Bisphosphonates for the Treatment of Postmenopausal Osteoporosis: An Update

Bisphosphonates are potent inhibitors of bone resorption, which prevent bone loss, improve bone strength and decrease the risk of fractures. This article reviews the results of recent studies on the efficacy and safety of bisphosphonates for the treatment of postmenopausal osteoporosis. Results of randomized trials using novel dosing regimens of bisphosphonates are discussed. Outcomes include bone mineral density, bone turnover markers fractures adverse events.     

Osteoporosis. Efficacy and safety of a bisphosphonate dosed once weekly

Trabecular and cortical bone is continuously being remodeled at microscopic loci called basic multicellular units (BMU). Estrogen deficiency in menopause contributes to an increase in osteoclastic resorption and/or a decrease in osteoblastic formation, which leads to microscopic bone loss at the BMUs. Drug treatments for osteoporosis are intended to inhibit bone resorption, reduce the rate of bone turnover, and increase bone mass. The bisphosphonate alendronate was recently approved for once-a-week dosing for the prevention and treatment of postmenopausal osteoporosis. A 70-mg, once-a-week dose of alendronate has been shown to be therapeutically equivalent to the standard daily 10-mg dose. Tolerability and safety of weekly dosing appear to be similar to daily dosing.     

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.     

Osteoporosis in HIV-infected patients

Bone disorders have emerged in the last 5 yr as additional long-term complications of human immunodeficiency virus (HIV) infection and its treatment. In particular, multiple studies suggest that HIV-infected patients receiving potent antiretroviral therapy have an increased prevalence of both osteopenia and osteoporosis. Studies prior to the era of potent antiretroviral therapy suggest that HIV infection has a modest effect on bone turnover. Treatment of HIV increases bone turnover with a greater effect on bone resorption. The mechanisms for increased bone demineralization in HIV-infected patients are unclear, although there is some evidence that specific drugs may inhibit bone formation in vitro. Small studies suggest that, in general, bone loss is not progressive over a short period of follow-up, and that the bisphosphonates may be useful in management; however, larger studies are needed to confirm these findings and assess the long-term implications of bone loss in HIV-infected persons.     

Bisphosphonate therapy for secondary osteoporosis: adult perspective

BACKGROUND: A number of disease states and drugs can upset the balance between bone formation and resorption resulting in increased fracture risk. Glucocorticoids are the most recognized cause of secondary osteoporosis. Hypogonadism, weight loss, and chronic inflammation are other contributors to bone loss in a variety of disease states. Bisphosphonates are potent inhibitors of bone resorption, and there is a variety of secondary osteoporosis where they produce substantial increases in bone density and reduce fracture risk by about 50%. Upper gastrointestinal tract intolerance with oral agents and a flu-like syndrome with intravenous bisphosphonates are the principal adverse effects associated with their use. CONCLUSIONS: Numerous disease states and medications can adversely affect the skeleton. Additional effects of aging and menopause can substantially increase an individual's fracture risk. It is important that physicians assess fracture risk in susceptible patients and initiate treatment when indicated.     

Risedronate once monthly: a potential new regimen for the treatment of postmenopausal osteoporosis

Postmenopausal osteoporosis increases susceptibility to low-trauma fractures due to reduced bone volume and microarchitectural deterioration. Daily nitrogen-containing bisphosphonates have shown antifracture efficacy in many studies and are the most commonly prescribed treatment for women with postmenopausal osteoporosis. However, optimal efficacy is often not achieved due to poor patient adherence to medication. Current dosing schedules are often inconvenient or impractical for patients. Poor adherence increases risk of fracture, which itself increases morbidity, healthcare costs and, potentially, mortality. Although weekly rather than daily dosing of bisphosphonates has improved adherence, significant problems remain. Efforts to reduce dosing frequency as a possible means for further improving adherence (compliance and persistence), and therefore treatment outcomes, are ongoing. Risedronate, a third-generation bisphosphonate, has been shown in multiple clinical trials to reduce fracture risk and improve bone mineral density in postmenopausal women with osteoporosis. Risedronate has a specific structure and set of characteristics that enable less frequent dosing. This paper reviews the structure of risedronate, and how this translates into high antiresorptive potency, favorable bone binding, persistence in bone, and good tolerability that permits less frequent dosing. The paper also reviews the clinical evidence for risedronate, demonstrating the viability of less frequent dosing, with its potential benefits for patient convenience and adherence to therapy. Two equivalence or non-inferiority bridging studies have demonstrated the option of novel risedronate dosing regimens. These studies are reviewed to demonstrate the efficacy and safety of two different monthly regimens of risedronate in the treatment of postmenopausal osteoporosis: 75 mg on 2 consecutive days a month and 150 mg once a month. Data for oral risedronate 150 mg once a month are limited to 1 year’s treatment duration. In previous clinical trials, patients receiving risedronate 5 mg daily have been followed for up to 7 years, with no evidence of loss of effectiveness. Risedronate 150 mg once a month has a comparable efficacy and safety to daily doses in the treatment of postmenopausal osteoporosis. These additional treatment options with risedronate provide easier dosing alternatives for patients.     

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.     

Changes in bone remodelling and antifracture efficacy of intermittent bisphosphonate therapy: implications from clinical studies with ibandronate

Bisphosphonates reduce the rate of bone resorption and bone remodelling. Given daily, they decrease the risk of fractures in postmenopausal osteoporosis. When bisphosphonates were given at extended drug-free intervals this antifracture efficacy was generally not seen. This may be due to the different pattern of bone remodelling changes. Data from randomised clinical studies of ibandronate, given orally or intravenously, at different doses and for variable time intervals to women with osteoporosis were examined to explore the relationship between intermittent bisphosphonate therapy, changes in bone resorption and fracture risk. The magnitude of the reduction of the rate of bone resorption at the end of the drug-free interval rather than its fluctuation pattern after bisphosphonate administration determines antifracture efficacy, provided that these fluctuations occur within the premenopausal range. Prolongation of the drug-free interval beyond 2 weeks should be compensated by a dose higher than the cumulative daily dose.     

Spontaneous non-traumatic stress fractures in bilateral femoral shafts in a patient treated with bisphosphonates

Bisphosphonates are potent inhibitors of bone resorption and widely used to treat osteoporosis. Extensive studies have shown that therapy with bisphosphonates improves bone density and decreases fracture risk. However, concerns have been raised about potential over-suppression of bone turnover during long-term use of bisphosphonates, resulting in increased susceptibility to and delayed healing of non-spinal fractures. We report a patient who sustained non-traumatic stress fractures in bilateral femoral shafts with delayed healing after long-term bisphosphonate therapy. She underwent open reduction and surgical internal fixation. Although bisphosphonates effectively prevent vertebral fractures, and their safety has been tested in randomized trials, we must emphasize the need for awareness of the possibility that long-term suppression of bone turnover with bisphosphonates may eventually lead to an accumulation of fatigue-induced damage and adverse skeletal effects such as delayed fracture healing.     

A review of bone pain relief with ibandronate and other bisphosphonates in disorders of increased bone turnover

Several disorders of increased bone turnover and low bone mineral density (BMD) are associated with severe pain that is refractory to treatment with conventional and even opioid analgesics. Because of their ability to effectively improve the underlying pathogenesis of these disorders (i.e., reduce bone resorption and increase BMD), bisphosphonates are considered part of the palliative care of malignant bone-related pain and also appear to have some analgesic efficacy in other, non-malignant conditions. Ibandronate, a potent, nitrogen-containing bisphosphonate that can be given orally and intravenously, has demonstrated robust effects in relieving the pain associated with several malignant disorders. Unlike other available intravenous (i.v.) bisphosphonates, i.v. ibandronate is not associated with renal side effects, even at high doses such as 6 mg every 3 weeks. In addition, oral ibandronate (50 mg daily) is currently the only oral bisphosphonate proven to reduce and maintain bone pain scores below baseline for 2 years in patients with metastatic bone disease. Lower dose, less intense dosing regimens of ibandronate relieve bone pain in non-malignant conditions: i.v. ibandronate (2 mg every 3 months with or without an initial 4 mg injection) provides pain relief for patients with corticosteroid-induced osteoporosis, localised transient osteoporosis (bone marrow oedema) and sternocostoclavicular hyperostosis. Both oral and i.v. ibandronate are well tolerated. In conclusion, ibandronate offers an effective and convenient choice for the relief of bone pain in a wide variety of underlying bone conditions.     

Clinical review 123: Anabolic therapy for osteoporosis

All currently available, approved therapies for osteoporosis inhibit bone resorption. By acting at this site in the bone remodeling cycle, estrogens, selective estrogen receptor modulators, calcitonin, and the bisphosphonates all have the capacity to increase bone mineral density and to reduce the risk of new fractures. There can be no doubt that these agents have had an enormous impact on our diagnostic and therapeutic approach to osteoporosis. Despite their great value, the antiresorptives are generally not associated with dramatic increases in bone mass, and their action to reduce fracture risk, although highly significant, is rarely more than 50% of the baseline risk. Another approach is anabolic therapy, in which bone formation is directly stimulated. In this review we will summarize the anabolic agents that have been studied and present a current view of their current standing. Fluoride, GH, insulin-like growth factor I, the statins, and PTH will be reviewed. Although still in development, approaches to combination therapy with antiresorptives and anabolic agents are also promising.     

Management of osteoporosis in liver disease

Osteoporosis resulting in a high risk for fracture is a common complication in patients with liver disease, particularly in those with chronic cholestasis and with end-stage cirrhosis. The pathogenesis of bone loss in liver patients is poorly understood but it mainly results from low bone formation as a consequence of cholestasis or the harmful effects of alcohol or iron on osteoblasts. Increased bone resorption has also been described in cholestatic women with advanced disease. The management of bone disease in liver patients is addressed to reduce or avoid the risk factors for osteoporosis and fracture. Bisphosphonates associated with supplements of calcium and vitamin D are safe and effective for increasing bone mass in patients with chronic cholestasis and after liver transplantation, though no clear achievements in descreasing the incidence of fractures have been described, probably because of the low number of patients included in the therapeutic trials. Randomized studies assessing bisphosphonates in larger series of patients, the development of new drugs for osteoporosis and the improvement in the management of liver transplant recipients may change the future.     

Glucocorticoid-induced osteoporosis: mechanisms for bone loss; evaluation of strategies for prevention

Osteoporosis is a common complication of chronic glucocorticoid therapy, especially in older patients who already are at risk of having a reduced bone mass. Glucocorticoids cause bone loss by altering the bone remodeling sequence: bone resorption by osteoclasts is increased, and bone formation by osteoblasts is decreased. Serum levels of osteocalcin, a protein made by osteoblasts, are decreased with glucocorticoid therapy, further evidence of decreased osteoblast function. Glucocorticoids decrease calcium absorption by the gastrointestinal tract and increase renal calcium excretion. Several recent studies suggest that low-dose glucocorticoid therapy is not associated with bone loss. Calcium supplementation with vitamin D is recommended. Several short-term studies have shown prevention of glucocorticoid-induced bone loss with bisphosphonates, calcitonin, and progesterone. Long-term clinical trials should be undertaken to determine strategies to prevent this type of osteoporosis.     

Ankylosing spondylitis and osteoporosis

PURPOSE: Ankylosing Spondylitis (AS) is an inflammatory rheumatism characterized by its disease course with flares leading to progressive ankylosis of the spine related to paravertebral ligamentous and discal structures ossification. AS patients suffer significantly more vertebral fractures than control groups. These fractures could affect cervical spine. They are due to either ankylosis-related flawed spine compliance or AS-induced osteoporosis. CURRENT KNOWLEDGE AND KEY POINTS: The physiopathology of this osteoporosis is multi-factorial, but essentially linked to AS-related inflammatory phenomenons. It is marked by reduced bone density (at lumbar spine and femoral neck), increased bone turnover (with increased urinary C-telopeptide cross-linked collagen type 1), but without any significant change in phosphocalcic blood parameters. Histological features are depressed bone formation, with either maintained or increased resorption. FUTURE PROSPECTS: The screening of this osteoporosis is based upon investigating people at risk (progressive inflammatory AS) using dual-energy x-ray absorptiometry and biochemical markers of bone turnover. Treatment is based upon a modulation of both inflammatory phenomenons and bone remodelling using bisphosphonates and anti-TNF alpha.     

Comparison of the efficacy of denosumab and bisphosphonates for treating secondary osteoporosis in patients with rheumatoid arthritis

Objectives: This study aimed to investigate the efficacy of denosumab (compared with that of bisphosphonates) for preventing secondary osteoporosis and inflammation caused by excessive bone resorption in Japanese rheumatoid arthritis (RA) patients never previously treated for osteoporosis.

Methods: Ninety-eight patients with coexisting RA and osteoporosis were enrolled. The patients were subdivided by whether they were treated with denosumab (n?=?49) or traditional bisphosphonates (n?=?49). RA disease activity, bone turnover markers, and bone mineral density (BMD) were compared between the two groups before treatment, and after 6 and 12 months of treatment.

Results: There was no significant difference between the groups in any of the disease activity indices and BMD at any of the measured time points. With regard to bone metabolism, denosumab significantly reduced bone-specific alkaline phosphatase at 6 and 12 months compared with pretreatment, but had no effect on tartrate-resistant acid phosphatase 5b levels, suggesting an effect on the bone formation rate, but not on the bone resorption rate.

Conclusions: Neither denosumab nor bisphosphonates could suppress inflammation or RA disease activity, but denosumab significantly suppressed a marker of bone metabolism in Japanese RA patients never previously treated for osteoporosis.     

An update on bisphosphonates

Over the past 15 years, bisphosphonates have been demonstrated as effective therapy for the treatment of osteoporosis based on their ability to suppress bone turnover resulting in increased bone mineral content and increased bone strength. The mechanism of action at the cellular level has been identified, and the more potent nitrogen-containing bisphosphonates clearly have reduced the risk of vertebral and nonvertebral fractures in patients with osteoporosis. Future use of these therapies is evolving to less frequent administration, and the interaction with anabolic therapies is presently being defined. Data to date support long-term safety with bisphosphonates in small numbers of patients treated for 5 to 10 years, and continued vigilant follow-up of the post-marketing experience will be necessary to determine if sustained bone turnover suppression is associated with rare musculoskeletal adverse events. Further development of bisphosphonates as adjunctive therapy to reduce bone metastases is in progress, and trials evaluating bisphosphonates as a structure modifying agent in osteoarthritis are nearing completion.     

Bisphosphonates for osteoporosis prevention and treatment

As potent inhibitors of bone resorption, bisphosphonates (BPs) have been used to treat a variety of disorders of calcium and bone metabolism, including osteoporosis. Paget's disease, and metastatic bone disease. Numerous clinical studies have shown BPs to be useful and cost-effective options for the prevention and treatment of fractures and bone loss associated with postmenopausal osteoporosis, senile osteoporosis in men, and glucocorticoid-induced osteoporosis. With proper self-administration in patients without underlying gastrointestinal (GI) disorders, oral bisphosphonates are usually safe, however, they can cause upper GI irritation. The most common side effects are nausea, diarrhea, gastritis, and esophageal irritation Newer, longer-acting BPs and parenteral administration have lead to options for patients who cannot tolerate oral BPs.     

Management of corticosteroid-induced osteoporosis

Corticosteroid (CS) therapy is widely used in the treatment of rheumatic diseases. Osteoporosis remains one of its major complications. The risk of low bone mineral density (BMD) and fracture may be already increased in some of the rheumatic diseases, regardless of CS therapy. However, in spite of this, preventative treatment for osteoporosis in patients on CS remains low. Patients on or about to start CS use for more than 6 months are at risk of corticosteroid-induced osteoporosis (CIOP). The pathogenesis of CIOP differs from post-menopausal osteoporosis in that bone formation is said to be more suppressed compared with bone resorption. The diagnosis of CIOP can be made on clinical risk factors and may not require measurement of BMD. Many agents used in post-menopausal osteoporosis such as activated vitamin D products, hormone replacement therapy, fluoride, calcitonin and the bisphosphonates have been shown to maintain or improve BMD in CIOP. However, there are few data on the reduction in fracture rates in CIOP, but the bisphosphonates seem the most promising in this regard.     

骨质疏松症的联合治疗与序贯治疗

联合和序贯治疗骨质疏松症是为了追求更大疗效的一种选择,本文检索分析近45年来发表的此类临床研究结果。目前尚无证据表明两种抗骨吸收联合治疗有降低骨折发生率的叠加作用（如双膦酸盐加ERT或雷洛昔芬,雌激素加降钙素）,仅观察到联合治疗可以降低骨转换和增加骨密度的结果。联合甲状腺激素（PTH）同抗骨吸收药物,随着药物的不同对骨密度的效果各异。在停止使用促进骨形成剂PTH后序贯使用双膦酸盐、雷洛昔芬或锶盐,可以防止因停用PTH后的骨丢失,可能成为未来治疗严重的绝经后骨质疏松症的重要选择。     

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.