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Little is known about whether substances inducing tissue protein degeneration in the oral cavity are associated with the number of teeth present in postmenopausal women. We sought to investigate the association of urinary pentosidine and serum homocysteine levels with the number of teeth and subsequent tooth loss in Japanese postmenopausal women.Among participants in the Nagano Cohort Study, 785 postmenopausal women (mean age, 68.1 years) participated in the present study. The number of teeth was re-counted at the time of follow-up in 610 women. Poisson regression analysis was used to investigate differences in the number of teeth among quartiles of pentosidine or homocysteine, adjusting for covariates that correlated with the number of teeth. A Cox proportional hazard model was used to evaluate the association of subsequent tooth loss with pentosidine or homocysteine levels.Pentosidine quartiles were not associated with the number of teeth at baseline. Participants in the highest homocysteine quartile had significantly fewer teeth at baseline than those in the third and lowest quartiles (p 0.001 for both). Those in the second quartile had fewer teeth than those in the third (p = 0.001) and lowest (p 0.001) quartiles. An increased risk of tooth loss during follow-up was significantly associated with higher urinary pentosidine (hazard ratio = 1.073 for 10 pmol/mgCre; p = 0.001).Postmenopausal women with higher homocysteine levels had fewer teeth at baseline. A higher pentosidine concentration increased the risk of subsequent tooth loss. High pentosidine or homocysteine concentrations may be associated with tooth loss in postmenopausal women.

Although changes in serum sclerostin levels at 12 months after infusion of zoledronic acid have been reported, the changes in sclerostin levels at earlier time points are poorly understood. We reanalyzed the study data of a previous phase 1 pharmacokinetic study and investigated the correlation between changes in sclerostin levels and relevant factors in calcium metabolism. A total of 24 Japanese female subjects with primary postmenopausal osteoporosis were administered a single 4- or 5-mg dose of zoledronic acid. Serum and urine samples were collected on days 15, 29, 90, 180, and 365 after administration. Serum levels of calcium, phosphate, intact parathyroid hormone (iPTH), and sclerostin were measured. Levels of serum sclerostin were unchanged from baseline on days 15 and 29, but increased significantly on day 90, subsequently decreased significantly on day 180, and returned to baseline levels on day 365. A significant negative correlation was observed between changes in iPTH levels at early time points and sclerostin levels at later time points. This suggests that sclerostin was negatively regulated by iPTH, and the decrease in sclerostin may indicate the start of bone formation during later time points after zoledronic acid injection. Supplementary Information The online version contains supplementary material available at 10.1007/s00223-021-00900-w.

In a clinical trial involving Japanese patients with osteoporosis, post hoc analyses were performed to evaluate the incidence of acute phase reactions (APRs) after infusion of zoledronic acid (ZOL). The results highlighted differences in baseline factors between patients with vs without APRs. Changes in efficacy indicators such as bone turnover markers (BTMs) also showed significant differences. We, therefore, investigated the factors involved in the development of APRs in Japanese patients treated with a once-yearly intravenous infusion of ZOL 5 mg for 2 years by assessing the relation between APRs and efficacy. APRs reported in patients with primary osteoporosis from the ZONE study were analyzed post hoc. Baseline factors were compared in patients with vs without APRs, and changes in BTMs and bone mineral density (BMD) were also investigated. In the ZOL group, 51.2% (169/330) of patients developed APRs after the first infusion and 12.3% (33/268) after the second infusion. Comparison of baseline factors showed that patients without APRs in the ZOL group had a significantly higher neutrophil/lymphocyte ratio, lower serum levels of procollagen type I N-terminal propeptide, older age, and higher likelihood of prior bisphosphonate use vs patients with APRs. Patients with APRs showed significantly higher increases in total hip BMD at 6 and 12 months and larger reductions in BTMs vs patients without APRs. Patient profiles differed significantly between patients with vs without APRs, with APRs after the first infusion of ZOL being related to increases in total hip BMD and suppression of BTMs.This study is registered with ClinicalTrials.gov (identifier: NCT01522521; January 31, 2012).

Aim Advanced glycation end-products (AGEs) are a known factor that accelerates vascular complications. AGEs (e.g. pentosidine or N-e-carboxy-methyl-lysine [CML]) have been particularly investigated in patients with diabetes or chronic kidney disease and have been associated not only with arteriosclerosis, but also with novel vascular events. On the contrary, the correlation of vascular events with AGEs has not been sufficiently investigated in groups excluding those with diabetes or chronic kidney disease. The present study aimed to evaluate the impact of AGEs on the history of vascular events in postmenopausal women excluding those with diabetes or renal insufficiency. Methods Japanese postmenopausal women were registered to the study after obtaining informed consent. Patients with critical illness, including diabetes mellitus and renal insufficiency, were excluded from the study. Participants were asked about their medical histories during the registration for the Nagano Cohort Study. Non-fasting serum and urine samples were collected to measure biochemical markers, including urinary pentosidine and serum CML levels. Results Among 357 postmenopausal women, 32 had a history of vascular events. After adjusting age and other variables known to be associated with the presence of vascular event history, positive correlations between AGEs and vascular event history were observed (standardized odds ratio of log[pentosidine] 1.38, 95% CI 0.96-2.00, P = 0.086; standardized odds ratio of log[CML] 1.73, 95% CI 1.10-2.74, P = 0.019). Discussion The present results showed a significant association between serum CML and the presence of vascular event history, suggesting that serum CML might play a role in vascular events. Geriatr Gerontol Int ••; ••: ••-•• Geriatr Gerontol Int 2021; ••: ••-••.

In this post hoc analysis of the Denosumab Fracture Intervention Randomized Placebo-Controlled Trial (DIRECT) in Japanese postmenopausal women and men with osteoporosis, we evaluated the relationship between vertebral fracture risk and both bone mineral density (BMD) T-score and percent change after 24 months of denosumab treatment at total hip, femoral neck, and lumbar spine. Logistic regression analysis was performed and the proportion of treatment effect explained by BMD in vertebral fracture risk was estimated. The results demonstrate that both total hip BMD T-score and change can be strong predictors of subsequent fracture risk, and that total hip BMD change explained 73%, while T-score explained 23%, of the treatment effect. In contrast, neither femoral neck BMD change nor T-score can predict the effect of denosumab on vertebral fracture risk. Furthermore, although lumbar spine BMD T-score was associated with vertebral fracture incidence, lumbar spine BMD change was inversely related to vertebral fracture risk. Because there was no relationship between lumbar spine BMD change and T-score at 24 months of denosumab treatment, and because there can be small undetectable vertebral deformities that may increase BMD values, these results suggest that lumbar spine BMD change is not a good surrogate for vertebral fracture risk assessment. It is suggested that both total hip BMD change and T-score can be good surrogates for predicting vertebral fracture risk in Japanese patients with osteoporosis under denosumab treatment. ClinicalTrials.gov identifier: NCT00680953.

STUDY DESIGN Retrospective observational study from the Nagano Cohort Study. OBJECTIVE Clarify the association between spinal osteoarthritis and loss of stature in postmenopausal women. SUMMARY OF BACKGROUND DATA Loss of stature with aging is known to deteriorate health-related quality of life and has been implicated with increased mortality. Although the association of vertebral fracture with height loss has been well documented, the relationship between stature loss and spinal osteoarthritis remains unclear. METHODS We retrospectively investigated Japanese postmenopausal women recruited from the Nagano Cohort Study. The participants were outpatients at a primary care institute in Nagano prefecture, Japan. A total of 977 postmenopausal patients (mean age: 65.8 yr) completed a minimum of 1 year of follow-up, with an average observation period of 7.6 years. Quartile analysis on the prevalence of spinal osteoarthritis and occurrence of incident fracture was performed based on the rate of stature change per year (Δ cm/yr). Multiple regression analysis was also conducted to identify the determinants of stature change. RESULTS The lower quartiles of stature change rate (i.e., more rapid stature loss) displayed a significantly higher prevalence of spinal osteoarthritis (P

In anti-osteoporosis drug trials, vitamin D and calcium (Ca) are common supplements; however, the optimal dose of each is unclear. Using data from the randomized, double-blind, placebo-controlled DIRECT trial, we assessed whether baseline serum 25-hydroxy vitamin D (25[OH]D) level influences the efficacy of denosumab co-administered with vitamin D and Ca.In this prespecified sub-analysis, subjects with primary osteoporosis who received denosumab or placebo, plus vitamin D (≥ 400 IU/day) and Ca (≥ 600 mg/day), were classified as 25(OH)D deficient ( 20 ng/mL), insufficient (≥ 20 to 30 ng/mL), and sufficient (≥ 30 ng/mL). Study endpoints included absolute serum 25(OH)D level at baseline, 12 months, and 24 months; change in serum 25(OH)D and bone mineral density (BMD) status from baseline; and incidence of new vertebral fractures at 24 months.In 475 denosumab-treated and 481 placebo-treated subjects, proportions with deficient/insufficient/sufficient 25(OH)D at baseline were 53.1%/37.1%/9.9% and 50.9%/42.0%/7.1%, respectively. Supplementation significantly increased mean serum 25(OH)D levels; at 24 months, mean levels were 30 ng/mL (sufficient) in both treatment groups. Increase in BMD over time was higher in the denosumab group vs. placebo group in all three vitamin D status groups. At month 24, denosumab-treated subjects with deficient/insufficient baseline 25(OH)D had a significantly lower risk of new vertebral fracture vs. placebo-treated subjects.Among DIRECT trial subjects supplemented with ≥ 400 IU/day of vitamin D and ≥ 600 mg/day of Ca, baseline 25(OH)D sufficiency may not influence the efficacy of denosumab in increasing BMD or preventing vertebral fractures.

Although nitric oxide (NO) is a known factor that regulates the bone physiology, few and discordant results have been obtained in human studies evaluating the effect of nitrates on bone health. We investigated for the relationship between serum NOx level and incident osteoporotic fracture rate prospectively in a cohort consisting of Japanese women. A total of 871 subjects (67.5 ± 10.8 y/o) were analyzed. During the observation period (8.8 ± 7.2 yrs), incident osteoporotic fractures occurred in 267 participants (209 vertebral fractures, 57 long-bone fractures, and 1 both types). Hazard ratio, by the Cox proportional hazards model, of serum NOx for incident fracture was 0.64 (95% confidence interval 0.53–0.78, p < 0.001) after adjustment for baseline age (1.13, 1.06–1.21, p < 0.001), lumbar bone mineral density (L-BMD; 0.85, 0.78–0.92, p < 0.001), presence of prevalent fracture (3.27, 2.49–4.32, p < 0.001), and treatment of osteoporosis (0.70, 0.53–0.92, p = 0.010). The relationships between serum level of NOx and bone-related parameters were examined by multiple regression analysis; body mass index (p < 0.001) and L-BMD (p = 0.011) were significantly associated with serum NOx level. These results suggest that the low circulating NOx is one of the independent predictors for osteoporotic fracture occurrence in postmenopausal women.

Zoledronic acid (ZOL) as a yearly infusion is effective in reducing fracture risk. An acute-phase reaction (APR), consisting of flu-like symptoms within 3 days after infusion, is commonly seen. The objective of this analysis was to investigate whether APR occurrence influences drug efficacy. This analysis uses data from the 3-year randomized clinical trial, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT). APRs were identified as adverse events within 3 days of first infusion with higher frequency in ZOL than placebo. To compare mean 3-year change in bone mineral density (BMD) in ZOL versus placebo, among women with and without APR, t tests were used. Logistic regression was used to examine the relationship between APR occurrence and odds of incident morphometric vertebral fracture. Cox regression was used to determine the risk of nonvertebral and hip fractures for women with versus without APR. Logistic and Cox models were used to determine the risk of incident fracture in ZOL versus placebo for women with and without an APR. The analysis included 3862 women in the ZOL group and 3852 in placebo, with 42.4% in ZOL versus 11.8% in placebo experiencing an APR. The difference in BMD mean change for ZOL versus placebo was similar for women with and without an APR (all p interaction >0.10). Among ZOL women, those with APR had 51% lower vertebral fracture risk than those without (odds ratio [OR] = 0.49, p

Context Although homocysteine accumulation is a reported risk factor for several age-related disorders, little is known about its relationship with osteoarthritis (OA). Objective We investigated for associations of homocysteine and C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR), which is involved in homocysteine clearance, with the development and progression of spinal OA through a combined cross-sectional and longitudinal cohort study. Methods A total of 1306 Japanese postmenopausal outpatients participating in the Nagano Cohort Study were followed for a mean 9.7-year period. Cross-sectional multiple logistic regression for spinal OA prevalence at registration by serum homocysteine level was performed with adjustment for confounders. In addition to Kaplan–Meier analysis, multivariate Cox regression was employed to examine the independent risk of MTHFR C677T variant for spinal OA progression. Results Multivariate regression analysis revealed a significant association between homocysteine and spinal OA prevalence (odds ratio 1.38; 95% CI 1.14-1.68). Kaplan–Meier curves showed a gene dosage effect of the T allele in MTHFR C677T polymorphism on the accelerated progression of spinal OA severity (P = 0.003). A statistically significant independent risk of the T allele for spinal OA advancement was validated by Cox regression analysis. Respective adjusted hazard ratios for the CT/TT and TT genotypes were 1.68 (95% CI, 1.16–2.42) and 1.67 (95% CI, 1.23–2.28). Conclusion Circulating homocysteine and C677T variant in MTHFR are associated with the prevalence rate and ensuing progression, respectively, of spinal OA. These factors may represent potential interventional targets to prevent OA development and improve clinical outcomes.

With the aging of society, the number of osteoporosis-related fractures is increasing. Prevention of osteoporosis and maintenance of the quality of life of osteoporosis patients require early diagnosis, effective treatment, and highly precise treatment monitoring. Although bone biopsy is clinically one of the essential techniques for diagnosis of osteoporosis, it is invasive and difficult to perform in general clinical practice. Bone mineral density measurement is another essential technique available in clinical practice that provides good precision. However, it is not effective for determining the appropriate treatment options or evaluating short-term treatment efficacy. On the other hand, bone turnover markers (BTMs) have gained attention because they provide information that is valuable for both the selection of treatment and short-term monitoring. BTMs are now positioned to become a tool for clinically assessing bone turnover outcomes. Since the Japan Osteoporosis Society issued its Guidelines for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis in 2012, new drugs, drug formulations, and combination drug therapies have been approved; therefore, we updated the 2012 guidelines in the Guide for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis (2018 Edition).

We recently uncovered an association between spinal osteoarthritis and height loss that was independent of incident vertebral fracture. However, the optimal cut-off value of historical height loss (HHL) for discriminating spinal osteoarthritis has not been reported. This cross-sectional study aimed to evaluate the implications of HHL for prevalent vertebral fracture, spinal osteoarthritis, and other co-morbidities in postmenopausal women from the Nagano Cohort Study. In total, 942 Japanese postmenopausal outpatients (mean age: 66.7 years) were investigated. HHL was estimated by arm span – body height difference. Multiple logistic regression analysis revealed significant independent associations of HHL with prevalent vertebral fracture (odds ratio [OR] 1.89; 95% confidence interval [CI] 1.55–2.29), spinal osteoarthritis (OR 1.57; 95% CI 1.31–1.88), and gastroesophageal reflux disease (GERD) (OR 1.75; 95% CI 1.34–2.28) after adjustment for other confounders. Receiver operating characteristic curve analysis of HHL was conducted to discriminate the prevalence of co-morbidities. The optimal cut-off value as defined by the Youden index for prevalent vertebral fracture, spinal osteoarthritis, and GERD was 4.95 cm (area under the curve [AUC] 0.740; 95% CI 0.704–0.776), 2.75 cm (AUC 0.701; 95% CI 0.667–0.735), and 5.35 cm (AUC 0.692; 95% CI 0.629–0.754), respectively. Better understanding of the above relationships and proposed cut-off values will be useful for improving the diagnosis, care management, and quality of life in elderly patients.

Backgroud Changes in bone mineral density (BMD) are a potential surrogate marker for fracture endpoints in clinical trials. However little is known whether the increase in BMD in response to combination treatment with alendronate plus alfacalcidol is associated with fracture risk reduction. We aimed to evaluate the impact of BMD on fracture risk in osteoporosis patients, using the data from the randomized clinical trial comparing alendronate plus alfacalcidol with alendronate alone. Methods We selected 412 patients with two or more prevalent vertebral fractures and who had BMD measurements at baseline and after 6, 12, and/or 24 months out of 2022 patients from the database of the Japanese Osteoporosis Intervention Trial. Patients in this subset who received combination treatment with alendronate plus alfacalcidol had shown a lower risk of fracture than patients treated with alendronate alone. We used Poisson regression model analysis to calculate the proportion of treatment effect (PTE) that was attributable to BMD increases in patients receiving combination treatment. Results The highest PTE attributable to changes in BMD was 1.2% in patients with a BMD increase of 3% or more in the lumbar spine. For BMD measurements of the radius, the highest PTE was 2.8% with a BMD increase of 0% or more. For BMD measurements of the metacarpal bone, the highest PTE was 1.2% with a BMD increase of 3% or more. In patients with a BMD greater than or equal to 70% of the young adult mean in the lumbar spine, the PTE attributable to BMD was 0.2%. In patients with a BMD greater than or equal to 70% of the young adult mean in the radius, the PTE attributable to BMD was 0.3%. Conclusions The additional effects of alfacalcidol in reducing fracture risk do not likely result from increased BMD; other mechanisms remain a possibility.

The associations of multiple vitamin deficiencies on incident fractures were uncertain, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women. The number of deficiencies was additively associated with incident fracture after adjustment for possible confounding factors including the treatment of osteoporosis. To evaluate the associations of multiple vitamin deficiencies on incident fractures, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women. This analysis used a subset of the ongoing cohort maintained by a primary care institution. Inclusion criteria of the present study were postmenopausal women aged ≥ 50 years, without vitamin supplementation and secondary osteoporosis. Baseline serum concentrations of 25-hydroxyvitamin D (25(OH)D), undercarboxylated osteocalcin (ucOC), and homocysteine (Hcy) were measured to assess vitamin D, vitamin K, and vitamin B, respectively. Since 25(OH) D positively relates to vitamin D, ucOC and Hcy negatively relate to vitamin K and vitamin B nutrients, respectively, the subjects with lower (25(OH)D) or higher (ucOC or Hcy) values than each median value was defined as subjects with the corresponding vitamin deficiency. Subjects were divided into four groups according to the number of deficiency: no deficiency, single deficiency, double deficiencies, and triple deficiencies. Relationships between the vitamin deficiencies and incident fractures were evaluated by Cox regression analysis. A total of 889 subjects were included in this analysis; their mean and SD age was 68.3 ± 9.5 years, and the follow-up period was 6.3 ± 5.1 years. The numbers of subjects in the four groups were 139 (15.6%), 304 (34.2%), 316 (35.5%), and 130 (14.6%) for the groups with no, single, double, and triple deficiencies, respectively. Incident fractures were observed in 264 subjects (29.7%) during the observation period. The number of deficiencies was significantly associated with incident fracture (hazard ratio 1.25, 95% confidence interval 1.04–1.50, P = 0.018) after adjustment for possible confounding factors including the treatment of osteoporosis. Accumulation of vitamin deficiencies was related to incident fractures.

Very few reports have described changes in bone mineral density (BMD) with long-term, once weekly administration of elcatonin, and its effects in reducing incident fractures remain unverified. Therefore, the efficacy and safety of once weekly elcatonin were examined over a 3 year period.This was a multicenter, double-blinded, randomized, placebo-controlled study. Postmenopausal women with primary osteoporosis received either 20 units of elcatonin (EL group, n = 433) or placebo (P group, n = 436) once a week for 144 weeks (3 years) intramuscularly. The primary endpoint was the incidence of new vertebral fractures at 24, 48, 72, 96, 120, and 144 weeks after the start. Secondary endpoints were the incidence of non-vertebral fractures, changes in lumbar, hip total and femoral neck BMD, and the incidence of adverse drug reactions (ADRs).No significant reduction in the incidence of new vertebral fractures was found in the EL group. The percentage increase in lumbar BMD was significantly higher in the EL group from 24 weeks to the last administration. Although the EL group showed tendencies toward smaller decreased hip total and femoral neck BMD, no significant differences were observed between groups. The incidence of ADRs was significantly greater in the EL group, although these have all been previously reported and no new safety concerns were identified.Once weekly injection of 20 units of elcatonin significantly increased lumbar BMD over a 3 year period and did not cause any safety problems, but no significant reduction in the incidence of vertebral or non-vertebral fractures was demonstrated.

Summary Annual intravenous administration of zoledronic acid is used in the treatment of osteoporosis. A mathematical model was developed to predict bone mineral density up to 2 years after two annual doses of zoledronic acid from the early values of a bone resorption marker in osteoporosis patients. Introduction The measurement of bone mineral density (BMD) has been used as a surrogate marker instead of the observation of incident fractures to detect the efficacy of treatment. However, this method requires a long time to obtain significant changes. On the other hand, bone resorption markers respond to bone resorption inhibitors within a few weeks. Therefore, the aim of this study was to develop a mathematical model predicting long-term BMD after two annual doses of zoledronic acid (ZOL) using the early response of a bone resorption marker in osteoporosis patients. Methods The model was constructed using 3410 tartrate-resistant acid phosphatase 5b (TRACP-5b) serum concentrations and 1146 lumbar spine (L2-L4) BMD values from 306 patients with primary osteoporosis. A mathematical model was developed to describe the time-dependent profiles of TRACP-5b and BMD. Results The percentage changes from baseline of the BMD (%BMD) at up to 2 years were predicted from patients’ baseline BMD and baseline and 12-week TRACP-5b values by the model obtained. The simulated 90% prediction interval almost covered the observed %BMD distribution at each time point, and the predictions were comparable to the observed %BMD. Conclusions This is the first model to predict BMD for up to 2 years following two annual doses of ZOL using patients’ background characteristics and the early response of TRACP-5b. This model allows us to inform patients at the initial stage of ZOL treatment of their predicted response to treatment. Electronic supplementary material The online version of this article (10.1007/s00198-018-4376-1) contains supplementary material, which is available to authorized users.

Decline of body weight with aging is a major risk factor for frailty, osteoporosis and fracture, suggesting that treatment for osteoporosis may affect body composition. Recently, we have shown that 5-year treatment with raloxifene prevented age-related weight loss, suggesting some other drugs for osteoporosis may also prevent a decrease in body weight with aging. The present study aimed to identify the relationship between bisphosphonate treatment and body composition markers. We measured bone mineral density (BMD), body composition, and bone remodeling markers in 551 Japanese postmenopausal women with bisphosphonate treatment, which included risedronate or alendronate treatment (BP-treatment group; N = 193) and without treatment by any osteoporosis drug (no-treatment group; N = 358) for 4–7 years (mean observation periods; 5.5 years) and analyzed the relationship of these with BMD, body mass index (BMI), body weight, and biochemical markers. The mean (SD) age of the participants was 68.6 (9.8) years in the BP-treatment group and 63.7 (10.6) years in the no-treatment group. Percent changes in body weight and BMI were significantly different between the BP-treatment and no-treatment groups (P

This study investigated the relationships between intakes of polyunsaturated fatty acids, omega-3 fatty acids, and omega-6 fatty acids and bone mineral density in Japanese women aged 19 to 25 years. Intakes of omega-3 fatty acids (n-3) were positively associated with peak bone mass at the hip. Lifestyle factors such as physical activity and nutrition intake are known to optimize the peak bone mass (PBM). Recently, intake of polyunsaturated fatty acids (PUFAs) has been reported to contribute to bone metabolism. In this study, the relationships of intakes of n-3 and omega-6 (n-6) fatty acids with PBM were evaluated in Japanese female subjects. A total of 275 healthy female subjects (19–25 years) having PBM were enrolled, and lumbar and total hip bone mineral density (BMD) and bone metabolic parameters were measured. Dietary intakes of total energy, total n-3 fatty acids, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and total n-6 fatty acids were assessed by a self-administered questionnaire. Physical activity information was also assessed. The mean ± SD age was 20.6 ± 1.4 years, and BMI was 21.2 ± 2.7 kg/m2. BMI and serum bone alkaline phosphatase contributed significantly to lumbar BMD on multiple regression analysis. Intake of n-3 fatty acids and physical activity were also significantly related to total hip BMD. Using EPA or DHA instead of total n-3 fatty acids in the model did not result in a significant result. Adequate total n-3 fatty acid intake may help maximize PBM at the hip.

Although associations among obesity, adipocytokines, and bone mineral density have been reported, the influence of adipocytokines on osteoporotic fractures remains unclear. This study aimed to assess the impact of the adipocytokines leptin and adiponectin on the risk of incident vertebral and long-bone fractures in postmenopausal women. Clinical data were obtained from the retrospective Nagano Cohort Study of outpatients followed at a single primary care institute in Nagano Prefecture, Japan, between 1993 and 2018. The primary outcome was the occurrence of incident vertebral or long-bone fractures. In total, 1167 Japanese postmenopausal women (mean age: 65.9 years) completed the follow-up and the average observation period was 7.2 years. The subjects were divided into 4 groups (quartile 1 to 4) based respective leptin and adiponectin values. Kaplan-Meier analysis demonstrated a significantly lower incident long-bone fracture rate in the higher quartiles of serum leptin levels (p = 0.002). A significantly higher and more rapid occurrence of incident vertebral fractures, but not long-bone fractures, was found in the highest adiponectin quartile (p 0.001). A Cox proportional hazards model adjusted for confounders including age, body weight, and either leptin or adiponectin revealed lower leptin levels and higher adiponectin levels as significant independent risk factors for incident long-bone fractures (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.50-0.96; p = 0.03) and vertebral fractures (HR 1.18, 95% CI 1.02-1.37; p = 0.02), respectively. Therefore, serum leptin and adiponectin may be independent risk factors for osteoporotic fractures affecting different bone types and sites. Determining patient adipocytokine levels may help predict the occurrence of specific osteoporotic fractures, thereby enabling optimal treatment for osteoporosis and improving quality of life.

Pentosidine is the most well-characterized advanced glycation end product (AGE). It has been measured by HPLC, although this approach cannot be adapted to analyze many clinical samples and is also time-consuming. Furthermore, the detection of pentosidine using a reported ELISA kit and HPLC system requires pretreatment by heating, which generates artificial pentosidine leading to overestimation. We developed a novel pentosidine ELISA system that don't require sample pretreatment for analyzing urine samples. We then analyzed the accuracy, precision, and reliability of this system. Urinary samples for analysis were obtained from healthy volunteers and stored urinary samples from the participants of the Nagano cohort study were also used. The LoB and LoD were 4.25 and 6.24 pmol/mL, respectively. Intra- and inter-assay coefficients of variation were less than 5%. The spiking and dilution recoveries were 101.4% and 100.5%, respectively. Analysis of the cross-reactivities against seven compounds representative of AGEs and structurally similar to pentosidine showed no significant cross-reactivity. The correlation coefficient between the concentrations of pentosidine obtained from HPLC and ELISA for the same urine samples was r=0.815. The urinary excretion of pentosidine upon overnight fasting was lower than that after a meal, suggesting the presence of diurnal variation in urinary pentosidine. In contrast, day-to-day variation was not observed. These results indicate that the ELISA system has sufficient reliability, accuracy, and precision for measuring urinary pentosidine. Sampling of fasting urine is suitable for minimizing variation. In conclusion, this ELISA system is promising to evaluate the effect of AGE on lifestyle-related diseases.

We conducted a head-to-head randomized trial of minodronate, a bisphosphonate, and raloxifene, a selective estrogen receptor modulator, to obtain clinical evidence and information about their efficacy and safety. The Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04) trial is a multi-center, open-labeled, blinded endpoints, head-to-head randomized trial of minodronate and raloxifene. Ambulatory elderly women with osteoporosis (age, >60 years) were randomly allocated to the raloxifene or minodronate group by central registration. The co-primary endpoints included any one of osteoporotic fractures (vertebral, humeral, femoral, and radial fractures), vertebral fractures, and major osteoporotic fractures (clinical vertebral, humeral, femoral, and radial fractures). The biological effects of each drug, patients’ quality of life, and drug safety were assessed based on the secondary outcomes. This study was registered at the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) under trial identification number UMIN000005433. A total of 3896 patients were randomized to the minodronate and raloxifene groups, and drug efficacy assessments were performed for 3247 patients (1623 and 1624 patients, respectively). Among these patients, 1176 and 1187 patients received allocated treatment for 2 years. The incidence rate ratios for osteoporotic, vertebral, and major osteoporotic fractures in the minodronate group were 0.94 (95% CI: 0.78–1.13, p = .494), 0.86 (95% CI: 0.70–1.05, p = .147), and 1.22 (95% CI: 0.86–1.74, p = .274), respectively. Compared to the raloxifene group, the minodronate group showed significantly increased bone mineral density of the lumbar spine for each visit (6 months: p = .007, 12 months: p = .0003, 24 months: p Overall, there were no statistical differences in the incidence rates of osteoporotic, vertebral, or major osteoporotic fractures between the two groups. Serious adverse reactions were rare in both groups.

This randomized, clinical trial investigated whether zoledronic acid combined with oral health maintenance can improve periodontal disease associated with osteoporosis, thus reducing the risk of tooth loss.Participants were those of the ZONE (ZOledroNate treatment in efficacy to osteoporosis) study. None of the participants had symptomatic periodontal disease at baseline. Participants received either zoledronic acid (5 mg; n = 333 [male 21, female 312]) or placebo (n = 332 [male 19, female 313]) once yearly for 2 years, and their age was 74.0 ± 5.3 (65-88) and 74.3 ± 5.4 (65-87) years, respectively. Participants were instructed to maintain good oral hygiene at baseline and every 3 months. Participants with signs or symptoms involving their oral cavity at the monthly visit with their physician were referred to dentists for examination of oral disease. All cases were included to analyze adverse events in this study. Testing for significance was conducted using Fisher exact test (P 0.05).The incidence of oral adverse events was significantly higher in the control group (67 cases, 20.2%) than in the zoledronic acid group (47 cases, 14.1%; P = 0.04). The frequency of symptomatic periodontal disease observed during the study was significantly higher in the control group (40 cases, 12.0%) than in the zoledronic acid group (18 cases, 5.4%; P = 0.002). Loss of teeth was more frequent in the control group (36 cases, 10.8%) than in the zoledronic acid group (24 cases, 7.2%), although the difference was not significant.Zoledronic acid effectively prevented symptomatic periodontal disease in patients with osteoporosis who maintained good oral hygiene. : Video Summary: Supplemental Digital Content 1, http://links.lww.com/MENO/A438.

To evaluate whether or not the urinary pentosidine level has clinical value in the assessment of the osteoporotic fracture risk, a novel ELISA for pentosidine was used in clinical samples. This study employed a cross-sectional design to analyze a subset of postmenopausal women in the Nagano Cohort Study. A total of 517 urine samples were analyzed using an ELISA system, which can measure urinary pentosidine without hydrolysis. Patients were asked about their history of non-vertebral osteoporotic fracture and the prevalence of vertebral fracture was semi-quantitatively assessed on X-ray films. A 10-year increase in age was related to a 1.09-fold increase in the urinary pentosidine level (95% CI 1.05–1.13, P

Although once-yearly intravenous administration of zoledronic acid has been reported to inhibit bone resorption and increase bone mineral density, no studies have evaluated its effectiveness in treating osteoporosis in Japanese patients. Therefore, the purpose of this study was to investigate the pharmacokinetics and assess the safety of and changes in bone metabolism associated with zoledronic acid treatment in Japanese patients with primary osteoporosis. This was a single-administration study with a single-blind parallel-group design. The study participants were 24 Japanese patients with primary osteoporosis. The patients were divided into two groups, with each group receiving a single injection of zoledronic acid (4 or 5 mg). Pharmacokinetics and urinary excretion were then compared, and drug-related adverse events and changes in the levels of bone turnover markers were assessed at 12 months. Mean plasma concentrations of zoledronic acid peaked in both groups immediately after administration, and decreased to 1% or less of peak levels after 24 h. Noncompartmental analysis revealed that C max and the area under the curve from time zero to infinity increased in proportion to the dose. The levels of bone resorption and formation markers decreased from day 15 and from 3 months after administration respectively, and suppression of these markers remained constant for the entire study period. No serious adverse events were reported. There was no large difference between the 4- and 5-mg groups in terms of pharmacokinetics, changes in the levels of bone turnover markers, and safety profiles. This study demonstrated acceptable pharmacokinetics and changes in bone metabolism associated with zoledronic acid treatment in female Japanese osteoporosis patients. Both the 4-mg dose and the 5-mg dose demonstrated acceptable safety and sustained antiresorptive effects for the duration of the study.

Calcium intake may play an important role on bone health. The recent national nutritional survey in Japan revealed the gradual decrease in calcium intake to around 480 mg/day. In addition, the patients with low level of vitamin D become too large in proportion. The present perspective proposes to increase calcium intake in Asian population.

The aim of this study was to investigate the efficacy of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis and to explore subsets of patients for which concurrent treatment is particularly efficacious. Women with osteoporosis aged 65 years or older were recruited from 123 institutes in Japan and allocated to take either vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate (2.5 mg/day or 17.5 mg/week) alone. The primary end point was the incidence of any fracture (vertebral and nonvertebral). The secondary end points were bone mineral density, height, undercarboxylated osteocalcin concentration, quality of life, and safety. Over a 2-year follow-up, vertebral or nonvertebral fractures occurred in 117 or 22 sites respectively among 931 patients in the risedronate and vitamin K2 group and in 104 or 26 sites respectively among 943 patients in the risedronate alone group. The rates of any incident fracture were similar between the two groups (incidence rate ratio 1.074, 95 % confidence interval 0.811-1.422, p = 0.62), implying that the primary end point was not met. There were no differences in the degree of increase in bone mineral density between the two groups. Undercarboxylated osteocalcin concentration decreased from 5.81 ± 3.93 ng/mL to 2.59 ± 1.52 ng/mL at 6 months in the risedronate and vitamin K2 group, whereas the change in the risedronate alone group was minimal (from 5.96 ± 4.36 ng/mL to 4.05 ± 3.40 ng/mL at 6 months) (p

Objective: Our previous questionnaire-based survey suggested that discontinuation of antiresorptive agents before tooth extraction may increase adverse events and disturb osteoporosis treatment without completely preventing osteonecrosis of the jaw (O.N.J.). We also found little cooperation between physicians and dentists in Japan. However, limitations of our previous study included a survey of doctors belonging to small clinics and a small sample size. Our current study aimed to confirm the results of our previous survey in doctors mainly belonging to academia.Methods: A structured questionnaire including 14 key clinical queries was sent to 1812 physicians of the Japan Osteoporosis Society, and 629 responses were received.Results: Dentists requested discontinuation of many medications that were not associated with the incidence of O.N.J. A total of 523 respondents had received discontinuation requests from dentists. Of these, 97 respondents experienced 119 adverse events including 25 fractures an...

We planned to conduct multi-center, open-labeled, blinded-endpoints, head-to-head randomized trial of minodronate and raloxifene to compare incidences of vertebral and non-vertebral fractures. The study is the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-4). Here, we present the pre-fixed study design. The inclusion criteria are ambulatory older women with osteoporosis, aged > 60 years, and without pre-specified risk factors for secondary osteoporosis and dementia. The subjects who meet selection criteria will be randomly allocated to the raloxifene (60 mg/day) or minodronate (1 mg/day or 50 mg/4 weeks) groups using the central registry. The co-primary endpoints are osteoporotic (vertebral, humeral, femoral, and radial), vertebral, and major osteoporotic (clinical vertebral, humeral, femoral, and radial) fractures. Furthermore, we plan to use the Hochberg procedure to preserve an overall type 1 error rate. In addition, changes in bone mineral density (BMD), hip-structure analysis (HSA) variables, height, bone turnover markers, serum cholesterol and triglyceride concentrations, dental health questionnaire, fall frequency, fall risk index, nursing care level, physical function, quality of life (QOL), and safety profiles were assessed as secondary endpoints. To detect 24% reduction of major osteoporotic fractures with 80% power and a two-sided significance level of 5% with a 2-year observation period, 1734 patients/treatment arm would be required. Subgroup analysis stratified to the following factors age, body mass index, BMD, 25-hydroxyvitamin D concentration, estimated glomerular filtration rate (eGFR), prevalent vertebral fracture number, hypertension status, and diabetes mellitus is pre-specified. The protocol is registered in the trial registry system, and the trial identification number is UMIN000005433.

Vitamin K is a multi-functional nutrient and various tissues modify their function in response to vitamin K bioavailability mainly through post-translational modification of vitamin K-dependent (VKD) proteins. In this review, we discuss five clinical topics of vitamin K nutrition and vitamin K-dependent Gla-containing proteins. Although the physiological roles of these VKD proteins need further elucidation, study of these proteins may open new avenues for therapy in the clinical field. The topics discussed in the review are focused on des-gamma-carboxyprothrombin (DCP) in relation to the pathogenesis of hepatocellular carcinoma, osteocalcin (OC) and undercarboxylated OC (ucOC) in relation to bone fractures and insulin sensitivity, matrix Gla protein (MGP) in relation to vascular calcification, and growth arrest-specific protein-6 (Gas6) in relation to inflammation and platelet aggregation. Finally, interaction among vitamins were discussed.

Genetic factors contribute to the development of obesity.The aim of this study was to identify novel genes that regulate body fat mass.We performed a search for single nucleotide polymorphisms (SNPs) associated with body fat percentage using SNP arrays and undertook a replication study and animal study.Baseline examinations were conducted in 251 (first-stage analysis), 499 (second-stage analysis), and 732 (additional analyses) Japanese postmenopausal women. The mean age (mean ± SD) of the subjects was 66.5 ± 9.4 years. We also analyzed the fat-related phenotypes of a candidate gene in knockout mice.In the analysis of total body fat, we focused on an SNP of SLC25A24 that showed the lowest significant P value obtained from multiple comparison tests among Japanese postmenopausal women. A significant association was also found between SLC25A24 SNPs and body mass index in the 1482 Japanese postmenopausal women examined in the study. The SLC25A24 SNPs affected the mRNA expression of SLC25A24 in human preadipocytes. Compared with wild-type mice, Slc25a24-KO mice had significantly lower body weights and white adipose tissue weights. Adipocyte differentiation was inhibited in Slc25a24-KO adipose tissues and Slc25a24-knockdown adipocytes.Genetic analyses in human and mouse models revealed the importance of SLC25A24/Slc25a24 in the regulation of body fat mass and adipogenesis.

The frequency of hip fractures associated with aging of the population is declining in many countries. Even in Japan, where this frequency has been increasing continually, a shift to decreasing frequency has been noted in recent reports. The objective of this study was to investigate the effects of this decrease and to estimate the number of hip fracture patients and the resulting reduction in national medical care expenditures. The differences in the number of patients were estimated by multiplying the population for each sex and each age group by the fracture rates before the decrease (2007) and after the decrease (2012). Total reduced cost was calculated by multiplying the treatment cost required for hip fracture and the annual medical cost of nursing care. The estimated number of hip fracture patients decreased by approximately 4000 in the elderly female population, and the resulting reduction in medical costs was approximately US$280 million. The number of patients with hip fractures has decreased in elderly Japanese women; as a result, the medical costs for treatment and nursing care might decrease.

Though various physiological actions have been attributed to vitamin D, its most important function is to promote absorption of calcium from the intestinal tract. While the absorption rate of calcium is generally low, it tends to decline further with age. In addition, calcium intake is decreasing in recent years in Japan. Therefore, it is important to increase the intestinal calcium absorption rate. Eldecalcitol has been shown to increase calcium absorption from the intestinal tract, suppress bone resorption, increase bone mineral density, and prevent fractures. Elocalcitol use leads to a lower systemic active vitamin D[1α,25(OH)

To clarify the additional efficacy and safety benefits of 24 months’ treatment with the once-weekly formulation of teriparatide, which is currently used for 72 weeks. This was a multicenter, open-label, single-arm study conducted in Japan. Subjects who were 65 years or older with prevalent vertebral fractures received once-weekly subcutaneous injection of 56.5 μg teriparatide for 24 months. The main outcome measure was percentage change from baseline in lumbar (L2–L4) BMD measured by dual-energy X-ray absorptiometry. A total of 189 subjects received at least one dose of the once-weekly formulation of teriparatide. Lumbar, femoral neck, and total hip BMD increased significantly compared with baseline at Weeks 24, 48, 72, and 104. In addition, significant increases in lumbar (+1.5%) and femoral neck (+0.8%) BMD were noted at Week 104 compared with Week 72. Significant increases from baseline in BMD for radius 1/10 were noted at Weeks 24 and 104. No substantial increases were noted in the cumulative incidences of new vertebral fracture and other types of fracture after Week 72. The safety profile seen in the first 72 weeks remained unchanged until 104 weeks. The once-weekly formulation of teriparatide is effective and safe for the treatment of osteoporosis over 24 months. The limitation of this study is that this was an open-label, single-arm study. Funding: Asahi Kasei Pharma Corporation. Clinical Trial Registration: JapicCTI-132276.

Populations of East Asian countries have been known to have low calcium intakes and low serum 25(OH)D concentrations, suggesting that Ca and vitamin D (VitD)-deficiencies are commonly observed. These nutritional imbalances may lead to low peak bone mass (PBM). The low PBM seen in Ca/VitD-deficient individuals may lead to osteoporosis, as well as an increased risk of fracture. A survey was conducted in young Japanese women (n = 296, 21.2 ± 2.3 years old) on their Ca/VitD intakes and serum 25(OH)D levels, which demonstrated a significant positive correlation between VitD intake and serum 25(OH)D levels (R 2 = 0.020, P = 0.016), and the proportion with serum 25(OH)D over 20 ng/mL was significantly increased with VitD intake (P = 0.013). Serum 25(OH)D was negatively correlated to serum intact parathyroid hormone (R 2 = 0.053, P

Increasing evidence suggests that osteocalcin is involved in the regulation of glucose homeostasis. However, the relationship between serum osteocalcin levels and risk of incident type 2 diabetes mellitus is not clear. The objective of this study is to investigate whether serum osteocalcin levels are associated with the risk of incident type 2 diabetes mellitus. This study included 1691 Japanese postmenopausal women, 61 incident diabetes cases, and 1630 non-diabetic control subjects in the observation period. Baseline concentrations of intact osteocalcin, HbA1c, bone-specific alkaline phosphatase, adiponectin, leptin, urinary N-telopeptides were assessed. Serum osteocalcin levels were significantly correlated with HbA1c levels among 1691 Japanese postmenopausal women (R = -0.12, P 0.0001). In receiver operating characteristic curve analysis, the optimal cut-off levels for serum osteocalcin to predict the development of type 2 diabetes mellitus was 6.1 ng/mL. The group with baseline osteocalcin levels6.1 ng/mL showed a significantly higher risk for developing diabetes than the group with baseline osteocalcin levels6.1 ng/mL (log-rank test, P 0.0001) during the mean observation period (7.6 ± 6.1 years; mean ± SD). In multiple Cox proportional hazard analysis, osteocalcin levels were significantly associated with development of type 2 diabetes mellitus during the observation period. Our results indicate that a decrease in serum osteocalcin levels is associated with future development of type 2 diabetes mellitus independent of conventional risk factors in Japanese postmenopausal women.

Bisphosphonate (BP)-associated osteonecrosis of the jaw (ONJ) was first reported in oncology patients in 2003 and subsequently in osteoporosis patients in 2004. Since oral surgical procedures, such as tooth extraction, are also considered one of the major risk factors for ONJ, there is confusion among physicians, dentists, and patients—particularly osteoporosis patients currently taking BPs—regarding the safety of remaining on therapy surrounding these procedures. Many papers about BP-related ONJ (BRONJ) have been published to date. In addition to BRONJ, recent studies have reported an association between ONJ and the antiresorptive therapy denosumab (Dmab; a RANKL-inhibitor). BRONJ and Dmab-related ONJ are together referred to as antiresorptive agent-related ONJ (ARONJ). The pathogenesis of ARONJ still remains unknown. It is forecasted that there will be an increased incidence of patients with osteoporotic fractures and an increased number of prescriptions for antiresorptive agents in Asia in the future. However, prescriptions for antiresorptives for osteoporosis may be restricted in the Asian population as the occurrence of ARONJ may be higher as compared with those in other countries. In this review, we focused on the following topics as it pertains to the Asian osteoporotic population: the oral condition specific for osteoporosis patients; definition, staging, prevalence and incidence of ARONJ; imaging modalities for ARONJ; specific risk factors for ARONJ; prevention strategies for ARONJ, and; cooperation between physicians and dentists in the prevention of ARONJ. Ideally, the Asian Federation of Osteoporosis Societies would cooperate with one another and find more population-specific evidence for the prevention of ARONJ.

Assessment of vertebral fracture is critically important for the diagnosis and treatment of osteoporosis. This study aimed to clarify the effectiveness of the semiquantitative (SQ) method in the assessment of vertebral fractures in Japanese clinical practice. Forty-four physicians (seven experts and 37 nonexperts) assessed the spinal radiographs of 40 patients participating in the Adequate Treatment of Osteoporosis (A-TOP) Japanese Osteoporosis Intervention Trial (JOINT)-02 at the baseline, 12 months, and 24 months using the SQ method. The proportion of diagnosed fracture cases per spine was higher in the nonexpert group than in the expert group at each time point, and was especially high in the upper thoracic spine (T4-T6). The least mean squares spinal fracture index was significantly higher in the nonexpert group than in the expert group for all time points. The kappa statistics were also higher in the expert group than in the nonexpert group for all vertebral levels at all time points. Assessment of vertebral fractures using the SQ method tended to be overestimated by nonexpert physicians compared with the experts, with poor nonexpert interobserver reliability and well-matched expert interobserver reliability. Conscious efforts to avoid overestimation and to obtain higher reliability with the SQ method should be made to achieve more precise diagnoses and treatment of osteoporosis in Japanese clinical practice.

BackgroundDeteriorated quality of life (QOL) is a major problem in osteoporotic women. However, little is known regarding the determinants of QOL in patients with osteoporosis.ObjectiveOur aim was to explore the role of vitamin D status on QOL score in osteoporosis with high fracture risk.MethodsPatients were osteoporotic women aged ≥70 years and with ≥1 risk factor for incident fracture, namely prevalent osteoporotic fracture, bone mineral density (BMD) >–3.0 SD of young adult mean, or high bone turnover marker. Health-related QOL was assessed using the Japanese Osteoporosis Quality of Life Questionnaire (JOQOL). When patients were classified into quartiles by total QOL score). Serum 25-hydroxyvitamin D (25[OH]D) level was measured by immunoassay.ResultsA total of 1585 osteoporotic women were included in the study (age range, 70–95 years). Age, body mass index, serum 25(OH)D status (low, normal, or high), bone mineral density, number of prevalent vertebral fractures, presence of hypertension, presence of osteoarthritis, and history of falls were significantly correlated with QOL quartile. Multivariate liner regression analysis indicated that low serum 25(OH)D level (20 ng/mL may be required to maintain patients’ QOL in osteoporosis.

In the original publication of the article, the following sentence under the abstract section was published incorrectly as “A multivariable logistic regression analysis revealed that urinary pentosidine was significantly associated with the prevalence of fracture after adjustment for known risk factors for fracture (odds ratio 1.92, 95% CI 1.09–3.37, P = 0.023).”

Aim Elevation of homocysteine is associated with an increased risk for bone fractures. We previously reported that the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism is associated with homocysteine levels and fracture. The association between the fracture and folate levels or their related gene polymorphisms is not completely clear. We speculated that the SLC25A32 gene, the mitochondrial inner membrane folate transporter, also could be implicated in the regulation of folate metabolism and fracture. Methods A total of 851 Japanese postmenopausal women participated in the association study between the single nucleotide polymorphism genotype and plasma homocysteine or folate. We also tested the association between the candidate single nucleotide polymorphism and 663 postmenopausal women. Results The AA genotype of rs2241777 single nucleotide polymorphism at the 3′UTR region in the SLC25A32 gene was associated with lower plasma folate concentration compared with the other genotypes in 851 postmenopausal women. A total of 674 postmenopausal ambulatory Japanese women were followed up for 5.5 ± 0.1 years (mean ± SE). The AA genotype groups also showed an apparently higher rate and earlier onset of incident fractures than the other genotypes. A total of 407 participants had >70% young-adult mean bone mineral density at the start of the observation. Conclusions These results show that the SLC25A32 gene polymorphism could be a risk factor for lower folate concentration and future fracture. Geriatr Gerontol Int 2014; 14: 942–946.

There is emergent evidence for divergent associations between 25(OH)D levels and fractures by race and ethnicity, but data on Asian populations are sparse. We investigated this association in a primary care cohort of 1470 postmenopausal Japanese women followed for a mean period of 7.2 years and explored a potential threshold of 25(OH)D. Endpoints were incident vertebral, proximal femur, and long bone fractures. Rate ratios were estimated using multivariate Poisson regression adjusted for lumbar or femur bone mineral density (BMD) less than -2.5 SD of the young adult mean (YAM), age, weight, presence of diabetes mellitus, parathyroid hormone, estimated glomerular filtration rate, prior fracture, back pain, present medications and past medical history. Mean age was 63.7 ± 10.7 years and osteoporosis patients were 41.3 %. The background data of the present participants were almost identical to the subjects participating in the National Health and Nutrition Survey of 2003. Overall, 49.6 % of the subjects had a 25(OH)D value20 ng/mL and 27.8 % had a 25(OH)D value from 20 to 24 ng/mL. The propensity score for exposure to 25(OH)D25 ng/mL in the present and independent community dwelling populations, namely the Miyama and Taiji cohorts, were not significantly different, suggesting no evidence for selection bias. The generalized additive models showed clear decreasing trends in incidence rates of proximal femur and long bone fractures at higher levels of 25(OH)D, and the annual incidence rate of proximal femur fracture was around 0.0005 in women with 25(OH)D25 ng/mL, probably leading to the decreasing trend in long bone fracture. Multivariate-adjusted rate ratios of 25(OH)D25 ng/mL were 1.01 (95 % confidence interval [CI], 0.84-1.22, p = 0.88) for vertebral fracture, 2.71 (95 % CI 0.94-7.83, p = 0.07) for proximal femur fracture, and 2.20 (95 % CI 1.37-3.53, p0.01) for long bone fracture. The respective rate ratios of a BMD level lower than -2.5 SD of the YAM were 1.61 (95 % CI 1.33-1.94, p0.01), 1.52 (95 % CI 0.67-3.45, p = 0.32), and 1.54 (95 % CI 1.02-2.33, p = 0.04). In conclusion, 25(OH)D is a leading risk factor for long bone fracture comparable to BMD in Japanese postmenopausal women. The contribution of 25(OH)D to fracture risks is substantial even below 25 ng/mL and is possibly site-specific. We recommend measuring the serum 25(OH)D level in primary care settings.

Concurrent treatments with bisphosphonates and vitamin K are promising given that bisphosphonates possibly interfere with vitamin K activation. This is a prospective, multi-center, open-labeled, randomized trial of the efficacy of concurrent treatment with vitamin K2 and risedronate compared with risedronate alone and to explore subsets of patients for which concurrent treatment is particularly efficacious (trial identification number UMIN000000991). Inclusion criteria are women who meet the criteria for pharmacological therapy for osteoporosis, aged ≥65 years, have any of pre-specified risk factors, can walk unassisted, and are able to answer questionnaires. Exclusion criteria are prior warfarin use, secondary osteoporosis or non-osteoporotic metabolic bone diseases, contraindication for vitamin K2 and risedronate, hyper- or hypoparathyroidism, mental disorders, prevalent vertebral fracture at ≥6 sites, severe degenerative spinal deformation between T4 and L4, serious heart, liver, or kidney disease, or bisphosphonate use within the previous 6 months. Patients were recruited from 123 institutes between January 2008 and February 2010, and allocated to vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate alone (2.5 mg/day or 17.5 mg/week) groups. Primary endpoint is a vertebral or non-vertebral fracture. Secondary endpoints are bone mineral density, height, undercarboxylated osteocalcin, JOQOL, EQ-5D and safety. A sample size of 910 subjects per group and 2-year follow-up will provide 80 % power to detect 35 % risk reduction for fracture, with a two-sided significance level of 5 %. Subgroup analysis stratified to adjustment factors for random allocation, body mass index, 25-hydroxyvitamin D, estimated glomerular filtration rate, grade of vertebral fracture, JOQOL, EQ-5D, and co-morbidity is pre-specified.

The aim of this cross-sectional cohort study was to clarify risk factors for severe vertebral fractures in postmenopausal Japanese women. Subjects were ambulatory volunteers age over 50 years who were recruited from a population of outpatients at a primary care institute. At registration, age, body mass index (BMI), bone mineral density (BMD), and present illness were investigated. Biochemical parameters including urinary levels of type I collagen cross-linked N-telopeptides (NTXs), and pentosidine and plasma levels of homocysteine were measured. Values were compared with different fracture grades (grade 0-3). A total of 1,475 postmenopausal women (66.6 ± 9.0 years) were included in the present study. Distributions of vertebral fracture grades were grade 1, 137 cases (9.3 %); grade 2, 124 cases (8.4 %); and grade 3, 162 cases (11.0 %). Age, BMI, BMD, NTX, pentosidine, and homocysteine were significantly associated with vertebral fracture in unadjusted analysis. In addition, a higher prevalence of hypertension was observed in patients with severe fracture. When comparing vertebral fracture grade 0 versus grade 2-3 by multiple regression analysis, pentosidine and homocysteine levels were a significant risk for moderate/severe vertebral fracture (odds ratio [OR] = 1.17, 95 % confidence interval [CI] 1.00-1.38, p = 0.049; OR = 1.22, 95 % CI 1.03-1.46, p = 0.013). Homocysteine levels were also a significant risk when comparing vertebral fracture grade 0 versus grade 3 (OR = 1.27, 95 % CI 1.04-1.58, p = 0.021). Plasma level of homocysteine was an independent risk for severe vertebral fractures.

Eldecalcitol, a vitamin D3 analogue, significantly reduces the risk of new vertebral fractures and increases bone mineral density (BMD) more than does alfacalcidol. To determine the effect of eldecalcitol on the incidence of all fragility fractures caused by osteoporosis, we conducted post hoc analyses of the phase III clinical trial to evaluate the incidence of the osteoporotic fractures defined in the World Health Organization (WHO) Technical Report, and, also, the incidence of the major osteoporotic fractures utilized in the WHO Fracture Risk Assessment Tool (FRAX), and compared those in the eldecalcitol group with those in the alfacalcidol group. We also analyzed the incidence of osteoporotic fractures stratified by prespecified risk factors for fractures. Eldecalcitol treatment reduced the incidence of osteoporotic fractures defined by the WHO more than alfacalcidol treatment (18.6 % vs. 25.2 %; hazard ratio, 0.70; 95 % CI, 0.54-0.93). Prevalent vertebral fractures, two or more prevalent vertebral fractures, and total hip BMD T score less than -2.5 were the risk factors for new osteoporotic fractures with significant differences between the two treatments. Eldecalcitol also decreased the incidence of major osteoporotic fractures in the FRAX more than alfacalcidol (11.1 % vs. 16.3 %; hazard ratio, 0.66; 95 % CI, 0.46-0.94). In conclusion, treatment with eldecalcitol reduced the risk of fragility fractures caused by osteoporosis compared with alfacalcidol administration, which may result from a potent effect of eldecalcitol on BMD, bone structure, and bone turnover.

In 1995, the Japanese Society for Bone and Mineral Metabolism (now the Japanese Society for Bone and Mineral Research) established the Osteoporosis Diagnostic Criteria Review Committee. Following discussion held at the 13th scientific meeting of the Society in 1996, the Committee, with the consensus of its members, proposed diagnostic criteria for primary osteoporosis. The Committee revised those criteria in 1998 and again in 2000. The Japanese Society for Bone and Mineral Research and Japan Osteoporosis Society Joint Review Committee for the Revision of the Diagnostic Criteria for Primary Osteoporosis aimed at obtaining international consistency and made a revised edition based on the new findings in 2012.

Summary In a 2-year randomized, placebo-controlled study of 665 Japanese patients with primary osteoporosis, once-yearly administration of zoledronic acid (5 mg) reduced the risk of new morphometric vertebral fractures. Introduction The purpose of this study was to determine the efficacy and safety of once-yearly intravenous infusion of ZOL in Japanese patients with primary osteoporosis. Methods This was a two-year multicenter, randomized, placebo-controlled, double-blind, parallel-group comparative study (ZONE Study). Subjects were 665 Japanese patients between the ages of 65 and 89 years who had prevalent vertebral fracture. Subjects were randomly assigned to receive once-yearly intravenous infusion of 5 mg of ZOL or placebo at baseline and 12 months. Results The 2-year incidence of new morphometric vertebral fracture was 3.0 % (10/330 subjects) in the ZOL group and 8.9 % (29/327) in the placebo group (p = 0.0016). The 24-month cumulative incidence of new morphometric vertebral fracture was 3.3 % in the ZOL group versus 9.7 % in the placebo group (log-rank test: p = 0.0029; hazard ratio: 0.35; 95 % confidence interval: 0.17–0.72). The cumulative incidence of any clinical fracture, clinical vertebral fracture, and non-vertebral fracture was significantly reduced in the ZOL group by 54, 70, and 45 %, respectively, compared to the placebo group. At 24 months, ZOL administration increased bone mineral density in the lumbar spine, femoral neck, and total hip (t test: p