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The overarching goal of osteoporosis management is to prevent fractures. A goal-directed approach to long-term management of fracture risk helps ensure that the most appropriate initial treatment and treatment sequence is selected for individual patients. Goal-directed treatment decisions require assessment of clinical fracture history, vertebral fracture identification (using vertebral imaging as appropriate), measurement of bone mineral density (BMD), and consideration of other major clinical risk factors. Treatment targets should be tailored to each patient's individual risk profile and based on the specific indication for beginning treatment, including recency, site, number and severity of prior fractures, and BMD levels at the total hip, femoral neck, and lumbar spine. Instead of first-line bisphosphonate treatment for all patients, selection of initial treatment should focus on reducing fracture risk rapidly for patients at very high and imminent risk, such as in those with recent fractures. Initial treatment selection should also consider the probability that a BMD treatment target can be attained within a reasonable period of time and the differential magnitude of fracture risk reduction and BMD impact with osteoanabolic versus antiresorptive therapy. This position statement of the ASBMR/BHOF Task Force on Goal-Directed Osteoporosis Treatment provides an overall summary of the major clinical recommendations about treatment targets and strategies to achieve those targets based on the best evidence available, derived primarily from studies in older postmenopausal women of European ancestry., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Introduction: This study aimed to compare treatment satisfaction with two dosing regimens (two teriparatide [TPTD] self-injection systems) in osteoporosis patients at high risk of fracture., Materials and Methods: In this open-label crossover randomized trial comparing self-injected once-daily (1/D)-TPTD with self-injected twice-weekly (2/W)-TPTD, three satisfaction variables were evaluated by questionnaire for 2 years. The primary endpoint was overall satisfaction and secondary endpoints were satisfaction with treatment effectiveness and with utility of the self-injection device. Changes in quality of life (QOL) assessed by EuroQol-5 Dimension, pain assessed by visual analogue scale (VAS), and anthropometric parameters were also analyzed. Safety was evaluated based on the incidence and severity of adverse events (AEs)., Results: The 1/D-TPTD and 2/W-TPTD groups consisted of 180 (75.9 ± 7.3 years) and 179 (age: 75.5 ± 6.9 years) patients, respectively. After 26 weeks of treatment, no significant between-group difference in the persistence rate (79.4% vs 72.6% in the 1/D-TPTD and 2/W-TPTD groups, respectively), distributions of overall satisfaction scores, and satisfaction with treatment (p > 0.05) were observed. However, several items of satisfaction with the utility of the injection device were significantly higher in the 2/W-TPTD group (p < 0.05). Statistical improvements from baseline values were observed in QOL and pain VAS in both groups (p < 0.05). No serious AEs were reported., Conclusion: The between-group similarity of overall treatment satisfaction and effectiveness scores and between-group difference in satisfaction with the utility of the self-injection device was useful information for real-world treatment of osteoporosis. Both medication regimens were well tolerated., (© 2024. The Author(s).)

Osteoporosis, vertebral fractures, and spinal degenerative diseases are common conditions that often coexist in older adults. This study aimed to determine the factors influencing low back pain and its impact on activities of daily living (ADL) and physical performance in older individuals with multiple comorbidities. This cross-sectional study was part of a large-scale population-based cohort study in Japan, involving 1009 participants who underwent spinal magnetic resonance imaging (MRI) to assess cervical cord compression, radiographic lumbar spinal stenosis, and lumbar disc degeneration. Vertebral fractures in the thoracolumbar spine were evaluated using sagittal MRI with a semi-quantitative method. Bone mineral density was measured using dual-energy X-ray absorptiometry. Low back pain, Oswestry Disability Index (ODI), and physical performance tests, such as one-leg standing time, five times chair-stand time, maximum walking speed, and maximum step length, were assessed. Using clinical conditions as objective variables and image evaluation parameters as explanatory variables, multiple regression analysis showed that vertebral fractures were significantly associated with low back pain and ODI. Vertebral fractures and osteoporosis significantly impacted physical performance, whereas osteoporosis alone did not affect low back pain or ODI. Our findings contribute to new insights into low back pain and its impact on ADL and physical performance., (© 2024. The Author(s).)

Introduction: Although synthetic glucocorticoids (GCs) are commonly used to treat autoimmune and other diseases, GC induced osteoporosis (GIOP) which accounts for 25% of the adverse reactions, causes fractures in 30-50% of patients, and markedly decreases their quality of life. In 2014, the Japanese Society for Bone and Mineral Research (JSBMR) published the revised guidelines for the management and treatment of steroid-induced osteoporosis, providing the treatment criteria based on scores of risk factors, including previous fractures, age, GC doses, and bone mineral density, for patients aged ≥18 years who are receiving GC therapy or scheduled to receive GC therapy for ≥3 months., Materials and Methods: The Committee on the revision of the guidelines for the management and treatment of GIOP of the JSBMR prepared 17 clinical questions (CQs) according to the GRADE approach and revised the guidelines for the management and treatment of GIOP through systematic reviews and consensus conferences using the Delphi method., Results: Bisphosphonates (oral and injectable formulations), anti-RANKL antibody teriparatide, eldecalcitol, or selective estrogen receptor modulators are recommended for patients who has received or scheduled for GC therapy with risk factor scores of ≥3. It is recommended that osteoporosis medication is started concomitantly with the GC therapy for the prevention of fragility fractures in elderly patients., Conclusion: The 2023 guidelines for the management and treatment of GIOP was developed through systematic reviews and consensus conferences using the Delphi method., (© 2024. The Author(s).)

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., (© 2023. The Japanese Society Bone and Mineral Research.)

Context: Abaloparatide reduced fracture risk in postmenopausal women with osteoporosis in the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE). Its effect in Japanese patients remains unexamined., Objective: This work aimed to determine the efficacy and safety of abaloparatide in increasing bone mineral density (BMD) in Japanese patients with osteoporosis at high fracture risk., Methods: This was a randomized, double-blind, placebo-controlled study conducted in Japan. Postmenopausal women and men with osteoporosis with high fracture risk were given daily subcutaneous 80 µg abaloparatide or placebo for 78 weeks (18 months). The primary end point was percentage change in lumbar spine (LS) BMD from baseline at the last visit. Secondary end points included time-course changes in LS, total hip (TH), and femoral neck (FN) BMDs and bone turnover markers, and cumulative number of fractures., Results: Abaloparatide increased LS, TH, and FN BMDs (mean [95% CI]) by 12.5% (10.3%-14.8%; P < .001), 4.3% (3.3%-5.3%), and 4.3% (2.9%-5.6%), respectively, vs placebo. Serum procollagen type I N-terminal propeptide increased rapidly to ~ 140% above baseline at 6 weeks and gradually decreased but was approximately 25% higher than baseline at 78 weeks. Serum carboxy-terminal cross-linking telopeptide of type I collagen gradually increased to 50% above baseline at 24 weeks and decreased gradually to the placebo-group level from 60 weeks. Four vertebrae of 3 participants in the placebo group, but none in the abaloparatide group, developed new vertebral fractures. The safety profile was similar to that in the ACTIVE study., Conclusion: In Japanese patients with postmenopausal and male osteoporosis with high fracture risk, abaloparatide for 78 weeks robustly increased LS, TH, and FN BMDs, suggesting a similar efficacy in Japanese patients vs the ACTIVE study population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: This study aimed to clarify the trends in the prevalence of osteoporosis among general inhabitants using population-based cohort data of the baseline and the survey 10 years later., Materials and Methods: The baseline survey of the Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) study was conducted in 2005-2007; 1690 participants (596 men, 1094 women, mean age 65.2 years) completed all examinations of osteoporosis, including a questionnaire of medical information in the present/past and bone mineral density measurement using dual-energy absorptiometry. The fourth survey was performed in 2015-2016; 1906 individuals (637 men, 1269 women, 65.0 years) completed assessments identical to those at the baseline survey. Osteoporosis was defined using the World Health Organization criteria., Results: The prevalence of lumbar spine (L2-L4) osteoporosis at the baseline survey was 13.6% (men, 3.4%; women, 19.2%) and that at the fourth survey was 9.7% (men, 1.4%; women, 13.9%), which decreased significantly (p < 0.01), while that of the femoral neck was not significantly different between the baseline and fourth surveys. Regarding the prevalence of osteoporosis of L2-L4 or the femoral neck, the prevalence of osteoporosis in women aged ≥ 70 was 38.8% at the fourth survey and 48.9% at the baseline study; thus, the prevalence at the fourth survey was significantly lower than that at the baseline survey (p < 0.01)., Conclusions: In the population-based survey with a 10-year interval, the prevalence of osteoporosis at lumbar spine tended to decrease significantly. This preferable change in osteoporosis could contribute to the decrease in the occurrence of osteoporotic fracture in the future., (© 2022. The Japanese Society Bone and Mineral Research.)

Introduction: Locomotive syndrome (LOCOMO) is defined by the Japanese Orthopaedic Association (JOA) as a condition requiring nursing care due to a decline in mobility resulting from musculoskeletal disorders. In 2020, the JOA announced the new definition of LOCOMO stage 3 and revision of clinical decision limits in stages of LOCOMO. However, there are few reports on the epidemiological indices of LOCOMO. This prospective cohort study aimed to investigate the prevalence, incidence, and association of poor prognosis with LOCOMO stages., Materials and Methods: The third survey of the Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) study was conducted during 2012-2013, examining a population-based cohort of 1575 participants (513 men and 1062 women, mean age 65.6 years). Three LOCOMO risk tests were performed, and patients were classified into LOCOMO stages 0, 1, 2, and 3. They were followed up for 6 years, and identical examination of LOCOMO was performed in 3- and 6-year follow-ups. Data on patients' prognoses, including disability and death, were collected., Results: The prevalence of LOCOMO stages 1, 2, and 3 was 41.3, 14.9, and 11.6%, respectively. The incidence of LOCOMO stages 1, 2, and 3 were 83.7, 23.0, and 18.6 per 1000 person-years, respectively. Compared with LOCOMO stage 0, logistic regression analysis showed that LOCOMO stage 3 significantly increased the risk of disability and mortality. In addition, each value of LOCOMO risk tests for LOCOMO stage 3 increased the risk of poor prognosis., Conclusion: LOCOMO stage 3 is a sensitive indicator of future disability and mortality., (© 2022. The Japanese Society Bone and Mineral Research.)

Objectives: This study investigated changes in bone mineral density (BMD) and erosion after denosumab discontinuation in rheumatoid arthritis (RA) patients without osteoporosis who participated in the DESIRABLE study., Methods: This multicentre observational study consisted of a prediscontinuation visit (date of final assessment in DESIRABLE) and a postdiscontinuation visit (2.5 years after the last administered dose of denosumab). Percentage change in lumbar spine (LS) BMD from baseline was assessed as the primary endpoint., Results: Fifty-nine patients were enrolled. The percentage change in LS BMD decreased to baseline levels at the postdiscontinuation visit. Compared with baseline, C-telopeptide of type I collagen levels increased after denosumab discontinuation but most patients had levels within the reference range. Bone erosion scores were not significantly different between the on-treatment period and after denosumab discontinuation (p = .0666) but there was a numerical increase postdiscontinuation. The progression in bone erosion score was significantly reduced in patients whose disease activity was in remission versus those not in remission (p = .0195)., Conclusions: In RA patients without osteoporosis, denosumab discontinuation can be explored while considering patient background factors (disease activity and risk of fracture) and accounting for progression of bone erosion and LS BMD decrease after withdrawal., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Introduction: Denosumab is a humanized IgG2 monoclonal antibody that was approved for the treatment of osteoporosis in Japan in 2013. This study aimed to investigate the long-term safety and effectiveness of denosumab in Japanese patients with osteoporosis in daily clinical practice., Materials and Methods: This 3-year, prospective, observational, post-marketing study included patients who initiated treatment with denosumab (60 mg/6 months) for osteoporosis. Data were assessed at baseline, 3, 6, 12, 24 and 36 months. Key endpoints were adverse events (AEs), adverse drug reactions (ADRs), occurrence of osteoporotic fractures, bone mineral density (BMD), and bone turnover markers. Multivariate analyses were conducted to identify predictors of hypocalcaemia and percent change in BMD., Results: Overall, 3534 patients were assessed (mean 75.7 years; 89.8% women). In total, 298 patients (8.4%) developed ADRs; the most common was hypocalcaemia (3.9%). Hypocalcaemia risk was significantly increased in patients with creatinine clearance < 30 mL/min, no prior use of bisphosphonates, prior use of calcium and vitamin D preparations, baseline serum calcium < 8.5 mg/dL, and no concomitant use of calcium or vitamin D preparations. Six patients had adjudicated osteonecrosis of the jaw. Lumbar spine BMD increased significantly from baseline (mean percent change: 11.4% at 36 months). All bone turnover markers decreased significantly from baseline. Over 3 years, 3.3% of patients developed a new osteoporotic fracture., Conclusions: This study confirmed the long-term safety and effectiveness of denosumab in Japanese patients with osteoporosis in daily clinical practice. No new safety signals were identified.

Introduction: This study compared the clinical usefulness of minodronate (50 mg/4 weeks) plus alfacalcidol (1 μg/day) (Group M) with that of alfacalcidol alone (1 μg/day) (Group A) for treating glucocorticoid-induced osteoporosis., Materials and Methods: The primary endpoints were the changes from baseline in lumbar spine (LS) bone mineral density (BMD) and the cumulative incidence of vertebral fracture at 24 months; secondary endpoints included the changes from baseline in total hip (TH) BMD and bone turnover markers., Results: Of 164 patients enrolled, 152 (Group M, n = 75; Group A, n = 77) were included in the analysis of efficacy. At each time point and at 24 months, LS BMD and TH BMD were significantly higher in Group M than in Group A. The 152 patients were divided into two subgroups that were previously treated with glucocorticoids for ≤ 3 months or > 3 months. In both subgroups, the changes from baseline in LS BMD and TH BMD from baseline at 24 months had increased more in Group M than in Group A. There were no differences found in the incidence of vertebral fracture between the groups, because the number of enrolled patients was lesser than that initially expected. In Group M, both bone formation and resorption markers significantly decreased from baseline at 3 months and maintained at 6, 12, and 24 months., Conclusions: Minodronate plus alfacalcidol was more effective than alfacalcidol alone in increasing BMD and was effective in increasing BMD for both prevention and treatment. Therefore, minodronate can be a good candidate drug for the treatment of glucocorticoid-induced osteoporosis.

Introduction: Eldecalcitol increases bone mineral density (BMD) and reduces vertebral fracture in patients with primary osteoporosis. However, the effect of eldecalcitol on BMD and fracture in glucocorticoid-induced osteoporosis (GIO) patients is unknown. This study was undertaken to compare the effect of eldecalcitol on BMD and fracture with that of alfacalcidol in GIO patients., Materials and Methods: A randomized, open-label, parallel group study was conducted to identify the effectiveness and safety of monotherapy with 0.75 μg eldecalcitol compared with 1.0 μg alfacalcidol in GIO patients., Results: Lumbar spine BMD increased with eldecalcitol, but decreased with alfacalcidol at 12 and 24 months (between group difference 1.29%, p < 0.01, and 1.10%, p < 0.05, respectively). Total hip and femoral neck BMD were maintained until 24 months by eldecalcitol, but decreased by alfacalcidol (between group difference 0.97%, p < 0.05 and 1.22%, p < 0.05, respectively). Both bone formation and resorption markers were more strongly suppressed by eldecalcitol than by alfacalcidol. Eldecalcitol showed better effect on BMD than alfacalcidol in patients with no prevalent fracture and BMD > 70% of the young adult mean, and with ≤ 3 months of previous glucocorticoid treatment. No significant difference in the incidence of vertebral fracture was found, and the incidence of adverse events was similar between the two groups., Conclusions: Eldecalcitol was more effective than alfacalcidol in maintaining BMD in GIO patients. Because eldecalcitol was effective in patients with no or short-term previous glucocorticoid treatment, as well as those without prevalent fracture or low BMD, eldecalcitol can be a good candidate for primary prevention of GIO., Clinical Trial Registration Number: UMIN000011700.

Absorption of oral immediate-release (IR) risedronate tablets is reduced by food intake, thus a delayed-release (DR) tablet has been developed to overcome the necessity of taking IR tablets under fasting conditions. This randomized, double-blind, phase II/III study compared efficacy and safety of risedronate IR once-daily (QD) and DR once-monthly (QM) tablets in Japanese patients with involutional osteoporosis. Patients received 2.5 mg IR on awakening QD, or 25 or 37.5 mg DR on awakening, following breakfast, or 30 min after breakfast, QM for 12 months. Primary endpoint was non-inferiority in mean percent change from baseline to end of study (month 12, last observation carried forward [M12, LOCF]) in mean lumbar spine (L 2 -L 4 ) bone mineral density (BMD) between risedronate IR on awakening and DR following breakfast. Mean percent changes in (L 2 -L 4 ) BMD at M12, LOCF were 5.07% (IR at awakening, n = 190), 3.36% (25 mg DR following breakfast, n = 194), and 4.11% (37.5 mg DR following breakfast, n = 181). Mean percent change in (L 2 -L 4 ) BMD was numerically lower in the DR following breakfast groups versus the respective on awakening and 30 min after breakfast DR groups. Overall incidences of treatment-emergent adverse events (TEAEs) were comparable between groups. In the DR groups, 1.5-4.0% of patients reported TEAEs potentially associated with acute-phase reactions versus 0% in the IR group. In this study, non-inferiority could not be declared for 37.5 or 25 mg DR following breakfast QM (p = 0.1346 or p = 0.6711, respectively) versus 2.5 mg IR on awakening QD.

This study aimed to estimate the prevalence of locomotive syndrome, sarcopenia, and frailty and clarify their co-existence in a population-based cohort. The third survey of Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) study was conducted between 2012 and 2013, examining 963 subjects (aged ≥ 60 years; 321 men, 642 women). Locomotive syndrome, sarcopenia, and frailty were defined using three tests proposed by Japanese Orthopaedic Association, Asian Working Group for Sarcopenia criteria, and Fried's definition, respectively. Prevalence of locomotive syndrome stages 1 and 2 were 81.0% (men, 80.4%; women, 81.3%) and 34.1% (men, 30.5%; women, 35.8%), respectively, and those of sarcopenia and frailty were 8.7% (men, 9.7%; women, 8.3%) and 4.5% (men, 2.8%; women, 5.3%), respectively. Locomotive syndrome stage 1, sarcopenia, and frailty co-existed in 2.1%; 6.5% had locomotive syndrome stage 1 and sarcopenia, 2.4% had locomotive syndrome stage 1 and frailty, while none had sarcopenia and frailty. Locomotive syndrome stage 1 presented alone in 70.0%, sarcopenia in 0.1%, and no frailty. The remaining 18.9% had none of these conditions. Co-existence of locomotive syndrome stage 2, sarcopenia, and frailty was observed in 2.0%; 5.0% had locomotive syndrome stage 2 and sarcopenia, 2.2% had locomotive syndrome stage 2 and frailty, and 0.1% had sarcopenia and frailty. Locomotive syndrome stage 2, sarcopenia, and frailty alone, presented in 24.9%, 1.7%, and 0.2%, respectively. The remaining 64.0% had none of these conditions. Most subjects with sarcopenia and/or frailty also had locomotive syndrome. Preventing locomotive syndrome may help prevent frailty and sarcopenia and subsequent disability.

To purpose of this study was to reveal the mean levels and positive proportion of serological markers related to rheumatoid arthritis, and clarify their relationship with osteoporosis and hand osteoarthritis (OA). A total of 1546 participants from the third survey of the research on osteoarthritis/osteoporosis against disability study were enrolled in the current study. Using participant blood samples, the levels of anti-cyclic citrullinated protein (CCP) antibody, rheumatoid factor (RF), matrix metalloproteinase-3 (MMP-3), C-reactive protein (CRP), and high-sensitivity CRP (hsCRP) were measured. Subjects with higher than normal levels were defined as being positive. Osteoporosis was defined according to the recommendations set by World Health Organization criteria in 1994. Radiographic hand OA was evaluated using the modified Kellgren-Lawrence (KL) scale. The positive proportion of anti-CCP antibody, RF, MMP-3, CRP, and hsCRP was 1.8, 7.1, 15.0, 6.7, and 6.4%, respectively. MMP-3 was associated with age, and was significantly higher in men than in women. Positive MMP-3 was not significantly related to osteoporosis or severe hand OA (KL grade ≥3) after adjustment for other factors including age, sex, and body mass index. The results from this study clarified the values and positive proportion of RA-related markers and revealed their relationship with osteoporosis and hand OA.

Zoledronic acid is a bisphosphonate with the most potent anti-bone resorbing activity. Several previous studies demonstrated that zoledronic acid once a year significantly reduced the risk of vertebral, non-vertebral, and hip fractures in postmenopausal women. In a phase Ⅲ 2-year placebo-controlled, randomized, double-blind comparative study in Japan(ZONE study)demonstrated that once-yearly infusion of zoledronic acid 5 mg increased lumbar spine and proximal femoral BMD, and reduced the incidence of vertebral and non-vertebral fractures in Japanese patients with primary osteoporosis compared to placebo.

Rheumatoid arthritis (RA) is an autoimmune diseases characterized by inflammation and destruction of bone and cartilage. Osteoclastogenesis induced by inflammatory cytokines contributes to focal and systemic bone and cartilage destruction including secondary osteoporosis. Recent progress in treatment enables us to prevent disease activity. Not only anti-inflammatory management but also therapies directly targeting bone metabolism can further prevent bone destruction in RA.

Aim: To examine the incidence of certified need of care in the national long-term care insurance (LTCI) system, and to determine its risk factors in the elderly of Japanese population-based cohorts of the Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) study., Methods: Of the 3040 participants in the baseline examination of the ROAD study, we enrolled 1773 (699 men, 1074 women) aged 65 years or older who were not certified as in need of care level elderly at baseline. Participants were followed for incident certification of need of care in the LTCI system. Associated factors in the baseline examination with occurrence were determined by multivariate Cox proportional hazards regression analysis. Muscle dysfunction was defined in accordance with the European Working Group on Sarcopenia in Older People algorithm for screening sarcopenia., Results: A total of 54 men and 115 women were certified as in need of care level elderly during the average 4.0-year follow up. The incidence was 2.0 and 2.5 per 100 person-years in men and women, respectively. Identified risk factors were region, age, body mass index <18.5 or ≥ 27.5 kg/m(2), grip strength, knee extension torque, usual gait speed, chair stand time and muscle dysfunction., Conclusions: Both underweight and obesity, as well as low muscle strength and physical ability, are risk factors for certification of need of care. Considering muscle dysfunction is a risk factor for occurrence, screened individuals are recommended to receive early intervention programs regardless of muscle volume., (© 2013 Japan Geriatrics Society.)

Context: Denosumab 60 mg sc injection every 6 months for 36 months was well tolerated and effective in reducing the incidence of vertebral, nonvertebral, and hip fracture in predominantly Caucasian postmenopausal women with osteoporosis., Objective: The objective of this phase 3 fracture study was to examine the antifracture efficacy and safety of denosumab 60 mg in Japanese women and men with osteoporosis compared with placebo., Design and Setting: A randomized, double-blind, placebo-controlled trial with an open-label active comparator as a referential arm was conducted., Patients: Subjects were 1262 Japanese patients with osteoporosis aged 50 years or older, who had one to four prevalent vertebral fractures., Intervention: Subjects were randomly assigned to receive denosumab 60 mg sc every 6 months (n = 500), placebo for denosumab (n = 511), or oral alendronate 35 mg weekly (n = 251). All subjects received daily supplements of calcium and vitamin D., Main Outcome Measure: The primary endpoint was the 24-month incidence of new or worsening vertebral fracture for denosumab vs placebo., Results: Denosumab significantly reduced the risk of new or worsening vertebral fracture by 65.7%, with incidences of 3.6% in denosumab and 10.3% in placebo at 24 months (hazard ratio 0.343; 95% confidence interval 0.194-0.606, P = .0001). No apparent difference in adverse events was found between denosumab and placebo during the first 24 months of the study., Conclusion: These results provide evidence of the efficacy and safety of denosumab 60 mg sc every 6 months in Japanese subjects with osteoporosis.

The aim of osteoporosis treatment is to reduce fracture risk. Many kinds of anti-osteoporosis drugs are available in these days, and most of them increase bone mineral density and reduce the risk of fractures. Japanese 2011 guidelines for prevention and treatment of osteoporosis documents the recommendation level of each osteoporosis drugs. It is important to select drugs appropriate for each osteoporosis patient considering the mechanisms of drug action and their clinical efficiency.

Osteoporosis and osteoporosis-related fractures tend to increase year by year around the world including Japan. Denosumab, a fully human monoclonal antibody to receptor activator of NF-κB ligand (RANKL) , a cytokine member of the TNF family essential for osteoclast differentiation has recently been approved in Japan, Europe and the US for the treatment of postomenopausal osteoporosis as well as bone metastasis. In some large clinical trials, denosumab significantly decreased bone resorption, increased bone mineral density (BMD) , and reduced the risk of vertebral, nonvertebral and hip fractures in postmenopausal women. However, the mechanism of adverse events of denosumab, such as hypocalcemia and osteonecrosis of the jaws, has not been completely explained. Therefore, further knowledge should be accumulated by additional basic researches and clinical studies on denosumab.

In rheumatoid arthritis (RA) , the osteoclast pathway is activated by abnormal immune conditions accompanied by chronic inflammation resulting in periarticular osteoporosis and local bone destruction around joints. In addition, multiple factors lead to systemic osteoporosis, including reduced physical activity and pharmacotherapies such as steroids. These conditions cause decreased bone mineral density and bone quality, and expose patients to an increased risk of fracture. When treating patients with RA osteoporosis, it is important to improve systemic osteoporosis using anti-osteoporotic agents, and to suppress fracture risk by controlling inflammation (which is associated with periarticular osteoporosis and bone destruction) with a combination of disease-modifying anti-rheumatic drugs or biological agents.

In rheumatoid arthritis (RA) , the osteoclast pathway is activated by an abnormal immune condition accompanied by chronic inflammation, resulting in periarticular osteoporosis and local bone destruction around joints. In addition, multiple factors including pharmacotherapies such as steroids, and reduced physical activity, lead to systemic osteoporosis. These conditions expose patients to increased fracture risk. In RA treatment, it is important to achieve suppression of fracture risk by controlling inflammation, which is associated with periarticular osteoporosis and bone destruction, using disease-modifying anti-rheumatic drugs or biologic agents and by improving systemic osteoporosis using anti-osteoporotic agents.

In osteoporosis, the risk of fracture is influenced by decrease of bone mineral density and deterioration of bone quality. The latter includes deterioration of the material and structural properties of bone. These changes arise from the influence of changes in hormonal balance, aging, changes in mechanical stress, lifestyle-related diseases, etc. on bone absorption and bone formation as the coupled functions of osteoclasts and osteoblasts. Deterioration of bone quality occurs at various levels ranging from the molecular to the tissue level, or even at the individual level, and leads to an increased fracture risk. Evaluating fracture risk on the basis of a sound understanding of the various etiologies of osteoporosis is important when treating osteoporosis.

Bone homeostasis is maintained by delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts. Bisphosphonates are widely used nowadays by suppressing bone resorption to treat patients with osteoporosis, which results from high bone turnover, causing excessive bone resorption phase. While bisphosphonates increase bone mineral density and improve back pain due to spinal compression fracture, they may have some problems such as osteonecrosis of jaw and excessive suppression of bone turnover. Cathepsin K inhibitor, which has a new mechanism in addition to function of suppressing bone resorption, is recently focused. Cathepsin K is a protease which specifically expresses in osteoclasts and plays an important role in resolution of bone collagen. Cathepsin K inhibitor has a potential of inhibiting bone resorption without suppressing bone formation and could be an attractive therapeutic target of osteoporosis.

Osteoporosis is a disease in which the density and quality of bone is reduced, leading to an increase in fragility fractures. Osteoporosis is a major health threat affecting more than 10 million people in Japan. Emerging evidence has shown that anti-resorptive drugs such as bisphosphonates and raloxifene efficiently increase bone mass and prevent osteoporotic fractures by maintaining bone homeostasis. In addition, anabolic drugs such as parathyroid hormone and novel anti-resorptive drugs such as anti-RANKL drugs and cathepsin K inhibitors, which directly target osteoclasts are under development. In this review, we would like to summarize the current status of the development of anti-osteoporotic drugs.

Mice lacking tob2, a member of the antiproliferative family genes, had decreased bone mass, and the number of osteoclasts differentiated from bone marrow cells was increased. Overexpression of Tob2 in stromal cells repressed vitamin D(3)-induced osteoclasts formation. Furthermore, expression of RANKL mRNA in stromal cells was increased in the absence of Tob2 and decreased in the presence of Tob2. Tob2 interacted with vitamin D(3) receptor (VDR), which suggests its involvement in vitamin D(3) receptor-mediated regulation of transcription. Because VDR regulates RANKL expression, our data suggest that Tob2 negatively regulates formation of osteoclasts by suppressing RANKL expression through its interaction with VDR.

We previously identified gamma-glutamyltransferase (GGT) by expression cloning as a factor inducing osteoclast formation in vitro. To examine its pathogenic role in vivo, we generated transgenic mice that overexpressed GGT in a tissue-specific manner utilizing the Cre-loxP recombination system. Systemic as well as local production of GGT accelerated osteoclast development and bone resorption in vivo by increasing the sensitivity of bone marrow macrophages to receptor activator of nuclear factor-kappaB ligand, an essential cytokine for osteoclastogenesis. Mutated GGT devoid of enzyme activity was as potent as the wild-type molecule in inducing osteoclast formation, suggesting that GGT acts not as an enzyme but as a cytokine. Recombinant GGT protein increased receptor activator of nuclear factor-kappaB ligand expression in marrow stromal cells and also stimulated osteoclastogenesis from bone marrow macrophages at lower concentrations. Thus, GGT is implicated as being involved in diseases characterized by accelerated osteoclast development and bone destruction and provides a new target for therapeutic intervention.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive bone destruction, in which proinflammatory cytokines such as tumor necrosis factor-alpha play essential roles. Recent studies have revealed an important involvement of osteoclasts in bone destruction of RA. In this review, I would like to explain the molecular mechanism of osteoclast development in RA, and propose the possibility of anti-osteoclast therapy to the disease.

Aim: To identify factors associated with locomotive syndrome (LS) using medical questionnaire data and machine learning. Methods: A total of 1575 participants underwent the LS risk tests from the third survey of the research on osteoarthritis/osteoporosis against disability study (ROAD) study. LS was defined as stage 1 or higher based on clinical decision limits of the Japanese Orthopaedic Association. A total of 1335 items of medical questionnaire data came from this study. The number of medical questionnaire items was reduced from 1335 to 331 in data cleaning. From the 331 items, identify factors associated with LS use by light gradient boosting machine‐based recursive feature elimination with cross‐validation. The performance of each set was evaluated using an average of seven performance metrics, including 95% confidence intervals, using a bootstrapping method. The smallest set of items is determined with the highest average of receiver operating characteristic area under the curve (ROC‐AUC) under 20 items as association factors of LS. Additionally, the performance of the selected items was compared with the LS risk tests and Loco‐check. Results: The nine items have the best average ROC‐AUC under 20 items. The nine items show an average ROC‐AUC of 0.858 (95% confidence interval 0.816–0.898). Age and back pain during walking were strongly associated with the prevalence of LS. The ROC‐AUC of nine items is higher than that of existing questionnaire‐based LS assessments, including the 25‐question Geriatric Locomotor Scale and Loco‐check. Conclusions: The identified nine items could aid early LS detection, enhancing understanding and prevention. Geriatr Gerontol Int 2024; 24: 806–813. [ABSTRACT FROM AUTHOR]

Bone turnover markers (BTMs) are commonly used in osteoporosis treatment as indicators of cell activities of bone-resorbing osteoclasts and bone-forming osteoblasts. The wide variability in their values due to multiple factors, such as aging and diseases, makes it difficult for physicians to utilize them for clinical decision-making. The progenitors of osteoclasts and osteoblasts are indispensable for a comprehensive interpretation of the variability in BTM values because these upstream progenitors strongly regulate the downstream cell activities of bone turnover. However, understanding the complex interactions among the multiple populations of bone cells is challenging. In this study, we aimed to gain a fundamental understanding of the mechanism by which the progenitor dynamics affect the variability in bone turnover through in silico experiments by exploring the cell dynamics with aging effects on osteoporosis. Negative feedback control driven by the consumptive loss of progenitors prevents rapid bone loss due to excessive bone turnover, and through feedback regulation, aging effects on osteoclast differentiation and osteoclast progenitor proliferation cause variability in the osteoclast and osteoblast activity balance and its temporal transition. By expressing the variability in the bone turnover status, our model describes the individualities of patients based on their clinical backgrounds. Therefore, our model could play a powerful role in assisting tailored treatment and has the potential to resolve the various health problems associated with osteoporosis worldwide. [ABSTRACT FROM AUTHOR]

We conducted a retrospective cohort study using a de-identified hospital administrative claims database to assess the risk of non-vertebral fracture in Japanese women with osteoporosis treated with raloxifene compared with alendronate. The study included Japanese women ≥50 years of age with newly initiated alendronate or raloxifene treatment between July 2008 and March 2013 (index date was defined as the day of first prescription for alendronate or raloxifene), and had any claim with an osteoporosis definition during the study period. A total of 37,056 patients in the database initiated treatment, and there were 4802 and 1250 patients included in the alendronate and raloxifene analysis groups, respectively. The mean observation period in the alendronate group (529.2 days) was significantly longer than that for the raloxifene group (473.5 days, P < 0.001). Non-vertebral fractures accumulated linearly, at a similar rate, for both study drugs: incidence at 1 year was 2.83 and 2.64% for the alendronate and raloxifene groups, respectively. For the relative risk of non-vertebral fracture within 1 year, the adjusted hazard ratio was 0.933 for raloxifene versus alendronate, indicating that the relative risk of non-vertebral fracture was similar for the two drugs. The effectiveness of raloxifene in preventing non-vertebral fractures in Japanese women with osteoporosis was similar to that of alendronate. Therefore, raloxifene may be worthy of consideration as an alternative treatment. [ABSTRACT FROM AUTHOR]

Objective. This study aimed to assess the mutual associations between musculoskeletal diseases (knee osteoarthritis [KOA], lumbar spondylosis [LS], osteoporosis [OP]) and metabolic syndrome components (obesity [OB], hypertension [HT], dyslipidemia [DL], impaired glucose tolerance [IGT]). Methods. Of the 1,690 participants (596 men, 1,094 women) at baseline, 1,384 individuals (81.9%; 466 men, 918 women) had complete data at the first follow-up in 2008. Logistic regression analysis included the occurrence or nonoccurrence of the musculoskeletal diseases or metabolic components as the outcome variable and the remaining musculoskeletal diseases and metabolic components at baseline as explanatory variables, adjusted for age, sex, residential region, smoking, and alcohol consumption. Results. The risk of KOA occurring increased significantly with HT (odds ratio [OR], 2.57; 95% confidence interval [CI], 1.22-5.42; p = 0.013) and IGT (OR, 1.99; 95%CI, 1.07-3.70; p = 0.029). The risk of OP occurring at the lumbar spine increased with OP at the femoral neck (OR, 4.21; 95%CI 1.46-12.1; p = 0.008), and vice versa (OR, 2.19; 95%CI, 1.01-479; p = 0.047). KOA increased the risk of HT (Kellgren-Lawrence [KL] grade = 0, 1 vs. KL = 2: OR, 1.84; 95%CI, 1.09-3.12; p = 0.024) and DL (KL = 0, 1 vs. KL ≥ 3: OR, 1.66; 95%CI, 1.05-2.61; p = 0.029) occurring. Reciprocal relationships existed between the presence of metabolic components and the occurrence of the other metabolic components. Conclusion. Mutual relationships existed between the occurrence and presence of musculoskeletal diseases, particularly KOA, and metabolic syndrome components. [ABSTRACT FROM AUTHOR]

Objectives. To examine the onset and resolution of pain and physical functional disability using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and their association with knee osteoarthritis (OA) in the longitudinal large-scale population of the nationwide cohort study, Research on Osteoarthritis/osteoporosis Against Disability (ROAD). Methods. Subjects from the ROAD study who had been recruited during 2005-2007 were followed up 3 years later. A total of 1,578 subjects completed the WOMAC questionnaire at baseline and follow up, and the onset and resolution rate of pain and physical functional disability were examined. We also examined the association of onset of pain and physical functional disability and their resolution with severity of knee OA as well as age, body-mass index and grip strength. Results. After a 3.3-year follow-up, the onset rate of pain was 35.0% and 35.3% in men and women, respectively, and the onset rate of physical functional disability was 38% and 40%, respectively. Resolution rate of pain was 20.3% and 26.2% in men and women, respectively, and resolution rate of physical functional disability was 16% and 14% in men and women, respectively. Knee OA was significantly associated with onset and resolution of pain and physical functional disability in women, but there was no significant association of knee OA with onset of pain and resolution of physical functional disability in men. Conclusions. The present longitudinal study revealed the onset rate of pain and physical functional disability as well as their resolution, and their association with knee OA. [ABSTRACT FROM AUTHOR]

Objective. The objective of the present study is to identify dietary nutrients associated with joint space narrowing (JSN) and osteophytosis at the knee in a population-based cohort of the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study. Methods. From the baseline survey of the ROAD study, 827 participants (305 men and 522 women) in a rural cohort were analyzed. Dietary nutrient intakes for the last month were assessed by a self-administered brief diet history questionnaire. Minimum joint space width (mJSW) and osteophyte area (OPA) in the medial compartment of the knee were measured using a knee osteoarthritis (OA) computer-aided diagnostic system. Results In men, there were no associations of dietary nutrient intakes with mJSW or OPA. In women, vitamins K, B1, B2, B6, and C were associated with mJSW after adjustment for age, body mass index, and total energy ( p < 0.05). Vitamins E, K, B1, B2, niacin, and B6 were significantly associated with OPA ( p < 0.05) in women. Vitamins K, B and C may have a protective role against knee OA in women and might lead to disease-modifying treatments. Conclusions. The present study revealed that low dietary intake of vitamins K, B, and C are associated with JSN and osteophytosis in women. [ABSTRACT FROM AUTHOR]

Objective: Intra-articular (IA) injection of hyaluronic acid (HA) has been shown to relieve osteoarthritis (OA)-related pain and improve joint structure within a 1-year period. We examined the mid-term (2-year) efficacy of IA-HA in Japanese subjects by using a large-scale population-based cohort of the Research on Osteoarthritis/Osteoporosis Against Disability study. Methods: We performed a nested case control study of 60 case control pairs matched for age (within 1 year), sex, Kellgren and Lawrence grade, and history of knee pain. The mean follow-up period after IA-HA series was 2.9 years in case patients. We examined the association of IA-HA with knee radiographic severity and knee pain. To estimate radiographic severity of OA, six distinct features-joint space area and the minimum joint space width at medial and lateral sides, osteophyte area, and tibiofemoral angle-were measured using a fully automatic computer-assisted program. Results: Comparison of the radiographic parameters between case patients and controls showed that the medial and lateral joint space areas were significantly bigger in case patients than in controls. After constructing a multivariate logistic regression model to examine the correlation of knee pain, IA-HA, and radiographic features, we found that unlike radiographic features, IA-HA was protectively associated with the presence of pain. Conclusion: IA-HA might effectively improve joint structure and relieve pain in patients with knee OA. [ABSTRACT FROM AUTHOR]

Objective Nitrogen-containing bisphosphonates are one of the most successful therapeutics for osteoporosis. The aim of this study was to elucidate the functional mechanism of one of the typical nitrogen-containing bisphosphonates, risedronate. Methods Osteoclasts generated from murine bone marrow macrophages were treated with risedronate in vitro, and its effects on apoptosis and bone-resorbing activity were examined. The mechanism of action of risedronate was examined by gene induction of constitutively active Akt-1 and constitutively active MEK-1, and by gene deletion of Bim. Bim−/− mice, in which osteoclasts were resistant to apoptosis, were treated with risedronate and analyzed radiographically, biochemically, and histologically. Results Risedronate induced osteoclast apoptosis through the mitochondria-dependent pathway with an increased expression of Bim, and the proapoptotic effect of risedronate was suppressed by Bim deletion and constitutively active MEK-1 introduction. In contrast, the risedronate-induced suppression of bone resorption was completely reversed by inducing constitutively active Akt-1, but not by Bim deletion or constitutively active MEK-1 introduction. These results suggested that apoptosis and bone-resorbing activity of osteoclasts were regulated through the ERK/Bim axis and the Akt pathway, respectively, both of which were suppressed by risedronate. Although osteoclast apoptosis in response to risedronate administration was suppressed in the Bim−/− mice, risedronate treatment increased bone mineral density in Bim−/− mice at a level equivalent to that in wild-type mice. Conclusion Our findings indicate that the antiresorptive effect of risedronate in vivo is mainly mediated by the suppression of the bone-resorbing activity of osteoclasts and not by the induction of osteoclast apoptosis. [ABSTRACT FROM AUTHOR]

To investigate the prevalence and incidence rates of sarcopenia in Japanese community-dwelling people according to the criteria of the Asian Working Group for Sarcopenia 2019 recommendations, using a large-scale population-based cohort over a 10-year follow-up period. Prospective cohort study. This study was conducted using data from the Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) study. In total, 1551 participants (521 men and 1030 women; mean age, 65.8 years) from the second ROAD survey (2008–2-10) were included in this study. The participants from the second survey were followed-up at 4, 7, and 10 years. Skeletal muscle mass, handgrip strength, and walking speed were assessed. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2019 criteria. The incidence of sarcopenia was calculated using the person-year method. Cox proportional hazard model was used to assess risk factors for incident sarcopenia. The prevalence of sarcopenia was 8.1% (8.8% in men and 7.7% in women), and the prevalence of severe sarcopenia was 2.9% (2.7% in men and 3.1% in women). The incidence rates of sarcopenia were 17.8 per 1000 and 14.5 per 1000 person-years in men and women, respectively. Additionally, the incidence rates of severe sarcopenia were 6.4 per 1000 and 4.2 per 1000 person-years in men and women, respectively. The significant risk factors for the incidence of sarcopenia were age [+1 year; hazard ratio (HR), 1.10; 95% CI, 1.08-1.12] and body mass index (−1 kg/m2; HR, 1.27; 95% CI, 1.20-1.35). The significant risk factors for the incidence of severe sarcopenia were age (+1 year; HR, 1.18; 95% CI, 1.14-1.22) and body mass index (−1 kg/m2; HR, 1.21; 95% CI, 1.10-1.33). The prevalence and incidence rates of sarcopenia in Japan were clarified in this study. [ABSTRACT FROM AUTHOR]

We examined the effect of teriparatide, and switching from teriparatide to anti-RANKL (receptor activator of nuclear factor κB ligand) monoclonal antibody, in ovariectomized mice. Twelve-week-old female C57BL/6 mice were ovariectomized or sham operated. Four weeks after surgery, ovariectomized mice were subjected to one of the following four treatments: phosphate-buffered saline (PBS) for 8 weeks; teriparatide for 4 weeks followed by PBS for 4 weeks (PTH4W group); teriparatide for 8 weeks (PTH8W group); or teriparatide for 4 weeks followed by anti-RANKL antibody (single subcutaneous injection of 5 mg/kg) (SWITCH group). Twelve weeks after the operation, bone mineral density was increased in PTH8W and SWITCH groups to broadly comparable levels, but these were significantly decreased in the PTH4W group after discontinuation of teriparatide. Histomorphometric analysis demonstrated that cancellous bone formation and resorption were profoundly suppressed in the SWITCH group. Bone formation was also suppressed on the endocortical surface of cortical bone but was maintained on the periosteal surface. Anti-RANKL antibody suppressed osteoclast activity immediately after treatment, while bone formation was only gradually decreased. These results suggest that anti-RANKL antibody may be a therapeutic option after discontinuation of teriparatide therapy. [ABSTRACT FROM AUTHOR]

Deletion of the c-src gene impairs osteoclast bone resorbing activity, causing osteopetrosis. Although it has been concluded that restoring only the Src adaptor function at least partly rescues the cell attachment and skeletal phenotypes, the contribution of Src kinase activity remains controversial. Src forms a complex with Pyk2 and Cbl after adhesion-induced stimulation of αvβ3 integrin. To demonstrate the importance of the Pyk2-Src association in osteoclasts and to distinguish the contributions of the Src adaptor and kinase activities in cytoskeletal organization and osteoclast function, we expressed mutants of Src and Pyk2 in osteoclasts using adenovirus vectors. Eliminating the Src-binding site on Pyk2 (Pyk2Y402F) markedly inhibited bone resorption by osteoclast-like cells, whereas kinasedead Pyk2 had little effect. Kinase-dead Src, unlike kinase-dead Pyk2, markedly inhibited the bone-resorbing activity of wild type osteoclasts and failed to significantly restore bone-resorbing activity to Src-/- osteoclast-like cells. Activation of Src kinase by overexpressing kinase-dead Csk failed to reverse the inhibitory effect of Pyk2Y402F suggesting that osteoclastic bone resorption requires both c-Src kinase activity and the targeting of Src kinase by Pyk2. Src-catalyzed phosphorylation of Cbl on Tyr-731 is reported to induce the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. Expressing the CblY731F mutant in osteoclasts markedly reduced their bone resorbing activity, suggesting that phosphorylation of CblY731 and the subsequent recruitment and activation of phosphatidylinositol 3-kinase may be critical signaling events downstream of Src in osteoclasts. [ABSTRACT FROM AUTHOR]