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.     

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.     

Aging bone and osteoporosis: strategies for preventing fractures in the elderly

As the older population increases, the incidence of osteoporotic fractures is expected to dramatically rise during the next few decades. Older patients are much more susceptible to fracture at any given bone mineral density (BMD) than are younger patients because of various factors, including the quality of aging bone, which involves more than BMD. Suppression of increased bone turnover by antiresorptive therapies, even with only small changes in BMD, can reduce fracture risk, especially in the lumbar spine. Bisphosphonate treatment can significantly reduce vertebral and nonvertebral fractures, including hip fractures, even in the very elderly. Prospective analyses show that risedronate therapy consistently and significantly reduces the risk of new morphometric vertebral fractures after 1 year in postmenopausal women. Post hoc analyses report significant reductions in the risk of 1 new clinical vertebral fracture after 6 months of risedronate therapy and after 1 year of alendronate therapy. Oral raloxifene therapy and salmon calcitonin nasal spray therapy have been shown to reduce the risk of vertebral fracture after 3 and 5 years, respectively, and post hoc data show a significant reduction in clinical vertebral fracture risk at 1 year with raloxifene use. However, neither raloxifene therapy nor calcitonin therapy reduce the risk of nonvertebral and hip fractures at currently approved doses. Bisphosphonates have been shown to be safe and efficacious with 7 years' risedronate sodium and 10 years' alendronate sodium data published, and bisphosphonates reduce bone turnover and increase BMD to a greater degree than raloxifene and calcitonin, which may partly account for their nonvertebral and hip fracture reduction effect. Therefore, bisphosphonate therapy with risedronate or alendronate should be considered in patients with low BMD at the hip and in older patients with osteoporosis and osteopenia, particularly those with an existing fracture.     

Preventing osteoporotic fractures with bisphosphonates: a review of the efficacy and tolerability

Although change in bone mineral density was the outcome most commonly measured in early clinical trials of osteoporosis therapies, it is now understood that the most clinically important outcome is reduction in the risk of fractures. Of currently available osteoporosis therapies, the bisphosphonates have been most thoroughly investigated in studies with fracture risk as the primary outcome. The most widely studied bisphosphonates include etidronate, alendronate and risedronate. Alendronate and risedronate have the most compelling evidence for vertebral and non-vertebral fracture reduction. This review provides a comprehensive overview of the anti-fracture efficacy of bisphosphonates at the spine, hip, and non-vertebral sites.     

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.     

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.     

Bisphosphonates

After the development of potent bisphosphonates including alendronate and risedronate, evidence has accumulated that not only vertebral but also non-vertebral fractures can be prevented by these agents. In addition, numbers needed to treat for both vertebral and non-vertebral fractures by alendronate and risedronate are around 30 to 90. Thus, these agents are expected to improve the socio-economical situation of osteoporosis treatment as well as the survival and quality of life of osteoporotic patients. Once-a-week oral bisphosphonates and long-acting intravenous formula that can successfully inhibit bone resorption for 3 months or longer are also under development. Although PTH and alendronate treatment in combination did not show much beneficial effects, there are results showing additive effect of sequential treatment with PTH followed by alendronate. From these studies, we can expect even better prospect for osteoporosis treatment by choosing from or sequentially combining these different modality of therapies.     

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.     

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.     

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.     

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.     

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.     

How to manage postmenopausal osteoporosis?

Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased fracture risk. Several therapeutic agents are now available to treat postmenopausal osteoporosis and prevent fractures. Combined calcium and vitamin D supplementation reduce the relative risk of non-vertebral fractures by about 18%. Hormone replacement therapy (HRT) should not be prescribed for osteoporosis in women who do not experience menopausal symptoms. The marked benefits of raloxifene on the reduction in invasive breast cancer and vertebral fracture risk are partially counterbalanced by a lack of effect on non-vertebral fracture risk, and an increased risk of venous thromboembolism and stroke. All four bisphosphonates available in Belgium, except ibandronate, have been shown to reduce the risk of vertebral, non-vertebral and hip fractures in prospective, placebo-controlled trials. Globally, the incidence of vertebral fractures is reduced by 41%-70%, and the incidence of non-vertebral fractures by 25%-39%. The anti-fracture efficacy of weekly or monthly doses of oral bisphosphonates has not been directly shown but is assumed from bridging studies based on BMD changes. To date, the various bisphosphonates have not been studied in head-to-head comparative trials with fracture endpoints. There are potential concerns that long-term suppression of bone turnover associated with bisphosphonate treatment may eventually lead to adverse effects, especially atypical femoral fractures and osteonecrosis of the jaw, but these cases are extremely rare. Teri-paratide (recombinant human 1-34 PTH) administered by daily subcutaneous injections decreases by 65% the relative risk of new vertebral fractures in patients with severe osteoporosis. Pivotal trials with strontium ranelate have shown a 41% reduction in new vertebral fractures and a 16% reduction in non-vertebral fractures over 3 years. Denosumab is a fully human monoclonal antibody to RANK Ligand that is administered as a 60-mg subcutaneous injection every 6 months. In the pivotal phase III trial, there was a 68% reduction in the incidence of new vertebral fractures, whereas the incidence of non-vertebral fractures was reduced by 20%. Several new approaches are being explored, including antibodies to sclerostin, cathepsin K inhibitors, src kinase inhibitors, and drugs that act on calcium sensing receptors.     

Pharmacological treatment of osteoporosis for people over 70

Osteoporosis has been defined as "a systemic disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with consequent increase in bone fragility and susceptibility to fracture". The impact of osteoporosis is most pronounced in elderly populations who run the greatest risk of fractures. The probability of developing mainly hip, vertebral and other non-vertebral fractures (for example, a Colles fracture) not only depends on bone mineral density (BMD) but also on age. Older patients are more susceptible to fracture than younger patients with the same BMD T-score. As the older population increases, the incidence of osteoporotic fractures is expected to rise dramatically over the next few decades. Although hip fractures are considered to be the most severe and economically important osteoporotic fracture, vertebral fractures also lead to adverse health outcomes, including back pain, height loss and kyphosis. These changes may result in significant declines in physical performance, function and, ultimately, loss of independence. The challenge for physicians is to prevent bone loss, to diagnose and treat osteoporosis before fractures occur, and to treat patients who have already experienced a fracture to prevent recurrent fractures. The objective of this review is to analyze the capacity to reduce fractures as the key element to evaluate the effectiveness of available medications: calcium and Vitamin D, bone formation drugs, antiresortive drugs, and dual-effect drugs. In view of the paucity of information about treatment of osteoporosis in the elderly population, available studies were not designed with this objective, so that this article reviews data mostly deriving from post-hoc analysis or sub-analysis of the main phase III clinical trials of each of the tested medications.     

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.     

Anabolic Agents for Osteoporosis

Antiresorptive agents for osteoporosis are a cornerstone of therapy, but anabolic drugs have recently widened our therapeutic options. By directly stimulating bone formation, anabolic agents reduce fracture incidence by improving other bone qualities in addition to increasing bone mass. Teriparatide (human parathyroid hormone[1-34]) has clearly emerged as a major approach for selected patients with osteoporosis. Teriparatide increases bone mineral density and bone turnover, improves bone microarchitecture, and changes bone size. The incidence of vertebral and non-vertebral fractures is reduced. Teriparatide is approved in many countries throughout the world for the treatment of both postmenopausal women and men with osteoporosis who are at high risk for fracture. Another anabolic agent, strontium ranelate, may both promote bone formation and inhibit bone resorption. Clinical trials support the use of strontium ranelate as a treatment for postmenopausal osteoporosis and have shown that strontium ranelate reduces the frequency of vertebral and non-vertebral fractures. Other potential anabolic therapies for osteoporosis, including other forms of parathyroid hormone, growth hormone, and insulin-like growth factor-I, have been examined, although less data are currently available on these approaches.     

Osteoporosebehandlung: Bisphosphonate, SERM’s, Teriparatide und Strontium

The therapy of osteoporosis is mostly based upon the use of drugs which inhibit bone resorption. Among these, the bisphosphonate family is the best known and mostly used by clinicians. Both second and third generation bisphosphonates, like alendronate and risedronate, are now available as weekly tablets which have facilitated the patient compliance to treatment together with a decreased occurrence of gastrointestinal side effects. These compounds are used efficiently to treat postmenopausal osteoporosis and osteoporosis of men as well. Their use did provide good evidence of increased bone mineral density (BMD) and a reduction in fracture rates. The use of intravenous bisphosphonates such as Zoledronate, Ibandronate and Pamidronate remains in most of the cases limited to special indications such as intolerance to the oral formulations and treatment of patients with bone metastases. The selective estrogen modulators (SERM's) family is limited to a single product on the market as of now, Raloxifene, which does inhibit bone resorption and is well documented by postmenopausal women to increase BMD and reduce vertebral fractures. In addition, a large range of positive nonosseous effects have been documented such as the reduction of the incidence of breast cancer. Other substances do have a strong anabolic effect such as Teriparatide, a recombinant human formulation of PTH 1-34. This compound has demonstrated good efficacy in postmenopausal women, increasing vertebral and hip BMD and reducing the incidence of fractures at both sites. The exact role of Teriparatide in the clinical setting is still open but its overall impact in the therapy of osteoporosis could be major due to its major efficiency over shorter periods of time. Strontium ranelate, a new divalent Strontium salt taken orally, acts both as an anti-catabolic and anabolic agent. The first results provided with strontium ranelate are very promising due to its major effect on the increase in BMD both at the vertebral and hip sites and its ability to reduce the incidence of fractures at both locations. Additional data are awaited to confirm these initial positive results.     

Bisphosphonates in the management of postmenopausal osteoporosis – optimizing efficacy in clinical practice

Nitrogen-containing bisphosphonates are potent inhibitors of osteoclastic bone resorption. With their individually proven efficacy to significantly reduce the incidence of vertebral and/or non-vertebral fractures and with their overall beneficial safety profile, alendronate, ibandronate, risedronate, and zoledronate are considered today a treatment of first choice in postmenopausal osteoporosis. However, treatment effects in an individual patient and cost-effectiveness in public health perspective are vitally dependent on the long-term patient adherence as well as on compliance and persistence. As compliance and persistence with daily oral bisphosphonates are shown to be suboptimal in many patients, leading to an increased fracture incidence in non-compliant patients, there is a need to improve overall adherence for bisphosphonate treatment in order to achieve maximum treatment effects. One option is to extend dosing intervals to weekly (alendronate, risedronate) or monthly (ibandronate) oral regimens. Less frequent oral regimens are generally preferred by majority of patients. Another alternative is intravenous, instead of oral application (ibandronate, zoledronate). Treatment acceptance could be further improved by IV bisphosphonates with their benefit of only quarterly, or even once-yearly, application. Treatment decisions should be based on anti-fracture efficacy data first. In addition, to ensure best possible patient adherence and maximum treatment benefits, physicians should consider individual patient conditions affecting compliance and persistence as well as patient preferences.     

Strontium ranelate: short- and long-term benefits for post-menopausal women with osteoporosis

Strontium ranelate is a bone-seeking element that has been assessed in post-menopausal osteoporosis in two large double-blind, placebo-controlled studies. This treatment is able to decrease the risk of vertebral fractures, by 41% over 3 yrs, and by 49% within the first year of treatment. This risk of non-vertebral fractures is decreased by 16% and, in patients at high risk for such a fracture, the risk of hip fracture is decreased by 36% over 3 yrs. Recent 5-yr data from these double-blind, placebo-controlled studies show that the anti-fracture efficacy is maintained over time. Treatment efficacy with strontium ranelate has been documented across a wide range of patient profiles: age, number of prevalent vertebral fractures, BMI, as well as family history of osteoporosis and addiction to smoking are not determinants of anti-fracture efficacy. During these clinical trials, safety was good. Its large spectrum of efficacy allows the use of strontium ranelate in the different subgroups of patients with post-menopausal osteoporosis.     

Strontium ranelate: vertebral and non-vertebral fracture risk reduction

Fractures are common at the spine and hip, but at least half the morbidity and mortality of fractures in the community come from fractures that involve other sites. Over half of all fractures arise in individuals without osteoporosis, whereas the highest risk group for fractures are individuals over 80 years of age. Reducing the burden of fractures should thus include an assessment of drug efficacy against all fractures in a wide range of individuals. For vertebral fractures, in the phase III Spinal Osteoporosis Therapeutic Intervention study of 1649 postmenopausal women with osteoporosis, 2 g strontium ranelate a day produced a risk reduction of 49% in the first year and 41% during 3 years. In the TReatment Of Peripheral OSteoporosis study, which was designed to examine the effect of strontium ranelate on non-vertebral fractures, of the 5091 patients, 3640 had spine X-rays. The vertebral fracture risk reduction was 45% at one year and 39% over 3 years. In a preplanned pooling of the above two studies, 1170 patients had vertebral osteopenia. Strontium ranelate reduced the risk of vertebral fracture in 3 years by 40% in these patients. In 409 patients with lumbar or femoral neck osteopenia, strontium ranelate reduced the risk of vertebral fractures by 62% over 3 years. In the pre-planned pooling of data from the two studies, in 1488 women aged between 80 and 100 years (mean age 84 +/- 3 years), the risk of vertebral fractures was reduced in one year by 59% and by 32% over 3 years. For non-vertebral fractures, in the TReatment Of Peripheral OSteoporosis study, treatment for 3 years reduced the fracture risk by 16%, and by 19% for major fragility fractures. In a post-hoc analysis of 1977 women at high risk of hip fracture (aged > or = 74 years and with a femoral neck bone mineral density T-score < or = -2.4) the hip fracture risk was reduced by 36%. In patients aged 80 and over in the pre-planned pooling of data from the two studies, the risk of an incident non-vertebral fracture was reduced by 41% in the first year and by 31% over 3 years. Strontium ranelate, a new anti-osteoporosis agent, has a broad range of antifracture efficacy.