Untitled

Review Article
Schattauer 2010
Non-steroidal anti-inflammatory
drugs inhibit bone healing: A review
Washington State University, Department of Veterinary Clinical Sciences, Veterinary Teaching Hospital, Pullman, Wash- Keywords
stems from prostaglandin inhibition and is crine and autocrine activity, have since been shown to regulate constitutive and in- Non-steroidal anti-inflammatory drugs, likely multifactorial. In human medicine ducible functions throughout the body, in- NSAID are known to prevent heterotopic ossi-fication, however the clinical importance of their effects on bone healing remains contro- anism of NSAID inhibition to bone healing The ability of non-steroidal anti-inflammatory versial. Although a small handful of reports is unknown, but is likely multifactorial. Re- drugs (NSAID) to inhibit bone healing has suggest that NSAID suppress bone healing in searchers have suggested that NSAID affect been established in experimental animal dogs and horses, there is little published infor- normal bone healing in multiple ways, with models using mice, rats, and rabbits. The mation to direct veterinary practice in do- emphasis often (but not exclusively) placed mechanism of action is largely unknown but mestic species. on processes related to the inflammatory stage. Correspondence to:
Vet Comp Orthop Traumatol 2010; 23: 385–392
doi:10.3415/VCOT-10-01-0017
fracture healing. Fracture healing presents an exquisitely orchestrated series of coor- Department of Veterinary Clinical Sciences dinated molecular and cellular events. Be- healing were appreciated, careful histologi- characterised histologically by osteonal ‘cutting cones’ directly crossing the fracture gap, bypassing the intermediate stages of cartilaginous callus and endochondral Introduction
directed by subsequent discoveries such as ossification (10–12). This type of healing is cyclooxygenase-2 (COX-2) and the bio- possible only with direct bone contact and The mechanism of action of non-steroidal logical mechanisms of bone healing. Today, rigid stabilisation. Osteonal activity in-anti-inflammatory drugs (NSAID) had NSAID are recognised as being effective in- creases near the injury – this phenomenon only recently been discovered when the hibitors of bone formation in experimental is referred to as ‘regional acceleratory phe-drugs’ ability to inhibit bone healing was models of fracture healing, spinal fusion, nomenon’ (RAP) and probably plays an first documented. In 1976, Ro and others bone ingrowth into implants, mechanically important role in direct fracture healing reported significantly reduced fracture induced bone remodelling, and hetero- healing in rats treated with indomethacin topic ossification (3). This review focuses but the phenomenon may be mediated by (1). In the same year, a 64-year-old man on the effects of NSAID on bone healing the same signalling molecules as seen in with an ankle fracture/luxation was pur- prevent callus formation in anticipation of can be classified into four histologically ob- surgery (2). The authors noted, “A dis- Mechanism of inhibition
placed fibular fracture usually heals even without external immobilisation. In the In 1971 Vane and others discovered that as- present case, however, the fracture did not pirin, indomethacin, and salicylate exert phase is characterised by haematoma unite in spite of external immobilisation their potent antiphlogistic effects by in- hibiting COX, the rate-limiting enzyme in creased local production of inflammatory These initial reports led to a flurry of re- prostaglandin synthesis (4). Prostagland- search which was periodically excited and ins, small signalling molecules with para- prostaglandins (6, 14). Mesenchymal stem 386 S. Barry: Non-steroidal anti-inflammatory drugs inhibit bone healing
cells are recruited from intra- and extra- wild type and COX-2-/- cell cultures to ap- osseous tissues to differentiate into chon- dral ossification in the osteogenic phase proximately the same degree. The authors drogenic and osteogenic cell types. In the (16). chondrogenic phase, a cartilaginous callus bridges the fracture fragments and intram- embranous ossification occurs under the known, the predominant theory supposes periosteum at the fracture edges. In the os- that NSAID, by inhibiting prostaglandin the relationship between COX-induced teogenic phase, the cartilaginous callus is synthesis, interfere with cell signalling dur- replaced by woven bone via endochondral ing the inflammatory phase leading to an phogenetic proteins. A selective COX-2 in-ossification in a process reminiscent of uncoordinated healing response. Endogen- physeal growth. In the remodelling phase, ous prostaglandins E and F increase locally human mesenchymal stem cells; this effect young woven bone is replaced by lamellar in the first seven days after fracture, sug- gesting a signalling function by prostag- The molecular mechanisms of bone landins in the early healing period (6–8). BMP-2 expression (24). Another study healing are complex and are the subjects of Attempts to simplify prostaglandin’s effects showed further support for this relation-current ongoing studies. Local and sys- ship, but indicated an opposite pathway in temic regulatory molecules including cyto- ficulty in simulating their naturally occur- kines, growth and differentiation factors, ring expression and environment in vitro. cultured murine osteoblasts (25). In the hormones, and extracellular matrix mol- The small, quickly metabolised and locally same study, BMP-2-induced ectopic ossifi- ecules regulate processes such as cellular acting molecules can promote bone resorp- cation was inhibited in COX-2-/- mice, indi- migration, proliferation, differentiation, tion, bone formation, or both depending cating that BMP-2 effects on bone extracellular protein synthesis, and apopto- on the extracellular environment and the formation are in part due to COX-2 acti- intracellular chemical milieu (9). Exogen- vation. Finally, immunohistochemistry de- ecules currently recognised in fracture ous prostaglandin E administration in- tected a simultaneous rise in BMP-7 (also creases regional acceleratory phenomenon known as osteogenic protein-1, or OP-1) egories: 1) pro-inflammatory cytokines, in- after rib fractures in dogs, increasing both and COX-2 at fracture calluses in mice. In cluding interleukin-1 (IL-1), interleukin-6 resorption and production in response to the same study, BMP-7-induced ectopic (IL-6), tumour necrosis factor-alpha injury (17, 18). Synthetic prostaglandin re- ossification was inhibited by diclofenac, an (TNF-α), platelet-derived growth factor ceptor agonists have an overall anabolic ef- NSAID (26). (PDGF), and others; 2) transforming fect and enhance bone healing in rats and Inhibition of angiogenesis has also been growth factor-beta superfamily members, dogs in experimental conditions (19, 20). suggested as a mechanism of NSAID effects Inhibitory effects on mesenchymal stem on bone healing. Cyclooxygenase-2 meta- teins (BMP), transforming growth factor cell differentiation and activity have been bolic products (mainly prostaglandins) are beta isoforms (TGF-β), growth differenti- stimulators of angiogenesis, which is essen- ation factors (GDF), activins, inhibins, and duced bone inhibition (21–23). In a no- tial for fracture healing (27, 28). Rofecoxib Müllerian inhibiting substance; and 3) an- table in vivo study involving an NSAID, di- clofenac profoundly reduced the number murs and significantly reduced blood flow dothelial growth factor (VEGF) and angio- of histologically visible osteoblasts at the within the femoral calluses (29). After ana- poietins (15, 16). Although there is con- injury site 10 days after bone drill defects lysing linear regression models, however, siderable overlap, these local molecules are were created in rat femora, suggesting in- the authors concluded that rofecoxib’s expressed in distinct temporal (and spatial) hibition of osteoblast differentiation or mi- negative effect on blood flow was indepen- patterns which can be loosely correlated to gration (23). Tibial fracture calluses in mice dent of rofecoxib’s negative effect on bone the histological stages of fracture healing lacking COX-2 expression (COX-2-/-) had healing. (14, 16). In general, inflammatory cyto- markedly fewer histologically visible os- kines are elevated in the inflammatory teoblasts and a higher incidence of fibrous
phase and partially during secondary bone nonunion compared with wild-type mice In vivo evidence
formation in the remodelling phase. Some (21). In a cell culture model by the same au-members of the TGF-β superfamily, such as thors, bone marrow cells from COX-2-/- Over thirty years of research have estab-bone morphogenetic protein-2 (BMP-2), mice failed to differentiate into osteoblasts lished that NSAID can slow fracture heal-are expressed at all stages of healing where- to the same degree as cells from wild-type ing in rodents. Using closed simple trans- as others are elevated at more specific mice when stimulated by osteogenic mol- verse long-bone fractures in rats and mice, times, such as during the cartilaginous ecules. The addition of prostaglandin E2 investigators have repeatedly documented phase (TGF-β) or during the osteogenic (PGE2) restored osteoblastogenesis to wild- bone healing inhibition as measured by phase (BMP-3, -8). Angiogenic factors, type levels. Bone morphogenetic protein-2 gross examination, nonunion rates, radio-though present throughout fracture heal- also induced osteoblastogenesis in both graphic scores, bone mineral density, S. Barry: Non-steroidal anti-inflammatory drugs inhibit bone healing
Table 1 Effect of non-steroidal anti-inflammatory drugs on rodent and rabbit models of bone healing.
Year, Author
Animal Drug(s)
Indomethacin Decreased radiographical and histological healing, decreased mechanical strength of healed Indomethacin Inhibited Haversian remodelling in response to osteotomy. Indomethacin, Both drugs caused dose-dependent decrease in fracture callus histological healing score. Aspirin Decreased dry weight, ash weight, and organic matter weight of healing bones. Indomethacin Decreased osteogenesis (strontium uptake) in Indomethacin No effect on Haversian remodelling close to a 2 mm drill defect, measured six weeks after Indomethacin, Indomethacin weakened mechanical strength of healed fractures at 6 weeks; ketorolac had no Ketoralac effect at 6 weeks (3 days of treatment). Indomethacin, Indomethacin lowered spinal fusion rate; celecoxib had no effect. Celecoxib Rats, mice Indomethacin, Part I: Indomethacin delayed bone healing temporarily; rofecoxib and celecoxib had more
Part II: Cox-2-/- mice had impaired bone healing.
Decreased bone density and mechanical strength of healing bone. Ketorolac decreased bone healing (histology and mechanical testing); parecoxib showed variable Decreased fracture healing (histomorphometry). Indomethacin Decreased spinal fusion rate. Indomethacin, Both drugs decreased histological healing scores; only indomethacin had effect on mechanical Celecoxib Decreased bony ingrowth into titanium chamber (histomorphometry). Time and duration-dependent reduction in fracture healing (radiographic scores and mechanical testing). Indomethacin Decreased heterotopic bone formation, decreased mineralisation of traumatised femurs. Rofecoxib decreased fracture healing (nonunion rate, radiographic score, histological score); Decreased fracture healing and blood flow across fracture callus. Duration-dependent decrease in fracture healing (histomorphometry). Duration-dependent decrease in fracture healing (nonunion rate, mechanical testing). Dose- and duration-dependent decrease in fracture healing (nonunion rate, radiographic score, and mechanical testing). Transient reduction in bone mineral density during early healing phase (treatment for 7 days).
Indomethacin, Both drugs reduced bone mineral density and mechanical parameters of healing fractures. Parecoxib Rofecoxib reduced mechanical strength more than ibuprofen. No effect on osteoconduction induced by β-tricalcium phosphate graft in femoral epiphyseal defects. Decreased fracture healing (micro-computed tomography, mechanical testing). 388 S. Barry: Non-steroidal anti-inflammatory drugs inhibit bone healing
particular time are studied (ǠTable 1). phometry, micro-computed tomography, lations. This research was contrasted by a Non-steroidal anti-inflammatory drugs and mechanical testing of fracture calluses study involving femoral fractures in male frequently used in veterinary medicine (ǠTable 1). The intensity and reliability of rats, where celecoxib inhibited fracture such as carprofen, meloxicam, deracoxib, this inhibition raises concerns about the healing as measured by radiographic scores firocoxib, and flunixin have not been clinical ramifications of prescribing and nonunion rate (35). Celecoxib failed to studied in vivo, with the exception of a re-NSAID to other animals in the period fol- produce significantly different mechanical cent abstract which evaluated carprofen in testing scores than in untreated rats, how- cedure. Although conclusions are limited ever. Four years later, the same authors
by experimental design and are sometimes showed that in female rats, celecoxib sig-
conflicting, the current experimental data nificantly delayed femoral fracture healing NSAID may have their greatest
would suggest the following points:
when measured by mechanical testing (7). effect during the early phase of
In their discussion, the authors pointed out bone healing
the discovery that intact male and female NSAID may have their greatest effect Sprague-Dawley rats have markedly differ- Rats given etodolac for only the first week ent celecoxib metabolism, and that the after a femoral fracture had substantial de- NSAID have a dose-dependent effect on plasma elimination half-life of celecoxib in creases in radiographic scores and callus bone healing female rats is nearly four times longer than strength measured three weeks after the frac- NSAID often have duration-dependent that of male rats. ture (37). Their decreases were comparable Cyclooxyenase-2 was discovered in 1991, to those of rats treated with etodolac for the NSAID use before bone injury does not and the first coxibs – NSAID designed spe- entire three weeks of their healing period. In cifically to be COX-2 selective – were re- contrast, rats treated for only the last of three leased soon thereafter (5). Initial studies weeks had scores which were not signifi-comparing selective to non-selective COX cantly different from untreated rats. The All NSAID studied to date
inhibitors argued that COX-2 selective seemingly permanent effects of short-term have the potential to inhibit
NSAID did not have as profound an effect treatment with etodolac in this study bone formation
against bone healing as indomethacin, a contrast with those of subsequent studies in traditional non-selective NSAID (32, 34, which the effects of short-term treatment From time to time, an article of research is 36). Subsequent genetic and in vivo studies with NSAID were reversible (7, 8, 39, 40). published which concludes that a particu- have provided strong evidence that inflam- However, in agreement with this study, other lar NSAID does not, like other NSAID, in- mation stimulated by the COX-2 isoenzyme studies also suggest that NSAID have their hibit bone formation (30–33). These is essential for fracture healing, and that greatest inhibitory effect in the early inflam-studies are often followed by subsequent COX-2 selective NSAID have an equal or matory phase of bone healing (7, 38, 45, 46). studies showing that with a different ex- greater negative effect on fracture healing in Simon and others included a ‘time delay’ rats than non-selective NSAID (7, 8, 21, group in which rats were allowed to heal un- hibit bone healing. For example, ketorolac 37–43). Thus, no single NSAID or group of treated for seven or 14 days after femoral (1 mg/kg/day) given for three days had no NSAID has been cleared as being ‘safe’, or fracture before receiving celecoxib for the effect on callus mechanical strength having no potential effect on bone healing. rest of the 28 day study period (7). Rats in the measured six weeks after fracture in rats Although adjusting the experimental group treated from seven to 28 days (21 day (31). However, ketorolac given at a higher design (increasing the dose or duration of treatment duration) had higher radio-dose (4 mg/kg/day) and for the entire time NSAID treatment) allows researchers to il- graphic scores and mechanical testing pa- lustrate fracture healing inhibition for al- ical strength and decreased histological most any NSAID studied in rodent models, with rats treated from zero to 21 days (same scores of fracture calluses compared with it is important to acknowledge that even treatment duration). However, in statistical untreated rats (34). Similarly, the authors fractures in the NSAID-treated groups analysis, the treatment groups were com-of an experiment involving spinal fusion in often go on to heal. Additionally, it some- pared to untreated controls, and direct com- rabbits concluded that while indomethacin times takes sensitive outcome measures parisons between the time delay and other reduced spinal fusion in their model (vali- (such as histomorphometry) to detect a treatment groups were not performed. dating their study as one that can detect significant difference between groups. It is
spinal fusion inhibition), celecoxib had no impossible to make conclusions about
significant effect (32). In their discussion, clinical relevance in other species based on NSAID have a dose-dependent
these authors admitted that the phar-
effect on bone healing
macokinetics of celecoxib in rabbits was unknown; the dose used in their study was geared towards human medicine, the most Few experiments include treatment groups extrapolated from recommended human promising NSAID for use in humans at a that differ in NSAID dose, however those S. Barry: Non-steroidal anti-inflammatory drugs inhibit bone healing
that do suggest that a higher dose is more tained significantly less bone and more car- tilage (39). Likewise, parecoxib given for would inhibit bone healing if discontinued pendent decrease in histological scores was seven days only transiently decreased bone at the time of bone trauma (7). This pre-seen in fracture calluses from rats given in- mineral density after tibial fractures in rats treatment with celecoxib had little to no ef- – bone mineral density returned to normal fect on fracture healing, suggesting that pa- pendent decrease in radiographic scores by three weeks (40). In a three-part study tients chronically taking NSAID, such as and mechanical properties was also ob- involving ketorolac and valdecoxib, the au- served in fracture calluses from rats given thors not only noted a more detrimental ef- suffer diminished bone healing as a result fect from both drugs when given for longer of the drug. Similar studies have not been durations – they also documented a drop in performed to investigate the effects of long-local prostaglandin E er or more chronic durations of pre-treat- NSAID often have duration-
during treatment followed by a rise in pros- dependent and reversible effects
taglandin E2 after the drugs were discon- on bone healing
tinued (8). When measured seven days after NSAID discontinuation, local prostagland- Human clinical evidence
Although some data suggest that effects of in E2 levels exceeded prostaglandin levels in early NSAID administration can persist untreated rats at the same time point after It is well-established that NSAID can pre-and be measured weeks after treatment has fracture, suggesting a rebound inflamma- vent heterotopic ossification in humans. ended, there is also evidence that NSAID- induced inhibition is proportional to the the clinical effects of NSAID on fracture duration of treatment, and that bone can healing and spinal fusion. Only a handful of heal normally once NSAID administration NSAID use before bone injury does clinical studies exist evaluating the effect of
is discontinued (8, 37–41, 43). Calluses not seem to adversely affect bone
NSAID on fracture healing or spinal fusion from rats given diclofenac for seven days healing
after osteotomy were not histologically dif- ferent than calluses from rats given placebo Simon and others included in their study a bone formation, commonly occurs in the when evaluated at 21 days, whereas calluses group of 23 rats that were treated with ce- soft tissues around the hip joint following from rats treated for the entire 21 days con- lecoxib for five days before femoral fracture hip surgery in humans. It is estimated that Table 2 Clinical research investigating non-steroidal anti-inflammatory drugs (NSAID) and bone healing in humans.
Year, Author
Prospective clinical trials
1988, Davis (52)
No effect on healing in patients treated with flurbiprofen for 2 weeks. No effect on healing in postmenopausal women treated with piroxicam for 8 weeks. Long-bone fractures Indomethacin Increased nonunion rate in patients treated with indomethacin for 6 weeks. No effect on spinal fusion evaluated in 1 year in patients treated with celecoxib for 5 days after surgery. Article retracted by publisher due to fabricated data. Retrospective observational studies
1998, Deguchi (63)
Various NSAID Increased nonunion rate in patients taking NSAID. Increased nonunion rate by approximately 5 times in patients taking ketorolac. Various NSAID Increased nonunion rate in patients taking NSAID. 2005, Bhattacharyya (53) Humeral fractures Various NSAID Increased nonunion rate in patients taking NSAID or opioids 61-90 days after fracture. No effect on spinal fusion evaluated 1 year after surgery in patients treated for 5 days with celecoxib, rofecoxib, or low-dose ketorolac; increased nonunion rate in patients treated with high-dose ketorolac. No effect on spinal fusion evaluated 1 year after surgery in patients treated with ketorolac for 48 hours.
390 S. Barry: Non-steroidal anti-inflammatory drugs inhibit bone healing
approximately one-third of humans the fracture site. Radiographic assessment Evidence in domestic
undergoing total hip arthroplasty will de- velop some degree of heterotopic ossifica- tion, which can cause pain and reduced angulation of the radius over time. The pir-range-of-motion if moderate or severe oxicam group had a statistically greater de- Information about the effects of NSAID in (48). The etiopathogenesis is unknown, but gree of dorsal angulation than the placebo domestic species is lacking. One publication stimulation by trauma or surgery suggests group at four weeks but not at eight weeks. suggests an effect on bone remodelling in an inflammatory component. The ability of Of 42 patients, data from six fractures were horses and two studies address the effect on NSAID to inhibit heterotopic ossification omitted because excessive redislocation osteotomy healing in dogs (44, 54, 55). has been recognised since 1977, and a re- (defined by these authors as increased radi- cent meta-analysis concluded that medium al shortening and dorsal angulation) decreased mineral apposition rate (a to high doses of perioperative NSAID pro- necessitated re-reduction and surgical ex- measure of Haversian remodelling) in bone duce a substantial reduction in the inci- ternal fixation; all six of these patients were adjacent to tibial biopsy sites in horses dence of radiographic signs of heterotopic in the piroxicam group. The authors justi- treated with phenylbutazone for two weeks ossification (48, 49). Non-steroidal anti-in- fied the omission by pointing out that ex- (54). Although the healing biopsy sites con- ternal fixation would have had an effect on tained less mineralised tissue at 16 and 30 scribed to high-risk patients to prevent het- the bone mineral content proximal to the days in phenylbutazone-treated horses erotopic bone formation after hip surgery. fracture site. than in control horses, this difference was Another prospective, double-blind, not significant. clinical study involving trauma patients with placebo-controlled study did not find that acetabular fractures and concurrent long- flurbiprofen, given for two weeks at various controlled, cross-over study in dogs was bone fractures, 282 patients were allocated doses, had an effect on the healing of distal performed to evaluate the effects of phe-into three groups after open reduction and radial fractures (52). While bone area nylbutazone and indomethacin on the internal fixation of their acetabular fractures measurements in the hand (indices of os- postoperative course following experimen- (50). One group received indomethacin for teoporosis), hand and wrist function, and tal metacarpal osteotomy (55). Bone heal-six weeks as prophylaxis against heterotopic pain were measured in the short term, frac- ing was evaluated by subjective assessment ossification, while the other two groups re- ture healing was not assessed until one year of radiographs taken two, four, six, and ceived either no prophylaxis or a single dose after fracture. If a transient delay in bone eight weeks after surgery. No attempt to ob-of local radiation to the soft tissues around healing had occurred during flurbiprofen jectively score the radiographs was re-the hip joint. The patients receiving indome- thacin had a significantly higher nonunion tected it. However, this study is clinically blinded was also not reported. In dogs rate of their long-bone fractures (29%) helpful because it indicates that short-term treated with phenylbutazone the authors compared with patients who did not receive use of flurbiprofen after distal radial frac- reported, “…radiographs taken four and indomethacin (7%; p <0.004), strongly sug- ture does not result in nonunion or signifi- six weeks after surgery … revealed tenden- cies in favour of placebo… After eight domethacin clinically inhibited long-bone Retrospective observational studies weeks, however, there were no noticeable differences.” No noticeable radiographic In contrast, a prospective, randomised, tween NSAID use and increased nonunion differences in bone healing were seen in double-blind, placebo-controlled clinical rates after fracture or spinal fusion surgery dogs treated with indomethacin. Given the study did not find piroxicam to affect the in humans (ǠTable 2). Few studies make lack of objective assessment and the fact healing of distal radial fractures in post- an effort to identify confounding factors that these two NSAID are rarely used in menopausal women despite treatment for however, and their retrospective designs small animal medicine today, it is difficult eight weeks (51). Unfortunately, the out- make inferences about causation difficult. to make clinical decisions based on this For example, a large and frequently-cited study. ing source for this study lead the reader to retrospective study involving 9,995 patients question the conclusion with regard to with humeral shaft fractures reported a experimental study designed to evaluate bone healing. The stated objective of this strong association between NSAID use and the effect of carprofen on bone healing in study was to determine whether piroxicam nonunion (53). Because this association dogs (44). Healthy dogs received either car-changed the degree of osteopenia in the was only significant in the latest time phase profen (2.2 mg/kg PO q 12 hrs) or no treat-nearby radius and ulna after coaptation for studied (61–90 days after fracture) and be- ment for four months after a tibial osteot- fracture, rather than whether piroxicam af- cause the same pattern was observed with omy was stabilised with an intramedullary fected bone healing. The outcome opioid use, the authors concluded that pin. The NSAID group had delayed bone measures were geared towards this objec- NSAID and opioid use were markers for healing compared with the control group tive, and included bone mineral content patients in pain from unstable fractures, as detected by radiographical, biomech-analysis of the radius and ulna proximal to rather than the cause of nonunion. S. Barry: Non-steroidal anti-inflammatory drugs inhibit bone healing
Discussion
chronic inflammatory disease, primary 8. Gerstenfeld LC, Al-Ghawas M, Alkhiary YM, et al. musculoskeletal disease), drug adminis- Selective and nonselective cyclooxygenase-2 in-hibitors and experimental fracture-healing. Re- tration (corticosteroids, chemotherapeutic versibility of effects after short-term treatment. J ing, there is insufficient evidence to sup- agents, antibiotics, anticoagulants, bisp- port withholding NSAID after a fracture or hosphanates, smoking), immobility, and 9. Blackwell KA, Raisz LG, Pilbeam CC. Prostagland-orthopaedic procedure in domestic others (56). The use of NSAID could have ins in bone: bad cop, good cop? Trends Endocrinol Metab 2010; 21: 294–301. species. Certainly, fractures and osteot- negative, additive, or synergistic effects on 10. McKibben B. The biology of fracture healing in long bones. J Bone Joint Surg Br 1978; 60-B: 150–162. ministration, and NSAID are important for conditions or environmental factors. To 11. Einhorn TA. The cell and molecular biology of frac-their potent anti-inflammatory and anal- date there is little to no information investi- ture healing. Clin Orthop Relat Res 1998; 355S: S7-S21. gesic effects after bone injury. However, gating these combined effects or identify- 12. Frost HM. The regional acceleratory phenomenon: when the speed and effectiveness of bone ing patients at greatest risk for NSAID-in- A review. Henry Ford Hosp Med J 1983; 31: 3–9. healing is of particular concern, such as in duced delayed fracture healing. 13. Einhorn TA. The science of fracture healing. J Or- 14. Cho TJ, Gerstenfeld LC, Einhorn TA. Differential paedic repairs, or in patients where delayed temporal expression of members of the transform- bone healing is expected, it is prudent to Conclusion
ing growth factor ß superfamily during murine frac- ture healing. J Bone Miner Res 2002; 17: 513–520. 15. Tsiridis E, Upadhyay N, Giannoudis P. Molecular aspects of fracture healing: Which are the impor- In rodent models, COX-2 selective provides strong evidence that NSAID tant molecules? Injury 2007; 38(S1): S11-S25. NSAID do not seem to offer a benefit with negatively affect bone healing. Whether 16. Al-Aql ZS, Alagl AS, Graves DT, et al. Molecular regards to bone healing compared with this effect is clinically important is contro- mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J nonselective NSAID. In humans, arguably versial in both human and veterinary medi- the most convincing study showing a clini- cine. Prospective experimental and clinical 17. Shih MS, Norridin RW. Effects of prostaglandins on cally relevant effect on bone healing in- trials involving domestic species and vet- regional remodeling changes during tibial healing volved indomethacin, a nonselective erinary NSAID are needed to guide veter- in beagles: a histomorphometric study. Calcif Tis-sue Int 1986; 39: 191–197. NSAID (50). In dogs, carprofen, a COX-2 inarians as they decide which, when, at 18. Shih MS, Norridin RW. Effects of prostaglandin E2 selective NSAID, inhibited bone healing what dose, and for how long NSAID should on rib fracture healing in beagles: histomorpho- (44). The decision to use a COX-2 selective be prescribed after bone injury. metric study on periosteum adjacent to the fracture site. Am J Vet Res 1986; 47: 1561–1564. 19. Paralkar VM, Borovecki F, Cameron KO, et al. An based on other criteria, such as the poten- Acknowledgements
EP2 receptor-selective prostaglandin E2 agonist in- tial for adverse effects, cost, and availability. duces bone healing. Proc Natl Acad Sci USA 2003; Experimental literature suggests that I gratefully acknowledge Dr. Steve Marti- 20. Tanaka M, Sakai A, Uchida S, et al. Prostaglandin E higher doses and longer durations of nez for his guidance and contribution to ceptor (EP4) selective agonist (ONO-4819.CD) accel- erates bone repair of femoral cortex after drill-hole in- ing. In addition, there is evidence to sup- jury associated with local upregulation of bone turn- over in mature rats. Bone 2004; 34: 940–948. 21. Zhang X, Schwarz EM, Young DA, et al. Cyclooxyge- hibition can be reversible once the NSAID References
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