Indomethacin for prevention of heterotopic ossification after hip arthroplasty: A randomized comparison between 4 and 8 days of treatment

Dorn, U.; Grethen, Claude; Effenberger, H.; Berka, Hans; Ramsauer, T.; Drekonja, Thomas

doi:10.3109/17453679809117607

Cited by 29 publications

(8 citation statements)

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“…A role of PGE in clinically significant bone formation in the acute inflammatory phase following injury or surgery has been intimated by multiple studies. Inhibition of PGE production with the use of short‐term nonsteroidal anti‐inflammatory drugs has been shown to inhibit clinical bone formation 40–45. Inhibition of IL‐1β or other inflammatory cytokine‐mediated PGE production, as seen in this study, may account for this clinical finding.…”

Section: Discussionsupporting

confidence: 55%

Biphasic effects of interleukin‐1β on osteoblast differentiation in vitro

Lin

Chang

McGuire

et al. 2010

Journal Orthopaedic Research

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A rat calvarial cell model of osteoblast differentiation using the formation of bone nodules in vitro as an endpoint was used to assess the effects of IL-1b on osteoblast differentiation. Short-term treatment (2 days) with IL-1b early in culture resulted in increased nodule number and size as well as calcium content in contrast to long-term treatment (6 days) in cultures assessed at 10-12 days. This increase in bone formation was blocked by IL-1 receptor antagonists. Short-term treatment increased COX-2, prostaglandin (PGE 2 ), and iNOS production. Exogenous PGE 2 with IL-1b enhanced this effect. COX-2 inhibitors, indomethacin and N-39, blocked 50% of nodule formation. NO donor did not modify effects of IL-1b, but iNOS inhibitor (1400W) partially blocked the effects. However, PGE 2 and NO donors could not rescue the decreased nodule number resulting from long-term IL-1b treatment. The results of this study suggest a biphasic effect of IL-1b on bone nodule formation activated by IL-1b binding with IL-1 receptors, and the anabolic effect of early short-term treatment with IL-1b is likely mediated by PGE without ruling out nitric oxide. Keywords: IL-1b; bone nodule; prostaglandin; osteoblast; differentiation Local factors regulating bone formation can be grouped into factors isolated from the matrix, factors synthesized by skeletal cells, and factors synthesized by cells from adjoining tissues.1 Inflammatory cytokines, which can be produced by osteoblasts or surrounding stromal or inflammatory cells may play a role in the local control of bone formation. Interleukin-1b (IL-1b), a potent cytokine with diverse biological activities, is produced by osteoblasts 2 and has receptors on osteoblasts. 3 IL-1 has been reported in association with both clinical bone loss and bone formation. Increased local levels of IL-1 in areas of clinical bone loss associated with chronic inflammatory reactions 4-6 have been described. In vitro models have confirmed the catabolic effects of continuous exposure to IL-1 to bone cells. [7][8][9] The anabolic effects of acute inflammatory reactants on bone formation have been largely neglected, although they were reported as early as 1941, when Kü ntscher described his ''callus without fracture '' experiments. 10 An acute inflammatory phase is an early and important phase of fracture healing. IL-1 protein or mRNA has been noted transiently at sites of impending bone formation. In the present study the time and dose effects of IL-1b on bone formation were investigated using cultures of rat calvarial cells that have the capability to form discrete nodules of woven bone.32 Each nodule is the clonal product of differentiation of a single osteoprogenitor cell, 33 allowing assessment of differentiation using bone formation as an endpoint. The role of NO and PGE as mediators of IL-1b effects were also investigated.A better understanding of the role of IL-lb in the local control of osteoblast differentiation may shed light on a variety of clinical problems in which bone formation, or la...

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Section: Discussionsupporting

confidence: 55%

Biphasic effects of interleukin‐1β on osteoblast differentiation in vitro

Lin

Chang

McGuire

et al. 2010

Journal Orthopaedic Research

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“…The minimum treatment period for NSAIDs appears to be 7 days (Neal et al 2000). Indomethacin used for 3 (van der Heide et al 1999) or 4 (Dorn et al 1998) days was found to show inferior results. Traditional non-steroidal anti-inflammatory drugs inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).…”

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confidence: 94%

Similar effects of rofecoxib and indomethacin on the incidence of heterotopic ossification after hip arthroplasty

et al. 2007

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Background Although indomethacin is effective in preventing heterotopic ossification (HO) after primary total hip arthroplasty, side effects are frequently observed. In the last decade a new class of drugs-the COX-2 selective nonsteroidal anti-inflammatory drugs-has been developed. To investigate the effect of these COX-2 selective NSAIDs on heterotopic ossification (HO) after primary total hip arthroplasty (THA), we conducted a randomized controlled trial using either indomethacin or rofecoxib for 7 days.Methods 186 patients received either indomethacin 3 times daily, or rofecoxib twice, and 1 placebo, daily for 7 days. HO was graded according to the 1-year postoperative radiographs according to the Brooker classification.Results 12 of the 186 patients included discontinued their medication before the end of the trial due to side effects. The remaining 174 patients were included in the analysis. In the indomethacin group (n = 89), 77 patients (87%) showed no HO, 9 showed HO of grade 1 and 3 showed HO of grade 2 according to the Brooker classification. In the rofecoxib group (n = 85) 73 patients (86%) showed no ossification, 9 showed grade 1, and 3 showed grade 2.Interpretation The prophylactic effect of rofecoxib for 7 days in preventing heteropic ossification after primary total hip arthroplasty is comparable to the effect of indomethacin given for 7 days. These results indicate that the development of HO follows a COX-2 pathway.

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“…10 Specifically in the treatment of fractures, time to healing and union rates are better in patients receiving ketorolac 3,20,34 than other nonsteroidal anti-inflammatory drugs (NSAIDs). 2,11,20 Our ketorolac analgesic regimen was well within the dosage and 1-week recommendation for NSAID administration. 13…”

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confidence: 71%