Celecoxib, NSAIDs and the skeleton.

Treating acute and chronic musculoskeletal pain is essential for improving healing of traumatic injuries and surgical procedures, and for improving patient quality of life. Physicians are limited primarily to treating musculoskeletal pain with nonsteroidal antiinflammatory drugs (NSAIDs), cyclooxygenase type 2 (COX-2)-selective NSAIDs such as celecoxib, or narcotics. Patients often treat their pain with over-the-counter NSAIDs. Unlike narcotics that target the central nervous system to alleviate pain, NSAIDs inhibit cyclooxygenase activity within the central nervous system and at the peripheral pain site to prevent the conversion of arachidonic acid into prostaglandins. Thus, NSAID use can and does alter certain fundamental processes involved in the normal healing of injured tissues. Cyclooxygenase activity and prostaglandin signaling are critical regulators of normal skeletal metabolism and inflammation related to injury or disease. Since most people only use NSAIDs sporadically to treat pain, few data indicate that short-term or repeated occasional use of NSAIDs is deleterious to skeletal health. However, clinical data suggest that chronic use of celecoxib, may impair normal skeletal function leading to decreased bone mineral density in older male patients. Experimental studies also have documented the negative effects of NSAIDs on healing of skeletal tissues. Fracture healing and tendon-to-bone healing appear to be particularly susceptible to inhibition by celecoxib. Limited retrospective clinical data tends to support the experimental data that COX-2 function is critical for normal bone healing. In contrast, NSAID use and perhaps COX-2-selective NSAID use may be beneficial for healing of other skeletal injuries. In particular, NSAID use does not appear to have a long-term negative effect on the ultimate healing of tendons and ligaments. Indeed, NSAID therapy may inhibit adhesion formation during tendon healing, which leads to a better functional recovery. Certainly, NSAID therapy following acetabular fractures, other hip fractures, or following hip replacement surgery is beneficial for reducing heterotopic ossification that can limit joint mobility. The effects of NSAID or celecoxib therapy on healing of other skeletal tissues is less clear. For instance, clinical data indicates that celecoxib therapy does not impair spinal fusion but experimental data indicates the opposite. Similarly, some reports suggest that NSAID therapy may prevent further erosion of cartilage in certain arthritic conditions while other reports indicate that NSAID treatment will exacerbate cartilage damage. The difference in effects caused by NSAID or celecoxib therapy likely relate to the role cyclooxygenase has in the biology of the injured tissue or its healing response. Differences in pharmacology between NSAIDs, treatment regimens, experimental models and potential off-target effects also may confuse many of these issues. It is clear, however, that cyclooxygenase activity is involved in the healing of many skeletal tissues, either directly or indirectly through modulation of the inflammatory response. Consequently, pharmacological manipulation of cyclooxygenase using NSAIDs or celecoxib can profoundly affect skeletal health.