Magnesium depletion adversely affects many phases of skeletal metabolism and has been implicated as a risk factor in several forms of osteoporosis. Magnesium deficiency has also been reported after cardiac transplantation. To evaluate whether altered magnesium homeostasis could be related to the pathogenesis of early bone loss after cardiac transplantation, we prospectively measured serum and urinary magnesium and evaluated them with respect to biochemical indices of mineral metabolism and rates of bone loss. The study population included 60 patients (45 men, 15 women) aged 53 +/- 11 years (SD) with measurements of biochemistries and bone mineral density by dual-energy X-ray absorptiometry before and 3 months after transplantation. All received prednisone, cyclosporine A, and azathioprine, plus calcium (1000 mg) and vitamin D (400 IU). After transplantation, serum magnesium decreased by 16 +/- 15% (SD) from 2. 0 +/- 0.3 mg/dl to 1.6 +/- 0.2 mg/dl (normal 1.8-2.2 mg/dl; p < 0. 0001), accompanied by an increase in the fractional excretion of magnesium (7.1 +/- 3.9% to 13.3 +/- 5.6%; p < 0.0017). Forty-three patients with low 3-month serum magnesium levels (</= 1.7 mg/dl) sustained 41% less bone loss at the lumbar spine (4.0 +/- 4.6% vs. 6. 8 +/- 5.3%; p = 0.051) and 58% less bone loss at the femoral neck (3. 1 +/- 5.9% vs. 7.3 +/- 5.6%; p < 0.01), despite receiving similar doses of prednisone and cyclosporine A. Of the biochemical parameters measured (including renal function, serum calcium, phosphorus, vitamin D metabolites, osteocalcin, urinary calcium, and markers of bone resorption), only intact parathyroid hormone (PTH) levels, which were 40% lower in patients with low serum magnesium levels differed significantly (45 +/- 23 pg/ml vs. 74 +/- 60 pg/ml; p = 0.019). Patients with low serum magnesium levels also had evidence of lower bone turnover. In summary, a highly significant decline in serum magnesium concentrations, associated with continued urinary magnesium losses, occurs after cardiac transplantation. Patients with low serum magnesium levels had significantly lower rates of bone loss, lower serum PTH concentrations, and lower bone turnover. Although the precise mechanisms by which the reduction in serum magnesium tends to protect against bone loss in the early post-transplantation period remain to be elucidated, reduced serum PTH and lower rates of bone turnover are likely to be important factors.