Sarcopenia phenotype and impaired muscle function in male mice with fast-twitch muscle-specific knockout of the androgen receptor.

Sarcopenia is distinct from normal muscle atrophy in that it is closely related to a shift in the muscle fiber type. Deficiency of the anabolic action of androgen on skeletal muscles is associated with sarcopenia; however, the function of the androgen receptor (AR) pathway in sarcopenia remains poorly understood. We generated a mouse model (fast-twitch muscle-specific AR knockout [fmARKO] mice) in which the AR was selectively deleted in the fast-twitch muscle fibers. In young male mice, the deletion caused no change in muscle mass, but it reduced muscle strength and fatigue resistance and induced a shift in the soleus muscles from fast-twitch fibers to slow-twitch fibers (14% increase, P = 0.02). After middle age, with the control mice, the male fmARKO mice showed much less muscle function, accompanied by lower hindlimb muscle mass; this phenotype was similar to the progression of sarcopenia. The bone mineral density of the femur was significantly reduced in the fmARKO mice, indicating possible osteosarcopenia. Microarray and gene ontology analyses revealed that in male fmARKO mice, there was downregulation of polyamine biosynthesis-related geneswhich was confirmed by liquid chromatography-tandem mass spectrometry assay and the primary cultured myofibers. None of the AR deletion-related phenotypes were observed in female fmARKO mice. Our findings showed that the AR pathway had essential muscle type- and sex-specific roles in the differentiation toward fast-twitch fibers and in the maintenance of muscle composition and function. The AR in fast-twitch muscles was the dominant regulator of muscle fiber-type composition and muscle function, including the muscle-bone relationship.

Average daily glucocorticoid dose, number of prescription days, and cumulative dose in the initial 90 days of glucocorticoid therapy are associated with subsequent hip and clinical vertebral fracture risk: a retrospective cohort study using a nationwide health insurance claims database in Japan.

PURPOSE: Fracture risk assessment is recommended at three months after glucocorticoid (GC) therapy initiation. This study aimed to assess whether GC exposure in the initial 90 days of GC therapy is associated with subsequent hip and clinical vertebral fracture risk using the nationwide health insurance claims database of Japan (NDBJ). METHODS: Patients aged ≥ 50 years who were prescribed GC (≥ 70 mg prednisolone or equivalent; PSL) in the initial 90 days of GC therapy and were followed for hip and clinical vertebral fracture incidences for the subsequent 1080 days were selected from NDBJ. Associations of GC exposure with hip or clinical vertebral fracture risk were evaluated by Cox regression analysis adjusted for potential confounders. RESULTS: We selected 316,396 women and 299,871 men for the GC-exposed group and 43,164 women and 33,702 men for the reference group. Higher GC doses and longer prescription days in the initial 90 days of GC therapy were significantly and dose-dependently associated with increased fracture risk relative to the reference group. Patients receiving GC ≥ 5 mg PSL/day had a significantly increased fracture risk in the stratum of 30-59 days of GC prescription. In addition, female patients who received GC (≥ 1 and < 2.5 mg PSL/day) for 90 days in the initial 90 days of GC therapy had a significantly increased fracture risk. CONCLUSIONS: GC exposure in the initial 90 days of GC therapy was dose-dependently associated with hip and clinical vertebral fracture risk. GC may increase fracture risk with lower doses for shorter durations than previously reported. Fracture risk assessment three months after glucocorticoid (GC) therapy initiation is recommended. We found that GC exposure in the initial 90 days of GC therapy at lower daily doses for shorter durations than previously reported were significantly and dose-dependently associated with fracture risk using a nationwide health insurance claims database.

Early-onset dementia and risk of hip fracture and major osteoporotic fractures.

INTRODUCTION: There is limited knowledge about early-onset dementia (EOD) on fracture risk. METHODS: Individuals ages 50 to 64 were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (2012 to 2019). The association between EOD and fractures and the association between cholinesterase inhibitors for EOD and fractures were evaluated using logistic regression analyses. RESULTS: We identified 13,614 EOD patients and 9,144,560 cognitively healthy individuals. The analysis revealed that EOD was associated with an increased risk of hip fractures (adjusted odds ratio, 95% confidence interval: 8.79, 7.37-10.48), vertebral fractures (1.73, 1.48-2.01), and major osteoporotic fractures (2.05, 1.83-2.30) over 3 years. The use of cholinesterase inhibitors was significantly associated with a reduction in hip fractures among EOD patients (0.28, 0.11-0.69). DISCUSSION: EOD patients have a higher risk of osteoporotic fractures than cognitively healthy individuals. The use of cholinesterase inhibitors may reduce the risk of hip fracture among EOD patients. HIGHLIGHTS: It is unknown whether early-onset dementia (EOD) increases the risk of fractures. We identified 13,614 individuals with EOD using a nationwide administrative database. Patients with EOD have a higher risk of hip, vertebral, and major osteoporotic fractures. The use of cholinesterase inhibitors may reduce hip fracture among patients with EOD.

The roles of sex hormones in the pathophysiology of age-related sarcopenia and frailty.

Background: Sarcopenia is an age-related condition characterized by a progressive and systemic decline in skeletal muscle mass, quality, and strength. The incidence of sarcopenia contains sex-specific aspects, indicating the contribution of sex hormones to its pathophysiology. This review focuses on changing trends in sarcopenia, discusses alterations in definitions and diagnostic criteria, and emphasizes the association between sarcopenia and sex hormones. Methods: A literature search was performed on PubMed for related articles published between 1997 and December 2023 using appropriate keywords. Main Findings Results: Advances in research have emphasized the significance of muscle quality and strength over muscle mass, resulting in new diagnostic criteria for sarcopenia. Androgens demonstrated anabolic effects on skeletal muscles and played a significant role in the pathophysiology of sarcopenia. In clinical settings, androgen replacement therapy has exhibited certain positive outcomes for treating sarcopenia, despite concerns about potential side effects. Conversely, estrogen is involved in skeletal muscle maintenance, but the detailed mechanisms remain unclear. Moreover, results regarding the clinical application of estrogen replacement therapy for treating sarcopenia remained inconsistent. Conclusion: The elucidation of molecular mechanisms that involve sex hormones is eagerly awaited for novel therapeutic interventions for sarcopenia.

Association between pharmacotherapy and secondary hip fracture in a real-world setting: a nationwide database study.

INTRODUCTION: This study aimed to assess the association between pharmacotherapy and secondary hip fracture incidence. MATERIALS AND METHODS: The correlation between secondary hip fracture incidence and the presence, type, and medication possession ratio (MPR) of pharmacotherapy was investigated using medical insurance data acquired from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. RESULTS: Data collected from female patients (n = 1,435,347) were analyzed. The 2-year secondary hip fracture incidence was 3.48% (n = 49,921). Secondary hip fracture was significantly more common in patients without medications (3.80%) than in those with medications (3.00%). Patients receiving selective estrogen receptor modulators (SERMs) had the lowest average age. The crude incidence of secondary hip fracture was the lowest in patients receiving SERMs (n = 2088 [2.52%]), followed by those taking bisphosphonates (n = 11,355 [2.88%]), denosumab (n = 1118 [2.90%]), no medications (n = 32,747 [3.80%]), and parathyroid hormone (PTH: n = 2163 [4.55%]), whereas the age-adjusted incidence was the lowest in patients administered denosumab (2.27%), followed by those taking bisphosphonates (2.47%), SERMs (2.55%), PTH (3.67%), and no medications (3.80%). The mean MPR was the highest in patients taking denosumab (64.9%), followed by those receiving bisphosphonates (58.7%), SERMs (58.2%), and PTH (40.6%) in the no hip fracture group. CONCLUSION: Secondary hip fractures were less likely to occur with medication versus no medication. Differences in the crude incidence of secondary hip fracture based on medications usage might be attributed to background characteristics.

Hip and vertebral fracture risk after initiating antidiabetic drugs in Japanese elderly: a nationwide study.

INTRODUCTION: We aimed to clarify the risks of initiating antidiabetic drugs for fractures using a nationwide health insurance claims database (NDBJ). MATERIALS AND METHODS: Patients aged ≥ 65 years initiating antidiabetic drugs at the outpatient department were enrolled after a 180-day period without prescribed antidiabetic drugs and followed with during 2012-2018 using NDBJ. The adjusted hazard risks (HRs) of each antidiabetic drug (thiazolidine, alpha-glucosidase inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, glinide, and insulin) for fractures compared with biguanide were obtained adjusting for age, gender, polypharmacy, dementia, and the other antidiabetic drugs. RESULTS: The DPP-4 inhibitor was the most often prescribed antidiabetic drug followed by biguanide with prescribed proportions of 71.7% and 12.9%. A total of 4,304 hip fractures and 9,388 vertebral fractures were identified among the 966,700 outpatient participants. Compared with biguanide, insulin, alpha-glucosidase inhibitor, and DPP-4 inhibitor were related to increased hip fracture risks. Vertebral fracture risk was higher in outpatients prescribed with insulin, thiazolidine, and DPP-4 inhibitor compared with biguanide. Patients prescribed insulin for hip and vertebral fractures' adjusted HRs were 2.17 (95% CI 1.77-2.66) and 1.45 (95% CI 1.24-1.70), respectively. Those prescribed DPP-4 inhibitor for hip and vertebral fractures' adjusted HRs were 1.27 (95% CI 1.15-1.40) and 1.20 (95% CI 1.12-1.28), respectively. CONCLUSIONS: Initiating insulin increased the risk of not only hip fractures but also vertebral fractures. Patients initiating antidiabetic drugs had increased risks of hip and vertebral fractures compared with those initiating biguanide independently for age, gender, polypharmacy, and dementia in the Japanese elderly.

Validation of the questionnaire for medical checkup of old-old (QMCOO) score cutoff to diagnose frailty.

BACKGROUND: Frailty is a state of increased vulnerability to poor resolution of homeostasis following a stress. Early diagnosis and intervention of frailty are essential to prevent its adverse outcomes. However, simple diagnostic criteria have not been established. The Questionnaire for Medical Checkup of Old-Old (QMCOO) is widely used for medical checkups of older adults in Japan. In our previous report, we developed a method to score the QMCOO and showed that frailty can be diagnosed with the highest accuracy when the score cutoff was set at 3/4 points. We aimed to validate the criteria in a larger cohort. METHODS: Participants aged 65 years or over were recruited in the western region of Japan. They answered all the items of the Kihon Checklist (KCL) and the QMCOO. Based on the KCL score, they were diagnosed as robust (3 or lower), prefrail (4 to 7), or frail (8 or over). Then we tested the effectiveness to diagnose frailty using the QMCOO cutoff of 3/4 points. We also aimed to determine the score cutoff to separate robust and prefrail. RESULTS: 7,605 participants (3,458 males and 4,147 females, age 77.4 ± 6.9 years) were recruited. 3,665 participants were diagnosed as robust, 2,448 were prefrail, and 1,492 were frail based on the KCL score. The diagnosis of frailty had a sensitivity of 84.0%, specificity of 82.5%, and accuracy of 82.8% with a QMCOO score cutoff of 3/4 points, suggesting its validity. To separate robust and prefrail, both the accuracy and the Youden index were the highest with the QMCOO cutoff of 2/3 points (sensitivity, specificity, and accuracy were 63.9%, 83.4%, and 75.6%, respectively). All the questions of the QMCOO except Q12 (about smoking) were significantly related to prefrailty status after a logistic regression analysis. CONCLUSION: Diagnosis of frailty using the QMCOO score cutoff of 3/4 points was validated. Prefrailty could be diagnosed using the score cutoff of 2/3 points.

Summary of the clinical practice manual for late-onset hypogonadism.

Testosterone plays an important role in maintaining both physical and mental function. Age-related testosterone depletion contributes to the development of angina, arteriosclerosis, obesity, metabolic syndrome, dementia, frailty, and a range of other conditions. A condition involving age-related testosterone depletion and the associated clinical symptoms is defined as late-onset hypogonadism (LOH). LOH is treated by testosterone replacement therapy. Indications for testosterone replacement therapy are determined by evaluating symptoms and signs.

Influence of oral health on frailty in patients with type 2 diabetes aged 75 years or older.

BACKGROUND: Poor oral health conditions are known to affect frailty in the older adults. Diabetes is a risk factor for both poor oral health and frailty, therefore, oral health status may affect frailty in diabetic patients more than in the general population. The purpose of this study was to evaluate the influence of oral health and other factors on frailty and the relationship among oral health, diabetes and frailty in older adult patients with type 2 diabetes. METHODS: Patients with type 2 diabetes aged 75 years or older were included in this cross-sectional study. Eligible patients were surveyed by questionnaire for frailty, oral health status, and cognitive and living functions. Factors influencing pre-frailty, frailty, and individual frailty screening index (FSI) classes were evaluated. RESULTS: Of the 111 patients analyzed, 66 cases (59.5%) were categorized as robust, 33 cases (29.7%) as pre-frailty, and 12 cases (10.8%) as frailty. The oral frailty index, the cognitive and living functions score, and BMI were found to be factors influencing pre-frailty or frailty. In the evaluation of individual FSI classes, BMI had an influence on those with a FSI ≤2. The cognitive and living functions score was a factor influencing those with FSI ≤3. The oral frailty index was found to have a significant influence on all FSI classes. CONCLUSIONS: Poor oral health has an influence on frailty in patients with type 2 diabetes aged ≥75. In this patient population, as frailty progresses, the impact of oral health on frailty may increase. TRIAL REGISTRATION: This study was retrospectively registered in UMIN-CTR ( UMIN000044227 ).

Insufficient persistence of and adherence to osteoporosis pharmacotherapy in Japan.

INTRODUCTION: Only a few large-scale studies have examined the care gap in Japan. The aim of this study was to investigate the persistence of and adherence to osteoporosis pharmacotherapy in Japan. MATERIALS AND METHODS: The rates of continuation (persistence) of and adherence to osteoporosis pharmacotherapy were investigated using medical insurance data, issued from July 2013 to December 2018, from the medical care system for elderly individuals in Hokkaido, Japan. RESULTS: The study included 7918 male and 52,585 female patients. Persistence rates were 62.1% in the first year and 45.3% in the second year. There were 33,096 patients who discontinued medication; 8296 patients resumed medication during the observation period of 730 days. The median time to the discontinuation of medication for all the patients was 702 days. The 2-year medication possession ratio (MPR) was 63.8%; 30,989 patients (51.2%) had an MPR ≥ 80% and 20,788 (34.4%) had an MPR < 50%. Both the persistence and adherence were better in females than in males and worsened with increasing age. Comparisons of fracture history showed that persistence and MPR were higher in the no hip or vertebral fracture group, followed by hip fracture, vertebral fracture, and hip and vertebral fracture groups. Meanwhile, more patients in the hip fracture group had an MPR ≥ 80%. CONCLUSION: Persistence of and adherence to osteoporotic pharmacotherapy are not very high in Japan. To bridge the care gap following osteoporosis pharmacotherapy, improvements are required for males, the elderly, and those with a history of vertebral fracture.