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,... Show moreObjective. 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). Show less
Objectives: To compare reliabilities of assessing synovitis in hand osteoarthritis (OA) using Magnetic Resonance Imaging (MRI) with/without gadolinium (Gd). Methods: Three readers scored synovitis... Show moreObjectives: To compare reliabilities of assessing synovitis in hand osteoarthritis (OA) using Magnetic Resonance Imaging (MRI) with/without gadolinium (Gd). Methods: Three readers scored synovitis on non-enhanced two-dimensional (2D) proton density (PD)weighted MRI and Gd-enhanced (3D) MRI of hand joints in 20 patients. Inter-reader reliabilities were examined. Results: Reliability was good for Gd-enhanced MRI, but poor for non-enhanced PD-weighted MRI (intraclass correlation coefficient 0.83 and 0.21, respectively). Agreement between the two sequences was poor (weighted kappa 0.18). Conclusion: Gd-enhanced MRI was more reliable than PD-weighted MRI for assessing synovitis. Gd-enhancement, but also resolution and tissue contrast, might have contributed to this. (c) 2021 Elsevier Inc. All rights reserved. Show less
Kroon, F.P.B.; Beest, S. van; Gandjbakhch, F.; Peterfy, C.G.; Chen, S.; Conaghan, P.G.; ... ; Kloppenburg, M. 2019
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... Show moreObjective 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. Show less
Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force... Show moreReports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis A case definition was developed so that subsequent studies report on the same condition The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features including their location in the subtrochantenc region and femoral shaft transverse or short oblique orientation minimal or no associated trauma a medial spike when the fracture is complete and absence of comminution be present to designate a femoral fracture as atypical Minor features include their association with cortical thickening a periosteal reaction of the lateral cortex prodromal pain bilaterality delayed healing, comorbid conditions and concomitant drug exposures including BPs other antiresorptive agents, glucocorticoids, and proton pump inhibitors Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation accumulation of microdamage and advanced glycation end products mineralization remodeling vascularity and angiogenesis lend biologic plausibility to a potential association with long-term BP use Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low particularly compared with the number of vertebral hip and other fractures that are prevented by BPs Moreover a causal association between BPs and atypical fractures has not been established However recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem Given the relative rarity of atypical femoral fractures the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs Research directions should include development of animal models, increased surveillance and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management (C) 2010 American Society for Bone and Mineral Research Show less
