Sequential therapy with once-weekly teriparatide injection followed by alendronate versus monotherapy with alendronate alone in patients at high risk of osteoporotic fracture: final results of the Japanese Osteoporosis Intervention Trial-05.

In this randomized, controlled trial, sequential therapy with once-weekly subcutaneous injection of teriparatide for 72 weeks, followed by alendronate for 48 weeks resulted in a significantly lower incidence of morphometric vertebral fracture than monotherapy with alendronate for 120 weeks in women with osteoporosis at high risk of fracture. PURPOSE: To determine whether the anti-fracture efficacy of sequential therapy with teriparatide, followed by alendronate is superior to that of monotherapy with alendronate, a prospective, randomized, open-label, blinded-endpoint trial was performed. METHODS: Japanese women aged at least 75 years were eligible for the study, if they had primary osteoporosis and if they were at high risk of fracture. Patients were randomly assigned (1:1) to receive the sequential therapy (once-weekly subcutaneous injection of teriparatide 56.5 µg for 72 weeks, followed by alendronate for 48 weeks) or monotherapy with alendronate for 120 weeks. The primary endpoint in the final analysis was the incidence of morphometric vertebral fracture during the 120-week follow-up period. RESULTS: Between October 2014 and June 2020, 505 patients in the sequential therapy group and 506 in the monotherapy group were enrolled. Of these, 489 and 496, respectively, were included in the main analysis. The incidence of morphometric vertebral fracture during the 120-week follow-up period in the sequential therapy group (64 per 627.5 person-years, annual incidence rate 0.1020) was significantly lower than that in the monotherapy group (126 per 844.2 person-years, annual incidence rate 0.1492), with a rate ratio of 0.69 (95% confidence interval 0.54 to 0.88, P < 0.01). After 72 weeks, no patient had a severe adverse event that was considered related to the study drug. CONCLUSION: Once-weekly injection of teriparatide, followed by alendronate resulted in a significantly lower incidence of morphometric vertebral fracture than alendronate monotherapy in women with osteoporosis who were at high risk of fracture. TRIAL REGISTRATION NUMBER, DATE OF REGISTRATION: jRCTs031180235 and UMIN000015573, March 12, 2019.

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.

Relationship Between Changes in Serum Levels of Intact Parathyroid Hormone and Sclerostin After a Single Dose of Zoledronic Acid: Results of a Phase 1 Pharmacokinetic Study.

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

Acute Phase Reactions After Intravenous Infusion of Zoledronic Acid in Japanese Patients with Osteoporosis: Sub-analyses of the Phase III ZONE Study.

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

Efficacy of once-weekly and twice-weekly injections of teriparatide by patient characteristics: A post hoc analysis of the TWICE study.

OBJECTIVES: To assess differences in efficacy of a 28.2-µg teriparatide formulation for twice-weekly use (2/W-TPTD) by patient characteristics. METHODS: A post hoc analysis was performed using data from a multicenter, randomized, double-blind, double-dummy, non-inferiority trial (TWICE study) conducted in Japan comparing the efficacies of once-weekly and twice-weekly injections of teriparatide (TPTD). Specifically, a stratified analysis of percentage changes from baseline was performed using the final data on lumbar spine bone mineral density (BMD) after a 48-week treatment period (n = 251, 2/W-TPTD; n = 239, a 56.5-µg teriparatide formulation for once-weekly use [1/W-TPTD]). RESULTS: Across all subgroups defined by patient characteristics that included 9 or more subjects, the lumbar spine BMD increased significantly in both groups. In the 2/W-TPTD group, the percentage change was significantly higher in subjects with no non-vertebral fractures without large external force occurring at or after age 50 years versus those with such fractures. The lower the stratification in baseline lumbar spine BMD, total hip BMD, or femoral neck BMD, the greater was the percentage change. CONCLUSIONS: Whereas all subgroups can expect a significant improvement in lumbar spine BMD, there were some patient characteristics that affected the percentage increase in BMD.

High glucose promotes mineralization via bone morphogenetic protein 4-Smad signals in early stage of osteoblast differentiation.

Diabetes mellitus is associated with bone fragility. Although osteoblast maturation is disturbed in patients with diabetes mellitus, the involvement of high glucose (HG) in different stages of osteoblast maturation is unclear. We used MC3T3-E1 cells, a murine osteoblastic cell line. The cells were incubated in high glucose medium (16.5 and 27.5 mM) with three different time courses: throughout 21 days, only first 7 days (early stage) and only last 7 days (late stage). Mineralization assay showed that HG throughout 21 days increased mineralization compared with control (5.5 mM). In the time course experiment, HG increased mRNA expression of Alp, osteocalcin (Ocn), runt-related transcription factor 2 and osterix on days 3 and 5. By contrast, long-term treatment with HG (14 and 21 days) decreased expression of these osteoblastic markers. HG only during early stage enhanced mineralization, while HG only during late stage had no effects. HG increased the expression of bone morphogenetic protein (BMP) 4 and enhanced phosphorylation of Smad1/5/8. Treatment with a BMP receptor antagonist LDN193189 prevented the HG-induced mineralization during early stage of osteoblast differentiation, indicating that HG in the early stage promotes mineralization by BMP4. In conclusion, the study demonstrates that continuous HG treatment might enhance early osteoblast differentiation but disturbs osteoblast maturation, and that BMP-4-Smad signal might be involved in the HG-induced differentiation and mineralization of osteoblasts.

Higher Serum Uric Acid is a Risk Factor of Reduced Muscle Mass in Men with Type 2 Diabetes Mellitus.

OBJECTIVE: Sarcopenia has been recognized as a diabetic complication, and hyperuricemia is often accompanied by type 2 diabetes mellitus (T2DM). However, it is unknown whether serum uric acid (UA) levels are associated with reduced muscle mass in T2DM. METHODS: We conducted a cross-sectional study to investigate the association of serum UA with muscle mass in 401 subjects with T2DM (209 men and 192 postmenopausal women). The relative skeletal muscle mass index (RSMI) was evaluated using whole-body dual-energy x-ray absorptiometry. RESULTS: Multiple regression analyses adjusted for body weight, age, serum creatinine, hemoglobin A1c (HbA1c), and duration of T2DM showed that serum UA was negatively associated with RSMI in all subjects and men with T2DM (ß=-0.13, p=0.001 and ß=-0.17, p=0.003, respectively). Moreover, logistic regression analyses adjusted for these confounding factors showed that a higher serum UA level was significantly associated with low RSMI in men with T2DM [odds ratio (OR)=1.94, 95% confidence interval (CI)=1.10-3.45 per SD increase, p=0.023]. In addition, higher serum UA levels were significantly associated with low RSMI after additional adjustment for age, duration of T2DM, HbA1c level, serum creatinine level, and sex in all subjects with T2DM [OR=1.80, 95% CI=1.20-2.72 per SD increase, p=0.005]. CONCLUSIONS: The present study showed for the first time that higher serum UA is an independent risk factor of reduced muscle mass in men with T2DM.

Which Is a Better Skeletal Muscle Mass Index for the Evaluation of Physical Abilities: The Present Height or Maximum Height?

Objective Sarcopenia and osteoporosis often coexist in older adults. Sarcopenia is diagnosed using the skeletal muscle mass index (SMI), which is calculated as the appendicular skeletal muscle mass (ASM)/(present height)2, although patients with osteoporosis frequently have a loss of body height. We therefore investigated whether the present height or maximum height is more useful for calculating the SMI in the evaluation of physical abilities. Methods We conducted a cross-sectional study to investigate the association of the SMI with physical abilities, such as the grip strength and gait speed, in 587 postmenopausal women. The SMI was evaluated using whole-body dual-energy X-ray absorptiometry (DXA). The SMI [(ASM)/(present height)2], modified SMI (mSMI) [(ASM)/(maximum height)2], and SMI difference (ΔSMI) (mSMI-SMI) were calculated. Results Age and body mass index (BMI)-adjusted regression analyses showed that the SMI (ß=0.30, p<0.001 and ß=0.14, p=0.034) and mSMI (ß=0.40, p<0.001 and ß=0.29, p<0.001) were positively associated while the ΔSMI was negatively associated with the grip strength and gait speed (ß=-0.15, p<0.001 and ß=-0.24, p<0.001, respectively). Furthermore, the age, BMI, and presence of osteoporotic fractures-adjusted logistic regression analyses showed that a low mSMI (<5.4 kg/m2) was significantly associated with a low grip strength (<18 kg) and slow gait speed (1.0 m/s) [odds ratio (OR) =2.45, 95% confidence interval (CI) =1.52-3.95 per SD increase, p<0.001; and OR=1.73, 95% CI=1.01-2.96, p=0.042, respectively], although a low SMI showed no such relationship (p=0.052 and p=0.813, respectively). Conclusion The mSMI using the maximum height is more useful for evaluating physical abilities than conventional SMI estimation in postmenopausal women.

A pregnant woman with an autonomously functioning thyroid nodule: a case report.

BACKGROUND: The epidemiology and natural history of autonomously functioning thyroid nodules (AFTNs) have not been elucidated. Here we report the pregnant Japanese woman with an AFTN. CASE PRESENTATION: The patient was a 31-year-old woman who was hospitalized due to the placenta previa associated with threatened abortion at the 16 weeks of her third pregnancy. At her second pregnancy, she was euthyroid but had a single, 2.3 cm nodule on her right thyroid lobe. Her thyroid hormone level was trended increased with her pregnancy progression, and the thyrotoxic state was remained after delivery. Before her third pregnancy, her hyper-vascular nodule enlarged to 3.4 cm at regular monitoring. When she visited our hospital, she was at 16 weeks of pregnancy and had thyrotoxicosis with negative TSH-receptor antibody. She delivered a baby weighing 2615 g without hypothyroidism at 39 weeks of pregnancy by natural delivery. After delivery, a 99mTc scintigram showed a hot spot in her right thyroid lobe. She was diagnosed with AFTN and treated with methimazole while nursing. CONCLUSIONS: This case showed that hCG stimulation during pregnancy caused thyroid nodule enlargement and enhanced thyroid hormone production. The pregnancy could be the pathological stimulus and provides chance to diagnosis for AFTNs.

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 clinical practice guide on fracture risk in lifestyle diseases.

Accumulating evidence has shown that patients with lifestyle diseases such as type 2 diabetes mellitus, chronic kidney disease, and chronic obstructive pulmonary disease are at increased risk of osteoporotic fracture. Fractures deteriorate quality of life, activities of daily living, and mortality as well as a lifestyle disease. Therefore, preventing fracture is an important issue for those patients. Although the mechanism of the lifestyle diseases-induced bone fragility is still unclear, not only bone mineral density (BMD) reduction but also bone quality deterioration are involved in it. Because fracture predictive ability of BMD and FRAX® is limited, especially for patients with lifestyle diseases, the optimal management strategy should be established. Thus, when the intervention of the lifestyle diseases-induced bone fragility is initiated, the deterioration of bone quality should be taken into account. We here review the association between lifestyle diseases and fracture risk and proposed an algorism of starting anti-osteoporosis drugs for patients with lifestyle diseases.

Relationship Between Bone Mineral Density and Risk of Vertebral Fractures with Denosumab Treatment in Japanese Postmenopausal Women and Men with Osteoporosis.

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

Efficacy of denosumab co-administered with vitamin D and Ca by baseline vitamin D status.

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

Association between elcatonin use and cancer risk in Japan: A follow-up study after a randomized, double-blind, placebo-controlled study of once-weekly elcatonin in primary postmenopausal osteoporosis.

OBJECTIVES: On July 20, 2012, the European Medicines Agency (EMA) provided a recommendation that limits the long-term use of calcitonin. Based on this recommendation, we investigate the presence or absence of a cancer diagnosis in subjects who participated in the ongoing clinical trial of elcatonin. METHODS: When the EMA gave this recommendation, we were conducting "a 3-year placebo-controlled clinical study for elcatonin" (hereinafter, referred to as "the original study"). In accordance with the recommendation of EMA, we performed an intermediate analysis on the subjects of the original study to assess whether the study could be safely continued. We also added a 2-year follow-up study to investigate the risk of carcinogenesis for 5 years from the start of administration. We compared the risk of carcinogenesis estimated by person-year method in elcatonin group with that in placebo group. RESULTS: In the original study, there were 433 subjects in the elcatonin group and 437 in the placebo group, of whom 322 and 323, respectively, agreed to participate in the additional follow-up study. The average cancer incidence rate per 100 person-years 5 years from the start of administration was 1.02 in the elcatonin group and 1.08 in the placebo group, respectively, and there was no clear difference. CONCLUSIONS: Since the number of cases in this study was small, we cannot completely deny the cancer risk due to long-term administration of this drug. However, the results do not suggest that once-weekly administration of 20 units of elcatonin increases the carcinogenic risk.

Graves' disease and vertebral fracture: Possible pathogenic link in postmenopausal women.

BACKGROUND AND OBJECTIVE: Thyrotoxicosis is associated with accelerated bone turnover and increases the risk of fractures and osteoporosis. Graves' disease is the most common cause of hyperthyroidism. However, studies that examined risk factors associated with fragility fractures only in patients with Graves' disease are limited. Here, we investigated whether the risk of vertebral fracture (VF) of postmenopausal Graves' disease patients is high and tried to identify the risk factors for VF in that population. DESIGN AND METHODS: Forty-three postmenopausal women with Graves' disease were enrolled. Physical and biochemical indices, thyroid indices and bone mineral density (BMD) were measured, and lateral X-rays were obtained to evaluate VFs. Age- and sex-matched healthy individuals were enrolled as the control group (n = 86). RESULTS: The prevalence of VFs (35% vs 17%, P < .05), osteoporosis (63% vs 33%, P < .01) and severe osteoporosis (40% vs 17%, P < .01) was significantly higher in the Graves' disease group. Although there was no significant difference in either thyroid hormone levels or the positive ratio of thyroid antibodies, the prevalence of thyroid-stimulating antibody (TSAb) was significantly higher in Graves' disease patients with VF compared to without (100% vs 68%, P < .05). Multivariate logistic regression analyses adjusted for age identified Graves' disease as being associated with the presence of VFs (OR 2.72, 95% CI: 1.13-6.54, P < .05) in postmenopausal women. CONCLUSIONS: Postmenopausal Graves' disease patients had high risks of VF and severe osteoporosis. TSAb could be involved as a risk factor for VF in postmenopausal Graves' disease.

Management manual for cancer treatment-induced bone loss (CTIBL): position statement of the JSBMR.

Androgen deprivation therapy and aromatase inhibitors are known to cause a decrease in bone mineral density and an increase in fractures. Patients receiving these treatments have been shown to have a fracture risk equal to or greater than that of patients with osteoporosis with prevalent fractures. This manual was created to prevent fractures in patients with cancer treatment-induced bone loss with high fracture risks who cannot be treated under the current Japanese guideline for the prevention and treatment of osteoporosis. This manual recommends drug treatment for patients with BMD - 2.0 ≤ T score < - 1.5 with the family history of hip fracture or 15% or more 10-year probability of major osteoporotic fractures by FRAX®; or in patients with BMD T score < - 2.0. It is important to verify whether the use of this manual can reduce fractures and improve the quality of life of patients with cancer treatment-induced bone loss by prospective studies.

Design of a randomized trial of teriparatide followed by alendronate: Japanese Osteoporosis Intervention Trial-05 (JOINT-05).

INTRODUCTION: Despite advances in drug treatment, the optimal treatment strategy for severe osteoporosis remains uncertain. MATERIALS AND METHODS: This article reports the design and rationale for the Japanese Osteoporosis Intervention Trial-05 (JOINT-05), a randomized, controlled trial that compares the efficacy and safety of teriparatide followed by alendronate with alendronate monotherapy for severe osteoporosis. RESULTS: Postmenopausal women aged at least 75 years were eligible for the study if they were at high risk of fracture. Patients were recruited from 113 institutions in Japan between October 2014 and December 2017. They were randomly assigned in a 1:1 ratio to the sequential therapy arm (once-weekly subcutaneous injections of teriparatide 56.5 µg for 72 weeks followed by alendronate for 48 weeks) or monotherapy arm (alendronate for 120 weeks). The regimens for alendronate are 5 mg (orally administered once daily), 35 mg (orally administered once weekly), or 900 µg (intravenously administered once every 4 weeks). The primary endpoint is the incidence of morphometric vertebral fracture at 72 weeks. The secondary endpoints include the incidence of morphometric vertebral fracture at 120 weeks; incidence of morphometric vertebral or non-vertebral fractures at 72 and 120 weeks; incidence of clinical vertebral fracture at 72 and 120 weeks; changes in bone mineral density, quality of life scores (EuroQol 5 Dimensions and the Japanese Osteoporosis Quality of Life Questionnaire short form), and a visual analog scale for back pain; and adverse events. CONCLUSION: We reported the design and rationale for the JOINT-05. The trial is registered with the Japan Registry of Clinical Trials (jRCTs031180235) and the University Hospital Medical Information Network-Clinical Trials Registry (UMIN000015573).

Modulators of Fam210a and Roles of Fam210a in the Function of Myoblasts.

Fam210a is a novel protein regulating muscle mass and strength in mice in vivo. However, detailed effects of Fam210a on the function of myoblasts as well as modulators of Fam210a are still unknown. We, thus, investigated (1) the roles of Fam210a in myoblast differentiation, proliferation, apoptosis and degradation, and (2) the factors that regulate Fam210a expression in murine C2C12 cells. We found that the level of Fam210a mRNA was reduced during myoblast differentiation. Reduction in endogenous Fam210a levels by siRNA suppressed mRNA levels of myogenic factors (Pax7, Myf5, Myogenin, and Mhc) and a muscle degradation factor (Murf1). On the other hand, Fam210a siRNA did not affect mRNA encoding the apoptotic factors Bcl-2 and Bax and the extent of apoptosis as measured by ELISA in C2C12 cells. In contrast, Fam210a siRNA increased the mRNA level of Mmp-12, which induces osteoclastogenesis. Interestingly, insulin and 1,25(OH)2D, which are known to affect cell metabolism and muscle function, significantly increased the level of Fam210a mRNA in a dose-dependent manner. In addition, a PI3-kinase inhibitor and reduction in endogenous levels of the vitamin D receptor (VDR) by siRNA suppressed insulin- and 1,25(OH)2D-induced expression of Fam210a, respectively. In conclusion, Fam210a might enhance myoblast differentiation and proteolysis. Moreover, insulin and 1,25(OH)2D may induce myoblast differentiation and degradation by enhancing the expression of Fam210a.

Phase II/III, randomized, double-blind, parallel-group study of monthly delayed-release versus daily immediate-release risedronate tablets in Japanese patients with involutional osteoporosis.

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 (L2-L4) bone mineral density (BMD) between risedronate IR on awakening and DR following breakfast. Mean percent changes in (L2-L4) 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 (L2-L4) 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.