate (ALD) or calcium and vitamin D (CON) therapy. Patients were excluded if they did not start osteoporosis therapy on or after their first clinical visit and did not have at least one follow-up bone density visit after initiating therapy. Furthermore, patients were excluded if they had been treated with calcitonin, fluoride or another bisphosphonate at any point during the two years preceding the study. A total of 269 men meet the inclusion criteria of the study. Of these men, 101, 42 and 125 were taking daily ETD, ALD, and CON therapy. Our primary outcome measures were differences between treatment groups in the percent change in lumbar spine and femoral neck bone mineral density (BMD) from baseline to one year follow-up. Multivariable regression analysis was conducted. Regression coefficient parameter estimates as well as 95% confidence intervals were calculated while controlling for possible confounding effects of the other variables. The coefficient estimates represent percent differences between groups in bone mineral density. Multiple imputation was used to impute missing data. Results are shown in table.

Differences between the CON and the bisphosphonate groups were observed at the lumbar spine but not at the femoral neck. There appears to be a trend towards a greater increase in BMD with alendronate therapy. In conclusion, ETD and ALD therapy appear to be effective in the treatment of osteoporosis in men.

 

Location

ETD vs. CON*

ALD vs. CON*

ETD vs. ALD*

Lumbar spine

2.26(0.67, 3.85)

5.23 (2.98, 7.47)

-1.94 (-3.91, 0.02)

Femoral neck

0.68 (-1.17, 2.53)

2.19(-0.53, 4.92)

-1.21 (-3.82, 1.39)

* reference group

 

[Programme]

 
P-263

PARTICIPANT CHARACTERISTICS THAT PREDICT 3-YEAR INCIDENT CLINICALLY RECOGNIZED VERTEBRAL DEFORMITY IN MENOPAUSAL WOMEN ENROLLED THE CANADIAN MULTICENTRE OSTEOPOROSIS STUDY (CAMOS)

W. P. Olszynski1*, G. Ioannidis2, C. Berger3, A. Papaioannou2, J. C. Prior4, L. Joseph3, D. A. Hanley5, L. Pickard2, T. M. Murray6, J. P. Brown7, A. Tenenhouse3, T. Anastassiades8, W. Hopman8, S. Kirkland9, C. Joyce10, S. Poliquin3, N. Kreiger6, J. D. Adachi2 and the CaMos Research Group

1University of Saskatchewan, Saskatoon, Saskatchewan, Canada

2McMaster University, Hamilton, Ontario, Canada

3McGill University, Montreal, Quebec, Canada

4University of British Columbia, Vancouver, British Columbia, Canada

5University of Calgary, Calgary, Alberta, Canada

6University of Toronto, Toronto, Ontario, Canada

7Laval University, Ste-Foy, Quebec, Canada

8Queen's University, Kingston, Ontario, Canada

9Dalhousie University, Halifax, Nova Scotia, Canada

10Memorial University, St. John's, Newfoundland, Canada

Osteoporosis is a silent disease, until the first fracture occurs. Given that bone densitometry screening of all women will not identify all individuals who will suffer a fracture, other characteristics are required to estimate fracture risk. Utilizing participants from CaMos, a nation-wide, random sample of the population, we performed a three-year prospective cohort study in community dwelling menopausal women to examine the association among various participant characteristics and clinically recognized incident vertebral deformities as reported on the yearly follow- up questionnaire (confirmed by x-ray or medical report). Participants were classified into two groups according to incident fracture status: those without incident fractures during the study period (n=4829), and those with an incident vertebral deformity (n=34). Fractures due to minimal trauma were included in our analysis. Follow-up was calculated as the time from baseline examination to the date of the incident deformity or three years. Characteristics examined in the Cox multivariate survival analysis included age, prevalent vertebral deformity status, change in height, current height, change in weight, current weight, body mass index, SF-36 physical component summary score, and baseline lumbar spine and femoral neck bone mineral density (BMD). Relative risk and 95% confidence intervals (CI) were calculated. The mean (standard deviation) age, height and weight of participants was 66 (10) years 159 (6) cm and 69 (14) kg for those without incident fractures and 74 (10) years, 156 (7) cm and 59 (11) kg for those with an incident vertebral deformity. The relative risk of sustaining an incident vertebral fracture was associated with the SF-36 physical component summary score (0.959; 95% CI: 0.924, 0.996) and femoral neck BMD (0.002; 95% CI: 0.00, 0.506). A prevalent vertebral deformity (2.337; 95% CI: 0.897, 6.088) and a loss of height (1.075; 95% CI: 0.970, 1.193) tended to be associated with incident fracture status but further evidence will need to be collected to verify these findings. Women with lower physical quality of life measures and femoral neck BMD were at higher risk for sustaining an incident vertebral deformity. The identification of high-risk women is essential to effectively use the growing number of available osteoporosis therapies.

[Programme]

 
P-264

RISK FACTORS THAT PREDICT THREE YEAR INCIDENT NON- VERTEBRAL FRAGILITY FRACTURE IN MENOPAUSAL WOMEN IN THE CANADIAN MULTICENTRE OSTEOPOROSIS STUDY (CAMOS)

J. P. Brown1*, G. Ioannidis2, C. Berger3, D. A. Hanley4, J. C. Prior5, L. Joseph3, W. P.

Olszynski6, A. Papaioannou2, L. Pickard2, T. M. Murray7, A. Tenenhouse3, T.

Anastassiades8, W. Hopman8, S. Kirkland9, C. Joyce10, S. Poliquin3, N. Kreiger6,

J. D. Adachi2 and the CaMos Research Group

1Laval University, Ste-Foy, Quebec, Canada

2McMaster University, Hamilton, Ontario, Canada

3McGill University, Montreal, Quebec, Canada

4University of Calgary, Calgary, Alberta, Canada

5University of British Columbia, Vancouver, British Columbia, Canada

6University of Saskatchewan, Saskatoon, Saskatchewan, Canada

7University of Toronto, Toronto, Ontario, Canada

8Queen's University, Kingston, Ontario, Canada

9Dalhousie University, Halifax, Nova Scotia, Canada

10Memorial University, St. John's, Newfoundland, Canada

A number of factors have been found to be associated with previous non-vertebral fragility fractures; they include advanced age, height, existing fracture, and propensity to falls. However, our understanding of risk factors related to incident non-vertebral fractures is still inadequate. Thus, the purpose of this study was to examine the association among various potential risk factors and incident non-vertebral fractures in a three-year prospective cohort study of menopausal women who were enrolled in CaMos. CaMos is a nation-wide, randomly selected sample of the Canadian population with a baseline bone mineral density, weight and height as well as extensive questionnaires and yearly fracture questionnaire follow-up. Fractures were confirmed by x-ray or medical report. Participants were classified into two groups according to incident fracture status: those without incident fractures during the study period (n=4829), and those with an incident non-vertebral fracture at the wrist, hip, humerus, pelvis or ribs (n=163). Only incident fractures resulting from minimal trauma were included in the analysis. Follow-up was calculated as time from baseline examination to the date of incident fracture or three years. Potential risk factors included in the Cox multivariate survival analysis were anthropometric, fracture history and family history of osteoporosis, current medications use, comorbid conditions, caffeine and alcohol intake, leisure and occupational physical activity levels; tobacco use, bone density and quality of life measures. Relative risk and 95% confidence intervals (CI) were calculated. The mean (standard deviation) age of the participants was 66 (10) and 71 (10) years for those without and with incident non- vertebral fractures. Results indicated that important risk factors that modified relative risk include previous minimal trauma forearm fracture after the age of 50 years (3.626; 95% CI: 1.876, 7.008), and other minimal trauma fractures (1.957; 95% CI: 1.082, 3.540), SF-36 physical component summary score (0.965; 95% CI: 0.939, 0.991), femoral neck bone density (0.036; 95% CI: 0.001, 0.937) and inflammatory bowel disease (2.207; 95% CI: 1.091, 4.465). In conclusion, this three-year analysis of an ongoing prospective study shows that several important historical and medical factors are associated with incident non-vertebral fractures. These should be assessed in osteoporosis management.

[Programme]

 
P-265

THE IMPACT OF FRACTURE SEVERITY ON HEALTH RELATED QUALITY OF LIFE IN A POPULATION BASED SAMPLE: RESULTS FROM THE OPUS STUDY

M. Glueer1*, D. M. Reid2, D. Felsenberg3, T. Blemk3, R. Eastell4, C. Roux5, C. Glueer1

1University Clinic Kiel, Germany

2Aberdeen Royal Infirmary, UK

3Benjamin Franklin Hospital Berlin, Germany

4University of Sheffield, UK

5Hopital Cochin, Paris, France

It is known that fracture severity plays an important role for the context of pain and limitations in everyday life (ADL) (Ettinger 1992). Nevertheless, it remains unclear if fracture severity also has an impact on other aspects of disease specific or generic Health related Quality of Life (HRQoL).

In a population based study (OPUS) with centers in Germany, Britain and France 2375 women (mean age: 67, range 55 to 79) underwent a broadrange of diagnostic examinations. Specifically, reduction in vertebral height was determined by vertebral morphometry on spinal radiographs. Measurements were performed by an experienced radiologist (T.B.) and the maximum vertebral height reduction was calculated for each participant. For HRQoL we employed the SF12 with the subscores physical and mental function and two overall scores of Health and QoL, symptoms (OQLQ), fears (OPTQoL), and the QualEFFO with the subscales pain, ADL, social function, health perception, and mood. All analyses were age-adjusted and regression models were employed.

Of the 2375 women 379 had fractures with more than 20% height reduction. Maximum vertebral height reduction in women with fractures ranged from 0,20 to 0,92. With increasing fracture severity, the probability of deterioration of HRQoL increased independent of age for physical SF12 (p<0,001), global health perception (p<0,027), symptoms (OQLQ, p<0,006), pain (QualEFFO, p<0,022) , ADL (QualEFFO, 0,003), and health (QualEFFO, p<0,046). Moreover, age turned out to be a significant covariate for all subscales except for the SF12-mental score and for the pain and social QualEFFO domains (p<0,04 to 0,001). Further analyses showed that investigated HRQoL aspects were also impaired in women with fractures, as compared to those without.

Our data shows that HRQoL is impaired in women with vertebral fractures when compared to the general population, independent of their age. Greater vertebral deformity is associated with worse generic and disease specific quality of life, especially their physical aspects.

[Programme]

 
P-266

EFFECTS OF GROWTH AND OVARIECTOMY IN THE TIBIA OF INDIVIDUAL RATS: AN IN-VIVO MICRO-CT STUDY

J. H. Waarsing1*, A. Leemans2, J. Day1, A. G. H. Ederveen4, D. Van Dyck2, E. Buelens3, N. De Clerck2, A. Sasov3, H. Weinans1

1Dept. of Orthopaedics, Erasmus Medical Centre, Rotterdam, The Netherlands

2Visielab & Microtomography, RUCA, Antwerp, Belgium

3Skyscan B.V.B.A, Antwerp, Belgium

4Dept of Pharmacology, Organon, Oss, The Netherlands

The purpose of this study was to develop, test and evaluate in-vivo micro-CT for the follow up study of bone architecture in small animals like the rat.

An in-vivo micro-CT scanner (Skyscan 1076) was developed in which the tibia of a rat, that is lying on a bed under gas-narcosis, can be scanned in 20 minutes, receiving a low radiation dose of 0.4 Gy. For this study, two female Wistar rats were scanned: a sham operated and an ovariectomised rat. The animals were scanned at week 0, just before surgery, at week 4 and at week 14. Architectural changes over time were detected by overlaying two data sets, using an automatic algorithm that searches for optimal matching. The scans were segmented into binary data sets using a local threshold algorithm. Trabecular thickness was calculated using a model independent (3D) method.

The ovariectomised rat showed trabecular bone loss (70% at week 4 + 5% at week 14) in the metaphysis vs. no bone loss in the sham operated rat. After 14 weeks the epiphysial bone of the ovariectomised rat showed 25% bone loss, due to thinning of trabeculae. We could see growth at the growth plate of the ovariectomised rat (80 microns at week 4 + 80 microns at week 14). At the lateral cortex, periostial bone was resorbed and endostial bone was appositioned (about 200 microns), resulting in a slight change in shape of the bone. No growth could be seen in the sham operated rat.

Matching of two data sets allows detection of local changes in bone, like growth and disappearance of trabeculae and thickness changes of remaining trabeculae. These new developments of in-vivo micro-CT scanning make it possible to perform longitudinal small animal studies and will greatly contribute to experimental rat/mouse studies on pharmacological intervention and transgenic models.

p266.gif (10822 bytes)

[Programme]

 
P-267

THE RELATIONSHIP AMONG OSTEOPOROTIC FRACTURES AND HEALTH RELATED QUALITY OF LIFE (HRQL) AS MEASURED BY THE HEALTH UTILITIES INDEX MARK II AND MARK III SYSTEMS

G. Ioannidis1*, E. A. Papadimitropoulos2, C. Berger3, A. Papaioannou1, J. P. Brown4, L. Joseph3, D. A. Hanley5, W.P. Olszynski6, J.C. Prior7, L. Pickard1 T.M. Murray8, A. Tenenhouse3, T. Anastassiades9, W. Hopman9, S. Kirkland10, C. Joyce11, S. Poliquin3, N. Kreiger6, J.D. Adachi1 and the CaMos Research Group

1McMaster University, Hamilton, Ontario, Canada

2Eli Lilly and Company, Toronto, Ontario, Canada

3McGill University, Montreal, Quebec, Canada

4Laval University, Ste-Foy, Quebec, Canada

5University of Calgary, Calgary, Alberta, Canada

6University of Saskatchewan, Saskatoon, Saskatchewan, Canada

7University of British Columbia, Vancouver, British Columbia, Canada

8University of Toronto, Toronto, Ontario, Canada

9Queen's University, Kingston, Ontario, Canada

10Dalhousie University, Halifax, Nova Scotia, Canada

11Memorial University, St. John's, Newfoundland, Canada

A total of 3394 women and 1122 men 50 years of age and older participating in the baseline assessment for the Canadian Multicentre Osteoporosis Study (CaMos) were evaluated in this cross-sectional population-based study. Lifetime fracture occurrences were classified into seven categories including hip, pelvis, spine, lower body (defined as upper and lower leg, knee, ankle and foot), upper body (defined as arm, elbow, sternum, shoulder and clavicle), wrist and hand (defined as forearm, hand or finger), and ribs. Given that two thirds of vertebral fractures are not recognized by the individual, participants with subclinical vertebral deformities were also examined. Spinal radiographs were used to confirm the existence of vertebral deformities for all participants. The Health Utilities Index (HUI) Mark II and III systems were used to assess HRQL. The Mark II and III systems assess current HRQL across six and eight attributes respectively. Multivariate linear regression analyses were performed to determine the association between various osteoporotic fracture types and HRQL, adjusting for possible confounders. We calculated regression coefficient estimates and 95% confidence intervals (CI) for all parameters. The regression coefficients for the fracture (yes/no for each fracture type) terms represent adjusted differences in HRQL scores between participants with and without fractures. Results indicated that the multi-attribute scores for the Mark II system were negatively related to hip (-0.05; 95% CI: -0.09, -0.01), lower body (-0.02; 95% CI: -0.03, -0.000) and subclinical vertebral fractures (-0.02; 95% CI: -0.03,-0.00) for women. The multi-attribute scores for the Mark III system in women were also negatively related to hip (-0.09; 95% CI: - 0.14, -0.03) and rib fractures (-0.06; 95% CI: -0.11, -0.00), in men for rib fractures (- 0.06; 95% CI: -0.12, -0.00). Duration (years) since last fracture was not strongly associated with the HUI attributes. For the most part, the largest differences in HRQL were observed between the 0-1 year and 10+ years categories. In conclusion, this study demonstrates a negative association between past osteoporotic fractures and HRQL in both women and men. Moreover, this study shows that the association between minimal trauma fractures and quality of life depends on fracture type and gender.

[Programme]

 
P-268

BARIUM SULFATE VS. POLYMETHYLMETHACRYLATE: DIFFERENCES IN BONE MINERAL DENSITY?

M. O. Cachizumba, S. B. Gonēalves, F. C. Pérez Manghi, V. E. Montangero, F. R. Spivacow, F. Massari*, J. R. Zanchetta

Instituto de Investigaciones Metabólicas, Universidad del Salvador, Buenos Aires, Argentina

Percutaneous vertebroplasty is a procedure in which bone cement is injected into a vertebral body to treat painful osteoporotic compression fractures, due to the restoration of stiffness and strength that induces. The more common cement used is the polymethylmethacrylate (PMMA), and although in the last years, barium sulfate (BaSO4) is added to increase its visibility under fluoroscopy, which is a well known cause of fake increased bone mineral density (BMD) using dual energy x-ray absorptiometry (DEXA), there is still very common to find patients with vertebroplasty with PMMA alone.

Objective: To evaluate in vitro, the potential changes in bone density induced by PMMA alone or associated to BaSO4.

Material and Methods: We performed 10 density scans (Hologic Delphi A) on 7 glass tubes with several materials: air; water; PMMA; PMMA + BaSO4, ground vertebral trabecular bone (VTB), VTB + PMMA, and VTB + PMMA + BaSO4.

The best monomer-to-powder ratio recommended (0.53ml/g) was used to maintain the greatest material properties of PMMA. The 20% by weight BaSO4 was used to maintain proportions of the solution, and the relationship 60 % VTB/ 40 % cement was used in vitro as is used in the practical setting.

Results: As expected, higher density values in all tubes using BaSO4 were found. PMMA density was similar to air tube (given by glass), and VTB + PMMA present 23 % lower density than VTB alone (0.551 vs. 0.712 grs/cm2 p: < 0.0001). In this model, the addition of PMMA + BaSO4 to VTB, induced an increase of density of 2.8 times (2.004 vs. 0.712 grs/cm2 p:< 0.0001).

Conclusions: The lower bone density induced by the PMMA alone or the increase induced by PMMA + BaSO4, could generate misinterpretation of lumbar spine DEXA's studies in vivo, and this could by clinically significant.

[Programme]

 
P-269

THE EFFECT OF PERIODICAL STRAIN ADAPTATION ON THE STOCHASTIC REMODELLING OF CANCELLOUS BONE STRUCTURES: AN ANABOLIC SIMULATION STUDY

C. A. Dobson1*, G. Sisias2, R. Phillips3, C. M. Langton4, M. J. Fagan1

11School of Engineering, University of Hull, UK

2Department of Computer Science, University of Bradford, UK

3Department of Computer Science, University of Hull, UK

4Centre for Metabolic Bone Disease, Hull, UK

A stochastic simulation of cancellous bone remodelling has previously been described [1] and applied to simple 2D lattice structures to simulate the effect of anabolic therapies on depleted bone structures [2]. The density and stiffness values of the structures showed a hysteresis effect, with a significant amount of rebuilding beyond the original density required to regain the intact stiffness value. The simulation has now been extended to model actual bone sections constructed from micro-CT scan data, with the incorporation of strain adaptation to produce a realistic simulation of anabolic treatment for osteoporosis after a period of bone resorption.

The chosen bone structure was subjected to a complex loading, chosen to encourage the structure to equilibrate to a realistic structure when subjected to iterative strain remodelling. The resulting stable structure was used as the original on which subsequent remodelling was applied. This procedure (equilibration) was repeated at various stages of the simulation runs studied.

The original equilibrium structure was stochastically depleted by 5% or 10% of its density and then rebuilt in one of three ways. Either a) stochastically, b) equilibrated at initial depletion and then stochastically rebuilt, or c) equilibrated after original depletion and also after being rebuilt to original density. Density and x- and y-stiffness values of the structures were evaluated at each step.

The effect of the equilibration of the structure will be presented, examining the effect of amount of initial depletion, original alignment of the structure and x and y stiffness, and the potential relationships to the histomorphometry of the structures.

[Programme]

 
P-270

EFFECT OF RALOXIFENE ON BONE MINERAL DENSITY AND MARKERS OF BONE REMODELING FOLLOWING ALENDRONATE THERAPY

D. Michalska1*, J. Stepan1, M. Terova2, D. Masanauskaite3, I. Pavo3

1Faculty of Medicine, Charles University, Prague, Czech Republic

2Eli Lilly, Prague, Czech Republic

3Lilly Area Medical Center, Vienna, Austria

Background: Alendronate (ALN) and raloxifene (RLX) increases bone mineral density (BMD) and decreases fracture incidence over 4 years in postmenopausal women with osteoporosis.

Aim: To compare the effect of one-year treatment with RLX or placebo (PLB) following ALN therapy versus continuous treatment with ALN.

Methods: 99 women with postmenopausal osteoporosis (age, 65 ± 7 yr, femoral neck NHANES T-score, -2.8 ± 0.8) who were treated with ALN (10 mg/d) for 43 ± 7 months were randomized to double-blinded RLX 60mg/day (N=33), PLB (N=33) or continuing open label ALN (N=33) for another 12 months. All patients received calcium (500 mg/day) and vitamin D (800 IU/day). BMD was assessed by Hologic Delphi A. Serum aminoterminal propeptide of type I collagen (PINP) was measured by a radioimmunoassay (Orion Diagnostica). Serum type 1 collagen cross?linked C?telopeptide (CTX) was measured using the Elecsys (Roche).

Results: No baseline differences were observed between the groups in age, weight, height, BMD and duration of previous ALN treatment. BMD data are summarized in the Table. Bone markers remained unchanged on ALN. CTX increased by 7.0 ± 7.8% in the PLB group, and by 5.1 ± 10.8% in the RLX group. PINP increased by 19.7 ± 10.8 % in the PLB group, and by 22.1 ± 16.9 % in the RLX group.

Conclusion: RLX is superior to PLB in increasing BMD in the total body after long-term ALN treatment. Continuing ALN or switching to RLX results in similar BMD changes. Bone remodeling markers in the PLB and RLX group increased only moderately and remained suppressed as compared with those prior the original ALN treatment.

 

Delta

% Spine

% Femur

% Neck

% Total body

ALN

-0.5 ± 3.9

1.6 ± 2.7

2.0 ± 4.2

2.1 ± 1.5

PLB

-2.7 ± 2.7 a

0.3 ± 2.1

1.1 ± 3.4

0.7 ± 1.6 b

RLX

-0.7 ± 3.2

1.4 ± 2.8

2.3 ± 3.0

2.0 ± 2.0

P < 0.05 a PLB vs. ALN, b PLB vs. ALN and RLX, ANOVA, mean ± SD

 

[Programme]

 
P-271

BALANCE DISORDERS ARE GREATER IN INDIVIDUALS WITH OSTEOPOROSIS AND KYPHOSIS

M. Sinaki1*, R. Brey2, C. Hughes3, K. Kaufman3

1Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN USA

2Vestibular and Balance Laboratory, Mayo Clinic, Rochester, MN USA

3Motion Analysis Laboratory, Mayo Clinic, Rochester, MN USA

Imbalance and posture sway are two important risk factors for falls. This study was designed to investigate the influence of kyphosis on postural sway, gait unsteadiness and falls in elderly individuals.

Methods: Osteoporotic individuals with thoracic hyperkyphosis (Cobb angle 50 to 65 degrees) were enrolled in the study along with healthy, age-matched controls. The age of the study subjects ranged from 66 to 83, average age 75.8; and controls ranged from 62 to 83, average age 71.1. Thoracic kyphosis was assessed from spinal radiographs. Prior to each test session all subjects were given the Dizziness Handicapped Inventory (DHI) that assesses the individual's perception of their balance impairment. Balance was also objectively assessed using Computerized Dynamic Posturography (Neurocom, Clackamas, Oregon). This test consists of two components, the Sensory Organization Test (SOT), and the Motor Control Test (MCT). The SOT consists of 6 conditions. A composite score is calculated made up of the mean of trials 1 and 2, and all scores for conditions 3-6 or for a total of 14 scores.

Results: The total DHI was significantly different between groups (osteoporotic mean 14.1; controls mean 0.18; p = 0.003). The osteoporotic individuals with hyperkyphosis also had statistically significantly greater balance abnormalities compared to the controls. The composite posturography score was significantly different between the groups (osteoporotic, mean 60.4; control, mean 73.8; p = 0.0006).

Conclusion: Osteoporotic/kyphotic individuals perceive themselves to have a greater balance handicap than controls. This was confirmed by objective balance assessment which demonstrated that osteoporotic/kyphotic individuals have significantly poorer balance than healthy controls.

[Programme]

 
P-272

3D STEREOLITHOGRAPHY MODELS OF CANCELLOUS BONE STRUCTURES FROM MICRO-CT DATA: PRODUCTION, TESTING AND VALIDATION OF FINITE ELEMENT RESULTS

C. A. Dobson1*, G. Sisias2, R. Phillips3, C. M. Langton4, M. J. Fagan1

1School of Engineering, University of Hull, UK

2Department of Computer Science, University of Bradford, UK

3Department of Computer Science, University of Hull, UK

4Centre for Metabolic Bone Disease, Hull, UK

A stochastic simulation of cancellous bone resorption that is integrated with a finite element package has been previously described [1], and the mesh density, model size and remodelling parameters validated [2]. The simulation was initially applied to two- dimensional idealised cancellous bone structures in a simulation of osteoporosis, and the finite element results were validated by the mechanical testing of stereolithography (STL) models of the depleted structures. This stereolithography validation method has proved to be promising and been extended into three- dimensions. This current paper will describe the extension of the method to realistic bone structures in three-dimensions, using micro-CT scan data from histological samples of human cancellous bone, and the subsequent testing of the stereolithography models.

Three-dimensional micro-CT datasets were obtained for human cancellous bone from the iliac crest, femoral head, calcaneus, and two lumbar spine locations. The highly complex structure of the cancellous bone samples caused the triangulation of the surface (necessary for compatibility with the manufacturing equipment) to result in file sizes in excess of the workable limits of the stereolithography machine. Sophisticated tessellation algorithms were developed to enable the datasets to be in a suitable form for stereolithography production whilst also minimising memory requirements [3]. Five models of each of the samples were produced and are in the process of being tested in compression to compare the stiffness with finite element results for the structures. Preliminary test results have been gathered and show the tests to be repeatable. The ratios of the directional properties of the models will be compared with those predicted by the finite element results.

The potential use of stereolithography as a validation tool is being investigated, with increasingly complex models being produced. It is believed that the finite element results and stereolithography models of the bone will allow us to fully explore the relationship between the stiffness and strength of the bone and its physical and geometric properties.

[Programme]

 
P-273

BONE HISTOMORPHOMETRIC EVALUATION OF DAILY AND INTERMITTENT ORAL IBANDRONATE IN POSTMENOPAUSAL OSTEOPOROSIS

P. J. Meunier1*, R. R. Recker2, R. S. Weinstein3, C. H. Chesnut Iii4, B. Bonvoisin5, P. Mahoney5

1Hōpital Edouard Herriot, Lyon Cedex, France

2Creighton University, Omaha, Nebraska, USA

3University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

4Deaconess Research Institute, Billings, Montana, USA

5F. Hoffmann-La Roche Ltd, Basel, Switzerland / Welwyn, UK

Recent results from a multinational, double-blind fracture-prevention study conducted in women with postmenopausal osteoporosis demonstrated that daily and intermittent regimens of oral ibandronate, a potent nitrogen-containing bisphosphonate, significantly reduce vertebral fractures by 62% and 50%, respectively, after 3 years (BONE: iBandronate Osteoporosis Trial in North America and Europe; Delmas et al. 2002). The objective of this analysis was to evaluate the effects of daily and intermittent ibandronate regimens on the quality of newly formed bone and on the bone remodelling process. In the phase III fracture-prevention study, patients were randomised to one of three groups: placebo; oral daily ibandronate (2.5mg/day); intermittent oral ibandronate (20mg every other day for 12 doses every 3 months). A total of 110 patients from this study were randomly assigned to undergo one transiliac crest bone biopsy at either month 22 or 34 of treatment. Two doses of tetracycline were administered prior to biopsy. According to qualitative histological assessment, newly formed bone was of normal quality following treatment with ibandronate. In addition, no evidence of osteomalacia, marrow fibrosis or cellular toxicity was observed. Quantitative histomorphometric analysis demonstrated no impairment in mineralisation of bone matrix. Osteoid thickness (primary safety parameter) and volume were reduced with active treatment compared with placebo (see Table). Furthermore, mineralising surfaces and activation frequency were only moderately decreased by ibandronate versus placebo, and hence excessive inhibition of bone turnover was not observed. In summary, this histomorphometric analysis confirms that normal-quality newly formed bone is produced after long-term treatment with oral ibandronate, even when administered with an extended between- dose interval. These results support the excellent safety profile of ibandronate.

Reference: Delmas PD, et al. Osteoporos Int 2002;13:S15

 

 

 

22 months

34 months

Treatment

Placebo

2.5mg daily

20mg intermittent

Placebo

2.5mg

daily

20mg

intermittent

Osteoid thickness (µm)

4.9

3.9**

4.6

4.8

4.3*

5.0

Osteoid volume (%)

0.9

0.2**

0.4

0.6

0.4*

0.7

Mineralisin g surface (%)

3.6

0.7*

2.2

3.1

2.0

2.1*

Activation frequency (per year)

0.2

0.1*

0.1

0.2

0.1

0.1

Osteoclast number (per mm2)

0.1

0.1

0.1

0.1

0.1

0.0

Bone formation rate (µm3/µm2/d)

0.02

0.01*

0.01

0.02

0.01

0.01

Trabecular thickness (µm)

131

110*

117

116

124

126

Trabecular number (µm)

1.1

1.3

1.3

1.1

1.2

1.3

Trabecular separation (µm)

872

742

792

895

805

732

* p<0.05 (derived from non-parametric Wilcoxon test: active group vs placebo). Note that as paired biopsies were not carried out, it is impossible to compare the findings at 22 and 34 months.

 

[Programme]

 
P-274

FEASIBILITY OF A STANDARDIZATION OF CALCANEUS QUS VARIABLES - RESULTS FROM THE OPUS STUDY

R. Barkmann1*, R. Eastell2, D. M. Reid3, C. Roux4, D. Felsenberg5, C. Glueer1

1University Clinic Kiel, Germany

2University of Sheffield, UK

3University of Aberdeen, UK

4Rene Descartes University, Paris, France

5Benjamin Franklin Hospital Berlin, Germany

Several Quantitative Ultrasound (QUS) devices are used for the assessment of osteoporosis. However, results cannot be compared directly between different machines. On the other hand standardization of DXA has proved very useful. We tested whether calcaneus QUS variables can be standardized across devices from different manufacturers.

In the Osteoporosis and Ultrasound (OPUS) study, 2837 women age 20-80 were recruited from random population samples at 5 centers in Aberdeen, Berlin, Kiel, Paris, and Sheffield. A subgroup of 1765 women had complete results on 4 QUS heel devices (Lunar Achilles+, Osteometer DTU-one, Quidel/Metra QUS-2, and DMS UBIS 5000). We tested if SOS resp. BUA on these devices could be standardized against each other.

Regression formulas were calculated for BUA and SOS separately for all combinations of devices and used for the standardization of the variables of the single devices against each other. We tested the validity of this approach by comparing the standardized residuals, after adjustment for the population standard deviation for the measurements in a young population.

All correlations were significant at p<0.001. Correlation coefficients ranged from R=0.69 to 0.80 for BUA and from R=0.84 to 0.89 for SOS. Relative residual errors of the standardized variables ranged from 0.65 SD to 0.76 SD for BUA and from 0.49 SD to 0.57 SD for BUA.

These data are higher than residual errors of the standardization of DXA BMD of spine and hip (0.3 SD to 0.4 SD, literature data). However, the performance for SOS approaches that of central DXA.

[Programme]

 
P-275

SUSTAINED EFFECT OF RISEDRONATE: A 7-YEAR STUDY IN POSTMENOPAUSAL WOMEN

O. Sorensen1*, S. Goemare2, D. Wenderoth3, A. Chines3, C. Roux4

1Osteoporosis Research Clinic, Hvidore, Denmark

2Ghent University Hospital, Unit for Osteoporosis & Metabolic Bone Disease, Belgium

3Procter & Gamble Pharmaceuticals, Mason, Ohio, USA

4Hopital Cochin, Paris, France

In a multinational, double blind, placebo controlled study in women with established osteoporosis risedronate (RIS) significantly decreased the incidence of vertebral fractures over 3 years.

In a 2 year extension of this study, RIS demonstrated a sustained antifracture effect. At the end of the 5 years, 164 women participated in a further 2 year extension in which all patients were given RIS 5 mg daily. We now report the results for these women who either continued another 2 years on RIS (7 yr RIS, n=83) or just initiated RIS (5 year PLBO/2 year RIS, n= 81). Throughout the 7 years of the study, all patients received 1000 mg/d calcium and if baseline levels were low, up to 500 IU/day of vitamin D.

Over 7 years, lumbar spine (LS) BMD increased from baseline by 11.5% in the 7 yr RIS group and 6.1% in the 5 yr PLBO/2 year RIS group. At the total hip, BMD increased by 3.9% and -1.0% in the respective groups. During years 6-7, increases in LS and total hip BMD were observed in both groups, with greater increases in the 5 yr PLBO/2 year RIS group, as expected. The annualized incidence of new vertebral fractures for this cohort is reported below. The cumulative incidence of osteoporosis- related nonvertebral fractures over 7 years was 25.9% and 15.7% in the 5 yr PLBO/2 yr RIS and 7 yr RIS groups, respectively. Overall adverse event profile was similar between the two groups, including the incidence of upper gastrointestinal adverse events.

Treatment with risedronate over 7 years demonstrated continued BMD increases. The results of this extension study strongly suggest sustained effects of risedronate on vertebral fractures.

 

 

 

Anualized incidence of new vertebral fractures

 

5 yr PLBO/2yr RIS

7 yr RIS

Year 0-3

7.6

4.7

Year 4-5

12.3

5.2

Year 6-7

3.8

3.8

[Programme]

 
P-276

ACUTE EFFECTS OF ORAL STABLE STRONTIUM LOAD ON BONE AND MINERAL METABOLISM IN HYPERCALCIURIC SUBJECTS

A. Rubinacci1*, M. Sirtori1, I. Villa1, R. Daverio2, A. Soldarini2, C. Bianchin3, G. Vezzoli3

1Bone Metabolic Unit, Scientific Institute H San Raffaele, Milano, Italy

2Dept of Clinical Chemistry, Scientific Institute H San Raffaele, Milano, Italy

3Division of Nephrology, Dialysis and Hypertension, Scientific Institute H San Raffaele, Milano, Italy

Recent observations raised the possibility that strontium as well as other divalent and trivalent cations (aluminum, gadolinium, etc.) might be involved in a complex cation sensing system interacting with bone remodeling and its hormonal regulators via calcium sensing receptors. We have therefore analyzed the short term (4 hours) effect on bone and mineral metabolism of an oral strontium load (30.2micromol/kg body weight of SrCl2in water solution to a final concentratio of 11.4 micromol/L) in hypercalciuric (under normocalcic (1g) and sodium (100mmol) restricted diet > 0.11mg/dL glomerular filtrate) subjects (n=22, 9 females and 13 males).

The results indicate that oral stable Sr load induced a significant (P<0.01) change in the level of plasma Sr. The higher mean plasma Sr concentration during the test was achieved at T180, i.e.180 minutes after the load (0.058mmol/L). AUC increased significantly (P<0.001) between T60 and T180 . After oral stable Sr load, PTH concentration in plasma decreased significantly (P<0.001) between T0 and T60, whereas no changes were observed in the control group. No significant changes in serum calcium, BGP and CT were observed. The urinary excretion of mean total Dpd did not change significantly and its variation throughout the experimental time did not differ from the control group. Serum beta-CTx decreased significantly (P<0.001) over time in Sr taking subjects whereas it did not change significantly in the control group not taking Sr.

This study suggest that strontium interacts with mineral metabolism by inhibiting PTH secretion. The possibility that this transient decrease mediates the Sr effect on bone is unlikely as PTH returned to basal level at three hours after Sr load, when strontium concentration was maximal and osteoclast activity inhibition was significant.

[Programme]

 
P-277

RISEDRONATE SIGNIFICANTLY REDUCES THE RISK OF VERTEBRAL FRACTURES IN ELDERLY POSTMENOPAUSAL WOMEN WITHIN 1 YEAR

S. Boonen1*, R. Eastell2, I. Barton3, M. R. Mcclung4, C. H. Chesnut5

1Center for Metabolic Bone Disease, Universitaire Ziekenhuizen, Leuven, Belgium

2Human Metabolism and Clinical Biochemistry, University of Sheffield, Sheffield, UK

3Procter & Gamble Pharmaceuticals, Geneva, Switzerland

4Oregon Osteoporosis Center, Portland, Oregon, USA

5Osteoporosis Research Group, University of Washington, Seattle, Washington, USA

Data are currently limited in determining the efficacy of anti-resorptive agents in elderly patients.The effects of risedronate (RIS) have been evaluated for the prevention and treatment of postmenopausal osteoporosis in women with ages spanning several decades. The objective of this analysis was to determine the efficacy of risedronate in reducing vertebral fracture risk in osteoporotic women aged > 75 years.

The analysis included elderly osteoporotic women (aged > 75 years) in the placebo (n=1507) and RIS 5 mg/day (n=1531) groups from the 3-year Hip Intervention Program (HIP) and Vertebral Fracture Efficacy with Risedronate (VERT-MN and VERT-NA) studies. Patients included those with a femoral neck BMD T-score <- 2.5SD and/or at least one prevalent vertebral fracture. All patients received 1000 mg/d calcium and up to 500 IU/d vitamin D, if baseline levels were low. Vertebral radiographs were taken at baseline and at yearly intervals to determine prevalent and incident vertebral fractures.

At baseline the mean femoral neck T-scores were -3.0SD and -2.9SD in the placebo and RIS 5 mg groups, respectively. Three quarters of the patients had at least one prevalent vertebral fracture. Compared with placebo, RIS significantly reduced the risk of new vertebral fractures by 65% at one year (95%CI: 46-77%, p<0.001). This early onset was consistent within each of the three studies. RIS significantly reduced the risk of both new vertebral and osteoporosis-related non-vertebral fractures over 3 years. RIS was well tolerated with a safety profile comparable to the placebo group.

In elderly postmenopausal women with osteoporosis, increased rates of bone resorption continue to be associated with bone loss. In these patients, risedronate provides rapid vertebral fracture risk reduction and long-term efficacy over 3 years for vertebral and non-vertebral fractures.

[Programme]

 
P-278

RISEDRONATE TREATMENT OF ESTABLISHED PRIMARY AND SECONDARY OSTEOPOROSIS IN MEN: 1-YEAR RESULTS FROM 218 PATIENTS

J. D. Ringe*, A. Dorst, H. Faber, K. Ibach

Medizinische Klinik IV, Klinikum Leverkusen, Leverkusen, Germany

Risedronate sodium has been shown to significantly increase bone mineral density (BMD) and to significantly reduce the risk of morphometric vertebral fractures in one year in postmenopausal osteoporosis. In the current three-year study, we examine the effects of risedronate treatment in men with primary and secondary osteoporosis.

In the single center, open label, randomized prospective clinical study we enrolled 218 male patients with T-score of lower than -2.0 SD at lumbar spine (LS) or femoral neck (FN) or lower than -1.0 SD at either site in the presence of an osteoporotic fracture. The patients were allocated in pair-wise fashion into two treatment groups. Patients in Group A (n=109) received risedronate 5 mg plus calcium 1000 mg and 800 IU Vit. D daily. In this group 56 patients had prevalent vertebral fractures (vert.fx) and 53 did not. There were a total of 109 patients in Group B. Those with a prevalent vert- fx (Subgroup B1 n=54) were treated with alfacalcidol 1 mg plus calcium 500 mg daily, whereas patients without prevalent vert.-fx (Subgroup B2, n=55) were treated with calcium 1000 mg plus 800 IU plain vitamin D daily. In group A 40 of 109 patients (37%) and in group B 43 of 109 patients (39%) had secondary osteoporosis. BMD measurements were performed at baseline and every 12 months thereafter.

After the first year of treatment men receiving risedronate showed a mean LS BMD increase of 4.5% compared with a mean increase of 0.7% in Group B patients (p<.0001). The mean change of total hip BMD was +2.5% and 0.2% for Groups A and B, respectively (p<.0001). Corresponding changes at the FN were 1.6% and 0.01% for the respective groups (p=0.001). Both therapies were well tolerated.

We conclude that 1 year of risedronate therapy produces favorable effects on BMD in men consistent with the results in women from phase 3 studies in postmenopausal osteoporosis. The average increase rates of BMD at the 3 measured sites were significantly higher than with alfacalcidol or vitamin D suggesting that risedronate is superior in the treatment of men with primary or secondary osteoporosis.

[Programme]

 
P-279

COST EFFECTIVENESS OF RALOXIFENE: AN ECONOMIC EVALUATION IN A UK SETTING

F. Borgström3, O. Johnell2, B. Jönsson1, D. Sykes5*, A. Oden4, J. Kanis1

1Centre for Health Economics, Stockholm School of Economics, Box 6501, S-113 81 Stockholm, Sweden

2Department of Orthopaedics, Malmö General Hospital, S-214 01 Malmö, Sweden

3WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK

4Independent Consulting Statistician, Göteborg, Sweden

5Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK

The aim of this study was to examine the cost-effectiveness of treatment with raloxifene in women at an increased risk of vertebral fractures compared to no intervention. Risk functions for vertebral fracture and breast cancer were based on epidemiological data from the UK, as were the data on costs following different types of events. The simulations used an annual intervention cost of GBP 369 (cost of raloxifene plus monitoring), given for 5 years. A risk reduction of 50% for vertebral fracture and 72% for breast cancer was assumed in the base case, in line with available outcome data. A utility loss of 0.26 for the first year and 0.05 for second and following years were assumed for spine fracture in line with new data.

Results are presented as cost per quality-adjusted life year gained from the intervention for from a health care perspective with direct costs only. Sensitivity analysis included variations in age, effectiveness, discount rates and baseline risk of vertebral fracture.

Cost-effectiveness of intervention in postmenopausal women with a relative risk (RR) for vertebral fracture of 2.0 was 19 900, 18 300 and 15 400 GBP/QALY at 60, 70 and 80 years of age respectively. The benefits of intervention increase with age for vertebral fracture and decreases for breast cancer, which explains the rather constant cost-effectiveness ratio. The cost-effectiveness ratio decreased with higher relative risk of fracture.

We conclude that raloxifene can be targeted cost-effectively to postmenopausal women at increased risk of vertebral fracture.

[Programme]

 
P-280

MODELLING THE EFFECTS OF PLACEBO AND CALCIUM/VITAMIN D SUPPLEMENTATION ON THE TIME COURSE OF BIOMARKERS OF BONE TURNOVER IN OSTEOPOROTIC POSTMENOPAUSAL WOMEN

R. Gieschke1*, N. Hayashi1, P. Vis2, P. Jacqmin2

1Pharma Development, F. Hoffmann-La Roche, Basel, Switzerland

2Exprimo Consulting LLP, Berenlaan 4, B-2340 Beerse, Belgium

Oral and intravenous (iv) formulations of ibandronate (IBN), a potent nitrogen- containing bisphosphonate, are currently under development for both the treatment and prevention of postmenopausal osteoporosis (OP) [1]. Bisphosphonates exert their action through inhibition of osteoclast-mediated bone resorption. IBN has demonstrated higher in-vivo potency compared with other currently licensed bisphosphonates in osteoporosis.

The objectives of the current investigations were: (a) to develop a mathematical model to describe the time course of both degradation markers of bone turnover (such as CTX, a collagen breakdown product indicative of changes in osteoclast activity) and formation markers of bone turnover (such as osteocalcin, indicative of changes in osteoblast activity) following treatment with placebo, calcium/vitamin D and IBN in osteoporotic postmenopausal females and (b) to explore the effects of covariates (age, weight, time since menopause, baseline values for markers of bone turnover and bone mineral density) on model parameters.

The effects of placebo (i.e. disease progression), calcium/vitamin D and IBN on the time course of biomarkers of bone turnover were described by direct and indirect response models by considering drug effects elicited through a dose rate rather than drug concentrations (K-PD model approach [2]). These models were applied to three studies comprising more than 700 patients who had received iv or oral treatment regimens. Validation of this model on other studies supported its credibility.

Modelling the effects of placebo and calcium/vitamin D is a prerequisite for modelling the overall effects on markers of bone turnover in response to bisphosphonates such as IBN. Such models will enable simulation of clinical trials to identify dosing regimens (iv and oral) that have the greatest probability of sustained long-term clinical efficacy.

References:

[1] Delmas PD, et al. Oral ibandronate significantly reduces fracture risk in postmenopausal osteoporosis when administered daily or with a unique drug-free interval: results from a pivotal phase III study. Osteoporos Int 2002;13 (Suppl. 1):S15 (Abstract O37).

[2] Jacqmin P, et al. Modeling drug induced changes in biomarkers without using drug concentrations: Introducing the K-PD Model. PAGE 2001 10th Meeting, 7-8 June 2001, Basel, Switzerland.

[Programme]

 
P-281

ONCE WEEKLY ALENDRONATE PRODUCES A GREATER INCREASE IN BONE MINERAL DENSITY THAN DAILY RISEDRONATE

D. Hosking1*, S. Adami2, D. Felsenberg3, J-Y. Reginster4, J. Cannata5, M. Valimaki6, A. Santora7, C. Yacik7, L. Zaru7

1Nottingham City Hospital, Nottingham, UK

2Ospedale Valeggio, Verona, Italy

3University Hospital, Berlin, Germany

4Chu de Liege, Liege, Belgium

5Hospital Central de Asturias, Asturias, Spain

6Helsinki University Central Hospital, Helsinki, Finland

7Merck Research Labs, Rahway, NJ

We report the 12-month Bone Mineral Density results of the first head-to-head trial designed to compare the efficacy of alendronate and risedronate for the treatment of osteoporosis. The 3-month, randomized, double-blind, multicenter international study with double-blind extensions for an additional 9 months (12 months in total), enrolled 549 postmenopausal women. Patients were 60-90 years old (mean, 69), with osteoporosis defined by low BMD T-score (either lumbar spine or total hip/femoral neck less than or equal to -2.5, or less than or equal to -2.0 at both sites). Patients maintained a calcium intake of at least 1000 mg daily through food and/or calcium supplements. Patients were randomized into three treatment groups: alendronate 70mg* once weekly using standard am dosing; risedronate 5mg daily dosed 2 hours after a meal and at least 2 hr before the next; or matching placebo for each. Results are based on a modified intention-to-treat approach of lumbar spine and hip BMD at month 12.

In this study, alendronate 70 mg once weekly produced significantly greater BMD increases over 12 months than did risedronate 5 mg daily, at the spine and all hip sites. These differences may be due to the superior anti-resorptive efficacy of alendronate 70 mg once weekly, reduced bioavailability of risedronate resulting from post-meal dosing, or both.

*Manufactured by Merck & Co., Inc., Whitehouse Station, NJ

 

[Programme]

 
P-282

PROSPECTIVE EVALUATION OF HIP-FRACTURE RISK IN INSTITUTIONALIZED ELDERLY USING RADIAL-, PHALANGEAL- AND CALCANEAL BONE ULTRASOUND MEASUREMENTS

H. Dobnig*, A. Fahrleitner, C. J. Piswanger-Sölkner, M. Roth, B. Obermayer-Pietsch, G. Leb

Div of Endocrinology, Karl Franzens University Graz, Austria

Fractures constitute a major clinical problem in institutionalized elderly. Here, annual incidence rates for hip fractures usually range between 3% to 5%. We sought to investigate whether bone ultrasound measurements would help to characterize patients at very high risk for hip fractures.

A total of 1859 institutionalized female patients above 70 years of age who lived in 95 homes for elderly in the southern and eastern part of Austria were followed for an average of 2 years. We excluded patients with hypercalcemia, malignancies, hepatic and renal dysfunction (s.creatinine >1.8 mg/dL). Baseline measurements for speed of sound (SOS) were performed at the distal radius (RAD), at the proximal phalanx (PLX) of the third finger (Sunlight Omnisense device), or at the calcaneal (CALC) site (including 'BUA' and 'stiffness'; Achilles Plus, Lunar).

A total of 118 hip fractures have occurred in these 2 years. Over the 8th, 9th and 10th decade there was a significant decrease in mean SOS values of 0.84 SD (RAD), 0.60 SD (PLX) and 0.65 SD (CALC). RAD- and PLX-SOS values correlated more closely with each other (r=0.45, p<0.001) than with CALC SOS-measurements (0.25 and 0.18, p<0.0001). Using Cox-regression analyses and adjusting the data for age and BMI we found an increase in the RR of hip fracture for each SD decrease in SOS of 1.12 (0.92-1.4) for the RAD,1.09 (0.89-1.3) for the PLX, 1.42 (1.02-2.0) for BUA CALC, 1.37 (0.97-1.9) for the SOS CALC and 1.30 (1.05-1.6) for the CALC 'stiffness' measurements. ROC-analyses was significant for CALC BUA and 'stiffness' parameters with resulting AUC of 0.59 (0.51-0.67) and 0.59 (0.52-0.66).

We conclude that mean bone ultrasound parameters are grossly decreased at all measurement sites in institutionalized female patients and further significant decreases occur over the 7th to 9th decade. The largest differences between hip fracture- and non-hip fracture cases was found for calcaneal 'stiffness' measurements (-0.39 SD, p=0.009). Together with the results of the ROC analyses our data seem, however, not to justify the introduction of bone ultrasound measurements as a screening tool for selection of institutionalized patients at very high risk of hip fractures.

[Programme]

 
P-283

VERTEBRAL X-RAYS IN THE RECORDING AND PREDICTION OF FRACTURE; WHEN SHOULD THEY BE ORDERED?

S. Kaptoge1*, M. Lunt2, D. Felsenberg3, T. W. O'Neill2, J. Reeve1, E. P. O. S. Epos Study Group1

1Department of Medicine & Institute of Public Health, University of Cambridge, Cambridge, UK

2ARC Epidemiology Unit, University of Manchester, Manchester, UK

3Department of Radiology, Frei University B Franklin, Berlin, Germany

Previous vertebral fracture increases risk of future vertebral and hip fractures by 2.6-8 fold independently of BMD. British data suggest that only 5-10% of subjects with a spine fracture are identified in primary care which impedes rational treatment. Our objective was to develop algorithms for predicting a spine fracture in men and women over 50 years of age if an X-ray is performed.

Data was analysed from 5,578 out of nearly 7,000 men and women over 50 in the European Prospective Osteoporosis Study (EPOS). Prevalent deformities were defined using the McCloskey-Kanis method. We modeled the risk of prevalent fracture as a function of age, statural height loss since age 25, gender and fracture history including limb fractures in the last 3 years using negative binomial regression modelling. Receiver operating characteristic curves (ROC) were used to compare predictive ability of models.

Risk of prevalent vertebral fracture significantly increased with age [RR 1.04, 95% CI (1.03, 1.05) per year], height loss [1.07, (1.05, 1.09) per cm decrease], history of vertebral fracture [7.08, (5.64, 8.88)], forearm fracture [1.54, (1.25, 1.89)], rib fracture [1.54, (1.16, 2.04)] and with incident lower limb fracture [2.04, (1.33, 3.14)]. Male gender was associated with increased risk of prevalent fracture [1.82, (1.53, 2.17)] and increasing body weight was associated with lower risk [0.98 (0.98, 0.99) per 1kg increase]. The ROC curve generated by the optimal model showed that at a sensitivity of 50% for identifying cases of at least one vertebral deformity (or 58% for at least 2), specificity was increased from 50 to 75% compared to a random allocation of X-rays. At a sensitivity of 75% the specificity was also improved by the same amount. In women, history of hip fracture [RR 4.61, CI (2.43, 8.74)] substituted for history of rib fracture and longer fertile period (age at menopause minus age at menarche) was associated with lower risk of vertebral fracture [RR 0.97, CI (0,94, 0.99) per year].

Decisions on whom to treat often depend on whether there is a pre-existing spine fracture. Whom should have a spine X-ray to identify spine fractures in primary care can be usefully guided by algorithms based on clinical history, height and weight.

[Programme]

 
P-284

MODELLING THE EFFECTS OF IBANDRONATE TREATMENT ON THE TIME COURSE OF BONE MINERAL DENSITY IN OSTEOPOROTIC POSTMENOPAUSAL WOMEN

R. Gieschke1*, N. Hayashi1, P. Vis2, P. Jacqmin2

1Pharma Development, F. Hoffmann-La Roche, Basel, Switzerland

2Exprimo Consulting LLP, Berenlaan 4, B-2340 Beerse, Belgium

Ibandronate (IBN), a potent nitrogen-containing bisphosphonate, is under investigation as oral and intravenous (iv) formulations for the treatment and prevention of postmenopausal osteoporosis (OP) [1]. Drug action is exerted by inhibition of osteoclast-mediated bone resorption, with higher potency compared with other currently licensed bisphosphonates in osteoporosis.

The objectives of the current investigations were to develop a pharmacologically realistic mathematical model for IBN using selected Phase I, II and III data in order to describe the relationship between iv and/or oral dose, the resulting plasma concentration exposure, the effect on markers of bone turnover and, finally, the effect on bone mineral density (BMD).

A three-compartment model adequately described the PK data and yielded estimates for bioavailability of IBN. Estimates for IBN bioavailability were low and confirmed previous results obtained from non-compartmental analyses. The IBN effects on the biomarker urinary CTX, a collagen breakdown product indicative of changes in osteoclast activity, were described by an indirect response model added to the PK model. Considerable reduction in the complexity of the model could be achieved by abstracting the PK and considering drug effects elicited through a dose rate rather than drug concentrations (K-PD model approach [2]). Changes in BMD were coupled to changes in urinary CTX alone using an effect compartment approach.

This modelling scenario was applied to three studies comprising more than 700 patients who had received iv or oral treatment regimens. Using the K-PD model, effects of placebo (i.e. disease progression), vitamin D/calcium supplementation and IBN could be estimated with an intersubject variability of about 30%CV. The equilibration half-life between urinary CTX and BMD was estimated to be 0.6 years. Validation of this model on other studies supported its credibility.

Simulation based on this model will be used in the future to identify dosing regimens (iv and oral) that have the greatest probability of sustained long-term clinical efficacy.

References:

[1] Delmas PD, et al. Oral ibandronate significantly reduces fracture risk in postmenopausal osteoporosis when administered daily or with a unique drug-free interval: results from a pivotal phase III study. Osteoporos Int 2002;13 (Suppl. 1):S15 (Abstract O37).

[2] Jacqmin P, et al. Modeling drug induced changes in biomarkers without using drug concentrations: Introducing the K-PD Model. PAGE 2001 10th Meeting, 7-8 June 2001, Basel, Switzerland.

[Programme]

 
P-285

EFFECT ON BONE REMODELLING PARAMETERS OF VARIOUS DOSES OF PAMIDRONATE WITH CONSTANT YEARLY DOSE IN WOMEN WITH OSTEOPOROSIS : A PILOT STUDY

O. Lamy*, C. Mischler, L. Sandini, M. A. Krieg, P. Burckhardt

Service de médecine A, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne - CHUV, Switzerland

Aims : Bisphosphonates are potent drugs for osteoporosis, but tolerance and compliance to oral treatment is often poor. Pamidronate (APD) administered iv every three months is well tolerated. However the best regimen is not known yet. We tested the effect on bone markers of various doses of pamidronate with constant yearly dose in post-menopausal women with osteoporosis.

Methods : 13 osteoporotic post-menopausal women (age 66±11, BMI 23.8±3.6) were randomised to receive 120 mg/year iv APD in 4x30 mg (n=4), 3x40 mg (n=4) or 2x60 mg (n=5) for two years. All got calcium and vitamin D. Corrected calcemia, osteocalcine (OC), urinary C-telopeptides (UCTX) were measured at months 0,1,2,3,4,5,6,8 and 12; PTH and vitamin D at months 0 and 12.

Results : UCTX decreased by 78, 69, 71, 90, 74, 74 and 74 % (group 30 mg), by 92, 85, 71, 61, 87, 74 and 71 % (group 40 mg), and by 79, 49, 48, 40, 38, 27 and 2 % (group 60 mg) at months 0, 1, 2, 3, 4, 5, 6 and 12. OC decreased by 10, 30, 43, 41, 39, 40 and 56 % (group 30), by 16, 27, 38, 36, 42, 42 and 50 % (group 40), and by 13, 29, 32, 34, 30, 18 and 37 % (group 60) at months 0, 1, 2, 3, 4, 5, 6 and 12. Corrected calcemia, PTH and vitamin D did not change during the study.

Conclusions : UCTX decreased by near 70 % and osteocalcin by near 40 to 50 % before the next injection, only when APD was given every 3 to 4 months. When APD was given every 6 months, the decrease of bone remodelling parameters after 5 to 6 months was particularly low. These results suggest that three to four months, but not six, is an appropriate interval between two intravenous doses of pamidronate.

[Programme]

 
P-286

DEFINING A BIOLOGICAL RESPONSE TO RALOXIFENE THERAPY USING ADHERENCE TO GREATER THEN 95% OF THERAPY

J. A. Clowes*, N. F. A. Peel, R. Eastell

Bone Metabolism Group, University of Sheffield, UK

Monitoring response to therapy using a surrogate marker may enable prediction of fracture risk reduction. The threshold percentage change, which defines an adequate response to therapy with bone turnover markers, is currently unclear. We have defined the biological response to therapy by identifying responders based on adherence to greater then 95% of prescribed therapy.

Fifty postmenopausal women (mean age 62 ±1 year) with osteopenia were randomised to treatment with raloxifene and calcium or no treatment for 24 months. Duplicate serum samples and 4 urine samples were obtained fasting at 24 weeks. Bone formation was measured using procollagen type I N terminal propeptide (PINP; Roche Elecsys) and osteocalcin (OC; Roche Elecsys). Bone resorption was measured using serum beta C terminal telopeptide of type I collagen (sBCTX; Roche Elecsys) and urine N terminal telopeptide of type I collagen (uNTX; Vitros ECi). Adherence was assessed using electronic monitoring devices.

The mean percentage change and least significant change (LSC) for multiple measurements are shown (Table). The signal (percentage change) to noise (CV) ratio was greatest for PINP. The biological response to therapy was determined from subjects (n = 10) adhering to greater then 95% of the prescribed therapy and calculated using percentage change in bone turnover markers and 80% confidence intervals (CI). If the 80% CI did not overlap with the LSC then bone turnover markers will discriminate between a responder and poor-adherence or poor-responder with 95% sensitivity and 95% specificity, any overlap will result in reduced sensitivity. PINP had the highest sensitivity and specificity at 24 months (Table).

In conclusion bone formation markers had a similar or greater signal to noise ratio compared to bone resorption markers. The percentage change in bone markers in response to therapy had a high specificity (95%) and sensitivity (65 to 95%) to discriminate between responders and poor-adherence or poor-responders.

 

 

 

 

 

Greater 95% Adherence to Raloxifene Therapy

Bone Marker

LSC

Mean % Change

Upper Limit 80 % CI

Lower Limit 80 % CI

Sensitivit y

Specificit y

Osteocalcin

26.7

- 34.0

- 9.8

- 58.2

65 %

95 %

PINP

24.5

- 45.5

- 22.2

- 68.7

95 %

95 %

sBCTX

46.7

- 65.5

- 6.1

- 124.9

66 %

95 %

uNTX

29.6

- 43.4

- 3.2

- 83.7

67 %

95 %

[Programme]

 
P-287

RISEDRONATE IS WELL TOLERATED IN OSTEOPOROTIC PATIENTS IN A CLINICAL PRACTICE SETTING: RESULTS FROM AN INTERIM ANALYSIS OF A PROSPECTIVE COHORT STUDY (ORFEO STUDY)

F. Morales1, P. Orozco2, F. I. Romero3, I. Aristegui3*, P. O'Shea4

1University of Valencia, Spain

2CAP Gotic, Barcelona, Spain

3Aventis Pharma, Spain

4Biometrica, Spain

Objective: The tolerability of risedronate has been assessed in placebo-controlled studies for up to 3 years, in which patients were not excluded because of either an underlying history of gastrointestinal (GI) disease or concomitant medication intake. The aim of this study was to confirm the safety profile of risedronate 5 mg/d in actual clinical practice. This is the first pharmacovigilance prospective study with an oral bisphosphonate conducted in Spain.

Patients and Methods: Patients: 2301 patients with postmenopausal or glucocorticoid-induced osteoporosis (median age: 64 years) were enrolled and followed up for up to six months in 202 primary care centres in Spain. For this interim analysis 2102 patients were evaluated, who had either completed the study or having withdrawn, with a filled in Study Discontinuation Form.

Methods: multicentre, observational, prospective cohort study. All the patients were requested to give their informed consent before entering the study.

Results: 1240 patients (59%) had an underlying history of upper GI disease prior to entering the study, and over 30% of the whole sample had been taking NSAIDs or aspirin for longer than 1 month.

Over 90% of the patients fully complied with risedronate's administration instructions.

127 (6%) of all the patients in the study reported at least one Adverse Event (AE), and in total 237 AEs were reported, among which 159 were Upper GI (UGI) AEs. The most common UGI AEs were Abdominal Pain (2.52% of all the study patients) and Dyspepsia (1.38%). The average time from the beginning of risedronate intake to the onset of any AEs was 35.8 days. Most of the AEs were mild to moderate. Patients' withdrawal due to tolerability complaints was 4.1%.

Conclusion: The results of this cohort study shows that oral daily riesdronate 5 mg is well tolerated in osteoporotic patients under actual clinical practice conditions, and its GI safety profile is comparable to that shown in placebo-controlled clinical trials.

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P-288

CLINICAL FACTORS RELATED WITH DIET-RELATED CALCIUM INTAKE

M. Ciria*, L. Perez-Edo, J. Blanch, M. J. Robles, M. Coll, P. Lisbona, X. Garcia, P. Benito, J. Carbonell

Rheumatology Service, IMAS

Objective: to assess the effect of different clinical parameters on diet-related calcium intake.

Patients and methods: calcium intake is measured by a semiquantitative questionnaire to people who made a densitometric exploration in our center between July and December of 2002. We measured the bone mineral density (BMD) in lumbar spine and femoral neck (four interest areas), body mass index, age, solar exposure level, tobacco and alcohol usage, existence of previous autoreferred fractures in vertebral spine, forearm or femur and its relationship with the previous performance of a first exploration or a control visit. BMD was measured with an Hologic QDR 1000 equipment. The statistical analysis included assessment of the normality of the variables, parametric and non-parametric tests, lineal regression and correlation tests.

Results: Five hundred and twenty explorations were reported. 163 were first explorations, and 357 were control visits. Both groups were comparated by age, sex, tobacco or alcohol usage and body mass index. Calcium intake was statistically different between people that did a first exploration and those that did a control visit. (x=0.623 ±0.257 versus x=0.701±0.305 mg/day, respectively; p=0.014), as well bone mass in every studied interest area except in trochanter, being higher in first explorations than in successive visits. Existence of previous fractures did not show correlation with lactic intake, neither BMD in any of the interest areas studied, body mass index, age, physical activity or tobacco usage. Alcohol intake was negatively correlated with the calcium intake (r:-0. 136; p=0.002), whereas solar exposure showed a very weak positive correlation (r: 0.098; p=0.026).

Conclusions: in our sample, calcium intake was only associated with the previous performance of a densitometry. The increase of diet-related calcium intake can be owed to the previous diagnosis of osteoporosis, but we can not assure this with a cross-sectional study. We emphasize the absence of correlation between the existence of previous fractures and the diet-related calcium intake and with the values of BMD.

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P-289

EVALUATION OF 3-D MICROARCHITECTURE OF HUMAN OSTEOPOROTIC SPINE IN VIVO BY USING HIGH-RESOLUTION COMPUTED TOMOGRAPHY

T. Mawatari1*, H. Miura1, S. Hamai1, T. Shuto1, Y. Nakashima1, T. Kawano1, N. Tsukamoto1, H. Higaki2, Y. Iwamoto1

1Department of Orthopaedics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

2Department of Mechanical Engineering, Faculty of Engineering, Kyushu Sangyo University, Fukuoka, Japan

While bone mineral density (BMD) is the established measure in clinical evaluation of osteoporosis, bone microarchitecture is also one of the major determinants of the bone strength, and has been evaluated by using microcomputed tomography only in laboratory study. The purpose of this study was to evaluate the 3D microarchitecuture of the human osteoporotic lumber spine by using high- resolution computed tomography (HRCT) in vivo. 19 normal postmenopausal women and 31 rheumatoid arthritis (RA) patients including 9 and 16 osteoporosis patients respectively according to the diagnostic criteria, were examined by dual X-ray absorptiometry (DXA) and the whole body of the third lumber vertebra was scanned by HRCT at a spatial resolution of 351 x 351 x 500 micron. All the gray-value slice images were then noise-eliminated, segmented, and transformed to binary images, which included local thresholding procedure. Preliminary experiments on the cadaveric human third

lumber spine were designed specifically to select the correct threshold value. Finally, from the reconstructed 3D volume data, arbitrary-shaped trabecular bone volume which cover the whole trabecular space were extracted.

Bone volume fraction (%), connectivity density (/mm3) (the first Betti number/total volume) as the measure of connectivity, and fractal dimension as the measure of complexity were calculated by custom-made software. Both in normal postmenopausal women group and RA patient group, the bone volume fraction, fractal dimension, and connectivity density decreased significantly in osteoporosis patients compared with the non-osteoporosis subjects. HRCT provided satisfactory in vivo assessment of consecutive slice images corresponding reasonably well to the histological sections, even though a resolution of 351 micron seems to be the lowest resolution level available for human trebecular bone. Despite this limitation, the relative differences in each group were revealed quantitatively, and our method must be useful for evaluation of efficacy of therapeutic intervention in vivo.

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P-290

PAIN AND HEALTH RELATED QUALITY OF LIFE IN WOMEN WITH VERTEBRAL FRACTURES

J. A. Falch*, H. Bentzen, A. A. Dahl

Aker University Hospital, Oslo, Norway

As Norwegian women have a very high risk of sustaining osteoporotic fractures, we wanted to study the impact of vertebral fractures (VFx) on the patients experience of pain and HQOL. Consecutively,100 women with VFx age 50-87 years attaining our outpatient clinic (Group A) were asked to complete a visual analog scale (VAS 0-10) for maximum, minimum and average backpain last week, the Hospital Anxiety and Depression Scale (HADS) questionnaire for scoring of anxiety and depression, and SF-12 (short form of SF-36) for HQOL. From Group A, 20 women with primary osteoporosis participated in an extension of the study, completing the osteoporosis specific QUALEFFO questionnaire (Group B). As controls for Group B, 21 women age 71 years without VFx completed the QUALEFFO. The age of Group A was 73 (8) and for Group B 72 (4) years. The maximum pain reported by Group A (VAS) was 5.3 (2.8), average 4.0 (2.4), and minimum 2.4 (2.2). In a large Norwegian population based study of rheumatoid arthritis, the VAS for pain was 4.6 (2.4). The HADS anxiety score was 6.2 (4.1) and the depression score 4.9 (3.0). These scores are below 8, which is suggested as the cut-off score for clinical disease. Compared to a large Norwegian population study using HADS, the scores are not clinically significantly higher than that norm. For SF-12, the normalized mental score was 46.2 (10.0) and the physical score 31.7 (7.7). The normal US population will for both scores have a value 50 (10), and although the mental score in the patients was significantly influenced, the deviation from the mean value was only 0.4 SD compared to nearly 2 SD for physical score. In Group B, the total score for QUALEFFO was significantly higher in patients than controls, indicating a reduced HQOL. This was significant for all five domains except the domain of mental function. In conclusion, our patients with osteoporotic

VFx experience a high degree of pain, reduced physical functional capacity and HQOL. However, in spite of this, they seem to have preserved a normal mental function without increased levels of anxiety and depression.

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P-291

SEX HORMONES INFLUENCE THE PEAK BONE MASS - A CASE OF 17 ALPHA-HYDROXYLASE DEFICIENCY

D. Kastelan*, Z. Giljevic, Z. Perkovic, M. Korsic

Division of Endocrinology, Department of Internal Medicine, University Hospital Zagreb, Zagreb, Croatia

17 alpha-hydroxylase is an enzyme required for production of cortisol in adrenal cortex and C-19 androgen precursors of the sex hormones in both, adrenals and gonads. Deficit of the enzyme is associated with hypertension, sex infantilism and female phenotype in both genetic sexes. Peak bone mass is influenced by genetic factors, nutrition, physical activity and sex hormones. Here we present a patient with 17 alpha-hydroxylase deficiency, a rare form of congenital adrenal hyperplasia, characterised by late puberty and consequent low bone mass.

A 23-yr old female patient was first diagnosed with primary amenorrhoea, absent secondary sexual development and hypertension. The patient had female external genitalia, with small uterus and ovaries as revealed by pelvic ultrasound. High level of progesterone and low levels of 17-hydroxyprogesterone and sex steroids were found. Bone mineral density was also decreased. Dual x-ray absorptiometry showed low bone mineral density of the lumbar spine (T score = -4,37) and the total hip (T score = -2,67). One year following treatment with sex hormone therapy, a significant gain of bone mass was observed at all measured sites.

Low bone mineral density observed in this patient and the subsequent increase in BMD, indirectly proves the role of sex hormone on bone mass.

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P-292

EVALUATION OF INHOMOGENEITY OF HUMAN VERTEBRAL CANCELLOUS BONE BY USING HIGH-RESOLUTION COMPUTED TOMOGRAPHY IN VIVO

S. Hamai1*, T. Mawatari1, H. Miura1, T. Shuto1, Y. Nakashima1, T. Kawano1, N. Tsukamoto1, H. Higaki2, Y. Iwamoto1

1Department of Orthopaedics,Graduate school of Medical Science, Kyusyu University, Fukuoka, Japan

2Department of Mechanical Engineering, Faculty of Engineering, Kyusyu Sangyo University, Fukuoka, Japan

Clinical evaluation of bone mineral density (BMD) is commonly performed in the lumber vertebrae by Dual X-ray absorptiometry (DXA), however, the localization of the bone inside the vertebral body which will contribute to the mechanical strength, cannot be taken into consideration. The purpose of this study was to evaluate the inhomogeneity of human vertebral cancellous bone by using high-resolution computed tomography (HRCT) in vivo. 19 normal postmenopausal women and 31 rheumatoid arthritis patients including 9 and 16 osteoporosis patients respectively, were examined by DXA, and the whole body of the third lumber vertebra was scanned by HRCT at a spatial resolution of 351x 351 x 500 micron. All the gray-value slice images were then noise-eliminated, segmented. Preliminary experiments on the cadaveric human third lumber spine were designed specifically to select the correct threshold value. Finally, from the reconstructed 3D volume data, arbitrary-shaped trabecular bone volume which is then divided into six parts (upper-anterior, upper- posterior, middle-anterior, middle-posterior, lower-anterior, lower-posterior) were extracted. Bone volume fraction (%) was calculated, and 3-D image reconstruction was done. The decreasing pattern of the cancellous bone were classified as the localized pattern which shows the zone specific loss remarkable at the upper and anterior half of the vertebral body, and the homogeneous pattern. Banse et al. examined 6 longitudinal cancellous bone cores from 9 autopsy lumber vertebrae samples, and have shown inhomogeneity of human vertebral cancellous bone. In accordance with their findings, we confirmed the localized pattern in most of the cases by in vivo whole body analyses of the lumber vertebrae using HRCT, whereas some vertebral body showed the homogeneous pattern. The pathogenesis of these differences of decreasing pattern is still unknown. Correct quantification of the decreasing pattern and identification of the weakest parts of the vertebra may lead to better prediction of fracture risk.

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P-293

EFFICACY OF TERIPARATIDE FOR FRACTURE RISK REDUCTION IN WOMEN WITH VARYING BASELINE RISK FOR OSTEOPOROTIC FRACTURE

J. H. Krege*, G. Crans, S. Vargas, W. H. Scheele

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

We hypothesized that teriparatide [rhPTH(1-34)] therapy is effective across the entire spectrum of baseline risk for fracture in postmenopausal women having osteoporosis, as estimated from baseline BMD and number of prior vertebral fractures. In the Fracture Prevention Trial (Neer, NEJM, 2001), women having osteoporosis and prevalent vertebral fractures were treated with teriparatide 20 or 40 µg once daily for a median of 19 months. Treatment reduced the relative risk for new vertebral fracture by 65% and 69%, respectively, compared with placebo. Of the original study population, 77% (1262/1637) volunteered for additional observation to determine the safety and long-term durability of teriparatide effects on fracture incidence. During the initial 18 months after stopping study drug, vertebral fracture efficacy was sustained [Lindsay, JBMR 2001;16 (Suppl 1):S163]. For patients receiving teriparatide 20 µg (the marketed dose), the relative risk (RR) for new fracture over the total 39 months of observation was 0.54, the absolute risk reduction (ARR) was 12.7% (P<0.0001), and the number needed to treat (NNT) to prevent a new fracture was 7.9. In women with more than 1 baseline vertebral fracture, the RR was 0.45, the ARR 18.5% (P<0.0001), and the NNT 5.4. Women with BMD T-scores at either the femoral neck or lumbar spine of -2.5 or less had RR of 0.54, ARR 14.6% (P<0.0001), and NNT 6.8. Women with both characteristics (low BMD T-score and baseline vertebral fractures) had RR of 0.44, ARR 21.7% (P<0.0001), and NNT 4.6. Thus, once-daily administration of teriparatide 20 µg/d robustly decreased fracture risk over an extended period (39 months), across a broad span of baseline fracture risk. Even patients most severely affected by osteoporosis and at high risk of fracture are likely to benefit from the bone forming activity of teriparatide.

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P-294

DIVERGING EFFECTS OF TERIPARATIDE AND ALENDRONATE ON BONE FORMATION IN POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS. A HISTOMORPHOMETRIC STUDY AFTER 6 MONTHS OF THERAPY

P. J. Meunier1*, M. E. Arlot1, J. San Martin2, G. Boivin1, D. W. Donley2, R. Correa- Rotter3, S. Jasqui3, J. Tamayo4, E. F. Eriksen2

1Laboratoire d'Histodynamique Osseuse and INSERM Unit 403, Faculty of Medicine R. Laennec, Lyon, France

2Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

3Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubiran, 14000 Mexico DF, Mexico

4COMOP Osteoporosis Research Center, Mexico DF Mexico

Teriparatide (rDNA origin) injection [rhPTH(1-34)], a bone formation agent for osteoporosis, and alendronate, a bisphosphonate, both increase bone mineral density and decrease the risk of fracture. To compare the effects of teriparatide (20 µg/d) and alendronate (10 mg/d) on bone remodeling, we conducted a cross-sectional bone biopsy study in a subset of patients enrolled in a randomized, double-blind, prospective clinical trial. After 6 months of treatment, biochemical markers of bone turnover were significantly increased by teriparatide and decreased by alendronate in postmenopausal women with osteoporosis. Tetracycline double-labeled iliac crest bone biopsies were obtained from patients treated with teriparatide (n=8) or alendronate (n=9) for 6 months. The histomorphometric analysis was performed separately for cortical, endocortical and cancellous bone. Despite the short treatment period, significant differences were demonstrated between groups. Activation frequency was markedly increased: 0.99 ±0.56 (mean ±SD)/yr in the teriparatide group vs. 0.02 ±0.03/yr in the alendronate group (P<0.0001). The marked suppression of bone formation with alendronate treatment was also reflected in the mineralizing surface (8.1 ±4.4% vs. 0.2 ±0.3%, P<0.0001), osteoid surfaces (17.3 ±7.9% vs. 6.8 ±5.2%, P<0.004), adjusted appositional rate (0.37 ±0.17 vs. 0.03 ±0.01 µm/d, P<0.002) and bone formation rate (0.062 ±0.035 vs. 0.002 ±0.001 µm/d, P<0.02) (teriparatide vs. alendronate). Eroded surfaces were similar between teriparatide and alendronate treated groups. In the endocortical envelope, similar pronounced reductions in bone formation were observed for alendronate as reflected by mineralizing surfaces (18.7 ±10.4% vs. 0.4 ±0.9%, P<0.0001) and bone formation rate (0.097 ±0.053 vs. 0.006 ±0.008 µg/d (P<0.04). In the latter envelope, the teriparatide group displayed an increase in erosion surface (5.6 ±3.8% vs. 2.8 ±1.3%, P<0.04). Cortical bone thickness, cortical porosity, and endosteal mineral apposition rates were not different between treatment groups.

In conclusion, these results demonstrate the marked difference in mechanism of action between teriparatide, which directly stimulates bone formation, and alendronate, which markedly reduces bone remodeling.

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P-295

WITHDRAWN

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P-296

ELECTRONIC MONITORING OF ADHERENCE TO THERAPY IN POSTMENOPAUSAL OSTEOPOROSIS: THE IMPACT STUDY

B. Vrijens1*, J. D. Ringe2, N. B. Watts3, H. A. P. Pols4, C. Roux5, R. Eastell6, L. van de Langerijt7, D. Cahall7, P.D. Delmas8

1AARDEX Ltd, Vise, Belgium

2Klinikum Leverkusen, University of Cologne, Leverkusen, Germany

3University of Cincinnati, Cincinnati, OH, USA

4Erasmus University, Rotterdam, The Netherlands

5Hōpital Cochin, University René-Descartes, Paris, France

6University of Sheffield, Sheffield, UK

7Aventis Pharmaceuticals, Bridgewater, New Jersey, USA

8INSERM Research Unit 403 and Claude Bernard University of Lyon, Lyon, France

Adherence to prescribed postmenopausal osteoporosis treatment is important for clinical effectiveness. While pill counts are widely used to assess adherence in clinical trials, they only give an average adherence level over the whole study period and they significantly overestimate actual compliance relative to that determined by electronic monitoring devices. The present paper focuses on the 1-year Improving Measurements of Persistence on Actonel Treatment (IMPACT) study to assess adherence to prescribed therapy in the control group where no reinforcement was given to the patients. This analysis includes a total of 1113 postmenopausal women aged 65 to 80 years with osteoporosis in 21 countries. Two measures of adherence were used: a) conventional pill counts in which the remaining number of tablets were counted at each visit; and b) electronic monitoring with the Medication Event Monitoring System (MEMS, AARDEX, Ltd.). The child-proof closure of the MEMS cap contains a microprocessor that records the date and time of each opening of individual drug containers over time. We observed vastly different temporal patterns of adherence both within and between patients and we found it useful to distinguish two dimensions of the adherence patterns: the patient's (a) persistence and (b) compliance to therapy. Persistence was defined as the time since first dose until discontinuation of treatment, with 'discontinuation' defined as the last day on which the patient has taken at least 7 doses over the 14 last days and at least 50% of the doses since first dose. 'Compliance' reflects the quality of execution of the drug regimen while the patient persists. Overall, 96.3% of women returned their MEMS caps. At 1 year, 77% of women were persistent by MEMS caps, while the average compliance with therapy over the study period was 95%, again by MEMS caps. These results indicate that compliance to risedronate 5 mg/d therapy in postmenopausal women with osteoporosis is very good while persistence can be improved. The results also showed that pill counts overestimate adherence to therapy as compared with MEMS cap monitoring (P=0.022). MEMS is therefore a useful method to monitor patient adherence of osteoporosis therapy.

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P-297

INFLUENCE OF PATIENT COMPLIANCE WITH RISEDRONATE THERAPY ON BONE TURNOVER MARKER AND BONE MINERAL DENSITY RESPONSE: THE IMPACT STUDY

R. Eastell1*, P. Garnero2, B. Vrijens3, L. van de Langerijt4, H. A. P. Pols5 J. D. Ringe6, C. Roux7, N. B. Watts8, D. Cahall4, P.D. Delmas9

1University of Sheffield, Sheffield, UK

2Hopital Edouard Herroit, Lyon, France and Synarc, Lyon, France

3AARDEX Ltd, Vise, Belgium

4Aventis Pharmaceuticals, Bridgewater, New Jersey, USA

5Erasmus University, Rotterdam, The Netherlands

6Klinikum Lverkusen, University of Cologne, Lverkusen, Germany

7Hōpital Cochin, University René-Descartes, Paris, France

8University of Cincinnati, Cincinnati, Ohio, USA

9INSERM Research Unit 403 and Claude Bernard University of Lyon, Lyon, France

Short-term (3-6 month) changes in bone turnover markers (BTMs) produced by risedronate are significantly correlated with reduced vertebral fracture risk. It is important to determine whether changes in BTMs are related to compliance. This analysis evaluated the effect of compliance with risedronate 5 mg/d on BTMs and bone mineral density (BMD) in 2302 postmenopausal women with osteoporosis aged 65 to 80 years enrolled in the IMPACT study. Urinary N-terminal cross-linking telopeptide of type I collagen (uNTX) and serum type I collagen C-telopeptide (sCTX) levels were measured at baseline after 2 weeks (mean = 19 days) of calcium treatment alone, and at weeks 10 and 22 of risedronate treatment. Spine BMD was measured at baseline and 1 year. Compliance was assessed using electronic monitoring caps (MEMS, AARDEX Ltd.). Change in uNTX, sCTX, and BMD from baseline were categorized and related to compliance using a proportional odds model. At 10 and 22 weeks, mean changes in uNTX were -35% and -39%, respectively (both P<0.0001) and mean changes in sCTX were -49% and -55%, respectively (both P<0.0001). Mean change in spinal BMD at 1 year was +4% (P<0.0001). Urinary NTX, sCTX, and BMD responses to treatment improved as compliance increased. For example (see figure), at week 22, a decrease in sCTX from baseline of >50% can be expected in about 20% of noncompliant patients (left-hand side of figure) and in more than 60% of compliant patients (right-hand side of figure). These results show that compliance of postmenopausal women with risedronate 5 mg/d is an important correlate of their achievement of better outcomes in terms of BTMs and BMD. Poor compliance should be considered in patients who have not responded to risedronate therapy. In conclusion, BTM change can reflect the degree of compliance to risedronate treatment in postmenopausal osteoporotic women.

 

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P-298

COST-EFFECTIVENESS OF PARATHYROID HORMONE IN THE TREATMENT OF OSTEOPOROSIS IN POSTMENOPAUSAL WOMEN IN SWEDEN

J. Lundkvist1*, O. Johnell2, D. Sykes3, L. Jönsson1

1Stockholm Health Economics, Stockholm, Sweden

2UMAS, Dept. of Orthopaedics, Malmö, Sweden

3UK Lilly Research Centre, Erl Wood Manor, Windlesham, UK

Background

Parathyroid hormone (PTH) is a new treatment for osteoporosis that has in clinical trials been shown to reduce the risks of vertebral and nonvertebral fractures in postmenopausal women. The objective of this study was to estimate the cost- effectiveness of PTH compared with no treatment, using a computer-based simulation model.

Method

The analysis was conducted for a cohort of 69-year old women in Sweden with at least one previous vertebral fracture and low BMD. The model simulated the course of events in individual patients until death or 100 years of age. The simulation was conducted in 6-month cycles. During each cycle the patients were at risk of having clinical hip, vertebral or wrist fractures, or to die. Total accumulated life time costs and quality adjusted life years (QALYs) were estimated. Swedish data on costs of fractures, utility reductions after fracture, fracture risks and mortality rates were used. The model took into account new epidemiological evidence which indicate that fracture risks and mortality rates are higher in subsequent years after a fracture.

Results

The incremental cost-effectiveness ratio was about 260,000 SEK (28,000 EUR) per QALYs gained for PTH treatment compared to no treatment. The result was based on a PTH price of 126 SEK (14 EUR) per day. The sensitivity analyses included variations in fracture costs, treatment efficacy, utility reductions, fracture risks and mortality rates, and showed that the results were fairly stable.

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P-299

QUANTITATIVE ULTRASOUND VARIANCE IN ELDERLY INSTITUTIONALIZED WOMEN

J. Zochling1*, L. M. March1, R. G. Cummming2, I. D. Cameron3, S. R. Lord4, J. Schwarz1, P. N. Sambrook1

1Institute of Bone and Joint Research, Department of Medicine, University of Sydney, Sydney, Australia

2Department of Public Health, University of Sydney, Sydney, Australia

3Rehabilitation Studies Unit, University of Sydney, Sydney, Australia

4Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia

Aim: To compare the reliability and reproducibility of two calcaneal ultrasound machines in a population of elderly institutionalized women, and how variance changed with age.

Methods: Subjects were 1210 female residents of nursing homes and hostels in the Northern Sydney area, participating in a multi-dimensional study of the risks of falls and fractures in the institutionalized elderly, the FREE study (Fracture Risk Epidemiology in the Elderly). Broadband ultrasound attenuation (BUA) was measured in all participants using the same CUBA Mark II ultrasound instrument (McCue Ultrasonics, London, UK). BUA was also measured using a Metra QUS2 ultrasound machine in 509 of the participants.

Results: The precision of BUA in normal individuals aged 18 to 80 in our laboratory for the CUBA machine is 2.4%. The mean difference between repeated BUA measures on the CUBA machine was 0.362 dB/MHz, standard deviation 2.292 (t=5.5, p<0.0001), which was statistically significant. The mean difference between repeated BUA measures on the QUS2 machine was 0.138 dB/MHz, standard deviation 2.775 (t=-1.1, p=0.3). Most of the variance in measurement is between- subjects not within subjects, suggesting good reproducibility. For CUBA, variance (age)=71.16 and variance (error)=260.07, and for QUS2 variance (age)=111.31 and variance (error)=107.22. Within subject variance increases with age with both machines. There is no significant difference in variability of repeated measures between the machines (F=1.8, p=0.2).

Conclusion: Quantitative ultrasound (QUS) is a reliable, reproducible instrument for measuring bone quality in the institutionalized elderly population, and has the advantage of portability and ease of use over the gold standard for bone density assessment, dual energy x-ray absorptiometry. Variance estimated with both methods was stable with increasing age suggesting this is a useful method for estimation fracture risk even in the frail elderly.

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P-300

BETWEEN CITY DIFFERENCES IN BONE TURNOVER, PTH AND 25(OH)D IN THE HEALTHY FEMALE POPULATION: ARE COMMON REFERENCE VALUES JUSTIFIED?

A. Blumsohn1*, C. C. Glüer2, D. M. Reid3, D. Felsenberg4, C. Roux5, R. Eastell1

1University of Sheffield, UK

2University Hospital Kiel, Germany

3University of Aberdeen, UK

4Free University Berlin, Germany

5Rene Descartes University, Paris

Geographical differences in skeletal metabolism in the healthy general population are poorly characterised. Studies may be biased by different selection criteria or exclusion, pre-analytical factors, non-concurrent sample collection or assay.

We established reference intervals for bone turnover, parathyroid hormone (PTH) and 25(OH) Vitamin D in 5 European centers (Aberdeen, Berlin, Kiel, Paris, Sheffield) participating in the Osteoporosis and Ultrasound study (OPUS). Serum (12:00 to 15:00 non fasting) and second void urine were obtained from 2780 female reference individuals selected from population registers (approx. 600 per center). Participants were classified by center, menopausal status, disease and confounding drug therapy. Collection was completed over 24 months ending April 2001. Assays included serum b Crosslaps (sbCTX), procollagen I N-terminal propeptide (PINP), osteocalcin (OC), PTH (Elecsys, Roche Diagnostics), urine N-terminal telopeptide of type I collagen (NTX/Cr; Ortho) and 25(OH)D. Storage was at -75C, and assays were performed in a single center in a randomised order.

There was no significant heterogeneity of variance for any analyte between center (Bartlett test, P>0.05). There were very small but significant (ANOVA P<0.001) differences between center for all analytes in the total postmenopausal population, but these were largely accounted for by differential use of HRT. 25(OH)D was slightly lower in Paris (41.1 ±1.9SEM nmol/L) in comparison with the other 4 centers (ANOVA P<0.01; Aberdeen 50.4 ±2.0, Berlin 54.0 ±2.3, Kiel, 52.3 ±1.9, Sheffield 49.9 ±1.8). After exclusion for disease and drug therapy there were no other substantial between-center differences for any analyte. In premenopausal women there were no substantial differences between center for any analyte apart from lower bone resorption in Paris and Kiel as judged by urine NTX/Cr and sbCTX (for uNTX/Cr: Paris 33.6 ±2.0nmol/mmol; Kiel 44.8 ±1.9; Sheffield 50.7 ±2.9, Aberdeen 48.8 ±3.0, Berlin 51.9 ±3.0; ANOVA P<0.01). In conclusion: Postmenopausal reference limits are similar between these European cities. Lower premenopausal bone resorption in Paris and Kiel would imply that T-scores may not be transferable between these centers. Sunshine behaviour, skin pigmentation and protection are probably more important determinants of 25(OH)D than latitude.

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P-301

ASSOCIATION BETWEEN TARGET ORGAN RESPONSES DURING HORMONE REPLACEMENT THERAPY: BONE VERSUS LIPIDS

S. Silvestri1*, A. B. Thomsen2, C. Christiansen2, M. L. Brandi3, N. H. Bjarnason2

1Department of Clinical Phatophysiology, University of Florence, Florence, Italy

2Center for Clinical and Basic Research, Ballerup, Denmark

3Department of Internal Medicine, University of Florence, Florence, Italy

The aim of the study was to investigate whether in postmenopausal women taking Hormone Replacement Therapy (HRT), those with a large response in bone mineral density (BMD) were also those with the most favourable response in lipid-profile.

Study design

A double blind placebo controlled trial including 278 postmenopausal women randomly assigned to five groups each receiving different combinations of 17beta- estradiol and gestodene. The study period was 3 years and a total number of 133 postmenopausal women were evaluated as valid completers.

The response in bone mass was expressed as the percentage change in BMD from the baseline calculated by linear regression from semi-annual measurements and analysed for between-group differences by one way analysis of variance.

The response in lipid-profile was evaluated as the percentage change from baseline during the study period.

Results

A significant correlation between the increase in BMD of the lumbar spine and hip with the decrease in serum total cholesterol and LDL was found (P<0.001).

Conclusions

Our study shows that it is the same woman who has a favourable response in BMD as in the lipid profile during HRT. The associations is most likely driven by a common response in FSH to exogenous estradiol therapy despite the same 17beta-estradiol plasma levels.

In conclusion these results might improve the selection of women who can benefit the most from HRT concerning both osteoporosis and cardiovascular disease.

[Programme]

 
P-302

IS THERE ANY ASSOCIATION BETWEEN THE RESPONSE TO LEVORMELOXIFENE AND RALOXIFENE IN DIFFERENT TARGET ORGANS?

S. Silvestri1*, A. B. Thomsen2, N. H. Bjarnason2, M. L. Brandi3, C. Christiansen2

1Department of Clinical Phatophysiology, University of Florence, Florence, Italy

2Center for Clinical and Basic Research, Ballerup, Denmark

3Department of Internal Medicine, University of Florence, Florence, Italy

Estrogen Replacement Therapy (ERT) is used to alleviate climateric complaints, to prevent bone loss and others chronic disease. To gain the full benefits ERT must be administered for several years but the compliance to its long-term use is poor due to side effects. Thus there is big interest in developing new drugs with the beneficial effects of ERT and without its side effects. Among Selective Estrogen Receptor Modulators (SERMs) Raloxifene has been proved to preserve Bone Mineral Density (BMD) and to lower serum atherogenic lipids without producing significant effect on the endometrium.

The Levormeloxifene (L-enantiomer of the racemic compound Ormeloxifene) has been shown to prevent bone loss in the ovariectomized rat model. It seemed to have the same estrogenic effects on bone and lipid profile without inducing endometrial hyperplasia, but unfortunally, due to its important side effect on female genitalia (uterovaginal prolapse) the development of this compound has been stopped.

Materials and Methods

Study I: phase II, double blind, placebo controlled, multicenter trial. 133 healthy postmenopausal women aged between 45-65 years, at least one year postmenopausal and with intact uterus, were randomly assigned to one of six groups (Levormeloxifene 1.25, 5, 10, or 20 mg/day; continuous combined HRT 1mg estradiol and 0.5 mg noretisterone acetate and placebo).

Study II: double blind, placebo controlled, multicenter trial. 248 healthy postmenopausal women aged between 45-60, within 2-8 years of menopause were randomly assigned to one of 4 groups (Raloxifene 30, 60, 150 mg/day or placebo)

All women in both studies received 400-600 mg Calcium per day. The participants were similar as far as baseline characteristics are concerned.

Results

No correlation was found between baseline lipid levels (total cholesterol, LDL, HDL, tryglicerides) and lumbar spine and hip BMD.

We found a highly significant correlation (P<0.01) between the response to Levormeloxifene and Raloxifene therapy as BMD of the lumbar spine and hip with the decrease in serum lipids (total cholesterol and LDL).

In addiction we confirmed that Levormeloxifene had a stronger estrogenic effect on serum lipids than 60 mg of Raloxifene, while the effect on BMD was of the same magnitude as that of 60 mg Raloxifene.

[Programme]

 
P-303

BONE MINERAL DENSITY MEASUREMENT IN ANKYLOSING SPONDYLITIS (AS)

M. Korkosz1*, P. Gluszko1, P. Marcinek2

1Jagiellonian University School of Medicine, Dept of Medicine, Div. of Rheumatology, Krakow, Poland

2Jagiellonian University School of Medicine, Dept of Medicine, Radiology Unit, Krakow, Poland

Objective: To determine whether there is a relationship between bone mineral density (BMD) measured at lumbar spine by quantitative computed tomography (QCT) and BMD of lumbar spine and proximal femur measured by dual-energy x-ray absorptiometry (DXA) in patients with AS. In addition, to assess possible correlations between BMD values, x-ray scores and various clinical data.

Material and methods: 38 male patients fulfilling the New York criteria of AS aged 23-67 years with disease duration of 3-30 years, underwent QCT (lumbar spine) and DXA (lumbar spine and proximal femur) measurements and x-ray (thoracic and lumbar spine). 12 male patients with lumbar spine osteoarthritis served as controls for QCT evaluation.

Results: Lumbar spine trabecular BMD (region of interest) measured by QCT correlated significantly only with BMDs of Ward's triangle measured by DXA (r=0,63; p<0,05) Both measurements (lumbar spine QCT and Ward's triangle DXA) correlated with disease duration (r=-0,51; p<0,05, and r=-0,37; p<0,05 respectively), however only QCT values of the lumbar vertebra negatively correlated with the radiological grading of disease progression at spine.

Conclusions: Our data indicate that in AS only trabecular bone BMD assessment regardless of the technique, i.e. DXA or QCT, carries valuable information which correlates with the duration of disease and radiological grading of the spine. The DXA

assessment of lumbar spine or femoral neck possess a significant accuracy error due to perivertebral calcification of the soft tissues and has no value for monitoring BMD changes in AS.

[Programme]

 
P-304

PERFORMANCE AND LIMITS OF IN VIVO MICRO-CT IMAGING OF TRABECULAR BONE IN RATS AND MICE, WITH CONSIDERATION OF ANIMAL WELFARE AND TISSUE-WEIGHTED DOSIMETRY

P. L. Salmon*, E. G. G. Buelens, A. Sasov

Skyscan, Aartselaar, Belgium

Important advantages to experimental design of preclinical bone studies are available, if trabecular bone of rats and mice can be imaged in vivo under anaesthesia. However, in vivo scanning of rodents imposes constraints on micro-CT scanner design, measurement geometry and imaging parameters, with the result that the 3D x- ray image resolution is reduced compared to that attainable in ex vivo scanners. The specific constraints include (a) rotating source-detector assembly around immobile subject, (b) fixed source-detector separation, (c) loss of image contrast due to x-ray absorption in live soft tissue surrounding bone, (d) limits to radiation dose to the animal, and (e) breathing and heart-related movement of the animal during scanning. A further constraint is stress to animals and consequent weight loss caused by anaesthesia, an important consideration when contemplating multiple sequential scans. We demonstrate that adequate resolution of trabecular bone structures can be achieved in rodents in vivo, while not compromising animal welfare by excessive periods of anaesthesia or excessive radiation dose. The scanner employed was the Skyscan 1076. 3D images with pixel size of 8.9 microns (Gaussian resolution of 12.5 microns) can be obtained at the rodent hindlimb knee with local absorbed dose of about 0.6 Gray and whole body effective dose equivalent of 10 milliSieverts (using ICRP tissue weighting factors). This resolution allows structural histomorphometric analysis of rat and mouse trabecular bone. X-ray source shuttering can reduce dose by a further 50%. The sensitivity of micro-CT-measured bone parameters to changes in resolution and contrast are systematically evaluated. Parameters vary in sensitivity, with connectivity parameters such as Euler connectivity being especially sensitive to resolution. It emerges that the fixed scanning parameters of the in vivo scanner are partly advantageous in that they impose standardisation on scanned images and calculated structural parameters of trabecular bone.

[Programme]

 
P-305

MICROMECHANICS OF OSTEOPOROTIC BONE MEASURED BY SCANNING ACOUSTIC MICROSCOPY

J. Brandt*, A. Franke, K. Raum

Laboratory of Experimental Orthopaedics, Martin-Luther University, Halle, Germany

The Scanning Acoustic Microscopy (SAM) reveals the possibility to deliver information on elastomechanical properties. The sound velocity depends on elastic moduli and the elastic stiffness directly correlates with the sound velocity in the direction of propagation. We used the acoustic impedance as a suitable parameter for characterization of bone. Latest SAM-devices with frequencies up 2 GHz gain a spatial resolution of about 0.5 micrometer, comparable with the light micropcopy, which allows distinction of cellular and subcellular structures. We developed the image processing software Multi Layer Analysis (MLA) to exclude the influence of surface topography and to focus the images for quantitative investigation at frequencies up to 900 MHz. Consecutively a well focussed output image was calculated by MLA finding the maximum V(z)-position for every pixel. The mechanical properties of osteoporotic bone were measured in iliac crest biopsies. The bone was embedded in PMMA and specimens with planparallel surfaces had been prepared by grinding and polishing. The acoustic procedure is nondestructively, the correlation with nanoindentation measurement of elastic moduli at the same location allows the calculation of material parameters. The results of impedance measurement in osteoporotic and normal bone will be presented at the session. Besides measurement the images deliver morphological information. Especially the transition of regions containing hydroxyapatite minerals to neighbouring structures of organic components and the process of maturation become clearly visible, contrasted without any staining or alteration of the tissue. By means of image processing we gain well focussed images and an extended procedure of calibrating ensures the reproducibility of measurements. Contemporary trials to model bone in biomechanical theories and to judge its loading capacity reveal a lack of measuring procedures, capable to deliver information on bulk properties of bone and on the distribution of these properties in two or three dimensions. But even loading capacity of bone becomes more and more interesting to evaluate the quality of bone in case of osteopathies. Scanning acoustic microscopy seems to be a valuable tool to detect elastomechanical properties via measurement of acoustic parameters.

[Osteoporosis: Pathophysiology, Genetics, Epidemiology]