Free radical scavengers versus methylprednisolone in the prevention of experimentally induced heterotopic ossification

Abstract

The etiology of heterotopic ossification (HO) is still obscure, it is difficult to devise an effective preventive or therapeutic approach. The options for the prevention of HO are still limited. The prophylactic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is insufficient. Moreover, NSAIDs increase the risk of nonunion and loosening in patients with multiple joint injuries. The present experimental study was designed to compare methylprednisolone with free radical scavengers for the prevention of HO. The model of Michelsson et al. was used to induce HO in the hind legs of 30 female New Zealand albino rabbits, weighing approx. 4 kg. The animals were randomized into three groups of 10 animals each, and received daily either placebo, a free radical scavenger cocktail [allopurinol and Nacetylcysteine (A/A)], or methylprednisolone in a randomized, double-blind fashion. Every four days, X-rays were obtained to measure the thickness and the length of new bone formation at the thigh. A statistically significant difference in thickness and length of newly formed bone was found between the three groups. In the placebo group HO increased from day 16 toward a medium length of 6 mm and a median thickness of 1.5 mm. In the A/A group, no signs of HO were found. In the methylprednisolone group, only one animal presented minor HO from day 32. Both free radical scavengers and methylprednisolone were found to inhibit HO, and may be considered effective measures for the prevention of heterotopic bone formation. However, it could not be demonstrated which of the two had the strongest inhibitory effect. Keywords: methylprednisolone; free radical scavengers; heterotopic ossification; prevention Strictly defined, heterotopic ossification (HO) is the formation of lamellar bone inside soft-tissue structures where bone normally does not exist. Myositis ossificans rather refers to a condition in which ectopic bone is formed within muscle or connective tissue following chemical or physical trauma.1-3 However, this term has fallen into disfavor because primary muscle inflammation is not necessarily a precursor, and ossification does not always occur in muscle tissue. For these reasons, the term heterotopic ossification has largely replaced myositis ossificans in the literature. 4 HO frequently complicates central nervous system disorders such as brain and spinal cord injuries, brain tumors, and encephalitis.5 HO is of common occurrence in orthopedic patients as a consequence of hip, knee, shoulder, and elbow arthroplasty. The reported incidence of HO after hip arthroplasty is as high as 53%. 6,7 Patients with a history of osteoarthritis, ankylosing spondylitis, diffuse idiopathic skeletal hyperostosis, and Paget's disease are at high risk for HO. The condition is also frequently present in burn patients, and has recently been reported to occur after long-term mechanical ventilation following trauma. 8Because nonsteroidal anti-inflammatory drugs (NSAIDs) have important systemic side effects and may increase the risk of ps...

Challenges of heterotopic ossification—Molecular background and current treatment strategies

“…Free radicals are extremely reactive and unstable complexes that can cause oxidative damage to cells and accelerate the process of heterotopic bone formation. Combined allopurinol and N‐acetylcysteine were used in a rabbit model of HO and showed preventive properties against HO formation equal to the effects of methylprednisolone …”

Patellar tendon ossification after retrograde intramedullary nailing for distal femoral shaft fracture

“…Additionally, radical rehabilitation training may cause small micro tears in the tendon, resulting in bleeding and inflammation. [ 21 , 22 ] We think that these hematomas and the inflammatory factor are the osteogenic inducer, which makes up the environment of the bone formation, results in forming further bone formation in the bone bed and tendon. However, the heterotopic ossification of the quadriceps tendon and the medial collateral ligament of the knee could not be explained by these theories.…”

Pharmacological treatment of heterotopic ossification following hip surgery: an update

“…Based on the latter assumption, FR scavengers like the combined allopurinol and N-acetylcysteine (A/A) may prevent HO formation. Limited in vivo data indicate that A/A is superior to indomethacin [16] and equivalent to methylprednisolone in preventing experimentally induced HO in rodents [17]. Two randomized, controlled trials comparing etidronate disodium versus placebo were reviewed recently by Haran and colleagues in Cochrane Reviews, showing that etidronate disodium delays rather than prevents HO mineralization [18].…”