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.     

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.     

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.     

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.     

Prevention and treatment strategies for glucocorticoid-induced osteoporotic fractures

Glucocorticoids are the most common cause of drug-related osteoporosis. We reviewed current evidence on risk factors for glucocorticoid-induced osteoporosis (GIOP) and prevention and treatment of GIOP-related fractures. Guidelines for GIOP management published since 2000 were also reviewed. Significant bone loss and increased fracture risk is seen with daily prednisone doses as low as 5 mg. Alternate-day glucocorticoid therapy can lead to similar bone loss. No conclusive evidence exists for a safe minimum dose or duration of glucocorticoid exposure. Physicians should consider risk factors for involutional osteoporosis such as older age, postmenopausal status, and baseline bone density measurements as they assess patients for prevention or treatment of GIOP. Bisphosphonates were reported to reduce GIOP-related vertebral fractures, but inconclusive data exist for hip fractures associated with glucocorticoid use. Hormone replacement therapy and parathyroid hormone analogs are effective in preserving bone density in GIOP. The risk of osteoporosis and fractures should be routinely assessed in patients receiving glucocorticoid therapy. Effective prevention and treatment options are available and can result in meaningful reduction of GIOP-related morbidity and mortality. Current guidelines for GIOP management recommend bisphosphonates, especially alendronate and risedronate, as first-line agents for GIOP, and these guidelines propose the preventive use of bisphosphonates early in the course of glucocorticoid therapy in high-risk patient subgroups.     

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.     

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.     

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.     

Management of primary osteoporosis

Although there is a great need for better therapeutic approaches to the patient who presents with a fracture, osteoporotic fractures will remain a condition that is more amenable to prevention than treatment. Hormone replacement therapy (HRT) is still considered by many the mainstay for the prevention and the treatment of posrmenopausal osteoporosis. However, there are several controversies regarding HRT, especially the duration of treatment and the risks/benefits ratio. Recent studies have challenged the assumption that HRT conveys real long-term beneficial effects. Raloxifene or other "selective estrogen receptor modulators" (SERMs) should progressively replace HRT in elderly women. Bisphosphonates have demonstrated a clearcut efficacy in the treatment of osteoporosis. Alendronate and risedronate have been the most extensively studied bisphosphonates under randomized controlled trials conditions. Both agents can reduce the risk of vertebral and hip fractures by one-fourth to one-half. However, oral bisphosphonates are not without gastro-intestinal toxicity and strict adherence to constraining therapeutic schemes is mandatory. Intermittent treatments are already in use. Weekly alendronate is as efficient as daily therapy and improves treatment compliance. Newer more potent bisphosphonates, such as oral ibandronate or intravenous zoledronic acid, will allow much less frequent administration. The anti-fracture efficacy of yearly zoledronic acid infusions is thus currently tested. On the other hand, bone-forming agents, such as daily subcutaneous injections of teriparatide (rhPTH 1-34) offer exciting perspectives for the treatment of severe osteoporosis despite the complexity of such therapy.     

Clinical Pharmacology of Potent New Bisphosphonates for Postmenopausal Osteoporosis

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.     

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.     

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.     

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.     

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.     

Treatment-related osteoporosis in men with prostate cancer

Osteoporosis is an important complication of androgen-deprivation therapy (ADT) for prostate cancer. ADT by either bilateral orchiectomies or treatment with a gonadotropin-releasing hormone (GnRH) agonist decreases bone mineral density (BMD) and increases the risk of fracture. Prospective data about treatment or prevention of osteoporosis in men with prostate cancer are limited. Supplemental calcium and vitamin D are recommended. Additional therapy may be warranted for men with osteoporosis or fractures. Intravenous pamidronate prevents bone loss in the hip and spine during ADT. Intravenous zoledronic acid not only prevents bone loss but also increases BMD. Alendronate is approved to treatmen with osteoporosis although the efficacy of alendronate or other oral bisphosphonates has not been evaluated during ADT. Additional prospective studies are needed to evaluate the long-term effects of bisphosphonates and other the rapies on fracture risk and disease-related outcomes.     

Drug insight: Bisphosphonates for postmenopausal osteoporosis

Bisphosphonates are potent antiresorptive agents, which have largely been used for the treatment of postmenopausal osteoporosis during the past 10 years. When embedded in bone matrix, bisphosphonates are taken up by osteoclasts engaged in bone resorption, leading--mainly by inhibition of farnesyl diphosphate synthase, a key enzyme of the mevalonate pathway--to osteoclast apoptosis. Bone resorption decreases, with consequent improvement in the mechanical properties of bone and a reduced risk of fracture. Alendronate and risedronate are oral nitrogen-containing bisphosphonates. Several randomized, placebo-controlled trials have shown the ability of these bisphosphonates to halve the risk of vertebral fracture when taken daily for 3 years. Nonvertebral fracture risk, including that at the hip, was also significantly decreased. Weekly regimens have simplified the administration of bisphosphonates and, probably, improved adherence to treatment. A significant reduction in the risk of vertebral fracture has also been demonstrated with an intermittent regimen of ibandronate, which is a new, potent, nitrogen-containing bisphosphonate. Ibandronate was recently marketed for use in an oral, once-monthly dose of 150 mg, with the goal of improving compliance. Bisphosphonates are usually well tolerated in the long term. Intravenous administration of bisphosphonates in women with osteoporosis, which is currently under investigation, might be an interesting future option for women who cannot tolerate oral regimens, and for enhancing compliance.     

Bisphosphonate mechanism of action

The nitrogen-containing bisphosphonates (N-BPs), alendronate and risedronate, are the only pharmacologic agents shown to prevent spine and nonvertebral fractures associated with postmenopausal and glucocorticoid-induced osteoporosis. At the tissue level, this is achieved through osteoclast inhibition, which leads to reduced bone turnover, increased bone mass, and improved mineralization. The molecular targets of bisphosphonates (BPs) have recently been identified. This review will discuss the mechanism of action of BPs, focusing on alendronate and risedronate, which are the two agents most widely studied. They act on the cholesterol biosynthesis pathway enzyme, farnesyl diphosphate synthase. By inhibiting this enzyme in the osteoclast, they interfere with geranylgeranylation (attachment of the lipid to regulatory proteins), which causes osteoclast inactivation. This mechanism is responsible for N-BP suppression of osteoclastic bone resorption and reduction of bone turnover, which leads to fracture prevention.     

The use of bisphosphonates in the treatment of osteoporosis

PURPOSE OF REVIEW: The bisphosphonates alendronate and risedronate, given orally once weekly, are the cornerstone of treatment of postmenopausal osteoporosis, as well as of male and secondary osteoporosis. They reduce significantly the risk of vertebral and nonvertebral fractures; their effects appear early, within 6-12 months, and appear to be sustained. Several questions remain unanswered, however. In addition, data on a new bisphosphonate became available in 2004. RECENT FINDINGS: The optimal duration of treatment has not been clearly established. Long-term data with alendronate are now available, indicating a persistence of alendronate effects on bone mineral density and bone turnover markers several years after stopping treatment given for 5 years. Whether these effects translate into sustained reduction of fractures needs to be further analyzed. Because of their efficacy, bisphosphonate use has been explored in other forms of osteoporosis, such as after androgen deprivation therapy for prostatic cancer. The challenge of long-term compliance with treatment of osteoporosis has triggered the use of intermittent bisphosphonate. The effects of intermittent oral and intravenous ibandronate on bone mineral density, bone turnover, and fractures have been recently reported. SUMMARY: The mechanism by which bisphosphonates improve bone strength is not yet fully understood but probably involves complex effects on different components of bone strength, such as microarchitecture.     

Bisphosphontes

The profitable effects of bisphosphontes on treatment of osteoporosis have been consistently reported in Japan as in the United States and European countries. Alendronate and risedronate increased bone mineral density and reduced the risk of vertebral fracture. Histomorphomeric analysis and microCT have confirmed that normal bone microarchitecture and mineralization are preserved after 3 or 5 years of treatment. Long-term (7 or 10 years) treatment with bisphosphonates seemed to have a sustained effect on BMD and bone turnover, however, the optimal duration of bisphosphonate treatment is unresolved.     

Corticosteroid-Induced Osteoporosis

Corticosteroid-induced osteoporosis is the leading cause of secondary osteoporosis and a significant cause of morbidity in both men and women. Long-term use of even low-dose corticosteroids has been associated with increased risk of bone loss. Recent large randomized controlled trials have generated new knowledge on treatment strategies for patients with corticosteroid-induced osteoporosis. However, the majority of individuals receiving corticosteroids are not receiving prophylaxis for osteoporosis. Calcium and vitamin D should be recommended to patients initiating therapy with corticosteroids (and should be adequate for those receiving corticosteroids for less than 3 months). For those receiving corticosteroids for greater than 3 months, bisphosphonates are the therapy of choice, with both alendronate (alendronic acid) and risedronate (risedronic acid) approved by the US FDA for use in this indication. Calcitonin can be considered a second-line agent and should be reserved for patients who are intolerant of bisphosphonates or who are experiencing pain from a vertebral fracture. Hormone replacement therapy or testosterone therapy may be offered to those individuals on long-term corticosteroid treatment who are hypogonadal. Teriparatide (recombinant human parathyroid hormone 1-34) shows promise as a future anabolic agent for the prevention and treatment of patients with corticosteroid-induced osteoporosis.