In clinical practice, several medications offering pain relief, anti-inflammation and a reduction of postoperative swelling are applied after bone surgery or trauma, although their potential side effects on bone healing have not been studied adequately. Non-steroidal anti-inflammatory drugs (NSAIDs) have for some time been suspected to affect fracture healing negatively [1-4] and might even cause bone loss after tooth extraction [5]. However, numerous disputes still exist and limited data are available with regard to diclofenac, which is one of the most often applied substances in clinical use. Through the inhibition of phospholipase A2, glucocorticoids act earlier in the same pathway as NSAIDs. Their possibly more serious consequences after short-term use for humans have been insufficiently examined in this context. They are known to affect bone remodelling [6-8] and fracture healing in animal models after long-term use [9, 10].
Recent molecular biological studies suggest that the early bone healing phase is crucial for the definitive success and stability of the bone [11]. This phase is characterised by an inflammatory reaction of the body with an increase in the secretion of prostaglandins (PGs) by osteoblasts [12].
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PGs are hormone-like substances with proinflammatory effect and play a key role in fracture healing. The cyclooxygenase (COX) isoenzymes 1 and 2 (COX-1 and -2) control the production of PGs: COX-2 is specifically involved in the inflammatory response, whereas COX-1 is rather involved universally in various physiological processes, such as platelet aggregation and cytoprotection in the gastrointestinal tract. NSAIDs inhibit unspecifically both the activity of COX-1 and -2 and effectively reduce pain and inflammation [13].
In vitro, diclofenac acts negatively on osteoblasts at early stages and appears to inhibit their function. This effect is seen even at relatively low concentrations corresponding to those commonly reached in vivo and might possibly lead to a delay of bone healing [11, 13]. Additionally, NSAIDs are used therapeutically to reduce heterotopic ossifications after elective joint-replacement or fractures, strongly suggesting their potential to inhibit or negatively affect endochondral ossification mechanisms [4]. Nevertheless, within the few animal studies previously carried out, the reported influence of diclofenac on bone healing is controversial and, thus, unclear [2, 13-15].
Physiological humane serum levels of glucocorticoids have shown a maximum stimulatory effect on osteoblasts in vitro. However, increasing the dose in vitro to supraphysiological doses leads to a decreased ability of osteoblasts to differentiate [6]. Corticosteroid treatment is commonly used in inflammatory and rheumatological diseases and to reduce postoperative pain and prolonged soft tissue swelling after elective surgery or accidental trauma [16]. Unlike NSAIDs, which do not interfere until the conversion of arachidonic acid to PGs in the biosynthetic pathway, glucocorticoids inhibit the production of arachidonic acid and thus interfere at an earlier point than NSAIDs in this pathway [17]. Arachidonic acid is the basis for the production of both PGs and leukotrienes. In addition to the PGs, the latter play a crucial role in the inflammation response of the body. Consequently, glucocorticoids might lead to a (more) serious delay of bone healing [7, 18, 19].
Both drugs are often administered in clinical use briefly after surgery or trauma. Therefore, the combined results of our study should allow to reduce uncertainties of former studies concerning the impact of medication on the early stage of fracture healing and should enrich our knowledge of the way in which these drugs act. Unlike precedent work, our evaluation was performed functionally, microstructurally and morphologically via the combination of biomechanics, micro-CT (μCT) and histology.
Summarised, our main objectives were to examine whether the tested substances (1) show the potential to reduce the load bearing capacity of the fracture callus of unstable mid-femural fractures expressed by a reduced breaking load in the three-point bending and (2) whether microstructural changes of the newly formed callus are evident by μCT and histology.
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