Anabolic skeletal therapy 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 bone qualities besides increasing bone mass. In this article, we review the role of anabolic treatment for osteoporosis. The only anabolic agent currently approved in the United States for osteoporosis, teriparatide [recombinant human parathyroid hormone(1-34)], has clearly emerged as a major approach to selected patients with osteoporosis. Teriparatide increases bone density and bone turnover, improves microarchitecture, and changes bone size. The incidence of vertebral and nonvertebral fractures is reduced. Teriparatide is approved for both postmenopausal women and men with osteoporosis who are at high risk for fracture. Other potential anabolic therapies for osteoporosis, including other forms of parathyroid hormone, strontium ranelate, growth hormone, and insulin-like growth factor-1, are also reviewed in this article.     

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.     

Clinical update on teriparatide

Teriparatide (recombinant human parathyroid hormone [1–34]) is an anabolic agent approved for the treatment of patients at high risk for fracture. The Fracture Prevention Trial administered teriparatide to treatment-naïve patients, leading to its US Food and Drug Administration approval in 2002. Clinical trial data using antiresorptive agents administered before, during, and after any parathyroid hormone (PTH) therapy, as well as alternative PTH dosing, have provided additional insight yet raise fundamental questions about the most appropriate use of teriparatide. This article provides an update on teriparatide, focusing on its mechanism of action compared with other antiresorptive agents, indications, adverse effects, therapy duration, combination therapy, contraindications, and cost effectiveness.     

Anabolic therapy for osteoporosis: Parathyroid hormone

Recombinant human parathyroid hormone (PTH 1–34) is the only anabolic agent currently approved for the treatment of osteoporosis. The term anabolic is based on mechanism of action. PTH stimulates bone formation, in contrast to antiresorptive agents, which reduce bone resorption and formation. Recent investigations involving the PTH(1-34) and PTH(1-84) peptides, alone and in combination or sequential regimens with antiresorptive agents, have provided a greater understanding of the place of PTH in the armamentarium against osteoporosis. These studies indicate that adding a bisphosphonate to PTH in previously untreated individuals does not produce additional bone benefit; however, sequential use of PTH followed-up by an antiresorptive agent is highly effective at increasing bone mineral density. Adding PTH after an antiresorptive agent also produces substantial bone density increments, though the magnitude of bone density increase may differ for different antiresorptive agents. PTH can repair underlying micro-architectural defects in bone, improve bone mass substantially, and perhaps change macro-architecture and geometry of bone. There are still many unanswered questions regarding PTH treatment of osteoporosis, including the optimal duration of treatment, optimal dosing regimen, mechanism of resistance to its effect after 18–24 months, and the effect of subsequent rechallenge.     

New perspectives on parathyroid hormone therapy

PURPOSE OF REVIEW: The prevention and treatment of osteoporosis has traditionally involved the use of antiresorptive therapies. The introduction of parathyroid hormone, an anabolic agent that enhances bone formation, has been accompanied by new treatment strategies. This article reviews combination and sequential therapy approaches with parathyroid hormone and antiresorptive agents to optimize efficacy outcomes. RECENT FINDINGS: The distinguishing features of the anabolic and antiresorptive therapies for the treatment of osteoporosis has led to the hypothesis that the appropriate use of both agents, either in sequence or in combination, may result in superior fracture protection compared with either anabolic or antiresorptive treatment alone. This enthusiasm has been tempered by the observations that the transition from daily bisphosphonate therapy may blunt the efficacy of teriparatide. By contrast, more recent studies suggest that once-weekly bisphosphonate therapy may provide a better option with parathyroid hormone either in combination or in sequence. These considerations are critical to understanding the benefits of sequential treatment (parathyroid hormone followed by an antiresorptive agent), which aims to maintain or build on the large gains in efficacy from short-term therapy with parathyroid hormone. Because patients may require an additional treatment course of parathyroid hormone in the future, the choice of antiresorptive agent should be carefully considered. In addition, more recent evidence suggests that the forms of parathyroid hormone may have important differences in action that influence combination and sequence outcomes. SUMMARY: Combination and sequential therapy with parathyroid hormone offers new options to maximize efficacy in patients at risk for osteoporotic fracture.     

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.     

Parathyroid hormone analogues in the treatment of osteoporosis

Osteoporosis is characterized by the occurrence of fragility fractures. Over the past years, various treatment options have become available, mostly antiresorptive agents such as bisphosphonates. However, antiresorptive therapy cannot restore bone mass and structure that has been lost due to increased remodeling. In this case, recombinant human parathyroid hormone (PTH) analogues-the full-length PTH(1-84) or the shortened molecule PTH(1-34), which is also known as teriparatide-present the possibility of increasing the formation of new bone substance by virtue of their anabolic effects. The bone formation induced by PTH analogues not only increases BMD or bone mass but also improves the microarchitecture of the skeleton, thereby leading to improved strength of bone and increased mechanical resistance. Controlled trials have shown that both analogues significantly reduce the incidence of vertebral fractures, and PTH(1-34) also reduces the risk of nonvertebral fractures. The need for daily self-injection and the higher cost compared with other forms of treatment limit the widespread use of PTH analogues. Nevertheless, treatment with PTH analogues should be considered in postmenopausal women and men with severe osteoporosis, as well as in patients on established glucocorticoid treatment with a high fracture risk. Concurrent therapy with antiresorptive agents should be avoided, but sequential therapy with these agents might consolidate the beneficial effects on the skeleton.     

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。     

The use of teriparatide and PTH(1–84) for the treatment of osteoporosis

Different therapeutic formulations of parathyroid hormone (PTH) have been studied for the treatment of osteoporosis: synthetic teriparatide [hPTH(1–34)], reconstituted from lysophilized powder; recombinant human teriparatide [rhPTH(1–34)], which has been commercially available since 2002; and PTH(1–84), which is under review by the US Food and Drug Administration (FDA). Teriparatide has demonstrated vertebral and nonvertebral vertebral antifracture efficacy, increases in BMD and biochemical markers of bone turnover, the cornerstones of judging success with an osteoporosis agent. PTH (1–84) may be an alternative consideration for the treatment of both the prevention of the first vertebral fracture as well as the reduction in future vertebral fracture risk in postmenopausal women with existing vertebral fractures. It remains to be seen if there are therapeutic differences between the already approved teriparatide and yet-to-be-approved PTH(1–84).     

Enhancement of fracture healing with parathyroid hormone

Since the approval of parathyroid hormone (PTH) as an anabolic treatment for osteoporosis, there has been an increasing interest in other potential clinical uses for this compound in musculoskeletal conditions. Fracture healing is one area of particular interest. It is now widely recognized that daily PTH administration is an effective therapy for increasing bone mineral density and preventing fractures in both male and female osteoporosis patients. More recently, a growing body of evidence supports the conclusion that PTH will also be an effective anabolic therapy for the enhancement of bone repair following fracture. Several animal studies have demonstrated that PTH therapy consisting of daily subcutaneous injections during repair leads to increased callus volumes and a more rapid return of bone strength. Additionally PTH, these reports demonstrated that PTH treatment enhanced repair in older animals, models of osteoporosis, and healthy sexually mature animals. These results underscore the potential of PTH as an anabolic therapy for enhancing the rate of bone repair and regain of mechanical strength in a broad spectrum of fracture patients.     

The anabolic effects of parathyroid hormone therapy

PTH represents an important new advance in the therapy of osteoporosis. As an anabolic agent, its potential might be substantially greater than that of antiresorptive agents. Clear evidence in human trials now documents the ability of PTH to stimulate cancellous bone formation and to reduce fractures. Because antiresorptive agents and PTH work by distinct mechanisms of action, it is possible that the combination of these agents could be significantly more potent than either agent alone. There are other unanswered questions about PTH. More studies are needed to document an anabolic effect on cortical bone. In addition, more large-scale studies are needed to further determine the reduction in nonvertebral fractures with PTH, especially at the hip. More information is also required to determine the possible need for antiresorptive therapy after PTH. Protocols to consider PTH as an intermittent recycling therapy would be of interest. In the future, PTH is likely to be modified for easier and more targeted delivery. Oral or transdermal delivery systems may become available. Recently, Gowen et al [78] have described an oral calcilytic molecule that antagonizes the parathyroid cell calcium receptor, thus stimulating the endogenous release of PTH. This approach could represent a novel endogenous delivery system for intermittent PTH administration. Ultimately, when the anabolic and catabolic mechanisms of PTH can be clearly distinguished, both mechanistically and in molecular terms, it may be possible to develop PTH analogs that are more purely anabolic.     

Combination therapy with anabolic and antiresorptive agents

Combination therapy, the use of an anabolic agent with an antiresorptive agent in some sequence, has been evaluated in a number of clinical trials. There is no fracture data on combination therapy except for a small trial using PTH and estrogen. It appears that simultaneous use of a bisphosphonate (alendronate 10 mg per day) with PTH offers no advantage (and appears to blunt PTH's effect) compared with the use of PTH alone based on bone density gains. Previous therapy with alendronate also blunts gains in bone density with PTH therapy. Estrogen and raloxifene, whether given before or with PTH, do not blunt its anabolic effect. Sequential therapy with PTH followed by an antiresorptive agent (alendronate) offers the greatest gains in bone mass. It is possible that alendronate or other bisphosphonates given in a different dosing regimes may have different effects on PTH's anabolic effect. More trial data on combination therapy is needed.     

Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use

All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog, teriparatide [recombinant human PTH(1-34)], represent a new class of anabolic therapies for the treatment of severe osteoporosis, having the potential to improve skeletal microarchitecture. Significant reductions in both vertebral and appendicular fracture rates have been demonstrated in the phase III trial of teriparatide, involving elderly women with at least one prevalent vertebral fracture before the onset of therapy. However, there is as yet no evidence that the antifracture efficacy of PTH will be superior to the bisphosphonates, whereas cost-utility estimates suggest that teriparatide is significantly more expensive. Teriparatide should be considered as treatment for postmenopausal women and men with severe osteoporosis, as well as for patients with established glucocorticoid-induced osteoporosis who require long-term steroid treatment. Teriparatide should also be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores < or = 3.5). Teriparatide therapy is not recommended for more than 2 yr, based, in part, on the induction of osteosarcoma in a rat model of carcinogenicity. Total daily calcium intake from both supplements and dietary sources should be limited to 1500 mg together with adequate vitamin D intake (< or =1000 U/d). Monitoring of serum calcium may be safely limited to measurement after 1 month of treatment; mild hypercalcemia may be treated by withdrawing dietary calcium supplements, reducing the dosing frequency of PTH, or both. At present, concurrent therapy with antiresorptive therapy, particularly bisphosphonates, should be avoided, although sequential therapy with such agents may consolidate the beneficial effects upon the skeleton after PTH is discontinued.     

Teriparatide - Indications beyond osteoporosis

Osteoporosis is a condition of impaired bone strength that results in an increased risk of fracture. The current and most popular pharmacological options for the treatment of osteoporosis include antiresorptive therapy, in particular, oral bisphosphonates (alendronate, risedronate, ibandronate). Anabolic agents like teriparatide have widened our therapeutic options. They act by directly stimulating bone formation and improving bone mass quantity and quality. Two forms of recombinant human parathyroid hormone (PTH) are available : full-length PTH (PTH 1-84; approved in the EU only) and the 1-34 N-terminal active fragment of PTH (teriparatide, US FDA approved). This review aims to discuss the benefits of teriparatide beyond the currently licensed indications like fracture healing, dental stability, osteonecrosis of jaw, hypoparathyroidism, and hypocalcemia.     

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.     

Parathyroid hormone: evolving therapeutic concepts

PURPOSE OF REVIEW: Osteoporosis results from a loss of bone mass and structure such that bones break with very little trauma. To reduce bone loss and improve strength, antiresorptive agents have been instituted. Just more than a year ago, a 34-amino acid fragment of parathyroid hormone (recombinant human parathyroid hormone 1-34) was approved for the treatment of osteoporosis. The parathyroid hormone treatment works by stimulating bone formation on all bone surfaces and is referred to as an osteoanabolic agent. The purpose of this article is to review initial phase 2 and phase 3 studies that establish the effectiveness of this agent to treat osteoporosis. RECENT FINDINGS: In addition, studies that use parathyroid hormone in combination with antiresorptive agents and sequentially are reviewed. Last, unresolved issues related to the duration of use of parathyroid hormone are discussed. SUMMARY: In summary, parathyroid hormone compounds are a major advance in the treatment of osteoporosis. Additional research will enlighten clinicians on the most efficacious way to use them.     

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.     

Osteoporosis in men: its pathophysiology and the role of teriparatide in its treatment

As the population ages, the burden of osteoporosis in men is expected to rise. Implementation of preventive measures such as falls prevention strategies, exercise and adequate calcium and vitamin D intake is recommended. However, when the diagnosis of osteoporosis is made, effective treatments need to be initiated to prevent fractures. As opposed to postmenopausal women, reduced bone formation is the predominant mechanism of age-related bone loss in men, making anabolic agents a logical treatment option for men with osteoporosis. Teriparatide is the only anabolic agent currently approved for treatment of osteoporosis in men. This paper summarizes the mechanism of action of teriparatide, as well as its tolerability and safety. Furthermore, the evidence supporting the efficacy of teriparatide treatment in men with osteoporosis is reviewed and its current role in the management of osteoporosis in men is discussed.     

The search for calcium receptor antagonists (calcilytics)

The Ca(2+) receptor on the surface of parathyroid cells is the primary molecular entity regulating secretion of parathyroid hormone (PTH). Because of this, it is a particularly appealing target for new drugs intended to increase or decrease circulating levels of PTH. Calcilytic compounds are Ca(2+) receptor antagonists which increase the secretion of PTH. The first reported calcilytic compound was NPS 2143, an orally active molecule which elicits rapid, 3- to 4-fold increases in circulating levels of PTH. These rapid changes in plasma PTH levels are sufficient to increase bone turnover in ovariectomized, osteopenic rats. When administered together with an antiresorptive agent (estradiol), NPS 2143 causes an increase in trabecular bone volume and bone mineral density in osteopenic rats. The magnitude of these changes are far in excess of those caused by estradiol alone and are comparable with those achieved by daily administration of PTH or a peptide analog. These anabolic effects of NPS 2143 on bone are not associated with hyperplasia of the parathyroid glands. Calcilytic compounds can increase endogenous levels of circulating PTH to an extent that stimulates new bone formation. Such compounds could replace the use of exogenous PTH or its peptide fragments in treating 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.