Abstract
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
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