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.     

Treatment-related osteoporosis in men with prostate cancer

Osteoporosis is an important complication of androgen-deprivation therapy (ADT) for prostate cancer. ADT by either bilateral orchiectomies or treatment with a gonadotropin-releasing hormone (GnRH) agonist decreases bone mineral density (BMD) and increases the risk of fracture. Prospective data about treatment or prevention of osteoporosis in men with prostate cancer are limited. Supplemental calcium and vitamin D are recommended. Additional therapy may be warranted for men with osteoporosis or fractures. Intravenous pamidronate prevents bone loss in the hip and spine during ADT. Intravenous zoledronic acid not only prevents bone loss but also increases BMD. Alendronate is approved to treatmen with osteoporosis although the efficacy of alendronate or other oral bisphosphonates has not been evaluated during ADT. Additional prospective studies are needed to evaluate the long-term effects of bisphosphonates and other the rapies on fracture risk and disease-related outcomes.     

Osteoporosis in elderly: prevention and treatment

Osteoporosis is a major clinical problem in older women and men. Almost any bone can fracture as a result of the increased bone fragility of osteoporosis. These fractures are associated with higher health care costs, physical disability, impaired quality of life, and increased mortality. Because the incidence of osteoporotic fracture increases with advancing age, measures to diagnose and prevent osteoporosis and its complications assume a major public health concern. BMD is a valuable tool to identify patients at risk for fracture, to make therapeutic decisions, and to monitor therapy. Several other modifiable and nonmodifiable risk factors for osteoporosis have also been identified. Treatment of potentially modifiable risk factors along with exercise and calcium and vitamin D supplementation forms an important adjunct to pharmacologic management of osteoporosis. Improved household safety can reduce the risk of falls. Hip protectors have been found to be effective in nursing home population. The pharmacologic options include bisphosphonates, HRT, SERMs and calcitonin. PTH had received FDA advisory committee approval. Alendronate has been approved for treatment of osteoporosis in men, and other treatments for men are under evaluation.     

Glucocorticoid-induced osteoporosis

Glucocorticoid-induced osteoporosis is the most frequent cause of secondary osteoporosis. Glucocorticoids cause a rapid bone loss in the first few months of use, but the most important effect of the drug is suppression of bone formation. The administration of oral glucocorticoid is associated with an increased risk of fractures at the spine and hip. The risk is related to the dose, but even small doses can increase the risk. Patients on glucocorticoid therapy lose more trabecular than cortical bone and the fractures are more frequent at the spine than at the hip. Calcium, vitamin D and activated forms of vitamin D can prevent bone loss and antiresorptive agents are effective for prevention and treatment of bone loss and to decrease fracture risk. Despite the known effects of glucocorticoids on bone, only a few patients are advised to take preventive measures and treat glucocorticoid-induced osteoporosis.     

How to manage postmenopausal osteoporosis?

Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased fracture risk. Several therapeutic agents are now available to treat postmenopausal osteoporosis and prevent fractures. Combined calcium and vitamin D supplementation reduce the relative risk of non-vertebral fractures by about 18%. Hormone replacement therapy (HRT) should not be prescribed for osteoporosis in women who do not experience menopausal symptoms. The marked benefits of raloxifene on the reduction in invasive breast cancer and vertebral fracture risk are partially counterbalanced by a lack of effect on non-vertebral fracture risk, and an increased risk of venous thromboembolism and stroke. All four bisphosphonates available in Belgium, except ibandronate, have been shown to reduce the risk of vertebral, non-vertebral and hip fractures in prospective, placebo-controlled trials. Globally, the incidence of vertebral fractures is reduced by 41%-70%, and the incidence of non-vertebral fractures by 25%-39%. The anti-fracture efficacy of weekly or monthly doses of oral bisphosphonates has not been directly shown but is assumed from bridging studies based on BMD changes. To date, the various bisphosphonates have not been studied in head-to-head comparative trials with fracture endpoints. There are potential concerns that long-term suppression of bone turnover associated with bisphosphonate treatment may eventually lead to adverse effects, especially atypical femoral fractures and osteonecrosis of the jaw, but these cases are extremely rare. Teri-paratide (recombinant human 1-34 PTH) administered by daily subcutaneous injections decreases by 65% the relative risk of new vertebral fractures in patients with severe osteoporosis. Pivotal trials with strontium ranelate have shown a 41% reduction in new vertebral fractures and a 16% reduction in non-vertebral fractures over 3 years. Denosumab is a fully human monoclonal antibody to RANK Ligand that is administered as a 60-mg subcutaneous injection every 6 months. In the pivotal phase III trial, there was a 68% reduction in the incidence of new vertebral fractures, whereas the incidence of non-vertebral fractures was reduced by 20%. Several new approaches are being explored, including antibodies to sclerostin, cathepsin K inhibitors, src kinase inhibitors, and drugs that act on calcium sensing receptors.     

Preventing osteoporotic fractures with bisphosphonates: a review of the efficacy and tolerability

Although change in bone mineral density was the outcome most commonly measured in early clinical trials of osteoporosis therapies, it is now understood that the most clinically important outcome is reduction in the risk of fractures. Of currently available osteoporosis therapies, the bisphosphonates have been most thoroughly investigated in studies with fracture risk as the primary outcome. The most widely studied bisphosphonates include etidronate, alendronate and risedronate. Alendronate and risedronate have the most compelling evidence for vertebral and non-vertebral fracture reduction. This review provides a comprehensive overview of the anti-fracture efficacy of bisphosphonates at the spine, hip, and non-vertebral sites.     

Are calcium and vitamin D supplements for everyone?: Pro

Calcium and vitamin D are essential for the health of our bones and various scientific societies recommend an intake of 1,000 mg of calcium and 800 IU of vitamin D daily. Most people with osteoporosis do not eat food with this amount of calcium and also have insufficient levels of vitamin D, so supplements are recommended to provide osteoporotic patients with these amounts. Calcium supplements and vitamin D improve the effectiveness of anabolic and anti-catabolic agents and may have a small effect in reducing the number of fractures. Calcium supplements alone have not shown efficacy preventing fractures in patients with osteoporosis and may increase cardiovascular risk in healthy elderly women and is therefore not recommended for widespread use. Vitamin D supplements are recommended in persons with 25-OH vitamin D levels below 30 ng/ml, in particular the elderly and osteoporotic patients, due to its ability to halt the remodeling resulting from secondary hyperparathyroidism and reduce the loss of bone mass. Vitamin D supplements could help reduce falls and fractures in the institutionalized elderly. In addition, supplements of vitamin D may have other beneficial effects due to extra-osseous regulatory functions on the immune response and cell differentiation and proliferation that is associated with vitamin D. Trials begun in recent years clearly indicate a beneficial effect of vitamin D supplements on mortality, cardiovascular risk,development of tumors and prevention of infections.     

Postmenopausal osteoporosis. What have we learned since the introduction of bisphosphonates?

Over the past 12 years bisphosphonates have become a mainstay of treatment for postmenopausal osteoporosis. As a class, bisphosphonates significantly suppress bone turnover and increase BMD at the lumbar spine and other site through their direct inhibitory effects on osteoclasts. Alendronate and risedronate reduce the incidence of clinical vertebral and non-vertebral fractures. Etidronate and both oral and intravenous ibandronate reduce the incidence of clinical vertebral fractures, but data from primary analyses for reduction in non-vertebral fractures are currently less robust. Intravenous administration of zoledronate is under late-stage investigation for use in postmenopausal osteoporosis. Combinations of alendronate with estrogen or raloxifene provide a greater reduction in bone turnover markers and greater increases in BMD, but fracture risk reduction has not been determined. Overall, bisphosphonates are well tolerated. The most common side effects of oral bisphosphonates are upper gastrointestinal symptoms. Newer safety concerns about the use of bisphosphonates include osteonecrosis of the jaw and oversuppression of bone turnover. The optimal duration of bisphosphonate treatment has not been clearly established.     

Does calcium supplementation increase cardiovascular risk?

Calcium supplementation is widely used for the prevention of osteoporosis in postmenopausal women and in men. While there has been ongoing debate regarding its effectiveness in fracture prevention, the underlying assumption has been that, even if it was not particularly effective, at least it was safe. The recent finding of the Auckland Calcium Study that myocardial infarctions were more common in women randomised to calcium calls this assumption into question, and consideration of vascular event data from other calcium trials does not refute the Auckland findings. Meta‐analyses of these data will be necessary to settle this matter. It is already accepted that calcium supplements increase vascular risk in patients with renal compromise, even in those not yet requiring dialysis. Also, there is substantial epidemiological evidence that serum calcium levels in the upper part of the normal range are a risk factor for vascular disease, and that calcium supplements acutely elevate serum calcium – a combination of findings that lends plausibility to supplementation increasing vascular risk. As there are reasonable grounds for doubting the safety of calcium supplements, and as the evidence for their efficacy in fracture prevention remains marginal, we suggest that there should be a reappraisal of their role in the management of osteoporosis, with a greater emphasis on agents known to prevent fractures.     

Prevention of osteoporotic fractures in post-menopausal women.

A number of pharmacological interventions are now available for the prevention of osteoporotic fractures in post-menopausal women. These include hormone replacement therapy, bisphosphonates, raloxifene, calcitonin, calcitriol and combined calcium and vitamin D. Factors influencing the positioning of these agents in clinical practice include their efficacy in preventing fractures at both the spine and the hip, tolerability, side-effects, cost and, in the case of raloxifene and hormone replacement therapy, the extra-skeletal risks and benefits of long-term treatment. The rates of onset and offset of the treatment effect are also important considerations; the observations that relatively short-term intervention produces a significant reduction in fracture risk in women with established osteoporosis, that treatment benefits are greatest in those with low bone mineral density and that the beneficial skeletal effects are not maintained after the withdrawal of treatment have resulted in a shift from long-term preventive strategies towards the targeting of high-risk individuals for intervention.     

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.     

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.     

Risk for osteoporosis and fracture with glucocorticoids

Glucocorticoid use is ubiquitous and is associated with multiple adverse reactions. Among them, osteoporosis and bone fractures are of our concern. In this review, we present current evidence on the effect of glucocorticoids on bone mineral density and the risk of fractures, the mechanisms underlying those effects, and the recommendations for monitoring and treating patients who take them.The bone mineral density of the lumbar spine and total hip is lower, and the risk of fractures is higher in glucocorticoid users than non-users. These effects have a rapid onset, are dose-dependent, and improve soon after discontinuation of glucocorticoids. They also appear to occur even with non-systemic routes of administration and with low doses.Glucocorticoids reduce bone mineral density by increasing osteoclast activity and decreasing osteoblast and osteocyte activity. Calcium metabolism and parathyroid hormone activity are less important than was initially thought.Treatment decisions are on risk stratification using clinical, radiographic, and prediction tools. Our armamentarium for the treatment and prevention of glucocorticoid-induced osteoporosis includes calcium and vitamin D, bisphosphonates, recombinant parathyroid hormone, monoclonal antibodies against receptor activator of nuclear factor kappa-B ligand, and hormone treatments.     

Bone metabolism alterations after kidney transplantation

Early after renal transplantation (RT) a rapid decrease in bone mineral density at the lumbar spine, femoral neck, and femoral shaft has been documented. In addition, an appreciable proportion of patients still remain losing bone late after RT. As a consequence, RT patients are at a high risk of bone fractures as compared to general population. Most fractures involve appendicular skeleton, particularly the feet and ankles, and the diabetic patient is at increased risk of fractures. Thus, early institution of preventive measures and treatment of established osteoporosis are central. The major cause of post-transplantation bone loss is corticosteroid treatment, and this should be used at the lower dose compatible with graft survival. Preexisting hyperparathyroidism also affects the early cancellous bone loss at the spine, and post-transplantation bone loss reflects variable individual susceptibility, resembling the polygenic determination of bone mineral density in general. Clinical trials have demonstrated that bisphosphonates or vitamin D plus calcium supplementation, prevent post-transplantation bone loss during the first 6-12 months. However, their role in preventing bone fractures has not been proven. Finally, recommendations for management, prevention and treatment, are summarized.     

Managing osteoporosis in ulcerative colitis: Something new?

The authors revise the latest evidence in the literature regarding managing of osteoporosis in ulcerative colitis(UC), paying particular attention to the latest tendency of the research concerning the management of bone damage in the patient affected by UC. It is wise to assess vitamin D status in ulcerative colitis patients to recognize who is predisposed to low levels of vitamin D, whose deficiency has to be treated with oral or parenteral vitamin D supplementation. An adequate dietary calcium intake or supplementation and physical activity, if possible, should be guaranteed. Osteoporotic risk factors, such as smoking and excessive alcohol intake, must be avoided. Steroid has to be prescribed at the lowest possible dosage and for the shortest possible time. Moreover, conditions favoring falling have to been minimized, like carpets, low illumination, sedatives assumption, vitamin D deficiency. It is advisable to assess the fracture risk in all UC patient by the fracture assessment risk tool(FRAX tool), that calculates the ten years risk of fracture for the population aged from 40 to 90 years in many countries of the world. A high risk value could indicate the necessity of treatment, whereas a low risk value suggests a followup only. An intermediate risk supports the decision to prescribe bone mineral density(BMD) assessment and a subsequent patient revaluation for treatment. Dual energy X-ray absorptiometry bone densitometry can be used not only for BMD measurement, but also to collect data about bone quality by the means of trabecular bone score and hip structural analysis assessment. These two indices could represent a method of interesting perspectives in evaluating bone status in patients affected by diseases like UC, which may present an impairment of bone quality as well as of bone quantity. In literature there is no strong evidence for instituting pharmacological therapy of bone impairment in UC patients for clinical indications other than those that are also applied to the patients with osteoporosis. Therefore, a reasonable advice is to consider pharmacological treatment for osteoporosis in those UC patients who already present fragility fractures, which bring a high risk of subsequent fractures. Therapy has also to be considered in patients with a high risk of fracture even if it did not yet happen, and particularly when they had long periods of corticosteroid therapy or cumulative high dosages. In patients without fragility fractures or steroid treatment, a medical decision about treatment could be guided by the FRAX tool to determine the intervention threshold. Among drugs for osteoporosis treatment, the bisphosphonates are the most studied ones, with the best and longest evidence of efficacy and safety. Despite this, several questions are still open, such as the duration of treatment, the necessity to discontinue it, the indication of therapy in young patients, particularly in those without previous fractures. Further, it has to be mentioned that a longterm bisphosphonates use in primary osteoporosis has been associated with an increased incidence of dramatic side-effects, even if uncommon, like osteonecrosis of the jaw and atypical sub-trochanteric anddiaphyseal femoral fractures.UC is a long-lasting disease and the majority of patients is relatively young.In this scenario primary prevention of fragility fracture is the best cost-effective strategy.Vitamin D supplementation,adequate calcium intake,suitable physical activity(when possible),removing of risk factors for osteoporosis like smoking,and avoiding falling are the best medical acts.     

Glucocorticoids and osteoporosis

Treatment with glucocorticoids (GC) has no alternative in many medical disciplines for their anti-inflammatory and immunosuppressive effect. However, osteoporosis and the related fractures are a serious complication brought about by long-term GC therapy. The risk of fractures, especially of the vertebras and the ribs, becomes higher as early as in the first months of oral GC therapy. It grows in proportion to the daily dose of GC, and is present even if low doses are administered (2.5-7.5 mg of prednisone per day). Decreasing bone density (BMD) is not accountable for the higher risk of fractures in GC therapy and fractures occur with higher values of BMD than in primary osteoporosis. There is still no tool that we could use to quantify the changes in the bone quality and the increased risk of fracture in clinical practice. The principal mechanism by which GC induces osteoporosis is inhibition of bone formation caused by the suppression of osteoblastogenesis as well as the activity of functional osteoblasts, with accelerated osteocyte and osteoblast apoptosis. There are significant differences between individuals in terms of GC sensitivity, the reasons of which have not yet been explained. Prior to planned long-term GC therapy (> 3 months) with daily doses higher than 2.5 mg of prednisone p.o. (or higher doses of inhaled GC), it is recommended to perform a densitometry exam using dual-energy X-ray absorptiometry (DXA) in the lumbar region of the spine and femoral collum to evaluate additional risk factors of osteoporosis and fractures for a more precise estimate of the risk of fracture in the specific patient. Sufficient intake of calcium (1,000-1,500 mg of elementary calcium per day) and of the vitamin D (800 IU per day) should be assured in all patients treated by GC. Endogenous production of sexagens should be evaluated and possible substitution therapy should be considered in premenopausal women and younger men. Today, bisphosphonates can be given to patients with a high risk of fracture, the effects of which in preventing the decrease of BMD and vertebral fractures have been documented in randomised clinical studies, even though the evaluation of the risk of fractures was not the primary endpoint of those studies. However, in view of the antiremodelling effect of bisphosphonates, it is clear that this therapy does not eliminate the cause of GC induced osteoporosis and drugs with stimulating effect on osteoblasts will certainly be preferred in the future. Very promising are the first clinical studies of injection parathormone (PTH 1-34) which stimulated bone formation in a continuing GC treatment.     

Osteoporosis treatment: Focus on safety

Osteoporosis results in approximately one-half of older white women and one-third of men sustaining fractures, which cause significant disability and increased mortality. Interventions are now available which reduce fracture risk by about one-half, and there is evidence that they also reduce mortality in frail elderly by about 10%. The mechanism of this reduced mortality is unclear but it has the potential to substantially impact on the cost-benefit of osteoporosis treatment. Available treatments are generally well-tolerated. Bisphosphonates cause gastrointestinal side-effects when administered orally, and acute phase responses when given intravenously. Osteonecrosis of the jaw is overwhelmingly a problem of cancer sufferers rather than those with osteoporosis, but atypical patterns of fracture in the upper femoral shaft sometimes occur in users of these drugs, though they are very rare in comparison with the other osteoporotic fractures which these drugs prevent. Thus, the cost-benefit of bisphosphonate use is clearly positive in those with osteoporosis. In contrast, calcium supplements probably increase the risk of myocardial infarction, admissions to hospital with acute gastrointestinal complaints and risk of renal calculi, whereas their impact on fracture is marginal (about a 10% reduction). Thus, they are not cost-effective, and a balanced diet is a safer way of obtaining one's calcium requirements.     

A cost effectiveness analysis of calcium and vitamin D supplementation,etidronate, and alendronate in the prevention of vertebral fractures in women treated with glucocorticoids

OBJECTIVE: To assess the relative costs and benefits of calcium and vitamin D supplements, cyclic etidronate, or alendronate in the prevention of vertebral fractures for women and with normal bone density and osteopenia who are about to initiate moderate dose glucocorticoid treatment. METHODS: Using a decision analysis model, we evaluated the following patients: 4 hypothetical cohorts: 30-yr-old women with normal lumbar spine (LS) bone mineral density (BMD) (t score = 0), 50-yr-old women with borderline osteopenia (t score = -1), 60-yr-old women with moderate osteopenia (t score = -1.5), and 70-yr-old women with severe osteopenia (t score = -2) treated with a mean prednisone dose of 10 mg/day for one year. The main outcomes included the development of vertebral fractures 10 years after glucocorticoid treatment and at age 80 (life-time risk) and direct and indirect costs. RESULTS: At 10 years, calcium and vitamin D supplements decreased fracture rates by 30-50% at a minimal cost (US$800 or less per vertebral fracture avoided) or at a cost saving compared to no treatment for women with osteopenia (t score -1 to -2). Etidronate and alendronate are most cost effective in women with borderline osteoporosis (t scores of -1.5 and -2) in the 10 year analysis. In the life-time analysis, calcium and vitamin D treatment yielded a cost savings compared to no treatment for all groups with osteopenia. Etidronate decreased fracture rates further in all groups at a cost of less than $2,000 per fracture prevented. Alendronate reduced the fracture risk further at cost of $3,000-7,000 per fracture avoided. CONCLUSION: Calcium and vitamin D supplements and low cost bisphosphonate regimens such as cyclic etidronate decrease the life-time vertebral fracture risk at acceptable costs and should be considered when initiating glucocorticoid treatment for women who do not have osteoporosis.     

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.