A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis

Teriparatide (rDNA origin) injection [recombinant human PTH (1-34)] stimulates bone formation, increases bone mineral density (BMD), and restores bone architecture and integrity. In contrast, bisphosphonates reduce bone resorption and increase BMD. We compared the effects of teriparatide and alendronate sodium on BMD, nonvertebral fracture incidence, and bone turnover in 146 postmenopausal women with osteoporosis. Women were randomized to either once-daily sc injections of teriparatide 40 micro g plus oral placebo (n = 73) or oral alendronate 10 mg plus placebo injection (n = 73). Median duration of treatment was 14 months. At 3 months, teriparatide increased lumbar spine BMD significantly more than did alendronate (P < 0.001). Lumbar spine-BMD increased by 12.2% in the teriparatide group and 5.6% in the alendronate group (P < 0.001 teriparatide vs. alendronate). Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one third distal radius decreased, compared with alendronate (P < or = 0.05). Nonvertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group (P < 0.05). Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. In conclusion, teriparatide, a bone formation agent, increased BMD at most sites and decreased nonvertebral fractures more than alendronate.     

Aging bone and osteoporosis: strategies for preventing fractures in the elderly

As the older population increases, the incidence of osteoporotic fractures is expected to dramatically rise during the next few decades. Older patients are much more susceptible to fracture at any given bone mineral density (BMD) than are younger patients because of various factors, including the quality of aging bone, which involves more than BMD. Suppression of increased bone turnover by antiresorptive therapies, even with only small changes in BMD, can reduce fracture risk, especially in the lumbar spine. Bisphosphonate treatment can significantly reduce vertebral and nonvertebral fractures, including hip fractures, even in the very elderly. Prospective analyses show that risedronate therapy consistently and significantly reduces the risk of new morphometric vertebral fractures after 1 year in postmenopausal women. Post hoc analyses report significant reductions in the risk of 1 new clinical vertebral fracture after 6 months of risedronate therapy and after 1 year of alendronate therapy. Oral raloxifene therapy and salmon calcitonin nasal spray therapy have been shown to reduce the risk of vertebral fracture after 3 and 5 years, respectively, and post hoc data show a significant reduction in clinical vertebral fracture risk at 1 year with raloxifene use. However, neither raloxifene therapy nor calcitonin therapy reduce the risk of nonvertebral and hip fractures at currently approved doses. Bisphosphonates have been shown to be safe and efficacious with 7 years' risedronate sodium and 10 years' alendronate sodium data published, and bisphosphonates reduce bone turnover and increase BMD to a greater degree than raloxifene and calcitonin, which may partly account for their nonvertebral and hip fracture reduction effect. Therefore, bisphosphonate therapy with risedronate or alendronate should be considered in patients with low BMD at the hip and in older patients with osteoporosis and osteopenia, particularly those with an existing fracture.     

Bisphosphonate treatment of osteoporosis

Bisphosphonates represent the agents of choice for most patients with osteoporosis. They are the best studied of all agents for the prevention of bone loss and reduction in fractures. They increase BMD, primarily at the lumbar spine, but also at the proximal femur. In patients who have established osteoporosis, bisphosphonates reduce the risk of vertebral fractures, and are the only agents in prospective trials to reduce the risk of hip fractures and other nonvertebral fractures. Bisphosphonates reduce the risk of fracture quickly. The risk of radiographic vertebral deformities is reduced after 1 year of treatment with risedronate [68]. The risk of clinical vertebral fractures is reduced after 1 year of treatment with alendronate [69] and just 6 months' treatment with risedronate [157]. The antifracture effect of risedronate has been shown to continue through 5 years of treatment [158]. Alendronate and risedronate are approved by the FDA for prevention of bone loss in recently menopausal women, for treatment of postmenopausal osteoporosis, and for prevention (risedronate) and treatment (alendronate and risedronate) of glucocorticoid-induced osteoporosis. Alendronate is also approved for treatment of osteoporosis in men. Other bisphosphonates (etidronate for oral use, pamidronate and zoledronate for intravenous infusion) are also available and can be used off label for patients who cannot tolerate approved agents. Although bisphosphonates combined with estrogen or raloxifene produce greater gains in bone mass compared with single-agent treatment, the use of two antiresorptive agents in combination cannot be recommended because the benefit on fracture risk has not been demonstrated and because of increased cost and side effects.     

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

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

Comparison of the effect of alendronate on lumbar bone mineral density and bone turnover in men and postmenopausal women with osteoporosis

The purpose of the present study was to compare the effect of alendronate treatment on lumbar bone mineral density (BMD) and bone turnover in men and postmenopausal women with osteoporosis. Sixty men with primary or secondary osteoporosis and 318 women with postmenopausal osteoporosis were treated with alendronate. The primary end points were lumbar BMD and urinary cross-linked N-terminal telopeptides of type I collagen (NTX) and serum alkaline phosphatase (ALP) levels. The secondary end point was the incidence of vertebral and nonvertebral fractures. Forty-seven (78.3%) men and 254 (79.9%) women who could complete the 12-month trial were analyzed. The mean ages of men and postmenopausal women were 69.1 and 70.4 years, respectively. Both men and postmenopausal women showed higher levels of urinary NTX as compared with normal range of premenopausal women. Alendronate treatment decreased urinary NTX level by 39.2% in men and 45.4% in postmenopausal women at 3 months and serum ALP level by 17.8 and 21.0%, respectively, at 12 months. Following reduction in bone turnover markers, lumbar BMD increased 5.8 and 7.6% in men and postmenopausal women, respectively, at 12 months. Reduction in urinary NTX level and increase in lumbar BMD were smaller in men than in postmenopausal women. The incidence of vertebral and nonvertebral fractures was 10.6 and 8.5%, respectively, in men and 8.3 and 7.5%, respectively, in postmenopausal women, with no significant difference in these incidences between them. These results suggested that alendronate treatment effectively increased lumbar BMD from baseline in men with primary or secondary osteoporosis following reduction in bone turnover, although its efficacy did not appear to be greater than in postmenopausal women with osteoporosis. We have no funding sources; we have no conflict of interest.     

Assessment of the Relationship Between Age and the Effect of Risedronate Treatment in Women with Postmenopausal Osteoporosis: A Pooled Analysis of Four Studies

OBJECTIVES: To quantify the effect of age on the incidence of osteoporosis‐related fractures and of risedronate treatment on fracture risk in different age groups in women with postmenopausal osteoporosis. DESIGN: Data from four randomized, double‐blind, placebo‐controlled, Phase III studies were pooled and analyzed. PARTICIPANTS: The analysis population (N=3,229) consisted of postmenopausal women with osteoporosis as determined on the basis of prevalent vertebral fractures, low bone mineral density (BMD), or both. INTERVENTION: Patients had received risedronate 5 mg daily or placebo for 1 to 3 years. MEASUREMENTS: The endpoints of interest were the incidence of osteoporosis‐related fractures, clinical fractures, nonvertebral fractures, and morphometric vertebral fractures. The effect of age on fracture risk and treatment benefit was examined using Cox regression models with age and treatment as explanatory variables. The 3‐year fracture risk was estimated for patients in each treatment group at a given age. RESULTS: Irrespective of treatment, fracture risks were greater in older patients (P<.001). On average, for every 1‐year increase in age, a patient's risk for osteoporosis‐related fracture increased 3.6% (95% confidence interval=2.3–5.0%). Irrespective of age, risedronate treatment reduced fracture risk 42%. Risedronate‐treated patients had fracture risks similar to those of placebo‐treated patients 10 to 20 years younger. CONCLUSION: Patients treated with risedronate have a significantly lower fracture risk, similar to that of untreated patients 10 to 20 years younger.     

Antiresorptive treatment of postmenopausal osteoporosis: comparison of study designs and outcomes in large clinical trials with fracture as an endpoint

Antiresorptive treatments for postmenopausal osteoporosis have been studied extensively, but due to the volume of published data and lack of head-to-head trials, it is difficult to evaluate and compare their fracture reduction efficacy. The objective of this review is to summarize the results from clinical trials that have fracture as an endpoint and to discuss the factors in study design and populations that can affect the interpretation of the results. Although there are numerous observational studies suggesting that estrogen and hormone replacement therapies may reduce the risk of vertebral and nonvertebral fractures, there is no large, prospective, randomized, placebo-controlled, double-blind clinical trial demonstrating fracture efficacy. The effects of raloxifene, alendronate, risedronate, and salmon calcitonin on increasing bone mineral density (BMD) and decreasing fracture risk have been shown in randomized, placebo-controlled, double-blind clinical trials of postmenopausal women with osteoporosis. Although the increases in lumbar spine BMD vary greatly in these trials, the decrease in relative risk of vertebral fractures is similar among therapies. However, nonvertebral fracture efficacy has not been consistently demonstrated. Combined administration of two antiresorptive therapies results in greater BMD increases, but the effects on fracture risk are unknown. Direct comparisons of clinical trial results should be considered carefully, given the differences in study design and populations. Differences in study design that may influence the efficacy of fracture risk reduction include calcium and vitamin D supplementation, primary fracture endpoints, definition of vertebral deformity or fracture, discontinuation rates, and statistical power. Factors in the study population that may influence fracture efficacy include the age of the population and the proportion of subjects with prevalent fractures. The use of surrogate endpoints such as BMD to predict fracture risk should be approached with caution, as the relationship between BMD changes and fracture risk reduction with antiresorptive therapies is uncertain. Consideration of these results from clinical trials can contribute to clinical judgment in selecting the best treatment option for postmenopausal osteoporosis.     

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.     

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.     

Effective strategies to identify postmenopausal women at risk for osteoporosis

The early identification of postmenopausal women at risk of fracture, followed by effective therapeutic intervention, can substantially improve patient outcomes. Bone mineral density measurements and comprehensive risk assessment are essential components in deciding when to intervene with osteoporosis pharmacologic treatment. Simple, easy-to-administer risk assessment tools are available to assist the physician in identifying patients in need of further evaluation or treatment and aid in patient counseling. Furthermore, effective pharmacologic treatments are available that have demonstrated reductions in the risk of vertebral and nonvertebral fractures. Some therapies, such as selective estrogen receptor modulators and bisphosphonates, are able to act early in the course of treatment to reduce this risk of vertebral and nonvertebral fractures. The tools to reduce the underrecognition and undertreatment of osteoporosis are readily available. Primary care physicians are in a unique position to use these tools as part of a more proactive approach to fracture prevention in postmenopausal patients.     

The effects of teriparatide and bisphosphonates on new fractures in postmenopausal women with osteoporosis: A protocol for systematic review and meta-analysis

Background:To systematically evaluate the efficacy of teriparatide and bisphosphonates in preventing fractures in postmenopausal women with osteoporosis.Materials and methods:We performed a systematic search of PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) that compared teriparatide and bisphosphonates for osteoporosis treatment. Searches were performed without language restrictions and included studies from beginning of time to March 2019. Two authors independently screened and extracted the selected article. The quality of the included studies was evaluated using the Cochrane system evaluation method. Data were extracted and analysed using RevMan 5.2 software.Results:Nine RCTs were included for a total of 2990 postmenopausal women with osteoporosis. Of these, 1515 patients were treated with teriparatide and 1475 were treated with bisphosphonates. After pooling the data of 9 studies, there were significant differences between teriparatide and bisphosphonates [relative risk (RR): 0.61, 95% confidence interval (CI) (0.51, 0.74)] in the prevention of fractures according to different follow-up durations (P < .05), whatever alendronate [RR: 0.51, 95% CI (0.27, 0.95)] and other bisphosphonates [RR: 0.63, 95% CI (0.51, 0.77)]. In addition, we found significant differences between teriparatide and bisphosphonates in the prevention of vertebral fractures [RR: 0.47, 95% CI (0.35, 0.64)] and non-vertebral fractures [RR: 0.76, 95% CI (0.58,0.99)]. There were no significant differences in adverse effects between teriparatide and bisphosphonates [RR: 0.89, 95% CI (0.76, 1.03)].Conclusions:Based on the results of our meta-analysis, teriparatide was better than bisphosphonates in preventing fractures in postmenopausal women with osteoporosis both in the short-term and long-term follow-up periods. Teriparatide was superior to bisphosphonates in preventing vertebral and non-vertebral fractures. These drugs did not differ in terms of their adverse effects. More high-quality studies are needed to compare other factors such as costs and adverse reactions.     

Intravenous pamidronate compared with oral alendronate for the treatment of postmenopausal osteoporosis

There are several options for the treatment of osteoporosis in postmenopausal women. One of the options is treatment with bisphosphonates, which are very potent inhibitors of osteoclast-mediated bone resorption in vitro and in vivo. The most potent bisphosphonates have a nitrogen side chain and can be given orally or intravenously (i.v.). In the present study we evaluated retrospectively the effect of intravenously administered pamidronate (60 mg monthly) in comparison with oral alendronate with regard to bone mineral density (BMD) and vertebral fractures. A total of 117 consecutive women aged 46 to 78 years were seen in the outpatient clinic because of postmenopausal osteoporosis. Three-year follow-up data were available for a total of 45 patients treated with pamidronate i.v. and 40 patients on alendronate for at least three years. In the pamidronate group mean T score of lumbar spine BMD increased from -3.49 +/- 0.72 to -2.81 +/- 0.74 SDs after three years of treatment (p < 0.001). In the 40 patients treated with alendronate we observed an increase in the T score from -2.95 +/- 0.67 to -2.33 +/- 0.74 SDs (p < 0.001) during the same observation period. X-rays of the lumbar and thoracic spine were analysed from 25 patients in each group who had been treated for at least three years. At baseline nine patients (36%) in the pamidronate group had one or more vertebral fractures compared with seven patients (28%) in the alendronate group. After three years of treatment no new fractures were observed, while only three women in the pamidronate group and two in the alendronate group showed a deterioration of one or more pre-existing vertebral fractures (p = ns between groups). This retrospective analysis demonstrates that monthly intravenous administration of pamidronate is at least as good as alendronate taken orally in the treatment of women with postmenopausal osteoporosis, with regard to improvement of bone mineral density of the lumbar spine. We conclude that it is a good alternative for the more widely used oral bisphosphonates as it is effective, well-tolerated and easy to administer.     

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.     

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.     

Meta-analyses of therapies for postmenopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women

OBJECTIVE: To review the effect of alendronate on bone density and fractures in postmenopausal women. DATA SOURCE: We searched MEDLINE, EMBASE, Current Contents, and the Cochrane Controlled trials registry from 1980 to 1999, and we examined citations of relevant articles and proceedings of international meetings. STUDY SELECTION: We included 11 trials that randomized women to alendronate or placebo and measured bone density for at least 1 yr. DATA EXTRACTION: For each trial, three independent reviewers assessed the methodological quality and abstracted data. DATA SYNTHESIS: The pooled relative risk (RR) for vertebral fractures in patients given 5 mg or more of alendronate was 0.52 [95% confidence interval (CI), 0.43-0.65]. The RR of nonvertebral fractures in patients given 10 mg or more of alendronate was 0.51 (95% CI 0.38-0.69), an appreciably greater effect than for the 5 mg dose. We found a similar reduction in RR across nonvertebral fracture types; in particular, RR reductions for fractures traditionally thought to be "osteoporotic," such as hip and forearm, were very similar to RR reductions for "nonosteoporotic" fractures. Individual studies showed similar results, reflected in the P values of the test of heterogeneity (P = 0.99 for vertebral and 0.88 for nonvertebral fractures). Alendronate produced positive effects on the percentage change in bone density, which increased with both dose and time. After 3 yr of treatment with 10 mg of alendronate or more, the pooled estimate of the difference in percentage change between alendronate and placebo was 7.48% (95% CI 6.12-8.85) for the lumbar spine (2-3 yr), 5.60% (95% CI 4.80-6.39) for the hip (3-4 yr), 2.08% (95% CI 1.53-2.63) for the forearm (2-4 yr), and 2.73% (95% CI 2.27-3.20) for the total body (3 yr). Heterogeneity of the treatment effect of alendronate was not consistently explained by any of our a priori hypotheses; in particular, the effect was very similar in prevention and treatment studies. The pooled RR for discontinuing medication due to adverse effects for 5 mg or greater of alendronate was 1.15 (95% CI 0.93-1.42). The pooled RR for discontinuing medication due to gastro-intestinal (GI) side effects for 5 mg or greater was 1.03 (0.81-1.30, P = 0.83), and the pooled RR for GI adverse effects with continuation of medication was 1.03 (0.98 to 1.07) P = 0.23. CONCLUSIONS: Alendronate increases bone density in both early postmenopausal women and those with established osteoporosis while reducing the rate of vertebral fracture over 2-3 yr of treatment. Reductions in nonvertebral fractures are evident among postmenopausal women without prevalent fractures and have bone mineral density (BMD) levels below the World Health Organization threshold for osteoporosis. The impact on fractures appears consistent across all fracture types, casting doubt on traditional distinctions between osteoporotic and nonosteoporotic 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.     

Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents

Some, but not all, antiresorptive agents have been shown to reduce the risk of nonvertebral fractures. Agents that significantly reduced nonvertebral fracture risk also appear to produce larger mean increases in bone mineral density (BMD) and reductions in biochemical markers (BCM) of bone turnover, compared with other agents. To examine the extent to which increases in BMD and reductions in BCM during antiresorptive therapy are associated with reductions in risk of nonvertebral fractures, we performed a meta-analysis of all randomized, placebo-controlled trials of antiresorptive agents conducted in postmenopausal women with osteoporosis (i.e. prior vertebral fracture or low BMD) with available relevant data. A total of 18 such trials with usable data were identified, including a total of 2,415 women with incident nonvertebral fractures over 69,369 women-years of follow-up. Poisson regression was used to estimate the association between changes in BMD or BCM during the first year and overall reductions in risk of nonvertebral fractures (vs. the placebo group) across all trials. Larger increases in BMD and larger reductions in BCM were significantly associated with greater reductions in nonvertebral fracture risk. For example, each 1% increase in spine BMD at 1 yr was associated with an 8% reduction in nonvertebral fracture risk (P = 0.02). Mean BMD changes at the hip were smaller than at the spine, but the predicted net effect on fracture risk was the same; an agent that increases spine BMD by 6% at 1 yr reduces nonvertebral fracture risk by about 39%, and an agent that increases hip BMD by 3% at 1 yr reduces nonvertebral fracture risk by about 46%. The results also predict that a 70% reduction in resorption BCM would reduce risk by 40%, and a 50% reduction in formation BCM would reduce risk by 44%. It appears that either BMD or BCM changes are able to explain the effect of treatment, because a separate variable for treatment was not independently significant in any models. These data demonstrate that larger increases in BMD at both the spine and hip and larger reductions in both formation and resorption BCM are associated with greater reductions in the risk of nonvertebral fractures. Antiresorptive agents that do not produce large increases in BMD or large reductions in BCM do not appear to and would not be expected to decrease the risk of nonvertebral fractures.     

Vertebral fracture assessment in patients presenting with incident nonvertebral fractures

Background Patients with fractures should be prioritized for assessment for osteoporosis so that they can benefit from treatment for the secondary prevention of osteoporotic fractures. Assessment is seldom offered to patients with vertebral fractures because these fractures are typically not diagnosed. Vertebral fractures can be identified by vertebral fracture assessment (VFA) using current dual‐energy X‐ray absorptiometry (DXA) scanners. Objective The purpose of this study was to assess the prevalence of vertebral fractures, using VFA, in patients presenting with nonvertebral fractures and to assess whether this impacts on the management of these patients. Design A cohort study undertaken in 577 patients aged 50 years or over including 455 women, who presented with nonvertebral fractures and who underwent routine post‐fracture assessment by a Fracture Liaison Service (FLS). Measurements The numbers and severity of vertebral fractures were assessed in evaluable vertebrae from TV4 to LV4 in addition to bone mineral density (BMD) assessment. Results Using DXA, 76% of vertebrae could be evaluated by VFA. Of the men and women with nonvertebral fractures, 19–20% had at least one vertebral fracture. The prevalence ranged from 6% in men with humeral fractures to 32% among women with hip fractures. The prevalence of vertebral fractures correlated most strongly with increasing age and with severity of reduction of BMD. Using local treatment protocols, VFA would result in only 3% more patients receiving treatment for fracture secondary prevention. Conclusions In patients with nonvertebral fractures, VFA identifies a substantial burden of prevalent vertebral fractures that have not hitherto been recognized. Nevertheless, VFA seldom influences the need for treatment for fracture secondary prevention after a nonvertebral fracture.     

Selective estrogen-receptor modulators

Tamoxifen is useful for adjuvant treatment of breast cancer and in some women for the prevention of breast cancer. The risk-benefit ratio in regard to the skeleton and perhaps other organ systems may very well be different for postmenopausal versus premenopausal women. In postmenopausal women, tamoxifen (20 mg/d) increased BMD in the spine and perhaps the hip; however, the effect on fracture risk is unclear. Therefore, for postmenopausal women with osteoporosis, consideration should be given to the addition of an agent that is shown to have efficacy against fractures (such as bisphosphonates), even while these women are on tamoxifen. For women at only modest or moderate risk, with bone density above the osteoporosis range (T score above -2.5) and no major fracture history, tamoxifen is probably adequate for 5 years of use. Potentially serious adverse effects include venous thromboembolism, uterine cancer, benign uterine disease, and cataracts. Raloxifene (60 mg/d) protects against vertebral fractures over 4 years in women with osteoporosis, produces small increases in bone mass of the spine, hip, and total body, and reduces bone turnover in postmenopausal women with or without osteoporosis. No significant effect has yet been demonstrated on nonvertebral fractures after 4 years of treatment. Raloxifene has the additional benefit of substantially reducing the risk of ER-positive invasive breast cancer and does not increase the risk of uterine disease. Raloxifene increases the risk of venous thromboembolic disease to the same degree as tamoxifen and estrogen. Therefore, SERMS and estrogens are generally contraindicated in women with a previous history of venous thromboembolism or those who are at significantly increased risk. Raloxifene is probably most useful in women who have osteoporosis (T score = -2.5) or who are at risk (T score less than -1.5 with clinical risk factors) in the middle menopausal period (age 55-65) or in the early menopausal period in women who have no significant hot flashes. At this stage in life, vertebral fractures are common, but hip fractures are not. Therefore, women who take raloxifene can expect a reduction in the likelihood of having a vertebral fracture, and possibly breast cancer. The lack of definitive efficacy against hip fracture is not a major deterrent to use of this agent in this age group because hip fracture risk is very low. Raloxifene might not be the treatment of choice for elderly women who are at particularly high risk of hip fracture.     

Sustained vertebral fracture risk reduction after withdrawal of teriparatide in postmenopausal women with osteoporosis

BACKGROUND: Teriparatide (recombinant human parathyroid hormone [1-34]) reduces fracture risk in postmenopausal women with osteoporosis. We assessed the safety and incidence of new vertebral fractures after withdrawal of teriparatide. METHODS: This study is a follow-up to the Fracture Prevention Trial (FPT), a randomized, placebo-controlled study of postmenopausal women with osteoporosis treated with teriparatide (20 or 40 microg) once daily for a mean of 18 months. More than 90% of the women remaining at the end of the FPT continued into the follow-up study (n = 1262). Patients and investigators were unblinded to original treatment group assignment. Women were treated according to standard clinical practice, including elective use of osteoporosis drugs. New vertebral fractures were determined by semiquantitative scoring of lateral thoracic lumbar spine radiographs 18 months after the end of the FPT. RESULTS: During the follow-up study, the reduction in fracture risk associated with previous treatment with teriparatide, 20 and 40 microg, was 41% (P = .004) and 45% (P = .001), respectively, vs placebo. The absolute reduction from the FPT baseline to the 18-month follow-up visit was 13% for both doses. Osteoporosis drugs were used by 47% of women during follow-up, with greater use in the former placebo group (P = .04); nevertheless, persistent fracture protection of previous teriparatide therapy was evident. Post hoc analysis also suggests that teriparatide treatment substantially reduced the increased risk of subsequent fracture in women who sustained a fracture during the FPT (P = .05). CONCLUSION: Vertebral fracture risk reduction by teriparatide administration persists for at least 18 months after discontinuation of therapy.