In humans and other species, ageing has a negative effect [43]. This may be mediated through the immune system and/or negative influences on angiogenesis, mesenchymal stem cell activity and reduced progenitor cell numbers and activity [43]. Clinical experience suggests that age also appears to be correlated with fracture healing in horses. It is likely that both size and healing capacity explain why young animals have a better chance of successful repair than adults.
Exogenous Factors That Influence Fracture Healing
Pharmacologic Influences
Various medications can have differing effects on cells, cell signalling, osteoimmunologic pathways and tissues at different times and thus may have positive or negative effects on fracture healing.
Non‐steroidal Anti‐inflammatory Drugs
Non‐steroidal anti‐inflammatory drugs (NSAIDs) are a mainstay of reducing pain in horses. Their effect on bone healing is controversial [44], and use in horses undergoing fracture repair is a source of debate [45]. In people and experimental animals, it has been well documented that the early inflammatory phase is key to bone healing (Section Cellular and Humeral Influences on Bone Healing). In addition to experimental animal evidence, there is some suggestion in humans that fracture healing can be delayed, and in most clinical situations, NSAIDs are avoided following fracture repair [46]. In one study, phenylbutazone decreased mineral apposition rate in cortical bone, but there was no difference in the percentage of mineralized tissue [45]. A recent study in dogs showed no significant difference in tibial osteotomy healing with short‐term administration of carprofen (two weeks); however, there was significant delay in healing with long‐term administration (eight weeks), leading to the conclusion that NSAIDs should only be used in the perioperative period [47]. The evidence is therefore inconclusive. The author is unaware of any clinical evidence to suggest that NSAIDs used in the perioperative period have a negative impact on fracture repair in horses. The potential negative effects on bone healing must also be weighed against the possible positive effects on healing, especially in the case of severe soft tissue trauma and ongoing inflammation [15], and on the overall status of the patient. Phenylbutazone, flunixin meglumine and firocoxib can all be considered.
Bisphosphonates
Bisphosphonate therapy has come into the equine market in recent years, and its use in fracture management has been debated [48]. Bisphosphonates have a number of pharmacologic properties. Of principal interest in relation to fractures is their ability to suppress osteoclastic activity [49]. However, they also exert anti‐inflammatory and analgesic effects [50–52]. There is evidence in experimental animals that bisphosphonate administration may inhibit osseous adaption responses and result in mechanically weaker bones [53] and delay fracture healing [54–56]. This is logical when considering the role of osteoclasts in bone healing. The potential impact on fracture healing also depends on the time of administration [57]. In the early stages, bisphosphonates can inhibit the essential immune cascade (macrophages and monocytes) while later, since osteoclasts are essential in the remodelling phase, they can also have a negative effect. Studies in experimental animals have shown no delay in the formation of a hard callus (which in fact grows larger in the face of bisphosphonate therapy) but a significant delay in remodelling from woven to lamellar bone [58]. Despite the large callus size, these fractures have been shown to be mechanically equivalent but not superior to those found in untreated animals. It also appears that the timing of bisphosphonate administration does not influence healing. In humans, the results have been mixed and no clear conclusions can be made. There appears to be some positive response to bisphosphonate therapy in human osteoporotic patients suffering fractures, but this condition has not been recognized in horses. The established impact on osteoclastic function and bone remodelling suggest use should be avoided, and a recent review has suggested caution in young racehorses and in the presence of active bone remodelling [52]. There is also anecdotal evidence in horses that bisphosphonate use in the face of fracture repair may have a detrimental effect (L. R. Bramlage, personal communication).
Antimicrobials
Antimicrobials are essential in surgical repair, especially in cases of open contaminated fractures. Many different drugs can be used, each with well‐documented systemic effects and potential toxicity; however, effects on bone healing in horses are lacking. In vitro and in vivo experimental studies have shown that systemic administration of antimicrobials in general seems to have little or no direct effect on bone cells. However, implantable delivery systems that release high concentrations over time have shown some detrimental effects on bone [59]. This has also been shown on metal implant coatings [60]. In a study of multiple antimicrobials, although detrimental effects on osteoblast number and activity were seen, amikacin, tobramycin and vancomycin were the least cytotoxic [61]. Despite the potential negative influences, the positive effects outweigh concerns. Ideally, use should be targeted (Chapter 14) but, in reality, antimicrobials are usually started before target organisms are known, and clinicians must choose drugs based on their understanding of likely pathogens, severity of infection and potential consequences.
Biological Techniques
Osteobiologics is an emerging field of study in all species [62]. Various blood products, cellular treatments and growth factors are included in this group. Each have shown some positive effect on bone healing when dissecting the reams of literature around their use.
The two main blood products used in horses that have potential for use in fracture management are interleukin‐1 receptor antagonist protein (IRAP) and platelet‐rich plasma (PRP). IRAP is usually used as an intra‐articular medication, and for fractures involving the joint in which articular cartilage damage is present, there is a logic to use. The author is unaware of intralesional IRAP use in fractures.
PRP has been suggested as a product that could be applied at fracture sites [63]. Analysis of data does not provide convincing proof of efficacy, but various experimental and clinical studies suggest that it has promise, especially in light of the critical role of the clotting cascade in fracture healing. PRP is defined as a blood derivative where the platelet concentration is above baseline levels. It is meant to provide high concentrations of growth factors that are presumed to be anabolic to healing of any tissue. Several studies have shown positive effects including evidence for antimicrobial activity of platelet lysate [64]. In a meta‐analysis of PRP use, 91% of studies showed positive effects; histologic assessment of positive outcome reduced this to 84%, and radiological and biomechanical analyses dropped the positive benefit to 75 and 73%, respectively. Potential use of PRP in bone defects therefore continues to be debated [63].
Cellular product such as mesenchymal stem cells have been advocated to enhance fracture healing. Mesenchymal stem cells can be acquired from many tissues, but for fracture management they are generally obtained from bone marrow. In horses, bone‐marrow‐derived stem cells have been used in multiple tissues, but beneficial effects in fractures have not been proven. In experimental studies in other species, positive effects have been seen using bone marrow injections alone [65]. Bone marrow aspirate has been clinically evaluated and found to have positive effects [66], and bone marrow grafting has been shown to be successful for treating non‐unions in human patients [67]. Autologous, culture‐expanded mesenchymal stem cells have been reported in clinical studies or case reports in people. Most of these have been combined with scaffolds to create a cell–scaffold composite which in itself has been challenging. Healing of large cortical bone defects have been reported, but use in clinical cases has not yet been defined. Bone marrow aspirate, bone marrow aspirate concentrate and culture‐expanded mesenchymal stem cells have been used for non‐unions, osteotomies, distraction osteogenesis, spinal fusion and fractures; although the outcomes appear positive, more work is needed [68].
In the horse, there is experimental evidence supporting use of stem cells in bone healing. Stem cells loaded onto a tricalcium phosphate (TCP) implant with BMP improved healing in a third metacarpal bone defect model [69]. Others have shown no improvement in healing with