J.-Y. Reginster

A Simple Tool to Identify Asian Women at Increased Risk of Osteoporosis

Abstract. Patients with low bone mineral density (BMD) have a high risk of future fractures, and should be actively considered for treatment to reduce their risk. However, BMD measurements are not widely available in some communities, because of cost and lack of equipment. Simple questionnaires have been designed to help target high-risk women for BMD measurements, thereby avoiding the cost of measuring women at low risk. However, such tools have previously focused on evaluation of non-Asian women. We collected information about numerous risk factors from postmenopausal Asian women in eight countries in Asia using questionnaires, and evaluated the ability of these risk factors to identify women with osteoporosis as defined by femoral neck BMD T-scores ≤–2.5. Multiple variable regression analysis and item reduction yielded a final tool based on only age and body weight. This risk index had a sensitivity of 91% and specificity of 45%, with an area under the curve of 0.79. Previously published risk indices based on larger numbers of variables performed similarly well in this Asian population. Large differences in risk were identified using our index to create three categories: 61% of the high-risk women had osteoporosis, compared with only 15% and 3% of the intermediate- and low-risk women, respectively. The low-risk group represented 40% of all women, for whom BMD measurements are probably not needed unless important risk factors, such as prior nonviolent fracture or corticosteroid use, are present. An existing population-based sample of postmenopausal Japanese women was used to validate our index. In this sample of Japanese women the sensitivity was 98% and specificity was 29%; the low-risk category, for whom BMD is probably unnecessary, represented 25% of all women. We conclude that our index performed well for classifying the risk of osteoporosis among postmenopausal Asian women and applying it would result in more prudent use of BMD technology.

Prevention of Early Postmenopausal Bone Loss by Strontium Ranelate: The Randomized, Two-Year, Double-Masked, Dose-Ranging, Placebo-Controlled PREVOS Trial

Abstract: Early postmenopausal women (n = 160) were randomised to receive placebo or strontium ranelate (SR) 125 mg/day, 500 mg/day or 1 g/day for 2 years (40 participants per group). All participants received calcium 500 mg/day. The primary efficacy parameter was the percent variation in lumbar bone mineral density (BMD), measured using dual-energy X-ray absorptiometry. Secondary efficacy criteria included hip BMD and biochemical markers of bone turnover. At month 24, SR 1 g/day significantly increased lumbar BMD compared with placebo [mean (SD) +5.53% (5.12); p<0.001] for measured values and [mean (SD) +1.41% (5.33%); p<0.05] for values adjusted for bone strontium content. The annual increase for adjusted values was +0.66% compared with −0.5% with placebo, with an overall beneficial effect after 2 years of about 2.4% with SR 1 g/day relative to placebo. There were no other significant between-group differences in adjusted lumbar BMD. Femoral neck and total hip BMD were also significantly increased at month 24 with SR 1 g/day compared with placebo [mean (SD): +2.46% (4.78) and +3.21% (4.68), respectively; both p<0.001)]. SR 1 g/day significantly increased bone alkaline phosphatase at all time points (p<0.05) compared with baseline and between-group analysis showed a significant increase, compared with placebo, at month 18 (p = 0.048). No effect on markers of bone resorption was observed. SR was as well tolerated as placebo. The minimum does at which SR is effective in preventing bone loss in early postmenopausal non-osteoporotic women is therefore 1 g/day.

Models for assessing the cost-effectiveness of the treatment and prevention of osteoporosis

Abstract:

Patient assessment using standardized bone mineral density values and a national reference database: implementing uniform thresholds for the reimbursement of osteoporosis treatments in Belgium.

AbstractDual-energy X-ray absorptiometry (DXA) devices from the three main manufacturers provide different bone mineral density (BMD) values, due in part to technical differences in the algorithms for bone mineral content (BMC) and area measurements and in part to the use of different manufacturer-derived reference databases. As a result, significant differences exist between Hologic, Lunar and Norland systems in the reported young normal standard deviation scores or T-scores. In a number of European countries, including Belgium, a T-score below −2.5 is one of the key criteria for reimbursement of osteoporosis treatments. This paper addresses the first attempt to implement a nationwide, uniform expression of BMD in patients, in order to harmonize drug reimbursement. To this end, measures were taken to implement a uniform expression of BMD in Belgian patients, by converting each manufacturers absolute BMD to standardized BMD (sBMD) values and by establishing a single national reference range.

Validation of OSIRIS®, a prescreening tool for the identification of women with an increased risk of osteoporosis

According to the recent recommendations of the European Community and the World Health Organization, identification of risk factors for fracture or low bone mineral density (BMD) should help health professionals to make a better use of bone densitometry. This includes helping patients to modify their behaviour and act on modifiable risk factors (correction of low calcium intake and vitamin D deficiencies, etc.) and also to provide evidence-based guidance for starting a treatment when necessary. In this context, we previously developed a clinical scoring index, OSIRIS®(OSteoporosis Index of RISk), for classifying women into three categories of risk of osteoporosis. In order to evaluate the discriminatory performance of OSIRIS, we performed the present prospective study in a sample of 889 postmenopausal women from France. The osteoporosis risk depends on the OSIRIS category. Thus, 62% of women in the ‘high-risk’ category (OSIRIS≤−3) were osteoporotic, compared to 34% of women in the ‘intermediate-risk’ category (OSIRIS ranged between −3 and +1) and only 16.8% of women in the ‘low-risk’ category (score OSIRIS>1). These results might contribute to the development of more efficient screening strategies for osteoporosis. The patients in the low-risk category do not require immediate BMD testing; women with ‘intermediate risk’ have to be carefully followed by their doctor with BMD testing decided on a case-by-case basis; for those within the high-risk category, treatment may be initiated immediately and BMD testing performed either to assess the efficacy of the treatment or to increase the long-term compliance of the patient. In conclusion, for clinical practice, a user-friendly tool has been developed. This tool, called OSIRIS, as far as a simple rule allows, identifies the level of osteoporosis risk in women.

Structure modifying effects of Strontium Ranelate in knee osteoarthritis

OC1 THE ECONOMIC BURDEN OF FRACTURES IN THE EUROPEAN UNION IN 2010 John Kanis, Juliet Compston, Cyrus Cooper, Emma Hernlund, Moa Ivergård, Helena Johansson, Eugene McCloskey, Anders Oden, Judy Stenmark, Axel Svedbom, Bengt Jönsson University of Sheffield, WHO Collaborating Centre, Sheffield, UK, Cambridge University, Department of Medicine, Cambridge, UK, University of Southampton, MRC Lifecourse Epidemiology Unit, Southampton, UK, Optum, OptumInsight, Stockholm, Sweden, International Osteoporosis Foundation, IOF, Nyon, Switzerland, Stockholm School of Economics, Department of Economics, Stockholm, Sweden

Design for an Ipriflavone Multicenter European Fracture Study

In order to investigate the efficacy of ipriflavone (IP) on the prevention of vertebral fractures and the effect on bone mineral density (BMD) in women with postmenopausal osteoporosis, a large multicentric European study was designed and is presently ongoing. Included in the study were 460 Caucasian, nonobese postmenopausal women aged < 45 and < 75 years, menopaused for at least 12 months. Inclusion was on the basis of a lumbar bone mineral density (BMD) lower than 2 SD compared with healthy women aged 50 years, corresponding to values below 0.860 g/cm2 (antero-posterior measurement) by Hologic QDR 1000. Women with prevalent vertebral fractures were excluded as well as those presenting secondary osteoporosis or having been treated with medications that could affect bone metabolism. This study was designed as a 3-year, doubleblind, placebo-controlled, parallel group study that randomized the women to the oral administration of either 3 × 200 mg/day of IP or placebo. All patients received a daily supplement of 500 mg calcium. The primary purpose of the study was to evaluate the efficacy of IP in preventing vertebral nontraumatic fractures. Fracture is defined here as a ≤20% decrease in any anterior, central, or posterior T4-L4 vertebral height. Blinded vertebral X-ray readings and vertebral morphometry have been centralized in an independent Center, with standardized evaluation of two experts. Power calculations have been based on the hypothesis that 21% of placebo-treated patients would fracture within 3 years and that treatment with IP would lead to a 50% reduction in the incidence of fracture. Statistical tests have been designed to have a power of 80%, with a type I error equal to 5%. Secondary endpoints were changes in vertebral, radial, and femoral BMD. Centralized controls on 100% BMD scans would ensure the good quality of BMD readings. This study should verify the hypothesis that IP significantly decreases the risk of vertebral fracture in postmenopausal, osteoporotic women.

Correction of vitamin D insufficiency with combined strontium ranelate and vitamin D3 in osteoporotic patients.

OBJECTIVE This study aims to investigate the efficacy and safety of oral fixed-dose combination of strontium ranelate 2  g/vitamin D₃ 1000  IU daily vs strontium ranelate 2  g daily for correcting vitamin D insufficiency in osteoporosis. DESIGN A 6-month international, randomized, double-blind, parallel-group, phase 3 study. METHODS A total of 518 men and postmenopausal women aged ≥50 years with primary osteoporosis (T-score ≤-2.5 s.d.) and serum 25-hydroxyvitamin D (25(OH)D) >22.5 nmol/l were included. Patients were allocated to strontium ranelate 2 g/vitamin D₃ 1000  IU daily (n=413) or strontium ranelate 2 g daily (n=105). The participants received calcium 1 g daily. The primary endpoint was serum 25(OH)D at last post-baseline evaluation during 3 months. RESULTS Both groups were comparable at baseline. Mean baseline of 25(OH)D was 44.1 ± 14.6 nmol/l. After 3 months, the percentage of patients with 25(OH)D ≥50 nmol/l was higher with strontium ranelate/vitamin D₃ vs strontium ranelate (84 vs 44%, P<0.001; adjusted between-group odds ratio=6.7; 95% CI, 4.2-10.9). The efficacy of the fixed-dose combination on 25(OH)D was maintained at 6 months (86 vs 40%, P<0.001). Mean 25(OH)D was 65.1 and 49.5 nmol/l, respectively, after 3 months and 66.9 and 45.4 nmol/l after 6 months. Physical performance improved in both groups. Falls were 17 and 20% in the strontium ranelate/vitamin D₃ and strontium ranelate groups respectively. Parathyroid hormone levels were inversely correlated with 25(OH)D. No clinically relevant differences in safety were observed. CONCLUSIONS This study confirms the efficacy and safety of fixed-dose combination of strontium ranelate 2 g/vitamin D₃ 1000 IU for correction of vitamin D insufficiency in osteoporotic patients.

Design for IMEFS (iprielavone multicentre european fracture study)

EFFECT OF CHRONIC TREATMENT WITH IPRIFLAVONE IN POSTMENOPAUSAL WOMEN WITH LOW BONE MASS. C. Gennari, Institute o f Internal Medicine and Medical Pathology, University of Siena, Italy Here we present the results of two multicentre, double-blind. placebo-controlled, 2-yr studies performed to evaluate the efficacy and tolerability of ipriflavone (IP) in post-menopausal women (PMW) with low bone mass, 453 PMW. aged 50-65 yrs. with BMD values lower than 1SD of age-matched controls, were randomly allocated to receive oral IP (200 mg t.i.d, at meals) or matching placebo (PL), plus 1 g oral calcium daily. Vertebral (study A, by DEXA) and radial (study B, by DPA) BMD. serum BGP, and urinary HOPICr were measured every six months. 134 in study A and 196 PMW in study B completed the 2-yr treatment. In study A, valid completers analysis showed a significant increase of BMD in IP treated women (p<0.05), while in PL group BMD significantly decreased, with a bone-sparing effect of 1,6%. The intention to treat analysis confirmed the results in PL group, with no changes in IP group. In study B both analyses showed an increase of radial BMD in IP treated women and a decrease in PL group, with a bone-sparing effect of 3.6%, The differences between treatments were significant (p<0.01) in both studies. Biochemical markers of bone turnover resulted decreased in IP treated patients, suggesting a reduction of bone turnover rate. 26 women in IP group and 28 in PL group dropped out for side-effects, mainly gastrointestinal. The compliance to the oral long-term treatment resulted excellent. The results of these studies show that IP is able to prevent both axial and peripheral bone loss in PMW with low bone mass and is well tolerated.

Effect of acute downhill running on bone markers in responders and non-responders

SummaryThis study showed that procollagen type 1 amino-terminal pro-peptide and N-MID osteocalcin significantly increased after exercise independent of the form of muscle contraction. Thus, these preliminary results will be useful for future studies that will consider bone turnover characteristics of responders and non-responders to acute and chronic aerobic exercise.IntroductionThe aim of the current study was to compare the effects of acute flat running (FR) and downhill running (DHR) on bone turnover markers in men.MethodsFourteen healthy young active men performed three exercise tests in a counterbalanced order, including rest condition, FR, and DHR, at 60% maximal aerobic capacity on a treadmill with 0 and − 12% inclines. Blood samples were taken in the pre-exercise, immediately post-exercise, and 24-h post-exercise periods, and bone markers included total procollagen type 1 amino-terminal pro-peptide (total PINP) and N-MID osteocalcin.ResultsTotal P1NP significantly increased after exercise independent of the form of muscle contraction (p > 0.05). N-MID osteocalcin increased after DHR by 17% compared to after pre-exercise, but the difference did not reach significance (p = 0.07; partial eta square, 0.21). Biomarker responses to exercise were dependent on the exercise form and independent of hormone type in half of the participants who were classified as responders. Physiological parameters and changes in muscle voluntary contraction did not explain the differences between responders and non-responders.ConclusionThe effect of acute DHR on bone turnover is determined by biomarker type and participant characteristics. Future studies should discriminate between the characteristics of responders and those of non-responders.