Osteoporotic fractures in older women constitute a major cause of disability, mortality, and economic burden.1 The incidence of fractures related to osteoporosis will increase worldwide over the next three decades as the proportion of women over the age of 65 increases.2 It is therefore important that we identify efficacious treatments that will reduce the incidence of osteoporotic fractures. In the past, randomised controlled trials have focused on the surrogate outcome of bone mineral density. The limitation of relying on a surrogate outcome was highlighted by the results of earlier trials, in which increases in bone density did not translate into decreased risk of fracture.3 As a result of stricter standards that required evidence of efficacy against fractures for drug approval, we now have large randomised trials with prevention of fractures as an outcome. Data from these trials provide information on the strength of the evidence for efficacy of the different treatments.
Evidence based reviews of treatments for postmenopausal osteoporosis have confirmed which treatments reduce the risk of fractures in women with osteoporosis.4-6 Most currently used drugs are antiresorptive agents that reduce osteoclast mediated resorption and bone remodelling. Potent bisphosphonates include alendronate and risedronate, which reduce the relative risk of vertebral fractures by 40-50%. Both of these bisphosphonates also reduce the relative risk of non-vertebral fractures (for example, fractures of the hip and wrist) by 40-50% and are now considered to be first line agents for the prevention and treatment of postmenopausal osteoporosis.
Etidronate is a first generation bisphosphonate with weaker evidence for reducing vertebral fractures. In addition, there is no evidence from randomised trials that it reduces non-vertebral fractures.
The selective oestrogen receptor modulator raloxifene produces smaller increases in bone mineral density than other treatments but reduces the risk of vertebral fractures by 36%. Evidence for its effect on non-vertebral fractures is lacking.
The evidence for nasal calcitonin, a polypeptide hormone, for preventing vertebral fractures is weak owing to the inconsistency of its effect across various doses and large losses to follow up of patients in the largest trial.6-7 There is no clear evidence that nasal calcitonin reduces non-vertebral fractures.
For years there was a paucity of randomised controlled trials evaluating the efficacy of hormone replacement in preventing fractures. The Women's Health Initiative trial confirmed the results of observational trials that had found that combined oestrogen and progestogen reduces the relative risk of both vertebral and hip fractures by 34%. However, the harms of long term hormone replacement seem to outweigh the benefits and limit its use as a treatment for osteoporosis.8
Tibolone is a synthetic steroid available in Europe that increases bone density but data about prevention of fractures are still pending.
Randomised controlled trials have confirmed that calcium and vitamin D in combination can reduce the risk of non-vertebral fractures in elderly people.9,10 Anabolic agents (which increase bone formation) such as recombinant human parathyroid hormone target the osteoblast. A large multicentred randomised controlled trial has confirmed the efficacy of the recombinant human parathyroid hormone hPTH 1-34 (teriparatide).11 In women with postmenopausal osteoporosis, daily injections of parathormone resulted in larger increases in bone mineral density of the lumbar spine than seen with antiresorptive treatments, and a decrease in the relative risk of both vertebral and non-vertebral fractures by 50-65%. Parathyroid hormone has been approved in some countries for the treatment of severe osteoporosis.
Non-pharmacological options to prevent hip fractures include the use of hip protectors. Systematic reviews have shown that hip protectors reduce the relative risk of hip fracture in frail elderly women. However, not all trials have found that hip protectors are efficacious, and compliance remains a problem.12
The lack of direct head to head trials of treatments for osteoporosis, with reduction in fractures as an end point, makes it difficult to determine the relative efficacy of the different treatments. Comparisons between drugs of efficacy, derived from meta-analyses, may be unreliable because of different baseline characteristics of populations studied and overlapping confidence intervals for the effect of treatment.6
Awareness has increased that bone mineral density alone does not predict response to treatment for osteoporosis and that increases in bone mineral density may not correlate directly with a reduction in fractures.13 At an individual level greater recognition has set in that treatments should be recommended to women who are at the highest risk of fracture. The strongest evidence for efficacy against fractures is in women at high risk with osteoporosis and with vertebral fractures.14 However, numerous retrospective studies have shown that women who have sustained a fragility fracture often did not start treatment for osteoporosis.
From a perspective of cost effectiveness it makes most sense to treat women with osteoporosis who are 65 years or older or have had a fragility fracture. However, from a population perspective, although large numbers of fractures occur in women at moderate risk, many treatments that are feasible in high risk groups, are not cost effective for them.
With all this evidence, which treatment should doctors prescribe when faced with a patient in their practice? Other aspects like individual values, absolute risk of fracture, extraskeletal effects, and costs need to be considered. If the goal is to decrease risk of vertebral fractures then the choices would include raloxifene, risedronate, or alendronate, If the goal is to reduce the risk of vertebral and non vertebral fractures then a newer biphosphonate like alendronate or risedronate would be preferable. For those women with severe osteoporosis at high risk of fracture parathormone would be an option.
Future research priorities include determination of optimal duration of treatment, evaluation of strategies directed at improving management of women with osteoporotic fractures, and the completion of head to head trials of treatments with clinically relevant outcomes of clinical fracture and quality of life.
Competing interests: AC has received fees for speaking and consultancy from Mercke, Procter & Gamble Co, Eli Lilly.
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