NSAIDs and COX-2 inhibitors impede tendon, bone and cartilage repair

NSAIDs are not appropriate for neurogenic pain with no prostaglandin-mediated inflammation.

INNSBRUCK, Austria — Recent biochemical research suggests that NSAIDs are appropriate for prostaglandin- mediated inflammation, not “neurogenic inflammation” associated with tendinopathy.

The upshot: COX-2 inhibitors impair tendon and bone healing, two leading experts said.

Physicians have typically treated patients with tendinopathy but no inflammation with NSAIDs. However, there are certain chemical and genetic factors that discourage NSAID use in some patients, said Hakan Alfredson, MD, of the University of Umea, Sweden.

“In earlier days, the only information we had to rely on was the information from biopsies,” Alfredson said at the 12th ESSKA Congress, here. “And those biopsies showed us irregular fiber structure, high concentrations of matrix, vascular ingrowth but no inflammatory cell traits. But, despite that, we gave these patients tons of NSAIDs. … We wanted to use a new method to try to evaluate whether there was any inflammation in these tendons.”

In vivo microdialysis

“If you use NSAIDs together with proteins, certain NSAIDs virtually block the protein synthesis in the muscle.”
— Hakan Alfredson, MD

Using in vivo microdialysis to study the biochemical properties of affected tendons, Alfredson and his colleagues tested 20 patients with tendinopathy and painful knee function. The control group included 12 patients with normal tendons and no pain. Another arm of the study focused on six patients with jumper’s knee. The control group had six patients with normal tendons, Alfredson said.

The specialists also assessed patients for prostaglandin E2, which is “essential for a so-called chemical inflammation,” Alfredson said. They found that prostaglandin E2 levels did not differ between the chronic painful tendons and the normal, pain-free tendons.

“So, the conclusion from those studies was that there is no prostaglandin-mediated inflammation inside those tendons,” he said.

Studying 1,178 knees, Alfredson’s group found that several pro-inflammatory cell proteins were not regulated in the tissue, again suggesting no prostaglandin-mediated inflammation in the tendons, Alfredson said.

“It cannot be justified to treat your patients with NSAIDs with this background,” Alfredson said. “It’s also important to remember that certain NSAIDs have negative effects on muscle protein metabolism. So, if you use NSAIDs together with proteins, certain NSAIDs virtually block the protein synthesis in the muscle, so that’s another negative factor.”

NSAIDs also inhibit tenocytes and, during exercise, decrease blood flow, Alfredson said. Other factors include heavy vascularity and “neurogenic inflammation,” as opposed to prostaglandin-mediated inflammation.

The benefits of prostaglandins

Norwegian specialist Sigbjørn Dimmen, MD, also noted the value of prostaglandins, which are “responsible for ensuring balance between bone resorption and bone formation.” Decreased prostaglandin may impair bone healing, and the COX-2 enzyme is critical for fracture healing, he said.

Dimmen and his group tested how short-term doses of parecoxib, a COX-2 inhibitor, and indomethacin, a COX-1 inhibitor, affect long-bone fracture healing. The parecoxib and indomethacin groups had lower bone mineral density than the control group.

Also, mechanical testing showed the parecoxib group and control group demonstrated significant differences in all properties, Dimmen said. However, parecoxib proved more detrimental.

“So, our findings with parecoxib had the higher delay in the fracture healing than indomethacin, with the assumption that the COX-2 enzyme is responsible for impaired fracture healing,” he said.

“Never give NSAIDs for stress fractures or for cartilage damage. NSAIDs hate chondrocytes.”
— Sigbjørn Dimmen, MD

No prospective, randomized clinical trials or evidence-based measurements have addressed the effects of NSAIDs and COX-2 inhibitors on long-bone fractures, Dimmen said. Some data show NSAIDs and COX-2 inhibitors cause no nonunions in acetabular fractures, which “might indicate that you can’t see any negative effects from NSAIDs or COX-2 inhibitors in fractures which normally heal well,” Dimmen said.

However, he advised colleagues to avoid NSAIDs or COX-2 inhibitors when treating stress fractures or even when repairing cartilage.

“We know that prostaglandins are necessary for fracture healing,” Dimmen said. “We know that COX-2 is critically involved in fracture healing in the first 3 weeks after a fracture. And NSAIDs and COX-2 inhibitors both impair fracture healing.

“I think one should probably avoid NSAIDs and COX-2 inhibitors in all shock fractures and also other fractures requiring unimpaired fracture healing,” he added. “Never give NSAIDs for stress fractures or for cartilage damage. NSAIDs hate chondrocytes.”

For more information:
  • Alfredson H, Dimmen S. Non-steriodal anti-inflammatory drugs and tissue healing. Mini symposium. Presented at the 12th ESSKA Congress and 5th World Congress on Sports Trauma. May 24-27, 2006. Innsbruck, Austria.