Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis

The purpose of this randomized, double-masked, placebo-controlled study was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis. The study was conducted at 80 study centers in Europe and Australia. Postmenopausal women (n= 1226) with two or more prevalent vertebral fractures received risedronate 2.5 or 5 mg/day or placebo; all subjects also received elemental calcium 1000 mg/day, and up to 500 IU/day vitamin D if baseline levels were low. The study duration was 3 years; however, the 2.5 mg group was discontinued by protocol amendment after 2 years. Lateral spinal radiographs were taken annually for assessment of vertebral fractures, and bone mineral density was measured by dual-energy X-ray absorptiometry at 6-month intervals. Risedronate 5 mg reduced the risk of new vertebral fractures by 49% over 3 years compared with control (p<0.001). A significant reduction of 61% was seen within the first year (p= 0.001). The fracture reduction with risedronate 2.5 mg was similar to that in the 5 mg group over 2 years. The risk of nonvertebral fractures was reduced by 33% compared with control over 3 years (p= 0.06). Risedronate significantly increased bone mineral density at the spine and hip within 6 months. The adverse-event profile of risedronate, including gastrointestinal adverse events, was similar to that of control. Risedronate 5 mg provides effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving bone density in women with established disease. Received: 29 September 1999 / Accepted: 10 November 1999     

Effects of risedronate on fracture risk in postmenopausal women with osteopenia

Summary This posthoc analysis of four trials studied the efficacy of risedronate to reduce fragility fractures in postmenopausal women with osteopenia (i.e., T-scores between −1 and −2.5). Risedronate reduced the fracture risk by 73% (p = 0.023) in this population of women with low femoral neck bone mass and no prevalent vertebral fractures. Introduction Low bone mass represents an increasing health risk and burden. Half of fragility fractures occur in osteopenic women underscoring the need for treatments reducing fracture risk. This analysis reports the effect of risedronate to reduce fragility fracture risk in osteopenic women without prevalent vertebral fractures. Methods Postmenopausal women with osteopenia, defined as femoral neck T-score between −1 and −2.5 by DXA and no prevalent vertebral fractures, were identified from four controlled randomized trials (BMD Multinational, BMD North America, VERT Multinational and VERT North America). The risk reduction for fragility fractures in patients receiving 5 mg risedronate daily for 1.5 to 3 years compared to placebo was assessed. An additional sensitivity analysis excluded patients who were osteopenic at the femoral neck but had a BMD lower than −2.5 SD at the lumbar spine. Results Six hundred and twenty postmenopausal women with osteopenia were included, receiving either placebo (n = 309) or risedronate 5 mg (n = 311). Risedronate reduced the risk of fragility fractures by 73% over 3 years versus placebo (p = 0.023); cumulative fragility fracture incidence was 6.9% in placebo-treated versus 2.2% in risedronate-treated patients. The magnitude of the effect was similar in the sensitivity analysis subset. Conclusion Risedronate significantly reduced the risk of fragility fractures in postmenopausal women with osteopenia (femoral neck T-score between −1 and −2.5 SD) and no prevalent vertebral fractures.     

Effects of Raloxifene on Fracture Severity in Postmenopausal Women with Osteoporosis: Results from the MORE Study

Raloxifene reduces the risk of new vertebral fractures, but its effect on the severity of these new fractures has not been determined. The MORE (Multiple Outcomes of Raloxifene Evaluation) trial studied the effects of placebo, raloxifene 60 or 120 mg/day in 7705 postmenopausal women with osteoporosis. Radiologists assessed new vertebral fractures from radiographs and graded the fracture severity as normal (no fracture) or mild, moderate or severe. New clinical vertebral fractures were defined as new vertebral fractures associated with symptoms, such as back pain, and confirmed in radiographs. In the total study population, the majority (76.4%) of the women who experienced clinical vertebral fractures were diagnosed with new moderate/severe vertebral fractures. In turn, women with moderate/severe vertebral fractures in the overall population were more likely to experience clinical symptoms suggestive of fracture than were women who had new mild-only vertebral fractures. The incidence of new mild-only and moderate/severe fractures was the same in women without prevalent vertebral fractures, but the incidence of new moderate/severe fractures was 2 to 3 times higher than that for new mild-only fractures in women with prevalent vertebral fractures. Raloxifene 60 mg/day decreased the risk of at least 1 new moderate/severe vertebral fracture by 61% in women without prevalent vertebral fractures [RR 0.39 (95% CI 0.17, 0.69)], and by 37% in women with prevalent vertebral fractures [RR 0.63 (95% CI 0.49, 0.83)] at 3 years. The risk reductions for at least 1 new moderate/severe vertebral fracture were not significantly different between the raloxifene doses, in women with and without prevalent vertebral fractures. The effects of raloxifene on significantly decreasing the risk of new moderate/severe vertebral fractures may explain the risk reduction for new painful clinical vertebral fractures observed with raloxifene, and is particularly important in postmenopausal women with severe osteoporosis who are at higher risk for moderate or severe fractures. Received: 11 April 2002 / Accepted: 19 June 2002 Correspondence and offprint requests to: Ethel Siris, MD, Toni Stabile Osteoporosis Center, Department of Medicine, College of Physicians and Surgeons, Columbia University, 180 Fort Washington Ave, New York, NY 10032, USA. Tel: +1 (212) 305 2529. Fax: +1 (212) 305 6482. e-mail: es27@columbia.edu     

Effects of Risedronate Treatment on Bone Density and Vertebral Fracture in Patients on Corticosteroid Therapy

Men and women (n = 518) receiving moderate-to-high doses of corticosteroids were enrolled in two studies with similar protocols and randomly assigned to receive either placebo or risedronate (2.5 or 5 mg) for 1 year. All patients received daily calcium supplementation (500–1000 mg), and most also received supplemental vitamin D (400 IU). The primary endpoint was the difference between the placebo and active groups in lumbar spine bone mineral density (BMD) at 1 year; changes in BMD at other sites, biochemical markers of bone turnover, and the incidence of vertebral fractures were also assessed. In the overall population, the mean (SE) lumbar spine BMD increased 1.9 ± 0.38% from baseline in the risedronate 5 mg group (P < 0.001) and decreased 1.0 ± 0.4% in the placebo group (P= 0.005). BMD at the femoral neck, trochanter, and distal radius increased or was maintained with risedronate 5 mg treatment, but decreased in the placebo group. Midshaft radius BMD did not change significantly in either treatment group. The difference in BMD between the risedronate 5 mg and placebo groups was significant at all skeletal sites (P < 0.05) except the midshaft radius at 1 year. The 2.5 mg dose also had a positive effect on BMD, although of a lesser magnitude than that seen with risedronate 5 mg. A significant reduction of 70% in vertebral fracture risk was observed in the risedronate 5 mg group compared with the placebo group (P= 0.01). Risedronate was efficacious in both men and women, irrespective of underlying disease and duration of corticosteroid therapy, and had a favorable safety profile, with a similar incidence of upper gastrointestinal adverse events in the placebo and active treatment groups. Daily treatment with risedronate 5 mg significantly increases BMD and decreases vertebral fracture risk in patients receiving moderate-to-high doses of corticosteroid therapy. Received: 11 October 1999 / Accepted: 1 May 2000 / Online publication: 27 July 2000     

Risedronate Rapidly Reduces the Risk for Nonvertebral Fractures in Women with Postmenopausal Osteoporosis

Prevention of nonvertebral fractures, which account for a substantial proportion of osteoporotic fractures, is an important goal of osteoporosis treatment. Risedronate, a pyridinyl bisphosphonate, significantly reduces clinical vertebral fracture incidence within 6 months. To determine the effect of risedronate on osteoporosis-related nonvertebral fractures, data from four large, randomized, double-blind, placebo-controlled, Phase III studies were pooled and analyzed. The population analyzed consisted of postmenopausal women, with and without vertebral fractures, who had low bone mineral density (lumbar spine T-score <–2.5). Patients received placebo (N = 608) or risedronate 5 mg daily (N = 564) for 1 to 3 years. At baseline, 58% had at least one prevalent vertebral fracture, and the mean lumbar spine T-score was –3.4. Among placebo-treated patients, the presence of prevalent vertebral fractures did not increase the risk of incident nonvertebral fractures overall, although fractures of the humerus and hip and pelvis were more common in patients who had prevalent vertebral fractures than in those who did not. Risedronate 5 mg significantly reduced the incidence of nonvertebral fractures within 6 months compared with control. After 1 year, nonvertebral fracture incidence was reduced by 74% compared with control (P = 0.001), and after 3 years, the incidence was reduced by 59% (P = 0.002). The results indicate that risedronate significantly reduces the incidence of osteoporosis-related nonvertebral fractures within 6 months.     

Impact of Hip and Vertebral Fractures on Quality-Adjusted Life Years

The objective of the study was to estimate the impact of hip and vertebral fractures on quality of life in postmenopausal women using a preference-based health measure that is appropriate for economic evaluations and to investigate correlates of health outcome. Interviews to assess health-related quality of life, which also documented other health conditions and characteristics, were undertaken in women age 50 years and older without osteoporotic fractures compared with women with hip and/or vertebral fracture(s). Health status was characterized by self-reported physical limitations and the mental and physical component summary scores of the SF-36. Quality-adjusted life years (QALYs), which reflect each individual’s assessment of her overall health utility, were estimated with time tradeoff values. Regression methods were used to examine QALY correlates (e.g. time since fracture) for each fracture group and to estimate differences in QALYs between fracture and non-fracture subjects after accounting for other patient characteristics. Among 382 women ages 50–96 years, fracture subjects were significantly older, less likely to use hormone replacement therapy and more likely to report physical limitations than non-fracture subjects. On the QALY scale, where 1 represents perfect health and 0 represents death, mean QALY values were 0.82 (95% CI: 0.76, 0.87) among 114 women with one or more vertebral fractures and 0.63 (95% CI: 0.52, 0.74) among 67 with hip fracture compared with 0.91 (95% CI: 0.88, 0.94) among 201 women without fracture. No significant correlates of QALYs were identified among women with vertebral fracture alone. Among hip fracture subjects, time since hip fracture and presence of a vertebral fracture were significant correlates of QALYs. In multiple regression analyses, estimated QALY differences (fracture minus non-fracture subjects) ranged from –0.05 to –0.55 and were equivalent to losses of 20–58 days, 23–65 days and 115–202 days per year for vertebral fracture (p= 0.001), hip fracture (p= 0.009) and hip plus vertebral fracture (p<0.001) subjects, respectively, depending on age. Thus to adequately assess the cost-effectiveness of osteoporosis treatment, the negative impact of vertebral fractures on QALYs, even among women who have survived a hip fracture, must be considered. Received: 2 February 2001 / Accepted: 23 July 2001     

Effects of Alendronate on Bone Density in Men with Primary and Secondary Osteoporosis

Alendronate has been reported to increase bone mineral density (BMD) and reduce fracture risk in women with osteoporosis. As there are no proven safe and effective treatments available for men with osteoporosis, we compared the effects of alendronate (10 mg/day) on BMD, measured using dual-energy X-ray absorptiometry, in a 12-month prospective, controlled, open label study involving (i) men with primary (n= 23) or secondary osteoporosis (n= 18), (ii) postmenopausal women with primary (n= 18) or secondary (n= 21) osteoporosis, and (iii) 29 male and 14 female untreated controls matched by age, height and weight. The patients had one or more vertebral fractures and ranged in age from 34.6 to 85.1 years. BMD was detectably increased relative to baseline by 6 months, and increased by comparable amounts in males and females with primary or secondary osteoporosis. At 12 months, lumbar spine BMD was 5.4%± 1.1% to 7.0%± 2.2% higher in the treated groups compared with baseline and controls (p<0.05 to 0.0001). Trochanteric BMD increased by 2.6%± 1.5% and 3.7%± 1.7% in treated men with primary and secondary osteoporosis, respectively (p = 0.06 to 0.08), and by 3.9%± 1.3% in treated women with primary osteoporosis (p<0.01) after 12 months. No significant changes were detected at the femoral neck or Ward’s triangle. BMD remained unchanged in controls. We infer that alendronate has comparable incremental effects on BMD in men and women with primary and secondary osteoporosis within 12 months of treatment. The changes are in the order of 0.5 SD – effects associated with a clinically worthwhile reduction in fracture risk. The data provide room for optimism regarding the role of alendronate in the treatment of osteoporosis in men. Randomized, double-masked and placebo-controlled trials are needed to confirm these preliminary findings and demonstrate antifracture efficacy using vertebral and nonvertebral fracture rates as the primary endpoint. Received: 23 February 1999 / Accepted: 2 June 1999     

Spinal Performance and Functional Impairment in Postmenopausal Women with Osteoporosis and Osteopenia without Vertebral Fracture

Previous studies have paid much attention to the impact on functional impairment or quality of life from vertebral fractures secondary to osteoporosis, but little research has addressed the function of osteoporotic women without fractures. The purposes of this study were: (1) to describe spinal performance and functional impairment in postmenopausal women with osteoporosis and osteopenia without vertebral fracture, and (2) to investigate the relationship between them. Thirty postmenopausal women diagnosed as having osteoporosis or osteopenia were recruited who fulfilled the following criteria: (1) menopause for at least 6 months; (2) no vertebral fracture; (3) no medication that would interfere with calcium intake. Measurements included assessment of functional impairment and spinal performance including trunk extension/flexion isokinetic strength, spinal range of motion (ROM) and movement velocity in three planes (sagittal, frontal and transverse). The results showed that spinal ROM and velocity were significantly reduced in the osteoporosis group compared with the osteopenia group (p<0.05), but no significant difference in trunk strength was shown. Functional impairment level showed a slight difference between the two groups (p= 0.042). There was a significant correlation between spinal ROM and motion velocity with bone mineral density; however, functional impairment correlated with motion velocity only in the transverse plane (trunk rotation) (p<0.05). Spinal strength did not show any correlation with other parameters. It was concluded that spinal motion performance declined and functional impairment increased in relation to the severity of bone mineral loss in postmenopausal women without vertebral fracture, but their physical performance was not correlated with functional impairments. Received: 13 March 2001 / Accepted: 23 November 2001     

Rapid prevention of vertebral fractures associated with osteoporosis

Osteoporosis affects postmenopausal women and patients on glucocorticoid therapy. Fractures are the most devastating outcome. Patients who experience an osteoporotic vertebral fracture are at substantial risk of experiencing another within 1 year. Risk can be reduced rapidly with antiresorptives. Risedronate reduced the risk of vertebral fracture in patients with post-menopausal or glucocorticoid-induced osteoporosis after 1 year by up to 71% in prospective studies. In post hoc analyses, significant reductions in clinical vertebral fractures were demonstrated after 6 months with risedronate and 1 year with alendronate and raloxifene. Rapid reduction in fracture risk is achievable with the potent therapeutic agents available.     

A Meta-analysis of Etidronate for the Treatment of Postmenopausal Osteoporosis

The aim of the study was to review the effect of etidronate on bone density and fractures in postmenopausal women. We searched MEDLINE from 1966 to 1998, examined citations of relevant articles, and the proceedings of international osteoporosis meetings. We contacted osteoporosis investigators to identify additional studies, primary authors, and pharmaceutical industry sources for unpublished data. We included 13 trials that randomized women to etidronate or an alternative (placebo or calcium and/or vitamin D) and measured bone density for at least 1 year. For each trial, three independent reviewers assessed the methodologic quality and abstracted data. The data suggested a reduction in vertebral fractures with a pooled relative risk of 0.63 (95% CI 0.44 to 0.92). There was no effect on nonvertebral fractures (relative risk 0.99, (95% CI 0.69 to 1.42). Etidronate, relative to control, increased bone density after 1–3 years of treatment in the lumbar spine by 4.06% (95% CI 3.12 to 5.00), in the femoral neck by 2.35% (95% CI 1.66 to 3.04) and in the total body by 0.97% (95% CI 0.39 to 1.55). Effects were larger at 4 years, though the number of patients followed much smaller. Etidronate increases bone density in the lumbar spine and femoral neck for up to 4 years. The pooled estimates of fracture reduction with etidronate suggest a reduction in vertebral fractures, but no effect on nonvertebral fractures. Received: 25 February 2000 / Accepted: 8 August 2000     

The efficacy and tolerability of risedronate on bone mineral density and bone turnover markers in osteoporotic Chinese women: a randomized placebo-controlled study

Osteoporosis has become an important health problem in postmenopausal Asian populations as the prevalence of hip and vertebral fractures in some Asian countries has risen to approach that of Caucasian populations. Risedronate, a pyridinyl-bisphosphonate agent, is a potent inhibitor of bone resorption. Risedronate increases bone mineral density (BMD), reduces markers of bone turnover, and reduces the risk of fractures in Caucasian postmenopausal women. To determine the efficacy and tolerability of risedronate in Chinese, a multicenter, randomized, double blind, placebo controlled study was performed in Hong Kong. Sixty-five (65) postmenopausal osteoporotic Southern Chinese women, aged 67+/-6 years, were randomly assigned to receive either risedronate 5 mg daily (n=31) or placebo (n=34) for 12 months. All women received calcium carbonate 500 mg daily and vitamin D 400 IU daily. Mean baseline BMD T-score at the spine and total hip was -3.4 and -2.6, respectively. A significant increase in spine BMD was already evident at month 3 of risedronate treatment (P<0.001). Risedronate significantly increased BMD and reduced bone turnover markers as compared with placebo. The risedronate group had significant increase in BMD at 12 months at both the spine and hip when compared with the placebo group (L1-4 6.6% vs. 0.4%, P<0.001; total hip 2.7% vs. 0.3, P<0.0001; femoral neck 1.8% vs. 1.1%, P<0.02; trochanter 4% vs. 1.1%, P<0.0001, respectively). Significant changes in urine N-telopeptide (NTx) and serum osteocalcin were evident as early as 1 and 3 months, respectively, with risedronate treatment. No significant changes were seen in both BMD and bone markers in the placebo group. Risedronate was well tolerated without major adverse effects. We conclude that risedronate is an effective and well-tolerated agent for the treatment of postmenopausal osteoporosis in Asian population.     

Quantitative Ultrasound and Symptomatic Vertebral Fracture Risk in Chinese Women

Quantitative ultrasound (QUS) is emerging as a simple, inexpensive and noninvasive method for assessing bone quality and assessing fracture risk. We assessed the usefulness of a contact calcaneal ultrasonometer by studying normal premenopausal women (group I, n= 53), normal postmenopausal women (group II, n= 198), and osteoporotic women without (group III, n= 141) and with vertebral fractures (group IV, n= 53). The osteoporotic subjects had a T-score of the spine or hip neck bone mineral density (BMD) <−2.5 based on the local Chinese peak young mean values. When compared with postmenopausal controls, mean broadband ultrasound attenuation (BUA), speed of sound (SOS), and quantitative ultrasound index (QUI) were 26%, 2.1% and 25% lower in women with vertebral fractures (p all <0.005). The correlation coefficients between QUS parameters and BMD of the spine and hip ranged between 0.4 and 0.5. The ability of the QUS to discriminate between patients groups was determined based on the mean value of normal premenopausal women in group I. The mean T-score for women with fractures was −2.87 ± 1.02 for BUA, −2.54 ± 0.79 for SOS, −3.17 ± 0.70 for QUI, −2.65 ± 0.86 for L2–4 BMD and −2.53 ± 0.66 for hip neck BMD. After adjustment for age and body mass index, the odds ratio of vertebral fracture was 1.71 (95% CI 1.2–2.6) for each 1 SD reduction in BUA, 2.72 (1.3–5.3) for SOS, 2.58 (1.4–4.6) for QUI, 2.33 (1.6–3.3) for L2–4 BMD, 2.09 (1.37–3.20) for femoral neck BMD and 1.88 (1.34–2.92) for total hip BMD. The association between the QUS parameters and vertebral fracture risk persisted even adjustment for BMD. The area under the receiver operating characteristic curve for BUA for vertebral fracture was 0.92, for SOS, QUI, L2–4 BMD and femoral neck BMD was 0.95, and for total hip was 0.91. Received: 7 January 1999 / Accepted: 18 May 1999     

Once‐Weekly Risedronate in Men With Osteoporosis: Results of a 2‐Year,Placebo‐Controlled,Double‐Blind,Multicenter Study

Male osteoporosis is increasingly recognized as a major public health issue. This multinational, 2‐yr, randomized, double‐blind, placebo‐controlled study was conducted to determine the efficacy and safety of 35 mg once‐a‐week risedronate in men with osteoporosis. Patients had to be men ≥30 yr old, with lumbar spine T‐score ≤ ?2.5 and femoral neck T‐score ≤ ?1 SD or lumbar spine T‐score ≤ ?1 and femoral neck T‐score ≤ ?2 SD (based on young normal men). Patients were randomized 2:1 to risedronate 35 mg once a week or placebo for 2 yr; all patients took 1000 mg elemental calcium and 400–500 IU vitamin D daily. Lumbar spine BMD at month 24 using last observation carried forward was the primary endpoint. Other endpoints included lumbar spine BMD at time points other than month 24, proximal femur BMD, bone turnover markers (BTMs), new vertebral fractures, clinical fractures, and adverse event (AE) assessment. There were 284 men enrolled in the study. Treatment with risedronate resulted in a significant increase from baseline to endpoint in lumbar spine BMD compared with placebo (4.5%; 95% CI: 3.5%, 5.6%; p < 0.001). Few new vertebral and nonvertebral fractures were reported, with no differences in fracture rates between the two groups. There was a significant (p < 0.01) reduction from baseline in BTMs for the risedronate group compared with placebo at all time points. No apparent differences in the pattern or distribution of AEs including serious and upper gastrointestinal AEs were observed. Risedronate therapy was well tolerated during this 2‐yr study and was rapidly effective as indicated by significant BTM decreases at month 3 and BMD increases at month 6 (the earliest time points tested). The effects of risedronate treatment on BMD and BTMs in this study were similar to those previously shown to be associated with fracture risk reductions in women with postmenopausal osteoporosis.     

Treatment of osteoporosis by risedronate-- speed, efficacy and safety

Risedronate (Actonel 35 mg), which was promoted in Croatia a few months ago, is the latest (III) generation of bisphosphonates, the most efficient anti-resorption drugs that inhibit osteoclast-mediated bone resorption and change the bone metabolism. The effect of risedronate is 10 times stronger than that of alendronate, and 10.000 times stronger than that of etidronate. The bone turnover is reduced while the osteoblast activity and bone mineralisation are preserved. Decreases in biochemical markers of bone turnover were observed as soon as within 1 month and reached a maximum in 3-6 months of Actonel 35 mg application once a week or 5 mg a day. Several major international, randomised and placebo controlled clinical studies (VERT-NA, VERT-MN, HIP...) on more than 15,000 patients over 3-5 years of therapy have confirmed the speed, efficacy and excellent tolerability of risedronate in treating postmenopausal and corticosteroid-induced osteoporosis. After only 6 months of treatment VERT-NA and VERT-MN have shown a significant reduction in vertebral fracture risk versus control group, radiographically by 62% and clinically by 69% in the first year, which remains significant even after 5 years of treatment (50%) of postmenopausal osteoporosis. All the best properties of bisphosphonates have also been confirmed through a significant reduction in the relative risk of femoral neck fracture over 3 years of treatment by 40%, or by as much as 60% in female patients with osteoporosis and prevalent vertebral fracture, compared with controls. With risedronate we can achieve a quick and significant reduction in vertebral fracture risk in postmenopausal women (65%), especially among a high-risk population such as patients on long-term glucocorticoid therapy (70%) in the very first year of treatment. Prevention and treatment of glucocorticoid-induced osteoporosis is recommended in the administration of 27,5 mg of prednisone or prednisone equivalent in a duration longer than 3 months, irrespective of age or gender. Tolerability and safety of risedronate administration in osteoporosis is very good, almost the same as in the control group, although patients with earlier described or ongoing gastrointestinal troubles were also included. The incidence of endoscopically confirmed gastric ulcer in treatment with alendronate is significantly higher (13,2%) versus controls than in treatment with risedronate (4,1%). Risedronate is hence the first line of bisphosphonates for the reduction of vertebral and non-vertebral fracture risks in postmenopausal women with osteoporosis or those with a high risk of osteoporosis. It also efficiently prevents bone loss or improves bone density in men and women on a long-term corticosteroid therapy.     

Risedronate decreases fracture risk in patients selected solely on the basis of prior vertebral fracture

The aim of this study was to examine the effects of risedronate (5 mg/daily) in patients identified solely on the basis of a prior fragility fracture, without BMD as an inclusion criterion. A total of 1,802 patients were examined from the VERT-NA and VERT-MN clinical trials. Lateral radiographs (T4 to L4) were obtained at baseline and annually; incident fractures were evaluated using quantitative and semiquantitative methods at the central facility. BMD was measured at the lumbar spine and femoral neck by dual-energy X-ray absorptiometry. Secondary analyses evaluated vertebral fracture efficacy in patient subgroups categorized according to the presence of risk factors for osteoporosis at baseline (age, femoral neck BMD, lumbar spine BMD, more severe BMD, height, weight, body mass index, prevalent nonvertebral fracture status, smoking, and bone turnover marker levels). Over 3 years, risedronate reduced the risk of new vertebral fractures by 44% (95% CI, 28% to 56%) compared with placebo. In patients subgrouped according to the presence or absence of putative risk factors, the efficacy of risedronate was comparable across all groups (all treatment-by-non BMD subgroup interactions p0.210). Adjustment for age, baseline BMD, and prevalent vertebral fractures on fracture risk gave results similar to the unadjusted analysis. In patients taking placebo, the incidence of new vertebral fracture was higher in several of the high-risk categories (elderly, T-score –2.5 SD). In conclusion, the findings of this study suggest that risedronate is effective in patients identified solely on the basis of a prior fragility fracture and that the efficacy of risedronate in the reduction of vertebral fractures is largely independent of the presence of clinical risk factors for osteoporotic fracture.Abbreviations LS Lumbar spine - VERT-MN Vertebral Efficacy with Risedronate Therapy Multinational - VERT-NA Vertebral Efficacy with Risedronate Therapy North American     

Performance of COLIA1 Polymorphism and Bone Turnover Markers to Identify Postmenopausal Women with Prevalent Vertebral Fractures

Some studies have suggested that bone turnover markers (BTM) and collagen type I alpha 1 gene (COLIA1) may be useful in the prediction of rates of future bone loss, and may therefore provide information about fracture risk. Our study aimed to examine the association of the COLIA1 genotype with the risk of vertebral fracture and to investigate the predictive value of this genetic factor in comparison with bone mineral density (BMD) and BTM, in ambulatory postmenopausal Spanish women. We determined the COLIA1 polymorphism by polymerase chain reaction, BMD by dual-energy X-ray absorptiometry and BTM in 43 postmenopausal women with prevalent vertebral fracture and a control group of 101 postmenopausal women without fracture. There was a significant overrepresentation of the ‘T’ allele in fractured women (p= 0.029). BTM exhibited no differences between women with or without fractures or COLIA1 genotype groups. After adjusting for all other variables, the osteoporosis densitometric criteria variable was the most strongly associated with fracture (OR = 5 [1.8–13.3]) followed by COLIA1 (OR = 2.1 [1–4.3] per copy of the ‘T’ allele). Our study shows that COLIA1 is associated with prevalent vertebral fracture independently of bone mass, and the performance of this genetic factor to assess prevalent vertebral fracture is better than bone turnover markers. Received: 29 June 2001 / Accepted: 11 December 2001     

Total Body Bone Measurements in Spinal Osteoporosis by Dual-Energy X-Ray Absorptiometry

Changes in total body bone mineral content (BMC_TB) and density (BMD_TB), and the T-score of BMC_TB and (BMD_TB) were evaluated in relation to the number of vertebral fractures in women with postmenopausal osteoporosis for the purpose of defining deviations in these parameters that could be predictive of the occurrence of vertebral fracture. The study group consisted of 62 women diagnosed with postmenopausal osteoporosis. All of them had two or more spinal fractures. Regression analysis of the number of fractures against each parameter studied indicated that the following were predictive of the risk of fracture: a reduction of −0.5 in the T-score of both BMC_TB and BMD_TB (P < 0.0001) and a loss of about 135 g of BMC_TB or 0.058 g/cm² of BMD_TB (P < 0.0001). The fact that such changes were found during the follow-up of women with osteoporosis highlights the importance of bone mass measurements during follow-up. Received: 9 July 1996 / Accepted: 3 January 1997     

Do Men and Women Fracture Bones at Similar Bone Densities?

When the World Health Organization (WHO) guidelines for the definition of osteoporosis in postmenopausal women were identified similar proposals were not developed for men as there was insufficient evidence about the relationship between bone density and fracture in men. We have therefore examined the relationship between bone density and vertebral fracture in men and women attending for assessment of possible osteoporosis. Two hundred and sixty-four women (age 64 [SD 10] years) and 37 men (age 55 [10] years) were studied. Bone density was measured in the lumbar spine and femoral neck by dual-energy X-ray absorptiometry and expressed both as bone mineral density (BMD; g/cm²) and as T-scores. In both sexes there was a sigmoid relationship between the cumulative frequency of vertebral fracture and bone density at both sites. There was a linear relationship between the log odds of fracture and bone mass for both sexes and both sites (r= 0.97–0.99; p<0.0001). The slope of these lines was significantly steeper for men than women. The BMD at which there was 50% risk of fracture was higher in men than women (0.908 vs 0.844 g/cm²). The difference between the slopes was similar when the bone mass was expressed as a T-score. However, the T-score associated with 50% prevalence of fracture was similar in the two sexes (F: −2.77 vs M: −2.60). We conclude that although there is a different relationship between bone density and fracture in the two sexes the current WHO definition of osteoporosis in postmenopausal women can be appropriately applied to men. Received: 24 February 1999 / Accepted: 12 July 1999     

Prevention of Bone Loss with Risedronate in Glucocorticoid-Treated Rheumatoid Arthritis Patients

The aim of the study was to assess risedronate’s effect on bone mineral density in postmenopausal women with rheumatoid arthritis receiving glucocorticoids. We carried out a two center, 2 year, double-masked, placebo-controlled trial with a third year of nontreatment follow-up. We studied 120 women requiring long-term glucocorticoid therapy at >2.5 mg/day prednisolone randomized to treatment with daily placebo; daily 2.5 mg risedronate; or cyclical 15 mg risedronate (2 out of 12 weeks). At 97 weeks, bone mineral density was maintained at the lumbar spine (+1.4%) and trochanter (+0.4%) in the daily 2.5 mg risedronate group, while significant bone loss occurred in the placebo group (–1.6%, p= 0.03; and 4.0%, p<0.005, respectively). At the femoral neck, there was a nonsignificant bone loss in the daily 2.5 mg risedronate group (–1.0%) while in the placebo group bone mass decreased significantly (–3.6%, p<0.001). The difference between placebo and daily 2.5 mg risedronate groups was significant at the lumbar spine (p= 0.009) and trochanter (p= 0.02) but did not reach statistical significance at the femoral neck. Although not significantly different from placebo at the lumbar spine, the overall effect of the cyclical regimen was similar to that of the daily 2.5 mg risedronate regimen. Treatment withdrawal led to bone loss in the risedronate groups that was significant at the lumbar spine. A similar number of patients experienced adverse events (including upper gastrointestinal events) across treatment groups and risedronate was generally well tolerated. Thus risedronate preserves bone mass in postmenopausal women with rheumatoid arthritis receiving glucocorticoids while patients receiving a placebo have significant bone loss. Received: 2 June 1999 / Accepted: 29 September 1999     

Vitamin D Receptor Gene Polymorphisms, Bone Mass, Bone Loss and Prevalence of Vertebral Fracture: Differences in Postmenopausal Women and Men

Bone mineral density (BMD), the major determinant of fracture risk, is under strong genetic control. Although polymorphisms of the vitamin D receptor (VDR) gene have been suggested to account for some of the genetic variation in bone mass, the influence of VDR genotypes on osteoporosis remains controversial. Previous published studies have focused mainly on women, but the pattern of response in men has not been determined. Using the BsmI restriction enzyme, we studied the influence of the different VDR genotypes on bone mass, bone loss and the prevalence of vertebral fractures in a population-based sample of both sexes (n = 326). BMD was measured at the lumbar spine and femoral neck, with a 4-year interval, using dual-energy X-ray absorptiometry. Vertebral fractures were assessed by two lateral radiographs at the beginning and end of the study. The prevalence of the three possible VDR genotypes was similar to those in other Caucasian populations and no differences were found between men and women. Women with the favorable bb genotype showed significantly higher BMD values at the lumbar spine and femoral neck, and a positive rate of BMD change at the femoral neck compared with women with the BB and Bb genotypes. Moreover, women with the bb genotype showed a trend toward a lower prevalence and incidence of vertebral fractures (p= 0.07). We have not found any differences between VDR genotypes in men. In conclusion, VDR gene polymorphisms are related to bone mass and bone loss in women; also a trend in the prevalence of vertebral fractures was observed in postmenopausal women but not in men. Received: 8 June 1998 / Accepted: 7 December 1998