tacrolimus and Osteoporosis

Transplantation is an established therapy for end-stage diseases of kidney, lung, liver, and heart among others. Osteoporosis and fragility fractures are serious complications of organ transplantation, particularly in the first post-transplant year. Many factors contribute to the pathogenesis of osteoporosis following organ transplantation. This review addresses the mechanisms of bone loss that occurs both in the early and late post-transplant periods, including the contribution of the immunosuppressive agents as well as the specific features to bone loss after kidney, lung, liver, cardiac, and bone marrow transplantation. Prevention and treatment for osteoporosis in the transplant recipient are also discussed.

Topics: Animals; Bone Marrow Transplantation; Glucocorticoids; Heart Transplantation; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Lung Transplantation; Organ Transplantation; Osteoporosis; Osteoporotic Fractures; Tacrolimus; Vitamin D Deficiency

After osteoporotic fracture or low bone mineral density measurements, it is necessary to look for secondary causes of osteoporosis, such as drugs. Corticosteroids are the most common cause of drug-induced metabolic bone disease. Other drugs responsible for bone disease include: aromatase inhibitors, GnRH agonists, anticonvulsants, heparin, and L thyroxin at TSH-suppressive doses. Confirmation is required of data about neuroleptics and antivitamin K.

Topics: Aged; Animals; Anticoagulants; Anticonvulsants; Antipsychotic Agents; Aromatase Inhibitors; Bone Density; Child; Cyclosporins; Densitometry; Disease Progression; Diuretics; Female; Follow-Up Studies; Fractures, Bone; Gonadotropin-Releasing Hormone; Humans; Hypoglycemic Agents; Iatrogenic Disease; Immunosuppressive Agents; Lithium Compounds; Male; Menopause; Methotrexate; Middle Aged; Osteomalacia; Osteoporosis; Osteoporosis, Postmenopausal; Placebos; Prospective Studies; Protease Inhibitors; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Tacrolimus; Thyroid Hormones; Time Factors

Early after renal transplantation (RT) a rapid decrease in bone mineral density at the lumbar spine, femoral neck, and femoral shaft has been documented. In addition, an appreciable proportion of patients still remain losing bone late after RT. As a consequence, RT patients are at a high risk of bone fractures as compared to general population. Most fractures involve appendicular skeleton, particularly the feet and ankles, and the diabetic patient is at increased risk of fractures. Thus, early institution of preventive measures and treatment of established osteoporosis are central. The major cause of post-transplantation bone loss is corticosteroid treatment, and this should be used at the lower dose compatible with graft survival. Preexisting hyperparathyroidism also affects the early cancellous bone loss at the spine, and post-transplantation bone loss reflects variable individual susceptibility, resembling the polygenic determination of bone mineral density in general. Clinical trials have demonstrated that bisphosphonates or vitamin D plus calcium supplementation, prevent post-transplantation bone loss during the first 6-12 months. However, their role in preventing bone fractures has not been proven. Finally, recommendations for management, prevention and treatment, are summarized.

Topics: Absorptiometry, Photon; Adrenal Cortex Hormones; Animals; Biomarkers; Bone and Bones; Bone Density; Calcineurin Inhibitors; Calcium; Diphosphonates; Diuretics; Female; Fractures, Spontaneous; Genetic Predisposition to Disease; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Transplantation; Male; Osteoporosis; Postoperative Complications; Prospective Studies; Rats; Renal Dialysis; Risk; Tacrolimus; Vitamin D

There is a paucity of randomized, controlled therapy studies of the extraintestinal manifestations of inflammatory bowel disease (IBD). Most current therapeutic approaches are empiric or based on approaches to therapy in other settings. In the past year anecdotal evidence has emerged for the use of therapies that neutralize tumor necrosis factor-a in both ankylosing spondylitis and the dermatologic extraintestinal manifestations. Topical tacrolimus has also emerged as a potentially useful therapy for dermatologic manifestations. Finally, patients with IBD occasionally become transplant recipients. One study reported worsening IBD after orthotopic liver transplantation for primary sclerosing cholangitis, and another reported the benefit of renal transplantation in amyloidosis-induced renal failure.

Topics: Antibodies, Monoclonal; Cholangitis, Sclerosing; Dermatitis, Atopic; Drug Combinations; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Myocarditis; Osteoporosis; Psoriasis; Pyoderma Gangrenosum; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha; Vitamin D

Treatment of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) with ursodeoxycholic acid (UDCA) has been in common use since 1985. In PBC, treatment with UDCA improves laboratory data, liver histology, enables a longer transplantation-free interval and prolongs disease survival. Because UDCA is unable to cure the disease newer drugs or combination therapies are still needed. Studies with UDCA and immunosuppressants such as prednisone, budesonide and azathioprine have shown that in selected patients combination therapy may be superior to UDCA monotherapy. PSC is treated successfully with UDCA and endoscopic dilatation of the bile duct strictures. Treatment of extrahepatic manifestations of cholestatic liver disease such as pruritus, fatigue, osteoporosis and steatorrhea can be problematic and time-consuming.

Topics: Azathioprine; Celiac Disease; Cholagogues and Choleretics; Cholangitis, Sclerosing; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Osteoporosis; Prednisolone; Pruritus; Tacrolimus; Ursodeoxycholic Acid

Topics: Antimetabolites; Bone Density; Cyclosporine; Glucocorticoids; Heart Transplantation; Humans; Immunosuppressive Agents; Osteoporosis; Postoperative Complications; Tacrolimus

Corticosteroid treatment may have an important effect on body composition and bone mineral density (BMD) in renal transplantation (RTx) patients. We investigated the effect of early steroid withdrawal on body composition and BMD of RTx patients in a prospective design. Post-transplant immunosuppression consisted of tacrolimus, mycophenolate mofetil, and prednisolone. Three months after RTx, 27 patients participating in a multi-center trial were randomized either to continue steroids (at a dose of 10 mg/day, n=17; steroid+) or be withdrawn from steroids within 2 weeks (n=10; steroid-). Body composition and BMD (lumbar spine (L2-L4) and femoral neck) were measured by dual-energy X-ray absorptiometry (DEXA) just before and 3 months after randomization. With regard to body composition, fat mass tended to increase in the steroid+ group (1.1+/-2.3 kg; P=0.084), but did not change in the steroid- group. Increase in body fat percentage tended to be higher (P=0.08) in the steroid+ group (0.6+/-2.7%) than in the steroid- group (-0.7+/-2.1%). The change in lean body mass was not significantly different between the two groups. BMD of the lumbar spine and femoral neck decreased significantly in the steroid+ group (-1.4+/-3.2% and -2.3+/-2.9%, respectively, P<0.05) while no changes were observed in the steroid- group. The change in BMD of the lumbar spine was significantly different between the steroid+ and the steroid- group, whereas the change in BMD of the femoral neck was not significantly different. Thus, the increase in fat mass tended to be higher in the group continuing on steroids, though not significant, due to large inter-individual variation. In general, the effect of early steroid withdrawal on body composition after RTx appears to be modest. In addition, early steroid withdrawal seems to have beneficial effects on BMD in RTx patients, especially in the lumbar region.

Topics: Adult; Aged; Body Composition; Bone Density; Female; Femur Neck; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Transplantation; Lumbar Vertebrae; Male; Middle Aged; Mycophenolic Acid; Osteoporosis; Prednisolone; Tacrolimus

Topics: Absorptiometry, Photon; Belgium; Bone Density; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Incidence; Kidney Transplantation; Male; Osteoporosis; Prednisolone; Risk Assessment; Severity of Illness Index; Tacrolimus; Transplantation Immunology

Osteoporosis is affecting the health of postmenopausal women in the world. In case of that, we explored whether FK-506 could ameliorate osteoporosis by inhibiting the activated CaN/NFAT pathway during oxidative stress.. First, the castrated rat model is constructed through the bilateral ovariectomy. Hologic Discovery (S/N 80347) dual-energy X-ray absorptiometry assessed bone mineral density (BMD) implemented at left femur of rats. Next, hematoxylin-eosin (H&E) staining observed and calculated the changes of bone trabecular, mean trabecular plate separation (Tb.Sp), mean trabecular plate thickness (Tb.Th), and bone volume fraction (BV/TV). Then, CCK-8 assay, TUNEL assay, ALP kit and alizarin red staining detected the viability, apoptosis, alkaline phosphatase (ALP) activity, and capacity of mineralization respectively. At last, commercially available kits detected the levels of ROS and SOD in transfected MC3T3-E1 cells and bone tissues, and Western blot analysis detected proteins related to apoptosis and CaN/NFAT pathway.. FK-506 ameliorates osteoporosis resulted from osteoblastic apoptosis which caused by suppressing the activated CaN/NFAT pathway during oxidative stress.

Topics: Alkaline Phosphatase; Animals; Apoptosis; Bone Density; Calcineurin; Cell Line; Cell Survival; Female; Femur; Immunosuppressive Agents; Mice; NFATC Transcription Factors; Osteoblasts; Osteoporosis; Oxidative Stress; Rats, Wistar; Signal Transduction; Tacrolimus; Tibia

Liver transplantation provides an important, often life-saving treatment for end-stage liver disease. Osteoporosis post-liver transplantation has been described in adults; however, this has not been described in the pediatric population to date. We present a case of a 13-year-old female patient who underwent an orthotopic liver transplant for cryptogenic liver cirrhosis. Her immunosuppressants were tacrolimus and prednisone. Four months posttransplant, she started complaining of bilateral lower limb pain and limping while walking, progressing to a point where she was almost immobile. Magnetic resonance imagining of the pelvis showed bilateral avascular necrosis involving the weight-bearing surfaces of both femoral heads, in addition to the extensive edema involving both hip joints. Bone mineral densitometry was below normal for her age at the hip and forearm. She was started on high-dose calcium and vitamin D supplement, as well as zoledronic acid with a remarkable symptomatic and functional improvement.

Topics: Adolescent; Bone Density; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Osteoporosis; Prednisone; Tacrolimus

The authors performed a longitudinal study of the microstructural changes occurring in the mandibular condyle during osteoporosis using the findings obtained from micro-CT. The subjects used in this study were eight Sprague-Dawley rats. Among them, five were administered the immunosuppressant drug FK506 by injection for five weeks, while the other three were administered saline solution in the same manner. Micro-CT images were taken of the bilateral mandibular condyle, hip, and knee joints in all animals on days 1, 8, 15, 22, 29, and 36 following injection. Six indices of morphometric analysis were compared between the two groups. Significant differences were observed in BV/TV, Tb.Th, Tb.N, and Tb.Sp in the mandibular condyle, while trabecular bone density appeared to decrease in the immunosuppressant group on three-dimensional (3D) imaging. And, in comparison with the mandibular condyle and femur, they were similar. These results suggested that osteoporosis affects not only the femur, but also the mandibular condyle.

Topics: Animals; Bone Density; Bone Marrow; Femur; Femur Head; Hip Joint; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Immunosuppressive Agents; Knee Joint; Longitudinal Studies; Male; Mandibular Condyle; Osteoporosis; Rats; Rats, Sprague-Dawley; Tacrolimus; X-Ray Microtomography

Immunosuppressant-related hip pain can greatly affect a patient's mobility and increase the number of total hip arthroplasties. We investigated risk factors and causes of hip pain after orthotopic liver transplant.. The medical records of 175 adult orthotopic liver transplant patients, who were followed-up for more than 2 years, were retrospectively reviewed. Data collected from the records included primary disease, medications, biochemical results, Child-Turcotte-Pugh score, death, rejection, and complications related to liver transplant.. A total of 11 patients (6.3%) complained of hip pain, which was diagnosed as calcineurin-inhibitor-induced pain syndrome in 4 patients (2.3%), osteonecrosis of the femoral head in 3 patients (1.7%), and osteoporosis in 2 patients (1.1%). The incidence of calcineurin-inhibitor-induced pain syndrome was related to the dosage of tacrolimus (P > .05) but independent of methylprednisolone use. The occurrence of osteonecrosis of the femoral head was independent of the dosage and early withdrawal of methylprednisolone (P > .05). Patients with methylprednisolone withdrawal within 6 months had significantly longer survival than those using methylprednisolone for more than 6 months (50 ± 15 vs 41 ± 18 mo; P = .007).. Calcineurin-inhibitor-induced pain syndrome and osteonecrosis of the femoral head are main causes of hip pain in adult orthotopic liver transplant patients. Osteonecrosis of the femoral head was not common, but the incidence of hip pain owing to calcineurin-inhibitor-induced pain syndrome was relatively high in orthotopic liver transplant patients. Early withdrawal of methylprednisolone could benefit the patients' survival.

Topics: Adult; Aged; Arthralgia; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Hip Joint; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Osteonecrosis; Osteoporosis; Retrospective Studies; Risk Factors; Tacrolimus

Post-transplantation bone disease is associated with a high degree of morbidity including pain and fractures. Glucocorticoid-induced osteoporosis on top of pre-existing renal osteodystrophy is considered the major pathogenic factor, while the role of non-glucocorticoid immunosuppressants is less well defined.. In this study, we investigated the influence of sirolimus (SRL) versus calcineurin inhibitor (CI)-based immunosuppressive regimens on biomarkers of bone resorption in renal transplant patients. In addition, the impact of SRL, tacrolimus and mycophenolate mofetil (MMF) on osteoclast activation and function was assessed in cell culture systems.. Using this approach, we demonstrated reduced serum levels of bone resorption markers in patients treated with SRL after kidney transplantation compared to a CI-based regimen. In line with this observation, we detected profoundly reduced osteoclast differentiation and subsequently diminished hydroxyapatite resorption in the presence of SRL compared to MMF and tacrolimus in vitro. Moreover, SRL significantly reduced osteoclast precursor proliferation in vitro compared to tacrolimus and led to augmented apoptosis in osteoclast precursors.. Taken together, SRL was shown to inhibit osteoclast formation in vivo and in vitro. SRL thus may have the potential to balance osteoclast promoting effects of glucocorticoids and CI, thereby counteracting the development of accelerated osteoporosis in renal transplant recipients.

Topics: Adult; Aged; Bone Resorption; Cell Differentiation; Cross-Sectional Studies; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Osteoclasts; Osteoporosis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Sirolimus; Tacrolimus; Young Adult

Topics: Aged; Asthma; Blood Vessels; Churg-Strauss Syndrome; Comorbidity; Eosinophilia; Female; Humans; Immunosuppressive Agents; Myasthenia Gravis; Osteoporosis; Prednisolone; Skin; Tacrolimus; Treatment Outcome

The main component of the metabolic by-products of fermentation by Propionibacterium freudenreichii ET-3 is 1,4-dihydroxy-2-naphthoic acid (DHNA), which has a naphthoquinone skeleton, as in vitamin K2. This study showed that DHNA improved bone mass reduction with osteoporosis model mice caused by FK506.. Growth of the intestinal bacterium Lactobacillus bifidus is specifically facilitated by DHNA. The present study used osteoporosis model mice to investigate the effects of DHNA on bone remodeling.. FK506, an immunosuppressant, was used to prepare osteoporosis model mice. Thirty mice were divided into three groups: FK group, FK+DHNA group, and control group. In the FK group, FK506 was administered to induce bone mass reduction. In the FK-DHNA group, FK506 and DHNA were administered concurrently to observe improvements in bone mass reduction. To ascertain systemic and local effects of DHNA, we investigated systemic pathological changes in colon, kidney function and cytokine dynamics, and morphological and organic changes in bone and osteoclast dynamics as assessed by culture experiments.. Compared to the FK group without DHNA, colon damage and kidney dysfunction were milder for FK+DHNA group, and production of inflammatory cytokines (interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha) was more suppressed. Furthermore, compared to the group without DHNA, histological analyses and radiography showed that bone resorption was suppressed for the DHNA group. Culture experiments using osteoclasts from murine bone marrow showed osteoclast suppression for the DHNA group compared to the group without DHNA.. These results show that DHNA has some effects for improving bone mass reduction caused by FK506.

Topics: Animals; Body Weight; Bone Density; Bone Density Conservation Agents; Cells, Cultured; Colon; Disease Models, Animal; Drug Evaluation, Preclinical; Eating; Femur; Immunosuppressive Agents; Inflammation Mediators; Kidney; Male; Mice; Mice, Inbred ICR; Naphthols; Osteoclasts; Osteoporosis; Tacrolimus

Low bone mineral density (BMD) has been reported in 30.4% of adult patients with atopic dermatitis (AD).. The aim of this study was to determine the prevalence of low BMD in children with moderate to severe AD and to investigate the relation between BMD and corticosteroid and cyclosporine therapy.. Lumbar spine BMD was measured by dual-energy X-ray absorptiometry in 60 children (age 5-16 years) with moderate to severe AD. BMD (in g/cm(2)) was expressed in Z-scores, the number of SD above or below the mean value of an age- and sex-matched reference population. In children, low BMD was defined as a Z-score less than -2. Information on lifestyle parameters and bone fractures were collected by use of a standardized questionnaire. The cumulative dose of corticosteroids and cyclosporine therapy was calculated for the previous 5-year period.. Three patients (5%) had low BMD; one patient (1.7%) had osteoporosis. The observed prevalence of low BMD in this study (6.7%; 95% confidence interval 1.8%-16.2%) does not differ from the expected prevalence of low BMD in the general population (P = .06). Overall, use of topical corticosteroids in the previous 5 years was not associated with a decrease in BMD (Z-score). When children received additional systemic treatment (oral corticosteroids and/or cyclosporine) in the previous 5 years, BMD decreased, although the decrease was not statistically significant. Correction for lifestyle parameters did not change these associations.. The number of patients studied was limited. The cumulative dose of corticosteroids and cyclosporine therapy was only registered for the previous 5 years, and relatively low amounts of topical corticosteroids were used. The definition of low BMD differs between adults (Z-score < -1) and children (Z-score < -2). Because there is no Dutch BMD reference population for children, normative BMD references were obtained from a different population (US children).. Low BMD did not occur more frequently in this population of children with moderate to severe AD compared with the general population. Use of topical corticosteroids in the previous 5 years was not associated with a decrease in BMD.

Topics: Absorptiometry, Photon; Adolescent; Adrenal Cortex Hormones; Bone Density; Child; Child, Preschool; Cyclosporine; Dermatitis, Atopic; Female; Fractures, Bone; Humans; Immunosuppressive Agents; Lumbar Vertebrae; Male; Osteoporosis; Prevalence; Risk Factors; Severity of Illness Index; Tacrolimus

Topics: Adult; Bone and Bones; Calcineurin Inhibitors; Cyclosporins; Everolimus; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Osteoporosis; Pain; Postoperative Period; Radiography; Radionuclide Imaging; Sirolimus; Syndrome; Tacrolimus; Time Factors

Two of the most commonly used immunosuppressants, cyclosporine A and tacrolimus (FK506), inhibit the activity of a ubiquitously expressed Ca(2+)/calmodulin-sensitive phosphatase, calcineurin. Because both drugs also cause profound bone loss in humans and in animal models, we explored whether calcineurin played a role in regulating skeletal remodeling. We found that osteoblasts contained mRNA and protein for all isoforms of calcineurin A and B. TAT-assisted transduction of fusion protein TAT-calcineurin Aalpha into osteoblasts resulted in the enhanced expression of the osteoblast differentiation markers Runx-2, alkaline phosphatase, bone sialoprotein, and osteocalcin. This expression was associated with a dramatic enhancement of bone formation in intact calvarial cultures. Calcineurin Aalpha(-/-) mice displayed severe osteoporosis, markedly reduced mineral apposition rates, and attenuated colony formation in 10-day ex vivo stromal cell cultures. The latter was associated with significant reductions in Runx2, bone sialoprotein, and osteocalcin expression, paralleled by similar decreases in response to FK506. Together, the gain- and loss-of-function experiments indicate that calcineurin regulates bone formation through an effect on osteoblast differentiation.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Cell Differentiation; Gene Deletion; Isoenzymes; Mice; Mice, Knockout; Osteoblasts; Osteogenesis; Osteoporosis; Tacrolimus

Immunosuppressant drugs are currently required by transplant recipients for the remainder of their lives, despite the many adverse effects associated with these therapies. Acute osteoporosis is one such effect, and a reproducible osteoporosis model has been established through the administration of the immunosuppressant drug FK506 in rats. The cause of this osteoporosis has been shown to be abnormal osteoclast proliferation, altering the process of bone remodeling. However, the reasons why FK506 induces osteoclast proliferation and whether this process is mediated by cytokine changes or an increase in bone resorption factors have been unclear. An investigation was therefore conducted focusing on the recent discoveries of osteoclast differentiation factor (ODF) and osteoclastogenesis inhibitory factor (OCIF). These factors led to elucidation of the osteoclast differentiation-maturation mechanism. An osteoporosis model was produced in rats utilizing intramuscular FK506 injection (1 mg/kg) for 28 consecutive days. Trabecular bone resorption was observed inferior to enchondral ossification in the FK506 group, and tartrate resistant acid phosphatase (TRAP) staining revealed a clear increase in osteoclasts at the site of enchondral ossification, relative to the control group. Real-time PCR and in situ hybridization (ISH) demonstrated minimal differences in OCIF expression between control and the treatment groups. However, Real-time PCR revealed clearly increased ODF expression in the treatment group. ODF expression was also shown to be increased in the treatment group using ISH. This was histologically consistent with a region of osteoclast proliferation inferior to enchondral ossification. The results of this study support the hypothesis that FK506-mediated osteoporosis occurs by action of the drug on osteoclasts, promoting expression of ODF messenger ribonucleic acid (mRNA) and thus prompting osteoclast differentiation and maturation.

Topics: Animals; Carrier Proteins; Gene Expression Regulation; Glycoproteins; Immunosuppressive Agents; Male; Membrane Glycoproteins; Osteoclasts; Osteoporosis; Osteoprotegerin; RANK Ligand; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Tacrolimus

We report a patient with polymyositis (PM) associated with myasthenia gravis (MG). Both disorders had been controlled for around 15 years by oral prednisolone and a cholinesterase inhibitor following surgical removal of invasive thymoma and radiotherapy, but muscular weakness due to myalgia and an increase in serum levels of myogenic enzymes, mainly ascribable to the recurrence of PM, reappeared immediately after cessation of these drugs, which was done because the patient had multiple bone fractures and severe osteoporosis due to the long-term corticosteroid therapy. Oral tacrolimus was therefore tried, and produced an improvement in muscular symptoms in association with normalization of myogenic enzymes. PM associated with MG as in this patient might be the best indication for tacrolimus, considering its efficacy in MG, but this drug should also be actively considered as a therapeutic option in refractory cases of PM alone, particularly when either corticosteroids or other immunosuppressive agents are not usable.

Topics: Adrenal Cortex Hormones; Adult; Female; Humans; Immunosuppressive Agents; Myasthenia Gravis; Osteoporosis; Polymyositis; Prednisolone; Tacrolimus; Treatment Outcome

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.

Topics: Amino Acids; Animals; Bone Density; Femur; Immunosuppressive Agents; Male; Osteocalcin; Osteoporosis; Rats; Rats, Sprague-Dawley; Tacrolimus; Tibia; Tomography, X-Ray Computed

Osteoporosis is a major cause of morbidity in liver transplant recipients and is associated with multiple factors.. To evaluate bone mineral density (BMD), bone turnover and calcium-regulating hormones in 29 patients (17 men, 12 women) 2-12 yrs following liver transplantation for non-alcoholic liver diseases.. Fifteen patients (52%) were on immunosuppressive treatment with tacrolimus and 14 (48%) with cyclosporine. Eleven patients (38%) were currently on prednisone, 18 patients (62%) had stopped glucocorticoid treatment 6 months to 11 yrs prior to the study. Nineteen patients (65.5%) had decreased BMD according to WHO criteria, 17 (58.2%) at the femoral neck, 13 (44.8%) at the lumbar spine. Nineteen patients (65.5%) had a subnormal (<15 ng/mL) serum level of 25 (OH) D3. These patients had significantly lower BMD at the femoral neck (p = 0.02). Femoral neck BMD negatively correlated with serum parathyroid hormone level (p = 0.06, r = -0.35), length of the post-transplantation period (p = 0.025, r = -0.416) and duration of glucocorticoid treatment (p = 0.029, r = -0.406), regardless of its cumulative dose. Symptomatic fractures were less frequent in tacrolimus treated patients than in cyclosporine users (p = 0.03).. Decreased BMD is frequent following liver transplantation and is affected by vitamin D deficiency, cyclosporine use, and the duration of glucocorticoid therapy, but not by its cumulative dose. Achievement and maintenance of optimal vitamin D status and shortening of glucocorticoid treatment period may have a favorable effect on bone preservation.

Topics: Absorptiometry, Photon; Alkaline Phosphatase; Amino Acids; Bone Density; Bone Remodeling; Cyclosporine; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Osteoporosis; Parathyroid Hormone; Regression Analysis; Risk Factors; Statistics, Nonparametric; Tacrolimus; Time Factors; Vitamin D Deficiency

Metabolic bone disease is one of the major long-term complications in liver transplant recipients, but it remains unclear which patients are at highest risk for developing severe bone disease following transplantation.. A total of 46 consecutive, adult patients with chronic liver disease accepted for a liver transplantation waiting list were prospectively included in the study. The patients were classified into two groups: group A--chronic cholestatic liver disease (n = 28), and group B--chronic non-cholestatic liver disease (n = 18). Bone mineral density (BMD) was measured at acceptance for the waiting list and at 3, 12 and 36 months following transplantation. Markers of bone turnover (serum-bone specific alkaline phosphatases (bALP), s-osteocalcin, s-1-collagen-C-terminal telopeptide (1-CTP) and urine N-terminal telopeptides u-Ntx) were measured at acceptance and at 3, 6, 12, 24 and 36 months following transplantation. BMD and markers of bone turnover were compared with similar values in a matched control group of 42 healthy individuals.. BMD decreased significantly during the early post-transplantation period (median bone loss femoral neck (FN) 3 months post-transplant 8.5%). BMD levels declined slightly from 3 to 12 months following transplantation and increased thereafter. The relative bone loss was greatest among group B patients (relative bone loss FN 3 months post-transplant: group A, 8% versus group B, 13%; P = 0.04). At 36 months, 8/17 group A and 2/9 group B patients had BMD levels that exceeded the pretransplant levels (P = 0.12). The early bone loss was positively correlated with an increase in resorption markers (s-1-CTP and u-Ntx). Group B had higher levels of both s-1-CTP and u-Ntx at 3 and 6 months post-transplant than group A patients (P = 0.03). Bone formation markers increased slowly from 6 months post-transplant and onwards. Relative bone loss was positively correlated to total glucocorticoid dose during the first 3 months post-transplant. There were no differences in BMD between patients receiving tacrolimus versus those receiving cyclosporin A.. Bone loss following liver transplantation is considerable in patients with both cholestatic and non-cholestatic liver disease, the first group has the poorest starting-point while the latter group has the greatest bone loss following transplantation. Bone loss is closely correlated with biochemical markers of bone resorption and total dose of glucocorticoids given post-transplant.

Topics: Adult; Aged; Alkaline Phosphatase; Biomarkers; Bone Density; Bone Resorption; Cholestasis; Collagen; Collagen Type I; Cyclosporine; Female; Femur Neck; Follow-Up Studies; Forearm; Fractures, Bone; Glucocorticoids; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Longitudinal Studies; Lumbar Vertebrae; Male; Middle Aged; Norway; Osteocalcin; Osteoporosis; Peptide Fragments; Peptides; Postoperative Complications; Survival Analysis; Tacrolimus; Treatment Outcome; Waiting Lists

Osteoporosis and related fractures are a major complication after organ transplantation. The aim of this study was to find out the frequency and predictors of osteoporotic fractures after cardiac or liver transplantation.. 235 consecutive patients who had a cardiac transplant (n=105; 88 men, 17 women) or a liver transplant (130; 75 men, 55 women) were followed. Vertebral fractures were assessed by a standardised analysis of spinal radiographs before and annually after transplantation. Clinical and non-vertebral fracture data were noted from hospital records.. In the first and second years after transplantation, the proportion of patients (Kaplan-Meier estimates) who had at least one vertebral fracture was slightly higher in the cardiac group (first year 21%, second year 27%) than in the liver group (first year 14%, second year 21%). In the third and fourth years, one third of patients from both groups had had one or more vertebral fractures. Non-vertebral fractures occurred in nine patients (7%) after liver transplantation and avascular necrosis of the hip head in three patients (3%) after cardiac transplantation. In both groups, no dose-dependent effect of immunosuppressive therapy on fracture development could be identified. Independent predictors assessed by multivariate analysis were age (hazard ratio [95% CI] increase of 5 years, 1.71 [1.1-2.7]) and lumbar bone-mineral density (decrease of 1 SD t score, 1.97 [1.2-3.2]) in cardiac transplantation patients, and vertebral fractures before transplantation (6.07 [1.7-21.7]) in the liver group.. The high frequency of osteoporotic fractures in the 2 years after transplantation and the limitations of reliable fracture-risk predictions, show the need to investigate preventive therapies.

Topics: Adult; Cyclosporine; Female; Follow-Up Studies; Fractures, Spontaneous; Germany; Heart Transplantation; Humans; Immunosuppressive Agents; Likelihood Functions; Liver Transplantation; Male; Middle Aged; Multivariate Analysis; Osteoporosis; Postoperative Care; Postoperative Complications; Proportional Hazards Models; Radiography; Risk Factors; Spinal Fractures; Tacrolimus

The purpose of this study was to compare the effects of Cyclosporine A (CyA) and FK506 on bone mass and mineral metabolism in liver transplantation (LT) patients. A prospective study was performed on 18 male patients who underwent LT treated with CyA, and 7 LT patients who received FK506. Bone mineral density (BMD) of the lumbar spine and proximal femur (DPX-L) was measured before and at 6, 12, and 24 months after transplantation. Moreover, intact parathyroid hormone (PTH) and 25-hydroxyvitamin D (25OHD) levels were determined at the same time. The cumulative dose of glucocorticoids was calculated in all patients. At 6 months, lumbar BMD decreased 5.2 +/- 1.2% (P = 0.0005) and 2.9 +/- 2.1% (p = ns) in CyA and FK506 groups, respectively. Lumbar BMD reached baseline values at 1 year in the FK506 group and 2 years after LT in the CyA group. Moreover, significant intergroup differences in femoral neck BMD changes after 2 years of transplant were observed (CyA: -5.2 +/- 1.97 versus FK506: +1.55 +/- 2.2%; P = 0.039). In the first year posttransplant both groups showed a marked increase in PTH and 25OHD levels. The mean cumulative dose of glucocorticoids was higher in the CyA group (CyA group 11.06 +/- 0.46 g versus FK 506 group 6.71 +/- 0.42 g; P < 0.001), and multiple linear regression analysis showed a negative correlation between BMD changes at the lumbar spine and mean cumulative dose of glucocorticoids (P = 0.022). In conclusion, our data suggest that after liver transplantation treatment with FK506 shows a more favorable long-term effect on bone mass evolution than CyA therapy. These differences seem to be associated with the lower dose of glucocorticoids used in the FK506 group.

Topics: Absorptiometry, Photon; Azathioprine; Bone Density; Cyclosporine; Drug Therapy, Combination; Femur Neck; Humans; Immunosuppressive Agents; Liver Transplantation; Lumbar Vertebrae; Male; Osteoporosis; Parathyroid Hormone; Postoperative Complications; Prednisone; Prospective Studies; Tacrolimus; Vitamin D

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

Immunosuppressant therpay is associated with osteoporosis both clinically, post-transplantation, and experimentally. In rats, cyclosporin A (CsA) and FK506 induce a state of high turnover rapid bone loss. After 14 days of administration in immunosuppressive doses, the more recently discovered immunosuppressant, rapamycin, resulted in no change of cancellous bone volume. A longer study over 28 days has now been carried out; contrasting the new drug with CsA and FK506. Sixty, 10-week-old Sprague-Dawley rats were randomly divided into five groups of 12 rats each. The first group served as an aging control. The remaining four groups received, by daily gavage, a combined vehicle placebo, CsA 15 mg/kg, FK506 5 mg/kg, and rapamycin 2.5 mg/kg, respectively. CsA- and FK506-treated rats, but not those treated with rapamycin, demonstrated high turnover osteoporosis with raised serum 1,25(OH)2D (p < 0.05) and elevated serum osteocalcin (p < 0.05). The trabecular bone area was decreased by 66% (p < 0.01) in the CsA group and 56% (p < 0.05) in the FK506-treated group compared with the control animals. The CsA- and the rapamycin-treated groups failed to gain weight and developed severe hyperglycemia (> 20 mmol/l, p < 0.001) by day 14 but which largely resolved by day 28. Unlike the groups treated with CsA and FK506, rapamycin-treated rats had no loss of trabecular bone volume but there was increased modeling and remodeling and a decreased longitudinal growth rate. Rapamycin may thus confer a distinct advantage over the established immunosuppressants in not reducing bone volume in the short term.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Animals; Blood Glucose; Blood Urea Nitrogen; Bone Density; Calcium; Cyclosporine; Dihydroxycholecalciferols; Disease Models, Animal; Immunosuppressive Agents; Male; Osteocalcin; Osteoporosis; Parathyroid Hormone; Polyenes; Radioimmunoassay; Random Allocation; Rats; Rats, Sprague-Dawley; Sirolimus; Tacrolimus; Tibia