Background: Heterotopic ossification is a common feature that follows total hip arthroplasty, and affects up to 70% of patients with clinical implications, such as pain and restricted hip movements. Previous clinical observation showed negligible heterotopic ossification in our patients who underwent total hip arthroplasty due to familial Mediterranean fever, and received colchicines on a daily basis.

Aims: To evaluate in vitro, in vivo and during clinical studies whether colchicines, given on a prophylactic daily basis to all total hip arthroplasty patients, was responsible for the negligible heterotopic ossification.

Methods: In vitro: cell lines of fibroblasts and osteoblasts were cultured with increasing concentrations of colchicines. Direct cell counts [3H]thymidine uptake, and mineralization were measure. In vivo: heterotopic ossification was induced in the thigh muscle of rabbits by injecting bone marrow. Animals were given colchicines, and X-ray radiographs, ultrasound the histological studies measured its effect on heterotopic ossification. Clinical study: Fifty-two patients admitted for total hip arthroplasty were randomly selected to receive colchicines on a daily basis, starting 10 days pre-operatively, and 6 weeks postoperatively. Clinical evaluation was made according to Harris Hip Score and heterotopic ossification according to Brooker classification.

Results: In vitro: colchicines was found to be a strong, nonselective inhibitor of cell proliferation, and an even greater inhibitor of tissue mineralization. In vivo: statistically significant reduction in the amount of hetero-topic ossification induced in the thigh muscle of rabbits was measured in the groups that received colchicines. Clinical study: Patients who received colchicines pre-operatively developed a negligible amount of hetero-topic ossification after total hip arthroplasty at 1-year follow-up without adversely affecting the Harris Hip Score.

Conclusions: Colchicine is a strong inhibitor of cell proliferation and tissue mineralization, and an effective means of reducing heterotopic ossification after total hip arthroplasty. These effects may be used in other bone-forming processes: after hip/pelvic trauma, head injury, and possibly in other bone-forming conditions.

Colchicine is often used in the treatment of diseases such as familial Mediterranean fever (FMF) and gout. We have previously reported that patients with FMF who had colchicine on a daily basis and who had a total hip arthroplasty showed no heterotopic ossification after surgery. The mechanism by which colchicine causes this clinical phenomenon has never been elucidated. We therefore evaluated the effect of various concentrations of colchicine on cell proliferation and mineralisation in tissue culture, using rat and human cells with and without osteogenic potential. Cell proliferation was assessed by direct cell counts and uptake of (³H)thymidine, and mineralisation by measuring the amount of staining by Alizarin Red.

Our findings indicate that concentrations of colchicine of up to 3 ng/ml did not affect cell proliferation but inhibition was observed at 10 to 30 ng/ml. Mineralisation decreased to almost 50%, which was the maximum inhibition observed, at concentrations of colchicine of 2.5 ng/ml. These results indicate that colchicine at low concentrations, of up to 3 ng/ml, has the capacity to inhibit selectively bone-like cell mineralisation in culture, without affecting cell proliferation. Further clinical and laboratory studies are necessary to evaluate the effects of colchicine on biological processes involving the proliferation of osteoblasts and tissue mineralisation in vivo, such as the healing of fractures, the formation of heterotopic bone and neoplastic bone growth.