Reliability of early stage symptoms/clinical findings of osteonecrosis of the jaw: Japanese Osteoporosis Intervention Trial-05 (JOINT-05).

INTRODUCTION: To investigate the differences in the incidence rates of suspected stage 0/1 osteonecrosis of the jaw (ONJ) and incidence risk of relevant clinical findings of suspected stage 0 ONJ between patients treated with sequential therapy comprising weekly teriparatide for 72 weeks followed by alendronate for 48 weeks vs. those who received monotherapy with alendronate for 120 weeks. MATERIALS AND METHODS: Suspected stage 0/1 ONJ was defined by non-specific symptoms. Tooth mobility and periodontal symptoms (gingival bleeding, swelling, and/or pain) were selected as clinical findings of suspected stage 0 ONJ. Poisson regression models were applied to calculate the incidence rate ratios of suspected stage 0/1 between the teriparatide group (TG) and alendronate group (AG). Generalized linear models were used to calculate the risk ratios of clinical findings between groups. RESULTS: Two hundred and sixty-one participants in the TG and 344 in the AG answered a structured questionnaire on oral health and were included in this study. There were no significant differences between the groups in the incidence rate of suspected stage 0/1 ONJ at both 72 and 120 weeks. The risk ratio of the TG to AG for tooth mobility was 0.34 (95% confidence interval [CI] 0.13-0.88, p = 0.02) at 72 weeks and 0.90 (95% CI 0.40-2.03, p = 0.83) at 120 weeks. The incidence rate of tooth mobility related to periodontal symptoms decreased in the TG and increased in the AG during the study. CONCLUSION: Tooth mobility accompanied by clinical periodontal symptoms may be a useful early sign of stage 0 ONJ.

Adverse Metabolic Effects on Glucose in Patients Receiving Anamorelin Using a Japanese Claims Database.

BACKGROUND: Anamorelin is the first drug approved for the treatment of cancer cachexia, a debilitating condition characterized by weight loss, anorexia, and muscle mass depletion. Cachexia negatively affects a patient's quality of life, survival, and response to chemotherapy. Studies describing anamorelin use are currently limited to a small number of pancreatic cancer cases. OBJECTIVES: We aimed to examine the incidence and risk factors of adverse metabolic effects on glucose levels in cachexia patients with various carcinomas treated with anamorelin. METHOD: We used real-world data of patients who received anamorelin between August 2021 and July 2022 and were registered in the JMDC claims database. We investigated the impact of metabolic adverse effects on glucose in patients receiving anamorelin with respect to the following factors: sex (male), age (>75 years), types of carcinoma, history of diabetes mellitus (DM), and concomitant use of steroids. RESULTS: The incidence of adverse metabolic effects on glucose was 12.3%, and pancreatic cancer and history of DM were associated with adverse metabolic effects on glucose. The median onset of adverse metabolic effects on glucose was 17 days after anamorelin treatment. CONCLUSIONS: This study highlights the need to monitor and manage hyperglycemia in cachexia patients receiving anamorelin, especially in those with pancreatic cancer and a history of DM.

An online survey on coping methods for genitourinary syndrome of menopause, including vulvovaginal atrophy, among Japanese women and their satisfaction levels.

BACKGROUND: This study aimed to explore the current situation and existing issues regarding the management of vulvovaginal atrophy (VVA) or the genitourinary syndrome of menopause (GSM). A nationwide web-based questionnaire survey was conducted among 1,031 Japanese women aged 40 years or older. MATERIALS AND METHODS: Eligible women were asked to complete a questionnaire about how they dealt with their symptoms and how satisfied they were with their coping methods. RESULTS: Of those highly conscious of their GSM symptoms (n = 208; 20.2%), 158 had sought medical consultation (15.3%), with only 15 currently continuing to seek consultation (11.5%). Of the specialties consulted, gynecology was the most frequently consulted (55%). Furthermore, those unwilling to seek medical consultation despite their symptoms accounted for the greatest proportion (n = 359; 34.8%), with 42 (23.9%) having never sought consultation. Topical agents, e.g., steroid hormone ointments/creams, were the most frequent treatments provided by the clinics (n = 71; 40.3%), followed by oral and vaginal estrogens (n = 27; 15.5%), suggesting that estrogen therapy was not the first choice of treatment at the clinics. While 65% of patients treated at the clinics reported satisfaction with the treatments, this was inconsistent with the fact that many were reported to have remained untreated and very few continued with treatment. CONCLUSIONS: Survey results suggest that GSM, including VVA, remains underdiagnosed and undertreated in Japan. Medical professionals should deepen their understanding of GSM and raise their level of care to select the appropriate treatment for the condition.

Effect of Bone Resorption Inhibitors on Serum Cholesterol Level and Fracture Risk in Osteoporosis: Randomized Comparative Study Between Minodronic Acid and Raloxifene.

The positive link between osteoporosis and hypercholesterolemia has been documented, and bone resorption inhibitors, such as nitrogen-containing bisphosphonates (N-BP) and selective estrogen receptor modulators (SERMs), are known to reduce serum cholesterol levels. However, the relationship between the baseline cholesterol level and incident fracture rate under the treatment using the bone resorption inhibitors has not been documented. We investigated the relation between vertebral fracture incident and the baseline cholesterol levels and cholesterol-lowering effect of N-BP and SERM in osteoporosis through a prospective randomized open-label study design. Patients with osteoporosis (n = 3986) were allocated into two groups based on the drug used for treatment: minodronic acid (MIN) (n = 1624) as an N-BP and raloxifene (RLX) as an SERM (n = 1623). Serum levels of cholesterol and incidence of vertebral fracture were monitored for 2 years. The vertebral fracture rates between the two groups were compared using the pre-specified stratification factors. The patients receiving MIN with baseline low-density lipoprotein (LDL)-cholesterol level of ≥ 140 mg/dL, high-density lipoprotein cholesterol level < 40 mg/dL, age group of ≥ 75 years, and T score of BMD ≥ -3 SD had significantly lower vertebral fracture rates than those receiving RLX (incidence rate ratios (IRR) 0.45 [95% confidence interval (CI) 0.30 0.75, p = 0.001], 0.25 [95% CI 0.09 0.65, p = 0.005], 0.71 [95% CI 0.56 0.91, p = 0.006], 0.47 [95% CI 0.30 0.75, p = 0.0012], respectively). The cholesterol-lowering effect was stronger in the RLX group than in the MIN group, regardless of prior statin use. These results indicated that MIN treatment was more effective in reducing fracture risk in patients with higher LDL cholesterol levels, although its cholesterol-lowering ability was lesser than the RLX treatment.Trial registration University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR), No. UMIN000005433; date: April 13, 2011.

Evaluation of the efficacy of Lactobacillus-containing feminine hygiene products on vaginal microbiome and genitourinary symptoms in pre- and postmenopausal women: A pilot randomized controlled trial.

As estrogen level decreases with aging, the vaginal mucosa gets thinner, and collagen amount decreases. In addition, the population of Lactobacillus in the vagina declines, increasing the risk of atrophic vaginitis, bacterial vaginosis, and genitourinary symptoms in the postmenopausal women. In this study, we evaluated the effects of Lactobacillus-containing feminine hygiene products on vaginal microbiome and genitourinary symptoms in pre- and postmenopausal women. This was a pilot randomized controlled trial in 35 premenopausal and 35 postmenopausal healthy women. For 4 weeks, treatment 1 group (14 premenopausal and 16 postmenopausal women) used the Lactobacillus-containing feminine soap and cream, and treatment 2 group (15 premenopausal and 14 postmenopausal women) used Lactobacillus-containing feminine gel in addition to soap and cream. The remaining 6 premenopausal and 5 postmenopausal women served as controls without using any products. We then compared the changes in the vaginal microbiota, genitourinary symptoms, and other related biomarkers after completion of treatment. Vaginal pH and pathogenic flora were reduced in both treatment groups compared to control group, which was more significant in the treatment 2 group of postmenopausal women. Genitourinary symptoms significantly improved in 60% of premenopausal women in treatment 1 group and 81.3% of postmenopausal women in treatment 2 group, compared to control group (0%, p = 0.043 and p<0.01 respectively). Overactive bladder symptom scores were significantly improved after using the products in eleven out of twelve postmenopausal women suspected of having overactive bladder. The use of Lactobacillus-containing feminine products was associated with improved vaginal ecosystem and urogenital health compared to control group, especially in those women using feminine gel.

Age-Related Changes, Influencing Factors, and Crosstalk Between Vaginal and Gut Microbiota: A Cross-Sectional Comparative Study of Pre- and Postmenopausal Women.

Objective: The ideal vaginal environment is maintained by Lactobacillus species, which keep the vagina clean and free of infections, boost fertility and immunity. Age-related decline in estrogen affects Lactobacillus population, leading to dominance of nonoptimal species and increased diversity in vaginal microbiota. In this study, we compared the differences between the vaginal microbiota of pre- and postmenopausal women. We also examined the relationships between vaginal and gut microbiota, their relationships with sex hormones and equol-producing ability. Materials and Methods: This was a cross-sectional study of 35 premenopausal and 35 postmenopausal women (age range: 27-76 years). We compared parameters such as the composition of the gut and vaginal microbiota, vaginal pH, estradiol, follicular stimulating hormone, and urinary equol concentration. Results: In the vaginal microbiota of premenopausal women, Lactobacillus species constituted ∼71.98%, and nonoptimal species constituted ∼16.87%. They were 10.08% and 26.78%, respectively, in the vaginal microbiota of postmenopausal women. The proportion of Lactobacillus was significantly low, whereas microbial diversity and vaginal pH were significantly high (p < 0.0001) in postmenopausal women. The compositions of the vaginal microbiota were significantly different in pre- and postmenopausal women. However, such differences were not noticeable in the gut microbiota. Urinary equol production had no significant correlation with vaginal microbiota, although it had significant relationships with gut microbiota in postmenopausal women. In both groups, the proportions of vaginal Lactobacillus were inversely correlated with vaginal microbial diversity and vaginal pH. Conclusion: Postmenopausal women had significantly low Lactobacillus and high nonoptimal species in their vaginal flora, whereas such age-related differences were not identified in gut microbiota. Urinary equol concentration had significant correlation with gut microbiota in postmenopausal women only. This study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (Trial registration No.: UMIN000043944).

TRACP-5b/BAP Score After 3 Months of Treatment With Combined SERM/E2 Therapy Can Predict Changes in Lumbar Spine Bone Mineral Density After 1 Year of Treatment in Early Postmenopausal Osteopenia.

Although changes in bone mineral density (BMD) are important indexes in osteoporosis treatment, no markers are available to predict them. Given the importance of assessing the therapeutic windows of antiresorptives, we explored potential biomarkers of bone remodeling in patients receiving treatment for osteopenia. Postmenopausal women with osteopenia (defined as a lumbar BMD T-score <-1.0 standard deviation (SD) below that of a reference population but >-2.5 SD) were administered estradiol 1 mg/d and bazedoxifene 20 mg/d. After 3 months of treatment, we evaluated their ratio of serum bone-specific tartrate-resistant acid phosphatase to bone-specific alkaline phosphatase (TRACP-5b/BAP), which is widely used for evaluating bone turnover in postmenopausal patients with osteoporosis in Japan because their minimum significant changes are smaller than other bone turnover markers such as carboxy-terminal collagen cross-links (CTX) or N-terminal propeptide of type I procollagen (P1NP) and thus, accurately reflect bone turnover. After 1 year of treatment, we assessed changes in lumbar BMD. The cut-off TRACP-5b/BAP scores for a ≤-2% decrease and ≥2% increase in lumbar spine BMD were 38.4 and 29.0, respectively. The TRACP-5b/BAP scores were associated with significantly greater areas under the curve than the other evaluated parameters. These results suggest that the TRACP-5b/BAP score after 3 months of osteopenia treatment can predict changes in lumbar BMD after 1 year of treatment. Moreover, a receiver operating characteristic curve analysis of TRACP-5b/BAP scores after 3 months of antiresorptive therapy and percent changes in BMD at 1 year revealed that the TRACP-5b/BAP score, as an index of the balance between bone resorption and formation markers, has the potential to serve as a modulator of the anabolic window reflective of bone remodeling. This study's findings also suggested a role for TRACP-5b/BAP score as a predictor of a non-response to antiresorptive therapy, thus offering health economic implications for osteoporosis treatment. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Clinical Outcomes and Prevalence of Sarcopenia in Patients with Moderate to Severe COVID-19.

Background: The purpose of this study was to investigate the effectiveness and clinical outcomes of inpatient rehabilitation for patients with severe COVID-19 in Japan. Methods: Patients with severe COVID-19 who underwent rehabilitation during hospitalization were included. The Medical Research Council (MRC) score and short physical performance battery (SPPB), such as physical function assessment and the intensive care unit (ICU) mobility scale, the functional status score for the ICU, and Barthel index as activities of daily living (ADLs) were evaluated at admission and discharge or transfer from the hospital. The correlation between SPPB at discharge and each factor at admission were also analyzed. Furthermore, the prevalence of sarcopenia was evaluated by defining SPPB of <9 points at discharge as sarcopenia. Results: The median age of the total of 23 patients was 59 years (interquartile range (IQR): 47−67), 73.9% were male, and the median PaO2/FiO2 at admission was 172.0 (IQR: 123.0−209.0). All physical function and ADL parameters were significantly improved from the time of admission to discharge (p = 0.014 for the MRC score and p < 0.001 for all others). Moreover, SPPB at discharge significantly correlated with WBC (Spearman's rho = −0.473, p = 0.041), C-reactive protein (Spearman's rho = −0.468, p = 0.044), and exhibited a significant trend with PaO2/FiO2 (Spearman's rho = 0.429, p = 0.067) and age (Spearman's rho = 0.409, p = 0.083). Although the median Barthel index at discharge was 90 points, 47% of patients had sarcopenia as defined by an SPPB of <9 points. Conclusions: Early rehabilitation for patients with severe COVID-19 improved physical function and ADLs during hospitalization. However, 47% of patients had the same level of sarcopenia at discharge.

Association of Urinary Pentosidine Levels With the Risk of Fractures in Patients With Severe Osteoporosis: The Japanese Osteoporosis Intervention Trial-05 (JOINT-05).

Associations between urinary pentosidine, one of the advanced glycation end products in collagen, and the risk of fracture in patients with severe osteoporosis are unknown. In this study, we investigated whether the urinary pentosidine level is associated with the incidence of morphometric vertebral fracture and nonvertebral fracture using data of a randomized, controlled trial, JOINT-05. JOINT-05 enrolled Japanese women aged 75 years or older with primary osteoporosis. Patients were randomly assigned (1:1) to receive sequential therapy (teriparatide followed by alendronate) or monotherapy with alendronate for 120 weeks. Incidences of vertebral and nonvertebral fractures were assessed morphologically. During treatment, urinary levels of pentosidine and serum levels of bone turnover markers (osteocalcin, procollagen type I amino-terminal propeptide, and tartrate-resistant acid phosphatase 5b) were measured. A total of 967 patients with baseline pentosidine levels were included in the study. Of these, 137 had vertebral fractures, and 42 had nonvertebral fractures. The rate ratios for vertebral fracture for the second (30-39 pmol/mL), third (40-49 pmol/mL), and fourth quartile (≥50 pmol/mL) groups divided by pentosidine level compared with the first quartile (<30 pmol/mL) group were 1.65 (95% confidence interval [CI] 0.99-2.75, p = 0.06), 1.51 (95% CI 0.87-2.61, p = 0.14), and 1.69 (95% CI 1.01-2.83, p = 0.05), respectively. The corresponding rate ratios for nonvertebral fracture were 3.07 (95% CI 0.88-10.70, p = 0.08), 2.34 (95% CI 0.61-8.95, p = 0.22), and 3.95 (95% CI 1.14-13.67, p = 0.03), respectively. The association of the urinary pentosidine level with the incidence of nonvertebral fracture was the strongest among the biomarkers assessed in the study. In conclusion, the urinary pentosidine level was associated with the risk of fracture in patients with severe osteoporosis receiving teriparatide or alendronate. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Influence of symptomatic periodontal disease on changes in skeletal bone density during medication therapy for osteoporosis in postmenopausal women: the Japanese Osteoporosis Intervention Trial (JOINT)-04 and JOINT-05.

Japanese postmenopausal women with symptomatic periodontal disease had a significantly smaller increase in the T-score for total hip bone density than those without periodontal disease during medication therapy for osteoporosis. Intervention to treat symptomatic periodontal disease before and/or during osteoporosis therapy could maintain the effect of osteoporosis medications. PURPOSE: Women with periodontal disease may be more likely to develop osteoporosis. We evaluated whether the presence of symptomatic periodontal disease can influence changes in skeletal bone mineral density (BMD) during medication therapy for osteoporosis in Japanese postmenopausal women. METHODS: A total of 4,258 postmenopausal women participated in the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04 trial) and number 5 (JOINT-05 trial), which were multi-center, open-label, randomized controlled trials in Japan. Of these, 3,670 non-edentulous subjects participated in the study. Subjects who had self-reported symptoms of periodontal disease at baseline were defined as having periodontal disease. The study outcome was the difference in BMD changes during the study between subjects with and without periodontal disease. Mixed models for repeated measures after adjusting for covariates were used to investigate the difference in the BMD changes during the study between subjects with and without periodontal disease. RESULTS: Subjects with periodontal disease had significantly lower T-scores for total hip (p = 0.035) and metacarpal (p = 0.048) BMD than those without periodontal disease at baseline. During medication therapy for osteoporosis, subjects with periodontal disease had a significantly smaller increase in T-score for total hip BMD than those without periodontal disease (p = 0.021), although no significant differences were observed in the changes in T-scores for other skeletal BMD measurements between subjects with and without periodontal disease. CONCLUSIONS: The presence of self-reported symptoms of periodontal disease may be associated with a decrease in the effect of osteoporosis medications in Japanese postmenopausal women.

Effects of an equol-containing supplement on advanced glycation end products, visceral fat and climacteric symptoms in postmenopausal women: A randomized controlled trial.

INTRODUCTION: Equol, an isoflavone derivative whose chemical structure is similar to estrogen, is considered a potentially effective agent for relieving climacteric symptoms, for the prevention of lifestyle-related diseases, and for aging care in postmenopausal women. We investigated the effect of an equol-containing supplement on metabolism and aging and climacteric symptoms with respect to internally produced equol in postmenopausal women. METHODS: A single-center, randomized controlled trial (registration number: UMIN000030975) on 57 postmenopausal Japanese women (mean age: 56±5.37 years) was conducted. Twenty-seven women received the equol supplement, while the remaining received control. Metabolic and aging-related biomarkers were compared before and after the 3-month intervention. Climacteric symptoms were assessed every month using a validated self-administered questionnaire in Japanese postmenopausal women. RESULTS: Three months post-intervention, the treatment group showed significant improvement in climacteric symptoms compared to the control group (81% vs. 53%, respectively, p = 0.045). We did not observe any beneficial effect on metabolic and aging-related biomarkers in the intervention group. However, in certain populations, significant improvement in skin autofluorescence, which is a measurement of AGE skin products, and visceral fat area was observed, especially among equol producers. CONCLUSION: Women receiving equol supplementation showed improved climacteric symptoms. This study offered a new hypothesis that there may be a synergy between supplemented equol and endogenously produced equol to improve skin aging and visceral fat in certain populations.

Risk factors for incident vertebral fractures in osteoporosis pharmacotherapy: a 2-year, prospective, observational study.

INTRODUCTION: To identify predictors for incident fractures in patients on pharmaceutical treatment for osteoporosis by a secondary analysis of the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04), which was a 2-year, randomized, parallel-group, controlled trial of minodronate and raloxifene in women with primary osteoporosis. MATERIALS AND METHODS: This was a prospective, observational study using JOINT-04 data, in which biomarkers, such as undercarboxylated osteocalcin (ucOC), N-telopeptide of type 1 collagen, tartrate-resistant acid phosphatase 5b (TRACP-5b), bone alkaline phosphatase, homocysteine, and pentosidine in blood, and physical functions, such as the timed up and go test and one-leg standing test with eyes open (OLST), and the fall risk index, were measured. The relationships of incident morphometric vertebral fractures during the treatment period, as well as prevalent vertebral fractures, and baseline data were analyzed. RESULTS: The full analysis set of the JOINT-04 included 3247 patients (1623 in the minodronate group and 1624 in the raloxifene group). The hazard ratio (95% confidence interval) for incident vertebral fractures over 2 years of pharmacotherapy, adjusted for confounders, was 0.93 (0.90-0.96) for ucOC, 1.15 (1.08-1.23) for TRACP-5b, 1.02 (1.01-1.03) for pentosidine, 0.91 (0.88-0.94) for the OLST, and 1.27 (1.01-1.60) for the fall risk index, which were all independent predictors. CONCLUSION: Evaluating fracture risk for patients with osteoporosis considering these potential risk factors for fracture in addition to the established risk factors may be useful when starting pharmaceutical treatment.

Impact of bone mineral density in reducing fracture risk in patients receiving alendronate plus alfacalcidol therapy.

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.

Randomized head-to-head comparison of minodronic acid and raloxifene for fracture incidence in postmenopausal Japanese women: the Japanese Osteoporosis Intervention Trial (JOINT)-04.

AIMS: 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. METHODS: 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. RESULTS: 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<.0001). Also, serious adverse reactions were observed for four and six patients in the minodronate and raloxifene groups, respectively. CONCLUSIONS: 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.

Executive summary of the Japan Osteoporosis Society Guide for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis (2018 Edition).

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).

Incidence of osteonecrosis of the jaw in Japanese osteoporosis patients taking minodronic acid.

Osteonecrosis of the jaw (ONJ) associated with bisphosphonate therapy is a rare but severe side effect in osteoporosis patients. Recently, the number of osteoporosis patients with ONJ has dramatically increased in Japan. This has contributed to an increase in the number of patients avoiding extractions. However, there has been no prospective study providing definitive incidence data for ONJ in Japanese patients. The purpose of this study was to elucidate the true as well as suspected incidence of ONJ. A total of 3229 subjects (1612 subjects in the minodronic acid group and 1617 subjects in the raloxifene group) in the Japanese Osteoporosis Intervention Trial protocol number 4 participated in this study. ONJ was diagnosed by experienced dentists. Suspected Stage 0 and 1 (bone exposure of the jaw) ONJ was assessed by a structured questionnaire at baseline and at 6, 12, 18, and 24 months. No established ONJ cases were diagnosed during the study. The incidence of suspected Stage 0 and/or Stage 1 ONJ was 6.14 per 1000 patient-years in the minodronic acid group and 3.38 per 1000 patient-years in the raloxifene group [hazard ratio (95% confidence interval) = 1.82 (0.84-3.93), P = 0.13]. Approximately 50-60% of bone exposures that appeared during the study had disappeared at the next observation. Although the subjects in this study may have developed a greater interest in the health of the oral cavity, the incidence of ONJ after minodronic acid treatment would be lower than the expected incident rate.

Inter-relationship between diet, lifestyle habits, gut microflora, and the equol-producer phenotype: baseline findings from a placebo-controlled intervention trial.

OBJECTIVE: Equol is an active metabolite of isoflavones produced by gut microbiota. It is beneficial to health; however, equol-producing ability varies greatly among individuals. These variations depend on the host's gut microbiota and lifestyle habits including diet. We investigated the relationship between the gut microbiota, lifestyle habits including diet, and equol-producing ability in postmenopausal Japanese women. METHODS: We studied 58 postmenopausal Japanese women aged 48 to 69 years who visited the Sendai Medical Center in January, 2018. Self-administered questionnaires assessed their recent and remote food intake histories and lifestyle habits. Fecal microbiome analysis was performed using a next-generation sequencer. Urinary equol was measured using an immunochromatographic strip test. Women with urinary equol concentration >1.0 µM were defined as equol producers. RESULTS: Equol-producing bacteria were identified in 97% (56) of women; however, only 13 (22%) were equol producers. Equol producers showed significantly higher microflora diversity (P = 0.002), and significantly different recent and remote food intake patterns compared with equol nonproducers. Higher consumption of foods such as meat, fish, soy, vegetables, and Japanese snacks positively affected microbial diversity and equol production, whereas a high intake of Ramen and smoking showed negative effects. CONCLUSION: Equol production might not depend on the quantity, but on the quality of equol-producing bacteria. High microbial diversity might enhance equol production. Increasing microbial diversity through healthy lifestyle habits and habitual consumption of a wide variety of foods might be useful to maintain a healthy gut environment for equol production.

Study design of multi-center, open-label randomized controlled, head-to-head trial comparing minodronic acid and raloxifene: Japanese Osteoporosis Intervention Trial (JOINT)-04.

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.

[Growth spurts of the bone from infancy to puberty.]

Growth spurts of the bone occur during infancy(1 to 4 years)and puberty(12 to 17 years). While, generally, pubertal spurts appear to draw more attention than infantile spurts, the latter constitute maximum growth spurts. Indeed, those during the first year of life lead to a 1.5-fold increase in height or a height increase of 25 cm, thus representing the greatest of all growth spurts that occur in humans during their lifetimes. Again, while height growth continues through the first 3 years of life, nutrition represents the single greatest contributing factor to height growth during this period. Again, while, as with other organ primordia, the bone primordium is formed during the organogenesis stage, calcification becomes most active during the third trimester of pregnancy. Thus, this review provides an overview of bone growth in humans, in relation to bone/calcium metabolism, which begins in the fetal stage before birth and continues through infancy and puberty, finally leading to attainment of peak bone mass in humans.

Effects of Equol Supplement on Bone and Cardiovascular Parameters in Middle-Aged Japanese Women: A Prospective Observational Study.

OBJECTIVE: To examine changes in the bone and cardiovascular parameters and tolerability in middle-aged Japanese women taking equol supplement for a year. DESIGN: This was a prospective observational study. SUBJECTS AND SETTING: Participants were 74 women receiving outpatient care at Hamasite Medical Clinic, Minato-ku, Tokyo, from 2013 to 2015. INTERVENTIONS: Participants received per oral equol-containing supplement, 10 mg/day. OUTCOME MEASURES: The primary outcome measures were percent changes in bone and cardiovascular parameters after 1 year supplementation with equol. The secondary measures included factors affecting the parameter changes and adverse effects associated with equol use for a year. RESULTS: Reduction in arterial stiffness was observed after 12 months of equol supplement (1402.3 cm/s vs.1367.3 cm/s, p < 0.001). Significant reductions in respective parameters were observed in women with moderate and high risk for arteriosclerosis (median [95% confidence interval]: -3.2% [-5.79 to -0.74]; -12.65% [-18.52 to -4.28]; respectively); hypertriglyceridemia -45.53% [-70.24 to -5.58]; bone resorption risk (-15.15% [-23.71 to 1.56]; and bone fracture risk -26.68% [-76.43 to -5.99]. All 15 women with high baseline parathyroid hormone levels had achieved a median of 50% [-54.11 to -31.69] reduction from their baseline values. These associations were further confirmed in the results of multiple linear regression analysis. There were no reported adverse events or abnormal findings in the blood chemistry, Pap smear, mammography, and transvaginal ultrasound during periodic follow-ups. CONCLUSION: One year equol supplement was tolerable and induced improvement of certain bone and cardiovascular parameters, especially in higher risk groups. Further controlled studies are needed to explore long-term equol use for wellbeing of middle-aged women.