The effect of long-term L-thyroxine (LT4) replacement therapy on bone mineral density and on biochemical markers of bone turnover were studied in children with congenital hypothyroidism (CH). Forty-four children and adolescents (mean age 8.5 +/- 3.5 years) with primary CH who began LT4 replacement therapy within the first month of life were studied. Bone mineral density (BMD) of the lumbar vertebrae and the upper femoral bone was measured by dual energy X-ray absorptiometry. Serum osteocalcin (OC) and bone alkaline phosphatase were measured as markers of bone formation and urinary deoxypyridinoline was taken as a marker of bone resorption. Bone mineral densities of CH children were not different from those in age-matched controls. The biochemical markers of bone turnover were normal except for the serum OC levels which were found to be higher than in controls and positively correlated with the free thyroid hormone levels (for FT4 r = 0.42, p = 0.02). Eight CH children demonstrated low BMD values (below -1 SDS) at -2 +/- 0.7 SDS for the lumbar spine and -1.6 +/- 0.5 SDS for the femoral site. These eight children showed lower mean weight (p < 0.05) and their dietary calcium intake tended to be less (p <0.06) than that seen in the normal BMD group. In conclusion, our results show that LT4 replacement therapy for 8 years is not detrimental to the skeletal mineralization of CH children. As in a healthy population, weight and current intake of calcium seem to be major determinants of bone density. Dietary recommendations, especially when calcium intake is below the recommended dietary allowance, may have to be reconsidered.