Bisphosphonate treatment of osteoporosis

Bisphosphonates represent the agents of choice for most patients with osteoporosis. They are the best studied of all agents for the prevention of bone loss and reduction in fractures. They increase BMD, primarily at the lumbar spine, but also at the proximal femur. In patients who have established osteoporosis, bisphosphonates reduce the risk of vertebral fractures, and are the only agents in prospective trials to reduce the risk of hip fractures and other nonvertebral fractures. Bisphosphonates reduce the risk of fracture quickly. The risk of radiographic vertebral deformities is reduced after 1 year of treatment with risedronate [68]. The risk of clinical vertebral fractures is reduced after 1 year of treatment with alendronate [69] and just 6 months' treatment with risedronate [157]. The antifracture effect of risedronate has been shown to continue through 5 years of treatment [158]. Alendronate and risedronate are approved by the FDA for prevention of bone loss in recently menopausal women, for treatment of postmenopausal osteoporosis, and for prevention (risedronate) and treatment (alendronate and risedronate) of glucocorticoid-induced osteoporosis. Alendronate is also approved for treatment of osteoporosis in men. Other bisphosphonates (etidronate for oral use, pamidronate and zoledronate for intravenous infusion) are also available and can be used off label for patients who cannot tolerate approved agents. Although bisphosphonates combined with estrogen or raloxifene produce greater gains in bone mass compared with single-agent treatment, the use of two antiresorptive agents in combination cannot be recommended because the benefit on fracture risk has not been demonstrated and because of increased cost and side effects.     

Treating osteoporosis to prevent fractures: current concepts and future developments

Antiresorptive drugs, such as the bisphosphonates and the RANKL inhibitor denosumab, are currently the most widely used osteoporosis medications. These drugs increase bone mineral density (BMD) and reduce the risk of vertebral (by 40–70%), nonvertebral (by 25–40%) and hip fractures (by 40–53%) in postmenopausal women with osteoporosis. Due to the risk of rare side‐effects, the use of bisphosphonates has been limited to up to 10 years with oral bisphosphonates and 6 years with intravenous zoledronic acid. Despite their well‐proven efficacy and safety, few women at high risk of fracture are started on treatment. Case finding strategies, such as fracture risk‐based screening in primary care using the fracture risk assessment tool (FRAX) and Fracture Liaison Services, have proved effective in increasing treatment rates and reducing fracture rates. Recently, anabolic therapy with teriparatide was demonstrated to be superior to the bisphosphonate risedronate in preventing vertebral and clinical fractures in postmenopausal women with vertebral fracture. Treatment with the sclerostin antibody romosozumab increases BMD more profoundly and rapidly than alendronate and is also superior to alendronate in reducing the risk of vertebral and nonvertebral fracture in postmenopausal women with osteoporosis. For patients with severe osteoporosis and high fracture risk, bisphosphonates alone are unlikely to be able to provide long‐term protection against fracture and restore BMD. For those patients, sequential treatment, starting with a bone‐building drug (e.g. teriparatide), followed by an antiresorptive, will likely provide better long‐term fracture prevention and should be the golden standard of future osteoporosis treatment.     

Calcitonin.

Calcitonin is FDA approved for the treatment of postmenopausal osteoporosis but not for prevention. The preferred delivery system is nasal. Nasal calcitonin is safe and well tolerated. The vertebral fracture efficacy of calcitonin is less robust than the two approved bisphosphonates (alendronate and risedronate) but is similar to raloxifene in the treatment of established osteoporosis. Calcitonin has not been demonstrated to reduce hip fracture risk, although a post-hoc pooled analysis suggests potential effectiveness of nasal calcitonin. Calcitonin produces small increments in bone mass of the spine and modestly reduces bone turnover in women with osteoporosis. Calcitonin may have analgesic benefit in patients with acute painful vertebral fractures. Treatment with calcitonin should be considered for older women with osteoporosis with painful vertebral fractures and for women who fail to respond to or cannot tolerate bisphosphonates. Calcitonin may also be indicated for women who are unable to take bisphosphonates because of impaired renal function.     

Treatment of osteoporosis with bisphosphonates

Bisphosphonates are safe and effective agents for treatment and prevention of osteoporosis. Alendronate and risedronate are the best studied of all agents for osteoporosis in terms of efficacy and safety. They increase bone mass. In patients who have established osteoporosis, they reduce the risk of vertebral fractures. They are the only agents shown in prospective trials to reduce the risk of hip fractures and other nonvertebral fractures. They are approved by the US FDA for prevention of bone loss in recently menopausal women, for treatment of postmenopausal osteoporosis, and for management of glucocorticoid-induced bone loss. Other bisphosphonates (e.g., etidronate for oral use, pamidronate for intravenous infusion) are also available and can be used off-label for patients who cannot tolerate approved agents. Bisphosphonates combined with estrogen produce greater gains in bone mass compared with either agent used alone; whether there is a greater benefit of combination therapy on fracture risk is not clear. Combining a bisphosphonate with raloxifene or calcitonin is probably safe, although data on effectiveness are lacking.     

Antiresorptive treatment of postmenopausal osteoporosis: comparison of study designs and outcomes in large clinical trials with fracture as an endpoint

Antiresorptive treatments for postmenopausal osteoporosis have been studied extensively, but due to the volume of published data and lack of head-to-head trials, it is difficult to evaluate and compare their fracture reduction efficacy. The objective of this review is to summarize the results from clinical trials that have fracture as an endpoint and to discuss the factors in study design and populations that can affect the interpretation of the results. Although there are numerous observational studies suggesting that estrogen and hormone replacement therapies may reduce the risk of vertebral and nonvertebral fractures, there is no large, prospective, randomized, placebo-controlled, double-blind clinical trial demonstrating fracture efficacy. The effects of raloxifene, alendronate, risedronate, and salmon calcitonin on increasing bone mineral density (BMD) and decreasing fracture risk have been shown in randomized, placebo-controlled, double-blind clinical trials of postmenopausal women with osteoporosis. Although the increases in lumbar spine BMD vary greatly in these trials, the decrease in relative risk of vertebral fractures is similar among therapies. However, nonvertebral fracture efficacy has not been consistently demonstrated. Combined administration of two antiresorptive therapies results in greater BMD increases, but the effects on fracture risk are unknown. Direct comparisons of clinical trial results should be considered carefully, given the differences in study design and populations. Differences in study design that may influence the efficacy of fracture risk reduction include calcium and vitamin D supplementation, primary fracture endpoints, definition of vertebral deformity or fracture, discontinuation rates, and statistical power. Factors in the study population that may influence fracture efficacy include the age of the population and the proportion of subjects with prevalent fractures. The use of surrogate endpoints such as BMD to predict fracture risk should be approached with caution, as the relationship between BMD changes and fracture risk reduction with antiresorptive therapies is uncertain. Consideration of these results from clinical trials can contribute to clinical judgment in selecting the best treatment option for postmenopausal osteoporosis.     

Selection of individuals for prevention of fractures due to bone fragility.

Most patients with fractures go untreated because of the lack of awareness of osteoporosis. Treatment is indicated for women and men with osteoporosis and women and men with fractures with either osteoporosis or osteopenia because (a) fractures increase morbidity and mortality, (b) the burden of fractures is increasing because longevity is increasing, and (c) bone loss accelerates, rather than decelerates in old age. The indication for drug therapy is less clear in women or men with osteopenia because drugs have not been proved to reduce fracture risk in this group. There is no evidence that treating individuals with only risk factors reduces the fracture rate. Screening has not been shown to reduce the burden of fractures. Altering the bone mineral density by a few percent in the population is likely to reduce the number of fractures, but how this can be achieved is unknown. The rigorously investigated drugs reducing the spine fracture rate are alendronate, raloxifene and risedronate. Calcium and vitamin D reduce hip fractures in nursing home residents but not community-dwellers. In the community, only alendronate and risedronate have been reported to reduce hip fractures in randomized trials. The evidence for hormone replacement therapy is less satisfactory. It is likely to reduce the number of spinal fractures, but its role in hip fracture prevention is uncertain. Only alendronate has been reported to reduce spine fractures in men with osteoporosis. Evidence for the use of other drugs (calcitonin, fluoride, anabolic steroids and active vitamin D metabolites) in women or men is insufficient to justify their use.     

The Treatment of Severe Postmenopausal Osteoporosis

Several chemical entities have shown their ability to reduce axial and/or appendicular fractures in patients with osteoporosis. Since patients who have experienced a previous fracture are at high risk for subsequent vertebral or hip fracture, it is of prime importance to treat such patients with medications that have unequivocally demonstrated their ability to reduce fracture rates in patients with prevalent fractures. Results obtained with calcium and vitamin D, in this particular population, are not fully satisfactory and these medications are probably better used in conjunction with other therapeutic regimens. Bisphosphonates have shown their ability to reduce vertebral (alendronate, risedronate, ibandronate) and non-vertebral (alendronate, risedronate) fractures in patients with established osteoporosis. Raloxifene has also shown similar properties, notwithstanding its effect on non-vertebral fractures, which has only been derived from a post hoc analysis limited to patients with prevalent severe vertebral fractures at baseline. This compound also has interesting non-skeletal benefits, including effects on the breast and heart. Teriparatide, a bone-forming agent, promptly reduces the rate of vertebral and all non-vertebral fractures, without significant adverse effects. Strontium ranelate, the first agent shown to concomitantly decrease bone resorption and stimulate bone formation, has also shown its ability to reduce rates of vertebral and non-vertebral fractures in patients with established osteoporosis. It significantly reduces hip fractures in elderly individuals at high risk for such events. Its safety profile is also excellent.     

Role of bisphosphonates and calcitonin in the prevention and treatment of osteoporosis

Bisphosphonates have been shown to increase bone mineral density in patients with established osteoporosis as well as those with osteopenia. The evidence conclusively shows a reduction in fracture rates in patients on the more potent nitrogen containing bisphosphonates. Indeed, significant vertebral fracture rate reduction has been demonstrated after only 1 year of therapy. Alendronate, a second-generation bisphosphonate, and risedronate, a third-generation bisphosphonate, are first line medications for the treatment of osteoporosis given their efficacy in preventing both vertebral and non-vertebral fractures. There is evidence that vertebral fractures may be prevented by intermittent cyclic therapy with etidronate. All three have been shown to increase bone mineral density in the spine, with alendronate and risedronate producing significant increases in hip bone density. Calcitonin has demonstrated the ability to reduce vertebral fracture rates with minimal changes in bone density. Calcitonin is also beneficial in reducing the bone pain associated with fractures.     

Raloxifene for older women: a review of the literature

Raloxifene is a non-steroidal selective estrogen-receptor modulator (SERM) which is used for prevention and treatment of postmenopausal osteoporosis. Raloxifene decreases the incidence of vertebral fractures by 30%–50% in postmenopausal women with osteoporosis but has not been shown to decrease the incidence of hip fractures or other non-vertebral fractures. At the present time, estrogen-replacement therapy and bisphosphonate treatment are the only medical treatments that are proven to prevent hip fractures with the exception of vitamin D and calcium replacement, which has been shown to prevent hip fractures in elderly individuals and nursing home residents. Raloxifene has been shown to have additive effects on bone turnover and bone mineral density (BMD) when used along with alendronate and teriparatide. Raloxifene could have a role in renal failure as it has been shown to increase BMD of the vertebra over 1 year of therapy. Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer. The increased incidence of venous thromboembolism is the main concern of raloxifene therapy and previous history of venous thromboembolism is a contraindication for use of raloxifene. Raloxifene has a role in treatment of vertebral osteoporosis in older women. The decision to use raloxifene should be based on evaluation of fracture risk and on potential other benefits than fracture reduction along with consideration of side effects.     

Treatment of postmenopausal osteoporosis

The aim of treatment of postmenopausal osteoporosis is to reduce the frequency of vertebral and non-vertebral fractures (especially at the hip), which are responsible for morbidity associated with the disease. Results of large placebo controlled trials have shown that alendronate, raloxifene, risedronate, the 1-34 fragment of parathyroid hormone, and nasal calcitonin, greatly reduce the risk of vertebral fractures. Furthermore, a large reduction of non-vertebral fractures has been shown for alendronate, risedronate, and the 1-34 fragment of parathyroid hormone. Calcium and vitamin D supplementation is not sufficient to treat individuals with osteoporosis but is useful, especially in elderly women in care homes. Hormone replacement therapy remains a valuable option for the prevention of osteoporosis in early postmenopausal women. Choice of treatment depends on age, the presence or absence of prevalent fractures, especially at the spine, and the degree of bone mineral density measured at the spine and hip. Non-pharmacological interventions include adequate calcium intake and diet, selected exercise programmes, reduction of other risk factors for osteoporotic fractures, and reduction of the risk of falls in elderly individuals.     

Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents

Some, but not all, antiresorptive agents have been shown to reduce the risk of nonvertebral fractures. Agents that significantly reduced nonvertebral fracture risk also appear to produce larger mean increases in bone mineral density (BMD) and reductions in biochemical markers (BCM) of bone turnover, compared with other agents. To examine the extent to which increases in BMD and reductions in BCM during antiresorptive therapy are associated with reductions in risk of nonvertebral fractures, we performed a meta-analysis of all randomized, placebo-controlled trials of antiresorptive agents conducted in postmenopausal women with osteoporosis (i.e. prior vertebral fracture or low BMD) with available relevant data. A total of 18 such trials with usable data were identified, including a total of 2,415 women with incident nonvertebral fractures over 69,369 women-years of follow-up. Poisson regression was used to estimate the association between changes in BMD or BCM during the first year and overall reductions in risk of nonvertebral fractures (vs. the placebo group) across all trials. Larger increases in BMD and larger reductions in BCM were significantly associated with greater reductions in nonvertebral fracture risk. For example, each 1% increase in spine BMD at 1 yr was associated with an 8% reduction in nonvertebral fracture risk (P = 0.02). Mean BMD changes at the hip were smaller than at the spine, but the predicted net effect on fracture risk was the same; an agent that increases spine BMD by 6% at 1 yr reduces nonvertebral fracture risk by about 39%, and an agent that increases hip BMD by 3% at 1 yr reduces nonvertebral fracture risk by about 46%. The results also predict that a 70% reduction in resorption BCM would reduce risk by 40%, and a 50% reduction in formation BCM would reduce risk by 44%. It appears that either BMD or BCM changes are able to explain the effect of treatment, because a separate variable for treatment was not independently significant in any models. These data demonstrate that larger increases in BMD at both the spine and hip and larger reductions in both formation and resorption BCM are associated with greater reductions in the risk of nonvertebral fractures. Antiresorptive agents that do not produce large increases in BMD or large reductions in BCM do not appear to and would not be expected to decrease the risk of nonvertebral fractures.     

Drug insight: Existing and emerging therapies for osteoporosis

Osteoporosis is a major public health problem that is characterized by microarchitectural deterioration, low bone mass, and increased risk of fractures. Currently, many women and men affected with this disease are not diagnosed or treated. As osteoporosis is often clinically silent, risk-factor assessment and measurement of BMD are needed to identify those who may benefit from osteoporosis therapy. Although adequate daily intake of calcium and vitamin D, and regular weight-bearing exercise are important for skeletal health, they are not adequate treatments for individuals with osteoporosis. Therapies approved for treatment and/or prevention of osteoporosis in the United States include oral bisphosphonates (alendronate, ibandronate and risedronate), calcitonin, estrogens, teriparatide (parathyroid hormone fragment [1-34]), and raloxifene. For most patients, oral bisphosphonates are the treatment of choice, given the large-scale randomized-trial data demonstrating efficacy in fracture reduction, although bisphosphonates that reduce spine and nonspine fractures (e.g. alendronate and risedronate) are preferred. For high-risk patients (those with very low bone density, or with fractures), teriparatide therapy for 2 years should be considered. The treatment paradigm for osteoporosis will evolve further as promising new treatments progress through clinical development.     

Postmenopausal osteoporosis. What have we learned since the introduction of bisphosphonates?

Over the past 12 years bisphosphonates have become a mainstay of treatment for postmenopausal osteoporosis. As a class, bisphosphonates significantly suppress bone turnover and increase BMD at the lumbar spine and other site through their direct inhibitory effects on osteoclasts. Alendronate and risedronate reduce the incidence of clinical vertebral and non-vertebral fractures. Etidronate and both oral and intravenous ibandronate reduce the incidence of clinical vertebral fractures, but data from primary analyses for reduction in non-vertebral fractures are currently less robust. Intravenous administration of zoledronate is under late-stage investigation for use in postmenopausal osteoporosis. Combinations of alendronate with estrogen or raloxifene provide a greater reduction in bone turnover markers and greater increases in BMD, but fracture risk reduction has not been determined. Overall, bisphosphonates are well tolerated. The most common side effects of oral bisphosphonates are upper gastrointestinal symptoms. Newer safety concerns about the use of bisphosphonates include osteonecrosis of the jaw and oversuppression of bone turnover. The optimal duration of bisphosphonate treatment has not been clearly established.     

Meta-analyses of therapies for postmenopausal osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis

This section summarizes the results of the seven systematic reviews of osteoporosis therapies published in this series [calcium, vitamin D, hormone replacement therapy (HRT), alendronate, risedronate, raloxifene, and calcitonin] and systematic reviews of etidronate and fluoride we have published elsewhere. We highlight the methodological strengths and weaknesses of the individual studies, and summarize the effects of treatments on the risk of vertebral and nonvertebral fractures and on bone density, including effects in different patient subgroups. We provide an estimate of the expected impact of antiosteoporosis interventions in prevention and treatment populations using the number needed to treat (NNT) as a reference. In addition to the evidence, judgements about the relative weight that one places on weaker and stronger evidence, attitudes toward uncertainty, circumstances of patients' and societal values or preferences will, and should, play an important role in decision-making regarding anti-osteoporosis therapy.     

Antiresorptive Therapy for the Prevention of Postmenopausal Osteoporosis

Osteoporosis is a condition associated with decreased bone strength and an increased fracture risk. It may be defined based on bone mineral density (BMD) with a T-score at the hip or spine of less than -2.5 standard deviations in young healthy individuals or from an osteoporotic fracture (i.e. a fracture occurring after low-energy trauma or no apparent trauma). Risk factors predisposing to fractures include: increasing age; female gender; low BMD; a prior fragility fracture; a family history of fragility fractures; low bodyweight; lack of estrogen in women (i.e. post menopause); corticosteroid use; smoking; a number of diseases; deficiency in calcium and vitamin D; an increased risk of falls (i.e. impaired vision); immobilization; and Caucasian race. The more risk factors that are present the higher the risk of fractures over the following 10 years. The need to initiate preventive therapy with anti-osteoporotic treatment increases steeply with the absolute fracture risk. Indications for referral for dual energy x-ray absorptiometry measurement of BMD include: age >65 years; age <65 years in postmenopausal women with any of the risk factors already mentioned; premature menopause (<45 years); prolonged amenorrhea (>1 year) in younger women; fragility fractures; and diseases or conditions known to lead to osteoporosis.Anti-resorptive therapies include calcium plus vitamin D, bisphosphonates (alendronate, etidronate, risedronate, ibandronate), selective estrogen receptor modulators (raloxifene), hormone replacement therapy, and calcitonin. Guidelines from several countries on when to initiate anti-resorptive therapy state that therapy may be started in patients with a prior fragility fracture (some guidelines state that in this situation no BMD measurements are necessary) or in patients with a T-score of less than -2.5 (some guidelines state that additional risk factors need to be present in this situation). Some guidelines state that anti-resorptive therapy may be initiated in patients with a T-score in the osteopenic range (from -1 to -2.5, i.e. not frank osteoporosis) in the presence of other risk factors. The cost effectiveness of anti-resorptive therapy increases with the absolute fracture risk. In some scenarios, treatment with bisphosphonates may be cost effective in a 50-year-old woman with an absolute hip fracture risk of >or=1.1% over the next 10 years.     

Postmenopausal osteoporosis: fracture consequences and treatment efficacy vary by skeletal site

At least half of all postmenopausal women will experience fractures during their lifetime, and the consequences are often serious, but most women at risk are not receiving adequate treatment. The objective of this paper is to summarize the literature concerning the consequences of osteoporotic fractures, and the effectiveness of pharmacologic agents for preventing fractures and their consequences, emphasizing a systematic, evidence-based summary of treatment results from randomized, controlled trials that were published previously. Osteoporosis is associated with increased risk of fractures at most skeletal sites. Hip fractures have much greater prognostic significance in terms of health than any other single type of fracture. However, symptomatic vertebral fractures and other non-hip fractures also represent enormous morbidity and economic burdens, and signal increased risk of future fractures of all types, including the hip. There is convincing evidence that two bisphosphonates (alendronate and risedronate) reduce the risk of both spine and non-spine fractures. The evidence for reducing hip fracture risk is greater for alendronate, with a consistent approximately 50% reduction in hip fractures across studies. Alendronate has also been demonstrated to maintain quality of life by reducing outcomes such as hospitalization and bed rest related to back pain. Among other agents, raloxifene reduces the risk of vertebral fractures by approximately 30%; the published evidence for most other agents is inconclusive. Osteoporosis should be regarded as seriously as other important chronic disorders such as hypertension and hyperlipidemia. Postmenopausal patients with a high risk of fractures--such as those with prior fractures or osteoporosis as measured by BMD--need to be treated. Although other therapeutic modalities are available, the evidence is most convincing for the bisphosphonates, alendronate and risedronate.     

Assessment of the Relationship Between Age and the Effect of Risedronate Treatment in Women with Postmenopausal Osteoporosis: A Pooled Analysis of Four Studies

OBJECTIVES: To quantify the effect of age on the incidence of osteoporosis‐related fractures and of risedronate treatment on fracture risk in different age groups in women with postmenopausal osteoporosis. DESIGN: Data from four randomized, double‐blind, placebo‐controlled, Phase III studies were pooled and analyzed. PARTICIPANTS: The analysis population (N=3,229) consisted of postmenopausal women with osteoporosis as determined on the basis of prevalent vertebral fractures, low bone mineral density (BMD), or both. INTERVENTION: Patients had received risedronate 5 mg daily or placebo for 1 to 3 years. MEASUREMENTS: The endpoints of interest were the incidence of osteoporosis‐related fractures, clinical fractures, nonvertebral fractures, and morphometric vertebral fractures. The effect of age on fracture risk and treatment benefit was examined using Cox regression models with age and treatment as explanatory variables. The 3‐year fracture risk was estimated for patients in each treatment group at a given age. RESULTS: Irrespective of treatment, fracture risks were greater in older patients (P<.001). On average, for every 1‐year increase in age, a patient's risk for osteoporosis‐related fracture increased 3.6% (95% confidence interval=2.3–5.0%). Irrespective of age, risedronate treatment reduced fracture risk 42%. Risedronate‐treated patients had fracture risks similar to those of placebo‐treated patients 10 to 20 years younger. CONCLUSION: Patients treated with risedronate have a significantly lower fracture risk, similar to that of untreated patients 10 to 20 years younger.     

Osteoporosis in postmenopausal women. Therapy options across a wide range of risk for fracture

Osteoporosis is a highly prevalent skeletal disorder characterized by compromised bone strength predisposing individuals to an increased risk of fractures. Fractures related to osteoporosis are frequently associated with chronic pain and decreased quality of life, as well as significant morbidity and mortality. Postmenopausal women are at higher risk for developing osteoporosis and osteoporosis-related fractures. Osteoporosis fractures are commonly asymptomatic, necessitating a need for proactive screening, diagnostic testing, and more importantly, therapeutic intervention that will rapidly reduce the risk of fractures in at-risk patients. Current pharmacologic prevention and treatment options for osteoporosis include antiresorptive therapies (alendronate, risedronate, ibandronate, raloxifene, hormone therapy, and calcitonin) and the anabolic agent teriparatide.     

Selective estrogen receptor modulators

Selective estrogen receptor modulators (SERMs) competitively bind to estrogen receptors to act as agonists or antagonists in certain tissues, distinguishing the various available SERMS. Although tamoxifen, toremifene, and additional new compounds are discussed briefly, raloxifene is the only SERM currently indicated for the prevention and treatment of postmenopausal osteoporosis in women. The effects of raloxifene on vertebral fractures, nonvertebral fractures, and bone mineral density (BMD) have been explored. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, vertebral fractures were significantly reduced in the raloxifene treatment group (relative risk of 0.60, 95% confidence interval 0.50–0.70, p<0.01). Raloxifene did not significantly reduce nonvertebral fractures with either 60 or 120 mg/d in the MORE trial. BMD increased by 0.4 to 1.20% at the lumbar spine and the effects have been documented for at least 7 yr in the Continuing Outcomes Relevant to Evista trial. Fracture prevention is greater than expected based on BMD changes. Adverse effects that should be considered with raloxifene include hot flushes and an increased risk for venous thromboembolism. Raloxifene is a viable option for postmenopausal patients with osteoporosis, particularly in patients at increased risk of invasive breast cancer. Although not yet indicated by the US Food and Drug Administration for breast cancer prevention, clinical trail data is encouraging.     

Preventing osteoporotic fractures with antiresorptive therapy: implications of microarchitectural changes

Prospective studies have demonstrated that low bone mass correlates well with increased risk of osteoporotic fractures at various skeletal sites. Trials have likewise confirmed that enhancing bone mass with antiresorptive therapy reduces fracture incidence in individuals at risk. However, correlation of bone mineral density (BMD) increases with therapeutic risk reduction has proved less consistent than correlation of BMD decreases with greater fracture risk in the untreated. Indeed, various analyses have indicated that - even during treatment with potent bisphosphonates like alendronate and risedronate - BMD changes from baseline account for <30% of the reduction in vertebral fractures in treated women. It is clearly, therefore, that factors other than BMD are involved in the reduction of fracture risk achieved by antiresorptive therapies. According to recent micro-computed tomography imaging and other studies, antiresorptive therapy can help rebuild the microarchitecture of bone as well as strengthen the materials that go into it. When treating individuals with osteoporosis, these microarchitectural changes contribute to the reduction of fracture risk achieved by antiresorptive therapies.