Effects of 24 months of treatment with romosozumab followed by 12 months of denosumab or placebo in postmenopausal women with low bone mineral density : a randomized, double-blind, phase 2, parallel group study

Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased bone mineral density (BMD) in postmenopausal women with low BMD (NCT00896532). Herein, we report the study extension evaluating 24 months of treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women aged 55 to 85 years with a lumbar spine (LS), total hip (TH), or femoral neck T-score =-3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70 mg, 140 mg, 210 mg monthly [QM]; 140 mg Q3M; 210 mg Q3M) for 24 months, or open-label alendronate for 12 months followed by romosozumab 140 mg QM for 12 months. Eligible participants were then rerandomized 1:1 within original treatment groups to placebo or denosumab 60 mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210 mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210 mg QM, bone formation marker P1NP initially increased after treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; bone resorption marker beta-CTX rapidly decreased after treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, whereas after transition to placebo, P1NP returned to baseline and beta-CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of romosozumab are reversible upon discontinuation and further augmented by denosumab

Goal-Directed Treatment for Osteoporosis: A Progress Report from the ASBMR-NOF Working Group on Goal-Directed Treatment for Osteoporosis.

The American Society for Bone and Mineral Research and the United States National Osteoporosis Foundation (NOF) formed a working group to develop principles of goal-directed treatment and identify gaps that need to be filled to implement this approach. With goal-directed treatment, a treatment goal would first be established choice of treatment determined by the probability of achieving that goal. Goals of treatment would be freedom from fracture, a T-score > -2.5, which is above the NOF threshold for initiating treatment, or achievement of an estimated risk level below the threshold for initiating treatment. Progress toward reaching the patient's goal would be periodically and systematically assessed by estimating the patient's compliance with treatment, reviewing fracture history, repeating vertebral imaging when indicated, and repeating measurement of bone mineral density (BMD). Using these data, a decision would be made to stop, continue, or change therapy. Some of these approaches can now be applied to clinical practice. However, the application of goal-directed treatment cannot be fully achieved until medications are available that provide greater increases in BMD and greater reduction in fracture risk than those that are currently approved; only then can patients with very high fracture risk and very low BMD achieve such goals. Furthermore, assessing future fracture risk in patients on treatment requires a new assessment tool that accurately captures the change in fracture risk associated with treatment and should also be sensitive to the importance of recent fractures as predictors of imminent fracture risk. Lastly, evidence is needed to confirm that selecting and switching treatments to achieve goals reduces fracture risk more effectively than current standard care. This article is protected by copyright. All rights reserved

Clinical Relevance of Pain Patterns in Osteoporotic Vertebral Compression Fractures

Few studies have been conducted to explain the pain patterns resulting from osteoporotic vertebral compression fractures (OVCF). We analyzed pain patterns to elucidate the pain mechanism and to provide initial guide for the management of OVCFs. Sixty-four patients underwent percutaneous vertebroplasty (N=55) or kyphoplasty (N=9). Three pain patterns were formulized to classify pains due to OVCFs: midline paravertebral (Type A), diffuse paravertebral (Type B), and remote lumbosacral pains (Type C). The degree of compression was measured using scale of deformity index, kyphosis rate, and kyphosis angle. Numerical rating scores were serially measured to determine the postoperative outcomes. As vertebral body height (VBH) decreased, paravertebral pain became more enlarged and extended anteriorly (p<0.05). Type A and B patterns significantly showed the reverse relationship with deformity index (p<0.05), yet Type C pattern was not affected by deformity index. Postoperative pain severity was significantly improved (p<0.05), and patients with a limited pain distribution showed a more favorable outcome (p<0.05). The improvement was closely related with the restoration of VBH, but not with kyphosis rate or angle. Thus, pain pattern study is useful not only as a guide in decision making for the management of patients with OVCF, but also in predicting the treatment outcome

The osteoporosis care gap in Canada

BACKGROUND: The presence of a fragility fracture is a major risk factor for osteoporosis, and should be an indicator for osteoporosis diagnosis and therapy. However, the extent to which patients who fracture are assessed and treated for osteoporosis is not clear. METHODS: We performed a review of the literature to identify the practice patterns in the diagnosis and treatment of osteoporosis in adults over the age of 40 who experience a fragility fracture in Canada. Searches were performed in MEDLINE (1966 to January 2, 2003) and CINAHL (1982 to February 1, 2003) databases. RESULTS: There is evidence of a care gap between the occurrence of a fragility fracture and the diagnosis and treatment of osteoporosis in Canada. The proportion of individuals with a fragility fracture who received an osteoporosis diagnostic test or physician diagnosis ranged from 1.7% to 50%. Therapies such as hormone replacement therapy, bisphosphonates or calcitonin were being prescribed to 5.2% to 37.5% of patients. Calcium and vitamin D supplement intake was variable, and ranged between 2.8% to 61.6% of patients. CONCLUSION: Many Canadians who experience fragility fracture are not receiving osteoporosis management for the prevention of future fractures

Hormone-Dependent Aging Problems in Women

One of the major social issues nowadays is the aging society. Korea is already an aging society, and 63 cities and districts are ultra-aged societies where the rate of people older than 65 yr exceeds 20%. Among them, more than 67% are women. These statistics reveal the importance of healthcare for older women. Disease and disability of older women are very closely related to the loss of female sex hormones after menopause. Major hormone-dependent aging problems in women such as osteoporosis, Alzheimer's disease (AD), urinary incontinence, and coronary atherosclerosis were surveyed in this review, and the key role of hormones in those diseases and hormone replacement therapy (HRT) were summarized. We expect that this review would provide some understanding of factors that must be considered to give optimal care to older women for healthy lives

Comparison of performance-based measures among native Japanese, Japanese-Americans in Hawaii and Caucasian women in the United States, ages 65 years and over: a cross-sectional study

BACKGROUND: Japanese (both in Japan and Hawaii) have a lower incidence of falls and of hip fracture than North American and European Caucasians, but the reasons for these differences are not clear. SUBJECTS AND METHODS: A cross-sectional study. We compared neuromuscular risk factors for falls using performance-based measures (chair stand time, usual and rapid walking speed, and grip strength) among 163 Japanese women in Japan, 681 Japanese-American women in Hawaii and 9403 Caucasian women in the United States aged 65 years and over. RESULTS: After adjusting for age, the Caucasian women required about 40% more time to complete 5 chair stands than either group of Japanese. Walking speed was about 10% slower among Caucasians than native Japanese, whereas Japanese-American women in Hawaii walked about 11% faster than native Japanese. Grip strength was greatest in Japan, which may reflect the rural farming district that this sample was drawn from. Additional adjustment for height, weight or body mass index increased the adjusted means of chair stand time and grip strength among Japanese, but the differences remained significant. CONCLUSIONS: Both native Japanese and Japanese-American women in Hawaii performed better than Caucasians on chair stand time and walking speed tests, and native Japanese had greater grip strength than Japanese in Hawaii and Caucasians. The biological implications of these differences in performance are uncertain, but may be useful in planning future comparisons between populations

A Cross-Species Analysis of a Mouse Model of Breast Cancer-Specific Osteolysis and Human Bone Metastases Using Gene Expression Profiling

<p>Abstract</p> <p>Background</p> <p>Breast cancer is the second leading cause of cancer-related death in women in the United States. During the advanced stages of disease, many breast cancer patients suffer from bone metastasis. These metastases are predominantly osteolytic and develop when tumor cells interact with bone. <it>In vivo </it>models that mimic the breast cancer-specific osteolytic bone microenvironment are limited. Previously, we developed a mouse model of tumor-bone interaction in which three mouse breast cancer cell lines were implanted onto the calvaria. Analysis of tumors from this model revealed that they exhibited strong bone resorption, induction of osteoclasts and intracranial penetration at the tumor bone (TB)-interface.</p> <p>Methods</p> <p>In this study, we identified and used a TB microenvironment-specific gene expression signature from this model to extend our understanding of the metastatic bone microenvironment in human disease and to predict potential therapeutic targets.</p> <p>Results</p> <p>We identified a TB signature consisting of 934 genes that were commonly (among our 3 cell lines) and specifically (as compared to tumor-alone area within the bone microenvironment) up- and down-regulated >2-fold at the TB interface in our mouse osteolytic model. By comparing the TB signature with gene expression profiles from human breast metastases and an <it>in vitro </it>osteoclast model, we demonstrate that our model mimics both the human breast cancer bone microenvironment and osteoclastogenesis. Furthermore, we observed enrichment in various signaling pathways specific to the TB interface; that is, TGF-β and myeloid self-renewal pathways were activated and the Wnt pathway was inactivated. Lastly, we used the TB-signature to predict cyclopenthiazide as a potential inhibitor of the TB interface.</p> <p>Conclusion</p> <p>Our mouse breast cancer model morphologically and genetically resembles the osteoclastic bone microenvironment observed in human disease. Characterization of the gene expression signature specific to the TB interface in our model revealed signaling mechanisms operative in human breast cancer metastases and predicted a therapeutic inhibitor of cancer-mediated osteolysis.</p

Association between bone mineral density and type 2 diabetes mellitus: a meta-analysis of observational studies

Type 2 diabetes mellitus (T2DM) influences bone metabolism, but the relation of T2DM with bone mineral density (BMD) remains inconsistent across studies. The objective of this study was to perform a meta-analysis and meta-regression of the literature to estimate the difference in BMD (g/cm2) between diabetic and non-diabetic populations, and to investigate potential underlying mechanisms. A literature search was performed in PubMed and Ovid extracting data from articles prior to May 2010. Eligible studies were those where the association between T2DM and BMD measured by dual energy X-ray absorptiometry was evaluated using a cross-sectional, cohort or case–control design, including both healthy controls and subjects with T2DM. The analysis was done on 15 observational studies (3,437 diabetics and 19,139 controls). Meta-analysis showed that BMD in diabetics was significantly higher, with pooled mean differences of 0.04 (95% CI: 0.02, 0.05) at the femoral neck, 0.06 (95% CI: 0.04, 0.08) at the hip and 0.06 (95% CI: 0.04, 0.07) at the spine. The differences for forearm BMD were not significantly different between diabetics and non-diabetics. Sex-stratified analyses showed similar results in both genders. Substantial heterogeneity was found to originate from differences in study design and possibly diabetes definition. Also, by applying meta-regression we could establish that younger age, male gender, higher body mass index and higher HbA1C were positively associated with higher BMD levels in diabetic individuals. We conclude that individuals with T2DM from both genders have higher BMD levels, but that multiple factors influence BMD in individuals with T2DM