Achieving osteoporosis treat-to-target goals with teriparatide or alendronate: sub-analysis of Japanese Osteoporosis Intervention Trial-05 (JOINT-05).

INTRODUCTION: The purpose of this study was to evaluate whether bone mineral density (BMD) ≥ -2.5 SD could be used as the treat-to-target (T2T) goal when treating osteoporosis with teriparatide (TPTD) and alendronate (ALN), and to investigate the relationship with incident vertebral fracture by re-analyzing data from a randomized, controlled trial (JOINT-05) involving postmenopausal Japanese women at high fracture risk. MATERIALS AND METHODS: Participants received sequential therapy with once-weekly TPTD for 72 weeks, followed by ALN for 48 weeks (TPTD-ALN group) or ALN monotherapy for 120 weeks (ALN group). BMDs were measured at the lumbar spine (L2-4), total hip, and femoral neck at 0, 24, 48, 72, and 120 weeks by dual-energy X-ray absorptiometry. The T2T goal was BMD ≥ -2.5 SD, and the endpoint was the proportion of participants with baseline BMD < -2.5 SD in three measurement sites achieving BMD ≥ -2.5 SD. RESULTS: A total of 559 participants were selected. BMD ≥ -2.5 SD at 120 weeks in the L2-4, total hip, and femoral neck sites was achieved in 20.5%, 23.1%, and 5.9%, respectively, in the TPTD-ALN group and 22.2%, 11.7%, and 7.3%, respectively, in the ALN group. Incident vertebral fractures occurred in areas of both lower and high BMD. CONCLUSION: During the 1.5-year treatment period, more than 20% of participants achieved BMD ≥ -2.5 SD as a T2T goal at L2-4. Since the achievement level differed depending on the BMD measurement site, the appropriate site should be selected according to the baseline BMD level.

A crossover comparison of patient satisfaction with two teriparatide regimens: primary results of the Japanese Osteoporosis Intervention Trial 06 (JOINT-06).

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.

The 2023 Guidelines for the management and treatment of glucocorticoid-induced osteoporosis.

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.

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.

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

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

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

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

Fracture risk associated with glucocorticoid-induced osteoporosis in Japan.

INTRODUCTION: Glucocorticoid-induced osteoporosis (GIOP) is associated with elevated fracture risk. Practice guidelines have been published to reduce this risk but are insufficiently followed in everyday practice. The objectives of this study were to estimate fracture incidence in patients exposed to oral glucocorticoids and to analyse the impact of glucocorticoid use on fracture incidence. MATERIALS AND METHODS: This retrospective cohort study was performed using the Medical Data Vision (MDV) claims database from Japan. All patients aged ≥ 18 years initiating oral glucocorticoids and fulfilling Japanese guideline criteria for starting prophylactic osteoporosis treatment between 2009 and 2019 were identified. These were matched to a cohort of unexposed controls using propensity score matching. Fracture incidence in the two cohorts were compared using a Fine-Gray proportional sub-distribution hazard model. RESULTS: 13,090 glucocorticoid-exposed cases were compared to 13,090 unexposed controls. The 1-year fracture rate (all sites) was 9.3 [95% CI 8.8-9.8] in cases and 5.8 [5.4-6.2] in controls. One-year vertebral fracture rates were 4.3 [4.0-4.7] and 2.3 [2.1-2.6] respectively. In the multivariate analysis, the use of glucocorticoids was associated with an increase in the incidence of osteoporotic fractures (hazard ratio: 1.63 [1.51-1.76]). The glucocorticoid-associated risk tended to be higher in subgroups of patients with rheumatoid arthritis, asthma, COPD and in those aged < 65 years. CONCLUSION: Oral glucocorticoid use is associated with an increase in fracture incidence. It is necessary to raise awareness of GIOP and to take public health measures to change the perceptions and behaviour of doctors prescribing glucocorticoids.

Efficacy of once-weekly teriparatide for primary prevention of glucocorticoid-induced osteoporosis: A post hoc analysis of the TOWER-GO study.

OBJECTIVES: A post hoc analysis of the Teriparatide Once-Weekly Efficacy Research for Glucocorticoid-induced Osteoporosis (TOWER-GO) study was performed to examine the effect of once-weekly administration of 56.5 µg teriparatide on primary prevention of glucocorticoid-induced osteoporosis (GIOP). METHODS: Of the subjects of the TOWER-GO study, 73 were included. The percentage changes from baseline in lumbar spine bone mineral density (BMD) and bone turnover markers were evaluated over 72 weeks with once-weekly teriparatide and once-weekly alendronate. RESULTS: The percentage change of lumbar spine BMD from baseline at 72 weeks was significantly increased in both groups. Bone formation markers were significantly increased by teriparatide administration, although they were slightly decreased by alendronate administration. Bone resorption markers were gradually decreased by teriparatide, whereas alendronate markedly decreased them within 4 weeks. No major safety concerns arose. CONCLUSIONS: In this primary prevention study of GIOP, comparable increases in BMD were observed between alendronate and once-weekly teriparatide. More desirable changes in bone markers were observed with teriparatide administration. These data suggest that once-weekly teriparatide is effective in primary prevention of GIOP.

Family caregiver burden of patients with osteoporotic fracture in Japan.

INTRODUCTION: Osteoporotic fractures are the most common serious consequence of osteoporosis. Patients who suffer such fractures often require caregiver assistance afterwards. This study characterized the humanistic burden experienced by family caregivers of patients with osteoporotic fractures in Japan. MATERIALS AND METHODS: Family caregivers were defined as individuals who provided non-professional care to an osteoporotic fracture patient (> 50 years old). Caregivers were asked through an online survey panel about their caregiving situation, health-related quality of life (HRQoL), work impairment, and the health status of their patient. The Zarit Caregiver Burden Interview (ZBI-22), 8-item Short Form Health Survey (SF-8), and Work Productivity and Activity Impairment Caregiver version (WPAI-CG) were used to better understand the impact of osteoporotic fracture caregiving. RESULTS: Respondents (n = 309) were family caregivers who were employed (81.6%) and cared for a parent (71.5%). Over 75% of caregivers had HRQoL physical and mental component scores below 50 on SF-8. Although most patients received welfare services (78.3%), the mean ZBI-22 score was 42.2 and 57.0% of caregivers perceived their burden to be moderate or severe (ZBI-22 score ≥ 41). Over half of caregivers changed their employment status due to their caregiving responsibilities and experienced 61.4% overall work impairment. The mean productivity loss for caregivers was estimated to be over 43,000 JPY per week. CONCLUSION: The substantial humanistic and financial burden of caregiving by family members to osteoporotic fracture patients should be considered when evaluating the impact of fragility fractures, disease management and support systems for osteoporosis.

Efficacy of once-weekly teriparatide in patients with glucocorticoid-induced osteoporosis: the TOWER-GO study.

INTRODUCTION: Bisphosphonates are the standard treatment for glucocorticoid-induced osteoporosis (GIOP) with teriparatide being another option. While daily teriparatide has been shown to be effective in increasing bone mineral density (BMD), the efficacy of once-weekly teriparatide (56.5 µg) has not yet been evaluated. The TOWER-GO study, a 72-week, multicenter, open-label, randomized controlled trial, was conducted in patients with GIOP to compare the effects of once-weekly teriparatide and once-weekly alendronate 35 mg on BMD. MATERIALS AND METHODS: Patients (N = 180) with GIOP for whom drug treatment was indicated according to the 2004 guidelines in Japan were randomized to receive once-weekly teriparatide (n = 89) or once-weekly alendronate (n = 91). The primary endpoint was the non-inferiority of percentage change in lumbar spine BMD at final follow-up. The secondary endpoints were the percentage change in BMD from baseline, incidence of bone fractures, and changes in bone turnover markers. RESULTS: While the non-inferiority of teriparatide to alendronate was not confirmed, BMD increased significantly from baseline with teriparatide and alendronate by 5.09% and 4.04%, respectively (both p < 0.05), at 72 weeks. The incidence of vertebral and non-vertebral fractures was similar in both groups. Bone formation markers increased in the teriparatide group and decreased in the alendronate group. CONCLUSIONS: The non-inferiority of once-weekly teriparatide versus once-weekly alendronate in BMD change at 72 weeks was not shown, but the increase in bone formation markers over time and the increase of BMD in GIOP patients treated with once-weekly teriparatide were confirmed.

Epidemiology of glucocorticoid-induced osteoporosis and management of associated fracture risk in Japan.

INTRODUCTION: Glucocorticoid-induced osteoporosis (GIOP) is associated with a high fracture risk. Practice guidelines by the Japanese Society for Bone and Mineral Research in 2014 recommend bone densitometry and appropriate treatment to reduce this risk. The study objectives were to describe characteristics of GIOP patients in Japan and to evaluate their management in a subgroup of patients without comorbid cancer. MATERIALS AND METHODS: This retrospective cohort study was performed using the Medical Data Vision (MDV) database from Japan. Adult patients initiating oral glucocorticoid treatment with a total GIOP risk score ≥ 3, based on the 2014 practice guideline, identified between 2009 and 2019 were eligible. A subgroup of patients without any cancer diagnosis was also identified. Data were extracted on demographics, concurrent medical conditions, use of bone densitometry, and osteoporosis treatment. RESULTS: 25,569 patients were eligible, of whom 12,227 had a confirmed cancer diagnosis. Mean age was 68.5 years and 12,356 patients (48.3%) were women. Concurrent medical conditions of interest were documented in 14,887 patients, most frequently rheumatoid arthritis (n = 4185) and asthma (n = 3085). Yearly bone densitometry was performed in 6.5% (n = 865) of the cancer-free subgroup; 51.8% (n = 6905) were prescribed an osteoporosis treatment, most frequently bisphosphonates (n = 5132; 74.3%). Between 2011 and 2018, rates of densitometry were stable, whereas prescription rates increased from 40.0 to 51.8%. CONCLUSION: In spite of publication of guidelines for GIOP management, there is an important treatment gap in their application in everyday practice. For this reason, public health measures to increase physician awareness of GIOP are needed.

Predictors of new bone erosion in rheumatoid arthritis patients receiving conventional synthetic disease-modifying antirheumatic drugs: Analysis of data from the DRIVE and DESIRABLE studies.

OBJECTIVE: To investigate new bone erosion and cartilage destruction predictors in rheumatoid arthritis (RA) patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). METHODS: Placebo-treated patient data from two 12-month, randomized, double-blind, phase 2 (DRIVE) and 3 (DESIRABLE) trials that evaluated denosumab efficacy in csDMARD-treated RA patients were used. Change from baseline in erosion score (ES) of ≥1.0 at 12 months was considered new bone erosion; predictors were identified using a multivariate model. RESULTS: Among 306 patients, mean ± standard deviation disease activity score 28-C-reactive protein (CRP) at baseline was 3.58 ± 1.03. New bone erosion was observed in 90 patients (29.4%). Univariate analysis identified female sex, anti-cyclic citrullinated peptide (CCP) antibody positivity, rheumatoid factor (RF) positivity, tender joint count ≥6, CRP ≥0.3 mg/dL, erythrocyte sedimentation rate (ESR) ≥28 mm/h, and baseline ES ≥3 as significant predictors for new bone erosion. In multivariate analysis, predictors were anti-CCP antibody positivity, CRP ≥0.3 mg/dL, and baseline ES ≥3; RF and ESR were excluded as they strongly correlated with anti-CCP antibody and CRP, respectively. CONCLUSION: In RA patients treated with csDMARDs, new bone erosion predictors were seropositivity, elevated inflammatory markers, and baseline ES ≥3. TRIAL REGISTRATION NUMBER: DRIVE, JapicCTI-101263; DESIRABLE, NCT01973569.

Eldecalcitol is superior to alfacalcidol in maintaining bone mineral density in glucocorticoid-induced osteoporosis patients (e-GLORIA).

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.

Minodronate combined with alfacalcidol versus alfacalcidol alone for glucocorticoid-induced osteoporosis: a multicenter, randomized, comparative study.

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.

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.

Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial.

OBJECTIVE: To evaluate the efficacy of denosumab in suppressing joint destruction when added to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy in patients with rheumatoid arthritis (RA). METHODS: This was a multi-centre, randomised, double-blind, parallel-group, placebo-controlled phase 3 study in Japan. Patients with RA aged ≥20 years receiving csDMARDs were randomly assigned (1:1:1) to denosumab 60 mg every 3 months (Q3M), denosumab 60 mg every 6 months (Q6M) or placebo. The change in the modified total Sharp score (mTSS) and effect on bone mineral density (BMD) at 12 months was evaluated. RESULTS: In total, 654 patients received the trial drugs. Denosumab groups showed significantly less progression of joint destruction. The mean changes in the mTSS at 12 months were 1.49 (95% CI 0.99 to 1.99) in the placebo group, 0.99 (95% CI 0.49 to 1.49) in the Q6M group (p=0.0235) and 0.72 (95% CI 0.41 to 1.03) in the Q3M group (p=0.0055). The mean changes in bone erosion score were 0.98 (95% CI 0.65 to 1.31) in the placebo group, 0.51 (95% CI 0.22 to 0.80) in the Q6M group (p=0.0104) and 0.22 (95% CI 0.09 to 0.34) in the Q3M group (p=0.0001). No significant between-group difference was observed in the joint space narrowing score. The per cent change in lumbar spine (L1-L4) BMD in the placebo, Q6M and Q3M groups were -1.03%, 3.99% (p<0.0001) and 4.88% (p<0.0001). No major differences were observed among safety profiles. CONCLUSIONS: Denosumab inhibits the progression of joint destruction, increases BMD and is well tolerated in patients with RA taking csDMARD.

Reduction of Hip and Other Fractures in Patients Receiving Teriparatide in Real-World Clinical Practice: Integrated Analysis of Four Prospective Observational Studies.

The phase 3 teriparatide Fracture Prevention Trial showed significant reductions in vertebral (VF) and nonvertebral (NVF) fractures; however, patient exposure was insufficient for full analysis of low-incidence fractures, including hip. We assessed fracture results in pooled data from four prospective, observational teriparatide studies. Ambulatory women and men with osteoporosis received subcutaneous teriparatide 20 µg/day for up to 24 months per routine clinical practice. Fracture rates were compared between 6-month periods, using 0 to 6 months of treatment as the reference period. Analyses used a piecewise exponential model for first fracture. Hip, NVF, clinical VF (CVF), any clinical, and wrist fractures were assessed. For 8828 patients analyzed, mean age was 71 years; mean (SD) treatment duration was 17.4 (8.6) months. The rate of hip fracture decreased significantly for the > 12 to 18-month (- 47.7%) and > 18-month periods (-85.2%) versus the first 6 months of therapy, and for the > 18 versus the > 6 to 12-month period. NVF, CVF, and all clinical fractures were all significantly decreased in each post-reference period, with maximum decreases (> 18-month period) of 52.7%, 69.4%, and 61.2%, respectively, versus 0 to 6 months. No significant reduction was seen for rates of wrist fracture. Teriparatide treatment was associated with statistically significant decreases in hip fracture rate, particularly for > 18 months of treatment, and in NVF, CVF, and all clinical fracture rate in real-world patients. These results should be interpreted in the context of the non-controlled design of the source studies.

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.

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

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