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Cyclosporine A (CsA) induces high turnover osteopenia in the rat and there is evidence for this in humans. Recent studies suggest that increases in parathyroid hormone (PTH) may be involved in posttransplantation bone loss. However, human studies are difficult to interpret since transplant patients usually receive a cocktail of immunosuppressants and have underlying disease. Our aim was to try to resolve the influence of the absence or presence of PTH on CsA-induced bone disease. Male Sprague Dawley rats aged 7-9 months, either sham operated or parathyroidectomized (PTX), were randomly divided into vehicle and CsA groups. All PTX rats were given oral calcium supplementation ad libitum. The rats were divided into groups: basal, sham/vehicle, sham/CsA, PTX/vehicle, and PTX/CsA. Serial biochemistry was performed 0, 14, and 28 days after the start of the experimental period; bone histomorphometry was performed 28 days after the start of the experimental period. Statistical analysis consisted of group comparisons and factorial analyses. The results showed that CsA alone produced a high turnover osteopenia consistent with previous studies. In the PTX animals there was an increase in bone mass. PTX also decreased osteoblast activity and recruitment, and serum 1,25OH2D levels. Serum levels of osteocalcin (BGP) were unaffected by PTX. The combination group (PTX/CsA) did not differ statistically from the controls in most of the histomorphometric parameters measured, with the exception of reduced mineral apposition and bone formation rates, reflecting the effects of PTX. Serum BGP and 1,25OH2D levels did not differ, but PTH was reduced from the control. Explanations for these results are (1) CsA and PTX exert their effects via separate mechanisms, negating each other; (2) in the absence of PTH, CsA managed to cause bone loss, and thus PTH may not be essential for CsA-induced bone loss; or (3) the profound accelerated bone loss produced by CsA in normal rats requires PTH. These findings may help explain the discrepancies found in clinical studies where bone loss occurs with either elevated or normal PTH levels.

Background: Posttransplantation bone disease is a well-described phenomenon; among its etiology is immunosuppressant-induced bone disease. Mycophenolate mofetil (MMF) has emerged as a promising new immunosuppressant. Our study was designed to investigate the effect of MMF on in vivo bone mineral metabolism., Methods: Twenty-four 6-month-old male Sprague-Dawley rats were randomized into two groups to receive either MMF vehicle daily for 28 days or 30 mg/kg MMF daily for 28 days. The serum was assayed for osteocalcin and 1,25-dihydroxy vitamin D3. Subsequent to double-labeling, the right tibiae were removed on day 28 for histomorphometry., Results: MMF suppressed bone gla protein (osteocalcin) levels on days 14 and 28 (P < 0.05). Except for percentage osteoid perimeter, there was no difference in bone histomorphometry between the two groups., Conclusion: In this relatively short-term study, MMF did not cause osteopenia in the rat model, but the suppressed bone gla protein merits further study.