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Calcitriol in prevention and therapy of osteoporosis after liver transplantation
Calcitriol in Prevention and Therapy of Osteoporosis After Liver Transplantation R. Neuhaus, A. Kubo, R. Lohmann, N. Rayes, J. Hierholzer, and P. Neuhaus
O
STEOPOROSIS is a frequent complication of endstage liver disease that often deteriorates after orthotopic liver transplantation (OLT) due to long-term immunosuppression including corticosteroids and other factors like early immobilization. In advanced cases, bone demineralisation increases the susceptibility of atraumatic fractures. Because there is no broadly accepted therapeutic concept for bone demineralisation after OLT the efficacy of calcitriol [1, 25(OH)2D3] in comparatively low dosages, either as single treatment or in combination with elemental calcium, as well as with calcium and a low dose of sodium fluoride, was evaluated in this study. PATIENTS AND METHODS Between 1989 and 1996, 860 patients underwent OLT at the Virchow Clinic, Berlin. Five hundred and nine patients (213 female and 296 male, mean age 47.5 years) were enrolled in this parallel group study. Patients with observation times of less than 24 months were excluded. For the evaluation of postoperative loss of bone mineralisation and for the control of treatment efficacy all patients underwent bone mineral density (BMD) measurements at the lumbar spine (LS) and the femoral neck (FN) by dual-energy x-ray absorptiometry (Lunar DPX Scanner, Lunar Radiation, Madison, Wis), which was initiated before OLT and repeated subsequently in 6-month intervals after transplantation up to 24 months. Therapy started 6 months postoperatively and was followed up for 18 months. Because the degree of bone mineralisation varied considerably between LS and FN both sites were analyzed separately. The results of female and male patients were summarised because no major differences were observed in both groups. Two hundred forty-six patients served as controls, and 283 patients were assigned to five treatment groups. The treated patients received 0.25 mg of calcitriol (group 1, 35 patients), 0.25 mg of calcitriol together with 1000 mg of calcium (group 2, 37 patients), 0.5 mg of calcitriol (group 3, 76 patients), 0.5 mg of calcitriol together with 1000 mg of calcium (group 4, 86 patients), and 0.5 mg calcitriol together with 1000 mg of calcium and a low dose of 25 mg of sodium fluoride (group 5, 49 patients). Baseline immunosuppression was provided by the administration of cyclosporine (310 patients) or tacrolimus (FK 506, 219 patients) initially combined with corticosteroids, which were generally tapered down and withdrawn after 6 to 9 months in the cyclosporine group (cumulative dose '2.3 g) and after 3 to 6 months in the FK 506 group (cumulative dose '1.4 g), depending on graft function. Levels of sex hormones were determined each time BMD was controlled. 0041-1345/99/$–see front matter PII S0041-1345(98)01713-8
RESULTS
Depending on the underlying liver disease significant differences in BMD were observed before OLT. In PBC and PSC, as well as in autoimmune cirrhosis, the lowest values of bone mineralisation at LS and FN were observed. Similarly, after OLT the highest loss of BMD was observed in patients with cholestatic cirrhosis. In addition, PSC patients showed marked demineralisation in the LS. During the first 6 months after OLT cyclosporine-treated patients developed a significantly higher decrease of BMD at the LS (26.3% of BMD) than FK 506 patients (23.5% of BMD). No major differences were observed for the demineralisation at the FN (24.9% of BMD) in the immunosuppressed groups. This correlates with the higher dose of steroids in the cyclosporin-treated patients. Overall, calcitriol led to an improvement of BMD at both measurement sites in all treatment groups, or at least prevented further demineralisation. Patients treated with 0.5 mg of calcitriol (treatment groups 3 and 4) showed superior results in regard to LS and the FN than patients treated with 0.25 mg. In groups 3 and 4 the mean increment rate of BMD was 10% for the LS and 5.6% for the FN. In contrast, patients in group 1 showed an increment rate of only 5.6% for the LS. The increment rate of 4% for the FN was even lower. Slightly better results were obtained in group 2 with an increment rate of 7.3% for the LS and 3.9% for the FN. Group 5 showed the best results for both sites. While the increment rate of 10.7% for the LS was insignificantly higher than in groups 3 and 4, BMD in the FN improved with an increment rate of 12.8%. Thus, the special impact of fluoride supplementation for the FN is obvious. The incidence of atraumatic fractures was significantly lower in the treated patients (2 of 238 5 0.7%). In contrast the fracture rate in the control group was threefold higher (7 of 246 5 0.7%). No major side effects occurred under treatment, and serum calcium and phosphorus levels stayed within the normal range. There was no significant difference in testosterone or estrogen levels between the different groups. From the Departments of Surgery (R.N., A.K., R.L., N.R., P.N.), and Radiology (J.H.), Campus Virchow Clinic, Berlin, Germany. Address reprint requests to Dr Ruth Neuhaus, Department of Surgery, Charite´, Campus Virchow Clinic, Humboldt University Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
472
Transplantation Proceedings, 31, 472–473 (1999)
PREVENTION AND THERAPY WITH CALCITRIOL
DISCUSSION
In this study, calcitriol was beneficial for all patients who suffered from osteoporosis after OLT. In contrast to other studies, which could not prove a positive effect of calcitriol on BMD in patients with cholestatic liver diseases,1 BMD improvement in PBC and PSC patients after OLT could be observed. Because glucocorticosteroids play an important role in bone metabolism it is expected that bone demineralisation occurs under long-term therapy with steroids. The deleterious effect on BMD depends on the cumulative daily dose of steroids.2 The higher cumulative daily dose of steroids in cyclosporine treated patients is a possible reason for the augmented bone loss at the LS in these patients as compared with FK 506 –treated patients who received a lower corticosteroid dosage. Similar to Monegal et al,3 we could not demonstrate an important role of testosterone and estrogen levels in the development of osteoporosis after OLT. So far, the best results in the treatment of osteoporosis after OLT have been demonstrated by Valero et al.4 They evaluated only BMD values of the LS. Their patients received 40 IU/d of calcitonin intramuscularly, or 400 mg sodium etidronate orally for 15 days every 3 months. The best increment rates for the LS over 12 months were
473
6.4% in the calcitonin group and 8.2% in the biophosphonate-treated patients. Our best results were achieved with daily doses of 0.5 mg of calcitriol, 1 g of calcium, and 25 mg of sodium fluoride. Increment rates after 18 months were 10.7% for the LS and 12.8% for the femoral neck. High dosages of fluoride were avoided because they may lead to augmented skeletal fragility.5 CONCLUSIONS
Calcitriol is effective and safe for treatment of osteoporosis after liver transplantation and, moreover, it reduces the incidence of atraumatic fractures. Calcitriol 0.5 mg is more effective than 0.25 mg. The best results are achieved with 0.5 mg calcitriol with supplementation of 1 g of calcium and 25 mg of sodium fluoride. REFERENCES 1. 2. 3. 4. 5.
Hay JE, et al: Hepatology 12:838, 1990 Katz IA, et al: J Bone Mineral Res 7:123, 1992 Monegal A, et al: Calcif Tissue Int 60:148, 1997 Velero MA, et al: Calcif Tissue Int 57:15, 1995 Riggs BL, et al: N Engl J Med 332:802, 1990
O
STEOPOROSIS is a frequent complication of endstage liver disease that often deteriorates after orthotopic liver transplantation (OLT) due to long-term immunosuppression including corticosteroids and other factors like early immobilization. In advanced cases, bone demineralisation increases the susceptibility of atraumatic fractures. Because there is no broadly accepted therapeutic concept for bone demineralisation after OLT the efficacy of calcitriol [1, 25(OH)2D3] in comparatively low dosages, either as single treatment or in combination with elemental calcium, as well as with calcium and a low dose of sodium fluoride, was evaluated in this study. PATIENTS AND METHODS Between 1989 and 1996, 860 patients underwent OLT at the Virchow Clinic, Berlin. Five hundred and nine patients (213 female and 296 male, mean age 47.5 years) were enrolled in this parallel group study. Patients with observation times of less than 24 months were excluded. For the evaluation of postoperative loss of bone mineralisation and for the control of treatment efficacy all patients underwent bone mineral density (BMD) measurements at the lumbar spine (LS) and the femoral neck (FN) by dual-energy x-ray absorptiometry (Lunar DPX Scanner, Lunar Radiation, Madison, Wis), which was initiated before OLT and repeated subsequently in 6-month intervals after transplantation up to 24 months. Therapy started 6 months postoperatively and was followed up for 18 months. Because the degree of bone mineralisation varied considerably between LS and FN both sites were analyzed separately. The results of female and male patients were summarised because no major differences were observed in both groups. Two hundred forty-six patients served as controls, and 283 patients were assigned to five treatment groups. The treated patients received 0.25 mg of calcitriol (group 1, 35 patients), 0.25 mg of calcitriol together with 1000 mg of calcium (group 2, 37 patients), 0.5 mg of calcitriol (group 3, 76 patients), 0.5 mg of calcitriol together with 1000 mg of calcium (group 4, 86 patients), and 0.5 mg calcitriol together with 1000 mg of calcium and a low dose of 25 mg of sodium fluoride (group 5, 49 patients). Baseline immunosuppression was provided by the administration of cyclosporine (310 patients) or tacrolimus (FK 506, 219 patients) initially combined with corticosteroids, which were generally tapered down and withdrawn after 6 to 9 months in the cyclosporine group (cumulative dose '2.3 g) and after 3 to 6 months in the FK 506 group (cumulative dose '1.4 g), depending on graft function. Levels of sex hormones were determined each time BMD was controlled. 0041-1345/99/$–see front matter PII S0041-1345(98)01713-8
RESULTS
Depending on the underlying liver disease significant differences in BMD were observed before OLT. In PBC and PSC, as well as in autoimmune cirrhosis, the lowest values of bone mineralisation at LS and FN were observed. Similarly, after OLT the highest loss of BMD was observed in patients with cholestatic cirrhosis. In addition, PSC patients showed marked demineralisation in the LS. During the first 6 months after OLT cyclosporine-treated patients developed a significantly higher decrease of BMD at the LS (26.3% of BMD) than FK 506 patients (23.5% of BMD). No major differences were observed for the demineralisation at the FN (24.9% of BMD) in the immunosuppressed groups. This correlates with the higher dose of steroids in the cyclosporin-treated patients. Overall, calcitriol led to an improvement of BMD at both measurement sites in all treatment groups, or at least prevented further demineralisation. Patients treated with 0.5 mg of calcitriol (treatment groups 3 and 4) showed superior results in regard to LS and the FN than patients treated with 0.25 mg. In groups 3 and 4 the mean increment rate of BMD was 10% for the LS and 5.6% for the FN. In contrast, patients in group 1 showed an increment rate of only 5.6% for the LS. The increment rate of 4% for the FN was even lower. Slightly better results were obtained in group 2 with an increment rate of 7.3% for the LS and 3.9% for the FN. Group 5 showed the best results for both sites. While the increment rate of 10.7% for the LS was insignificantly higher than in groups 3 and 4, BMD in the FN improved with an increment rate of 12.8%. Thus, the special impact of fluoride supplementation for the FN is obvious. The incidence of atraumatic fractures was significantly lower in the treated patients (2 of 238 5 0.7%). In contrast the fracture rate in the control group was threefold higher (7 of 246 5 0.7%). No major side effects occurred under treatment, and serum calcium and phosphorus levels stayed within the normal range. There was no significant difference in testosterone or estrogen levels between the different groups. From the Departments of Surgery (R.N., A.K., R.L., N.R., P.N.), and Radiology (J.H.), Campus Virchow Clinic, Berlin, Germany. Address reprint requests to Dr Ruth Neuhaus, Department of Surgery, Charite´, Campus Virchow Clinic, Humboldt University Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
472
Transplantation Proceedings, 31, 472–473 (1999)
PREVENTION AND THERAPY WITH CALCITRIOL
DISCUSSION
In this study, calcitriol was beneficial for all patients who suffered from osteoporosis after OLT. In contrast to other studies, which could not prove a positive effect of calcitriol on BMD in patients with cholestatic liver diseases,1 BMD improvement in PBC and PSC patients after OLT could be observed. Because glucocorticosteroids play an important role in bone metabolism it is expected that bone demineralisation occurs under long-term therapy with steroids. The deleterious effect on BMD depends on the cumulative daily dose of steroids.2 The higher cumulative daily dose of steroids in cyclosporine treated patients is a possible reason for the augmented bone loss at the LS in these patients as compared with FK 506 –treated patients who received a lower corticosteroid dosage. Similar to Monegal et al,3 we could not demonstrate an important role of testosterone and estrogen levels in the development of osteoporosis after OLT. So far, the best results in the treatment of osteoporosis after OLT have been demonstrated by Valero et al.4 They evaluated only BMD values of the LS. Their patients received 40 IU/d of calcitonin intramuscularly, or 400 mg sodium etidronate orally for 15 days every 3 months. The best increment rates for the LS over 12 months were
473
6.4% in the calcitonin group and 8.2% in the biophosphonate-treated patients. Our best results were achieved with daily doses of 0.5 mg of calcitriol, 1 g of calcium, and 25 mg of sodium fluoride. Increment rates after 18 months were 10.7% for the LS and 12.8% for the femoral neck. High dosages of fluoride were avoided because they may lead to augmented skeletal fragility.5 CONCLUSIONS
Calcitriol is effective and safe for treatment of osteoporosis after liver transplantation and, moreover, it reduces the incidence of atraumatic fractures. Calcitriol 0.5 mg is more effective than 0.25 mg. The best results are achieved with 0.5 mg calcitriol with supplementation of 1 g of calcium and 25 mg of sodium fluoride. REFERENCES 1. 2. 3. 4. 5.
Hay JE, et al: Hepatology 12:838, 1990 Katz IA, et al: J Bone Mineral Res 7:123, 1992 Monegal A, et al: Calcif Tissue Int 60:148, 1997 Velero MA, et al: Calcif Tissue Int 57:15, 1995 Riggs BL, et al: N Engl J Med 332:802, 1990