Osteopetrosis: pathogenesis and rationale for the use of interferon-γ-1b

Congenital osteopetrosis is a group of disorders resulting in decreased osteoclastic function and hence decreased bone resorption. Various medical treatments have been attempted to ameliorate the osteopetrotic condition. A calcium-deficient diet has limited further sclerosis in some patients. Prednisone therapy has improved haematological function in some patients, but has not resulted in a reduction in bone mass. Calcitrophic hormones, such as parathyroid hormone (PTH) infusions and oral calcitriol, stimulate osteoclastic activity, and calcitriol in particular has stimulated osteoclastic bone resorption in some patients with osteopetrosis. Bone marrow transplantation, although curative, is limited by paucity of donors, risk of graft-versus-host disease and relapse of the disease. The demonstration of defective leucocyte superoxide production in osteopetrotic patients and the premise that osteoclasts appear to arise from the granulocyte macrophage lineage have led to attempts at treating osteopetrosis with immunomodulators. Since treatment with recombinant interferon-γ-1b (interferon γ-1b, IFNγ-1b) has resulted in increased level of superoxide generation and clinical improvement in chronic granulomatous disease, a similar strategy has been employed using IFNγ-1b to treat patients with osteopetrosis. IFNγ-1b has been demonstrated to increase osteoclastic bone resorption and leucocytic function. Long term therapy with IFNγ-1b by subcutaneous injection 3 times weekly resulted in marked clinical improvement, a decreased incidence of infections, a decreased trabecular bone mass, and an increased marrow space resulting in improved haemopoiesis. The therapy has been associated with few adverse effects, mainly fever and diarrhoea which have been managed with a reduction in IFNγ-1b dosage. The low-calcium diet occasionally results in hypocalcaemic tetany, which may be corrected by increased dietary calcium intake. Thus, IFNγ-1b has a distinct place in the therapeutic armamentarium for patients with osteopetrosis and is a feasible treatment option in such patients.