Role of bisphosphonates and calcitonin in the prevention and treatment of osteoporosis

Bisphosphonates have been shown to increase bone mineral density in patients with established osteoporosis as well as those with osteopenia. The evidence conclusively shows a reduction in fracture rates in patients on the more potent nitrogen containing bisphosphonates. Indeed, significant vertebral fracture rate reduction has been demonstrated after only 1 year of therapy. Alendronate, a second-generation bisphosphonate, and risedronate, a third-generation bisphosphonate, are first line medications for the treatment of osteoporosis given their efficacy in preventing both vertebral and non-vertebral fractures. There is evidence that vertebral fractures may be prevented by intermittent cyclic therapy with etidronate. All three have been shown to increase bone mineral density in the spine, with alendronate and risedronate producing significant increases in hip bone density. Calcitonin has demonstrated the ability to reduce vertebral fracture rates with minimal changes in bone density. Calcitonin is also beneficial in reducing the bone pain associated with fractures.     

Calcitonin Therapy in Osteoporosis

Osteoporosis is the most prevalent metabolic bone disease and is characterized by diminished bone strength predisposing to an increased risk of fracture. Its incidence is particularly high in postmenopausal women but it can also affect other groups, such as men and patients receiving corticosteroid therapy. Calcitonin is a naturally occurring peptide which acts via specific receptors to strongly inhibit osteoclast function. It has been used in the treatment of osteoporosis for many years. Historically, calcitonin was administered as a parenteral injection, but the intranasal formulation is now the most widely used because of its improved tolerability. New approaches are currently being investigated to enhance the bioavailability and effects of calcitonin, including oral, pulmonary, and transdermal routes of administration, and novel allosteric activators of the calcitonin receptor. Several controlled trials have reported that calcitonin stabilizes and in some cases produces a short-term increase in bone density at the lumbar spine level. The most relevant clinical trial to evaluate the effect of calcitonin in the prevention of fractures was the Prevent Recurrence of Osteoporotic Fractures (PROOF) study, a 5-year double-blind, randomized, placebo-controlled trial showing that salmon calcitonin nasal spray at a dosage of 200 IU/day can reduce the risk of vertebral osteoporotic fractures by 33% (relative risk [RR] = 0.67; 95% CI 0.47, 0.97; p = 0.03). However, the 100 and 400 IU/day dosages did not significantly reduce vertebral fracture risk. Effects on nonvertebral fractures were not significant (RR = 0.80; 95% CI 0.59, 1.09; p = 0.16). There is mounting evidence to show that calcitonin diminishes bone pain in osteoporotic vertebral fractures, which may have clinical utility in vertebral crush fracture syndrome. A recent study suggests that nasal salmon calcitonin appears to be a promising therapeutic approach for the treatment of men with idiopathic osteoporosis, although long-term trials are necessary to confirm these results and evaluate fracture rate as an endpoint in men. The role of calcitonin in corticosteroid-induced osteoporosis remains controversial, hence it can only be considered a second-line agent for the treatment of patients with low bone mineral density who are receiving long-term corticosteroid therapy.     

Raloxifene for older women: a review of the literature

Raloxifene is a non-steroidal selective estrogen-receptor modulator (SERM) which is used for prevention and treatment of postmenopausal osteoporosis. Raloxifene decreases the incidence of vertebral fractures by 30%–50% in postmenopausal women with osteoporosis but has not been shown to decrease the incidence of hip fractures or other non-vertebral fractures. At the present time, estrogen-replacement therapy and bisphosphonate treatment are the only medical treatments that are proven to prevent hip fractures with the exception of vitamin D and calcium replacement, which has been shown to prevent hip fractures in elderly individuals and nursing home residents. Raloxifene has been shown to have additive effects on bone turnover and bone mineral density (BMD) when used along with alendronate and teriparatide. Raloxifene could have a role in renal failure as it has been shown to increase BMD of the vertebra over 1 year of therapy. Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer. The increased incidence of venous thromboembolism is the main concern of raloxifene therapy and previous history of venous thromboembolism is a contraindication for use of raloxifene. Raloxifene has a role in treatment of vertebral osteoporosis in older women. The decision to use raloxifene should be based on evaluation of fracture risk and on potential other benefits than fracture reduction along with consideration of side effects.     

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.     

Pharmacological therapy of osteoporosis

The aim of pharmacological therapy for osteoporosis is to prevent osteoporotic fractures. Low bone mineral density, previous fractures, high values of bone turnover markers, and age are the independent risk factors for osteoporotic vertebral fractures. These clinical parameters should be utilized to start and choose the drugs for osteoporosis.     

Idiopathic osteoporosis: a heterogeneous entity

DEFINITION: Idiopathic osteoporosis refers to the development of osteopenia and fractures with minimal or no trauma in otherwise young, healthy individuals who are not postmenopausal or have other, identifiable secondary causes of osteoporosis. EPIDEMIOLOGY: It is a relatively rare disorder, with an incidence of 0.4 cases per 100,000 person-years. It appears to affect both sexes equally and results primarily in the development of trabecular bone fractures such as vertebral compression fractures and Colles' fractures, although hip fractures are also seen. PATHOPHYSIOLOGY: The disease may be temporally related to pregnancy and/or lactation in some patients, although it is unclear whether pregnancy plays a pathophysiological role or, more likely, simply leads to the clinical presentation of the disease in individuals who are already affected. Various pathophysiological abnormalities have been described in these patients, including hypercalciuria, abnormalities in vitamin D metabolism, and in the production of insulin-like growth factor I and interleukin 1. Findings on bone biopsy have been variable, with some patients having evidence of a defect in osteoblast function, whereas others having evidence for increased bone resorption. TREATMENT: No specific therapy has been proven to be effective in these patients. However, an individualized approach based on an assessment of bone turnover may be reasonable and may decrease the bone loss and subsequent fracture risk.     

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.     

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.     

Vitamin K2 (menatetrenone) and bone quality

Vitamin K2 (menatetrenone) treatment was reported to significantly prevent new clinical fracture (chi2 = 10.935;p = 0.0273) in a 2-year group comparison study of patients with osteoporosis, although it only maintained the baseline bone mineral density. This result strongly suggested that another factor was involved in promoting bone strength apart from an increase in bone mineral density. With respect to the therapeutic effect of menatetrenone treatment on corticosteroid-induced osteoporosis over 2 years, the incidence of a new vertebral fracture was 13.3% in the menatetrenone treatment group versus 41% in the control group, indicating that this treatment could prevent fractures. Multivariate logistic regression analysis was performed to investigate independent risk factors for new vertebral fractures, and treatment with menatetrenone showed a preventive effect on fracture with an odds ratio of 0.03 and a risk rate of 0.003.     

Ankylosing spondylitis and bone mineral density—what is the ideal tool for measurement?

Ankylosing spondylitis (AS) is characterised by chronic inflammation and partial ossification, yet vertebral fractures due to osteoporosis, although common, are frequently unrecognised. The aim of this study was to (1) show the frequency of changes in the progress of osteopenia/osteoporosis in AS depending on duration and stage of the disease and (2) assess the ranking of two different methods of bone density measurement in this clinical pattern. We measured bone density in 84 male and female patients with both dual X-ray absorptiometry (DXA) and single energy quantitative computed tomography (SE-QCT). In the initial and advanced stages of the disease, a high decrease in axial bone density could be verified (DXA: osteopenia in 5% and osteoporosis in 9.2%; SE-QCT: osteopenia in 11.8% and osteoporosis in 30.3%). Peripheral bone density decrease as in osteopenia could be proven in 17.6% by DXA measurement. With SE-QCT, a decrease in vertebral trabecular bone density could already be observed in the initial stage and continued steadily during the course of the disease; cortical bone displayed the same trend up to stages of ankylosis. With DXA, valid conclusions are more likely to be expected in less marked ankylosing stages of AS. In stages of advanced ankyloses in the vertebral region (substantial syndesmophytes), priority should be given to SE-QCT, due to the selective measurement of trabecular and cortical bone. The DXA method often yields values that are too high, and the replacement of vertebral trabecular bone by fatty bone marrow is not usually recorded as standard. There may already be an increased risk of bone fracture in AS in osteopenia on DXA along with an osteoporosis already established on SE-QCT.     

Background for studies on the treatment of male osteoporosis: state of the art

Male osteoporosis represents an important, although long underestimated, public health problem. Both in men and in women aging is accompanied by continuous bone loss and by an exponential increase in the incidence of osteoporotic fracture, with a female to male incidence ratio of about 2 to 3 to 1 in the elderly for hip and vertebral fractures. Morbidity after osteoporotic fractures appears to be more serious and mortality more common in men than in women. To date, no single treatment has been proved to be effective and safe in published prospective studies. The present report, based on a systematic search of the literature on male osteoporosis, summarises the state of the art on the clinical consequences of male osteoporosis and its risk factors, in relation to the present state of knowledge about female osteoporosis. This constitutes the background for the design of rational clinical development strategies for therapeutic interventions in male osteoporosis. From this review of the literature it is apparent that notwithstanding the existing sex differences in pathophysiology of osteoporosis and the difference in age-specific incidence of osteoporotic fractures, there are also important similarities between osteoporosis in women and men. The higher incidence of fracture in women than in men results from quantitative differences in risk factors rather than from different risk factors. Even though there are sex differences in bone geometry, incidence of fracture seems to be similar in men and women for a same absolute areal bone mineral density. However, the lack of data on the changes in fracture rates in men resulting from pharmacological intervention, leading to changes in bone mineral density or bone turnover, remains the main limitation for extrapolation of established treatment outcomes from women to men.     

Osteoporosis in men

Osteoporosis is characterized by a reduction in bone density, associated with skeletal fragility and an increased risk of fracture after minimal trauma. Although osteoporosis is generally considered to be a condition affecting post-menopausal women, it is now clear that substantial bone loss occurs with advancing age in men, such that up to 20% of symptomatic vertebral fractures and 30% of hip fractures occur in men. This chapter highlights the incidence and prevalence of osteoporotic fractures in men and reviews the associated morbidity, excess mortality and health and social service expenditure. The determinants of peak bone mass and bone loss in men are discussed, as is the pathogenesis of osteoporosis and vertebral and hip fractures. The criteria for the diagnosis of osteoporosis in men are reviewed, together with the most appropriate investigations for secondary osteoporosis. The management of osteoporosis in men is also discussed, highlighting the most appropriate treatment options.     

Prevention of osteoporosis in cardiac transplant recipients

Osteoporosis is a leading cause of pretransplant and posttransplant morbidity. The need for early detection by measuring bone mineral density, even before transplant, must be emphasized. Preventive measures are not comparable. The use of calcium and vitamin D supplements, although recommended, is inadequate for the prevention of bone loss and complications such as vertebral fractures. Bisphosphonates have been shown to attenuate the bone loss and reduce fractures associated with steroid-induced osteoporosis. Small studies in transplant recipients suggest similar results. Other preventive measures such as hormone replacement therapy are also helpful. There are limited data on the administration of nasal calcitonin in transplant recipients.     

The concept and treatment of osteoporosis

Osteoporosis is a dynamic process, thought to be caused by an uncoupling between osteoblast and osteoclast activity. Altered pulsatile secretion of growth hormone and parathyroid hormone (PTH) have been proposed as pathogenetic factors for this unbalanced coupling. The anatomical lesions are believed to be reversible until trabecular perforations develop, if fractures already occurred the anatomical defect is permanent. It is helpful to classify osteoporosis in stages of increasing severity depending on bone density and the presence of fractures. Theoretically, if the bone density is above the fracture threshold, then the only therapeutic goal is to maintain the bone mass. If instead the mineral density is below the threshold, an active therapy is needed with drugs that can possibly increase the skeletal mass. Osteoporosis with multiple fractures cannot be reversed. The authors propose a promising pharmacologic treatment for osteoporosis, based on the combination of human PTH-(1-38) and intranasal salmon calcitonin. If started in the early stages of the osteoporotic process, this regimen may restore the initial bone mass. In more advanced stages, only a correction of the metabolic defect is possible, but the irreversible vertebral deformities are not affected. On the basis of the results, cyclic therapy with human PTH-(1-38) and salmon calcitonin represents a good treatment choice for 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.     

Comparative efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women with osteoporosis: The Yamaguchi Osteoporosis Prevention Study

PURPOSE: To assess the comparative effectiveness of several medications on bone mineral density, biochemical bone markers, and the incidence of vertebral fractures in postmenopausal women with osteoporosis. METHODS: A total of 396 postmenopausal women, aged 50 to 75 years, were allocated randomly to six equal-sized groups: hormone replacement therapy, etidronate, eel calcitonin, alfacalcidol, vitamin K (menatetrenone), or control (no treatment). Thoracic and lumbar spine radiographs, bone mineral density at the distal radius, and markers of bone turnover were assessed at baseline and every 3 months during the 2-year study. RESULTS: Compared with baseline, the 2-year mean changes in bone mineral density were 2.0% for hormone replacement therapy, -0.5% for etidronate, 1.6% for calcitonin, -3.6% for alfacalcidol, -1.9% for vitamin K, and -3.3% for control. Seventeen (26%) of the 66 control patients developed new vertebral fractures. Compared with controls, the relative risks of vertebral fracture were 0.35 (95% confidence interval [CI]: 0.14 to 0.83) for hormone replacement therapy, 0.40 (95% CI: 0.17 to 0.92) for etidronate, 0.41 (95% CI: 0.17 to 0.93) for calcitonin, 0.56 (95% CI: 0.26 to 1.12) for alfacalcidol, and 0.44 (95% CI: 0.20 to 0.99) for vitamin K. CONCLUSION: We observed significant reductions in the incidence of vertebral fractures with hormone replacement therapy, etidronate, and calcitonin, and significant improvements in bone mineral density with hormone replacement therapy and calcitonin.     

SERM & bone metabolism: protective effects of SERM against fracture risk and its long-term beneficial effects

The Multiple Outcomes of Raloxifene Evaluation (MORE) Trial enrolled 7,705 women with osteoporosis, defined by prevalent vertebral fractures and/or a bone mineral density (BMD) T score at -2.5 or below, who were treated with placebo or raloxifene at a dosage of 60 or 120 mg/day for 3 years. Raloxifene hydrochloride therapy significantly reduces the risk for vertebral fractures at 3 and 4 years administration group. The fact that Raloxifene administration causes the significant 25% reduction in overall risks in postmenopausal women indicate a favorable risk-benefit profile. These data suggested that raloxifene is effective to protect from the occurrence of bone fracture without causing increases of breast cancer and endometrial cancer, and improve overall health conditions in postmenopausal women.     

Therapies for symptomatic primary osteoporosis

There is no universally accepted pharmacologic treatment for primary symptomatic osteoporosis. However, three agents discussed in this review show varying degrees of promise. Calcitonin increases bone density and has the added benefit of analgesic properties. Etidronate disodium, a diphosphonate approved for symptomatic Paget's disease, has been shown to increase bone density and decrease fractures in osteoporosis. Sodium fluoride, although an effective stimulator of bone growth in low turnover osteoporosis, has been associated with toxicity and increased fractures.     

Drug insight: Existing and emerging therapies for osteoporosis

Osteoporosis is a major public health problem that is characterized by microarchitectural deterioration, low bone mass, and increased risk of fractures. Currently, many women and men affected with this disease are not diagnosed or treated. As osteoporosis is often clinically silent, risk-factor assessment and measurement of BMD are needed to identify those who may benefit from osteoporosis therapy. Although adequate daily intake of calcium and vitamin D, and regular weight-bearing exercise are important for skeletal health, they are not adequate treatments for individuals with osteoporosis. Therapies approved for treatment and/or prevention of osteoporosis in the United States include oral bisphosphonates (alendronate, ibandronate and risedronate), calcitonin, estrogens, teriparatide (parathyroid hormone fragment [1-34]), and raloxifene. For most patients, oral bisphosphonates are the treatment of choice, given the large-scale randomized-trial data demonstrating efficacy in fracture reduction, although bisphosphonates that reduce spine and nonspine fractures (e.g. alendronate and risedronate) are preferred. For high-risk patients (those with very low bone density, or with fractures), teriparatide therapy for 2 years should be considered. The treatment paradigm for osteoporosis will evolve further as promising new treatments progress through clinical development.     

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.