Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates

Robin K Dore Inc, Tustin, CA, USA.
Annals of the rheumatic diseases (Impact Factor: 10.38). 10/2009; 69(5):872-5. DOI: 10.1136/ard.2009.112920
Source: PubMed


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.

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    • "In contrast, RANKL is not influenced by the treatment, showing that the ratio RANKL/OPG is of major importance in regulating bone resorption rather than each of the markers taken alone [15]. Then, it is not surprising that deleterious effects of RANKL on BMD can be prevented by denosumab which is an anti-RANKL monoclonal antibody, increasing BMD and reducing bone turnover in RA patients [16]. Bone formation is also decreased during inflammation as shown in mice. "
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    ABSTRACT: Bone loss in rheumatoid arthritis (RA) patients results from chronic inflammation and can lead to osteoporosis and fractures. A few bone remodeling markers have been studied in RA witnessing bone formation (osteocalcin), serum aminoterminal propeptide of type I collagen (PINP), serum carboxyterminal propeptide of type I collagen (ICTP), bone alkaline phosphatase (BAP), osteocalcin (OC), and bone resorption: C-terminal telopeptide of type 1 collagen (I-CTX), N-terminal telopeptide of type 1 collagen (I-NTX), pyridinolines (DPD and PYD), and tartrate-resistant acid phosphatase (TRAP). Bone resorption can be seen either in periarticular bone (demineralization and erosion) or in the total skeleton (osteoporosis). Whatever the location, bone resorption results from activation of osteoclasts when the ratio between osteoprotegerin and receptor activator of nuclear factor kappa-B ligand (OPG/RANKL) is decreased under influence of various proinflammatory cytokines. Bone remodeling markers also allow physicians to evaluate the effect of drugs used in RA like biologic agents, which reduce inflammation and exert a protecting effect on bone. We will discuss in this review changes in bone markers remodeling in patients with RA treated with biologics.
    Mediators of Inflammation 04/2014; 2014(2):484280. DOI:10.1155/2014/484280 · 3.24 Impact Factor
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    • "Like MIP-1c, targeting these factors could inhibit the osteoclastogenesis and the following bone sorption (Dimitrova et al., 2012; Park et al., 2012). Using antibodies that specifically targeted to RANKL, clinical trials were conducted to treat osteoporosis and rheumatism arthritis , and showed promising results (Cohen et al., 2008; Cummings et al., 2009; Dore et al., 2010). Okamatsu et al. (2004) reported that among all the mediators screened, MIP- 1c was the most strongly upregulated cytokines in osteoclasts derived from RANKL-stimulated monocytes/macrophages. "
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    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; 24(10). DOI:10.1089/hum.2012.189 · 3.76 Impact Factor
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    • "The ability of these agents to promote healing of bone in PsA has not been evaluated. Another molecule with potent effects on bone is anti-RANKL antibody (denosumab), currently approved for the treatment of osteoporosis [48–50]. This agent blocks bone degradation but can also promote new bone formation, as shown by the increased bone density in osteoporotic patients treated with this agent and in preclinical models. "
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    ABSTRACT: Psoriatic arthritis (PsA) is characterized by focal bone erosions mediated by osteoclasts at the bone-pannus junction. The bulk of research over the past decade has centered on mechanisms that underlie osteoclastogenesis along with new insights into osteoimmunology; however, recent advances that focus on steps that lead to new bone formation are beginning to emerge. New revelations about bone formation may have direct relevance to PsA given the presence of enthesophytes, syndesmophytes, and bony ankylosis frequently observed in patients with this disorder. In this review, we discuss current developments in the pathogenesis of new bone formation, novel imaging approaches to study bone remodeling and highlight innovative approaches to study the effect of inflammation on bone. Lastly, we discuss promising therapies that target joint inflammation and osteitis with the potential to mediate pathologic bone formation.
    Current Rheumatology Reports 05/2012; 14(4):349-57. DOI:10.1007/s11926-012-0259-1 · 2.87 Impact Factor
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