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.     

The use of parathyroid hormone in the treatment of osteoporosis

Anabolic skeletal agents have recently broadened our therapeutic options for osteoporosis. By directly stimulating bone formation, they reduce fracture incidence by improving bone qualities in addition to increasing bone mass. Teriparatide [recombinant human parathyroid hormone(1–34)], the only anabolic agent currently approved in the United States for osteoporosis, has emerged as a major therapeutic approach to selected patients with osteoporosis. Teriparatide is approved for both postmenopausal women and men with osteoporosis who are at high risk for fracture. With the use of this anabolic agent, bone density and bone turnover increase, microarchitecture improves, and bone size is beneficially altered. The incidence of vertebral and nonvertebral fractures is reduced with teriparatide use. Combination therapy with parathyroid hormone and an antiresorptive does not appear to offer definitive advantages over the use of PTH or an antiresorptive alone, although recent ideas about combining these agents may offer new insights. In order to maintain increases in bone density acquired during PTH therapy, it is important to follow its use with an antiresorptive agent.     

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.     

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.     

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.     

Anabolic therapy in primary osteoporosis

Antiresorptive therapy for osteoporosis has been a mainstay during the past 50 yr. But an entirely new class of agents known as anabolic drugs has recently been introduced. These drugs “grow new bone,” reconstitute the destroyed skeletal architecture of osteoporosis, and thereby reduce the risk of new fractures. Teriparatide is the first such drug to fulfill these requirements, but other agents look promising such as growth hormone and strontium renalate. On the horizon are native and analogs of parathyroid hormone also. But these are only the beginning of a vast array of possibilities, which will arise from an understanding of the regulatory pathways of osteoblast function. This review focuses on old and new agents, which are prospects for bone growth based on in vivo data from human or other animal studies. It covers drugs that are in use, or nearly so, and discusses a variety of potential target sites for future drug development.     

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.     

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.     

How to grow bone to treat osteoporosis and mend fractures

There is a need for “anabolic” drugs that can directly stimulate bone growth, improve bone microarchitecture, accelerate fracture healing, and, thus, restore bone strength to osteoporosis patients and, hopefully, regenerate eroded bone in arthritis patients. The anabolic agents currently leading the way to the clinic are the parathyroid hormone (PTH) and some of its adenylyl cyclase-stimulating fragments. This article is a summary of what is known about how PTHs stimulate bone growth. The controversial bone anabolic activities of the cholesterol-lowering lipophilic statins are also described, and mechanisms by which they may stimulate bone growth are presented. Finally, evidence is presented for the body’s “fat-ostat” cytokine —leptin— indirectly restraining bone growth via a hypothalamic factor, while at the same time serving as a local PTH-like autocrine/paracrine stimulator of osteoblast activity, as well as an inhibitor of osteoclast generation.     

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.     

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.     

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 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.     

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).     

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.     

PTH

Injectable forms of parathyroid hormone (PTH) and its N-terminal fragments are bone anabolic agents proven by randomized clinical trials. Alternate delivery forms of parathyroid hormone are under clinical or preclinical studies, including nasal, transdermal, and pulmonary formulations of PTH (1-34). Oral forms of PTH (1-34) and its analogs or orally active calcium sensing receptor antagonist, which induces PTH secretion from parathyroid gland, are also under development. PTH will be the one of the major therapeutic agents for osteoporosis treatment.     

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.     

Osteoporosebehandlung: Bisphosphonate, SERM’s, Teriparatide und Strontium

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

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.     

Idiopathic or Hypogonadal Osteoporosis in Men

Osteoporosis is being recognized increasingly in men, and represents a substantial public health problem. As the male population ages and lives longer, the incidence of osteoporotic fractures is expected to increase. The current lifetime risk for a fragility fracture is approximately 27% in men aged 50 years or more, and will increase further over the next 20 years. A major problem with osteoporosis in men is that it continues to be unrecognized, and the majority of men with fragility fractures due to osteoporosis are not being treated. A higher level of awareness is required amongst both general practitioners and the general public that osteoporosis is a treatable condition that can affect men. Secondary causes for osteoporosis are more common in men than in women, and require rigorous exclusion and treatment. Undiagnosed clinical hypogonadism is a common cause of osteoporosis in men, and is readily treatable. The cause of primary osteoporosis in men is unknown, but it results in an osteoblast defect. Genetic factors are likely to be important. In some but not all men, relative estrogen deficiency contributes to rapid rates of age-related bone loss and fractures. An adequate calcium intake, regular weight-bearing exercise, and normal vitamin D status are all very important, particularly with increasing age. The role of testosterone in treating eugonadal men with osteoporosis is currently unclear, and larger prospective studies will be required to carefully evaluate the benefits and risks of therapy. First-line treatment of osteoporosis in hypogonadal or eugonadal men is with bisphosphonates. Alendronate increases bone density and reduces vertebral fractures measured using a semiquantitative method in eugonadal or hypogonadal men with osteoporosis. In the near future, it is likely that subcutaneous human parathyroid hormone (1-34) or teriparatide will also be available as an important new anabolic treatment for men with osteoporosis. Teriparatide treatment also increases bone density in men. Selective estrogen receptor modulating drugs require further evaluation in men, but would appear to theoretically benefit men, especially those with low estradiol levels. In the future, selective androgen receptor modulating drugs may be useful in the prevention and treatment of osteoporosis, and in increasing lean body mass in men, without having adverse effects on prostate and breast tissue.