Drug utilization pattern of romosozumab and other osteoporosis treatments in Japan, 2019-2021.

INTRODUCTION: Describe real-world treatment of osteoporosis and romosozumab treatment patterns in Japan. MATERIALS AND METHODS: Data for patients initiating romosozumab or other antiosteoporotic medications between March 01, 2018, and May 31, 2022, were extracted from the Medical Data Vision (MDV) and Japan Medical Data Center (JMDC) databases. Patients were categorized into four cohorts: those who newly initiated romosozumab within the first (MDV: n = 4782; JMDC: n = 2578) or second (MDV: n = 3888; JMDC: n = 2446) year after launch and those who initiated teriparatide (TPTD; MDV: n = 14,576; JMDC: n = 8259) or non-TPTD antiosteoporotic medications within the first year of romosozumab launch (MDV: n = 352,142; JMDC: n = 185,785). RESULTS: Mean age, sex, baseline cardiovascular history, comorbidities, and concomitant medications were similar across cohorts. In the MDV database, fracture history was higher in the romosozumab year-1 (59.3%), year-2 (64.1%), and TPTD (65.5%) cohorts versus the non-TPTD cohort (24.4%). Similar rates were identified in the JMDC database: romosozumab year-1 (64.7%), year-2 (66.6%), TPTD (67.5%), and non-TPTD (27.8%). Vertebral fractures were most common in all cohorts. 12-month romosozumab discontinuation varied between the year-1 and year-2 cohorts in MDV (62.4% and 58.8%) and JMDC (57.1% and 52.7%), whereas mean number of injections remained consistent (MDV: 9.7 and 9.8; JMDC: 7.3 and 7.8). Romosozumab persistence was lower in year-1 versus year-2 (MDV: 37.6% and 42.9%; JMDC: 41.2% and 47.3%). CONCLUSION: Patients initiating romosozumab and TPTD had a high fracture history. Given the dual effects of promoting bone formation and suppressing resorption, improving romosozumab adherence and persistence over time may be important for antiosteoporotic therapy.

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.

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.

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.

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.

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.

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.

Abaloparatide Increases Lumbar Spine and Hip BMD in Japanese Patients With Osteoporosis: The Phase 3 ACTIVE-J Study.

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

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.

Influence of symptomatic periodontal disease on changes in skeletal bone density during medication therapy for osteoporosis in postmenopausal women: the Japanese Osteoporosis Intervention Trial (JOINT)-04 and JOINT-05.

Japanese postmenopausal women with symptomatic periodontal disease had a significantly smaller increase in the T-score for total hip bone density than those without periodontal disease during medication therapy for osteoporosis. Intervention to treat symptomatic periodontal disease before and/or during osteoporosis therapy could maintain the effect of osteoporosis medications. PURPOSE: Women with periodontal disease may be more likely to develop osteoporosis. We evaluated whether the presence of symptomatic periodontal disease can influence changes in skeletal bone mineral density (BMD) during medication therapy for osteoporosis in Japanese postmenopausal women. METHODS: A total of 4,258 postmenopausal women participated in the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04 trial) and number 5 (JOINT-05 trial), which were multi-center, open-label, randomized controlled trials in Japan. Of these, 3,670 non-edentulous subjects participated in the study. Subjects who had self-reported symptoms of periodontal disease at baseline were defined as having periodontal disease. The study outcome was the difference in BMD changes during the study between subjects with and without periodontal disease. Mixed models for repeated measures after adjusting for covariates were used to investigate the difference in the BMD changes during the study between subjects with and without periodontal disease. RESULTS: Subjects with periodontal disease had significantly lower T-scores for total hip (p = 0.035) and metacarpal (p = 0.048) BMD than those without periodontal disease at baseline. During medication therapy for osteoporosis, subjects with periodontal disease had a significantly smaller increase in T-score for total hip BMD than those without periodontal disease (p = 0.021), although no significant differences were observed in the changes in T-scores for other skeletal BMD measurements between subjects with and without periodontal disease. CONCLUSIONS: The presence of self-reported symptoms of periodontal disease may be associated with a decrease in the effect of osteoporosis medications in Japanese postmenopausal women.

Cost-effectiveness analysis of branded and authorized generic celecoxib for patients with chronic pain in Japan.

OBJECTIVES: The aim of this study was to examine the cost-effectiveness of branded and authorized generic (AG) celecoxib for chronic pain patients with osteoarthritis (OA), rheumatoid arthritis (RA), and low back pain (LBP), using real-world cost information for loxoprofen and pharmacotherapy for gastrointestinal bleeding. METHODS: This cost-effectiveness analysis was performed as a long-term simulation using the Markov model from the Japanese public healthcare payer's perspective. The analysis was conducted using loxoprofen with real-world weighted price by branded/generic distribution (hereinafter, loxoprofen with weighted price) as a comparator. In the model, we simulated the prognosis of patients with chronic pain by OA, RA, and LBP treated with loxoprofen or celecoxib, over a lifetime period. RESULTS: A cost-increase of 129,688 JPY (1,245.00 USD) for branded celecoxib and a cost-reduction of 6,268 JPY (60.17 USD) for AG celecoxib were recognized per patient in lifetime horizon, compared to loxoprofen with weighted price. No case was recognized to reverse the results of cost-saving by AG celecoxib in one-way sensitivity analysis. The incremental cost-effectiveness ratio of branded celecoxib attained 5,403,667 JPY/QALY (51,875.20 USD/QALY), compared to loxoprofen with the weighted price. CONCLUSION: The current cost-effectiveness analysis for AG celecoxib revealed its good value for costs, considering the patients' future risk of gastrointestinal injury; also, the impact on costs due to AG celecoxib against loxoprofen will be small. It implies that the disadvantage of AG celecoxib being slightly more expensive than generic loxoprofen could be offset by the good cost-effectiveness during the prognosis.

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.

Effects of Denosumab in Japanese Patients With Rheumatoid Arthritis Treated With Conventional Antirheumatic Drugs: 36-month Extension of a Phase III Study.

OBJECTIVE: To evaluate the safety and efficacy of long-term denosumab 60 mg every 6 months (Q6M) or every 3 months (Q3M) in patients with rheumatoid arthritis (RA). METHODS: This 12-month, randomized, double-blind, placebo-controlled, multicenter, phase III trial with an open-label extension period from 12 to 36 months (DESIRABLE) enrolled Japanese patients with RA treated with placebo (P) for 12 months followed by either denosumab Q6M (P/Q6M) or denosumab Q3M (P/Q3M) for 24 months; denosumab Q6M for 36 months (Q6M/Q6M); or denosumab Q3M for 36 months (Q3M/Q3M). Efficacy was assessed by van der Heijde modified total Sharp score (mTSS), bone erosion score (BES), and joint space narrowing (JSN) score. RESULTS: Long-term treatment better maintained mTSS and BES suppression in the P/Q3M and Q3M/Q3M vs P/Q6M and Q6M/Q6M groups; changes from baseline in total mTSS (standard error) at 36 months were 2.8 (0.4) and 1.7 (0.3) vs 3.0 (0.4) and 2.4 (0.3), respectively, and corresponding changes in BES were 1.3 (0.2) and 0.4 (0.2) vs 1.4 (0.2) and 1.1 (0.2), respectively. No JSN effect was observed. Bone mineral density consistently increased in all groups after denosumab initiation, regardless of concomitant glucocorticoid administration. Serum C-terminal telopeptide of type I collagen decreased rapidly at 1 month postdenosumab administration (in both the initial 12-month [Q3M and Q6M groups] and long-term treatment [P/Q3M and P/Q6M groups] phases). Adverse event incidence leading to study drug discontinuation was similar across treatment groups. CONCLUSION: Denosumab treatment maintained inhibition of progression of joint destruction up to 36 months. Based on effects on BES progression, higher dosing frequency at an earlier treatment stage may be needed to optimize treatment. Denosumab was generally well tolerated. (ClinicalTrials.gov: NCT01973569).

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.

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.

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.

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.

Identifying the preferable rheumatoid arthritis subgroups for intervention with the anti-RANKL antibody denosumab to reduce progression of joint destruction.

OBJECTIVES: To clarify which rheumatoid arthritis (RA) patients benefit most from the anti-receptor activator of nuclear factor-κB ligand antibody denosumab to reduce the progression of joint destruction. METHODS: We pooled patient data from the 12-month, double-blind, placebo-controlled DRIVE (phase II) and DESIRABLE (phase III) studies. In DRIVE, concomitant treatment was limited to methotrexate, salazosulfapyridine and bucillamine. In DESIRABLE, patients could receive any disease-modifying antirheumatic drug. RA patients were randomised to denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or placebo. Efficacy was assessed by van der Heijde-modified total Sharp score (mTSS), bone erosion score (ES) and joint space narrowing score (JSNS). Change in mTSS was assessed in subgroups stratified by risk factors for radiographic damage if the interaction factor was significant. RESULTS: The pooled analysis included 909 patients. Denosumab reduced worsening of mTSS (mean (SD)) at 12 months in the Q6M (0.88 (3.30), p=0.0024) and Q3M (0.66 (2.16), p=0.0002) groups versus placebo (1.50 (3.73)). This reduction in mTSS progression was due to the change in ES (Q6M, 0.44 (1.89), p=0.0006; Q3M, 0.20 (0.86), p<0.0001) versus placebo (0.98 (2.54)); no effect was observed on JSNS. Anti-cyclic citrullinated peptide (CCP) antibodies, glucocorticoid use and baseline ES showed a significant interaction. Denosumab was particularly effective in patients who were anti-CCP antibody positive (p<0.05). Changes in mTSS versus placebo were observed in all denosumab dose groups, regardless of glucocorticoid use and baseline ES. CONCLUSIONS: Denosumab broadly reduced the progression of joint destruction in RA patients with risk factors for radiographic damage such as especially anti-CCP antibody positivity.