New anabolic therapies in osteoporosis

While antiresorptive drugs have been the cornerstone of osteoporosis therapy, anabolic drugs are an important new advance in the treatment of osteoporosis. By directly stimulating bone formation, anabolic agents might have greater potential than the antiresorptives to increase bone mass and to decrease fractures. It is also possible that the combination of an antiresorptive agent with an anabolic agent could be more potent than either agent alone. Potential anabolic therapies for osteoporosis, including fluoride, growth hormone, insulin-like growth factor-I, strontium, and parathyroid hormone, are reviewed here. Of these, parathyroid hormone has clearly emerged as the most promising treatment at this time.     

Emerging anabolic treatments for osteoporosis

Therapy for osteoporosis is principally centered on the use of agents that block bone resorption and supplementation with vitamin D and calcium. Although these drugs are effective in reducing the risk of subsequent fractures, and modestly increasing bone density, most patients being treated for osteoporosis still have low bone mass and a greater risk of fracture. Anabolic agents stimulate bone formation, strength, and mass. In addition, there is emerging evidence that anabolic agents can reduce subsequent fracture risk. The two most promising agents, parathyroid hormone (PTH) and GH/IGF-I, act to increase osteoblast mediated bone formation. A review of the potential usefulness of PTH and GH/IGF-I is presented.     

Emerging therapies in osteoporosis

The approval of alendronate in 1994 marked a watershed in the treatment of osteoporosis. Before that time there was no therapy for which unequivocal proof of efficacy existed. Since then several more agents, all from the anti-resorptive class, have also been approved for use in the treatment of this disease and the range of indications for alendronate has been extended to include the prevention of osteoporosis in women with lesser degrees of bone loss, the treatment of glucocorticoid-induced osteoporosis and, most recently, the treatment of male osteoporosis. Despite this there are still several areas of unmet medical need in this disease, including the availability of well tolerated and convenient therapies and treatments that will go beyond the levels of efficacy offered by current therapies. An intense effort is now being directed towards meeting these unmet needs with the improvement of existing therapies and the development of novel agents that will provide superior long term benefit. Important and exciting drug targets are yielding novel compounds with anti-resorptive activity or anabolic effects to complement current anti-resorptives. Despite this effort considerable obstacles to the successful development of these compounds remain, not least the stringent safety requirements needed to provide an acceptable risk-to-benefit profile and the increasing difficulties of conducting placebo controlled studies in patients at high risk of fracture.     

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.     

Combination therapies on osteoporosis

Combination therapies of bisphosphonates with conjugated equine estrogen (CEE) , vitamin D or parathyroid hormone (PTH) on osteoporotics have been discussed. Combined therapy of bisphosphonate with CEE increased lumbar bone mineral density (LBMD) and femoral neck bone mineral density (FBMD) in elderly patients. Furthermore combination therapy of bisphosphonate with CEE reduced new vertebral fractures in elderly osteoporotics. Similarly combination therapy of bisphosphonate with vitamin D is also advantageous to the increase of LBMD and FBMD. It is likely that the merit of combination therapy is to increase not only the lumbar BMD, but also the femoral BMD, although monotherapy is only to increase lumbar BMD. In contrast to CEE vitamin D seems to assist the effect of bisphosphonate in non-respondent patients to bisphosphonate. However, combination therapy of bisphosphonate with PTH might be complex in reducing the effect of alendronate.     

Emerging therapies for osteoporosis

This article reviews the conceptual framework for agents that are antiresorptive or anabolic, including pathways that affect bone formation and resorption, and the steps in those pathways that are targets for new therapeutic agents. This article discusses novel antiresorptive and anabolic agents in development. Recent developments that link bone remodeling with serotonin in the gastrointestinal system and the central nervous system via the sympathetic nervous system may change the paradigm for skeletal remodeling. Novel anabolic agents in development include antibodies that target molecules involved in Wnt signaling.     

Miscellaneous hormone therapies for osteoporosis

Miscellaneous hormones, such as oral contraceptives (OCs) and tibolone, have not been evaluated as extensively as other hormonal therapies, but remain an option for the prevention and management of osteoporosis. OCs have been conside red for osteoporosis treatment since the 1970s and have demonstrated significant bone mineral density (BMD) increases with high doses that contained 50 μg of ethinyl estradiol. As OCs have evolved with lower doses of ethinyl estradiol (25–40 μg), the literature continues to report improved or maintained BMD in older women. Data are more controversial about OC fracture prevention abilities, the most clinically important end point in osteoporosis trials. Tibolone has not been approved for use in the United States, but it has been used in Europe for almost two decades for the management of osteoporosis. It has unique tissue-specific effects, including estrogen effects on bone and vaginal tissue, progestational effects on the endometrial tissue, and androgenic effects on the brain and liver tissue. Although fracture data are lacking, patients receiving 1.25 to 2.5 mg of tibolone have shown significant improvements in BMD. Tibolone can be regarded as an alternative to conventional hormone therapy for the prevention of postmenopausal bone loss based on similar BMD efficacy and minimal side effects, but its effects would still be less than bisphosphonates. Data supporting the use of oral contraceptives and tibolone for osteoporosis prevention and management will be discussed in this article.     

Compliance and persistence with osteoporosis therapies

The US Food and Drug Administration has approved a diverse group of effective osteoporosis therapies. However, these therapies obviously only work when patients with osteoporosis take them. Data from retrospective observational databases have shown poor compliance and persistence with all osteoporosis drugs, particularly oral bisphosphonate therapy. Patients on weekly therapies are more compliant and persistent than those on daily dosing. Data have also shown decreased fracture risk, decreased health care utilization, and lower costs in compliant and persistent patients.     

Glucocorticoid-induced osteoporosis and anabolic effect of PTH on bone

Glucocorticoid-induced osteoporosis(GIO)is the major cause of secondary osteoporosis, and prevention of GIO is thought to be essential to avoid bone fracture. Direct inhibitory effect of glucocorticoid on bone formation is considered as the main mechanism of GIO. Clinical guidelines have recommended that bisphosphonate is the first choice for the treatment of GIO. Bone mineral density in patients with GIO has recently been reported to be increased by the treatment with parathyroid hormone(PTH)at a low dose and by intermittent administration.     

Selection of antiresorptive or anabolic treatments for postmenopausal osteoporosis

Osteoporosis is a common, chronic disease that can be treated effectively by pharmacological interventions. Antiosteoporotic drugs reduce fracture risk via different mechanisms of action. Available therapies are broadly distinguished into inhibitors of bone turnover, stimulators of bone formation, and therapies with as-yet unclear mechanisms of action. No direct comparison studies with fracture end points have yet been done, which makes selection of one drug over another difficult. Identification of individuals who might derive particular benefit from a specific therapy has been explored in post-hoc analyses of clinical studies with bisphosphonates and recombinant parathyroid hormone (PTH). Their findings showed that the efficacy of these therapies in reducing fracture risk was largely independent of the prevalent rates of bone turnover. Selection of a specific antiosteoporotic therapy should, therefore, be made according to the results of trials specifically designed to assess fracture risk, safety, tolerability, patient preference and cost-effectiveness rather than on characteristics specific to patients or the disease. Studies of sequential administration of PTH and bisphosphonates suggest advantages over single-therapy regimens, particularly in patients with severe disease. However, the optimum duration of PTH administration, as well as the efficacy of such regimens in reducing the risk of fractures, remain to be determined.     

Meta-analyses of therapies for postmenopausal osteoporosis. VI. Meta-analysis of calcitonin for the treatment of postmenopausal osteoporosis

OBJECTIVE: To review the effect of calcitonin on bone density and fractures in postmenopausal women. DATA SOURCE: We searched MEDLINE and EMBASE from 1966 to 2000 and examined citations of relevant articles and the proceedings of international osteoporosis meetings. We contacted osteoporosis investigators to identify additional studies and primary authors for unpublished data. STUDY SELECTION: We included 30 studies that randomized women to calcitonin or an alternative (placebo or calcium and/or vitamin D) and measured bone density or fracture incidence for at least 1 yr. DATA EXTRACTION: For each trial, three independent reviewers assessed the methodological quality and abstracted data. DATA SYNTHESIS: Calcitonin reduced the incidence of vertebral fractures, with a pooled relative risk (RR) of 0.46 [95% confidence interval (CI) 0.25-0.87, P = 0.02, n = 1404, 4 trials]. However, the RR from the one relatively large randomized controlled trial (RCT) was 0.79 (95% CI 0.62-1.00, P = 0.05, n = 1108). For nonvertebral fractures, the pooled RR was 0.52 (95% CI 0.22-1.23, P = 0.14, n = 1481, 3 trials). Once again, the single large trial showed a less impressive effect than the smaller trials (RR 0.80, 95% CI 0.59-1.09, P = 0.16, n = 1245). For bone density of the lumbar spine, the pooled weekly dose of 250 to 2800 IU per week resulted in significant increase in the weighted mean difference (WMD) of 3.74 (2.04-5.43, P < 0.01, n = 2260, 24 trials). The combined forearm showed a similar effect, with a WMD of 3.02 (95% CI 0.98-5.07, P < 0.01, n = 468, 9 trials). At the femoral neck, the pooled weighted mean difference showed a nonsignificant trend toward benefit, WMD 3.80 (95% CI -0.32-7.91, P = 0.07, 9 trials, n = 513). Methodologically weaker studies tended to show greater effects on bone density, and the lumbar spine results suggested the possibility of publication bias. CONCLUSIONS: Calcitonin likely increases bone density in postmenopausal women predominantly at the lumbar spine and forearm for weekly doses of greater than 250 IU, although the true effect may be smaller than the pooled estimate would suggest. Calcitonin likely reduces the risk of vertebral fracture; its effect on nonvertebral fracture remains uncertain.     

Meta-analyses of therapies for postmenopausal osteoporosis. III. Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis

OBJECTIVE: To review the effect of risedronate on bone density and fractures in postmenopausal women. DATA SOURCES: We searched MEDLINE from 1966 to the end of 2000 and examined citations of relevant articles and the proceedings of international osteoporosis meetings. STUDY SELECTION: We included eight randomized, placebo-controlled trials of postmenopausal women receiving risedronate or placebo with a follow-up of at least one year and providing data on bone density or fracture rate. DATA EXTRACTION: For each trial, two independent reviewers assessed the methodological quality and abstracted data. DATA SYNTHESIS: The major methodological limitation of the trials was the loss to follow-up, which was over 20% in most trials and over 35% in the largest study. However, the magnitude of the treatment effect was unrelated to loss to follow-up, and in one of the largest trials, more high-risk patients were lost to follow-up in the control than in the treatment group. The pooled relative risk (RR) for vertebral fractures in women given 2.5 mg or more of risedronate was 0.64 [95% confidence interval (CI) 0.54, 0.77]. The pooled RR of nonvertebral fractures in patients given 2.5 mg or more of risedronate was 0.73 (95% CI 0.61, 0.87). Risedronate produced positive effects on the percentage change in bone density of the lumbar spine, combined forearm, and femoral neck that were generally larger with the 5-mg daily dose than with cyclical administration or the 2.5-mg dose. The pooled estimate of the difference in percentage change between 5 mg risedronate and placebo after the final year of treatment (1.5-3 yr) was 4.54% (95% CI 4.12, 4.97) for the lumbar spine, and 2.75% (95% CI 2.32, 3.17) at the femoral neck. CONCLUSIONS: Risedronate substantially reduces the risk of both vertebral and nonvertebral fractures. This fracture reduction is accompanied by an increase in bone density of the lumbar spine and femoral neck in both early postmenopausal women and those with established osteoporosis.     

Effects of anticatabolic and anabolic therapies at the tissue level

The recent decade has seen the emergence of a wide variety of new effective therapies for osteoporosis. Although hormone replacement therapy and calcium supplementation were the only available therapies 20 yr ago, we now have a wide variety of anticatabolic (antiresorptive) therapies (bisphosphonates, calcitonin, selective estrogen receptor modulators [SERMs]) and anabolic therapies in the form of recombinant parathyroid hormone [PTH(1–34) and PTH(1–84)] approved and commercially available. Our initial perceptions around these therapies were quite primitive, being mainly based on bone mineral density measurements. However, recent progress in imaging technology and structural and histological evaluation of bone has yielded important new insights into the mechanism of action of the various treatments. This article summarizes current knowledge about both anticatabolic and the more recent anabolic therapies, with special emphasis on the results obtained from histological and structural analyses of bone biopsies. The evidence currently available indicates that anticatabolic therapies exert their significant antifracture efficacy through a pronounced reduction of bone turnover. This reduction in remodeling activity causes preservation of trabecular structure and a decrease in cortical porosity, both effects that will preserve bone biomechanical strength. Although anticatabolic drugs preserve bone architecture, bone-forming (anabolic) therapies, in this context exemplified by PTH, are able to reverse the deterioration of cancellous and cortical bone architecture seen during age-dependent bone loss and osteoporosis. Recent analyses using techniques enabling analysis of bone matrix constituents suggest that both anticatabolic and anabolic therapies also alter the properties of bone tissue components like mineralization and collagen crosslinking.     

The development of parathyroid hormone as anabolic therapy for osteoporosis

At first glance, parathyroid hormone (PTH) peptides seem rather unlikely candidates as treatments for osteoporosis. For the better part of the last century, we focused almost exclusively on the catabolic action of these peptides on bone, despite the fact that anabolic activity had been demonstrated as early as 1929. The intent of this article is to provide snapshots, of the key events that occurred during the ensuing 74 yr that led to the development of PTH peptides as approved treatments for osteoporosis.     

Effectiveness of anti-resorption therapies of postmenopausal osteoporosis

The aim of this article is to justify a need for evaluation of the absolute risk of fractures, to compare efficacy of antiresorptive therapies as indicated by large clinical trials, and to review currently available methods to assess efficacy of therapies in individual patients. It is emphasized that adherence to therapies is influenced not only by the individual bone efficacy and safety of the drug but also by beneficial impacts of the treatment on tissues other than bone.