Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates
ABSTRACT To report results of subgroup analyses of bone mineral density (BMD) and bone turnover markers from a randomised, double-blind, placebo-controlled, phase II study of denosumab, an investigational RANKL inhibitor, in patients with rheumatoid arthritis (RA) concurrently receiving treatment with bisphosphonates or glucocorticoids.
Patients received subcutaneous placebo (n=75), denosumab 60 mg (n=71) or denosumab 180 mg (n=72) at baseline and 6 months. Assessments included dual x-ray absorptiometry scans of the lumbar spine and hip, and determination of levels of serum type I C-telopeptide (sCTx-I) and serum procollagen 1N-terminal peptide (P1NP).
Denosumab treatment increased mean lumbar spine and hip BMD and reduced sCTx-I and P1NP compared with placebo through 12 months, regardless of baseline BMD or marker levels or concomitant bisphosphonate or glucocorticoid use.
This study extends evidence that denosumab increases BMD and reduces bone turnover in patients with RA and may provide a new therapeutic option for reducing systemic bone loss in patients with RA.
- SourceAvailable from: Chia-Sing Lu[Show abstract] [Hide abstract]
ABSTRACT: Immune cells are involved in the pathogenesis of osteoarthritis (OA). CD4+ T cells were activated during the onset of OA and induced macrophage inflammatory protein (MIP)-1γ expression and subsequent osteoclast formation. We evaluated the effects of local knockdown of MIP-1γ in a mouse OA model induced by anterior cruciate ligament-transection (ACLT). The mouse macrophage cell lines and osteoclast-like cells generated from immature hematopoietic monocyte/macrophage progenitors of murine bone marrow were co-cultured with either receptor activator of NFκB ligand (RANKL) or CD4+ T cells. The levels of MIP-1γ, RANKL in cells and mice were examined by enzyme-linked immunosorbent assay (ELISA). The osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase (TRAP) and cathepsin K staining. OA was induced in one hind-leg knee joint of B6 mice. Lentiviral vector encoding MIP-1γ small hairpin RNA (shRNA) and control vector were individually injected intraarticularly into these knee joints. The knee joints were histologically assessed for manifestations of OA. The expression of MIP-1γ, MMP-13, the infiltration of CD4+ T cells, macrophages and osteoclastogenesis in tissues were examined using immunohistochemistry (IHC). CD4+ T cells were involved in osteoarthritis by inducing MIP-1γ expression in osteoclast progenitors and the subsequent osteoclast formation. Neutralizing MIP-1γ with a specific antibody abolishes RANKL- and CD4+ T cell-stimulated osteoclast formation. MIP-1γ levels were significantly higher in synovium and the chondro-osseous junction of joints 90 days post-surgery. The number of infiltrated CD4+ T cells, macrophages and IL-1β expression was reduced in the synovial tissues of mice treated with MIP-1γ shRNA. Histopathological examinations revealed that mice treated with MIP-1γ shRNA had less severe osteoarthritis than control mice had, as well as decreased osteoclast formation and matrix metalloproteinase (MMP)-13 expression. Locally inhibiting MIP-1γ expression may ameliorate disease progression and provide a new OA therapy.Human gene therapy 09/2013; DOI:10.1089/hum.2012.189 · 3.62 Impact Factor
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