Development and validation of the Chinese osteoporosis screening algorithm (COSA) in identification of people with high risk of osteoporosis.

Objectives: To enhance the public awareness and facilitate diagnosis of osteoporosis, we aim to develop a new Chinese Osteoporosis Screening Algorithm (COSA) to identify people at high risk of osteoporosis. Methods: A total of 4747 postmenopausal women and men aged ≥ 50 from the Hong Kong Osteoporosis Study were randomly split into a development (N = 2373) and an internal validation cohort (N = 2374). An external validation cohort comprising 1876 community-dwelling subjects was used to evaluate the positive predictive value (PPV). Results: Among 11 predictors included, age, sex, weight, and history of fracture were significantly associated with osteoporosis after correction for multiple testing. Age- and sex-stratified models were developed due to the presence of significant sex and age interactions. The area under the curve of the COSA in the internal validation cohort was 0.761 (95% CI, 0.711-0.811), 0.822 (95% CI, 0.792-0.851), and 0.946 (95% CI, 0.908-0.984) for women aged < 65, women aged ≥ 65, and men, respectively. The COSA demonstrated improved reclassification performance when compared to Osteoporosis Self-Assessment Tool for Asians. In the external validation cohort, the PPV of COSA was 40.6%, 59.4%, and 19.4% for women aged < 65, women aged ≥ 65, and men, respectively. In addition, COSA > 0 was associated with an increased 10-year risk of hip fracture in women ≥ 65 (OR, 4.65; 95% CI, 2.24-9.65) and men (OR, 11.51; 95% CI, 4.16-31.81). Conclusions: We have developed and validated a new osteoporosis screening algorithm, COSA, specific for Hong Kong Chinese.

Nitrogen-Containing Bisphosphonates Are Associated With Reduced Risk of Pneumonia in Patients With Hip Fracture.

The objective of this work was to study the risk of pneumonia and pneumonia mortality among patients receiving nitrogen-containing bisphosphonates (N-BPs), non-N-BP anti-osteoporosis medications, and no anti-osteoporosis medications after hip fracture. We studied a historical cohort using a population-wide database. Patients with first hip fracture during 2005-2015 were identified and matched by time-dependent propensity score. The cohort was followed until December 31, 2016, to capture any pneumonia and pneumonia mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox-proportional hazards regression. Absolute risk difference (ARD) and number needed to treat (NNT) were calculated. We identified 54,047 patients with hip fracture. Of these, 4041 patients who received N-BPs and 11,802 without anti-osteoporosis medication were propensity score-matched. N-BPs were associated with a significantly lower risk of pneumonia compared with no treatment (6.9 versus 9.0 per 100 person-years; HR 0.76; 95% CI, 0.70 to 0.83), resulting in an ARD of 0.02 and NNT of 46. A similar association was observed with pneumonia mortality (HR 0.65; 95% CI, 0.56 to 0.75). When N-BPs were compared with non-N-BP anti-osteoporosis medications, the association remained significant. N-BPs were associated with lower risks of pneumonia and pneumonia mortality. Randomized controlled trials are now required to determine whether N-BPs, non-vaccine-based medications, can reduce pneumonia incidence in high risk groups. © 2020 American Society for Bone and Mineral Research.

25-Hydroxyvitamin D and the risk of incident diabetes in Hong Kong Chinese.

OBJECTIVE: To investigate the relationship between serum 25-hydroxyvitamin D (25(OH)D) and risk of incident diabetes in Hong Kong Chinese, after accounting for the effect of multiple bone- and mineral-related markers. DESIGN: We conducted a retrospective study on the Hong Kong Osteoporosis Study cohort. Incident diabetes was ascertained using electronic medical records. Serum 25(OH)D was measured at baseline and its association with incident diabetes was evaluated using multivariable Cox proportional-hazard regression. PARTICIPANTS: Individuals (n 4342) aged 20 years or above (1395 men, 2947 women; mean age 54·3 (sd 16·5) years) from the Hong Kong Osteoporosis Study, who were free of diabetes at baseline, were included. RESULTS: During 40 124·7 person-years of follow-up (a median of 9·2 years), 443 participants developed diabetes. Mean 25(OH)D was 63·34 (sd 13·07) nmol/l. Age-, sex- and BMI-adjusted Cox proportional-hazard regression showed no significant difference in the risk of incident diabetes between the lowest and the highest quintiles of 25(OH)D. In the analysis of the interaction effect between 25(OH)D and serum Ca, the interaction term did not affect the risk of incident diabetes significantly (P = 0·694). Similarly, there was no significant interaction of different subgroups (age, sex, BMI, femoral-neck T-score, serum Ca levels) with serum 25(OH)D. CONCLUSIONS: The present study finds that serum vitamin D level is not associated with the risk of incident diabetes in Hong Kong Chinese and this relationship is not modified by serum Ca level.

Association of Alendronate and Risk of Cardiovascular Events in Patients With Hip Fracture.

The risk of cardiovascular events (CVEs) with alendronate use in real-world hip fracture patients is unknown. This study aimed to investigate the risk of CVE with and without use of alendronate in patients with hip fracture. We conducted a retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with hip fracture from 2005 through 2013 were followed until November 6, 2016. Alendronate and other antiosteoporosis medications use during the study period were examined. We matched treated and nontreated patients based on time-dependent propensity score. The risks of cardiovascular mortality, myocardial infarction, and stroke between treatment groups were evaluated using conditional Cox regression stratified by match pairs. To examine the associations over time, outcomes were assessed at 1 year, 3 years, 5 years, and 10 years. Among 34,991 patients with newly diagnosed hip fracture, 4602 (13.2%) received antiosteoporosis treatment during follow-up. Physical functioning or survival prospect was not significantly different between treated and nontreated patients. A total of 4594 treated patients were matched with 13,568 nontreated patients. Results of Cox regression analysis revealed that alendronate was associated with a significantly lower risk of 1-year cardiovascular mortality (HR 0.33; 95% CI, 0.17 to 0.65) and incident myocardial infarction (HR 0.55; 95% CI, 0.34 to 0.89), whereas marginally significant reduction in risk of stroke was observed at 5 years and 10 years (HR at 5 years: 0.82; 95% CI, 0.67 to 1.00; p = 0.049; HR at 10 years: 0.83; 95% CI, 0.69 to 1.01; p = 0.065). The strength of the association declined over time but remained significant. Similar results were observed when all nitrogen-containing bisphosphonates (N-BPs) were analyzed together. These findings were robust in multiple sensitivity analyses. Additional studies in other population samples and randomized clinical trials may be warranted to further understand the relationship between use of various antiosteoporosis medication and risk of CVE in patients with hip fracture. © 2018 American Society for Bone and Mineral Research.

Optimal vitamin D status and its relationship with bone and mineral metabolism in Hong Kong Chinese.

BACKGROUND: Although 25-hydroxyvitamin D (25[OH]D) is commonly used to define vitamin D status, there is no consensus on the cutoff levels for vitamin D deficiency and insufficiency. In this study, we aimed to identify the 25(OH)D threshold that maximally suppressed parathyroid hormone (PTH) in Hong Kong Chinese population. METHODS: The study included 5276 participants (70% female) of the Hong Kong Osteoporosis Study aged 20 or above who had total 25(OH)D measured. Three-phase segmented regression was used to identify the optimal break-point between 25(OH)D and PTH. RESULTS: The prevalence of vitamin D deficiency observed was 43.8% and the prevalence of insufficient (<75nmol/L) or deficient (<50nmol/L) vitamin D levels was 90.1% in our study population. Using unadjusted three-phase segmented regression, the estimated first and second break-point of 25(OH)D on PTH suppression were 32nmol/L (95% CI: 29-35) and 89nmol/L (95% CI: 77-101) with an r2 of 0.048, whereas the estimated first and second break-point of 25(OH)D were 27nmol/L (95% CI: 24-30) and 47nmol/L (95% CI: 37-56) after adjusting for factors affecting bone and mineral metabolism. In addition, the relationship between 25(OH)D and PTH significantly differed by sex and age. CONCLUSION: The threshold for 25OHD at the point of maximal suppression of PTH estimated in this study was lower than the suggested threshold of vitamin D deficiency in the literature, perhaps due to race or assay differences, and the relationship between vitamin D and PTH changed with sex and age. Standardization in the methodology of searching for the optimal break-point is desirable so that a consensus on cutoff points can be obtained.

Safety of bazedoxifene in a randomized, double-blind, placebo- and active-controlled Phase 3 study of postmenopausal women with osteoporosis.

BACKGROUND: We report the safety findings from a 3-year phase 3 study (NCT00205777) of bazedoxifene, a novel selective estrogen receptor modulator under development for the prevention and treatment of postmenopausal osteoporosis. METHODS: Healthy postmenopausal osteoporotic women (N = 7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. Safety and tolerability were assessed by adverse event (AE) reporting and routine physical, gynecologic, and breast examination. RESULTS: Overall, the incidence of AEs, serious AEs, and discontinuations due to AEs in the bazedoxifene groups was not different from that seen in the placebo group. The incidence of hot flushes and leg cramps was higher with bazedoxifene or raloxifene compared with placebo. The rates of cardiac disorders and cerebrovascular events were low and evenly distributed among groups. Venous thromboembolic events, primarily deep vein thromboses, were more frequently reported in the active treatment groups compared with the placebo group; rates were similar with bazedoxifene and raloxifene. Bazedoxifene showed a neutral effect on the breast and an excellent endometrial safety profile. The incidence of fibrocystic breast disease was lower with bazedoxifene 20 and 40 mg versus raloxifene or placebo. Reductions in total and low-density lipoprotein levels and increases in high-density lipoprotein levels were seen with bazedoxifene versus placebo; similar results were seen with raloxifene. Triglyceride levels were similar among groups. CONCLUSION: Bazedoxifene showed a favorable safety and tolerability profile in women with postmenopausal osteoporosis. TRIAL REGISTRATION NUMBER: NCT00205777; Trial registration date: September 16, 2005.

Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass.

UNLABELLED: Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner. INTRODUCTION: BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied. MATERIALS AND METHODS: Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing. RESULTS: For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct. CONCLUSIONS: This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance.