Long-term safety and effectiveness of denosumab in Japanese patients with osteoporosis: 3-year post-marketing surveillance study.

INTRODUCTION: Denosumab is a humanized IgG2 monoclonal antibody that was approved for the treatment of osteoporosis in Japan in 2013. This study aimed to investigate the long-term safety and effectiveness of denosumab in Japanese patients with osteoporosis in daily clinical practice. MATERIALS AND METHODS: This 3-year, prospective, observational, post-marketing study included patients who initiated treatment with denosumab (60 mg/6 months) for osteoporosis. Data were assessed at baseline, 3, 6, 12, 24 and 36 months. Key endpoints were adverse events (AEs), adverse drug reactions (ADRs), occurrence of osteoporotic fractures, bone mineral density (BMD), and bone turnover markers. Multivariate analyses were conducted to identify predictors of hypocalcaemia and percent change in BMD. RESULTS: Overall, 3534 patients were assessed (mean 75.7 years; 89.8% women). In total, 298 patients (8.4%) developed ADRs; the most common was hypocalcaemia (3.9%). Hypocalcaemia risk was significantly increased in patients with creatinine clearance < 30 mL/min, no prior use of bisphosphonates, prior use of calcium and vitamin D preparations, baseline serum calcium < 8.5 mg/dL, and no concomitant use of calcium or vitamin D preparations. Six patients had adjudicated osteonecrosis of the jaw. Lumbar spine BMD increased significantly from baseline (mean percent change: 11.4% at 36 months). All bone turnover markers decreased significantly from baseline. Over 3 years, 3.3% of patients developed a new osteoporotic fracture. CONCLUSIONS: This study confirmed the long-term safety and effectiveness of denosumab in Japanese patients with osteoporosis in daily clinical practice. No new safety signals were identified.

Gender difference in the urinary excretion of organic anions in rats.

This study was aimed at clarifying the gender differences in the urinary excretion of organic anions and the gene expression of organic anion transporters in rats. The renal clearance with regard to the plasma concentration (CL(urine,p)) of taurocholate, dibromosulfophthalein (DBSP), and zenarestat, all substrates and/or inhibitors of organic anion transporting polypeptide 1 (Oatp1), was much higher in female than in male rats. The following results imply that the transport system(s) for the reabsorption of zenarestat across the luminal side exhibits a gender difference: 1) the renal uptake clearance assessed by an in vivo integration plot analysis of zenarestat from the blood side does not show any clear gender differences; 2) the renal clearance with regard to the kidney concentration (CL(urine,k)) of zenarestat in female rats was approximately 30 times higher than in male rats; and 3) both CL(urine,p) and CL(urine,k) were increased in male rats by the coinfusion of DBSP, which is an inhibitor of organic anion transporters. Northern and Western blot analyses confirmed a previous finding that the gene expression of Oatp1, which is localized at the apical plasma membrane of the kidney, was much higher in the kidneys of male rats. Overall, a gender difference in urinary excretion is commonly observed for several organic anions, including Oatp1 substrates and inhibitors, and Oatp1 and/or transporters that have a similar substrate specificity to Oatp1 could be involved in such a phenomenon involving its substrates.