tacrolimus and Bone-Diseases--Metabolic

CYP3A enzymes are involved in the metabolism of calcineurin inhibitor tacrolimus as well as vitamin D. In this review, we summarize the clinical aspects of CYP3A-mediated metabolism of tacrolimus and vitamin D with emphasis on the influence of single-nucleotide polymorphisms on tacrolimus disposition. We describe the utility of 4β hydroxycholesterol as a marker of CYP3A activity. Then, we discuss the possible interaction between calcineurin inhibitors and vitamin D in solid organ transplant recipients. Also, we review other mechanisms which may contribute to side effects of calcineurin inhibitors on bone. Lastly, suggestions for future research and clinical perspectives are discussed.

Topics: Animals; Biomarkers; Bone Density; Bone Diseases, Metabolic; Calcineurin Inhibitors; Cytochrome P-450 CYP3A; Humans; Hydroxycholesterols; Kidney Transplantation; Polymorphism, Single Nucleotide; Tacrolimus; Vitamin D

We performed a prospective, randomized, double-blind study to determine whether calcium and calcitriol prevents posttransplant bone loss. Thirty-eight nondiabetic and 26 diabetic patients without prior steroid exposure undergoing their first kidney or kidney-pancreas transplant were randomized to calcium, calcium plus calcitriol, or placebo. Lumbar spine (LS), femoral neck (FN), and distal radius (DR) bone mineral density scans (BMDs) were obtained at baseline, 6, and 12 months. At 1 year, patients treated with placebo experienced a 2% decline in BMD at the LS and DR and a 1.3% increase at the FN. In contrast, patients treated with calcium and vitamin D had a 0.1% decline at the LS and 2.9% and 4.8% increases at the DR and FN, respectively. Patients receiving cyclosporine had more bone loss than those receiving tacrolimus. Our results demonstrate a small therapeutic effect of calcium and calcitriol and suggest that tacrolimus is less osteotoxic than cyclosporine.

Topics: Absorptiometry, Photon; Bone Density; Bone Diseases, Metabolic; Calcitriol; Calcium; Calcium Channel Agonists; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Femur Neck; Humans; Immunosuppressive Agents; Kidney Transplantation; Lumbar Vertebrae; Pancreas Transplantation; Radius; Tacrolimus; Vitamin D

Topics: Alkaline Phosphatase; Bilirubin; Bone Diseases, Metabolic; Creatinine; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Parathyroid Hormone; Phosphates; Tacrolimus; Time Factors

Tacrolimus, a calcineurin inhibitor, affects bone metabolism and increases the risk of fracture due to marked bone loss. Bisphosphonates increase the bone mineral density (BMD) in osteoporosis patients. Menatetrenone has less positive effects on BMD but reduces the risk of fracture by improving bone quality. In this study, we investigated the effectiveness of the combined administration of risedronate and menatetrenone against bone loss induced by tacrolimus. Wistar rats were divided into four groups: [1] control, [2] tacrolimus at 1.5 mg/kg, [3] tacrolimus + risedronate at 1.0 mg/kg, and [4] tacrolimus + risedronate + menatetrenone at 20 mg/kg. After the drugs were administered for 4 weeks, bone histomorphometric analysis was performed and bone strength was evaluated using a three point bending method. BMD was measured using quantitative computed tomography. Tacrolimus significantly reduced the BMD and strength properties of the lower limb bones. These tacrolimusinduced decreases were suppressed by risedronate treatment. The combined administration of risedronate and menatetrenone more significantly improved bone strength properties than risedronate alone. Bone histomorphometric analysis revealed a significant increase in bone resorption with tacrolimus. Risedronate alone significantly suppressed the tacrolimus-induced increase in bone resorption but simultaneously reduced bone formation. On the other hand, the combined administration of risedronate and menatetrenone suppressed the tacrolimus-induced increase in bone resorption, in addition to the significant risedronate-induced decrease in bone formation. This study suggests that the combined administration of risedronate and menatetrenone improves bone strength in tacrolimus-treated rats by preventing and ameliorating the risedronate-induced suppression of bone formation.

Topics: Animals; Bone Density; Bone Diseases, Metabolic; Drug Therapy, Combination; Femur; Immunosuppressive Agents; Male; Osteogenesis; Rats, Wistar; Risedronic Acid; Tacrolimus; Tibia; Vitamin K 2

Our laboratory has demonstrated that the immunosuppressants Cyclosporin A (CsA) and tacrolimus (FK506), in vivo in the rat, produce a high-turnover osteopenia. CsA is known to decrease serum testosterone (Test) levels both in the rat and in human transplant patients. Less is known of FK506's effect on androgens. CsA-induced hypogonadism may contribute to the aforementioned bone loss because hypogonadism itself is a risk factor for osteoporosis and fracture. The aim of this study was to assess serum androgen levels following CsA and FK506 therapy and to see wether Test replacement therapy, in the form of 28-day controlled release subcutaneous pellet implants, could prevent CsA-induced osteopenia. Two experiments were conducted. In experiment I, four groups of 6-month-old male Sprague-Dawley rats received the following: (A) CsA vehicle and placebo pellet, (B) Test 15 mg pellet and CsA vehicle, (C) CsA 10 mg/kg and placebo pellet, (D) Test 15 mg pellet and CsA 10 mg/kg. In experiment II, two groups of rats received (E) FK506 vehicle and (F) FK506 4 mg/kg. CsA, FK506, and vehicles were given for 28 days by daily oral gavage. The rats were weighted and bled on days 0, 14, and 28. All rats received double fluorescent labeling, and on day 28 the tibiae were removed for histomorphometry. Whole blood was assayed for CsA and FK506 levels. Serum was assayed for total and free Test as well as for osteocalcin (BGP), blood urea nitrogen (BUN), creatinine, and calcium. Whole blood monoclonal CsA levels measured by fluorescent immunoassay were in the therapeutic range, while a drug concentration profile showed good absorption of FK506. Those rats receiving Test and FK506 lost weight, while those receiving CsA remained constant. BUN was only marginally elevated in the CsA-treated groups on day 28 (p < 0.05), while creatinine was unchanged. On day 28, total and free Test was significantly reduced in the CsA-treated rats versus control (p < 0.05), while Test replacement therapy maintained total Test levels above vehicle (p < 0.01) and free Test levels similar to vehicle on day 28. FK506 did not lower total or free Test levels. BGP levels were significantly increased in the CsA (p < 0.01) and FK506 (p < 0.001) groups on day 28. BGP in the groups receiving Test alone and in combination with CsA remained similar to vehicle. Histomorphometry confirmed CsA- and FK506-induced high-turnover osteopenia. The Test alone group marignally increased bone formation. Test replacement fail

Topics: Animals; Blood Urea Nitrogen; Body Weight; Bone Diseases, Metabolic; Calcium; Creatinine; Cyclosporine; Drug Synergism; Humans; Immunosuppressive Agents; Male; Organ Transplantation; Osteocalcin; Osteoporosis; Rats; Rats, Sprague-Dawley; Tacrolimus; Testosterone