Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy.

Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, raloxifene-treated patients had a statistically significantly lower vertebral fracture risk compared with placebo-treated patients. The decrease in fracture risk with raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with raloxifene therapy are poor predictors of vertebral fracture risk reduction with raloxifene therapy.     

Six and Twelve Month Changes in Bone Turnover are Related to Reduction in Vertebral Fracture Risk During 3 Years of Raloxifene Treatment in Postmenopausal Osteoporosis

We studied the relationship between change in bone turnover and vertebral fracture risk during raloxifene therapy using 3-year data from the MORE trial, where 2622 of the 7705 randomized women had measurement of bone markers at baseline and after 6 and 12 months participation. Change in bone turnover was significantely related to future risk of vertebral fracture, also after adjusting for baseline vertebral fracture status and BMD. Thus, for a decrease of 9.3 mg/l in serum osteocalcin after 1 year’s raloxifene therapy, the odds ratio (OR) for a new vertebral fracture during 3 years was 0.69 (0.54–0.88), p= 0.003. Similarly, for a decrease of 5.91 mg/l in serum bone alkaline phosphatase, OR was 0.75 (0.62–0.92), p= 0.005. The change in BMD over 12 and 24 months was not related to fracture risk in any of the analyses. The strongest predictor for vertebral fracture was prevalent vertebral fracture – even during therapy. The predictive value of baseline BMD was in the same order of magnitude as bone turnover change during raloxifene treatment. In conclusion, the change in bone turnover is related to fracture risk during raloxifene therapy. In contrast the change in BMD is not related to fracture risk. The strongest predictor for vertebral fracture is prevalent vertebral fracture. Received: 2 January 2001 / Accepted: 30 May 2001     

Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover

INTRODUCTION: Teriparatide is a bone formation agent that increases bone turnover and mass, resulting in an increase in bone strength and a decrease in fracture risk. METHODS: The primary purpose of this analysis was to evaluate the association between pretreatment bone turnover marker (BTM) concentrations and the absolute and relative fracture risks after adjusting for baseline femoral neck BMD, number of prevalent vertebral fractures, and age. Because femoral neck BMD is commonly attained in the assessment of patients at risk for osteoporosis, we examined the ability of a multivariate assessment including pretreatment BTM concentration and femoral neck BMD to predict future fracture risk after adjusting for the number of prevalent vertebral fractures. We examined data from the Fracture Prevention Trial, a study designed to determine the effect of teriparatide 20 mcg/day and teriparatide 40 mcg/day on vertebral and nonvertebral fracture risk in postmenopausal women with osteoporosis. BTM were analyzed in two subsets of women within the Fracture Prevention Trial, and included serum bone-specific alkaline phosphatase (BSAP), serum carboxy-terminal extension peptide of procollagen type I (PICP), serum amino-terminal extension peptide of procollagen type I (PINP), urinary free deoxypyridinoline (DPD), and urinary N-terminal telopeptide (NTX). RESULTS: Teriparatide significantly reduced the risk of fracture [four BTM subset (n = 520), placebo = 14.3%, teriparatide = 5.8%, P < 0.05; PINP subset (n = 771), placebo = 17.7%, teriparatide = 5.5%, P < 0.05]. Subjects with the highest pretreatment BTM concentrations had the greatest fracture risk. Teriparatide-mediated absolute risk reduction was greatest for women with high pretreatment bone turnover; however, the relative fracture risk reduction was independent of pretreatment bone turnover. After adjusting for pretreatment BTM and number of prevalent vertebral fractures, baseline femoral neck BMD was not a significant predictor of fracture risk. CONCLUSION: Teriparatide-mediated relative fracture risk reduction was independent of pretreatment bone turnover, demonstrating that this therapy offers clinical benefit to patients across a range of disease severity.     

Reduction in PINP, a marker of bone metabolism, with raloxifene treatment and its relationship with vertebral fracture risk

In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis, defined by low bone mineral density and/or prevalent vertebral fractures (VF), were randomized to placebo or raloxifene (60 or 120 mg/day). All women received daily calcium (500 mg) and vitamin D (400-600 IU) supplements. Our previous analyses found that changes in BMD and biochemical markers of bone turnover are poorly predictive of the reduction in VF risk observed with raloxifene. This present study evaluated the effects of raloxifene on type I procollagen N-terminal propeptide (PINP), a new marker of bone turnover. Logistic regression analysis models evaluated the relationships between the changes at 1 year in PINP, serum osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), and urinary excretion of type I collagen C-telopeptide fragments normalized to creatinine (CTx/Cr), and the risk of new VF at 3 years for placebo and pooled raloxifene. A subset of 967 women (mean age = 68 years) from the MORE cohort had PINP, OC, BSAP, and CTx evaluated at baseline. Both doses of raloxifene significantly decreased (P < 0.001) all biochemical markers of bone turnover from baseline. Compared to baseline, PINP levels were decreased by medians of 11.0% and 40.8% in the placebo and pooled raloxifene groups, respectively. In addition, the placebo and pooled raloxifene groups decreased serum OC by 8.5% and 31.8%, BSAP by 15.8% and 34.6%, and urinary CTx/Cr excretion by 5.6% and 46.5%, respectively, from baseline. In the pooled raloxifene group, the logistic regression relationship between 3-year VF risk and 1-year percentage change for each biochemical marker was statistically significant with PINP (slope estimate = 0.0085, P = 0.009), OC (slope estimate = 0.0068, P = 0.035), and BSAP (slope estimate = 0.0056, P = 0.039), but not with CTx/Cr (slope estimate = 0.0027, P = 0.192). Furthermore, the percent decrease in PINP at 1 year could account for 28% of the total reduction in vertebral fracture risk. In conclusion, a 1-year decrease in PINP, BSAP, or OC, but not CTx/Cr, may be predictive of the 3-year VF risk reduction with raloxifene therapy in this subset of postmenopausal women with osteoporosis.     

Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial

Prevalent vertebral fractures and baseline bone mineral density (BMD) predict subsequent fracture risk. The objective of this analysis is to examine whether baseline vertebral fracture severity can predict new vertebral and nonvertebral fracture risk. In the randomized, double-blind 3-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis (low BMD or prevalent vertebral fractures) were randomly assigned to placebo, raloxifene 60 mg/day, or raloxifene 120 mg/day. Post hoc analyses studied the association between baseline fracture severity and new fracture risk in the placebo group and the effects of placebo, raloxifene 60 mg/day, and raloxifene 120 mg/day on new fracture risk in women with the most severe prevalent vertebral fractures (n = 614). Vertebral fracture severity was visually assessed using semiquantitative analysis of radiographs and categorized by estimated decreases in vertebral heights. Reported new nonvertebral fractures were radiographically confirmed. Baseline vertebral fracture severity predicted vertebral and nonvertebral fracture risk at 3 years. In women without prevalent vertebral fractures, 4.3 and 5.5% had new vertebral and nonvertebral fractures, respectively. In women with mild, moderate, and severe prevalent vertebral fractures, 10.5, 23.6, and 38.1% respectively had new vertebral fractures, whereas 7.2, 7.7, and 13.8% respectively experienced new nonvertebral fractures. Number of prevalent vertebral fractures and baseline BMD also predicted vertebral fracture risk, but the severity of prevalent vertebral fractures was the only predictor of nonvertebral fracture risk and remained a significant predictor after adjustment for baseline characteristics, including baseline BMD. In patients with severe baseline vertebral fractures, raloxifene 60 mg/day decreased the risks of new vertebral [RR 0.74 (95% Cl 0.54, 0.99); P = 0.048] and nonvertebral (clavicle, humerus, wrist, pelvis, hip, and leg) fractures [RH 0.53 (95% CI 0.29, 0.99); P = 0.046] at 3 years. To prevent one new fracture at 3 years in women with severe baseline vertebral fractures with raloxifene 60 mg/day, the number needed to treat (NNT) was 10 for vertebral and 18 for nonvertebral fractures. Similar results were observed in women receiving raloxifene 120 mg/day. In summary, baseline vertebral fracture severity was the best independent predictor for new vertebral and nonvertebral fracture risk. Raloxifene decreased new vertebral and nonvertebral fracture risk in the subgroup of women with severe vertebral fractures at baseline. These fractures may reflect architectural deterioration, independent of BMD, leading to increased skeletal fragility.     

Associations between baseline risk factors and vertebral fracture risk in the Multiple Outcomes of Raloxifene Evaluation (MORE) Study.

Different risk factors may influence the effectiveness of osteoporosis therapies. The interaction of 30 baseline risk factors and the effectiveness of raloxifene in the MORE study were assessed. The efficacy of raloxifene in reducing vertebral fractures is largely independent of the presence of clinical risk factors for osteoporotic fractures. INTRODUCTION: The aim of this analysis was to determine the effect of different risk factors on the effectiveness of raloxifene to reduce vertebral fractures in the Multiple Outcomes of Raloxifene Evaluation (MORE) study using logistic regression models. MATERIALS AND METHODS: The association was assessed using univariate analyses and a multivariate model between 30 potential risk factors at baseline and the risk of vertebral fractures after 3 years in the placebo group, as well as the interaction of risk factors with raloxifene therapy (at a dose of 60 or 120 mg/day). RESULTS AND CONCLUSIONS: In the univariate analysis of the placebo group, after adjusting for baseline lumbar spine BMD (LS BMD), short stature (odds ratio [OR] = 1.18), age (OR = 1.38), years since menopause (OR = 1.38), impaired cognitive function, visuospatial capabilities (OR = 1.19), impaired musculoskeletal strength (OR = 1.23), low femoral neck BMD (OR = 1.21), and prior vertebral fracture (OR = 4.95) were significantly associated with the incidence of new vertebral fractures. In the univariate analysis, significant interactions were observed between raloxifene treatment and age (p = 0.04), serum triglycerides (p = 0.03), LS BMD (p = 0.08), and diabetes mellitus (p = 0.04). In the multivariate analysis, the effectiveness of raloxifene was independent of almost all risk factors, with the exception of baseline serum triglyceride level and LS BMD, suggesting an increased efficacy of raloxifene in patients with increased triglyceride levels (p = 0.006) and lower LS BMD values (p = 0.008) at baseline. These data suggest that the efficacy of raloxifene in reducing vertebral fractures is largely independent of the presence of clinical risk factors for osteoporotic fractures.     

Femoral neck bone loss predicts fracture risk independent of baseline BMD.

Whereas low BMD is known to be a risk factor for fracture, it is not clear whether loss of BMD is also a risk factor. In elderly women, greater loss of BMD at the femoral neck was associated with increased risk of fracture, independent of baseline BMD and age. INTRODUCTION: Baseline measurement of BMD predicts fracture risk. However, it is not clear whether short-term bone loss is an independent risk factor for fractures. This study was designed to investigate the relationship between changes in BMD and fracture risk in elderly women in the general population. MATERIALS AND METHODS: A total of 966 women > or = 60 years of age (mean, 70 +/- 6.7 [SD] years), who had been followed for an average of 10.7 years, were studied. Atraumatic fracture of the proximal femur (hip), symptomatic vertebral fracture, and other major fractures, excluding pathological fractures or those resulting from severe trauma, were recorded and confirmed by radiographs. Femoral neck and lumbar spine BMD was measured by DXA. RESULTS: During the follow-up period, 224 had sustained a fracture (including 43 hip, 71 symptomatic vertebrae, 37 proximal humerus, 46 forearm and wrist, and 27 rib and pelvis fractures). The annual rate of change in BMD in fracture women (-2.1 +/- 4.2%) was significantly higher than that in nonfracture women (-0.8 +/- 2.8%; p = 0.005). In the multivariable Cox's proportional hazards analysis, the following factors were significant predictors of fracture risk: femoral neck bone loss (relative hazard [RH], 1.4; 95% CI, 1.1-1.8 per 5% loss), baseline femoral neck BMD (RH, 2.0; 95% CI, 1.7-2.7 per SD), and advancing age (RH, 1.2; 95% CI, 1.1-1.4). The proportion of fractures attributable to the three factors was 45%. For hip fracture, the attributable risk fraction was approximately 90%. CONCLUSION: Bone loss at the femoral neck is a predictor of fracture risk in elderly women, independent of baseline BMD and age.     

Efficacy of risedronate administration in osteoporotic postmenopausal women affected by inflammatory bowel disease

Patients with inflammatory bowel disease (IBD) have frequently a bone mineral density (BMD) significantly lower than age-matched healthy subjects. The low BMD observed in IBD patients is related also to a higher incidence of bone fractures. In this prospective randomized study we evaluated the effect of 1-year risedronate administration on bone mass and turnover, and on vertebral fractures in osteoporotic postmenopausal women with IBD in remission. Ninety osteoporotic postmenopausal women were randomized to receive oral risedronate 35 mg/week (risedronate group) or placebo tablets (placebo group; one tab/week). The duration of treatment was 12 months. At entry and after treatment, lumbar spine and hip BMD, and serum osteocalcin (OC) and urinary deoxypyridinoline/creatinine ratio (DPD-Cr) levels were evaluated. Vertebral fractures were assessed from thoracic and lumbar lateral and anterior-posterior spinal radiographs taken at baseline, and from lateral spinal radiographs taken at the end of the study. At study entry, no difference between groups was also detected in BMD and in bone turnover markers. At the end of the study, lumbar spine, trochanter and femoral neck BMD was significantly ( p <0.05) higher in comparison with baseline in the risedronate group, whereas a significant ( p <0.05) decrease was observed in the placebo group. For the same visit, a significant ( p <0.05) difference in lumbar spine, trochanter and femoral neck BMD was detected between groups. After 12-month follow-up, serum OC and urinary DPD-Cr levels were significantly ( p <0.05) lower and higher in comparison with basal values in risedronate and placebo group, respectively. At the same time, a significant ( p <0.05) difference in serum OC and urinary DPD-Cr levels was observed between groups. Throughout the study, the incidence of vertebral fractures was significantly ( p <0.05) lower in the risedronate group than in the placebo group (12.5% vs 34.1%). The relative risk (RR) to develop a new vertebral fracture after 1 year of risedronate administration was of 0.36 (95% confidence interval, 0.14–0.85). In conclusion, risedronate administration is an effective anti-osteoporotic treatment in osteoporotic postmenopausal women with IBD in remission.     

Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study.

In the CORE breast cancer trial of 4011 women continuing from MORE, the incidence of nonvertebral fractures at 8 years was similar between placebo and raloxifene 60 mg/day. CORE had limitations for assessing fracture risk. In a subset of 386 women, 7 years of raloxifene treatment significantly increased lumbar spine and femoral neck BMD compared from the baseline of MORE. INTRODUCTION: The multicenter, double-blind Continuing Outcomes Relevant to Evista (CORE) trial assessed the effects of raloxifene on breast cancer for 4 additional years beyond the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial. MATERIALS AND METHODS: In CORE, placebo-treated women from MORE continued with placebo (n = 1286), whereas those previously given raloxifene (60 or 120 mg/day) received raloxifene 60 mg/day (n = 2725). As a secondary endpoint, new nonvertebral fractures were analyzed as time-to-first event in 4011 postmenopausal women at 8 years. A substudy assessed lumbar spine and femoral neck BMD at 7 years, with the primary analysis based on 386 women (127 placebo, 259 raloxifene) who did not take other bone-active agents from the fourth year of MORE and who were > or =80% compliant with study medication in CORE. RESULTS: The risk of at least one new nonvertebral fracture was similar in the placebo (22.9%) and raloxifene (22.8%) groups (hazard ratio [HR], 1.00; Bonferroni-adjusted CI, 0.82, 1.21). The incidence of at least one new nonvertebral fracture at six major sites (clavicle, humerus, wrist, pelvis, hip, lower leg) was 17.5% in both groups. Posthoc Poisson analyses, which account for multiple events, showed no overall effect on nonvertebral fracture risk, and a decreased risk at six major nonvertebral sites in women with prevalent vertebral fractures (HR, 0.78; 95% CI, 0.63, 0.96). At 7 years after MORE randomization, the differences in mean lumbar spine and femoral neck BMD with raloxifene were 1.7% (p = 0.30) and 2.4% (p = 0.045), respectively, from placebo. Compared with MORE baseline, after 7 years, raloxifene treatment significantly increased lumbar spine (4.3% from baseline, 2.2% from placebo) and femoral neck BMD (1.9% from baseline, 3.0% from placebo). BMDs were significantly increased from MORE baseline at all time-points at both sites with raloxifene. CONCLUSION: Raloxifene therapy had no effect on nonvertebral fracture risk after 8 years, although CORE had limitations for fracture risk assessment. BMD increases were maintained after 7 years of raloxifene.     

Effects of Bazedoxifene on BMD and Bone Turnover in Postmenopausal Women: 2‐Yr Results of a Randomized,Double‐Blind,Placebo‐, and Active‐Controlled Study

Osteoporosis is an increasingly common health concern in postmenopausal women. In a 2‐yr phase III study, bazedoxifene prevented bone loss, reduced bone turnover, and was well tolerated in early postmenopausal women with normal or low BMD. Introduction : Bazedoxifene is a novel selective estrogen receptor modulator that has increased BMD and bone strength in experimental models, without stimulating breast or uterus. This 24‐mo, randomized, double‐blind study assessed the efficacy and safety of three doses of bazedoxifene compared with placebo and raloxifene in the prevention of postmenopausal osteoporosis. Materials and Methods : Healthy postmenopausal women with a BMD T‐score at the lumbar spine or femoral neck between –1.0 and ?2.5 or clinical risk factors for osteoporosis were randomly assigned to one of five groups: bazedoxifene 10, 20, or 40 mg/d, placebo, or raloxifene 60 mg/d. All women received elemental calcium. Efficacy outcomes included changes from baseline through 24 mo in BMD of the lumbar spine, hip, femoral neck, and femoral trochanter and biomarkers of bone metabolism. Results : The intent‐to‐treat population included 1434 women (mean age, 58 yr; mean time from last menstrual period, 11 yr). All doses of bazedoxifene and raloxifene prevented bone loss, whereas in the placebo group, there was significant loss of BMD at all skeletal sites. Mean differences in percent change in lumbar spine BMD from baseline to 24 mo relative to placebo were 1.08 ± 0.28%, 1.41 ± 0.28%, 1.49 ± 0.28%, and 1.49 ± 0.28% for 10, 20, and 40 mg bazedoxifene and 60 mg raloxifene, respectively (p < 0.001 for all comparisons). Comparable BMD responses were observed at other body sites. Significant and comparable decreases in serum osteocalcin and C‐telopeptide levels from baseline and relative to placebo with active treatment were observed as early as 3 mo and were sustained through study conclusion (p < 0.001). Overall incidences of adverse events, serious adverse events, and discontinuations caused by adverse events were similar between groups. The most common adverse events included headache, infection, arthralgia, pain, hot flush, and back pain. Conclusions : Treatment with bazedoxifene prevented bone loss and reduced bone turnover equally as well as raloxifene and was generally well tolerated in postmenopausal women with normal/low BMD.     

Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis: a reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial

Raloxifene reduces vertebral fracture risk in postmenopausal women with osteoporosis and established osteoporosis, but its efficacy in women with osteopenia has not been studied. The objective of this study was to evaluate the effect of raloxifene hydrochloride on the risk of vertebral fractures in postmenopausal women with osteopenia and to compare this effect with that in women with osteoporosis as defined by the bone mineral density (BMD) T-score at the hip. We studied the 3204 postmenopausal women with osteopenia or osteoporosis without vertebral fractures at baseline in the Multiple Outcomes of Raloxifene Evaluation trial. Compared with placebo, 60 mg/day raloxifene reduced the risk of new vertebral fractures at 3 years independent of baseline total hip BMD. The relative risk for new vertebral fractures for the raloxifene group compared with placebo was 0.53 (95% CI, 0.32-0.88) for those with osteopenia and 0.31 (0.06-0.71) for those with osteoporosis. In raloxifene-treated women the rate of vertebral fracture was similar in women with osteoporosis (2%) to that in women with osteopenia (1.9%). For clinically apparent vertebral fractures, the relative risk of fracture in the osteopenia group for raloxifene was 0.25 (0.04-0.63) compared with placebo. There were no new clinical vertebral fractures in women with osteoporosis receiving raloxifene, whereas four occurred in the placebo group. We conclude that treatment with 60 mg/day raloxifene significantly decreases the risk of new vertebral fractures and new clinical vertebral fractures in postmenopausal women without baseline vertebral fracture who have osteopenia or osteoporosis.     

Relationships Between Changes in Bone Mineral Density or Bone Turnover Markers and Vertebral Fracture Incidence in Patients Treated with Bazedoxifene

We analyzed the relationships between bone mineral density (BMD) or bone turnover marker (BTM) changes and vertebral fracture incidence in women treated with bazedoxifene using a post hoc analysis from a 3-year randomized, placebo-controlled study evaluating the effect of bazedoxifene (20 or 40?mg) on fracture risk reduction. BMD was assessed at baseline and every 6?months for 3?years. Osteocalcin and C-telopeptide of type I collagen were assessed at baseline and at 3, 12, and 36?months. Vertebral fractures were assessed with a semiquantitative visual assessment. Data were available for 5,244 women, of whom 3,476 were treated with bazedoxifene. Using a logistic regression analysis and the classical Li approach, the proportion of fracture incidence explained by BMD change after 3?years of bazedoxifene treatment was 29?% for the total hip and 44?% for the femoral neck. The proportion of treatment explained by lumbar BMD change could not be quantified accurately because of the significant interaction between treatment and change in BMD. With the same model, the 12-month BTM changes explained up to 29?% of the fracture risk reduction observed with the two forms of bazedoxifene. In women treated with bazedoxifene, changes in femoral neck BMD, hip BMD, or BTMs explained a moderate proportion of the fracture risk reduction observed during the 3?years of follow-up. However, BMD or BTM changes cannot be recommended for individual monitoring of women treated with bazedoxifene.     

Fracture prediction from bone mineral density in Japanese men and women.

In a cohort of 2356 Japanese elderly, after adjusting for age and prevalent vertebral fracture, baseline BMD predicted the risk of spine and hip fracture with similar RR to that obtained from previous reports in whites. The RR per SD decrease in BMD for fracture declined with age. INTRODUCTION: Low bone mineral density (BMD) is one of the most important predictors of a future fracture. However, we are not aware of any reports among Japanese in Japan. MATERIALS AND METHODS: We examined the association of BMD with risk of fracture of the spine or hip among a cohort of 2356 men and women aged 47-95 years, who were followed up by biennial health examinations. Follow-up averaged 4 years after baseline measurements of BMD that were taken with the use of DXA. Vertebral fracture was assessed using semiquantitative methods, and the diagnosis of hip fracture was based on medical records. Poisson and Cox regression analysis were used. RESULTS: The incidence was twice as high in women as in men, after adjusting for age. After adjusting for baseline BMD and prevalent vertebral fracture, however, the gender difference was no longer significant. Age, baseline BMD of spine and femoral neck, and prior vertebral fracture predicted vertebral fracture and hip fracture. Loss of absolute BMD of the femoral neck predicted spine fracture, after adjusting for baseline BMD; rates of change in percent BMD, weight, height, body mass index, and age at menopause did not. The predictive value of baseline BMD for vertebral fracture risk was similar in men and women. The relative risk (RR) for vertebral fracture and hip fracture per SD decrease in BMD declined with age, after adjustment for prevalent vertebral fractures. CONCLUSIONS: Baseline BMD, loss of femoral neck BMD, and prior vertebral fracture predict the risk of spine and hip fracture in Japanese with similar RR to that obtained from previous reports in whites. The RR per SD decrease in BMD for fracture declined with age, suggesting that factors other than BMD might play a greater role in the elderly.     

A comprehensive review of treatments for postmenopausal osteoporosis

 The aim of this review is to assess the efficacy of treatments for postmenopausal osteoporosis in women with low bone mass or with an existing vertebral fracture. We searched the literature for studies (randomized, double-masked, placebo-controlled and prospective) that reported on drugs registered in Europe or North America. We included 41 reports on 12 agents. To assess the consistency among the studies for each drug, we plotted the percent change in bone mineral density (BMD) for the control group against the percent change in BMD for the treated group for lumbar spine and femoral neck. We used methods of cluster analysis to determine consistency among the studies. For each agent we summarized the relative risk for vertebral fracture (patients with new fracture) and for hip fractures. The duration of the studies ranged from 1 to 4.3 years. The proportion of patients who discontinued treatment ranged from 4% to 80%. Most of the studies reported on change in BMD. Twenty-six studies (10 drugs) provided data on new vertebral fractures and 12 (6 drugs) on hip fractures. Apart from fluoride effects on spine BMD, increases in BMD with bisphosphonates were greater than those seen with the remaining treatments. Generally, for each agent the changes in BMD (relative to placebo) were consistent among the studies. The exceptions were calcitriol and calcitonin for changes in BMD of the spine and of the femoral neck. Alendronate, calcitonin, risedronate and raloxifene caused significant reductions in the risk of vertebral fractures. Alendronate, risedronate or the combination of calcium plus vitamin D had a significant effect on the risk of hip fracture. Most therapies are effective in increasing BMD; some decrease the risk of vertebral fracture. For hip fracture, alendronate and risedronate reduce the risk in women with osteoporosis, and calcium and vitamin D reduce the risk in institutionalized patients. Received: 15 October 2001 / Accepted: 18 July 2002 Acknowledgement We acknowledge the invaluable help of J. Jeger, MD, for useful discussion, D. Thompson, PhD, for statistical advice, and D. Koch for data collection. We thank Mrs M. Perez for secretarial assistance. This work was partially supported by a grant from the Merck Sharp and Dohme-Chibret Company (Glattbrugg, Switzerland).     

The effect of raloxifene treatment in postmenopausal women with CKD

It is unknown whether treatment for osteoporosis with raloxifene is safe or effective in those with chronic kidney disease (CKD). With data from a multicenter, randomized, placebo-controlled trial of 7705 postmenopausal women with osteoporosis, the effect of raloxifene on rate of change of bone mineral density (BMD), incidence of fractures, and adverse events by stage of CKD was examined over 3 yr. Baseline serum creatinine values were available for 7316 women, and these values were used to assign a category of creatinine clearance (CrCl) using the Cockcroft-Gault formula (CrCl < 45, 45 to 59, and > or = 60 ml/min). BMD was measured at baseline and annually by dual x-ray absorptiometry. Within the placebo group, lower baseline CrCl was associated with a trend for higher annual losses of BMD at the femoral neck; however, within the raloxifene group, lower baseline CrCl was associated with greater increases in femoral neck BMD. This interaction between category of CrCl and treatment assignment was significant for rate of change of BMD at the hip. Irrespective of kidney function, raloxifene treatment was associated with a greater increase in spine BMD, a reduction in vertebral fractures, and no effect on nonvertebral fractures compared with placebo. Within each category of kidney function, adverse events were similar between the raloxifene and placebo groups. In conclusion, raloxifene increases BMD at both the hip and the spine and reduces the risk for vertebral fractures among individuals with CKD. The effect ofraloxifene on hip BMD is greater among those with mild to moderate CKD.     

Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures

Dual-energy X-ray absorptiometric bone mineral density (DXA BMD) is a strong predictor of fracture risk in untreated patients. However, previous patient-level studies suggest that BMD changes explain little of the fracture risk reduction observed with osteoporosis treatment. We investigated the relevance of DXA BMD changes as a predictor for fracture risk reduction using data from the FREEDOM trial, which randomly assigned placebo or denosumab 60 mg every 6 months to 7808 women aged 60 to 90 years with a spine or total hip BMD T-score < -2.5 and not < -4.0. We took a standard approach to estimate the percent of treatment effect explained using percent changes in BMD at a single visit (months 12, 24, or 36). We also applied a novel approach using estimated percent changes in BMD from baseline at the time of fracture occurrence (time-dependent models). Denosumab significantly increased total hip BMD by 3.2%, 4.4%, and 5.0% at 12, 24, and 36 months, respectively. Denosumab decreased the risk of new vertebral fractures by 68% (p < 0.0001) and nonvertebral fracture by 20% (p = 0.01) over 36 months. Regardless of the method used, the change in total hip BMD explained a considerable proportion of the effect of denosumab in reducing new or worsening vertebral fracture risk (35% [95% confidence interval (CI): 20%-61%] and 51% [95% CI: 39%-66%] accounted for by percent change at month 36 and change in time-dependent BMD, respectively) and explained a considerable amount of the reduction in nonvertebral fracture risk (87% [95% CI: 35% - >100%] and 72% [95% CI: 24% - >100%], respectively). Previous patient-level studies may have underestimated the strength of the relationship between BMD change and the effect of treatment on fracture risk or this relationship may be unique to denosumab.     

Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial.

The influence of pretreatment bone turnover on alendronate efficacy is not known. In the FIT, we examined the effect of pretreatment bone turnover on the antifracture efficacy of daily alendronate given to postmenopausal women. The nonspine fracture efficacy of alendronate was significantly greater among both osteoporotic and nonosteoporotic women with higher baseline levels of the bone formation marker PINP. INTRODUCTION: Previous trials have shown that high bone turnover is associated with greater increases in BMD among bisphosphonate-treated women. The influence of pretreatment bone turnover levels on antifracture efficacy has not been well studied. MATERIALS AND METHODS: We randomized women 55-80 years of age with femoral neck BMD T scores < or = -1.6 to alendronate (ALN), 5-10 mg/day (n = 3105), or placebo (PBO; n = 3081). At baseline, 3495 women were osteoporotic (femoral neck BMD T score < or = -2.5 or prevalent vertebral fracture), and 2689 were not osteoporotic (BMD T score > -2.5 and no prevalent vertebral fracture). Pretreatment levels of bone-specific alkaline phosphatase (BSALP), N-terminal propeptide of type 1 collagen (PINP), and C-terminal cross-linked telopeptide of type 1 collagen (sCTx) were measured in all participants using archived serum (20% fasting). The risk of incident spine and nonspine fracture was compared in ALN- and PBO-treated subjects stratified into tertiles of baseline bone marker level. RESULTS AND CONCLUSIONS: During a mean follow-up of 3.2 years, 492 nonspine and 294 morphometric vertebral fractures were documented. Compared with placebo, the reduction in nonspine fractures with ALN treatment differed significantly among those with low, intermediate, and high pretreatment levels of PINP levels (p = 0.03 for trend). For example, among osteoporotic women in the lowest tertile of pretreatment PINP (<41.6 ng/ml), the ALN versus PBO relative hazard for nonspine fracture was 0.88 (95% CI: 0.65, 1.21) compared with a relative hazard of 0.54 (95% CI: 0.39, 0.74) among those in the highest tertile of PINP (>56.8 ng/ml). Results were similar among women without osteoporosis at baseline. Although they did not reach statistical significance, similar trends were observed with baseline levels of BSALP. Conversely, spine fracture treatment efficacy among osteoporotic women did not differ significantly according to pretreatment marker levels. Spine fracture treatment efficacy among nonosteoporotic women was related to baseline BSALP (p = 0.05 for trend). In summary, alendronate nonspine fracture efficacy is greater among both osteoporotic and nonosteoporotic women with high pretreatment PINP. If confirmed in other studies, these findings suggest that bisphosphonate treatment may be most effective in women with elevated bone turnover.     

Sex steroids and bone turnover markers in men with symptomatic vertebral fractures

Sex steroids play an important role in the maintenance of bone density in men and women, but the circulating, biologically active unbound fraction is influenced by the concentration of sex hormone binding globulin (SHBG). SHBG increases with advancing age in men and leads to a reduction in serum free testosterone and oestradiol, which may then affect bone turnover, bone mineral density (BMD) and the risk of fractures. We have therefore measured total and unbound sex steroids, SHBG, bone turnover markers and BMD in 57 men with symptomatic low trauma vertebral fractures and 57 age-matched male control subjects. Fasting blood and urine samples were collected from all subjects, who also underwent BMD measurement of the lumbar spine and hip. Serum testosterone, oestradiol, SHBG, bone specific alkaline phosphatase (bone ALP) and urine free deoxypyridinoline/creatinine ratio (fDPD/Cr) were measured. Free sex steroid concentrations were calculated using their ratio with SHBG and albumin and bioavailable testosterone was measured using radioimmunoassay. The two groups were then compared and regression models developed to determine the best predictors of BMD and fracture. Men with vertebral fractures had significantly lower weight and BMD at all sites than control subjects (p<0.0001). Serum total testosterone and oestradiol did not differ between the two groups, but calculated free androgen and free oestradiol indices were lower in the fracture group than the control subjects (p=0.04), due to higher SHBG (46.6 versus 36.1 nmol/L: p=0.005). The men with vertebral fractures had significantly higher mean bone ALP (15.8 versus 11.8 microg/L: p=0.002) and fDPD/Cr (5.5 versus 4.0 nmol/mmol: p=0.03). Stepwise multiple regression analysis in both fracture and control groups found body weight to be the best predictor of BMD. In the fracture group weight predicted between 19.7 and 30.7% of the variance in BMD and in control subjects this was between 12.3 and 13.2%. SHBG contributed to the model for hip BMD in the fracture group alone, so that weight and SHBG together accounted for 32 to 42.9% of the variance. A model combining BMD at the spine, total femur and femoral neck with height loss best predicted fracture. In conclusion, men with symptomatic vertebral fractures have higher SHBG and lower calculated free sex steroid indices, increased bone turnover and lower BMD. Whilst body weight was the best predictor of BMD, symptomatic vertebral fracture was best predicted by BMD and height loss.     

Impaired development of bone mineral density during chemotherapy: a prospective analysis of 46 children newly diagnosed with cancer.

Osteopenia and osteoporosis are becoming increasingly recognized in children with cancer, though reasons for these changes are poorly understood. The purpose of the present study was to evaluate longitudinal changes in bone mineral density (BMD) and bone turnover in newly diagnosed children with a malignancy. Lumbar spine (L2-L4) and femoral neck bone mineral density (BMDareal, g/cm2) was measured by dual-energy X-ray absorptiometry in 46 children (age 2.9-16.0, median 8.0 years; 15 leukemias, 12 lymphomas, 19 solid tumors) at diagnosis, and after 6 months from the baseline. The apparent volumetric bone mineral density (BMDvol) was calculated to minimize the effect of bone size on BMD. Serum levels of osteocalcin (OC), type I collagen carboxy-terminal propeptide (PICP), and type I collagen carboxy-terminal telopeptide (ICTP) were analyzed at diagnosis, and during a 6-month follow-up. A significant decrease in lumbar BMDvol (-2.1%, p < 0.05), and in femoral BMDareal (-9.9%, p = 0.0001) and BMDvol (-8.5%, p = 0.0001) was observed after 6 months when compared with baseline measurements. The markers of bone formation (PICP, OC) were significantly decreased, and the marker of bone resorption (ICTP) was significantly increased at diagnosis as compared with normal values. By the end the follow-up, the levels of PICP and OC were normalized, whereas the level of ICTP continued to increase indicating that there was a negative balance in bone turnover. A deficient accumulation of bone mass might predispose children with a malignancy to impaired development of peak bone mass. A controlled study determining the benefits of an early intervention on bone turnover should be considered in these patients.     

A haplotype of MATN3 is associated with vertebral fracture in Chinese postmenopausal women: Peking Vertebral Fracture (PK-VF) study

The Matrilin3 gene (MATN3) encodes an extracellular matrix protein, which modulates chondrocyte differentiation. The aim of this study was to test for association of MATN3 polymorphisms with bone mineral density (BMD), fracture, vertebral fracture, bone turnover or 25-hydroxyvitamin D [25(OH)D] in postmenopausal women. A community-based population of 1488 postmenopausal women was randomly selected in Beijing. The history of fracture and vertebral fracture was obtained via questionnaire and vertebral X-ray respectively. BMD of lumbar spine (2-4), femoral neck and total hip were measured by dual energy X-ray absorptiometry. Serum N-terminal procollagen of type 1 collagen (P1NP), β-isomerized type I collagen C-telopeptide breakdown products (β-CTX) and 25(OH)D were quantified. Binary logistic regression revealed that Haplotype-4 was significantly associated with vertebral fracture risk in both additive model (p=0.023, OR=1.521) and dominant model (p=0.028, OR=1.623). The significance remained after 10,000 permutation tests to correct multiple testing (p=0.042). Re-selected age matched vertebral fracture case-control groups revealed similar associations in additive model (p=0.014, OR=1.927, 95%CI=1.142-3.253) and in dominant model (p=0.011, OR=2.231, 95%CI=1.200-4.148). However, no significant association was found between MATN3 polymorphisms and serum β-CTX, P1NP, 25(OH)D levels, or BMD. In linear regression, Haplotype-2 approached marginal significance in association with femoral neck BMD T-score (p=0.050), but this would account for only 0.2% of BMD variation in our sample. This study suggests that Haplotype-4 of MATN3 is associated with vertebral fracture risk independent of BMD in Chinese postmenopausal women. Efforts should be made to replicate our finding in other, similar and ethnically diverse, populations.