ROCHESTER, Minnesota—TNF-α and interleukin-1 (IL-1) not only contribute to the rheumatoid arthritis (RA) disease process, but also play independent roles in postmenopausal bone loss, Mayo Clinic researchers report in the Journal of Bone and Mineral Research.1 Lead author Natthinee Charatcharoenwitthaya, MD, et al show for the first time that blocking either of these two cytokines in humans reduces postmenopausal bone resorption. The researchers are with the Mayo Clinic College of Medicine, in Rochester, Minnesota.

"The main cause of osteoporosis in postmenopausal women and, to a lesser extent, in aging men is estrogen deficiency. This explains in part the mechanism of the bone loss and offers a potentially new approach for intervention."—B. Lawrence Riggs, Jr, MD.
"It is of interest that blocking the action of either TNF-α or IL-1 resulted in a decrease in serum CTX [carboxyl-terminal telopeptide of type 1 collagen, a marker for resorption] by about one half. Whether simultaneous blockade of both cytokines would have resulted in a near complete suppression in the rise in bone resportion markers after induction of acute estrogen deficiency is unclear," the investigators write.

Etanercept or anakinra given after cessation of estrogen withdrawal

The investigators enrolled 42 early postmenopausal women (1 to 10 years after cessation of menstruation) who were initially treated with transdermal estradiol (.1 mg/d for 60 days).The women were then randomized to one of three intervention groups: one receiving .9% saline injections for 3 weeks (control group), one receiving anakinra (100 mg/d; Kineret®, Amgen Inc), and one receiving etanercept (25 mg/twice weekly; EnbrelR, Amgen Wyeth Pharmaceuticals).

Outcome measures were bone resorption, assessed by levels of CTX and NTX (amino-terminal telopeptide of type 1 collagen), and bone formation, assessed by level of PINP (amino-terminal propeptide of type 1 collagen). These measures were taken during the last 2 days of estrogen treatment and again on days 20 and 21 of intervention.

The researchers found that etanercept significantly reduced the increase in both bone resorption markers (P = .034 for CTX, P = .048 for NTX). Anakinra reduced the increase of CTX to just below the level of significance (P = .048).

"On discontinuation of estrogen treatment in the control group, serum CTX and urine NTX increased by 43% and 12%, respectively. Compared with controls, both anakinra and etanercept treatment reduced the rise in serum CTX observed in the control group by about one half," the authors write. Serum PINP, the marker for new bone formation, decreased by 41% in the control group after estrogen withdrawal. This decline was reduced in both treatment groups, but the change did not reach statistical significance.

Senior author B. Lawrence Riggs, Jr, MD, told CIAOMed that these data suggest that women with RA, who are already taking etanercept of anakinra, might be getting extra benefit in terms of bone preservation. "Patients with RA have an increased incidence of osteoporosis, even when adjusting for steroid usage and decreased activity," he said.

Dr. Riggs also said that this study helps fill in an important part of the picture of osteoporosis. "The main cause of osteoporosis in postmenopausal women and, to a lesser extent, in aging men is estrogen deficiency. This explains in part the mechanism of the bone loss and offers a potentially new approach for intervention," he said.

However, Dr. Riggs warned that since toxicity concerns precluded testing anakinra and etanercept concurrently in this study, potential roles for other cytokines, such as RANK ligand, cannot be ruled out.

Reference

1. Charatcharoenwitthaya N, Khosla S, Atkinson EJ, et al. Effect of blockade of TNF-α and interleukin-1 action on bone resorption in early postmenopausal women. J Bone Miner Res. 2007;22:724-729.