Increased bone marrow-specific adipogenesis by clofazimine causes impaired fracture healing, osteopenia and osteonecrosis without extra-skeletal effects in rats.

Mycobacterium leprae infection causes bone lesions and osteoporosis, however, the effect of anti-leprosy drugs on the bone is unknown. We, therefore, set out to address it by investigating osteogenic differentiation from bone marrow (BM)-derived mesenchyme stem cells (MSCs). Out of seven anti-leprosy drugs, only clofazimine (CFZ) reduced MSCs viability (IC50 ∼1μM) and their osteogenic differentiation but increased adipogenic differentiation on a par with rosiglitazone, and this effect was blocked by a peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, GW9662. CFZ also decreased osteoblast viability and resulted in impaired bone regeneration in a rat femur osteotomy model at 1/3rd human drug dose owing to increased callus adipogenesis as GW9662 prevented this effect. CFZ treatment decreased BM-MSCs population and homing of MSCs to osteotomy site despite drug levels in BM being much less than it's in vitro IC50 value. In adult rats, CFZ caused osteopenia in long bones marked by suppressed osteoblast function due to enhanced adipogenesis and increased osteoclast functions. A robust increase in marrow adipose tissue (MAT) by CFZ did not alter hematologic parameters but likely reduced BM vascular bed leading to osteonecrosis (ON) characterized by empty osteocyte lacunae. However, CFZ had no effect on visceral fat content and was not associated with any metabolic and hematologic changes. Levels of unsaturated fatty acids in MAT were higher than saturated fatty acids and CFZ further increased the former. From these data, we conclude that CFZ has skeletal toxicity and could be used for creating a rodent ON model devoid of extra-skeletal effects.