Regulation of bone metabolism in immunosuppressant (FK506)-treated rats

Abstract

After organ transplantation, severe osteoporosis is occasionally seen, and the use of immunosuppressants is thought to be one of the causes of such osteoporosis. In the present study, we investigated the effects of FK506 monotherapy on bones and determined the mechanism of onset of osteoporosis, both by assessing chronological changes in bone metabolism and by identifying factors that facilitate bone resorption. In 8-week-old male Sprague-Dawley rats, FK506 (1 mg/kg) was injected intraperitoneally every day for 5 weeks (FK506-treated group), and for comparison, physiological saline was administered in the same manner in a control group of rats. Serum and urine samples were collected at weeks 0, 1, 3, and 5 of administration. The femur and tibia were collected within 24 h of the final administration. When compared to the control group, findings on three-dimensional micro-computed tomography of the femur for the FK506-treated group showed a significant decrease in trabecular bone volume. The level of serum osteocalcin in the FK506-treated group at week 1 of administration was significantly higher than the control. Throughout the administration period, the sum of urinary pyridinoline (PYD) and deoxypyridinoline (Dpd) was significantly higher in the FK506-treated group. Of the various bone resorption factors tested, the level of serum parathyroid hormone (PTH) in the FK506-treated group was significantly higher than the control at week 3 of administration. The results of the present study confirmed that FK506 monotherapy in rats induced high-turnover osteoporosis. Soon after the start of FK506 administration, bone formation and resorption were elevated, and PTH appeared to have been involved in the maintenance of the elevated bone resorption.

Pathogenesis and Prevention of Bone Loss in Patients Who Have Kidney Disease and Receive Long-Term Immunosuppression

“…Testosterone did not retard the changes significantly (59). Effects of tacrolimus in the same rat model are broadly similar to those of cyclosporine (60). Clinically, there is more uncertainty.…”

Contribution of Intestinal Calcium Absorption to 1,25-Dihydroxyvitamin D3-Induced Calcium Action in the Total Parenteral Nutrition Rat

“…Regarding the response of the urinary Dpd in rats, Dpd produced a marked continuous increase from one week to five weeks after dosing, whereas serum Ca and BGP produced a marked increase in one or 3 week (its peak) (Kirino et al, 2004). These changes in Dpd reflect the high constancy of Dpd, and it was considered the marker that needs time in order to reflect change of bone resorption (Tsuruoka et al, 2002).…”

Osteoporose após transplante de órgãos sólidos

“…investigaram as ações do tacrolimus sobre o metabolismo mineral ósseo. Nesse estudo caso-controle, os autores administraram tacrolimus por 6 semanas a cobaias e verificaram que: 1) após um aumento inicial da concentração sérica de osteocalcina, o tacrolimus provocou diminuição deste marcador de formação óssea para níveis inferiores ao basal, enquanto que as concentrações urinárias de piridinolina e de desoxipiridinolina foram progressivamente maiores; 2) a calcemia manteve-se constante ao longo do estudo apesar do significativo aumento da calciúria; 3) na 3ª semana, o nível sérico de PTH já era significativamente maior nas cobaias submetidas ao imunossupressor; 4) comparado com o grupo controle, as cobaias apresentavam trabéculas ósseas mais estreitas, cavidade medular mais ampla em algumas regiões e relação do volume ósseo com o volume tissular bastante diminuída (16). A ciclosporina causa elevação da osteocalcina e da 1,25(OH) 2 D 3 , além de diminuição da testosterona (17,18).…”