Etanercept does not impair healing in rat models of tendon or metaphyseal bone injury

Abstract

Background and purpose: Should blockade of TNF-α be avoided after orthopedic surgery? Healing of injuries in soft tissues and bone starts with a brief inflammatory phase. Modulation of inflammatory signaling might therefore interfere with healing. For example, Cox inhibitors impair healing in animal models of tendon, ligament, and bone injury, as well as in fracture patients. TNF-α is expressed locally at increased levels during early healing of these tissues. We therefore investigated whether blocking of TNF-α with etanercept influences the healing process in established rat models of injury of tendons and metaphyseal bone.

Methods: Rats were injected with etanercept, 3.5 mg/kg 3 times a week. Healing of transected Achilles tendons and bone healing around screws implanted in the tibial metaphysis were estimated by mechanical testing. Tendons were allowed to heal either with or without mechanical loading. Ectopic bone induction following intramuscular BMP-2 implants has previously been shown to be stimulated by etanercept in rodents. This was now tested as a positive control.

Results: Tendon peak force after 10 days was not significantly influenced by etanercept. Changes exceeding 29% could be excluded with 95% confidence. Likewise, screw pull-out force was not significantly influenced. More than 25% decrease or 18% increase could be excluded with 95% confidence. However, etanercept treatment increased the amount of bone induced by intramuscular BMP-2 implants, as estimated by blind histological scoring.

Interpretation: Etanercept does not appear to impair tendon or metaphyseal bone healing to any substantial degree.

Figure 1.

Peak force (N) at tensile testing of transected tendons that were allowed to heal either with voluntary loading or with muscle paralysis induced by Botox.

Figure 2.

Data from pull-out testing of screws 14 days after insertion in the proximal tibial metaphysis. Etanercept was given early, late, or continuously over the 14-day period.

Figure 3.

Ossicles induced by BMP-2 in a collagen scaffold. Row A: control. Row B: continuously etanercept-treated. Column I: raw image. Column II: low threshold (ossicle size). Column III: high threshold (estimate of bone density).

Figure 4.

Radiographic data from rh-BMP 2 implants, with two different gray-scale thresholds for blind examination. Ossicle size (A) was measured with a low threshold, and “bone area” (B) with a higher threshold, giving a visual impression of being related to bone density. For comparison, both estimates are presented in mm2. Ossicle size was larger with etanercept treatment (pooled; p = 0.02).