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Requests for reprints should be addressed to Elizabeth Shane, MD, Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032
Affiliations
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA
Within the past 2 decades, organ transplantation has become established as effective therapy for endstage renal, hepatic, cardiac, and pulmonary disease. Regimens to prevent rejection after transplantation commonly include high-dose glucocorticoids and calcineurin-calmodulin phosphatase inhibitors (the cyclosporines and tacrolimus), which are detrimental to bone and mineral homeostasis, and are associated with rapid bone loss that is often superimposed upon an already compromised skeleton. The incidence of fracture ranges from 8% to 65% during the first year after transplantation. In general, fracture rates are lowest in renal transplant recipients and highest in patients who receive a liver transplant for primary biliary cirrhosis. Rates of bone loss and fracture are greatest during the first 6 to 12 months after transplantation. Postmenopausal women and hypogonadal men appear to be at increased risk. Although no pretransplant densitometric or biochemical parameter has yet been identified that adequately predicts fracture risk in the individual patient, low pretransplant bone mineral density does tend to increase the risk of fracture, particularly in women. However, patients may sustain fractures despite normal pretransplant bone mineral density. Although the pathogenesis of the rapid bone loss is multifactorial, prospective biochemical data suggest that uncoupling of bone formation from resorption may be in part responsible, at least during the first 3 to 6 months. Prevention of transplantation osteoporosis should begin well before transplantation. Patients awaiting transplantation should be evaluated with spine radiographs, bone densitometry, thyroid function tests, serum calcium, vitamin D, parathyroid hormone, and testosterone (in men). Therapy for osteoporosis, low bone mass, and potentially reversible biochemical causes of bone loss should be instituted during the waiting period before transplantation. In patients with normal pretransplant bone density, therapy to prevent early posttransplant bone loss should be instituted immediately following transplantation. Most pharmacologic agents available for therapy of osteoporosis have not been subject to prospective controlled studies in organ transplant recipients. However, antiresorptive drugs, such as biphosphonates, appear to hold therapeutic promise.
Within the past 2 decades, organ transplantation has become established as effective therapy for endstage renal, hepatic, cardiac, and pulmonary disease. In the United States alone, between 1988 and 1995, 131,850 patients survived organ transplantation (
). The majority received kidney transplants, followed by liver, heart, pancreas, lung, and heart-lung. Overall 1-year patient survival now ranges from 62.7% for heart-lung recipients to 97.3% for living donor kidney recipients (
). Survival 5 years after organ transplantation is also quite good, ranging from 41.4% for heart-lung recipients to 90.3% for living donor kidney recipients. Moreover, many patients are alive 10 years after transplantation (
). These agents have lowered the incidence of organ rejection and have markedly improved long-term survival of transplant recipients. Although the use of cyclosporines has permitted reduction in glucocorticoid doses, many transplant recipients develop symptomatic osteoporosis and fractures that reduce their quality of life (
). Patients who survive transplantation may then suffer with another, often painful and debilitating illness.
Within the past 10 years, there have been important advances in our understanding of osteoporosis in organ transplant recipients. These have been based upon the studies of Epstein and colleagues (
) who have delineated the effects of cyclosporines and other immunosuppressive agents on the rat skeleton, and also of other investigators who have described the natural history, pathogenesis, and more recently, the prevention and management of transplantation osteoporosis. In this article, we will review the effects of commonly used immunosuppressive agents on the skeleton and the clinical features of osteoporosis that follows kidney, heart, lung, and liver transplantation. Finally, we will present an approach to the prevention and management of transplantation osteoporosis, based upon the limited data that are now available.
Skeletal effects of immunosuppressive drugs
Glucocorticoids
Glucocorticoids have long been associated with osteoporosis, and their effects on bone and mineral homeostasis have been extensively reviewed (
). However, although low bone mass or fractures are present in 30% to 50% of patients treated with oral glucocorticoids for more than 6 months, the true incidence of osteoporosis in these patients is unclear. In part this is because few prospective studies have compared glucocorticoid-treated patients to patients with the same disease who are not receiving glucocorticoids. It is generally accepted, however, that nearly all patients taking glucocorticoids at doses in excess of 10 mg/day of prednisone or its equivalent, sustain substantial bone loss, regardless of age, race, gender, or menopausal status. In general, bone loss is most rapid during the first 12 to 18 months of therapy and is directly related to dose and duration of glucocorticoid exposure. However, even rather small doses of glucocorticoids (7.5 to 10 mg/day of prednisone) may cause demineralization, particularly when administered for long periods of time. Areas of the skeleton rich in trabecular or cancellous bone (ribs, vertebrae, and distal ends of long bones) and the cortical rim of the vertebral body are most severely affected, and are also the most common sites for fracture. Postmenopausal women may be at greater risk for fracture than other groups, because glucocorticoid-related bone loss is superimposed upon that already sustained because of aging and estrogen deficiency.
The pathogenesis of steroid-induced bone loss is multifactorial. Glucocorticoids have many systemic actions that indirectly affect bone and mineral homeostasis (Table 1). Pharmacologic doses are associated with a generalized defect in calcium transport across biological membranes (
). Net intestinal calcium absorption is reduced in patients receiving glucocorticoids, although the mechanisms responsible are incompletely understood (
). Hyperparathyroidism, secondary to both negative calcium balance and decreased calcium transport across the parathyroid cell membrane, has been demonstrated in some but not all studies of patients on glucocorticoids (
). Glucocorticoids also blunt gonadotropin release, and their administration is associated with decreased gonadal secretion of estrogen and androgens (
). Similarly, glucocorticoid-induced suppression of adrenocorticotropic hormone (ACTH) is associated with reduced secretion of adrenal androgens and estrogens (
). The resulting hypogonadal state may contribute indirectly to bone loss. Glucocorticoids inhibit pituitary secretion of growth hormone and decrease the production or bioactivity of certain skeletal growth factors (eg, insulin-like growth factor 1, transforming growth factor β), thus indirectly reducing bone formation (
Glucocorticoids also have a number of direct effects on bone. They directly inhibit bone formation by decreasing osteoblast recruitment and differentiation, and they inhibit synthesis of type I collagen. These effects are reflected histologically by marked decreases in osteoid surface and mineral apposition rate (
) and biochemically by low serum levels of osteocalcin (bone gla protein), a major noncollagenous bone matrix protein. Glucocorticoids also increase bone resorption by directly enhancing osteoclast activity, as well as by indirect effects that may be mediated by reductions in gonadal steroid production and altered sensitivity of osteoclasts to parathyroid hormone. The sum of these effects on bone and mineral metabolism results in rapid bone loss. Glucocorticoid-induced myopathy may also contribute to bone loss by altering gravitational forces on the skeleton and reducing weight-bearing activity and mobility. Myopathy may also affect fracture rates by increasing the propensity to fall.
Glucocorticoids are included in most posttransplant immunosuppressive regimens. High doses (up to 120 mg of prednisone or its equivalent daily) are commonly prescribed immediately after transplantation and during episodes of severe rejection, with gradual reduction over several weeks. Total dosage varies with the organ transplanted, the number and management of rejection episodes, and the practice of individual transplantation programs. In recent years, there has been a trend toward more rapid lowering of glucocorticoid doses after transplantation or rejection, and an increase in the use of alternative drugs to treat rejection. However, even in those programs that have embraced the use of lower doses of glucocorticoids, there is still sufficient use in the initial year to cause bone loss.
The cyclosporines
The introduction of cyclosporines to the field of organ transplantation in the early 1980s was associated with a marked reduction in episodes of rejection and improvement in graft survival (
). Cyclosporine A, the most commonly used of these drugs, suppresses immune responsiveness by inhibition of T-cell function. The incorporation of cyclosporine A into posttransplant immunosuppressive regimens permitted glucocorticoid dosages to be reduced in organ transplant recipients, and it was assumed that the deleterious effects of organ transplantation on the skeleton would be ameliorated. Unfortunately, this has not proved to be the case. While this may be because glucocorticoids continue to be used, the discovery that cyclosporine A has independent effects on bone remodeling in animal models (Table 1) may also have relevance.
When cyclosporine A is administered to rats in doses comparable to those used after transplantation, severe bone loss (
), most pronounced in trabecular bone, occurs. Bone turnover is accelerated, with evidence of increased bone resorption and bone formation, reflected biochemically by elevated serum osteocalcin concentrations. In addition, renal 1 α hydroxylase activity and serum concentrations of 1,25-dihydroxyvitamin D (1,25(OH)2D) are also increased. The effects of cyclosporine A on the rat skeleton appear to be mediated, at least in part, by increased expression of interleukin-1, a cytokine that stimulates bone resorption. In rats, cyclosporine A also causes gonadal dysfunction that may indirectly cause bone loss (
Sass DA, Bowman AR, Marshall I, et al. The bisphosphonate, alendronate, reverses cyclosporine induced osteopenia in the aged rat. J Bone Miner Res 1995;10:S256. Abstract.
In the majority of transplantation regimens, cyclosporine A is used in conjunction with pharmacologic doses of glucocorticoids. Thus, it has been difficult to determine whether cyclosporine A has specific effects on bone and mineral metabolism in humans. However, cyclosporine A may stimulate bone formation, an effect opposite to that usually observed with glucocorticoids. Serum osteocalcin, usually reduced in patients receiving glucocorticoids alone, has been reported to be increased in renal (
) transplant recipients receiving both drugs. However, it remains possible that these observations reflect decreased renal clearance of osteocalcin, secondary to the known nephrotoxicity of cyclosporine A (
Cyclosporine G, an analog of cyclosporine A, is occasionally used for posttransplant immunosuppression. It is an equally potent immunosuppressant with less observed nephrotoxicity and hyperglycemia, although its effects on the rat skeleton are similar to those of cyclosporine A (
Tacrolimus (FK506) and other immunosuppressive agents
Tacrolimus, a fungal macrolide produced by streptomyces tsukubaensis, is a newer immunosuppressive agent used most commonly after liver transplantation. The immunosuppressive actions of tacrolimus are more potent than those of cyclosporine A, and therefore, steroid doses may be even more reduced in patients treated with tacrolimus (
). As with cyclosporine A, tacrolimus is generally used in conjunction with glucocorticoids, and therefore its independent effects in humans have not been well defined. However, rates of bone loss are similar in cardiac (
Stempfle HU, Wehr U, Meiger B, et al. Effect of FK506 (Tacrolimus) on trabecular bone loss shortly after cardiac transplantation. J Bone Miner Res 1996;11:S127. Abstract.
Apostlinas S, Sheiner P, Genyk Y, et al. Prospective comparison of bone loss with tacrolimus and cyclosporin A after organ transplantation. J Bone Miner Res 1997;12S. Abstract.
) transplant recipients treated with tacrolimus or cyclosporine A.
Azathioprine, a derivative of mercaptopurine, is frequently used in conjunction with glucocorticoids and cyclosporine A after organ transplantation. Short-term studies in rats show no effect on bone volume but do document an increase in osteoclast number (
). Rapamycin is a newer immunosuppressive agent currently under investigation. In rats, rapamycin does not cause bone loss, although there is evidence for increased remodeling and decreased growth rates (
). Mycophenate mofetil is replacing azathioprine with increasing frequency in immunosuppressive regimens. No effect upon bone volume was observed in the rat (
Dissanayake I, Goodman C, Bowman A, et al. Mycophenolate mofetil: a promising new immunosuppressant which does not cause bone loss in the rat. 1997. Transplantation. 1998. In press.
). No data are available on the effects of these agents on bone mass or remodeling in humans.
Clinical features of transplantation osteoporosis
The clinical presentation of transplantation osteoporosis may vary somewhat, depending on the organ transplanted. To some extent, this may be related to differing effects of the diseased organ on pretransplant bone and mineral homeostasis. Moreover, posttransplant management may vary somewhat according to the specific organ transplanted.
Kidney transplantation
Most patients undergoing kidney transplantation already have at least some evidence of renal osteodystrophy, a general term encompassing all histological derangements of bone that can occur in uremic patients. These may include hyperparathyroidism (with or without osteitis fibrosa), osteomalacia, osteosclerosis, and adynamic or aplastic bone disease (
). In some patients, more than one of these conditions may be present. In addition, patients with endstage renal disease are commonly hypogonadal and many already have been exposed to medications—such as glucocorticoids or cyclosporine A for immune complex disease, loop diuretics or aluminum-containing phosphate binders—that can affect bone and mineral metabolism. Although renal transplantation is generally associated with gradual resolution of hyperparathyroidism, aluminum-related bone disease and amyloidosis (
), immunosuppressive therapy constitutes an additional insult to a skeleton.
The rates of bone loss and fracture after renal transplantation may be somewhat lower than after liver and cardiac transplantation, perhaps because lower doses of glucocorticoids and cyclosporine A are used or because rejection is more easily detected and therefore treated earlier, resulting in lower total doses of immunosuppression. Recent prospective studies indicate that lumbar spine bone loss following renal transplantation varies from 3% to 7%. Bone loss is greatest during the first 6 months after transplantation and predominantly affects cancellous bone (
). However, there is also evidence for ongoing vertebral bone loss (approximately 2% per year) in patients followed up longitudinally between 8 and 10 years after transplantation (
). Fractures more commonly involve the long bones or metatarsals than the vertebral bodies or ribs and occur relatively late in the posttransplant period, usually more than 3 years after transplantation. This may be due, in part, to the detrimental effects of pretransplant hyperparathyroidism or persistent posttransplant hyperparathyroidism on cortical bone, rendering it thin, porous, and vulnerable to further insult. Genetic factors may also play a role in the degree of bone loss. Patients with the “favorable” bb genotype for the vitamin D receptor gene have been shown to recover more bone between 3 and 12 months after renal transplantation than those with the Bb and BB genotypes (
In contrast to renal or hepatic failure, congestive heart failure has not been associated with a well-defined disorder of bone and mineral metabolism. However, mean bone mineral density may be lower in patients before heart transplantation than in age- and gender-matched controls (
) compared bone mineral density measurements at the spine and hip with those of a young normal population of the same gender (T score). As defined by the World Health Organization (WHO), T score measurements between −1.0 and −2.5 standard deviations below the young normal mean indicate low bone mass or osteopenia, while those below −2.5 indicate osteoporosis (
). Of these patients with congestive heart failure, only 50% had normal lumbar spine bone mineral density and 47% had normal total hip bone mineral density (T score >−1.0). The etiology of low bone mineral density in patients with congestive heart failure was unclear. However, low serum concentrations of 25-hydroxyvitamin D (25-OHD) and 1,25(OH)2D were quite common, occurring in 18% and 30% of the patients, respectively. Moreover, vitamin D deficiency was significantly more common in the patients with more severe heart failure (
). Other factors that may contribute to low bone mineral density in patients with severe congestive heart failure include dietary calcium deficiency, therapy with loop diuretics, prerenal azotemia, hepatic congestion, and hypogonadism.
Osteoporosis, defined by densitometric criteria, and fractures are common in cardiac transplant recipients. The prevalence of vertebral fractures ranges from 18% to 50% (
) demonstrated that 36% of patients sustained one or more fractures during the first year following transplantation despite adequate supplementation with calcium (1,000 mg/day) and vitamin D (400 IU/day). The majority of fractures involved the spine, and 85% of the fractures occurred during the first 6 months following transplantation. Although no pretransplant bone mineral density or biochemical parameters predicted fractures in individual patients after transplantation, lower pretransplant bone mineral density was associated with a trend toward increased fracture risk. Moreover, women with low femoral neck bone mineral density were significantly more likely to sustain posttransplant fractures. Similar findings have been reported in a European study of 159 cardiac transplant recipients (
). In general, lumbar spine bone mineral density falls by approximately 6% to 10% during the first 6 months after transplantation, after which there is little further deterioration (Figure 1)(
). Bone loss slows or stops in the majority of patients after the first year; lumbar spine bone mineral density may increase slightly in the third year (
). Biochemical changes after cardiac transplantation include sustained decreases in serum 1,25(OH)2D and transient decreases in markers of bone formation (osteocalcin) and testosterone (in men), with return to pretransplant concentrations by 6 months (
). Higher rates of bone loss were associated with greater exposure to prednisone, lower serum concentrations of vitamin D metabolites, higher levels of bone resorption markers (
). In contrast, a recent study has demonstrated progressive increases in serum osteocalcin concentrations during 18 months following cardiac transplantation (
), a pattern that differs from the suppression of osteocalcin concentrations observed in patients on glucocorticoids. Since many of these patients were withdrawn from glucocorticoids and maintained on cyclosporine A alone, this observation may reflect an independent effect of cyclosporine A to increase bone formation or simply the withdrawal of steroids. Markers of bone resorption have been shown to increase transiently after cardiac transplantation (
Figure 1Annual rates of bone loss (percent) during the first 3 years after cardiac transplantation. A. Lumbar spine bone mineral density (BMD). B. Femoral neck bone mineral density. C. Proximal radius bone mineral density. The numbers next to each bar indicate the numbers of patients included in the analysis. a, P <0.001 compared with year 2; b, P <0.001 compared with year 3; c, P <0.02 compared with year 3; d, P <0.001 compared with year 2; e, P <0.03 compared with year 3. Reprinted from Shane et al (51) with permission.
). Decreased mobility, hypoxemia, malnutrition, vitamin D deficiency, tobacco use, and prior glucocorticoid therapy may all contribute to pretransplant osteopenia. Cystic fibrosis, a common disease for which patients undergo lung transplantation, is itself associated with osteopenia (
>Donovan DS Jr, Papadopoulos A, Staron RB, et al. Osteoporosis is associated with vitamin D deficiency in adults with severe cystic fibrosis. J Bone Miner Res. 1996;11:541. Abstract.
), calcium malabsorption, and hypogonadism. A recent cross-sectional study revealed that 45% of 55 pretransplant patients and 73% of 45 posttransplant patients had bone mineral density more than 2 SD below age- and gender-matched controls (
). A similar study of 70 patients awaiting lung transplantation revealed that only 34% had normal spine bone mineral density and 22% had normal hip bone mineral density (Figure 2)(
). In both studies, glucocorticoid exposure was inversely related to bone mineral density. Fracture prevalence was 29% in patients with chronic obstructive pulmonary disease and 25% in patients with cystic fibrosis (
Figure 2Frequency distribution of bone mineral density (BMD) measurements of the lumbar spine (A) and femoral neck (B) in patients with end-stage pulmonary disease awaiting lung transplantation. The data are expressed as T scores, which relate bone mineral density measurements of individual patients to those of a young normal population of the same gender. T score measurements falling between −1.0 and −2.5 SD below the mean (hatched bars) indicate low bone mass or osteopenia while those below −2.5 SD below the mean (cross-hatched bars) indicate osteoporosis. Reprinted from Shane et al (56) with permission.
Low bone mass and abnormal mineral metabolism are common in several forms of chronic liver disease. Chronic cholestatic liver diseases, such as biliary cirrhosis, are associated with selective impairment of osteoblast activity related to accumulation of toxins normally excreted or metabolized by the liver (
). Therefore, liver transplant recipients are highly likely to develop symptomatic transplantation osteoporosis.
The natural history of osteoporosis after liver transplantation is similar to that observed after cardiac transplantation, although rates of bone loss and fracture may be higher (
). Lumbar spine bone mineral density falls by 3.5% to 24%, primarily in the initial 6 to 12 months. Fracture incidence is also highest in the first 6 months and ranges from 24% to 65%, the latter in a group of women with primary biliary cirrhosis (
). As with cardiac transplantation, no pretransplant indicator reliably predicts fracture risk in the individual patient. Stress fractures of the sacrum have also been reported after liver transplantation (
). Similar to solid organ transplantation, osteopenia is probably related to both pretransplant and posttransplant factors. In preparation for transplantation patients receive myeloablative therapy (alkylating agents or total body irradiation) that decreases bone formation and accelerates bone resorption (
Since bone disease is so common in patients awaiting organ transplantation, it is our opinion that all patients should be evaluated for osteoporosis and disorders of mineral metabolism prior to transplantation. An important risk factor for bone loss and osteoporosis is hypogonadism, commonly associated with chronic illness in both men and women. In women, premature menopause, postmenopausal status, and a history of eating disorders or prolonged amenorrhea are important risk factors. Patients with thyrotoxicosis, hyperparathyroidism, vitamin D deficiency, or immobilization, and those with a history of exposure to heparin, loop diuretics, glucocorticoids, or suppressive doses of thyroxine, may also have reduced bone mineral density. Patients with renal osteodystrophy should be evaluated and treated according to accepted clinical practice (
). Osteoporosis and disorders of mineral metabolism such as vitamin D deficiency, that could predispose to fractures after transplantation, can then be addressed during the waiting period before transplantation, which may last for 1 or 2 years in many patients.
The most important diagnostic study prior to transplantation (Table 2)is measurement of bone mineral density of the hip and spine. Bone mineral density of the proximal radius, a site comprised almost exclusively of cortical bone, should be measured if available, since bone mineral density at this site has been shown to decline during the second and third years after cardiac transplantation (Figure 1). In our studies and those of other investigators, pretransplant bone mineral density did not reliably predict fracture in the individual patient (
). However, low pretransplant bone mineral density did tend to increase the risk of fracture in the group as a whole, and particularly in postmenopausal women. We, therefore, believe that pretransplant screening is valuable to identify and treat those patients who already have osteoporosis or other abnormalities of bone and mineral metabolism, particularly vitamin D deficiency. Although no data are yet available that pretransplantation therapy increases bone mass and reduces posttransplant fracture risk, hormone replacement or bisphosphonate therapy clearly increase bone mineral density and reduce fracture rates in other patients (
). We therefore believe that individuals awaiting transplantation who meet WHO criteria for diagnosis of osteoporosis or low bone mass should receive appropriate evaluation and therapy, similar to other patients with or at risk for osteoporosis.
Table 2Pretransplant Osteoporosis Evaluation
1. History and physical examination with attention to risk factors for osteoporosis
2. Bone densitometry by dual energy x-ray absorptiometry
3. Thoracic and lumbar spine radiographs
4. Serum calcium, parathyroid hormone, 25-hydroxyvitamin D and testosterone levels (in men); thyroid function tests
5. Urine for calcium and markers of bone resorption (optional)
). Biochemical evaluation should include serum calcium, thyroid function tests, intact parathyroid hormone, 25-OH vitamin D, and testosterone in men. Markers of bone formation (bone specific alkaline phosphatase and serum osteocalcin) and resorption (urinary pyridinium crosslink or N-telopeptide excretion) can also be measured, although they are primarily useful in the research setting.
All patients should receive the recommended daily allowance of vitamin D (400 to 800 IU) and elemental calcium (1,000 to 1,500 mg, depending on dietary intake and menopausal status). Hormone replacement therapy should be considered in postmenopausal and premenopausal amenorrheic women and hypogonadal men who do not have contraindications. Since there are no data on hormone replacement therapy in women who are awaiting transplantation, it is reasonable to treat them with doses that have been associated with increases in bone mineral density in other studies. The usual dose is 0.625 mg of conjugated equine estrogen or 0.05 mg of transdermal estrogen daily, given with a progestin if the patient has an intact uterus. Premenopausal women with amenorrhea are generally managed with oral contraceptives. Hypogonadal men should be treated with injectable or transdermal testosterone preparations, in doses individualized to maintain serum testosterone levels within the normal range. Patients who are found to have osteoporosis before transplantation may also be treated with a bisphosphonate or calcitonin. The pretransplant waiting period is often long enough (1 to 2 years) for improvement in bone mass to occur before transplantation. Serious consideration should be given to the advisability of transplanting individuals with multiple fractures or densitometric evidence of severe osteoporosis (bone mineral density more than 3 to 4 SD below peak normal), since such patients may experience more fractures after transplantation.
After transplantation
As rapid bone loss and fractures typically occur during the first 3 to 12 months after organ transplantation, strategies to prevent bone loss and fractures should be instituted immediately following transplantation. Prospective controlled studies evaluating particular therapies for prevention and treatment of transplantation osteoporosis are few in number. Our recommendations are based upon data from animal studies, experience with management of glucocorticoid-induced osteoporosis, and some experience with transplant recipients.
Several categories of drugs are currently available for therapy of transplantation osteoporosis. These include drugs that inhibit bone resorption such as bisphosphonates, calcitonin, and estrogen; those that stimulate bone formation, such as fluoride; and those whose mechanism of action is not well-defined, such as testosterone and analogues of vitamin D. Several studies have documented that markers of bone resorption increase transiently during the immediate posttransplant period (
). Moreover, at least one study has observed a direct association between rates of bone loss and levels of bone resorption markers after transplantation (
). Therefore, attempts to prevent posttransplantation bone loss—and perhaps fractures—by inhibition of bone resorption are a logical first step.
Bisphosphonates
Bisphosphonates inhibit bone resorption. At least three randomized studies have shown that cyclical etidronate therapy prevents glucocorticoid-induced bone loss (
), and some studies suggest that these drugs can prevent bone loss and fractures after organ transplantation. In a nonrandomized study of cardiac transplant recipients treated with a single intravenous infusion of 60 mg of pamidronate within 2 weeks of transplantation followed by 4 cycles of oral etidronate (400 mg/day for 14 days every 3 months), lumbar spine bone mineral density declined by only 1.3% versus 7.4% in historical controls (
Shane E, Thys-Jacobs S, Papadopoulos A, et al. Antiresorptive therapy prevents bone loss after cardiac transplantation (CTX). J Bone Miner Res 1996;11:635. Abstract.
). Bone loss at the femoral neck was also significantly reduced. The incidence of fracture 1 year after transplantation was 11% in the treated group compared with 35% in the untreated group (
Shane E, Thys-Jacobs S, Papadopoulos A, et al. Antiresorptive therapy prevents bone loss after cardiac transplantation (CTX). J Bone Miner Res 1996;11:635. Abstract.
). Similarly, lumbar spine and femoral neck bone loss were prevented in a randomized study of patients who received two intravenous infusions of pamidronate immediately and 1 month after renal transplantation (
Fan S, Almond MK, Ball E, et al. Randomized prospective study demonstrating prevention of bone loss by pamidronate during the first year after renal transplantation. J Am Soc Nephrol 1996;7:A2714. Abstract.
). In contrast, oral cyclical etidronate, calcium, and 1 α hydroxycholecalciferol (1 μg/day) failed to prevent bone loss and fractures after liver transplantation (
). Alendronate is a more potent oral bisphosphonate, recently approved in the United States for prevention and treatment of postmenopausal osteoporosis. In a recent double-blind, randomized study, alendronate has been shown to increase bone mineral density and prevent bone loss in patients on glucocorticoid therapy (
), and our anecdotal experience suggests that it is also effective in organ transplant recipients. Clinical trials are currently under way with alendronate in prevention of transplantation osteoporosis after cardiac, liver, and renal transplantation.
Although bisphosphonates are promising agents for the prevention and therapy of bone loss in organ transplant recipients, they must be used with caution in certain clinical situations. Because they are renally excreted, bisphosphonates are not recommended in patients with moderate-to-severe renal insufficiency (serum creatinine >3.0 mg/dL; creatinine clearance <30 mL/min). Since both alendronate and pamidronate therapy are associated with decreases in serum phosphorous and calcium and increases in serum intact parathyroid hormone concentrations, these drugs could exacerbate or prolong the resolution of secondary hyperparathyroidism after renal transplantation. Finally, these drugs are not approved for use in pediatric patients, in whom they may affect skeletal growth.
Calcitonin
Calcitonin, another antiresorptive drug, has been used successfully to treat glucocorticoid-induced osteoporosis (
). A recent study that randomly assigned patients to receive oral etidronate or injectable calcitonin after liver transplantation demonstrated significant increases of 6% to 8% in vertebral bone mineral density with both treatments with no significant difference between the groups (
). However, our anecdotal experience with injectable calcitonin in the posttransplantation setting suggests that this drug may be relatively ineffective in preventing bone loss or fractures. No published data are available evaluating the efficacy of intranasal calcitonin in transplant recipients.
Estrogen
Many postmenopausal women undergo organ transplantation, and premenopausal women with severe chronic illness may have hypothalamic amenorrhea. Both postmenopausal women and amenorrheic premenopausal women have rates of bone loss that exceed those of women with regular menses. Hormone replacement therapy effectively prevents bone loss related to estrogen deficiency. Although no studies have been published regarding the effects of hormone replacement therapy in organ transplant recipients, estrogens improve bone mineral density in women treated with glucocorticoids, and animal studies suggest that estrogen prevents cyclosporine A-induced bone loss. Therefore, it is reasonable that postmenopausal women or premenopausal women with amenorrhea receive hormone replacement therapy, as described above, both before and after transplantation if no contraindications exist. Progesterone must be given concomitantly to prevent endometrial hyperplasia in patients with an intact uterus. Daily dosing of estrogen and progesterone is preferred after transplantation as estrogen enhances hepatic metabolism of cyclosporine A, and a cyclic regimen in which estrogen is taken for 25 days each month could result in fluctuating cyclosporine A levels. Premenopausal women with hypothalamic amenorrhea of chronic illness often begin menstruating within 3 to 6 months of successful transplantation, and estrogen therapy may often be discontinued 6 months after surgery. However, although estrogen therapy is of theoretical benefit after transplantation, our clinical experience suggests that estrogen replacement therapy alone is not sufficient to prevent bone loss during the first posttransplant year in postmenopausal women.
Analogues of vitamin D
Pharmacologic doses of vitamin D are often recommended to prevent glucocorticoid-induced (
). Whether vitamin D should be prescribed as the parent compound (50,000 IU once weekly), calcifediol (25OHD; 20 to 50 μg daily), or calcitriol (1,25(OH)2D; 0.5 to 1.5 μg daily) is unclear. Calcitriol, at an average daily dose of 0.6 μg, has been shown to prevent lumbar spine bone loss in asthmatic patients treated with glucocorticoids (
). Addition of calcitonin did not provide further benefit. Moreover, cardiac transplant recipients receiving vitamin D analogues had significantly less bone loss than those receiving cyclic etidronate; fractures were also more common in the etidronate group (
). The precise mechanism by which vitamin D analogues prevent bone loss in this setting is unknown. However, vitamin D administration may overcome glucocorticoid-induced inhibition of both osteoblast function and intestinal calcium absorption. Hypercalcemia and hypercalciuria are frequent side effects of vitamin D therapy, and frequent monitoring of serum and urinary calcium is required. Toxicity due to calcitriol resolves more rapidly because it is the most polar analogue of vitamin D with less accumulation in fat. Therefore, it may be the preferable analogue.
Testosterone
Hypogonadism is common in men with chronic hepatic, renal, or cardiac disease; and the suppressive effects of cyclosporine A and glucocorticoids on the hypothalamic-pituitary-gonadal axis often lower serum testosterone levels. In most cases, testosterone levels return to normal by 6 to 12 months after transplantation (
). However, in our experience, approximately 25% of men evaluated 1 to 2 years after transplantation will have biochemical hypogonadism.
Hypogonadism is a well-known cause of osteoporosis in men. Moreover, men with low serum testosterone concentrations prior to and during the first year after cardiac transplantation lose bone more rapidly (
). There is general agreement that men who are truly hypogonadal should be treated with testosterone. However, there are no data on the effect of testosterone replacement on rates of bone loss after organ transplantation; and whether testosterone replacement is advisable to counter the generally transient decreases observed during the early months after transplantation is controversial.
Potential risks of testosterone therapy include acceleration of hyperlipidemia in patients already prone to atherosclerosis from hypertension, diabetes, glucocorticoid, and cyclosporine A therapy, as well as prostatic hypertrophy and abnormal liver enzymes. Therefore, it is necessary to monitor levels of serum lipids and liver enzymes, and perform regular prostate examinations in men receiving injectable or transdermal testosterone. Potential benefits include increased lean body mass and hemoglobin levels and, possibly, an increase in bone mineral density.
Fluoride
Fluoride is one of the few available drugs that can stimulate bone formation. As such, it is an appealing approach to disorders such as transplantation or glucocorticoid-induced osteoporosis, in which inhibition of osteoblast function may play a pathogenetic role. Disodium monofluorophosphate administration was associated with a 63% increase in trabecular bone mineral density in patients with glucocorticoid-induced osteoporosis (
). Treatment with disodium monofluorophosphate, elemental calcium, and calcidiol was also associated with a significant increase in bone mineral density in patients with established osteoporosis after cardiac transplantation, compared with patients receiving calcium and calcidiol alone (
). However, increases in bone mineral density in response to fluoride therapy are not consistently associated with improvement in bone quality and strength, or reduction in fracture rates. Moreover, high doses (50 to 75 mg daily) of sodium fluoride have troubling gastrointestinal side effects. The potential approval of slow-release sodium fluoride in the United States may, however, provide alternative or adjunctive therapy for transplantation osteoporosis.
Conclusion
Solid organ and bone marrow transplantation are associated with exposure to high doses of glucocorticoids, cyclosporine A, and tacrolimus, all of which may have deleterious effects on the skeleton. In general, rapid bone loss and symptomatic fractures are confined to the first posttransplant year. However, as survival improves and age-related bone loss is superimposed upon that sustained in the early posttransplant period, a secondary increase in fracture rates is likely. Early posttransplantation bone loss is associated with biochemical uncoupling of bone turnover, with increases in markers of bone resorption and decreases in markers of bone formation. Since bone disease frequently antedates transplantation, patients awaiting transplantation should be evaluated with bone densitometry, spine radiographs, and pertinent biochemistries so that those with osteoporosis and abnormal mineral metabolism can be identified and any potentially reversible causes of bone loss can be corrected. In addition, since no pretransplant densitometric or biochemical parameter reliably predicts fracture in the individual patient, most patients should be placed on appropriate pharmacologic therapy to prevent bone loss and fractures immediately after transplantation. Although few data are available from randomized, controlled clinical trials, antiresorptive therapy with bisphosphonates shows promise in the prevention of transplantation osteoporosis.
References
United Network of Organ Sharing (UNOS) OPTN/SR 1996 annual report—graft/patient survival.
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