Bisphosphonates for post-menopausal osteoporosis: are they all the same?

Overdiagnosis and Overtreatment of Osteoporosis: A Wolf in Sheep's Clothing.

Bone strength and surrogate markers: The first, second, and third fiddle

Meta-analyses conducted >15 years ago reported that improvements in bone mineral density (BMD) were associated with reduction in vertebral and nonvertebral fractures in osteoporosis trials. Numerous studies have been conducted since then, incorporating new therapies with different mechanisms of action and enrolling many more subjects. To extend these prior analyses, we conducted a meta-regression of 38 placebo-controlled trials of 19 therapeutic agents to determine the association between improvements in BMD and reductions in fracture risk. We used a linear model to examine the relationship between mean percent difference in BMD change between treatment and placebo groups and the logarithm of the relative risk. We found that greater improvements in BMD were strongly associated with greater reductions in vertebral and hip fractures but not nonvertebral fractures. For vertebral fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.56, 0.54, and 0.63, respectively (p ≤ 0.0002). For a 2% or 6% improvement in total hip BMD, we might expect a 28% or 66% reduction, respectively, in vertebral fracture risk. For hip fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.48 (p = 0.01), 0.42 (p = 0.02), and 0.22 (ns), respectively. For a 2% or 6% improvement in total hip BMD, we might expect a 16% or 40% reduction in hip fracture risk. In conclusion, our results extend prior observations that larger improvements in dual-energy X-ray absorptiometry (DXA)-based BMD are associated with greater reductions in fracture risk, particularly for vertebral and hip fractures. Although these results cannot be directly applied to predict the treatment benefit in an individual patient, they provide compelling evidence that improvements in BMD with osteoporosis therapies may be useful surrogate endpoints for fracture in trials of new therapeutic agents. © 2019 American Society for Bone and Mineral Research.

Osteoporosis: Trials and tribulations

Bisphosphonates are potent inhibitors of bone resorption, used in most bone diseases associated with high bone resorption levels. Several bisphosphonates, developed to prevent and treat postmenopausal osteoporosis, increase bone mineral density and decrease biochemical markers of bone turnover, and more importantly, reduce fracture risk. Alendronate and risedronate have proven their efficacy to reduce vertebral and hip fracture risk among postmenopausal osteoporotic women, using daily regimens. Weekly intermittent schedules, however, are now most commonly prescribed, because they have shown pharmacologic equivalence to the daily regimen. Ibandronate has been the first bisphosphonate to demonstrate vertebral fracture risk reduction using an intermittent regimen. Studies using ibandronate as intravenous injections every 3 months are under way. Zoledronic acid may also be an attractive option for the treatment of postmenopausal osteoporosis if a large ongoing trial proves that a single annual injection of this compound allows osteoporotic fracture risk reduction.

Use of low potency estrogens does not reduce the risk of hip fracture

Recognition of the problem of age-related bone fragility emerged in the middle of the last century when Fuller Albright drew attention to the common occurrence of vertebral fractures in postmenopausal women [1]. With increasing numbers of individuals living into old age, hip fractures gained recognition because of the high incidence, morbidity, mortality and cost imposed by this type of fracture [2]. More recently, several insights have emerged that require attention if the burden of fractures is to be minimized. First, although vertebral and hip fractures are important, from a global perspective, 80–90% of all fragility fractures and the disutility they cause are peripheral in origin (non-hip, nonvertebral) [3, 4]. Second, over 50% of all fragility fractures arise from the larger segment of the population with osteopenia, not osteoporosis [5, 6]. These are fragility fractures, but the basis for the bone fragility is only beginning to be defined [7]. Third, with the changing demographics of the population, over 80 year olds comprise ∼10% of the population but contribute 20–25% of all fragility fractures because this segment of the population have the highest prevalence of risk factors (osteoporosis, prevalent fractures, falls) and the highest morbidity and mortality [8]. Fourth, fractures in men are common [9]. Fifth, two major impediments to fracture prevention are failure of uptake of treatments and failure of adherence to treatment in 50% within 12 months of initiating treatment [10]. These issues are compounded by corresponding deficiencies in treatment. Vertebral fracture risk reduction, although credibly reported with several agents, is only 30–50% [11]. Anti-hip fracture efficacy is also only 30– 50% and has only been reported with alendronate, risedronate [11], and zoledronate [12]. Anti-hip fracture efficacy has also been reported in a post hoc analysis with strontium ranelate [13]. Hip fracture risk reduction has been studied as a primary endpoint in only one pivotal trial and several smaller studies with risedronate [11, 14–16]. For peripheral (non-vertebral non-hip) fractures, fracture risk reduction is modest, 16 to 20%, and has been demonstrated with risedronate, PTH 1–34 and strontium ranelate [11], but planned as a primary endpoint only with strontium ranelate [13]. Peripheral fracture risk reduction has also been reported with alendronate in the FOSIT study and after pooling of patients in the fracture intervention trial (FIT 1) with those patients with osteoporosis in FIT 2 [11, 17]. Issues concerning the design and execution of trials of calcitonin, calcitriol and other vitamin metabolites make inferences concerning anti-fracture efficacy difficult. Recent studies of calcium supplementation had methodological problems, particularly compliance [18–20]. Although lower fracture rates in compliers were reported in each trial is encouraging, whether this was due to the calcium supplement is uncertain. Random allocation assures that known and unknown confounders that independently influence fracture rates are equally prevalent in placebo and calcium arms. With adherence of ∼50%, this assurance is lost. In women with osteopenia alone, only raloxifene and strontium ranelate have been reported to reduce vertebral fracture risk [21, 22]. Alendronate has also been reported to reduce vertebral fracture risk in women with osteopenia and Osteoporos Int (2007) 18:569–573 DOI 10.1007/s00198-007-0350-z

Osteoporotic fractures are one of the major causes of increased morbidity and mortality in postmenopausal women and the overall aging population. One of the major issues in the management of postmenopausal osteoporosis is to find a safe and effective treatment in the long term (>3 years) to achieve and maintain a reduction in the risk of fracture. Strontium ranelate (PROTELOS(®)) is a relatively novel drug, currently approved in Europe for the treatment of postmenopausal osteoporosis. Strontium ranelate is the first agent of a new therapeutic class in osteoporosis, capable of both promoting bone formation and, to a lesser extent, inhibiting bone resorption. This uncoupling in bone turnover results in a net gain in bone mineral density (BMD), bone quality improvement and reduction in risk of vertebral and nonvertebral fractures, as initially demonstrated in the preplanned long-term registrative trials SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment of Peripheral Osteoporosis) at 5 years. Recently, open-label extensions of the SOTI and TROPOS trials up to 8 and, recently, 10 years have confirmed the sustained efficacy of strontium ranelate in increasing BMD, the long-term safety profile and the high compliance to treatment, independently from baseline BMD or other risk factors for osteoporotic fractures. Recent economic impact analyses have proved that long-term treatment with strontium ranelate is highly cost effective, especially in women older than 70 years of age. Histomorphometric analyses in animals and humans participating in the phase III trials have proved that the quality of mineralization is preserved in the long term and bone microarchitecture is ameliorated, with increased bone strength. Thus, strontium ranelate has been confirmed to be an effective compound for the long-term, chronic treatment of postmenopausal osteoporosis.

Fractures of the proximal femur (hip fractures) occur predominantly in older populations, with an average age around 80 years. Around 80% of people sustaining hip fractures are female and many...

Low body mass index (BMI) is a well-documented risk factor for future fracture. The aim of this study was to quantify this effect and to explore the association of BMI with fracture risk in relation to age, gender and bone mineral density (BMD) from an international perspective using worldwide data. We studied individual participant data from almost 60,000 men and women from 12 prospective population-based cohorts comprising Rotterdam, EVOS/EPOS, CaMos, Rochester, Sheffield, Dubbo, EPIDOS, OFELY, Kuopio, Hiroshima, and two cohorts from Gothenburg, with a total follow-up of over 250,000 person years. The effects of BMI, BMD, age and gender on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson regression model in each cohort separately. The results of the different studies were then merged. Without information on BMD, the age-adjusted risk for any type of fracture increased significantly with lower BMI. Overall, the risk ratio (RR) per unit higher BMI was 0.98 (95% confidence interval [CI], 0.97-0.99) for any fracture, 0.97 (95% CI, 0.96-0.98) for osteoporotic fracture and 0.93 (95% CI, 0.91-0.94) for hip fracture (all p <0.001). The RR per unit change in BMI was very similar in men and women ( p >0.30). After adjusting for BMD, these RR became 1 for any fracture or osteoporotic fracture and 0.98 for hip fracture (significant in women). The gradient of fracture risk without adjustment for BMD was not linearly distributed across values for BMI. Instead, the contribution to fracture risk was much more marked at low values of BMI than at values above the median. This nonlinear relation of risk with BMI was most evident for hip fracture risk. When compared with a BMI of 25 kg/m(2), a BMI of 20 kg/m(2) was associated with a nearly twofold increase in risk ratio (RR=1.95; 95% CI, 1.71-2.22) for hip fracture. In contrast, a BMI of 30 kg/m(2), when compared with a BMI of 25 kg/m(2), was associated with only a 17% reduction in hip fracture risk (RR=0.83; 95% CI, 0.69-0.99). We conclude that low BMI confers a risk of substantial importance for all fractures that is largely independent of age and sex, but dependent on BMD. The significance of BMI as a risk factor varies according to the level of BMI. Its validation on an international basis permits the use of this risk factor in case-finding strategies.

Strontium ranelate is a novel therapy for the treatment of postmenopausal osteoporosis with actions to reduce bone resorption and increase bone formation. In vitro, strontium ranelate has anabolic and antiresorptive activity, increasing collagen and non-collagen protein synthesis, enhancing pre-osteoblast differentiation, inhibiting osteoclast differentiation, and reducing osteoclast function. In animal models, the increase in bone density is closely correlated with increases in biomechanical bone strength. Histomorphometry demonstrates reduced osteoclast surfaces with increased bone formation. Clinical trials in postmenopausal women have demonstrated 3-year fracture efficacy. Reductions in vertebral fracture were seen in patients with and without prevalent vertebral fracture. Nonvertebral fractures were also significantly reduced. In a subgroup of patients at high risk for hip fracture, there was a significant reduction in hip fracture risk. Strontium ranelate is well tolerated with nausea, diarrhea, headache, and dermatitis more frequent in treated patients only for the first 3 months of therapy. Together, these data suggest that strontium ranelate is a well-tolerated and effective therapy for postmenopausal osteoporosis reducing vertebral and nonvertebral fracture by a novel dual antiresorptive and anabolic action on bone.

Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials

The evidence for antiresorptive osteoporosis treatment in the elderly and old

Treatment options for postmenopausal osteoporosis

Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs