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.

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).

FAM210A is a novel determinant of bone and muscle structure and strength.

Osteoporosis and sarcopenia are common comorbid diseases, yet their shared mechanisms are largely unknown. We found that genetic variation near FAM210A was associated, through large genome-wide association studies, with fracture, bone mineral density (BMD), and appendicular and whole body lean mass, in humans. In mice, Fam210a was expressed in muscle mitochondria and cytoplasm, as well as in heart and brain, but not in bone. Grip strength and limb lean mass were reduced in tamoxifen-inducible Fam210a homozygous global knockout mice (TFam210a-/- ), and in tamoxifen-inducible Fam210 skeletal muscle cell-specific knockout mice (TFam210aMus-/- ). Decreased BMD, bone biomechanical strength, and bone formation, and elevated osteoclast activity with microarchitectural deterioration of trabecular and cortical bones, were observed in TFam210a-/- mice. BMD of male TFam210aMus-/- mice was also reduced, and osteoclast numbers and surface in TFam210aMus-/- mice increased. Microarray analysis of muscle cells from TFam210aMus-/- mice identified candidate musculoskeletal modulators. FAM210A, a novel gene, therefore has a crucial role in regulating bone structure and function, and may impact osteoporosis through a biological pathway involving muscle as well as through other mechanisms.

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.

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.

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.

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).

Papillary thyroid carcinoma is a risk factor for severe osteoporosis.

INTRODUCTION: Thyroid-stimulating hormone (TSH)-suppressive therapy is recommended after surgical treatment in high-risk papillary thyroid carcinoma (PTC) patients. TSH-suppressive therapy is a known risk factor for osteoporosis and fractures. However, whether patients with PTC themselves are at a higher risk of osteoporosis than healthy individuals remains unclear. This study aimed to clarify whether PTC is a risk factor for osteoporosis. MATERIALS AND METHODS: Serum and urinary biochemical parameters, bone mineral density (BMD), and presence of vertebral fractures (VFs) and non-VFs were evaluated in 35 PTC patients and 35 age- and sex-matched healthy individuals. We compared the parameters between PTC and control subjects and performed multiple logistic regression analyses after adjustments for variables. RESULTS: Patients with PTC had higher body mass index (BMI) and hemoglobin (Hb)A1c, as well as lower eGFR and intact PTH than controls (p < 0.05, each). There were no significant differences in the prevalence of osteoporosis and VFs and non-VFs between patients with PTC and controls. However, the prevalence of severe osteoporosis diagnosed according to WHO criteria was significantly higher in PTC subjects (34.3%) than in controls (11.4%, p < 0.05). Multivariate logistic regression analyses adjusted for age, BMI, eGFR and HbA1c identified PTC as being associated with the presence of severe osteoporosis (odds ratio, 4.20; 95% confidence interval, 1.05-16.8; p < 0.05). CONCLUSIONS: We identified PTC as a risk factor for severe osteoporosis, independent of BMI, renal function and glucose profile.

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.

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.

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.

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.

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.

Bazedoxifene Ameliorates Homocysteine-Induced Apoptosis via NADPH Oxidase-Interleukin 1ß and 6 Pathway in Osteocyte-like Cells.

Homocysteine (Hcy) increases oxidation and inflammation; however, the mechanism of Hcy-induced bone fragility remains unclear. Because selective estrogen modulators (SERMs) have an anti-oxidative effect, SERMs may rescue the Hcy-induced bone fragility. We aimed to examine whether oxidative stress and pro-inflammatory cytokines such as interleukin (IL)-1ß and IL-6 are involved in the Hcy-induced apoptosis of osteocytes and whether bazedoxifene (BZA) inhibits the detrimental effects of Hcy. We used mouse osteocyte-like cell lines MLO-Y4-A2 and Ocy454. Apoptosis was examined by DNA fragmentation ELISA and TUNEL staining, and gene expression was evaluated by real-time PCR. Hcy 5 mM significantly increased expressions of NADPH oxidase (Nox)1, Nox2, IL-1ß, and IL-6 as well as apoptosis in MLO-Y4-A2 cells. Nox inhibitors, diphenyleneiodonium chloride and apocynin, significantly suppressed Hcy-induced IL-1ß and IL-6 expressions. In contrast, an IL-1ß receptor antagonist and an IL-6 receptor monoclonal antibody had no effects on Hcy-induced Nox1 and Nox2 expressions, but significantly rescued Hcy-induced apoptosis. BZA (1 nM-1 µM) and 17ß estradiol 100 nM significantly rescued Hcy-induced apoptosis, while an estrogen receptor blocker ICI 182,780 reversed the effects of BZA and 17ß estradiol. BZA also rescued Hcy-induced apoptosis of Ocy454 cell, and ICI canceled the effect of BZD. Moreover, BZA significantly ameliorated Hcy-induced expressions of Nox1, Nox2, IL-1ß, and IL-6, and ICI canceled the effects of BZA on their expressions. Hcy increases apoptosis through stimulating Nox 1 and Nox 2-IL-1ß and IL-6 expressions in osteocyte-like cells. BZA inhibits the detrimental effects of Hcy on osteocytes via estrogen receptor.

Insulin-Like Growth Factor-I Protects Against the Detrimental Effects of Advanced Glycation End Products and High Glucose in Myoblastic C2C12 Cells.

Previous studies suggested that advanced glycation end products (AGEs) and insulin-like growth factor-I (IGF-I) are involved in the mechanism of diabetes-induced sarcopenia. In this study, we examined effects of treatments with AGEs and/or IGF-I for 24 h on myogenic differentiation and apoptosis in mouse myoblastic C2C12 cells. Real-time PCR and Western blot were performed to investigate mRNA and protein expressions, and apoptosis was examined by using a DNA fragment detection ELISA kit. AGE3 significantly decreased mRNA and protein expressions of MyoD and Myogenin, whereas IGF-I significantly increased them and attenuated the effects of AGE3. AGEs significantly decreased endogenous IGF-I mRNA expression and suppressed IGF-I-induced Akt activation. High glucose (22 mM) significantly increased mRNA expression of Rage, a receptor for AGEs, while IGF-I significantly decreased it. DNA fragment ELISA showed that AGE2 and AGE3 significantly increased apoptosis of C2C12 cells, whereas IGF-I significantly suppressed the AGE2- and AGE3-induced apoptosis. In contrast, high glucose enhanced AGE3-induced apoptosis. IGF-I significantly attenuated the effects of high glucose plus AGE3 on the mRNA and protein expressions of MyoD and Myogenin as well as the apoptosis. These findings indicate that AGEs inhibit myogenic differentiation and increase apoptosis in C2C12 cells, and that high glucose increases RAGE and enhances the AGE3-induced apoptosis, suggesting that AGEs and high glucose might contribute to the reduction of muscle mass and function. Moreover, IGF-I attenuated the detrimental effects of AGEs and high glucose in myoblastic cells; thus, IGF-I-Akt signal could be a therapeutic target of DM-induced sarcopenia.

Overweight and underweight are risk factors for vertebral fractures in patients with type 2 diabetes mellitus.

The aim of this cross-sectional study was to examine the association between body mass index (BMI) and the prevalence of vertebral fracture (VF) in Japanese patients with type 2 diabetes (T2DM). A total of 798 patients with T2DM were enrolled. VF was determined semi-quantitatively using lateral X-ray films. The association between BMI quartiles (Q1: ≤ 21.2 kg/m2, Q2: 21.3-23.4 kg/m2, Q3: 23.5-25.8 kg/m2, Q4: 25.9≤ kg/m2) and the presence of VF was examined. Multiple logistic regression analyses adjusted for age, sex, diabetes duration, hemoglobin A1c (HbA1c), estimated glomerular filtration rate, and albumin showed that Q1, Q3, and Q4 were significantly associated with an increased VF risk compared to Q2, which served as a reference [Q1; odds ratio (OR) = 1.91, 95% confidence interval (CI) 1.24-2.95, p = 0.004, Q3; OR = 1.65, 95% CI 1.07-2.55, p = 0.023, and Q4; OR = 2.18, 95% CI 1.39-3.41, p < 0.001]. Moreover, these associations remained significant after additional adjustment for femoral neck T-score, a bone resorption marker, urinary N-terminal cross-linked telopeptide of type-I collagen, and use of insulin and thiazolidinedione. Our study shows for the first time that both overweight and underweight were associated with the bone mineral density (BMD)-independent risk of VF in patients with T2DM. Therefore, body weight control should be considered as a protective measure against diabetes-related bone fragility.

Osteoporosis and vertebral fracture are associated with deterioration of activities of daily living and quality of life in patients with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fracture. However, whether diabetes-related osteoporosis independently contributes to the deterioration of activities of daily living (ADLs) and quality of life (QOL) is unclear. This cross-sectional study investigated the association between osteoporosis, ADLs, and QOL in 309 patients with T2DM. ADLs and QOL were assessed using Barthel Index (BI) and a SF-36 questionnaire. Multiple logistic regression analyses adjusted for age, gender, T2DM duration, body mass index, hemoglobin A1c, estimated GFR, diabetic neuropathy, retinopathy, nephropathy, cardiovascular disease, cerebrovascular disease, peripheral artery disease, and anti-diabetic treatments were conducted. The number of patients with osteoporosis or vertebral fracture was 166 (53.7%) and 118 (38.2%), respectively. Osteoporosis was significantly associated with lower general health (GH), social functioning (SF), and role emotional (RE) (OR 2.56, 1.79, and 1.92, respectively; all p values < 0.05 at least) and marginally associated with lower BI (OR 2.39, p = 0.068). Moreover, the presence of vertebral fracture grade 2 or 3 was significantly associated with lower BI, bodily pain (BP), GH, vitality, SF, and RE (OR 2.58, 2.01, 3.64, 1.99, 2.18, and 1.97, respectively; all p values < 0.05 at least). Osteoporosis and severe vertebral fracture were associated with the deterioration of ADLs and QOL independently of other diabetic complications. Therefore, the management of diabetes-related osteoporosis is an important strategy to avoid the deterioration of ADLs and QOL in T2DM.

Changes in quality of life in patients with postmenopausal osteoporosis receiving weekly bisphosphonate treatment: a 2-year multicenter study in Japan.

We investigated changes in quality of life (QOL), including pain, in Japanese women aged ≥ 55 years who were diagnosed as having osteoporosis at 265 centers across Japan and treated continuously with once-weekly bisphosphonates for 24 months. In 2650 evaluable patients, a significant improvement in QOL was observed from 3 months after enrollment onward and maintained throughout the 2-year observation period. A significant improvement in scores was observed for all domains of the Euro QOL 5 Dimension (EQ-5D), and the "pain", "health perception", and "posture, figure" domains of the Japanese Osteoporosis QOL Questionnaire (JOQOL). Factors identified as significantly contributing to QOL change were "fractures within the year before enrollment", "presence of spondylosis deformans", "presence of osteoarthritis", "use of activated vitamin D3", and "age" based on the JOQOL, and "presence of spondylosis deformans", "use of activated vitamin D3", and "age" based on the EQ-5D. The results suggested that the patients' perception of treatment effects, such as improvement in pain, contributes to treatment continuation. Osteoporosis patients should be informed that continuous treatment with once-weekly bisphosphonates can lead to a significant improvement in QOL regardless of concomitant locomotor diseases, to encourage them to remain on treatment. In conclusion, continuous bisphosphonate treatment improved the QOL even in patients with locomotor diseases, and the concomitant use of activated vitamin D3 may also facilitate further improvement in QOL.

Efficacy and safety of once-monthly risedronate in osteoporosis subjects with mild-to-moderate chronic kidney disease: a post hoc subgroup analysis of a phase III trial in Japan.

Limited data are available on the safety and efficacy of anti-resorptive agents, particularly once-monthly bisphosphonates, for use in osteoporotic patients with chronic kidney disease (CKD). We conducted a post hoc analysis of data from a 12-month, randomized, double-blind, phase III study to evaluate the safety and efficacy of once-monthly risedronate (RIS-OM) 75 mg tablets in Japanese osteoporosis patients with mild-to-moderate CKD. Patients who received RIS-OM 75 mg were stratified by baseline estimated glomerular filtration rate (eGFR; ≥ 90, ≥ 60 to < 90, or ≥ 30 to < 60 mL/min/1.73 m2). Safety endpoints were incidence of adverse events (AEs) and percent change from baseline in eGFR, serum creatinine, calcium, and phosphorus. Efficacy endpoints were percent change from baseline in lumbar spine bone mineral density (BMD) and bone turnover markers (BTMs). In 420 patients included (age 67.7 ± 6.7 years, women 98.8%), the incidence of all AEs, gastrointestinal disorders, acute phase reaction, non-vertebral fractures, and renal and urinary disorders was not significantly different among subgroups. Interaction between subgroups and time was significant for eGFR (p = 0.010) and serum creatinine (p = 0.001) but considered to be regression to the mean and clinically insignificant. BMD significantly increased while BTMs significantly decreased from baseline with a similar degree of change among the subgroups. In conclusion, RIS-OM 75 mg showed consistent safety and efficacy in suppressing bone turnover and increasing BMD in Japanese primary osteoporosis patients with mild-to-moderate CKD. These results should, however, be interpreted with caution because the number of patients with moderate CKD was limited.