Prevention Of Nonvertebral Fractures Research Articles

Clinical efficacy of denosumab, teriparatide, and oral bisphosphonates in the prevention of glucocorticoid-induced osteoporosis: a systematic review and meta-analysis

BackgroundContinuous use of glucocorticoids (GCs) has become the primary cause of secondary osteoporosis. Bisphosphonate drugs were given priority over denosumab and teriparatide in the 2017 American College of Rheumatology (ACR) guidelines but have a series of shortcomings. This study aims to explore the efficacy and safety of teriparatide and denosumab compared with those of oral bisphosphonate drugs.MethodsWe systematically searched studies included in the PubMed, Web of Science, Embase, and Cochrane library databases and included randomized controlled trials that compared denosumab or teriparatide with oral bisphosphonates. Risk estimates were pooled using both fixed and random effects models.ResultsWe included 10 studies involving 2923 patients who received GCs for meta-analysis, including two drug base analyses and four sensitivity analyses. Teriparatide and denosumab were superior to bisphosphonates in increasing the bone mineral density (BMD) of the lumbar vertebrae [teriparatide: mean difference [MD] 3.98%, 95% confidence interval [CI] 3.61–4.175%, P = 0.00001; denosumab: MD 2.07%, 95% CI 0.97–3.17%, P = 0.0002]. Teriparatide was superior to bisphosphonates in preventing vertebral fractures and increasing hip BMD [MD 2.39%, 95% CI 1.47–3.32, P < 0.00001]. There was no statistically significant difference between serious adverse events, adverse events, and nonvertebral fracture prevention drugs.ConclusionsTeriparatide and denosumab exhibited similar or even superior characteristics to bisphosphonates in our study, and we believe that they have the potential to become first-line GC-induced osteoporosis treatments, especially for patients who have previously received other anti-osteoporotic drugs with poor efficacy.

Comparative effectiveness and cardiovascular safety of abaloparatide and teriparatide in postmenopausal women new to anabolic therapy: A US administrative claims database study

Mini abstractReal-world evidence on the comparative effectiveness and safety of abaloparatide versus teriparatide in women with osteoporosis may help inform treatment decisions. Following 18 months of treatment, abaloparatide was comparable to teriparatide for prevention of nonvertebral fractures, resulted in a 22% risk reduction for hip fractures, and demonstrated similar cardiovascular safety.SummaryOsteoporotic fracture risk can be reduced with anabolic or antiresorptive medications. In addition to efficacy and safety data from controlled clinical trials, real-world evidence on comparative effectiveness and safety may help inform treatment decisions.IntroductionThe real-world effectiveness of abaloparatide versus teriparatide on nonvertebral fracture (NVF) incidence and cardiovascular safety during the 19-month period after treatment initiation were evaluated (NCT04974723).MethodsAnonymized US patient claims data from Symphony Health, Integrated Dataverse (IDV)®, May 1, 2017 to July 31, 2019, included women aged ≥ 50 years with ≥ 1 prescription of abaloparatide or teriparatide and no prior anabolic therapy. Most were enrolled in commercial and Medicare health plans. Index was the date of the initial prescription dispensed during the identification period. In 1:1 propensity score matched cohorts, time to first NVF following index date, major adverse cardiovascular events (MACE), and MACE + heart failure (HF) were compared between cohorts using a Cox proportional hazards model.ResultsPropensity score matching yielded 11,616 patients per cohort. Overall median age (interquartile range) was 67 (61, 75) years, and 25.6% had a fracture history. Over 19 months, 335 patients on abaloparatide and 375 on teriparatide had a NVF (hazard ratio [95% confidence interval]: 0.89 [0.77, 1.03]), and 121 and 154 patients, respectively, had a hip fracture [HR (95% CI): 0.78 (0.62, 1.00)]. The MACE and MACE + HF rates were similar between cohorts.ConclusionsFollowing 18 months of treatment, abaloparatide was comparable to teriparatide for prevention of NVF and similar cardiovascular safety was demonstrated between cohorts.

Bones and the sex hormones

Sex hormones act in multiple ways to maintain a strong skeleton. In men, estrogen regulates cortical bone turnover, but testosterone maintains trabecular turnover. In normal men, sex hormone-binding protein is an independent risk factor for fractures. This led Aleksova and colleagues to measure the sex hormones and their binding protein in men receiving dialysis. Both higher sex hormone-binding globulin and higher total testosterone were associated with prevalent nonvertebral fractures, adding another layer of complexity to renal osteodystrophy.

Geography of Fracture Incidence in Postmenopausal Women with Osteoporosis Treated with Abaloparatide

Geographic heterogeneity has been observed in fracture risk and efficacy of therapeutic intervention in postmenopausal osteoporosis. The objectives of these analyses were to assess across geographic and ethnic subgroups the heterogeneity of fracture incidence and baseline risk, and consistency of effect of abaloparatide-SC vs placebo on fracture risk reduction in the 18-month, phase 3, multinational, ACTIVE randomized controlled trial. Prespecified exploratory analyses of geographic subgroups (North America, South America, Europe, Asia) and post hoc analyses of ethnic subgroups (Hispanic or Latino, other) of postmenopausal women with osteoporosis enrolled in the abaloparatide-SC and placebo cohorts (n = 1645) were performed. Country-specific FRAX models were used to calculate 10-year absolute fracture risks. Relative risk reductions for vertebral fractures and hazard ratios for non-vertebral, clinical, and major osteoporotic fractures were calculated. Forest plots were constructed to assess treatment-by-subgroup interactions for each geographic region and ethnicity. Baseline prevalence of vertebral fractures was similar across geographies; baseline prevalence of non-vertebral fractures was more variable. Ten-year major osteoporosis fracture and hip fracture risks were variable across and within regions. The effects of abaloparatide-SC on reducing the risk of vertebral, non-vertebral, clinical, and major osteoporotic fractures were similar across regions, and for Hispanic or Latino vs other ethnicities. A limitation was the limited power to detect interactions with few events. In conclusion, despite geographic variability in fracture incidence and risk at baseline, no differences were detected in the effects of abaloparatide-SC in reducing vertebral, non-vertebral, clinical, and major osteoporotic fracture risk across assessed geographic regions and ethnicities.

Lower serum P1NP/βCTX ratio and hypoalbuminemia are independently associated with osteoporotic nonvertebral fractures in older adults.

PurposeTo estimate the discriminative value of serum P1NP/βCTX ratio and albumin levels in hospitalized orthogeriatric patients with and without nonvertebral fractures.MethodsIn 1,239 orthogeriatric patients (mean age 78.1±9.52 years, 69.1% women) including 854 (68.9%) with osteoporotic nonvertebral fractures (455 [36.7%] with hip fracture [HF]) and 385 (31.1%) without fractures, markers of bone formation (procollagen type 1 N-terminal propeptide [P1NP], osteocalcin [OC], and bone resorption (beta-C-terminal cross-linking telopeptide of type 1 collagen [βCTX]), indices of mineral metabolism, and parameters of liver and renal functions were assessed; data on clinical and laboratory characteristics were collected prospectively.ResultsBoth lower serum P1NP/βCTX ratio and albumin concentration (as continuous or categorical variables) were independently associated with fracture presence in multivariate logistic regressions. Compared with the highest P1NP/βCTX tertile, the prevalence of HF, after adjustment for multiple covariates, was 3-fold higher in the lowest tertile and 1.5 times higher in the middle tertile; presence of any fracture was 2.3- and 1.6-fold higher, respectively; patients with albumin levels in the lowest tertile had multivariate odds ratio (OR) of 4.6 for HF and 2.8 for any fracture, in the middle tertile the ORs were 2.2 and 1.3, respectively. The P1NP/βCTX <100.0 (median) and hypoalbuminemia (<33 g/L) demonstrated area under the curve values for HF of 0.802 and 0.806, respectively, and for any fractures of 0.711 and 0.706, respectively. When both characteristics were combined, the ORs for HF or any fracture, compared with the nonfractured group, were 7.8 and 3.2, respectively, with an accuracy of 79.6% and 71.6%, respectively.ConclusionsIn orthogeriatric patients, both serum P1NP/βCTX ratio and albumin levels demonstrated an inverse dose–effect relationship with the prevalence of nonvertebral fractures and independently indicated fracture presence with acceptable discriminatory power. Lower P1NP/βCTX (<100) and hypoalbuminemia could be useful simple additive prognostic tools for fracture risk stratification in the elderly.

Ten-year incidences of self-reported non-vertebral fractures in Japanese patients with rheumatoid arthritis: discrepancy between disease activity control and the incidence of non-vertebral fracture.

Despite improvements in rheumatoid arthritis disease activity of in the past 10 years, the incidence of self-reported non-vertebral fractures did not decrease in our cohort of 9,987 patients. This study may indicate that osteoporosis treatment and non-vertebral fracture prevention remain important regardless of the rheumatoid arthritis disease activity. Although rheumatoid arthritis (RA) is a risk factor for osteoporosis and fractures, few studies have described the association between disease activity and the fracture incidence in patients with RA. This study aimed to investigate changes in the non-vertebral fracture incidence between 2001 and 2010 in our Institute of Rheumatology Rheumatoid Arthritis (IORRA) cohort. The IORRA is a prospective observational cohort study of Japanese RA patients. A total of 9,987 patients with RA were enrolled in this cohort from 2000 to 2010. The clinical parameter and non-vertebral fracture occurrence data were collected biannually through self-reported questionnaires. Incidences of self-reported non-vertebral fractures were also analyzed via standardization according to gender, age, and disease activity during each 2-year period. From 2001 to 2010, the percentage of patients with 28-joint disease activity score remission increased from 7.8 to 39.7%, prednisolone intake decreased from 51.4 to 41.3%, and bisphosphonate intake increased from 5.0 to 23.4%. The non-vertebral fracture incidence rates were 24.6/1,000 person-years in 2001 and 35.5/1,000 person-years in 2010, with no apparent change even after standardization. The overall non-vertebral fracture incidence was significantly higher in the autumn/winter than in the spring/summer (p = 0.02). Despite improvements in disease activity and functional disability, the non-vertebral fracture incidence exhibited no apparent change between 2001 and 2010 in our patients with RA. Osteoporosis treatment and non-vertebral fracture prevention remain important regardless of the disease control in patients with RA.

Increased low-density lipoprotein cholesterol level is associated with non-vertebral fractures in postmenopausal women.

Although a high serum low-density lipoprotein cholesterol (LDL-C) level is an established risk factor for atherosclerosis, it is unclear whether it is associated with osteoporosis. In this study, the associations between the serum LDL-C level and bone mineral density (BMD), bone metabolic markers, and the presence of prevalent vertebral or non-vertebral fractures were examined. A total of 211 healthy postmenopausal women (age range, 46-80 years) who visited a community health center were recruited consecutively. Their radiographic and biochemical characteristics were collected. Prevalent vertebral and non-vertebral fractures were found in 49 (23.2%) and 36 (17.1%) subjects, respectively. Simple regression analyses showed that the serum LDL-C level was not significantly correlated with lumbar or femoral BMD or serum levels of total amino-terminal propeptide of type I collagen (PINP) or carboxy-terminal telopeptide of type I collagen (CTX). Logistic regression analyses adjusted for age and BMI showed that the increased serum LDL-C level was selected as an index affecting the presence of prevalent non-vertebral fractures, but not vertebral fractures. This result was still significant after additional adjustments for years since menopause, physical activity, previous cardiovascular events, bone markers, BMD, serum Ca, P, Cr, 25(OH)D, grip strength, tandem gait test, and use of drugs for hyperlipidemia [odds ratio 1.76 (1.13-2.73), p=0.012]. These findings suggest that a high serum LDL-C level may be a risk factor for prevalent non-vertebral fragility fractures independent of bone turnover, bone mass, vitamin D insufficiency, or frail status in postmenopausal women, and that it may be detrimental to bone, as well as blood vessels.

Bazedoxifene versus Oral Bisphosphonates for the Prevention of Nonvertebral Fractures in Postmenopausal Women with Osteoporosis at Higher Risk of Fracture: A Network Meta-Analysis

ObjectiveTo compare the efficacy of bazedoxifene and oral bisphosphonates for the prevention of nonvertebral fractures (NVFs) in women with higher risk of postmenopausal osteoporosis (i.e., the Fracture Risk Assessment Tool [FRAX] score ≥ 20%), based on currently available evidence from randomized controlled trials. MethodsRandomized controlled trials evaluating the NVF relative risk reduction (RRR) with oral bisphosphonates or bazedoxifene were identified by a systematic literature review and combined by means of a network meta-analysis. A subgroup of patients with a FRAX score of 20% or more in the bazedoxifene phase III osteoporosis study was selected as the population of interest on the basis of the bazedoxifene label. In one analysis (analysis 1), the placebo response of the subgroup with a FRAX score of 20% or more was the benchmark to select comparable bisphosphonate trials. Additional analyses incorporated the aggregate data from the bisphosphonate trials with all the FRAX subgroups (analysis 2) or with the individual patient data from the bazedoxifene trial (analysis 3). ResultsNine identified bisphosphonate trials (alendronate, ibandronate, risedronate; N = 23,440 patients) with a similar placebo response as observed for the subgroup of high risk patients in the bazedoxifene trial were included in analysis 1. The results of the network meta-analysis of this study set suggest that bazedoxifene is expected to have an RRR of 0.43 (95% credible interval [CrI] −0.19 to 0.72) versus alendronate, 0.58 (95% CrI 0.05–0.81) versus ibandronate, and 0.39 (95% CrI −0.29 to 0.70) versus risedronate. Analyses in which treatment effects with bisphosphonates were projected to a population with a FRAX score of 20% or more with meta-regression approaches (analysis 2 and analysis 3) provide similar findings. ConclusionBased on an indirect comparison of randomized trials, bazedoxifene is expected to have at least a comparable RRR of NVF as alendronate, ibandronate, and risedronate in women with higher risk of postmenopausal osteoporosis.

Prevention of incident fractures in patients with prevalent fragility fractures: Current and future approaches.

Fragility fractures are a significant, independent risk factor for new fractures, but treatment uptake in subjects with prevalent fractures is disappointing. We addressed the question of the efficacy of pharmacological interventions in reducing the risk of incident fractures in patients with prevalent fragility fractures. For this, we reviewed randomised controlled trials (RCTs), pre-planned and post-hoc analyses of RCTs of approved agents for the treatment of osteoporosis. Results showed that a number of agents decrease the risk of incident vertebral and nonvertebral fractures in subjects with prevalent vertebral fractures, justifying the recommendation of treating such patients independently of the level of bone mineral density (BMD). By contrast, the evidence of antifracture efficacy of these agents in patients with prevalent nonvertebral fractures is limited. Advances in our understanding of the regulation of bone metabolism at the molecular level have identified targets for the development of new therapeutics for osteoporosis, some of which are currently in phase 3 clinical development.

Comparative Effectiveness of Osteoporosis Drugs in Preventing Secondary Nonvertebral Fractures in Taiwanese Women

The evidence for relative effectiveness of osteoporosis drugs in secondary prevention of nonvertebral fractures was unclear and could not be extrapolated to the Asian population. The objective of the study was to compare the relative effectiveness of different classes of osteoporosis drugs in secondary prevention of nonvertebral fractures in Taiwanese women. This was a retrospective cohort study from 2003 to 2007, with up to 6 years of follow-up. The study included enrollees in Taiwan National Health Insurance. Patients older than 50 years, with vertebral/hip fracture and were new to osteoporosis therapy, were recruited. Patients were classified into the alendronate, calcitonin, or raloxifene group, according to their exposure after follow-up. The primary outcome of our study was the risk of incident nonvertebral fracture (hip, humerus, or radius fractures). A multivariate Cox proportional hazard model adjusted for fracture risk factors was used to compare the relative fracture risk among three treatment groups under on-treatment scenarios. Propensity score-matched hazard ratios were examined, and interactions between fracture incidence and patients' compliance were investigated as well. There were 19 840, 9534, and 25 483 patients in the alendronate, raloxifene, and calcitonin groups, respectively. The fracture rates were highest in calcitonin recipients (4.57 per 100 person-years), followed by raloxifene and alendronate. Results from Cox analyses showed raloxifene (hazard ratio 1.47; 95% confidence interval 1.29-1.67) and calcitonin (hazard ratio 1.51; 95% confidence interval 1.29-1.75) had higher nonvertebral fracture risks as compared with alendronate. The risk differences were more pronounced in compliant patients. We found alendronate users had the lowest secondary nonvertebral fracture risk, as compared with raloxifene and calcitonin users. Consistent results were found in a series of sensitivity analyses.

THU0400 Effect of Systematic Implementation of Vertebral Fracture Assessment (VFA) in Patients with a Recent Non-Vertebral Fracture

BackgroundPatients presenting at a fracture liaison service (FLS) with a prevalent non-vertebral fracture have a high prevalence of vertebral fractures. However, the diagnosis of a vertebral fracture can only be...

Risk of Hip Fracture in Community-dwelling and Institutionalized Osteoporotic Patients: A 3-year Study

Summary Background and aims It has been previously suggested that the incidence of hip fracture is higher among people living in nursing homes than among community-dwelling people. However, it is not clear whether this is a consequence of nursing home residency or of the greater age of the residents. We have examined the relationship between the place of residence and hip fracture incidence, in a prospective 3-year study. Methods Women from nine countries included in this study were part of the placebo group of a randomized controlled trial having assessed the long-term effect of a new antiosteoporotic drug. All women were osteoporotic and received placebo and vitamin D during the 3 years of follow-up. All the institutionalized (nursing home, medical house) women ( n = 217) were included in this post hoc analysis and three noninstitutionalized age- and country-matched controls were included ( n = 651). Results The mean (and standard deviation) age of the patients was 80.4 (5.6) years in the institutionalized women and 80.2 (5.8) years in the noninstitutionalized women ( p = 0.87). After 3 years of follow-up, 37 fractures occurred: 12 (5.5%) in institutionalized women and 25 (3.8%) in noninstitutionalized women. The difference between the two groups was not statistically significant ( p = 0.29). After controlling for age, body mass index, femoral neck bone mineral density and prevalent nonvertebral fracture, the residence status of the patient (institutionalized vs. noninstitutionalized) was not significantly associated with hip fracture incidence ( p = 0.63). Conclusion We suggest that living in an institutionalized place is not an independent risk factor for hip fracture for osteoporotic women receiving calcium and vitamin D.

Prevalence and Risk Factors for Non-Vertebral Fractures in Patients Receiving Oral Glucocorticoids

Background: Glucocorticoids taken orally increase the risk of fractures. It has been noted that a dose as low as 2.5 mg/day increases the risk of vertebral fracture. What is less clear is the possible influence of other risk factors for osteoporosis on the presence of non-vertebral fractures in patients taking glucocorticoids. Objectives: A cross-sectional study, performed on 513 men and women from Spain, who were taking at least 7.5 mg/day of oral prednisone for a minimum of 3 months. A questionnaire was developed, through which information on risk factors was collected. Patients and Methods: A cross-sectional study, performed on 513 men and women from Spain, who were taking at least 7.5 mg/day of oral prednisone for a minimum of 3 months. A questionnaire was developed, through which information on risk factors was collected. Results: 28.3% of the patients who were taking glucocorticoids at a daily oral dose of 7.5 mg/day for a minimum of 3 months had suffered at least one non-vertebral fracture. The risk increased with age, the number of months the glucocorticoids had been taken, the presence of falls in the last year and, above all, with a maternal history of hip fracture. Conclusions: In patients taking oral glucocorticoids for over 3 months at doses higher than 7.5 mg/day of prednisone or equivalent, the prevalence of non-vertebral fractures was 28.3%. Some risk factors associated with the presence of these fractures were identified. The duration of glucocorticoid use appears to be more strongly related to the presence of non-vertebral fractures than the daily dose.

Clinical utility of risedronate in postmenopausal osteoporosis: patient considerations with delayed-release formulation.

Bisphosphonates are the most widely prescribed treatment for postmenopausal osteoporosis, secondary osteoporosis, and male osteoporosis. Notwithstanding their high effectiveness and favorable safety profile, the adherence to bisphosphonate treatment remains low. Different treatment strategies aim to improve the clinical effectiveness of bisphosphonate therapy. This review paper assesses the clinical utility of oral intermittent risedronate in the treatment of postmenopausal osteoporosis. The new delayed-release risedronate formulation is a safer and easy to use alternative to other risedronate therapy. Oral risedronate, a potent nitrogen-containing bisphosphonate, has been extensively studied using daily regimens. A new intermittent (weekly) dosing regimen confirmed its clinical effectiveness in relation to vertebral and nonvertebral fracture prevention. The absence of significant differences in the incidence of adverse effects confirmed the favorable tolerability of the weekly dosage. In efforts to improve patient adherence to treatment, an innovative, delayed-release formulation of risedronate, which ensures adequate bioavailability of the active compound when taken with food, was introduced. The once-weekly delayed-release formulation of risedronate proved to be noninferior to the daily dosage of risedronate in terms of bone mineral density and markers of bone turnover. In addition, the incidence of new morphometric vertebral fractures was comparable in both treatment regimens. The new delayed-release formulation of risedronate showed a favorable safety profile. Delayed-release risedronate is a promising, new, effective, and convenient alternative to current bisphosphonate treatments. It appears to allow better patient adherence to antiresorptive treatment.

Mixed-treatment comparison of anabolic (teriparatide and PTH 1-84) therapies in women with severe osteoporosis

Purpose:The recent development of compounds with anabolic action on bone have increased the range of therapeutic options for the treatment of osteoporosis and the prevention of fractures. Two major PTH analogs, the synthetic full-length 1-84 PTH molecule and the recombinant 1-34 N-terminal fragment (teriparatide), are available for the treatment of osteoporosis in many countries. There have bee no comparative trials on the bone anabolic effects of these compounds.Materials and methods:In this study we applied a mixed treatment comparison (MTC) to compare the efficacy of teriparatide versus PTH 1-84 for the prevention of vertebral and non-vertebral fractures in women with severe osteoporosis. With this approach the relative treatment effect of one intervention over another can be obtained in the absence of head-to-head comparison. Among the candidate papers selected for analysis, two randomized controlled trials investigating the effects of teriparatide and PTH 1-84 met the selection criteria and underwent MTC analysis.Results:Based on a fixed-effect MTC model analysis of data from two RCTs, teriparatide (20 µg/day) showed a 70% and 94% probability of being the best treatment for the prevention of vertebral and non-vertebral fractures, respectively. Together with a lack of statistical significance, this study has additional limitations. Some differences in trial procedures and populations exist; another limitation concerns the impossibility of carrying out a randomized-effect model MTC, due to sample exiguity. Furthermore, in order to consider unknown or unmeasured differences of covariates across trials, a random-effects approach would be preferred in order to assess the presence of heterogeneity across comparisons. In contrast, in our analysis a fixed-effect MTC model only was used.Conclusions:Teriparatide is expected to provide a greater efficacy over PTH 1-84 with both vertebral and non-vertebral fracture prevention in postmenopausal women with severe osteoporosis.

Evidence of Sustained Vertebral and Nonvertebral Antifracture Efficacy with Ibandronate Therapy: A Systematic Review

The antifracture efficacy of ibandronate at vertebral and nonvertebral sites was assessed. A literature review of randomized phase III clinical trials, meta-analyses or observational studies that reported fracture endpoints or surrogate markers, and compared ibandronate with placebo or an active comparator. In a phase III study, 2.5 mg daily oral ibandronate reduced the incidence of new vertebral fractures versus placebo and the relative risk reduction (RRR) was sustained over 3 years (62%; p = 0.0001). In two bridging studies, oral ibandronate 150 mg once monthly and 3 mg quarterly intravenous (i.v.) were superior to oral 2.5 mg daily in producing bone mineral density (BMD) increases at all sites over 2 years (p < 0.05). These improvements were sustained over 5 years. In meta-analyses of pivotal ibandronate studies, doses equivalent to annual cumulative exposure (ACE) ≥ 10.8 mg (including 150 mg once monthly and 3 mg quarterly i.v.) significantly reduced the incidence of nonvertebral fractures versus placebo or ACE 5.5 mg (2.5 mg daily) (RRR 29.9% and 38%, respectively; p < 0.05). Therefore, prevention of nonvertebral fractures was found in all patients with the commercially available highest doses, and not only in high-risk patients as observed in randomized clinical trials with lower doses. Finally, a 12-month, observational study of claims databases reported comparable rates of nonvertebral fractures and a statistically significantly lower rate of vertebral fractures (p < 0.01) with ibandronate versus weekly bisphosphonates. A large body of evidence suggests that ibandronate has sustained vertebral and nonvertebral antifracture efficacy in women with postmenopausal osteoporosis.

Lasofoxifene, from the preclinical drug discovery to the treatment of postmenopausal osteoporosis

Introduction: Estrogen replacement is traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women as well as for the management of menopausal symptoms. However, estrogen may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter is considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remains uncertain. Hence, there is a need for additional effective medications to prevent fractures in postmenopausal women that provide additional benefits.Areas covered: This article reviews lasofoxifene, a new SERM for the treatment of postmenopausal osteoporosis and urogenital atrophy. The medical literature is reviewed for articles containing the terms ‘lasofoxifene’ and ‘SERMs’. The manuscript reviews the discovery strategies and preclinical development of lasofoxifene as well as its clinical development.Expert opinion: Recent evidence suggests that the ideal SERM profile for one patient may be far from ideal for another. Thus, it could be favorable that different SERMs may be available in the future, each with a somewhat different profile that may be rationally applied to various patients with a spectrum of needs. In this context, lasofoxifene, while retaining some of the adverse effects of other SERMs (i.e., hot flushes and risk of venous thromboembolic events), may offer an improved skeletal efficacy over raloxifene, addressing other postmenopausal conditions, including reduction in breast cancer risk and treatment of vaginal atrophy.

Efficacy of vitamin D3 supplementation in preventing fractures in elderly women: A meta-analysis

Background:The efficacy of vitamin D3 in preventing fractures and falls has been explored in a number of clinical trials. However, recent evidence revealed new questions about the adequate doses of vitamin D3 supplementation and its efficacy in fracture prevention independent of calcium supplements for various types of fractures.Objective:To conduct a meta-analysis to estimate the effectiveness of 800 IU daily vitamin D3 supplementation for increasing bone mineral density (BMD) and preventing fractures in postmenopausal women.Methods:Medline and EMBASE were searched for controlled trials comparing the effectiveness of cholecalciferol (vitamin D3) against placebo with or without background calcium supplementation in the treatment of postmenopausal women.Results:Eight controlled trials evaluating the effect of vitamin D3 supplementation with or without calcium were assessed. Of 12 658 women included in a Bayesian meta-analysis, 6089 received vitamin D3 (with or without calcium) and 6569 received placebo (with or without calcium). Compared to placebo, vitamin D3 with calcium supplementation showed beneficial effects on the incidence of non-vertebral (odds ratio [OR] 0.77, 95% credibility limit [CL] 0.6–0.93) and hip (OR 0.70, 95% CL 0.53–0.90) fractures, while the effects on non-vertebral-non-hip fractures (OR 0.84, 95% CL 0.67–1.04) % point increase) were associated with more uncertainty. Vitamin D3 supplementation showed a 70% probability of being a better treatment than placebo for the prevention of non-vertebral fractures, hip fractures, and non-vertebral, non-hip fractures. Compared to calcium supplementation, vitamin D3 plus calcium reduced non-vertebral fractures (OR 0.68, 95% CL 0.43–1.01) and non-vertebral, non-hip fractures (OR 0.64, 95% CL 0.38–0.99), but did not reduce hip fractures (OR 1.03, 95% CL 0.39–2.25). Key limitations to this analysis include a small number of studies and heterogeneity in the study populations.Conclusions:This meta-analysis supports the use of vitamin D3 of 800 IU daily to reduce the incidence of osteoporotic non-vertebral, hip, and non-vertebral-non-hip fractures in elderly women. Vitamin D3 with calcium appears to achieve benefits above those attained with calcium supplementation alone for non-vertebral and non-vertebral-non-hip fractures.

Selective estrogen receptor modulator (SERM) for the treatment of osteoporosis in postmenopausal women: focus on lasofoxifene.

Selective estrogen receptor modulators (SERMs) represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This article reviews lasofoxifene, a new-generation SERM that has completed phase III development for the prevention and treatment of osteoporosis in postmenopausal women. Consistent with preclinical observations, this new SERM demonstrated improved skeletal efficacy over raloxifene and at an oral dose of 0.5 mg/day was effective in the prevention of both vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. At the same dosage, lasofoxifene treatment also reduced estrogen receptor-positive breast cancer risk and the occurrence of vaginal atrophy, but, like the other SERMs, was associated with hot flushes and an increased risk of venous thromboembolic events. With its increased efficacy on the prevention of nonvertebral fractures than current available SERMs and its positive effects on the vagina, this new compound may represent an alternative and cost-effective therapy for osteoporosis in postmenopausal women.

Serum Lipids and Bone Metabolism in Spanish Men: The Camargo Cohort Study

There is growing evidence of a link between lipid and bone metabolism, although data on this association in European men are scarce. This cross-sectional study from a community-based prospective cohort aims to explore the association of serum lipids with different aspects of bone metabolism in Spanish men. Demographic and anthropometric measurements, biochemical parameters including serum lipids, bone remodelling markers and calciotropic hormones, bone mineral density (BMD) assessed by dual X-ray absorptiometry and heel quantitative ultrasound, and prevalent vertebral and non-vertebral fractures, were evaluated in 289 men. Calciotropic hormones or bone markers were not associated with serum lipids. Serum total (TC) and LDL cholesterol, as well as LDL/HDL ratio were positively correlated to BMD at lumbar spine and hip. No significant correlation was noted for triglycerides or HDL. We observed a positive association between triglycerides, LDL/HDL ratio and BUA, and between TC/HDL ratio and both, QUI and BUA. BMD at the femoral neck and total hip was significantly higher in men with hypercholesterolemia after controlling for all the covariates (p=0.007). We did not observe any association between serum lipids and prevalent vertebral fractures. However, we found that TC (p=0.03) and LDL (p=0.04) were lower in subjects with non-vertebral fractures. In conclusion, we have found that a more unfavorable lipid profile (mainly higher LDL-C levels) is associated with higher BMD at lumbar spine and hip in Spanish men. Moreover, we did not observe any association between hypercholesterolemia and prevalent vertebral fractures, but we found lower serum TC and LDL-C levels in men with prevalent non-vertebral fractures.