Pierre D. Delmas

Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis

BACKGROUND Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis. METHODS We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. RESULTS As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. CONCLUSIONS Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)

Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women.

BACKGROUND Long-term estrogen therapy can reduce the risk of osteoporotic fracture and cardiovascular disease in postmenopausal women. At present, however, these beneficial effects are not separable from undesirable stimulation of breast and endometrial tissues. METHODS We studied the effect of raloxifene, a nonsteroidal benzothiophene, on bone mineral density, serum lipid concentrations, and endometrial thickness in 601 postmenopausal women. The women were randomly assigned to receive 30, 60, or 150 mg of raloxifene or placebo daily for 24 months. RESULTS The women receiving each dose of raloxifene had significant increases from base-line values in bone mineral density of the lumbar spine, hip, and total body, whereas those receiving placebo had decreases in bone mineral density. For example, at 24 months, the mean (+/-SE) difference in the change in bone mineral density between the women receiving 60 mg of raloxifene per day and those receiving placebo was 2.4+/-0.4 percent for the lumbar spine, 2.4+/-0.4 percent for the total hip, and 2.0+/-0.4 percent for the total body (P<0.001 for all comparisons). Serum concentrations of total cholesterol and low-density lipoprotein cholesterol decreased in all the raloxifene groups, whereas serum concentrations of high-density lipoprotein cholesterol and triglycerides did not change. Endometrial thickness was similar in the raloxifene and placebo groups at all times during the study. The proportion of women receiving raloxifene who reported hot flashes or vaginal bleeding was not different from that of the women receiving placebo. CONCLUSIONS Daily therapy with raloxifene increases bone mineral density, lowers serum concentrations of total and low-density lipoprotein cholesterol, and does not stimulate the endometrium.

European guidance for the diagnosis and management of osteoporosis in postmenopausal women

Summary Guidance is provided in a European setting on the assessment and treatment of postmenopausal women at risk of fractures due to osteoporosis. Introduction The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2008. This manuscript updates these in a European setting. Methods Systematic literature reviews. Results The following areas are reviewed: the role of bone mineral density measurement for the diagnosis of osteoporosis and assessment of fracture risk, general and pharmacological management of osteoporosis, monitoring of treatment, assessment of fracture risk, case finding strategies, investigation of patients and health economics of treatment. Conclusions A platform is provided on which specific guidelines can be developed for national use.

Predictive Value of BMD for Hip and Other Fractures.

The relationship between BMD and fracture risk was estimated in a meta‐analysis of data from 12 cohort studies of ∼39,000 men and women. Low hip BMD was an important predictor of fracture risk. The prediction of hip fracture with hip BMD also depended on age and z score.

Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study.

The mechanisms leading to increased bone loss and skeletal fragility in women with postmenopausal osteoporosis are still poorly understood. Increased bone resorption, low serum estradiol and high serum sex‐hormone‐binding globulin (SHBG) recently have been reported as predictors of vertebral and hip fractures in elderly women. In a cohort of healthy untreated younger postmenopausal women aged 50–89 years (mean, 64 years), we compared baseline levels of bone markers and endogenous hormones in 55 women who subsequently had a fracture (20 vertebral and 35 peripheral fractures) with levels in the 380 women who did not fracture during a mean 5 years of follow‐up. Women with levels in the highest quartile of four bone resorption markers including urinary‐free deoxypyridinoline (D‐Pyr), urinary type I collagen N‐telopeptides (NTX), and urinary and serum type I collagen C‐telopeptides (CTX) had about a 2‐fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 1.8 (1.0‐3.4) for free D‐Pyr, 1.7 (0.9‐3.2) for urinary NTX, 2.3 (1.3‐4.1) for urinary CTX, and 2.1 (1.2‐3.8) for serum CTX. Serum levels of bone alkaline phosphatase (BAP) in the highest quartile were associated with an RR of fracture of 2.4 (1.3‐4.2). Women with serum levels of estradiol and dehydroepiandrosterone (DHEA) sulfate in the lowest quartile had an RR of fracture of 2.2 (1.2‐4.0) and 2.1 (1.2‐3.8), respectively. Increased levels of SHBG and intact parathyroid hormone (PTH) were moderately associated with an increased risk of fracture. Similar results were obtained when the analysis was restricted to symptomatic vertebral and nonvertebral fractures. Adjustment of biochemical markers by hormone levels did not significantly alter the results. Women with both high bone resorption markers and low estradiol (or low DHEA sulfate) had a higher risk of fracture with RRs of 3.0‐3.3 (p < 0.001). After adjustment for bone mineral density (BMD) of the hip, spine, radius, or total body, bone markers and hormones were still predictive of fracture risk with similar RRs. We conclude that high levels of some biochemical markers of bone turnover, low serum estradiol, low DHEA sulfate, high SHBG, and high PTH are associated with increased risk of osteoporotic fracture in postmenopausal women, independently of each other and of BMD. The mechanism by which some postmenopausal women have an increased rate of bone turnover leading to an increased risk of fracture remains to be elucidated.

Exercise Before Puberty May Confer Residual Benefits in Bone Density in Adulthood: Studies in Active Prepubertal and Retired Female Gymnasts

Exercise during growth may contribute to the prevention of osteoporosis by increasing peak bone mineral density (BMD). However, exercise during puberty may be associated with primary amenorrhea and low peak BMD, while exercise after puberty may be associated with secondary amenorrhea and bone loss. As growth before puberty is relatively sex hormone independent, are the prepubertal years the time during which exercise results in higher BMD? Are any benefits retained in adulthood? We measured areal BMD (g/cm2) by dual‐energy X‐ray absorptiometry in 45 active prepubertal female gymnasts aged 10.4 ± 0.3 years (mean ± SEM), 36 retired female gymnasts aged 25.0 ± 0.9 years, and 50 controls. The results were expressed as a standardized deviation (SD) or Z score adjusted for bone age in prepubertal gymnasts and chronological age in retired gymnasts. In the cross‐sectional analyses, areal BMD in the active prepubertal gymnasts was 0.7–1.9 SD higher at the weight‐bearing sites than the predicted mean in controls (p < 0.01). The Z scores increased as the duration of training increased (r = 0.32–0.48, p ranging between <0.04 and <0.002). During 12 months, the increase in areal BMD (g/cm2/year) of the total body, spine, and legs in the active prepubertal gymnasts was 30–85% greater than in prepubertal controls (all p < 0.05). In the retired gymnasts, the areal BMD was 0.5–1.5 SD higher than the predicted mean in controls at all sites, except the skull (p ranging between <0.06 and <0.0001). There was no diminution across the 20 years since retirement (mean 8 ± 1 years), despite the lower frequency and intensity of exercise. The prepubertal years are likely to be an opportune time for exercise to increase bone density. As residual benefits are maintained into adulthood, exercise before puberty may reduce fracture risk after menopause.

Interim report and recommendations of the World Health Organization Task-Force for Osteoporosis.

Harry K. Genant (Chairman) , Cyrus Cooper (Rapporteur) , Gyula Poor (Rapporteur) , Ian Reid (Rapporteur) , George Ehrlich (Editor), J. Kanis (Editor), B. E. Christopher Nordin (Editor), Elizabet h Barrett-Connor , Dennis Black, J.-P. Bonjour, Bess Dawson-Hughes , Pierre D. Delmas, J. Dequeker , Sergio Ragi Eis, Carlo Gennari , Olaf Johnell , C. Conrad Johnston, Jr, Edith M. C. Lau, Uri A. Liberman, Robert Lindsay, Thomas John Martin, Basel Masri, Carlos A. Mautalen, Pierre J. Meunier, Paul D. Miller , Ambrish Mithal, Hirotoshi Morii , Socrates Papapoul os, Anthony Woolf, Wei Yu and Nikolai Khaltaev (WHO Secretariat) 30

The Use of Biochemical Markers of Bone Turnover in Osteoporosis

The assay features of biochemical markers of bone turnover have markedly improved in the past few years. The most sensitive and specific markers of bone formation include serum bone alkaline phosphatase, total osteocalcin (including the intact molecule and the large N-Mid fragment) and the N extension peptide of type I collagen (PINP) measured with a recently developed radioimmunoassay. Among the various markers of bone resorption, measurements of the urinary excretion of the (deoxy) pyridinoline crosslinks and of N- and C- related telopeptides (NTX and CTX respectively) are the most sensitive and specific ones. In addition, a two-site immunoassay of serum CTX is now widely available. Bone markers can be used to predict the rate of bone loss in postmenopausal women. Three independent studies have shown that high bone turnover is associated with increased bone loss over 4 to 15 years in women aged 50 to 70 years. In addition, we have shown in elderly women that increased bone resorption, i.e. above the premenopausal range, is associated with a two-fold increase in the risk of hip fractures and that those with both a low BMD (T score < -2.5) and increased bone resorption have a 4- to 5- fold increase in hip fracture risk. We have recently confirmed that increased bone turnover predicts the risk of fragility fractures in a younger cohort of postmenopausal women followed for an average of 5 years. The mechanisms underlying the increased bone turnover in some (but not all) postmenopausal women are unknown. The increase appears to be independent from the residual secretion of 17 s estradiol (E2), assessed by a highly sensitive radioimmunoassay. Indeed, we found that a low serum E2 predicts the risk of fragility fractures in late postmenopausal women (but not in the elderly) independently of the rate of bone turnover. Bone markers can be used to monitor the efficacy of antiresorptive therapy such as hormone replacement therapy, raloxifene and bisphosphonates. We and others have shown that the short-term (3 to 6 months) decrease of bone turnover is significantly correlated with the long-term (2 years) increase in BMD of the spine. In addition, the decrease of serum osteocalcin is associated with the risk of vertebral fractures in osteoporotic women treated with raloxifene. Similar studies in patients using alendronate or risedronate show that the short-term decrease of bone turnover markers is correlated with the risk of subsequent fractures. Thus, with adequate cut-offs, individual patients can be monitored with bone markers earlier than with DXA. It remains to be assessed if such a monitoring can improve long-term compliance with therapy.

The collagenolytic activity of cathepsin K is unique among mammalian proteinases.

Type I collagen fibers account for 90% of the organic matrix of bone. The degradation of this collagen is a major event during bone resorption, but its mechanism is unknown. A series of data obtained in biological models strongly suggests that the recently discovered cysteine proteinase cathepsin K plays a key role in bone resorption. Little is known, however, about the actual action of cathepsin K on type I collagen. Here, we show that the activity of cathepsin K alone is sufficient to dissolve completely insoluble collagen of adult human cortical bone. We found that the collagenolytic activity of cathepsin K is directed both outside the helical region of the molecule, i.e. the typical activity of cysteine proteinases, and at various sites inside the helical region, hitherto believed to resist all mammalian proteinases but the collagenases of the matrix metalloproteinase family and the neutrophil elastase. This property of cathepsin K is unique among mammalian proteinases and is reminiscent of bacterial collagenases. It is likely to be responsible for the key role of cathepsin K in bone resorption.

Relationship of Early Changes in Bone Resorption to the Reduction in Fracture Risk With Risedronate

Changes in the level of biochemical markers of bone resorption with risedronate treatment for osteoporosis were examined as a surrogate for the decrease in fracture risk. Greater decreases in bone resorption markers were associated with greater decreases in vertebral (and nonvertebral) fractures.