Session Type: Abstract Submissions (ACR)
Anti-inflammatory treatment of rheumatoid arthritis (RA) with glucocorticoids (GC) and/or non-steroidal anti-inflammatory drugs (NSAIDs) is supposed to negatively influence bone metabolism and healing. It should be noted, however, that RA itself is suspected to promote bone healing complications. However, studies addressing the number of afflicted patients and/or quantifying the negative impact of preexisting comorbidities and treatment with GC and/or NSAIDs on the bone fracture healing process are scarce. Thus, we hypothesized that both (i) suffering from RA and (ii) treatment with either GC or NSAIDs represent risk factors of bone healing disorders.
To test our hypothesis, we performed a single-center retrospective study based on the database of the Center for Musculoskeletal Surgery at Charité University Hospital Berlin to measure the impact of RA, GC and NSAID on bone healing complications. All patients who underwent surgery at our institution for treating fracture healing complications in 2012 were included. Exclusion criteria were patients with an age below 18 years at initial fracture, open fracture, and metastases close to fracture location. A control group matched for age and type of fracture at the ratio of two was considered for comparison. In parallel, we conducted in vitro experiments analyzing the impact of GC and NSAID on osteogenic differentiation of mesenchymal stromal cells (MSC) and the counteracting ability of hypoxia and the hypoxia-inducible factor (HIF) stabilizer deferoxamine (DFO). To this end, human bone marrow derived MSC were cultured, characterized and differentiated into osteoblasts under normoxic (37°C, 5% CO2, 18% O2) or hypoxic (37°C, 5% CO2, 1% O2) conditions using varying doses of dexamethasone (10-3 – 10-8 M), ibuprofen (5×10-3 – 5×10-5) and desferrioxamine (DFO; 125-500µM). The calcification process during osteogenesis was analyzed using a quantifiable alizarin red staining method.
Retrospective analysis included 93 patients with fracture-healing complications and 193 controls; both groups equally represented both sexes. We found a 10.6% higher probability (p=0.036) of fracture healing disorders in RA patients compared to the controls with a higher rate of these patients being treated with GC and NSAID, respectively. In our in vitro studies, we could demonstrate a concentration-dependent significant inhibitory effect of dexamethasone and ibuprofen on the osteogenetic capacity of MSC which could be considerably antagonized by either hypoxia or DFO.
The results we have obtained so far support the hypothesis that both RA and GC medication have a negative impact on the outcome of fracture healing. Our results also demonstrate that GC and NSAID inhibit MSC differentiation which could contribute to explain impaired fracture healing. In addition, we demonstrate a positive effect of (chemically induced) hypoxia promoting osteogenic differentiation and being a promising tool to overcome bone healing disorders which result from anti-inflammatory treatment.
Horizon Pharma, Inc,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/impaired-bone-healing-in-patients-suffering-from-rheumatoid-arthritis-anti-inflammatory-therapy-as-confounder/