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.     

Role of estrogens in the management of postmenopausal bone loss

It is well known that estrogen deficiency is the major determinant of bone loss in postmenopausal women. Estrogen is important to the bone remodeling process through direct and indirect actions on bone cells. The largest clinical experience exists with estrogen therapy, demonstrating its successful prevention of osteoporosis as well as its positive influence on oral bone health, vasomotor and urogenital symptoms, and cardiovascular risk factors, which may not occur with other nonestrogen-based treatments. Compliance with HRT, however, is typically poor because of the potential side effects and possible increased risk of breast or endometrial cancer. Nevertheless, there is now evidence that lower doses of estrogens in elderly women may prevent bone loss while minimizing the side effects seen with higher doses of estrogen. Additionally, when adequate calcium, vitamin D, and exercise are used in combination with estrogen-based treatments, more positive increases occur in bone density. The benefits and risks of HRT must be assessed on a case-by-case basis, and the decision to use HRT is a matter for each patient in consultation with her physician. Estrogen-based therapy remains the treatment of choice for the prevention of osteoporosis in most postmenopausal women, and there may be a role for estrogen to play in the prevention of corticosteroid osteoporosis. Combination therapies using estrogen should probably be reserved for patients who continue to fracture on single therapy or should be used in patients who present initially with severe osteoporosis.     

The use of intermittent human parathyroid hormone as a treatment for osteoporosis

Parathyroid hormone (PTH), given intermittently, is an anabolic agent. PTH has been demonstrated to increase bone mass and reduce vertebral and nonvertebral fractures, and has been approved for use in the US and Europe. PTH is a genetically engineered 34 amino acid protein with the designation teriparatide (recombinant DNA origin) or recombinant human PTH 1-34. A recombinant DNA preparation with all 84 amino acids of the native PTH molecule is in clinical trials. These PTH preparations are selfadministered daily injections, and it is approved for women and men at high risk for fractures, including patients with prevalent fractures, low bone mass, and multiple risk factors. PTH is likely to be used most frequently in patients who fracture on therapy, but can be used in high-risk treatment-naíve patients. Previous treatment with alendronate appears to impair the anabolic response of PTH preparations. Patients who have Paget’s disease, prior radiation therapy to the skeleton, as well as children and young adults with open epiphyses, are at higher risk for osteosarcoma and should not be given PTH. Patients with hypercalcemia and hyperparathyroidism also should not receive the drug.     

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.     

Bisphosphonates in Corticosteroid-Induced Osteoporosis

Corticosteroid osteoporosis is a common clinical problem with the risk of fracture, highest in postmenopausal women. The first choice for prevention is a potent oral bisphosphonate such as alendronate or risedronate. In patients intolerant of oral bisphosphonates, intravenous bisphosphonates should be used. Prophylactic therapy should be continued whilst patients continue significant doses of corticosteroid therapy. In patients receiving chronic low-dose corticosteroids where the BMD is substantially reduced, other therapies such as PTH should be considered, followed by a bisphosphonate.     

Does estrogen adequately protect postmenopausal women against osteoporosis: an iconoclastic perspective.

In sum, the skeletal benefits provided by hormone replacement therapy are important, and estrogen should be justifiably considered one of the fundamentals of menopausal management. However, its efficacy in the prevention of osteoporotic fractures should not be overstated. Low bone mass and fractures remain serious threats in older postmenopausal women, even in the presence of hormone replacement. With the recognition of that reality comes a variety of challenges to clinicians and investigators. Clinicians should use estrogen to its best advantage, though, at the same time, remain vigilant of its limitations. Older postmenopausal women who are, or who have been, taking estrogen should not be a priori considered adequately protected against fracture. The same careful clinical evaluation recommended for the protection of those at increased fracture risk, including bone mass measures, should be available to estrogen-taking women in the later postmenopausal period. Recognizing this need, the National Osteoporosis Foundation has recently recommended bone mineral density testing in older women, regardless of estrogen status, and HCFA reimbursement has become available for this indication. In the presence of low bone density, estrogen-taking women should be afforded appropriate levels of diagnostic and therapeutic attention, with the intent to further reduce fracture risk. Once estrogen therapy has been elected, patients and their clinicians should be aware that bone loss can still be expected in the later postmenopausal years. Periodic reevaluations of bone density and other risks for fracture (e.g. falls) may be appropriate. In the face of continued good health, those reevaluations can be infrequent, but women who have medical conditions associated with adverse skeletal effects should be followed more closely despite their estrogen therapy. If we are to build on the value of estrogen to improve our approach to osteoporosis, additional data are needed. When fracture risk has been considered in complex models that adjust for account other medical and lifestyle variables, a greater protective effect of estrogen has emerged (12), suggesting that there are factors whose actions attenuate those of estrogen. Prominent candidates include genetics, tobacco and alcohol use, medications, body composition, and propensity to fall. There are undoubtedly others yet unidentified. These should be further defined, and the basic mechanisms for interactions between them and estrogen should be examined. It would be clinically advantageous to use these factors to accurately identify not only the women who would benefit from estrogen replacement but also those who would not. Because estrogen has important beneficial effects, an essential research objective should be the development of therapeutic strategies that combine the advantages of estrogen with other modalities (pharmacological or otherwise), to maximally protect the many estrogen-taking women who may be considered at continued risk for fracture. To whit, the initial reports of combination therapy with bisphosphonates are encouraging (13, 14). Other important skeletal agents can be anticipated to interact with estrogen in as-of-yet unforeseen ways. On another front, it can be anticipated that selective estrogen receptor modulators will be subject to estrogen-like limitations when used for osteoporosis prevention/therapy, and their effects will be influenced by a similar, but distinct, array of covariates. Our vision of the role of hormone replacement in the reduction of osteoporotic fracture risk should be considerably sharpened. At one time, estrogen was the lone best hope for the avoidance of fracture, but no longer should we be satisfied with that imperfect solution. The development of much more efficient and effective methods for osteoporosis risk assessment, prevention, and treatment now provides a chance to surpass previous expectations. (ABSTRACT TRUNCATED)     

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.     

Risedronate: a clinical review

BACKGROUND: Risedronate sodium has recently been approved for the prevention and treatment of postmenopausal and corticosteroid-induced osteoporosis. METHODS: Studies of risedronate were obtained from the MEDLINE database (1966 to the present) of references using risedronate, risedronic acid, osteoporosis, and human subject as keywords. Additional references were sought from the reference lists of the articles obtained. RESULTS: Nine randomized controlled trials and 7 other clinical trials were obtained. In postmenopausal women with normal bone density, risedronate increases lumbar spine bone density and preserves femoral neck density. In postmenopausal women with prior vertebral fracture, risedronate decreases new vertebral and nonvertebral fracture incidence. In patients who experienced breast cancer and who have chemotherapy-induced menopause, risedronate preserves bone. Risedronate prevents vertebral bone loss in patients beginning long-term corticosteroid therapy. Risedronate decreases pagetic bone pain and induces radiological improvement in pagetic lesions. Risedronate induces normalization of biochemical abnormalities and may be more effective than etidronate disodium for Paget disease. Only one study, a trial in patients with postmenopausal osteoporosis using a low dose (2.5 mg) of risedronate, did not have a positive result. Adverse effects in patients with postmenopausal osteoporosis, breast cancer, and Paget disease and in those taking corticosteroids are similar to those of patients taking placebo, and do not include notable upper gastrointestinal tract adverse event rates or serious adverse events. CONCLUSIONS: Risedronate prevents postmenopausal bone loss, decreases fracture in those with established postmenopausal osteoporosis, effectively treats Paget disease, and prevents corticosteroid-induced bone loss. Long-term toxic effects and efficacy, particularly fracture end point data, are unknown. Also undefined are optimal duration of therapy, potential for use in combination with other agents, and direct comparison with other bisphosphonates used for osteoporosis.     

Prevention and treatment strategies for glucocorticoid-induced osteoporotic fractures

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

Parathyroid hormone update

PTH is an exciting new treatment option for postmenopausal women and hypogonadal men who have osteoporosis. As an anabolic agent that affects bone metabolism, it represents an entirely new class of medication for osteoporosis and a novel approach to reducing fracture risk. Numerous clinical trials have demonstrated increases in trabecular and cortical BMD (trabecular more than cortical) in men and women, and reduction in vertebral and nonvertebral fractures in postmenopausal women. Studies suggest that it is safe for use for up to 2 years, but further studies are needed to tes longer intervals of use. Although the combination of PTH and bisphosphonates does not seem to be additive, sequential therapy of PTH followed by bisphosphonate yields maximum gains in BMD compared with combined use or monotherapy with antiresorptive agents. As our knowledge of PTH grows, this is an exciting time for researchers, clinicians, and patients who study, treat, and live with the devastating consequences of progressive osteoporosis.     

The management of secondary osteoporosis

Secondary osteoporosis is common among patients being evaluated for osteoporosis. All men and premenopausal women with unexplained bone loss or a history of a fragility fracture should undergo a work-up for secondary osteoporosis. Also, postmenopausal women with risk factors for secondary osteoporosis should be carefully evaluated. The evaluation should include a thorough history, physical examination, bone mineral density testing, and laboratory testing. While there is no consensus for a cost-effective laboratory evaluation, some recommendations include: 25-hydroxyvitamin D, parathyroid hormone (PTH), serum and urine calcium, phosphate, creatinine, liver function tests, a complete blood count, testosterone in men, and thyroid-stimulating hormone. After a thorough review of the evaluation for secondary osteoporosis, this chapter reviews the pathophysiology and treatment of secondary osteoporotic disorders, including vitamin D insufficiency, osteomalacia, the osteoporosis of erosive inflammatory arthritis, ankylosing spondylitis, systemic lupus erythematosus, and osteoporosis related to anti-androgenic therapy for prostate cancer and aromatase inhibitor therapy for breast cancer. Physicians have a significant responsibility to evaluate and treat the underlying medical problem that is the cause of secondary osteoporosis and to optimize bone health in the individual patient.     

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.     

Treating osteoporosis to prevent fractures: current concepts and future developments

Antiresorptive drugs, such as the bisphosphonates and the RANKL inhibitor denosumab, are currently the most widely used osteoporosis medications. These drugs increase bone mineral density (BMD) and reduce the risk of vertebral (by 40–70%), nonvertebral (by 25–40%) and hip fractures (by 40–53%) in postmenopausal women with osteoporosis. Due to the risk of rare side‐effects, the use of bisphosphonates has been limited to up to 10 years with oral bisphosphonates and 6 years with intravenous zoledronic acid. Despite their well‐proven efficacy and safety, few women at high risk of fracture are started on treatment. Case finding strategies, such as fracture risk‐based screening in primary care using the fracture risk assessment tool (FRAX) and Fracture Liaison Services, have proved effective in increasing treatment rates and reducing fracture rates. Recently, anabolic therapy with teriparatide was demonstrated to be superior to the bisphosphonate risedronate in preventing vertebral and clinical fractures in postmenopausal women with vertebral fracture. Treatment with the sclerostin antibody romosozumab increases BMD more profoundly and rapidly than alendronate and is also superior to alendronate in reducing the risk of vertebral and nonvertebral fracture in postmenopausal women with osteoporosis. For patients with severe osteoporosis and high fracture risk, bisphosphonates alone are unlikely to be able to provide long‐term protection against fracture and restore BMD. For those patients, sequential treatment, starting with a bone‐building drug (e.g. teriparatide), followed by an antiresorptive, will likely provide better long‐term fracture prevention and should be the golden standard of future osteoporosis treatment.     

Clinical Question: What is the best approach to managing glucocorticoid‐induced osteoporosis?

Glucocorticoid-induced osteoporosis is common, and the resulting fractures cause significant morbidity and mortality. Rapid bone loss and increased fracture risk occur soon after the initiation of glucocorticoid therapy and are dose dependent. The increase in fracture risk is partly independent of bone mineral density, probably as a result of changes in bone material properties and increased risk of falling. Fracture risk can be assessed using the FRAX algorithm, although risk may be underestimated in patients taking higher doses of glucocorticoids. Because of the rapidity of bone loss and increase in fracture risk after the start of glucocorticoid therapy, primary prevention should be advised in high-risk individuals, for example older women and men, individuals with a previous fracture history and those with low bone mineral density. Bisphosphonates are the front-line choice for the prevention of fracture in the majority of glucocorticoid-treated patients, with teriparatide as a second-line option. Calcium and vitamin D supplements should be co-prescribed unless there is evidence of an adequate dietary calcium intake and vitamin D status.     

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.     

Treatment of osteoporosis with bisphosphonates

Bisphosphonates are safe and effective agents for treatment and prevention of osteoporosis. Alendronate and risedronate are the best studied of all agents for osteoporosis in terms of efficacy and safety. They increase bone mass. In patients who have established osteoporosis, they reduce the risk of vertebral fractures. They are the only agents shown in prospective trials to reduce the risk of hip fractures and other nonvertebral fractures. They are approved by the US FDA for prevention of bone loss in recently menopausal women, for treatment of postmenopausal osteoporosis, and for management of glucocorticoid-induced bone loss. Other bisphosphonates (e.g., etidronate for oral use, pamidronate for intravenous infusion) are also available and can be used off-label for patients who cannot tolerate approved agents. Bisphosphonates combined with estrogen produce greater gains in bone mass compared with either agent used alone; whether there is a greater benefit of combination therapy on fracture risk is not clear. Combining a bisphosphonate with raloxifene or calcitonin is probably safe, although data on effectiveness are lacking.     

Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis

Glucocorticoid-induced bone loss should be prevented, and if present, should be treated (Table 2). Supplementation with calcium and vitamin D at a dosage of 800 IU/day, or an activated form of vitamin D (e.g., alfacalcidiol at 1 microg/day or calcitriol at 0.5 microg/day), should be offered to all patients receiving glucocorticoids, to restore normal calcium balance. This combination has been shown to maintain bone mass in patients receiving long-term low-to-medium-dose glucocorticoid therapy who have normal levels of gonadal hormones. However, while supplementation with calcium and vitamin D alone generally will not prevent bone loss in patients in whom medium-to-high-dose glucocorticoid therapy is being initiated, supplementation with calcium and an activated form of vitamin D will prevent bone loss. There are no data available to support any conclusion about the antifracture efficacy of the combination of calcium supplementation plus an activated form of vitamin D. Antiresorptive agents are effective in the treatment of glucocorticoid-induced bone loss. All of these agents either prevent bone loss or modestly increase lumbar spine bone mass and maintain hip bone mass. While there are no randomized controlled trials of prevention of glucocorticoid-induced bone loss or radiographic vertebral fracture outcomes with HRT or testosterone, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered HRT. The bisphosphonates are effective for both the prevention and the treatment of glucocorticoid-induced bone loss. Large studies have demonstrated that bisphosphonates also reduce the incidence of radiographic vertebral fractures in postmenopausal women with glucocorticoid-induced osteoporosis. Treatment with a bisphosphonate is recommended to prevent bone loss in all men and postmenopausal women in whom long-term glucocorticoid treatment at > or =5 mg/day is being initiated, as well as in men and postmenopausal women receiving long-term glucocorticoids in whom the BMD T-score at either the lumbar spine or the hip is below normal. While there is little information on the prevention or treatment of bone loss in premenopausal women, these women, too, may lose bone mass if they are being treated with glucocorticoids, so prevention of bone loss with antiresorptive agents should be considered. If bisphosphonate therapy is being considered for a premenopausal woman, she must be counseled regarding use of appropriate contraception. The therapies to prevent or treat glucocorticoid-induced bone loss should be continued as long as the patient is receiving glucocorticoids. Data from large studies of anabolic agents (e.g., PTH) and further studies of combination therapy in patients receiving glucocorticoids are eagerly awaited so additional options will be available for the prevention of this serious complication of glucocorticoid treatment.     

Osteosarcoma in rats receiving long-term PTH injection

Daily injection of human PTH (1-34) to osteoporotics has been shown to increase bone mineral density and reduce fracture risk within 18 months. Despite its impressive effects on human bone, safety became a big issue when it was revealed that up to 53% of rats received hPTH (1-34) for 2 years developed osteosarcoma. On the interpretation of the data, most experts agreed that this is unlikely to predict an increased risk of osteosarcoma in human osteoporotic patients. Some of the reasonings are as follows: (1) fundamental differences in bone metabolism between rat and human, (2) rats received PTH at a dose 12-25 folds of the human dosage, for 80-90% of their life span whereas in human PTH would be used for only 2-3% of the life span.     

Recent concerns surrounding HRT

Millions of women are treated with hormone replacement therapy (HRT) for relief of menopausal symptoms, including vasomotor flushes and sweats for which oestrogen is uniquely and highly effective. Others may continue longer-term treatment in the hope that HRT will help to prevent chronic disease. The preservation of bone mass with continuing oestrogen therapy and reduction of subsequent risk of fracture is well established. Observational studies of the metabolic and vascular effects of oestrogens have suggested a potential benefit in reducing the risk of vascular disease, but recently published randomized controlled trials demonstrate no evidence of benefit in women with established vascular disease or in apparently healthy women. The increased risks of breast cancer and thromboembolic disease have been confirmed in these trials, with evidence of increased risk of stroke. Observational data suggest there may be a small increased risk of ovarian cancer associated with longer-term use of HRT. The premature termination of one arm of the Women's Health Initiative randomized controlled trial caused concern among patients, doctors and pharmaceutical companies. There are difficulties in extrapolating the results from trials using a specific HRT product to advise women on the wide range of other hormone products, doses, combinations and routes of administration. However, in the absence of evidence that other products are safer, the data suggest that for many women the risks associated with long-term use of HRT outweigh the benefits. There are nonhormonal strategies for the prevention and treatment of osteoporosis. HRT is not, and has never been, licensed in the UK for the prevention or treatment of vascular disease, and the data suggesting potential benefit should now be regarded as biased. The absolute incidence of an adverse event is low, and the risk in an individual woman in a single year is very small, but the risks are cumulative over time with long-term use. The risk-benefit balance of each woman needs regular reappraisal with continued use.     

Calcitonin.

Calcitonin is FDA approved for the treatment of postmenopausal osteoporosis but not for prevention. The preferred delivery system is nasal. Nasal calcitonin is safe and well tolerated. The vertebral fracture efficacy of calcitonin is less robust than the two approved bisphosphonates (alendronate and risedronate) but is similar to raloxifene in the treatment of established osteoporosis. Calcitonin has not been demonstrated to reduce hip fracture risk, although a post-hoc pooled analysis suggests potential effectiveness of nasal calcitonin. Calcitonin produces small increments in bone mass of the spine and modestly reduces bone turnover in women with osteoporosis. Calcitonin may have analgesic benefit in patients with acute painful vertebral fractures. Treatment with calcitonin should be considered for older women with osteoporosis with painful vertebral fractures and for women who fail to respond to or cannot tolerate bisphosphonates. Calcitonin may also be indicated for women who are unable to take bisphosphonates because of impaired renal function.