The effects of abaloparatide on hip geometry and biomechanical properties in Japanese osteoporotic patients assessed using DXA-based hip structural analysis: results of the Japanese phase 3 ACTIVE-J trial.

Daily subcutaneous injection of 80 µg abaloparatide increased bone mineral density in Japanese patients with osteoporosis at high fracture risk in the ACTIVE-J trial. Dual-energy X-ray absorptiometry-based hip structural analysis from ACTIVE-J data showed improved hip geometry and biomechanical properties with abaloparatide compared with placebo. PURPOSE: Abaloparatide (ABL) increased bone mineral density (BMD) in Japanese patients with osteoporosis at high fracture risk in the ACTIVE-J trial. To evaluate the effect of ABL on hip geometry and biomechanical properties, hip structural analysis (HSA) was performed using ACTIVE-J trial data. METHODS: Hip dual-energy X-ray absorptiometry scans from postmenopausal women and men (ABL, n = 128; placebo, n = 65) at baseline and up to week 78 were analyzed to extract bone geometric parameters at the narrow neck (NN), intertrochanteric region (IT), and proximal femoral shaft (FS). Computed tomography (CT)-based BMD and HSA indices were compared between baseline and week 78. RESULTS: ABL treatment showed increased mean percent change from baseline to week 78 in cortical thickness at the NN (5.3%), IT (5.3%), and FS (2.9%); cross-sectional area at the NN (5.0%), IT (5.0%), and FS (2.6%); cross-sectional moment of inertia at the NN (7.6%), IT (5.1%), and FS (2.5%); section modulus at the NN (7.4%), IT (5.4%), and FS (2.4%); and decreased mean percent change in buckling ratio (BR) at the IT (- 5.0%). ABL treatment showed increased mean percent change in total volumetric BMD (vBMD; 2.7%) and trabecular vBMD (3.2%) at the total hip and decreased mean percent change in BR at femoral neck (- 4.1%) at week 78 vs baseline. All the changes noted here were significant vs placebo (P < 0.050 using t-test). CONCLUSION: A 78-week treatment with ABL showed improvement in HSA parameters associated with hip geometry and biomechanical properties vs placebo. TRIAL REGISTRATION: JAPIC CTI-173575.

Abaloparatide dose-dependently increases bone mineral density in postmenopausal women with osteoporosis: a phase 2 study.

INTRODUCTION: This study aimed to determine the efficacy of abaloparatide in increasing bone mineral density (BMD) and its safety in postmenopausal Japanese women with osteoporosis. MATERIALS AND METHODS: Randomized, double-blind, placebo-controlled, dose-finding study of abaloparatide in postmenopausal Japanese women at high fracture risk. The primary endpoint was the change in lumbar spine (LS) BMD from baseline at the last visit after daily subcutaneous injections of placebo or 40 or 80 µg abaloparatide. Other endpoints included time-course changes in LS BMD at 12, 24, and 48 weeks, in total hip (TH) and femoral neck (FN) BMDs, and in bone turnover markers. RESULTS: Increases in LS BMD with 40 and 80 µg abaloparatide were significantly higher than that with placebo (6.6% and 11.5%, respectively), with significant between-group differences for the abaloparatide groups (4.9%). TH BMD increased by 0.4%, 1.6%, and 2.9% and FN BMD increased by 0.6%, 1.5%, and 2.4% in the placebo and 40 and 80 µg abaloparatide groups, respectively. Serum PINP rapidly increased by 67.3% and 140.7% and serum CTX slowly increased by 16.4% and 34.5% in the 40 and 80 µg abaloparatide groups, respectively. Although more adverse events were observed in the abaloparatide groups, they were mild to moderate and not dose dependent. CONCLUSION: In postmenopausal Japanese women with osteoporosis at high fracture risk, abaloparatide for 48 weeks dose-dependently increased LS, TH, and FN BMDs, supporting further investigation with 80 µg abaloparatide for the treatment of osteoporosis in this population. TRIAL REGISTRATION NUMBER: JapicCTI-132381.

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.

Effects of Korean red ginseng on three-dimensional trabecular bone microarchitecture and strength in growing rats: Comparison with changes due to jump exercise.

OBJECTIVES: The preventive effects of Korean red ginseng (KRG) on bone loss and microarchitectural deterioration have been extensively studied in animal models. However, few results have been reported for the effects of KRG on the trabecular microarchitecture as compared to changes resulting from physiological stimuli such as exercise load. We compared the effects of KRG and jump exercise on improvements in trabecular microarchitecture and strength of the distal femoral metaphysis in rats. METHODS AND MATERIALS: Eleven-week-old male Wistar rats were divided into sedentary (CON), KRG-administered (KRG), and jump-exercised (JUM) groups. Rats were orally administered KRG extract (200 mg/kg body weight/day) once a day for 6 weeks. The jump exercise protocol comprised 10 jumps/day, 5 days/week at a jump height of 40 cm. We used microcomputed tomography to assess the microarchitecture, volumetric bone mineral density (vBMD), and fracture load as predicted by finite element analysis at the right distal femoral metaphysis. The left femur was used for the quantitative bone histomorphometry measurements. RESULTS: Although KRG produced significantly higher trabecular bone volume (BV/TV) than CON, BV/TV was even higher in JUM than in KRG, and differences in vBMD and fracture load were only significant between JUM and CON. In terms of trabecular microarchitecture, KRG increased trabecular number and connectivity, whereas the JUM group showed increased trabecular thickness. Bone resorption showed significant decrease by JUM and KRG group. In contrast, bone formation showed significant increase by JUM group. CONCLUSIONS: These data show that KRG has weak but significant positive effects on bone mass and suggest that the effects on trabecular microarchitecture differ from those of jump exercise. The effects of combined KRG and jump exercise on trabecular bone mass and strength should be investigated.

Clinical application of single-shot echo-planar diffusion-weighted imaging with compressed SENSE in prostate MRI at 3T: preliminary experience.

OBJECTIVES: Image quality (IQ) of diffusion-weighted imaging (DWI) with single-shot echo-planar imaging (ssEPI) suffers from low signal-to-noise ratio (SNR) in high b-value acquisitions. Compressed SENSE (C-SENSE), which combines SENSE with compressed sensing, enables SNR to be improved by reducing noise. The aim of this study was to compare IQ and prostate cancer (PC) detectability between DWI with ssEPI using SENSE (EPIS) and using C-SENSE (EPICS). MATERIALS AND METHODS: Twenty-five patients with pathologically proven PC underwent multi-parametric magnetic resonance imaging at 3T. DW images acquired with EPIS and EPICS were assessed for the following: lesion conspicuity (LC), SNR, contrast-to-noise ratio (CNR), mean and standard deviation (SD) of apparent diffusion coefficient (ADC) of lesion (lADCm and lADCsd), coefficient of variation of lesion ADC (lADCcv), and mean ADC of benign prostate (bADCm). RESULTS: LC were comparable between EPIS and EPICS (p > 0.050), and SNR and CNR were significantly higher in EPICS than EPIS (p = 0.001 and p < 0.001). In both EPIS and EPICS, lADCm was significantly lower than bADCm (p < 0.001). In addition, lADCcv was significantly lower in EPICS than in EPIS (p < 0.001). CONCLUSION: Compared with EPIS, EPICS has improved IQ and comparable diagnostic performance in PC.

Clinical impact of ultra-high b-value (3000 s/mm2) diffusion-weighted magnetic resonance imaging in prostate cancer at 3T: comparison with b-value of 2000 s/mm2.

OBJECTIVE: High b-value diffusion-weighted imaging (hDWI) with a b-value of 2000 s/mm2 provides insufficient image contrast between benign and malignant tissues and an overlap of apparent diffusion coefficient (ADC) between Gleason grades (GG) in prostate cancer (PC). We compared image quality, PC detectability, and discrimination ability for PC aggressiveness between ultra-high b-value DWI (uhDWI) of 3000 s/mm2 and hDWI. METHODS: The subjects were 49 patients with PC who underwent 3T multiparametric MRI. Single-shot echo-planar DWI was acquired with b-values of 0, 2000, and 3000 s/mm2. Anatomical distortion of prostate (AD), signal intensity of benign prostate (PSI), and lesion conspicuity score (LCS) were assessed using a 4-point scale; and signal-to-noise ratio, contrast-to-noise ratio, and mean ADC (×10-3 mm2/s) of lesion (lADC) and surrounding benign region (bADC) were measured. RESULTS: PSI was significantly lower in uhDWI than in hDWI (p < 0.001). AD, LCS, signal-to-noise ratio, and contrast-to-noise ratio were comparable between uhDWI and hDWI (all p > 0.05). In contrast, lADC was significantly lower than bADC in both uhDWI and hDWI (both p < 0.001). In comparison of lADC between tumors of ≤GG2 and those of ≥GG3, both uhDWI and hDWI showed significant difference (p = 0.007 and p = 0.021, respectively). AUC for separating tumors of ≤GG2 from those of ≥GG3 was 0.731 in hDWI and 0.699 in uhDWI (p = 0.161). CONCLUSION: uhDWI suppressed background signal better than hDWI, but did not contribute to increased diagnostic performance in PC. ADVANCES IN KNOWLEDGE: Compared with hDWI, uhDWI could not contribute to increased diagnostic performance in PC.

Effects of Different Types of Mechanical Loading on Trabecular Bone Microarchitecture in Rats.

Mechanical loading is generally considered to have a positive impact on the skeleton; however, not all types of mechanical loading have the same beneficial effect. Many researchers have investigated which types of mechanical loading are more effective for improving bone mass and strength. Among the various mechanical loads, high-impact loading, such as jumping, appears to be more beneficial for bones than low-impact loadings such as walking, running, or swimming. Therefore, the different forms of mechanical loading exerted by running, swimming, and jumping exercises may have different effects on bone adaptations. However, little is known about the relationships between the types of mechanical loading and their effects on trabecular bone structure. The purpose of this article is to review the recent reports on the effects of treadmill running, jumping, and swimming on the trabecular bone microarchitecture in small animals. The effects of loading on trabecular bone architecture appear to differ among these different exercises, as several reports have shown that jumping increases the trabecular bone mass by thickening the trabeculae, whereas treadmill running and swimming add to the trabecular bone mass by increasing the trabecular number, rather than the thickness. This suggests that different types of exercise promote gains in trabecular bone mass through different architectural patterns in small animals.

Quantitative diffusion-weighted imaging and dynamic contrast-enhanced MR imaging for assessment of tumor aggressiveness in prostate cancer at 3T.

PURPOSE: To compare diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MR imaging (DCE-MRI) for characterization of prostate cancer (PC). METHODS: 104 PC patients who underwent prostate multiparametric MRI at 3T including DWI and DCE-MRI before MRI-guided biopsy or radical prostatectomy. Apparent diffusion coefficient (ADC) with histogram analysis (mean, 0-25th percentile, skewness, and kurtosis), intravoxel incoherent motion model including D and f; stretched exponential model including distributed diffusion coefficient (DDC) and a; and permeability parameters including Ktrans, Kep, and Ve were obtained from a region of interest placed on the dominant tumor of each patient. RESULTS: ADCmean, ADC0-25, D, DDC, and Ve were significantly lower and Kep was significantly higher in GS ≥ 3 + 4 tumors (n = 89) than in GS = 3 + 3 tumors (n = 15), and also in GS ≥ 4 + 3 tumors (n = 57) than in GS ≤ 3 + 4 tumors (n = 47) (P < 0.001 to P = 0.040). f was significantly lower in GS ≥ 4 + 3 tumors than in GS ≤ 3 + 4 tumors (P = 0.022), but there was no significant difference between GS = 3 + 3 tumors and GS ≥ 3 + 4 tumors, or between the remaining metrics in both comparisons. In metrics with area under the curve (AUC) >0.80, there was a significant difference in AUC between ADC0-25 and D, and DDC for separating GS ≤ 3 + 4 tumors from GS ≥ 4 + 3 tumors (P = 0.040 and P = 0.022, respectively). There were no significant differences between metrics with AUC > 0.80 for separating GS = 3 + 3 tumors from GS ≥ 3 + 4 tumors. ADC0-25 had the highest correlation with Gleason grade (ρ = -0.625, P < 0.001). CONCLUSIONS: DWI and DCE-MRI showed no apparent clinical superiority of non-Gaussian models or permeability MRI over the mono-exponential model for assessment of tumor aggressiveness in PC.

Risk factors for incident vertebral fractures in osteoporosis pharmacotherapy: a 2-year, prospective, observational study.

INTRODUCTION: To identify predictors for incident fractures in patients on pharmaceutical treatment for osteoporosis by a secondary analysis of the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04), which was a 2-year, randomized, parallel-group, controlled trial of minodronate and raloxifene in women with primary osteoporosis. MATERIALS AND METHODS: This was a prospective, observational study using JOINT-04 data, in which biomarkers, such as undercarboxylated osteocalcin (ucOC), N-telopeptide of type 1 collagen, tartrate-resistant acid phosphatase 5b (TRACP-5b), bone alkaline phosphatase, homocysteine, and pentosidine in blood, and physical functions, such as the timed up and go test and one-leg standing test with eyes open (OLST), and the fall risk index, were measured. The relationships of incident morphometric vertebral fractures during the treatment period, as well as prevalent vertebral fractures, and baseline data were analyzed. RESULTS: The full analysis set of the JOINT-04 included 3247 patients (1623 in the minodronate group and 1624 in the raloxifene group). The hazard ratio (95% confidence interval) for incident vertebral fractures over 2 years of pharmacotherapy, adjusted for confounders, was 0.93 (0.90-0.96) for ucOC, 1.15 (1.08-1.23) for TRACP-5b, 1.02 (1.01-1.03) for pentosidine, 0.91 (0.88-0.94) for the OLST, and 1.27 (1.01-1.60) for the fall risk index, which were all independent predictors. CONCLUSION: Evaluating fracture risk for patients with osteoporosis considering these potential risk factors for fracture in addition to the established risk factors may be useful when starting pharmaceutical treatment.

Comparison of Biparametric and Multiparametric MRI for Clinically Significant Prostate Cancer Detection With PI-RADS Version 2.1.

BACKGROUND: Biparametric MRI (bpMRI) without dynamic contrast-enhanced MRI (DCE-MRI) results in an elimination of adverse events, shortened examination time, and reduced costs, compared to multiparametric MRI (mpMRI). The ability of bpMRI to detect clinically significant prostate cancer (csPC) with the Prostate Imaging and Reporting Data System version 2.1 (PI-RADS v2.1) compared to standard mpMRI has not been studied extensively. PURPOSE: To compare the interobserver reliability and diagnostic performance for detecting csPC of bpMRI and mpMRI using PI-RADS v2.1. STUDY TYPE: Retrospective. POPULATION: In all, 103 patients with elevated prostate-specific antigen (PSA) levels who underwent mpMRI and subsequent MRI-ultrasonography fusion-guided prostate-targeted biopsy (MRGB) with or without prostatectomy. FIELD STRENGTH/SEQUENCES: T2 -weighted imaging (T2 WI), diffusion-weighted imaging (DWI), and DCE-MRI at 3T. ASSESSMENT: Three readers independently assessed each suspected PC lesion, assigning a score of 1-5 for T2 WI, a score of 1-5 for DWI, and positive and negative for DCE-MRI according to PI-RADS v2.1 and determined the overall PI-RADS assessment category of bpMRI (T2 WI and DWI) and mpMRI (T2 WI, DWI, and DCE-MRI). The reference standard was MRGB or prostatectomy-derived histopathology. STATISTICAL TESTING: Statistical analysis was performed using the kappa statistic and McNemar and Delong tests. RESULTS: Of the 165 suspected PC lesions in 103 patients, 81 were diagnosed with csPC and 84 with benign conditions. Interobserver variability of PI-RADS assessment category showed good agreement for bpMRI (kappa value = 0.642) and mpMRI (kappa value = 0.644). For three readers, the diagnostic sensitivity was significantly higher for mpMRI than for bpMRI (P < 0.001 to P = 0.016, respectively), whereas diagnostic specificity was significantly higher for bpMRI than for mpMRI (P < 0.001 each). For three readers, the area under the receiver operating characteristic curve (AUC) was higher for bpMRI than for mpMRI; however, the difference was significant only for Reader 1 and Reader 3 (Reader 1: 0.823 vs. 0.785, P = 0.035; Reader 2: 0.852 vs. 0.829, P = 0.099; and Reader 3: 0.828 vs. 0.773, P = 0.002). DATA CONCLUSION: For detecting csPC using PI-RADS v2.1, the interobserver reliability and diagnostic performance of bpMRI was comparable with those of mpMRI. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

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.

Differential effects of jump versus running exercise on trabecular bone architecture and strength in rats.

PURPOSE: This study compared differences in trabecular bone architecture and strength caused by jump and running exercises in rats. METHODS: Ten-week-old male Wistar rats (n=45) were randomly assigned to three body weight-matched groups: a sedentary control group (CON, n=15); a treadmill running group (RUN, n=15); and a jump exercise group (JUM, n=15). Treadmill running was performed at 25 m/min without inclination, 1 h/day, 5 days/week for 8 weeks. The jump exercise protocol comprised 10 jumps/day, 5 days/week for 8 weeks, with a jump height of 40 cm. We used microcomputed tomography to assess microarchitecture, mineralization density, and fracture load as predicted by finite element analysis (FEA) at the distal femoral metaphysis. RESULTS: Both jump and running exercises produced significantly higher trabecular bone mass, thickness, number, and fracture load compared to the sedentary control group. The jump and running exercises, however, showed different results in terms of the structural characteristics of trabecular bone. Jump exercises enhanced trabecular bone mass by thickening the trabeculae, while running exercises did so by increasing the trabecular number. FEA-estimated fracture load did not differ significantly between the exercise groups. CONCLUSION: This study elucidated the differential effects of jump and running exercise on trabecular bone architecture in rats. The different structural changes in the trabecular bone, however, had no significant impact on trabecular bone strength.

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.

Comparison of PI-RADS version 2 and PI-RADS version 2.1 for the detection of transition zone prostate cancer.

PURPOSE: To compare the diagnostic performance of PI-RADS v2 and v2.1 for detecting transition zone prostate cancer (TZPC) on multiparametric prostate MRI (mpMRI). METHOD: Fifty-eight patients with elevated PSA levels underwent mpMRI at 3 T including T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI), and subsequent MRI-transrectal ultrasonography fusion-guided prostate-targeted biopsy (MRGB). The standard of reference was MRGB-derived histopathology. Two readers independently assessed each TZ lesion, assigning a score of 1-5 for T2WI, a score of 1-5 for DWI, and the overall PI-RADS assessment category according to PI-RADS v2 and v2.1. The diagnostic performance of the two methods was compared in terms of inter-reader agreement, diagnostic sensitivity, diagnostic specificity, and area under the ROC curve (AUC). RESULTS: Of the 58 patients, 26 were diagnosed with PC (GS = 3 + 3, n = 9; GS = 3 + 4, n = 9; GS = 3 + 5, n = 1; GS = 4 + 3, n = 4; GS = 4 + 4, n = 3) and 32 with benign lesions. Regarding inter-reader agreement of overall PI-RADS assessment category, the kappa value was 0.580 for v2 and 0.645 for v2.1. For both readers, there was no difference in diagnostic sensitivity between the versions (p ≥ 0.500). For reader 1, the diagnostic specificity was higher for v2.1 (p = 0.002), and was similar for reader 2 (p = 1.000). For both readers, AUC tended to be higher for v2.1 than for v2, but the difference was not significant (0.786 vs. 0.847 for reader 1, p = 0.052; and 0.808 vs. 0.858 for reader 2, p = 0.197). CONCLUSIONS: These results suggest that compared with PI-RADS v2, PI-RADS v2.1 could be preferable for evaluating TZ lesions.

Multidimensional analysis of clinicopathological characteristics of false-negative clinically significant prostate cancers on multiparametric MRI of the prostate in Japanese men.

PURPOSE: To clarify clinicopathological features of false-negative clinically significant prostate cancer (csPC) at multiparametric prostate MRI (mpMRI). METHODS: 95 patients with 139 csPC undergoing 3T mpMRI before radical prostatectomy were included. Two radiologists were independently evaluated mpMR images using PI-RADS v2. Clinicopathological findings were compared between (a) detectable and undetectable lesions using overall mpMRI criteria (o-mpMRI criteria) and (b) lesions with early enhancement effect (EEE) and lesions without EEE at DCE-MRI. RESULTS: The detection rate of csPS using cutoff value of category 3 or more in PI-RADS v2 for positive lesion was 72.1% (98/136 lesions). In 38 false-negative lesions with less than PI-RADS v2 category 3, the DCE-MRI detected 14 lesions. 17 undetectable lesions on o-mpMR criteria had lower PSA and D'amico risk classification, and higher tumor apparent diffusion coefficient (ADC) than those of 118 detectable lesions (p ≤ 0.048). 89 lesions with EEE showed higher PSA, tumor size, prostatectomy GS grade, frequency of lesions with GS ≥ 4 + 3 and lower tumor ADC than those in 38 lesions without EEE (p ≤ 0.046). CONCLUSION: Tumor detectability of csPC with PI-RADS v2 was limited compared with o-mpMRI criteria in Japanese men. Moreover, false-negative lesions on o-mpMRI criteria were characterized as small in size, low risk and low cellularity.

A randomized, double-blind, placebo-controlled study of once weekly elcatonin in primary postmenopausal osteoporosis.

OBJECTIVE: Very few reports have described changes in bone mineral density (BMD) with long-term, once weekly administration of elcatonin, and its effects in reducing incident fractures remain unverified. Therefore, the efficacy and safety of once weekly elcatonin were examined over a 3 year period. METHODS: This was a multicenter, double-blinded, randomized, placebo-controlled study. Postmenopausal women with primary osteoporosis received either 20 units of elcatonin (EL group, n = 433) or placebo (P group, n = 436) once a week for 144 weeks (3 years) intramuscularly. The primary endpoint was the incidence of new vertebral fractures at 24, 48, 72, 96, 120, and 144 weeks after the start. Secondary endpoints were the incidence of non-vertebral fractures, changes in lumbar, hip total and femoral neck BMD, and the incidence of adverse drug reactions (ADRs). RESULTS: No significant reduction in the incidence of new vertebral fractures was found in the EL group. The percentage increase in lumbar BMD was significantly higher in the EL group from 24 weeks to the last administration. Although the EL group showed tendencies toward smaller decreased hip total and femoral neck BMD, no significant differences were observed between groups. The incidence of ADRs was significantly greater in the EL group, although these have all been previously reported and no new safety concerns were identified. CONCLUSIONS: Once weekly injection of 20 units of elcatonin significantly increased lumbar BMD over a 3 year period and did not cause any safety problems, but no significant reduction in the incidence of vertebral or non-vertebral fractures was demonstrated.