MONTREAL, Canada–Data from the Canadian Multicentre Osteoporosis Study show that daily use of cyclooxygenase-2 (COX-2) inhibitors decreases bone mineral density (BMD) in men but increases it in postmenopausal women who are not taking estrogen replacement therapy. Reporting in Osteoporosis International, the researchers advise men who have used COX-2 inhibitors to consider having their BMD measured to assess their fracture risk.¹

"Our findings emphasize the important role that prostaglandins (especially PGE2) play mediating bone turnover in humans and how this can affect the development of osteoporosis. Thus, our study emphasizes that prostaglandins can importantly mediate bone formation resulting from mechanical loading, which is a beneficial effect, but can also mediate the proinflammatory state occurring after the menopause, which is a detrimental effect. Therefore, inhibition of COX-2 can lead either to harmful or beneficial effects on bone mass, depending on the sex and the menopausal status of the COX-2 inhibitor recipient," senior author David Goltzman, MD, told CIAOMed.

Dr. Goltzman, who is at the Bone and Calcium Research Laboratories, Royal Victoria Hospital, Montreal, said that his group also found that BMD increased even more in postmenopausal women not taking estrogen who took both a COX-2 inhibitor and aspirin (acetyl salicylic acid, or ASA).

BMD Change Is Clinically Significant In Many Patients

The Canadian investigators analyzed data from 2004 men and 2776 postmenopausal women aged 65 or older who had BMD measurements and underwent a structured interview in the fifth year of the Canadian Multicentre Osteoporosis Study. Daily use of a COX-2 inhibitor was reported in 394 study participants, and 1109 reported daily aspirin use.

In men, daily COX-2 inhibitor use was associated with 2.4% to 5.3% lower BMD in the hip and lumbar spine (although the 95% confidence interval for the lumbar spine crossed the null value). In postmenopausal women not taking estrogen, daily COX-2 inhibitor use was associated with 0.9% to 5.7% higher BMD at the hip and spine, including 3.0% higher BMD at the hip, compared with women who had not taken a COX-2 inhibitor. COX-2 inhibitors had no significant effect on BMD in women who were taking estrogen. The investigators point out that "small changes in BMD (less than 5%) predict large changes in fracture rate."

A few of the subjects (31 men [1.5%] and 54 women [1.9%]) had taken both daily COX-2 inhibitors and aspirin. "Generally, the combined adjusted effect of COX-2 inhibition and ASA use exaggerated the aforementioned relationship between COX-2 inhibition and BMD. In men, the use of both daily ASA and COX-2 inhibitors was associated with a markedly lower BMD at all hip sites and with a possible reduction in BMD at the lumber spine... In women not using estrogen... the addition of daily ASA further increased the effect of COX-2 inhibition in BMD by a factor of 2.4," the authors write.

Study Confirms Role of Inflammation in Postmenopausal Bone Loss

"We were in a sense surprised at the findings because although there is good basic science to support the results, the regulation of bone turnover is so complex that it could be difficult to identify the importance of individual mediators. I believe our ability to see the changes we observed indicates that prostaglandins play a key role that can be clearly identified through the use of COX-2 inhibitors," Dr. Goltzman said.

This study underscores the growing recognition that inflammation plays a major role in postmenopausal bone loss. COX-2 inhibitors such as celecoxib and rofecoxib prevent prostaglandin production, and prostaglandins are central mediators of load-induced bone formation and of menopause-associated bone loss. Repeated mechanical trauma increases PGE2 production, apparently as a result of inducible COX-2 enzyme activity. Estrogen withdrawal ramps up a PGE2-dependent proinflammatory state that results in bone loss. According to Dr. Goltzman, this is because T-cells in postmenopausal women secrete proinflammatory cytokines that trigger osteoblast production of the receptor activator of nuclear factor κB ligand (RANKL), a powerful stimulator of bone resorption. COX-2 appears to protect bone mass in postmenopausal women by decreasing RANKL production.

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