NSAID therapy effects on healing of bone, tendon, and the enthesis

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of skeletal injuries. The ability of NSAIDs to reduce pain and inflammation is well-established. However, the effects of NSAID therapy on healing of skeletal injuries is less defined. NSAIDs inhibit cyclooxygenase activity to reduce synthesis of prostaglandins, which are proinflammatory, lipid-signaling molecules. Inhibition of cyclooxygenase activity can impact many physiological processes. The effects of NSAID therapy on healing of bone, tendon, and the tendon-to-bone junction (enthesis) have been studied in animal and cell culture models, but human studies are few. Use of different NSAIDs with different pharmacological properties, differences in dosing regimens, and differences in study models and outcome measures have complicated comparisons between studies. In this review, we summarize the mechanisms by which bone, tendon, and enthesis healing occurs, and describe the effects of NSAID therapy on each of these processes. Determining the impact of NSAID therapy on healing of skeletal tissues will enable clinicians to appropriately manage the patient's condition and improve healing outcomes.

Keywords: cyclooxygenase; fracture healing; nonsteroidal anti-inflammatory drugs; tendon healing; tissue repair.

Fig. 1.

Arachidonic acid metabolism and signaling. Summarized are 3 of the 4 major arachidonic acid metabolic pathways: the Land's cycle, conversion into prostaglandins which requires cyclooxygenase activity, and conversion into leukotrienes and lipoxins via 5-lipoxygenase activity. Not shown is cytochrome P-450 metabolism of arachidonic acid. Enzyme or enzymatic processes are shown in red text, substrates and products are shown in black text, and G protein-cell surface receptors are shown in green text. Known effects of receptor activation on downstream cyclic adenosine monophosphate (cAMP) or intracellular calcium levels are shown at the bottom. COX-1, cyclooxygenase-1; COX-2, cyclooxygenase-2; 5-LO, 5-lipoxygenase; FLAP, 5-lipoxygenase activating protein; PGH₂, PGD₂, PGE₂, PGF_2a, and PGI₂, are prostaglandins H₂, D₂, E₂, F_2a, and I₂, respectively; TXA₂: thromboxane A₂; 5-HpETE, 5S-hydroperoxy-6E,8Z,11Z,14Z-eicosatetraenoic acid; 5-HETE, 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid; LTA₄, LTB₄, LTC₄, LTD₄, and LTE₄ are leukotrienes A₄, B₄, C₄, D₄, and E₄, respectively; LXA₄ and LXB₄, lipoxins A₄ and B₄; DP1, EP1-EP4, FP, and IP, prostaglandin receptors; TP, thromboxane A₂ receptor; BLT₁ and BLT₂, leukotriene B₄ receptor; CysLT1 and CysLT2: cysteinyl leukotriene receptors; ALXR: lipoxins receptor.

Fig. 2.

Model of COX-2 function during fracture healing. During fracture healing, mesenchymal cells recruited to the fracture site can differentiate into chondrocytes in the absence of COX-2. However, COX-2 activity is required for the chondrocytes to progress into hypertrophy during which the hypertrophic chondrocytes secrete angiogenic and osteoclastogenic factors necessary for endochondral ossification. Whether COX-2 functions cell autonomously, in a cell-dependent manner via prostaglandin signaling, or using a combination of both remains to be determined. VEGF, vascular endothelia growth factor; Cyr61, also called CCN2; RANKL, receptor activator of nuclear factor kappa-B ligand.