Mycophenolate Mofetil: A Promising New Immunosuppressant That Does Not Cause Bone Loss in the Rat1,2

Dissanayake, Imara; Goodman, Grant R.; Bowman, Andrew R.; Ma, Yang; Pun, S; Jee, W.S.S.; Epstein, Sol

doi:10.1097/00007890-199801270-00025

Cited by 69 publications

(24 citation statements)

References 8 publications

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“…In the past, azathioprine was frequently used in combination with prednisone and CsA or FK506 to prevent organ rejection. However, it has largely been supplanted by mycophenolate mofetil, which does not have deleterious effects on bone in the rat [56]. The skeletal effects of other immunosuppressant agents such as mizoribine, deoxyspergualin, brequinar sodium, liflunomide, and azaspirane, are unclear.…”

Section: Azathioprine Mycophenolate Mofetil and Other Drugsmentioning

confidence: 99%

Osteoporosis in Organ Transplant Patients

Stein

Shane

2013

Osteoporosis

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As transplantation osteoporosis results from alterations in the bone remodeling system, a review of normal bone remodeling is helpful to understanding the pathogenesis of this disease. The bone remodeling cycle is an orderly progression of events in which old, microdamaged bone is replaced by new, mechanically stronger bone. The complete remodeling cycle at each remodeling site requires approximately 3-6 months. Bone remodeling occurs by two main processes, resorption [1] followed by formation [2], which take place on both cancellous and cortical bone surfaces. Resorption begins with activation of macrophage precursors to form osteoclasts, giant multinucleated cells that excavate a cavity on the bone surface. Osteoclasts express receptors for receptor activator of receptor activator of nuclear factor-kappaB ligand (RANKL), which is produced by osteoblasts and osteocytes, and for calcitonin, prostaglandins (PGs), calcium, and vitronectin (integrin α 1 β 3 ). Approximately 0.05 mm 3 of bone tissue is resorbed by each osteoclast, leaving small resorption pits on the bone surface called Howship's lacunae in a process that takes approximately 2-3 weeks. A brief rest period called the reversal phase follows. Next, local mesenchymal bone marrow stem cells differentiate into osteoblasts that are attracted to the empty resorption pits where they accumulate as clusters of plump cuboidal cells along the bone surface. Osteoblasts produce the collagenous and noncollagenous proteins that constitute the matrix of the newly formed bone and are responsible for mineralization of the matrix or osteoid after a period of maturation that lasts approximately 20 days. Osteoblasts express receptors for several hormones (thyroid and parathyroid hormones, estrogens, vitamin D 3 ), cell adhesion molecules (integrins), and cytokines. RANKL, receptor activator of nuclear factor-kappaB (RANK), and osteoprotegerin (OPG) are three members of the tumor necrosis factor (TNF) ligand and receptor-signaling family that are final mediators of bone resorption [3,4]. RANKL is expressed in osteoblasts, osteocytes, and bone marrow stromal cells. When sufficient concentrations of macrophage colony stimulating factor (M-CSF) are present, RANKL binds to RANK, which is expressed on the surface of osteoclast lineage cells. This binding results in rapid differentiation of osteoclast precursors in bone marrow to mature osteoclasts, increased osteoclast activity, and reduced apoptosis of mature osteoclasts. RANKL is neutralized by binding to OPG, which is secreted by cells of the osteoblast lineage. Competitive binding of RANKL to either RANK or OPG regulates bone remodeling by increasing (RANK) or decreasing (OPG) osteoclastogenesis. Immunosuppressants exert their effects on bone remodeling by interacting with the RANK/RANKL/ OPG system [5].In healthy adults, declines in bone mass as a result of remodeling imbalance occur, but are small. When bone remodeling becomes "uncoupled," such that the rate of resorption exceeds the rate of formation, bone loss will occur...

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Section: Azathioprine Mycophenolate Mofetil and Other Drugsmentioning

confidence: 99%

Osteoporosis in Organ Transplant Patients

Stein

Shane

2013

Osteoporosis

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“…The drugs that exhibit the most dangerous general toxicity are relatively benign as far as the skeleton is concerned. Immunosuppressive agents of the cytotoxic group, including azathioprine, cyclophosphamide, chlorambucil, and mycophenolate mofetil, have not been demonstrated as causing abnormal bone loss (48,49). This probably is because the toxicity of these agents is determined largely by rates of cell turnover-even in areas of high bone turnover, the mitotic rate in bone cells is relatively low.…”

Section: Effects Of Immune Suppressive Therapiesmentioning

confidence: 99%

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

Cunningham¹

2007

Journal of the American Society of Nephrology

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The coexistence of kidney disease with a need for immunosuppressive therapy leads to the convergence of several threats to bone. These comprise general effects of the primary disease, e.g., inflammatory state, more specific effects of acute renal failure or chronic kidney disease, and effects of therapies. Multisystem inflammatory disease that requires immunosuppression is associated frequently with kidney damage, and any reduction of kidney function that takes the patient into or beyond chronic kidney disease stage 2 for more than a short time is likely to have a negative impact on bone health. Bone mineral density frequently is low and fracture rates are high, although correlations often are poor. Chronic inflammation leads to local and systemic imbalance between bone formation and resorption. Upregulation of NF-␤ ligand (RANKL) and variable downregulation of osteoprotegerin are implicated, and bone health may improve in response to treatment of the inflammatory state. Certain immunosuppressive agents, especially glucocorticoids and calcineurin inhibitors, contribute further to bone loss. Antiresorptive agents such as bisphosphonates are used widely and, although able to prevent loss of bone mineral density, have uncertain effects on fracture rates. Augmentation of anabolic activity is desirable but elusive. Synthetic parathyroid hormone is untested but has potential. Manipulation of the RANKL/osteoprotegerin system now is feasible using antibodies to RANKL or synthetic osteoprotegerin. In the future, manipulation of the calcium-sensing receptor using calcimimetic or calcilytic agents may allow the anabolic effects of parathyroid hormone to be harnessed to good effect. With all of these therapies, it will be important to assess response in relation to important clinical end points such as fracture.

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“…mostraram que azatioprina não modifica a massa óssea (21). Sirolimus e micofenolato de mofetil são duas drogas mais recentes, também utilizadas na terapia imunossupressora e que não mostraram efeitos deletérios sobre a densidade mineral óssea (22,23). Goodman GR e cols.…”

Section: Outros Imunossupressoresunclassified

Osteoporose após transplante de órgãos sólidos

Cipriani

Farias

2005

Arq Bras Endocrinol Metab

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RESUMOA osteoporose é uma complicação comum após os transplantes de rim, coração, fígado e pulmão. Os esquemas imunossupressores para evitar a rejeição do órgão enxertado após o transplante freqüentemente incluem glicocorticóides, ciclosporina A e tacrolimus, os quais possuem efeitos danosos sobre a homeostase mineral óssea, impostos a um esqueleto já comprometido. Outros fatores que provavelmente contribuem para a patogênese da osteoporose pós-transplante são deficiência de vitamina D, hiperparatireoidismo secundário e hipogonadismo. Medidas para avaliação da saúde óssea antes do transplante deveriam ser realizadas: densitometria mineral óssea, radiografia da coluna, avaliação do nível de vitamina D e dos hormônios gonadais. Todos os pacientes transplantados deveriam ser submetidos à profilaxia da perda óssea. Estudos clínicos sugerem que os bisfosfonatos são os agentes mais promissores para a prevenção e o tratamento da osteoporose pós-transplante. ABSTRACT Osteoporosis After Solid Organs Transplantation.Osteoporosis is a common complication following kidney, heart, liver and lung transplantation. Immununosuppressive regimens to prevent graft rejection after transplantation commonly include glucocorticoids, cyclosporin A and tacrolimus which are detrimental to bone and mineral homeostasis and are superimposed on an already compromised skeleton. Additional factors likely to contribute to post-transplantation osteoporosis pathogenesis are vitamin D insufficiency, secondary hyperparathyroidism and hypogonadism. Measures should be taken to optimize bone health prior transplantation: bone mineral density and spinal Xrays should be performed, and vitamin D and gonadal status assessed. Prophylaxis against bone loss after transplantation should be considered for all patients. Data from clinical trials suggest that bisphosphonates are the most promising agents for the prevention and treatment of post-transplantation osteoporosis. EMBORA A IDÉIA MAIS COMUM seja de que a osteoporose acometa primariamente as mulheres pós-menopausa, outras populações também são de alto risco. Um desses grupos é formado pelos receptores de transplante de órgãos, e quanto maior a sobrevida desses pacientes, maior será o tempo de exposição aos riscos de fraturas. Nas últimas décadas, os transplantes vêm se tornando uma terapia efetiva para doenças renais, hepáticas, cardíacas e pulmonares em estágios finais. O Brasil acompanha essa progressão no número revisão

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Mycophenolate Mofetil: A Promising New Immunosuppressant That Does Not Cause Bone Loss in the Rat1,2

Abstract: In this relatively short-term study, MMF did not cause osteopenia in the rat model, but the suppressed bone gla protein merits further study.

Cited by 69 publications

References 8 publications

Osteoporosis in Organ Transplant Patients

Osteoporosis in Organ Transplant Patients

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

Osteoporose após transplante de órgãos sólidos

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