Heterotopic ossification prophylaxis with indomethacin increases the risk of long-bone nonunion

Burd, Timothy A.; Hughes, Michael S.; Anglen, Jeff

doi:10.1302/0301-620x.85b5.13970

Cited by 234 publications

(170 citation statements)

References 30 publications

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“…Our data suggest the process of ectopic bone formation is initiated shortly after a traumatic insult, findings consistent with those of others [4,44]. Wounds in which HO developed exhibited an elevated, protracted inflammatory state and may account for the increased levels of mRNA transcripts observed at the final débridement.…”

Section: Resultssupporting

confidence: 91%

“…The minimum time for radiographic followup was selected based on previous studies from this and other surgical patient populations showing that HO is reliably evident radiographically within 2 months of the inciting event [4,16,34,35,39]. A two-author blinded independent review of radiographs was performed to determine the presence of ectopic bone with complete agreement between reviewers.…”

Section: Methodsmentioning

confidence: 99%

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Osteogenic Gene Expression Correlates With Development of Heterotopic Ossification in War Wounds

Evans

Potter

Brown

et al. 2013

Clin Orthop Relat Res

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Background Heterotopic ossification (HO) is a frequent complication of modern wartime extremity injuries. The biological mechanisms responsible for the development of HO in traumatic wounds remain elusive. Question/purposes The aims of our study were to (1) characterize the expression profile of osteogenesis-related gene transcripts in traumatic war wounds in which HO developed; and (2) determine whether expression at the mRNA level correlated with functional protein expression and HO formation. Methods Biopsy specimens from 54 high-energy penetrating extremity wounds obtained at the initial and final surgical débridements were evaluated. The levels of selected osteogenic-related gene transcripts from RNA extracts were assessed by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. As a result of its key role in osteogenesis, the concentration of BMP-2 in the effluent of 29 wounds also was determined. Conclusions Important differences exist in the osteogenic gene expression profile of wounds in which HO developed compared with wounds in which it did not develop. The upregulation of multiple osteogenesis-related gene transcripts indicates the presence of a proosteogenic environment necessary for ectopic bone formation in traumatic wounds.

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Section: Resultssupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Osteogenic Gene Expression Correlates With Development of Heterotopic Ossification in War Wounds

Evans

Potter

Brown

et al. 2013

Clin Orthop Relat Res

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“…More recently, inhibition of a neural patterning gene in the Hedgehog pathway has been shown to diminish a hereditary predilection toward formation of HO [26]. Given that current HO treatments such as radiation and nonsteroidal antiinflammatory drugs have potentially severe side effects [5,6,24], transient muscle paralysis and/or focal inhibition of neuromuscular signaling presents an alternative intervention with potential for preventing heterotopic bone after orthopaedic trauma. However, translation of this approach to the clinic will require a better understanding of the cellular mechanisms controlling muscle/bone/nerve interactions so that optimal inhibition of HO can be achieved while the potentially adverse effects of transient neuromuscular inhibition are minimized [2,23].…”

Section: Discussionmentioning

confidence: 99%

Botulinum Toxin-induced Muscle Paralysis Inhibits Heterotopic Bone Formation

Ausk

Gross

Bain

2015

Clinical Orthopaedics &Amp; Related Research

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Background Short-term muscle atrophy induced by botulinum toxin A (BTxA) has been observed to impair osteogenesis in a rat closed femur fracture model. However, it is unclear whether the underlying mechanism is a direct effect of BTxA on muscle-bone interactions or an indirect effect that is driven by skeletal unloading. Because skeletal trauma in the closed fracture model also leads to disuse atrophy, we sought to mitigate this confounding variable by examining BTxA effects on muscle-bone interactions in two complementary in vivo models in which osteogenesis is induced in the absence of skeletal unloading. The overall aim of this study was to identify a potential strategy to inhibit pathological bone formation and heterotopic ossification (HO). Questions/purposes (1) Does muscle paralysis inhibit periosteal osteogenesis induced by a transcortical defect? (2) Does muscle paralysis inhibit heterotopic bone formation stimulated by intramuscular bone morphogenetic protein (BMP) injection? Methods Focal osteogenesis was induced in the right hindlimb of mice through surgical initiation of a small transcortical defect in the tibia (fracture callus; n = 7/group) or intramuscular injection of BMP-2 (HO lesion; n = 6/group), both in the presence/absence of adjacent calf paralysis. High-resolution micro-CT images were obtained in all experimental groups 21 days postinduction and total volume (ie, perimeter of periosteal callus or HO lesion) and bone volume (calcified tissue within the total volume) were quantified as primary outcome measures. Finally, these outcome measures were compared to determine the effect of muscle paralysis on inhibition of local osteogenesis in both studies.Results After a transcortical defect, BTxA-treated mice showed profound inhibition of osteogenesis in the periosteal fracture callus 21 days postsurgery compared with saline-treated mice (total volume: 0.08 ± 0.06 versus 0.42 ± 0.11 mm 3 , p \ 0.001; bone volume: 0.07 ± 0.05 versus 0.32 ± 0.07 mm 3 , p \ 0.001). Similarly, BMP-2-induced HO formation was inhibited by adjacent muscle paralysis at the same time point (total volume: 1.42 ± 0.31 versus 3.42 ± 2.11 mm 3 , p = 0.034; bone volume: 0.68 ± 0.18 versus 1.36 ± 0.79 mm 3 , p = 0.045). Conclusions Our data indicate that BTxA-induced neuromuscular inhibition mitigated osteogenesis associated with both a transcortical defect and BMP-2-induced HO. Clinical Relevance Focal neuromuscular inhibition represents a promising new approach that may lead to a new clinical intervention to mitigate trauma-induced HO, a healthcare challenge that is severely debilitating for civilian and war-wounded populations, is costly to both the patient and the healthcare system, and currently lacks effective treatments.

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“…NSAIDs are used widely to cover a variety of situations where patients are at risk of developing HO, and reports concerning the efficacy of these drugs vary [11]. There is evidence that, in addition to their normal side effect profile, NSAIDs increase the risk of non-union after acetabular fixation and inhibit bone remodelling [12,13]. Additionally, NSAID administration carries the risk of gastric irritation, occasionally preventing (20-37%) patients from completing treatment [14].…”

Section: Clinical Problemsmentioning

confidence: 99%