Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. INTRODUCTION: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). METHODS: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted ß-coefficients. RESULTS: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. CONCLUSION: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.

Association between Dairy Product intake and Risk of Osteoporotic Fractures in Postmenopausal Japanese Women: Secondary Analysis of 15-Year Follow-Up data from the Japanese Population-Based Osteoporosis (JPOS) Cohort Study.

OBJECTIVES: Few prospective cohort studies have evaluated the relationship between dairy product intake frequency and risk of osteoporotic fractures in Asians. This study aimed to investigate the association between habitual dairy product intake and risk of osteoporotic fractures. DESIGN: Secondary analysis of prospective cohort study. SETTING: Five municipalities of Japan. PARTICIPANTS: This study included 1,429 postmenopausal Japanese women (age ≥45 years at baseline). MEASUREMENTS: Baseline milk-intake frequency was obtained using nurse-administered questionnaires. Intakes of yogurt and cheese, and estimated calcium intake, were assessed using a validated food frequency questionnaire. Osteoporotic fracture was defined as a clinical fracture diagnosed using radiography. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. RESULTS: Over a median follow-up period of 15.1 years (interquartile range [IQR], 10.1-15.4 years; total, 18,118 person-years), 172 women sustained at least one osteoporotic fracture. The proportions of participants with milk intakes <1, 1, and ≥2 cups/d were 34.4%, 48.0%, and 17.6%, respectively. After adjustment for age, frequency of yogurt intake, frequency of cheese intake, body mass index, history of osteoporotic fractures, and frequency of natto intake, the HRs compared with that for milk intake <1 cup/d were 0.71 (95% CI: 0.51-0.98) and 0.57 (95% CI: 0.35-0.92) for 1 cup/d and ≥2 cups/d, respectively. After adjustment for bone mineral density, HR significance for milk intakes ≥2 cups/d remained significant. Yogurt and cheese intakes were not related to the risk of osteoporotic fractures. CONCLUSION: High habitual milk intake, but not a habitual yogurt or cheese intake is associated with a decreased risk of osteoporotic fractures, independent of bone mineral density, in postmenopausal Japanese women.

Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan.

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. INTRODUCTION: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. METHODS: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. RESULTS: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. CONCLUSIONS: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

Guideline adherence by physicians for management of glucocorticoid-induced osteoporosis in Japan: a nationwide health insurance claims database study.

Risk of fracture due to glucocorticoid-induced osteoporosis (GIO) can be reduced by anti-osteoporosis (OP) medications. The proportion of patients on long-term glucocorticoid therapy who received anti-OP medications according to the GIO management guidelines has increased in recent years, but is still suboptimal. INTRODUCTION: Adherence of physicians to guidelines for glucocorticoid (GC)-induced osteoporosis (GIO) management is currently unclear. This study aimed to clarify the state of guideline adherence by physicians in Japan and identify factors associated with guideline adherence using a nationwide health insurance claims database (NDBJ). METHODS: Patients aged ≥ 50 years who were prescribed GC for ≥ 90 days after 180 days without a GC prescription and who were followed up for osteoporosis (OP) management for the subsequent 360 days during the period spanning 2012-2018 were selected from the NDBJ. Guideline adherence was evaluated with the proportion of patients who received OP management as recommended by the Japanese guidelines. Information on previous vertebral and hip fractures, dementia, and polypharmacy was obtained. Factors associated with OP management were evaluated by logistic regression analysis. RESULTS: A total of 512,296 patients were considered to be at high risk of fracture according to the guidelines. Proportions of patients receiving OP management (BMD testing or anti-OP medications) have increased in recent years. In 2017, 33.7% of men and 55.3% of women received OP management in the initial 90 days of GC therapy. Female sex, previous anti-OP medications, polypharmacy, and higher GC dose were significantly associated with receiving OP management, while dementia showed an inverse association. A prior history of hip fracture, a strong risk factor for future fracture, was not significantly associated with receiving OP management. CONCLUSIONS: Although guideline adherence by physicians has increased in recent years, it remains suboptimal. Further efforts to improve guideline adherence are necessary. TRIAL REGISTRATION NUMBER: The present study is not registered.

Predictive ability of novel volumetric and geometric indices derived from dual-energy X-ray absorptiometric images of the proximal femur for hip fracture compared with conventional areal bone mineral density: the Japanese Population-based Osteoporosis (JPOS) Cohort Study.

Areal BMD (aBMD) from DXA is not a sufficiently accurate predictor of fracture. Novel volumetric BMD derived from 3D modeling of the hip from DXA images significantly improved the predictive ability for hip fracture relative to aBMD at the femoral neck, but not aBMD at the total hip. INTRODUCTION: To clarify whether volumetric and geometric indices derived from novel three-dimensional (3D) modeling of the hip using dual-energy X-ray absorptiometric (DXA) images improve hip fracture prediction relative to areal bone mineral density (aBMD). METHODS: We examined 1331 women who had completed the baseline survey and at least one follow-up survey over 20 years (age 40-79 years at baseline). Each survey included aBMD measurement at the hip by DXA. Volumetric and geometric indices of the hip at baseline and the 10-year follow-up were estimated from DXA images using a 3D modeling algorithm. Incident hip fractures during the 20-year follow-up period were identified through self-report. Cox proportional hazards regression models allowing for repeated measurements of predictors and outcomes were constructed, and their predictive ability for hip fracture was evaluated using areas under receiver operating characteristic curves (AUCs) and net reclassification improvement (NRI) over aBMD at the femoral neck (FN) and total hip (TH) as references. RESULTS: During a median follow-up of 19.8 years, 68 incident hip fractures were identified (2.22/1000 person-years). A significantly larger AUC of trabecular volumetric BMD (vBMD) at the total hip (AUC = 0.741), femoral neck (AUC = 0.748), and intertrochanter (AUC = 0.738) and significant NRI (0.177, 0.149, and 0.195, respectively) were observed compared with FN-aBMD (AUC = 0.701), but not TH-aBMD. CONCLUSIONS: vBMD obtained from 3D modeling using routinely obtained hip DXA images significantly improved hip fracture risk prediction over conventional FN-aBMD, but not TH-aBMD. TRIAL REGISTRATION: The Japanese Population-Based Osteoporosis (JPOS) Cohort Study was retrospectively registered as UMIN000032869 in the UMIN Clinical Trials Registry on July 1, 2018.

Estimates of hip fracture incidence in Japan using the National Health Insurance Claim Database in 2012-2015.

Using the nationwide health insurance claims database, we found that the age-standardized hip fracture incidence rates in Japan indicated significant increase in males but no significant change in females during 2012-2015. The fracture risk in subjects aged 75-84 years indicated decrease in females but no change in males. INTRODUCTION: Nationwide registry data on hip fractures have not yet been established in Japan. Using the newly developed National Database of Health Insurance Claims (NDB), which covers the entire Japanese population, we investigated the incidence rates of hip fractures and the associated regional differences. We also assessed the frequency of osteoporosis prescriptions, bone turnover marker (BTM) level, and bone mineral density (BMD) measurements. METHODS: The annual numbers of hip fractures, osteoporosis prescriptions, and BTM level and BMD measurements by prefecture from 2012 to 2015 were obtained from NDB data. We calculated the standardized claims-data ratio (SCR) in each prefecture. RESULTS: The age-standardized incidence rates from 2012 to 2015 indicated no significant change in females and significant increase in males (p value for trend; 0.920, 0.002, respectively). The fracture risk decreased in females aged 75-84 years and indicated no increase in females aged 85-89 years during 2012-2015, while the fracture risk indicated no change in males aged 75-84 years and increased in males aged 85-89 years. The frequency of osteoporosis prescriptions, BTM level measurements, and BMD measurements in the general population in the corresponding period increased with statistical or marginal significance in females and males. West-east regional differences were observed in the incidence rates; the highest SCR values in the western prefectures were approximately double the lowest values in the eastern prefectures. CONCLUSIONS: The age-standardized hip fracture incidence rates indicated no significant change in females and significant increase in males in Japan from 2012 to 2015.

Correction to: Age-related normative values of trabecular bone score (TBS) for Japanese women: the Japanese Population-based Osteoporosis (JPOS) study.

I have, as the Principal Investigator of this study, identified an error in the computation of TBS values in the JPOS cohort, which resulted in the publication of incorrect TBS absolute values [1]. This error was linked to the calibration process for calculating standardized TBS values in the R&D TBS.

Total 25-hydroxyvitamin D levels predict fracture risk: results from the 15-year follow-up of the Japanese Population-based Osteoporosis (JPOS) Cohort Study.

We found that community-dwelling women with 25-hydroxyvitamin D levels <20 ng/mL compared to levels ≥20 ng/mL indicated increased risks for clinical, non-vertebral, and fragility fractures during 5 years. Furthermore, the increased risks of non-vertebral fractures remained significant in 10 and 15 years after adjusting for age and bone mineral density. INTRODUCTION: We examined whether total 25-hydroxyvitamin D (25[OH]D) levels are associated with fracture risk over 15 years in a Japanese female cohort. METHODS: Of 1437 community-dwelling women aged ≥50 years in the baseline survey, 1236 provided information regarding fractures during a 15-year follow-up period. The analysis included 1211 women without early menopause or diseases affecting bone metabolism. RESULTS: Over 15 years, 269 clinical (224 non-vertebral, 149 fragility) fracture events were confirmed. Incidence rates categorized by 25(OH)D levels (<10, 10-20, 20-30, and ≥30 ng/mL) indicated a significant divergence for any clinical fractures in 5 years (log rank test p = 0.016) and for non-vertebral fractures in 5, 10, and 15 years (p < 0.001, p = 0.001, p = 0.017, respectively). Hazard ratios (HRs) for 25(OH)D levels <10 and 10-20 ng/mL compared to levels ≥30 ng/mL during 5 years indicated significances for clinical fractures (HR 4.93 with p = 0.009, HR 3.00 with p = 0.034) and for non-vertebral fractures (HR 6.55 with p = 0.005, HR 3.49 with p = 0.036). Those with levels <20 ng/mL compared to those with levels ≥20 ng/mL indicated significant increased risks for clinical fractures (HR 1.72 with p = 0.010), non-vertebral fractures (HR 2.45 with p < 0.001), and fragility fractures (HR 2.00 with p = 0.032) in 5 years. The HR of non-vertebral fractures for levels <20 ng/mL remained significant during 15 years (HR 1.42 with p = 0.012) after adjustment for age and femoral neck bone mineral density. CONCLUSIONS: Low 25(OH)D levels, especially <20 ng/mL, were associated with elevated fracture risks in Japanese women.

Incident fracture associated with increased risk of mortality even after adjusting for frailty status in elderly Japanese men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Cohort Study.

Frail elderly individuals have elevated risks of both fracture and mortality. We found that incident fractures were associated with an increased risk of death even after adjusting for pre-fracture frailty status as represented by physical performance tests and laboratory tests for common geriatric diseases in community-dwelling elderly Japanese men. INTRODUCTION: While fractures reportedly increase the risk of mortality, frailty may complicate this association, generating a false-positive result. We evaluated this association after adjusting for pre-fracture levels of frailty. METHODS: We examined 1998 community-dwelling ambulatory men aged ≥65 years at baseline in the Fujiwara-kyo Osteoporosis Risk in Men Study for frailty status as represented by activities of daily living (ADL), physical performance tests (grip strength, one-foot standing balance with eyes open, timed 10-m walk), and laboratory sera tests. Participants were then followed for 5 years for incident clinical fractures and death. Effects of incident fracture on death were determined by Cox proportional hazards model with the first fracture during follow-up as a time-dependent predictor and with frailty status indices as covariates. RESULTS: We identified 111 fractures in 99 men and 138 deaths during the follow-up period (median follow-up, 4.5 years). Participants with incident fractures did not have significantly worse frailty statuses, but did show a significantly higher cumulative mortality rate than those without fractures (p = 0.0047). Age-adjusted hazard ratio (HR) of death for incident fracture was 3.57 (95 % confidence interval: 2.05, 6.24). When adjusted for physical performance, this decreased to 2.77 (1.51, 5.06), but remained significant. The HR showed no significant change when adjusted for laboratory test results (3.96 (2.26, 6.94)). Exclusion of deaths within the first 24 months of follow-up did not alter these results. CONCLUSION: Incident clinical fracture was associated with an elevated risk of death independently of pre-fracture levels of frailty in community-dwelling elderly men.

Trabecular bone score may improve FRAX® prediction accuracy for major osteoporotic fractures in elderly Japanese men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Cohort Study.

UNLABELLED: FRAX® is widely used to evaluate fracture risk of individuals in clinical settings. However, FRAX® prediction accuracy is not sufficient, and improvement is desired. Trabecular bone score, a bone microarchitecture index, may improve FRAX® prediction accuracy for major osteoporotic fractures in community-dwelling elderly Japanese men. INTRODUCTION: To improve fracture risk assessment in clinical settings, we evaluated whether the combination of FRAX® and Trabecular Bone Score (TBS) improves the prediction accuracy of major osteoporotic fractures (MOFs) in elderly Japanese men compared to FRAX® alone. METHODS: Two thousand and twelve community-dwelling men aged ≥65 years completed the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Baseline Study comprising lumbar spine (LS) and femoral neck areal bone mineral density (aBMD) measurements, and interviews regarding clinical risk factors required to estimate 10-year risk of MOF (hip, spine, distal forearm, and proximal humerus) using the Japanese version of FRAX® (v.3.8). TBS was calculated for the same vertebrae used for LS-aBMD with TBS iNsight software (v.2.1). MOFs that occurred during the follow-up period were identified by interviews or mail and telephone surveys. Prediction accuracy of a logistic model combining FRAX® score and TBS compared to FRAX® alone was evaluated by area under receiver-operating characteristic curves (AUCs), as well as category-free integrated discrimination improvement (IDI) and net reclassification improvement (NRI). RESULTS: We identified 22 men with MOFs during 8140 person-years (PY) of follow-up among 1872 men; 67 men who suffered from fractures other than MOFs were excluded. Participants with MOFs had significantly lower TBS (p = 0.0015) and higher FRAX® scores (p = 0.0089) than those without. IDI and NRI showed significant improvements in reclassification accuracy using FRAX® plus TBS compared to FRAX® alone (IDI 0.006 (p = 0.0362), NRI 0.452 (p = 0.0351)), although no difference was observed in AUCs between the two. CONCLUSIONS: TBS may improve MOF prediction accuracy of FRAX® for community-dwelling elderly Japanese men.

Greater milk intake is associated with lower bone turnover, higher bone density, and higher bone microarchitecture index in a population of elderly Japanese men with relatively low dietary calcium intake: Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Study.

UNLABELLED: The effects of milk intake on bone health are not clear in elderly Asian men with low dietary calcium intake. This study showed that greater milk intake is associated with lower bone turnover, higher bone density, and higher bone microarchitecture index in community-dwelling elderly Japanese men. INTRODUCTION: The consumption of milk or dairy products is widely recommended for maintaining bone health regardless of gender or age. However, little evidence exists on the beneficial effects of milk intake on bone health in elderly Japanese men characterized with relatively low dietary calcium intake. Here we examined whether or not greater milk intake was associated with lower bone turnover, higher bone density, and stronger bone microarchitecture in community-dwelling elderly Japanese men. METHODS: Interviews were conducted to obtain information on medical history and lifestyle, including the amount of habitual milk intake, nutrient intake calculations based on a 1-week food diary, and measurements of areal bone mineral density (aBMD) at the lumbar spine (LS), total hip (TH), and femoral neck (FN) by dual-energy x-ray absorptiometry (DXA), trabecular bone score (TBS) using DXA images at LS, and biochemical markers of bone turnover in sera. Participants with a history of diseases or medications that affect bone metabolism, or with missing data, were excluded from the analysis. RESULTS: The median intake of milk in the 1479 participants (mean age, 73.0 ± 5.1 years) was one glass of milk per day. Bone turnover markers showed a decreasing trend (p < 0.05) and aBMD at TH (p = 0.0019) and FN (p = 0.0057) and TBS (p = 0.0017) showed increasing trends with greater milk intake after adjusting for demographic and behavioral confounding factors. This association was attenuated after further adjusting for nutrient intake, in particular, calcium intake. CONCLUSIONS: Greater milk intake was associated with lower bone turnover, higher aBMD, and higher TBS in community-dwelling elderly Japanese men.

Age-related normative values of trabecular bone score (TBS) for Japanese women: the Japanese Population-based Osteoporosis (JPOS) study.

UNLABELLED: Trabecular bone score (TBS), a surrogate measure of bone microarchitecture, represents fracture risk independently of bone density. We present normative TBS values from a representative population study of Japanese women. This database would enhance our understanding of trabecular bone microarchitecture and improve osteoporosis management. INTRODUCTION: TBS is a texture parameter that quantifies local variation in gray level distribution within dual-energy X-ray absorptiometry (DXA) images of the lumbar spine. While TBS is associated with fracture risk independently of areal bone mineral density (aBMD), normative TBS values have only been reported for Caucasian women. This study provides age-specific normative values of TBS from a representative sample of Japanese women. METHODS: We randomly selected 4,550 women aged 15-79 years from 7 areas throughout Japan. Women younger than 20 years and those with any medical history which might affect bone metabolism were excluded, and the remaining 3,069 with at least two assessable vertebrae from the first to the fourth vertebrae were subjected to analysis. TBS values were calculated from spine DXA images using TBS iNsight software (Med-Imaps, France). Age-related models of TBS were constructed using piecewise linear regression analysis. RESULTS: Participant age, body mass index (BMI), spine aBMD, and TBS (mean ± SD) were 48.7 ± 16.8 years, 22.9 ± 3.4, 0.888 ± 0.169 g/cm(2), and 1.187 ± 0.137, respectively. A three-piece linear regression model of TBS on age explained 70.7% of the total variance in TBS and comprised very small age-related changes in the youngest segment of the regression line, rapid loss in the middle segment, and small loss in the oldest segment. TBS was lower in Japanese women than in Caucasian women across all age ranges, with the difference increasing with age up through 65 years. CONCLUSIONS: The normative values of TBS for Japanese women presented here would enhance our understanding of trabecular bone microarchitecture and help improve the management of osteoporosis.

Biochemical markers for bone turnover predict risk of vertebral fractures in postmenopausal women over 10 years: the Japanese Population-based Osteoporosis (JPOS) Cohort Study.

UNLABELLED: We evaluated how bone turnover might predict vertebral fracture risk in postmenopausal women over 10 years. After adjusting for age and femoral neck bone mineral density, high bone-specific alkaline phosphatase and total and free deoxypyridinoline at baseline predicted increased vertebral fracture risk in women with ≥ 5 years since menopause. INTRODUCTION: The aim was to evaluate the ability of bone turnover markers (BTMs) in predicting vertebral fractures. METHODS: Participants in the 1996 baseline survey of the JPOS Cohort Study included 522 postmenopausal women, with no diseases or medications affecting bone metabolism. Vertebral fractures were ascertained in three follow-up surveys (1999, 2002, and 2006). Initial fracture events were diagnosed morphometrically. The Poisson regression model was applied to estimate the rate ratio (RR) of the following log-transformed BTM values at baseline: osteocalcin and bone-specific alkaline phosphatase (BAP) in serum and C-terminal cross-linked telopeptide of type I collagen, total deoxypyridinoline (tDPD), and free deoxypyridinoline (fDPD) in urine. RESULTS: Eighty-three fracture events were diagnosed over a median follow-up period of 10.0 years. RR per standard deviation (SD) (95 % confidence interval) for BAP was 4.38 (1.45, 13.21) among 65 subjects with years since menopause (YSM) < 5 years. RRs per SD (95 % confidence interval) for BAP, tDPD, and fDPD were 1.39 (1.12, 1.74), 1.32 (1.05, 1.67), and 1.40 (1.12, 1.76), respectively, after adjusting for age and femoral neck bone mineral density (FN BMD) among 457 subjects with YSM ≥ 5 years. Of the 451 women followed at least once until 2002, RRs per SD for BAP, tDPD, and fDPD adjusted for age and FN BMD over 6 years were not significantly different from those over 10 years. CONCLUSION: BAP was associated with vertebral fracture risk among early postmenopausal women. BTMs can predict vertebral fractures independently of BMD among late postmenopausal women over a 10-year follow-up period.

Serum undercarboxylated osteocalcin levels are inversely associated with glycemic status and insulin resistance in an elderly Japanese male population: Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Study.

SUMMARY: Recent animal studies have demonstrated that undercarboxylated osteocalcin upregulates insulin secretion via osteoblast-insulin signaling. However, it remains unclear whether such a pathway exists in humans. This study showed that serum undercarboxylated osteocalcin levels were inversely associated with fasting plasma glucose, hemoglobin A(1c), and homeostasis model assessment of insulin resistance (HOMA-IR) levels in community-dwelling elderly Japanese men. INTRODUCTION: Undercarboxylated osteocalcin (ucOC) was reported to increase insulin secretion and improve glucose tolerance via osteoblast-insulin signaling in animal-based studies. Whether this pathway also exists in humans is unknown. We aimed to clarify whether serum ucOC levels are associated with glycemic status and insulin resistance in the general Japanese population. METHODS: We included 2,174 Japanese men (≥65 years) who were able to walk without aid from others and lived at home in four cities of Nara Prefecture. We excluded participants with a history of diseases or medications that affect bone metabolism, other than type 2 diabetes mellitus (T2DM). Fasting plasma glucose, glycated hemoglobin A(1c), and HOMA-IR levels were determined as outcome measures. RESULTS: Of the 1,597 participants included in the analysis, both intact OC (iOC) and ucOC levels showed significant inverse correlations with all outcome measures, even after adjusting for potential confounders. Mean values of outcome measures showed a significant decreasing trend with higher quintiles of iOC or ucOC after adjusting for confounders. This trend remained significant for ucOC quintiles after further adjustment for iOC levels, but was not significant for iOC quintiles after adjusting for ucOC levels. These results were attenuated, but still apparent, after excluding participants receiving drug therapy for T2DM. CONCLUSIONS: Levels of ucOC, but not iOC, were inversely associated with glycemic index and insulin resistance in a population of Japanese men. These findings will need to be confirmed with longitudinal studies.

Association between vitamin K intake from fermented soybeans, natto, and bone mineral density in elderly Japanese men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study.

SUMMARY: A cross-sectional analysis of 1,662 community dwelling elderly Japanese men suggested that habitual natto intake was significantly associated with higher bone mineral density (BMD). When adjustment was made for undercarboxylated osteocalcin levels, this association was insignificant, showing the natto-bone association to be primarily mediated by vitamin K. INTRODUCTION: Low vitamin K intake is associated with an increased risk of hip fracture, but reports have been inconsistent on its effect on BMD. Our first aim was to examine the association between BMD and intake of fermented soybeans, natto, which contain vitamin K1 (20 µg/pack) and K2 (380 µg/pack). Our second aim was to examine the association between undercarboxylated osteocalcin (ucOC), a biomarker of vitamin K intake, and BMD to evaluate the role of vitamin K in this association. METHODS: Of the Japanese men aged ≥65 years who participated in the baseline survey of the Fujiwara-kyo Osteoporosis Risk in Men study, 1,662 men without diseases or medications known to affect bone metabolism were examined for associations between self-reported natto intake or serum ucOC levels with lumbar spine or hip BMD. RESULTS: The subjects with greater intake of natto showed significantly lower level of serum ucOC. Analysis after adjustment for confounding variables showed an association of greater intake of natto with both significantly higher BMD and lower risk of low BMD (T-score < -1 SD) at the total hip and femoral neck. This association became insignificant after further adjustment for ucOC level. CONCLUSION: Habitual intake of natto was associated with a beneficial effect on bone health in elderly men, and this association is primarily due to vitamin K content of natto, although the lack of information on dietary nutrient intake, including vitamin K1 and K2, prevented us from further examining the association.

Association between weight changes and changes in hip geometric indices in the Japanese female population during 10-year follow-up: Japanese Population-based Osteoporosis (JPOS) Cohort Study.

UNLABELLED: During a 10-year follow-up of 893 women of various ages from the Japanese Population-based Osteoporosis Cohort Study, we evaluated the relationship between weight changes and hip geometric strength assessed by hip structure analysis. Our findings suggest that maintaining weight may help retain geometric strength and reduce hip fracture risk. INTRODUCTION: The effects of changes in anthropometric indices on hip geometry in women of various ages are unclear. We evaluated these effects by analyzing 10-year longitudinal data from a representative sample of Japanese women. METHODS: Dual-energy X-ray absorptiometry scans of the proximal femur were performed at baseline and at the 10-year follow-up. Data were analyzed with the Hip Structure Analysis (HSA) program, which yields geometric strength indices including cross-sectional area (CSA), section modulus (SM) and subperiosteal diameter (PD) at regions of interest (ROIs) in the narrow neck (NN), intertrochanter, and femoral shaft (FS) regions. Annual percent change of each HSA index was determined. Height and weight were measured at baseline and follow-up. RESULTS: After excluding subjects with factors affecting bone metabolism, we evaluated 893 women (18-79 years old at baseline). The greatest changes in most HSA indices during the follow-up were observed in subjects aged ≥ 70 years at all ROIs. PD modestly but significantly expanded with age, but this change was not significant in subjects aged ≥ 70 years or those who had entered menopause ≥ 20 years before baseline. An increasing trend in weight was associated with an increase or smaller decline in CSA and SM at the NN and FS regions regardless of menopausal status after adjusting for age, height, and weight at baseline and change of estimated volumetric bone mineral density. Changes in height showed a much weaker association with HSA indices. CONCLUSIONS: Maintaining weight may help retain hip geometric strength and reduce the risk of hip fracture.

Fracture risk prediction using FRAX®: a 10-year follow-up survey of the Japanese Population-Based Osteoporosis (JPOS) Cohort Study.

UNLABELLED: We evaluated the predictive ability of FRAX® in a cohort of 815 Japanese women. The observed 10-year fracture rate did not differ significantly from that predicted by FRAX®. The predictive ability of FRAX® without femoral neck bone mineral density (BMD) was similar to that with femoral neck BMD. INTRODUCTION: We evaluated the ability of the Japanese version of FRAX®, a World Health Organization fracture risk assessment tool, to predict the 10-year probability of osteoporotic fracture. METHODS: Self-reported major osteoporotic fracture (N = 43) and hip fracture (N = 4) events were ascertained in the 10-year follow-up survey of the Japanese Population-Based Osteoporosis Cohort Study. Participants were 815 women aged 40-74 years at the baseline survey. Receiver operating characteristic curve analysis compared FRAX® with multiple logistic models based on age, body weight, and femoral neck BMD. RESULTS: The number of observed major osteoporotic or hip fracture events did not differ significantly from the number of events predicted by the FRAX® model (with or without BMD). The area under the curve (AUC) value for FRAX® with BMD for predicting major osteoporotic fractures was similar to that of a logistic model with age, body weight, and BMD (0.69 vs. 0.71, respectively; p = 0.198); the AUC of FRAX® with BMD for predicting hip fractures was similar to that of a model based on age and BMD (0.88 vs. 0.89, respectively; p = 0.164). The AUCs of FRAX® without BMD for predicting major osteoporotic and hip fractures were similar to those with BMD (0.69 vs. 0.67, respectively; p = 0.121; 0.88 vs. 0.86, respectively; p = 0.445). CONCLUSIONS: The Japanese version of FRAX® without BMD estimated the 10-year probability of osteoporotic fracture in this population with few clinical risk factors as similar to that of FRAX® with BMD.

Impact of smoking on bone mineral density and bone metabolism in elderly men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study.

UNLABELLED: Our cross-sectional analysis of 1,576 men aged ≥65 years examined smoking effects on bone status. Number of smoking years was associated with decreased bone mineral density (BMD), after adjusting for age, height, weight, and number of cigarettes smoked daily. Smoking did not affect biochemical marker serum values for bone turnover. INTRODUCTION: The impact of smoking on bone status in men has not been conclusively established. We examined how smoking and its cessation influence bone status and metabolism in men. METHODS: We analyzed 1,576 men among a baseline survey of Japanese men aged ≥65 years, the Fujiwara-kyo Osteoporosis Risk in Men study, conducted during 2007-2008. RESULTS: Lumbar spine (LS) BMD values among never, former, and current smokers were 1.045 ± 0.194, 1.030 ± 0.189, and 1.001 ± 0.182 g/cm(2) (P = 0.005), respectively, while total hip (TH) BMD values were 0.888 ± 0.120, 0.885 ± 0.127, and 0.870 ± 0.124 (P = 0.078), respectively. The significant trend for LS BMD remained after adjusting for the covariates; age, height, weight, physical activity, milk consumption, and drinking habit (P = 0.036). Among never and ever (current and former) smokers, LS and TH BMD decreased with the number of pack years or the number of smoking years, respectively, adjusted for those covariates. Among ever smokers, LS and TH BMD decreased with the number of smoking years after adjusting for age, height, weight, and number of cigarettes smoked daily. Smoking did not reveal significant effect for serum osteocalcin or tartrate resistant acid phosphatase isoenzyme 5b. CONCLUSION: The impact of smoking on bone status is mainly associated with the number of smoking years in elderly men.

Age-specific reference values of hip geometric indices from a representative sample of the Japanese female population: Japanese Population-based Osteoporosis (JPOS) Study.

UNLABELLED: We analyzed 2,107 hip dual-energy X-ray absorptiometry (DXA) images from the Japanese Population-based Osteoporosis Study with the Hip Structure Analysis (HSA) program to obtain age-specific reference values of HSA indices for the Japanese female population. These references may help physicians accurately assess HSA results and aid researchers in making interracial comparisons of the indices. INTRODUCTION: Hip geometry is expected to improve hip fracture risk assessment, which is usually assessed by bone mineral density (BMD) alone. We aimed to establish a reference database for Japanese women. METHODS: We studied 2,107 Japanese women (15-79 years old) with no history of bone metabolism-related diseases from the Japanese Population-based Osteoporosis Study performed in 1996. Hip geometry was conducted on DXA images with the HSA program, which yielded data for cross-sectional area (CSA), subperiosteal diameter (PD), endocortical diameter (ED), mean cortical thickness (CT), section modulus (SM), and buckling ratio at the narrow neck (NN), intertrochanter (IT), and femoral shaft (FS) regions. Mean HSA indices were determined for each 5-year age group after adjustment for height and weight based on most recent Japanese population values. RESULTS: Age-related changes in HSA indices were evident for the 50-54 year group in the NN and IT regions and for the 55-59 year group in the FS region; these changes increased with age thereafter. Age-related changes in CSA and CT were almost identical to that of BMD. Japanese subjects exhibited BMD and CT values similar to those reported for US non-Hispanic white women, but had 16-23% smaller SM values. CSA and CT were highly correlated with conventional BMD, whereas ED, SM, and PD showed lower correlations. CONCLUSIONS: Age-specific reference values of HSA indices for the Japanese female population were obtained. This database will form the foundation for accurate HSA result evaluation.