Bone Loss after Cardiac Transplantation
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《新英格兰医药杂志》
Although clinicians generally consider osteoporosis to be a disease primarily affecting postmenopausal women, other populations are also at high risk. One such group is recipients of organ transplants, who, as their long-term survival improves, have begun to face other medical problems, including osteoporosis. Transplant recipients have generally had long-standing, chronic disease and must receive high doses of antirejection medications designed to suppress their immune system. In this issue of the Journal, Shane et al. (pages 767–776) present data from a randomized trial in which patients who had received a cardiac transplant were given either a bisphosphonate (alendronate) or calcitriol, the active metabolite of vitamin D. Both active therapies appeared to ameliorate the process of post-transplantation bone loss, in comparison with the bone loss that occurred in a reference group. To understand why two quite disparate drugs might be effective in this situation, it is important to consider how transplant recipients lose bone and how osteoporosis and fractures develop.
By the time of cardiac transplantation, many patients already have clinically significant bone disease; osteoporosis occurs in at least 10 percent of these patients. The long period of illness before transplantation, often accompanied by poor nutrition, limited mobility, weight loss, gonadal dysfunction (in patients of both sexes), and treatment with medications that are detrimental to the skeleton are all contributing factors. Postmenopausal women who require a cardiac transplant are likely to have the added problem of bone loss related to estrogen deficiency. In the rare case of a child who receives a heart transplant, the failure to attain peak bone mass may contribute to post-transplantation bone disease. In addition to the effects of chronic illness, various metabolic changes that occur before and after transplantation and other risk factors may also lead to bone loss. Before transplantation, for example, renal insufficiency and secondary hyperparathyroidism and abnormal vitamin D metabolism may contribute to bone loss, as would liver failure and related undernutrition and aberrant hepatic vitamin D metabolism. Many patients who are on waiting lists for cardiac transplantation have received medications such as loop diuretics, which affect the skeleton by causing urinary calcium loss.
To make matters worse, further bone loss occurs after transplantation, with a prevalence of 2 to 20 percent during the first year. The rate of fractures begins to increase within months after transplantation, and fractures may occur at higher levels of bone mineral density than would be expected in otherwise healthy patients. Contributing to these changes are the metabolic consequences of transplantation, including the very medications that are used to protect the graft — particularly glucocorticoids and calcineurin inhibitors. In the period after transplantation, bone resorption increases (an effect of calcineurin inhibitors such as cyclosporine), and bone formation decreases (probably a specific effect of high-dose glucocorticoids). The skeletal effects of newer immunosuppressive agents such as mycophenolate mofetil and sirolimus are unclear but require monitoring. Furthermore, after cardiac transplantation, renal function often declines, possibly leading to hyperparathyroidism, as well as to a decrease in the level of 1,25-dihydroxyvitamin D, the active metabolite of vitamin D. After transplantation, gonadal function declines at least transiently, and it often remains poor for many months. The combination of all these factors results in the removal of bone by osteoclasts without concomitant repair by osteoblasts — an effect that is often referred to as the uncoupling of bone formation and resorption.
The process of bone-tissue loss, irrespective of the circumstance, results from the interruption of the normal bone-remodeling process that is necessary to ensure that bone tissue remains healthy and mechanically sound (see Figure). Bone remodeling, a complex and incompletely elucidated process, repairs any skeletal microdamage and contributes to the release of calcium that is needed to maintain physiologic plasma calcium levels. Too much remodeling harms the skeleton, but so does too little, by allowing an accumulation of microdamage.
Figure. Regulation of Bone Remodeling.
The schematic illustrates the key factors that are thought to be involved in the activation, resorption, and formation phases of the bone-remodeling cycle. PTH denotes parathyroid hormone, TNF- tumor necrosis factor , GM-CSF granulocyte–macrophage colony-stimulating factor, M-CSF macrophage colony-stimulating factor, RANK receptor activator of nuclear factor B; RANK L RANK ligand, 1,25(OH)2D 1,25-dihydroxyvitamin D, OPG osteoprotegerin, PGE2 prostaglandin E2,TGF- transforming growth factor , FGF fibroblast growth factor, BMP bone morphogenetic protein, Cbfa-1 core binding factor 1, Runx-2 runt-related transcription factor 2, and IGF-I insulin-like growth factor I.
Bone remodeling takes place in microscopic subunits of osteoblasts and osteoclasts called bone multicellular units or "remodeling units." Within each unit, osteoclasts organize as a cutting vanguard, dissolving the crystals and enzymatically removing the organic component, and osteoblasts sweep in behind them, synthesizing new osteoid and filling in the defect. The new osteoid then mineralizes to form mature bone, generating a new osteon.
In young adults, there is a balance within each bone multicellular unit whereby the bone that is removed is replaced by an equal amount of newly synthesized material. Anything that disturbs this balance will cause either a net gain or a net loss of bone tissue. The removal of greater amounts of bone (because there are more osteoclasts or more active osteoclasts) or the synthesis of less bone (because there are fewer osteoblasts or less active ones) will result in a net loss of tissue. When such an imbalance occurs, an increase in the number of sites of active remodeling compounds the problem. Negative effects are more readily apparent within cancellous bone, which has greater remodeling activity than cortical bone, but both types of bone are affected. In addition to the loss of bone mass, the structural consequences include the loss of trabeculae, the thinning and increased porosity of the cortex, and the impairment of the quality of the tissue. An increase in the number of remodeling sites in cancellous bone increases the risk of trabecular perforation. Finally, the presence of active remodeling units in cancellous bone results in weak points through which microfractures can occur.
In patients who undergo cardiac transplantation, rapid bone loss occurs because new remodeling units continue to be activated — and at faster rates — after transplantation. Bone resorption within each remodeling unit is excessive (driven by calcineurin inhibitors) and is followed by inadequate bone formation (due to depression by glucocorticoid therapy). Thus, the concerned clinician must evaluate and protect the bones of cardiac-transplantation candidates and patients. The assessment of bone mineral density before transplantation, the identification of risk factors, and planning for post-transplantation monitoring and bone care are crucial. In addition, radiography of the spine, the evaluation of vitamin D status (through the measurement of serum levels of calcium, parathyroid hormone, and vitamin D metabolites), and the assessment of thyroid and gonadal function should be considered, as indicated. If available, measurements of markers of bone remodeling, such as N-telopeptide, may be useful in the assessment of the severity of metabolic bone disease. Treatment with antiresorptive agents, vitamin D, or other strategies should be considered during the waiting period before transplantation, with the aim of correcting metabolic abnormalities. Post-transplantation therapy should be initiated as early as is feasible, although specific guidelines are not available.
The report by Shane and colleagues suggests that alendronate and calcitriol may improve bone density after transplantation. How would these agents do so? Alendronate, an amino bisphosphonate, increases osteoclast apoptosis and reduces the overall number of active osteoclasts, thereby reducing bone resorption. Alendronate may also reduce the frequency with which new units are activated. These effects have been well documented in postmenopausal women with osteoporosis. In addition, alendronate may prolong the survival of osteoblasts.
Calcitriol therapy, which has also been investigated in postmenopausal women with osteoporosis, reduces bone resorption at low doses but increases bone resorption at higher doses. The decrease in resorption occurs through an indirect mechanism: the reduction of the circulating parathyroid hormone level, as was seen in the study by Shane et al. The primary effect of calcitriol is the stimulation of intestinal calcium absorption — hence the requirement to control and monitor calcium excretion.
Shane et al. report a nonsignificant trend toward fewer fractures in the treatment groups; the study, however, was limited both by its small size and by the lack of randomized controls, so this observation is of unclear import. Although one may speculate that combination treatment with calcitriol and a bisphosphonate might confer an additive skeletal benefit, it is important to conduct further studies in order to assess this possibility. Ultimately, post-transplantation immunosuppressive protocols that minimize the use of glucocorticoids, calcineurin inhibitors, and other medications that have adverse effects on the skeleton will go a long way toward reducing the prevalence of fractures after cardiac transplantation.
Source Information
From the Regional Bone Center, Helen Hayes Hospital, West Haverstraw, N.Y.
Related Letters:
Alendronate versus Calcitriol for Prevention of Bone Loss after Cardiac Transplantation
Gutteridge D. H., Dejardin A., Devogelaer J.-P., Goffin E., Hoefle G., Holzmueller H., Drexel H., Shane E.(Robert Lindsay, M.D.)
By the time of cardiac transplantation, many patients already have clinically significant bone disease; osteoporosis occurs in at least 10 percent of these patients. The long period of illness before transplantation, often accompanied by poor nutrition, limited mobility, weight loss, gonadal dysfunction (in patients of both sexes), and treatment with medications that are detrimental to the skeleton are all contributing factors. Postmenopausal women who require a cardiac transplant are likely to have the added problem of bone loss related to estrogen deficiency. In the rare case of a child who receives a heart transplant, the failure to attain peak bone mass may contribute to post-transplantation bone disease. In addition to the effects of chronic illness, various metabolic changes that occur before and after transplantation and other risk factors may also lead to bone loss. Before transplantation, for example, renal insufficiency and secondary hyperparathyroidism and abnormal vitamin D metabolism may contribute to bone loss, as would liver failure and related undernutrition and aberrant hepatic vitamin D metabolism. Many patients who are on waiting lists for cardiac transplantation have received medications such as loop diuretics, which affect the skeleton by causing urinary calcium loss.
To make matters worse, further bone loss occurs after transplantation, with a prevalence of 2 to 20 percent during the first year. The rate of fractures begins to increase within months after transplantation, and fractures may occur at higher levels of bone mineral density than would be expected in otherwise healthy patients. Contributing to these changes are the metabolic consequences of transplantation, including the very medications that are used to protect the graft — particularly glucocorticoids and calcineurin inhibitors. In the period after transplantation, bone resorption increases (an effect of calcineurin inhibitors such as cyclosporine), and bone formation decreases (probably a specific effect of high-dose glucocorticoids). The skeletal effects of newer immunosuppressive agents such as mycophenolate mofetil and sirolimus are unclear but require monitoring. Furthermore, after cardiac transplantation, renal function often declines, possibly leading to hyperparathyroidism, as well as to a decrease in the level of 1,25-dihydroxyvitamin D, the active metabolite of vitamin D. After transplantation, gonadal function declines at least transiently, and it often remains poor for many months. The combination of all these factors results in the removal of bone by osteoclasts without concomitant repair by osteoblasts — an effect that is often referred to as the uncoupling of bone formation and resorption.
The process of bone-tissue loss, irrespective of the circumstance, results from the interruption of the normal bone-remodeling process that is necessary to ensure that bone tissue remains healthy and mechanically sound (see Figure). Bone remodeling, a complex and incompletely elucidated process, repairs any skeletal microdamage and contributes to the release of calcium that is needed to maintain physiologic plasma calcium levels. Too much remodeling harms the skeleton, but so does too little, by allowing an accumulation of microdamage.
Figure. Regulation of Bone Remodeling.
The schematic illustrates the key factors that are thought to be involved in the activation, resorption, and formation phases of the bone-remodeling cycle. PTH denotes parathyroid hormone, TNF- tumor necrosis factor , GM-CSF granulocyte–macrophage colony-stimulating factor, M-CSF macrophage colony-stimulating factor, RANK receptor activator of nuclear factor B; RANK L RANK ligand, 1,25(OH)2D 1,25-dihydroxyvitamin D, OPG osteoprotegerin, PGE2 prostaglandin E2,TGF- transforming growth factor , FGF fibroblast growth factor, BMP bone morphogenetic protein, Cbfa-1 core binding factor 1, Runx-2 runt-related transcription factor 2, and IGF-I insulin-like growth factor I.
Bone remodeling takes place in microscopic subunits of osteoblasts and osteoclasts called bone multicellular units or "remodeling units." Within each unit, osteoclasts organize as a cutting vanguard, dissolving the crystals and enzymatically removing the organic component, and osteoblasts sweep in behind them, synthesizing new osteoid and filling in the defect. The new osteoid then mineralizes to form mature bone, generating a new osteon.
In young adults, there is a balance within each bone multicellular unit whereby the bone that is removed is replaced by an equal amount of newly synthesized material. Anything that disturbs this balance will cause either a net gain or a net loss of bone tissue. The removal of greater amounts of bone (because there are more osteoclasts or more active osteoclasts) or the synthesis of less bone (because there are fewer osteoblasts or less active ones) will result in a net loss of tissue. When such an imbalance occurs, an increase in the number of sites of active remodeling compounds the problem. Negative effects are more readily apparent within cancellous bone, which has greater remodeling activity than cortical bone, but both types of bone are affected. In addition to the loss of bone mass, the structural consequences include the loss of trabeculae, the thinning and increased porosity of the cortex, and the impairment of the quality of the tissue. An increase in the number of remodeling sites in cancellous bone increases the risk of trabecular perforation. Finally, the presence of active remodeling units in cancellous bone results in weak points through which microfractures can occur.
In patients who undergo cardiac transplantation, rapid bone loss occurs because new remodeling units continue to be activated — and at faster rates — after transplantation. Bone resorption within each remodeling unit is excessive (driven by calcineurin inhibitors) and is followed by inadequate bone formation (due to depression by glucocorticoid therapy). Thus, the concerned clinician must evaluate and protect the bones of cardiac-transplantation candidates and patients. The assessment of bone mineral density before transplantation, the identification of risk factors, and planning for post-transplantation monitoring and bone care are crucial. In addition, radiography of the spine, the evaluation of vitamin D status (through the measurement of serum levels of calcium, parathyroid hormone, and vitamin D metabolites), and the assessment of thyroid and gonadal function should be considered, as indicated. If available, measurements of markers of bone remodeling, such as N-telopeptide, may be useful in the assessment of the severity of metabolic bone disease. Treatment with antiresorptive agents, vitamin D, or other strategies should be considered during the waiting period before transplantation, with the aim of correcting metabolic abnormalities. Post-transplantation therapy should be initiated as early as is feasible, although specific guidelines are not available.
The report by Shane and colleagues suggests that alendronate and calcitriol may improve bone density after transplantation. How would these agents do so? Alendronate, an amino bisphosphonate, increases osteoclast apoptosis and reduces the overall number of active osteoclasts, thereby reducing bone resorption. Alendronate may also reduce the frequency with which new units are activated. These effects have been well documented in postmenopausal women with osteoporosis. In addition, alendronate may prolong the survival of osteoblasts.
Calcitriol therapy, which has also been investigated in postmenopausal women with osteoporosis, reduces bone resorption at low doses but increases bone resorption at higher doses. The decrease in resorption occurs through an indirect mechanism: the reduction of the circulating parathyroid hormone level, as was seen in the study by Shane et al. The primary effect of calcitriol is the stimulation of intestinal calcium absorption — hence the requirement to control and monitor calcium excretion.
Shane et al. report a nonsignificant trend toward fewer fractures in the treatment groups; the study, however, was limited both by its small size and by the lack of randomized controls, so this observation is of unclear import. Although one may speculate that combination treatment with calcitriol and a bisphosphonate might confer an additive skeletal benefit, it is important to conduct further studies in order to assess this possibility. Ultimately, post-transplantation immunosuppressive protocols that minimize the use of glucocorticoids, calcineurin inhibitors, and other medications that have adverse effects on the skeleton will go a long way toward reducing the prevalence of fractures after cardiac transplantation.
Source Information
From the Regional Bone Center, Helen Hayes Hospital, West Haverstraw, N.Y.
Related Letters:
Alendronate versus Calcitriol for Prevention of Bone Loss after Cardiac Transplantation
Gutteridge D. H., Dejardin A., Devogelaer J.-P., Goffin E., Hoefle G., Holzmueller H., Drexel H., Shane E.(Robert Lindsay, M.D.)