Keywords

FormalPara Key Points

  • Osteoporosis is prevalent among organ transplant candidates. Patients awaiting transplant should be assessed, and treatment initiated if they have osteoporosis.

  • Rapid bone loss and fractures commonly occur in the first year after transplant, though rates of bones loss have declined in recent years.

  • Bisphosphonates are the most well-studied and consistently effective agents for prevention of bone loss in organ transplant recipients.

  • Primary prevention therapy should be initiated immediately after transplantation.

  • Long-term transplant recipients should be screened and treated for osteoporosis.

Introduction

The introduction of cyclosporine to transplantation immunology in the early 1980s resulted in marked improvement in short-term graft and patient survival and ushered in a new era for patients with end-stage renal, hepatic, cardiac, pulmonary, and hematopoietic disease. The addition of cyclosporine, and later tacrolimus, to post-transplantation immunosuppression regimens permitted the use of lower doses of glucocorticoids (GCs). Therefore, it was initially expected that glucocorticoid-induced osteoporosis would be less of a problem in the cyclosporine era. During the past two decades, however, it has become clear that, despite reduced GC exposure, organ transplant recipients continue to experience rapid bone loss and fragility fractures [1,2,3,4]. Moreover, transplantation-related bone loss and fractures may become increasingly prevalent as more patients are undergoing transplantation each year and survival continues to improve [5]. The epidemiology, natural history, and pathogenesis of bone loss and fracture after various types of organ transplantation will be reviewed. Recommendations for prevention of the acute phase of bone loss after organ transplantation, and treatment of established osteoporosis in organ transplantation candidates and recipients will be summarized.

Skeletal Effects of Immunosuppressive Drugs

The Bone-Remodeling System

Transplantation osteoporosis, as with most adult metabolic bone diseases, is the result of alterations in the bone remodeling system, an orderly progression of events by which bone cells remove old bone tissue and replace it with new. Thus, it is helpful to review the orderly sequence of events that constitutes normal bone remodeling in order to understand the pathogenesis of transplantation osteoporosis. The two main processes by which remodeling occurs are known as resorption [6] and formation [7]. Conceptually, these processes are somewhat akin to the repair of cracks and potholes that develop in surfaces of highways. Remodeling occurs on the surfaces of both cancellous and cortical bone. The first step is activation of macrophage precursors to form osteoclasts, giant multinucleated cells that excavate or resorb a cavity on the bone surface. Osteoclasts express receptors for receptor activator of NFκB ligand (RANKL) produced by osteoblasts, calcitonin, prostaglandins, calcium, and vitronectin (integrin α1β3). In general, 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. This process takes approximately 2–3 weeks. After a brief rest period known as the reversal phase, local mesenchymal bone marrow stem cells differentiate into osteoblasts that are attracted to the empty resorption pits. There they accumulate as clusters of plump cuboidal cells along the bone surface. Osteoblasts have two major functions. They produce the proteins, both collagenous and non-collagenous, that constitute the matrix of the newly formed bone. Osteoblasts are also responsible for mineralization of the matrix or osteoid, a process that takes place approximately 10 days after the osteoid was synthesized. Osteoblasts express receptors for parathyroid hormone, estrogens, vitamin D3, cell adhesion molecules (integrins) and several cytokines. The complete remodeling cycle at each remodeling site requires approximately 3–6 months. This process serves to replace old, micro-damaged bone with new and ultimately mechanically stronger bone. RANKL, RANK, and osteoprotogerin (OPG) are three members of the tumor necrosis factor (TNF) ligand and receptor-signaling family that are final effectors of bone resorption [8, 9]. RANKL is expressed in osteoblasts and bone marrow stromal cells. When sufficient concentrations of macrophage colony stimulating factor (mCSF) are present, binding of RANKL to RANK, which is expressed on surfaces of osteoclast lineage cells, through cell-to-cell contact, 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, another member of the TNF-receptor superfamily 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 [10].

In normal adults, bone remodeling results in no net change in bone mass. Bone loss develops in any situation in which bone remodeling becomes “uncoupled,” such that the rate of resorption exceeds the rate of formation. This most often occurs when the rate of resorption is so elevated that it is beyond the capacity of the osteoblasts to restore the original amount of bone volume. However, bone loss may also develop in the setting of depressed bone formation, such that even normal amounts of resorbed bone cannot be replaced. It is very likely that transplantation-related bone loss results from both a primary decrease in the rate of bone formation and a primary increase in the rate of resorption [1, 11].

Glucocorticoids

Glucocorticoids (GCs) , an integral component of most transplant immunosuppression regimens, are notorious for causing osteoporosis. Prednisone or methylprednisolone may be prescribed in high doses (50–100 mg of prednisone or its equivalent daily) immediately after transplantation and during episodes of severe rejection, with gradual reduction over weeks to months. Total exposure varies with the organ transplanted, the number and management of rejection episodes, and the practice of individual transplantation programs.

GCs cause bone loss and fractures by mechanisms summarized in Table 22.1 and several recent reviews [12,13,14] and as detailed in Chap. 21. The main effect is an immediate and profound inhibition of bone formation by decreasing osteoblast recruitment and differentiation, synthesis of type I collagen, and induction of apoptosis of osteoblasts and osteocytes both in vitro and in vivo [15].

Table 22.1 Glucocorticoid actions that contribute to bone loss
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GCs also increase bone resorption, through both direct effects on osteoclasts and indirect effects. GCs indirectly increase resorption by impairing calcium transport across cell membranes, causing reduced intestinal calcium absorption, increased urinary calcium losses and negative calcium balance. Secondary hyperparathyroidism may result, although it is unlikely that it plays a major role in the pathogenesis of associated bone loss when GCs are administered in the absence of calcineurin inhibitors [16]. GCs also cause hypogonadotrophic hypogonadism and reduced secretion of adrenal androgens and estrogens, which may also be associated with increases in bone resorption.

Patients taking GCs generally sustain significant bone loss [13, 14]. Bone loss occurs in all races, at all ages, and in both genders. However, postmenopausal women are at greater risk for fracture than men or premenopausal women, because glucocorticoid-related bone loss is superimposed upon that already sustained because of aging and estrogen deficiency. In general, bone loss is most rapid during the first 12 months and is directly related to dose and duration of therapy. Areas of the skeleton rich in cancellous bone (ribs, vertebrae, and distal ends of long bones) and the cortical rim of the vertebral body are most severely affected and also fracture most frequently.

In recent years, there has been a trend toward more rapid lowering of glucocorticoid doses after transplantation or rejection episodes, and an increase in the use of alternative drugs to treat rejection [17,18,19,20]. In more recently transplanted patients who have received lower doses of steroids, significant bone loss persists although it may be less rapid than previously documented [21,22,23,24]. Moreover, it should be noted that even rather small doses of GCs are associated with increased fracture risk. A large retrospective general practice database study found that doses of prednisolone as low as 2.5 mg daily were associated with a significant 55% increase in the relative risk of spine fractures; doses between 2.5 and 7.5 mg daily were associated with a 2.6-fold increase in the risk of spine fracture and a 77% increase in the risk of hip fracture [25]. Thus, even in those programs that have embraced the use of lower doses of GCs, there is likely still sufficient exposure in the initial year to cause significant bone loss.

Cyclosporines

Cyclosporine (CsA) is a small fungal cyclic peptide. Its activity depends upon the formation of a heterodimer consisting of cyclosporine and its cycloplasmic receptor, cyclophilin. This cyclosporine–cyclophilin heterodimer then binds to calcineurin [26]. CsA, and similarly tacrolimus, inhibits the phosphatase activity of calcineurin through interaction with distinct domains on the calcineurin subunit [27]. Calcineurin may regulate both osteoblast [28] and osteoclast differentiation [29]. Although the gene for calcineurin, which is integral to the immunosuppressive action of CsA, has been identified in osteoclasts and extracted whole rat bone, it does not appear to be altered by CsA administration [30].

Animal studies suggest that CsA has effects on bone and mineral metabolism that may contribute to bone loss after organ transplantation (Table 22.2) [11, 31]. When administered to rodents in doses higher than those currently used to prevent allograft rejection, CsA causes rapid and severe cancellous bone loss [32, 33], characterized histologically by a marked increase in bone resorption. In contrast to the effects of GCs, bone formation is increased in CsA-treated animals, although insufficiently to compensate for the increase in resorption. The stimulatory effects of CsA on osteoclast formation are likely mediated via T lymphocytes [34,35,36]. CsA also increases gene expression of osteocalcin and of bone-resorbing cytokines, such as IL-1 and IL-6 [37]. Parathyroid hormone (PTH) may facilitate CsA-induced bone loss [38]. Drugs that inhibit bone resorption, including estrogen, raloxifene, calcitonin, and alendronate, prevent or attenuate CsA-induced bone loss in the rat [39,40,41,42]. Similarly, 1,25 dihydroxyvitamin D and prostaglandin E2 also prevent bone loss in CsA-treated rats [43, 44]. In contrast, testosterone does not ameliorate CsA-induced bone loss [45].

Table 22.2 Skeletal effects of cyclosporine (and tacrolimus)a
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Studies examining the effects of CsA on the human skeleton have yielded conflicting results. Several have shown that kidney transplant patients receiving cyclosporine in a steroid-free regimen did not lose bone [46,47,48]. In contrast, a small study of kidney transplant recipients detected no difference in bone loss between those who received CsA monotherapy and those who received azathioprine and prednisolone [49], and a prospective study found that cumulative CsA dose was associated with bone loss in the 2 years following transplant, independent of the effect of steroids [50].

Tacrolimus (FK506)

FK506 is a macrolide that binds to an immunophilin FK binding protein and blocks T-cell activation in a manner similar to CsA. FK506 has been shown to cause bone loss in the rat model comparable to that observed with CsA [51], and accompanied by similar biochemical and histomorphometric alterations (Table 22.2). In humans, rapid bone loss has been documented after both cardiac [52] and liver transplantation [53], when FK506 is used for immunosuppression. However, other studies suggest that FK506 may cause less bone loss than CsA in humans [54, 55], likely because lower doses of GCs are required for immunosuppression. It remains unclear whether FK506 confers any benefit over cyclosporine with regard to fracture incidence.

Sirolimus (Rapamycin)

Rapamycin is a macrocyclic lactone. Although it is structurally similar to FK506 and binds to the same binding protein, the mechanism by which rapamycin induces immunosuppression is distinct from both FK506 and CsA. When combined with low-dose CsA, rapamycin was bone sparing in rat studies [56]. In a recent open label study, markers of bone turnover (N-telopeptide and osteocalcin) were lower in kidney transplant recipients who received sirolimus rather than CsA; unfortunately, BMD was not measured, so it remains unclear whether this translated into lower rates of bone loss [57]. However, combining immunosuppressive agents in lower doses may provide hope for achieving adequate immunosuppression while protecting the skeleton.

Azathioprine, Mycophenolate Mofetil, and Other Drugs

Short-term administration of azathioprine is associated with decreases in serum osteocalcin but does not cause bone loss in the rat model [58]. No adverse effects of azathioprine administration alone on bone mass have been reported in human subjects. 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 [59]. The skeletal effects of other immunosuppressant agents are unclear.

Effect of Transplantation on Bone and Mineral Metabolism

Bone Loss Before Transplantation

In many cases, individuals with chronic diseases severe enough to warrant organ transplantation have already sustained considerable bone loss [60,61,62] (Table 22.3). The majority of candidates for organ transplantation have one or more accepted risk factors for osteoporosis, including debilitation, loss of mobility and physical inactivity, poor nutrition and cachexia. They are commonly exposed to drugs known to cause bone loss, such as GCs, heparin, loop diuretics, excessive doses of thyroid hormone, and anticonvulsants. Postmenopausal women are estrogen deficient, as are many chronically ill premenopausal women. Similarly, men with chronic illness often have hypogonadotrophic hypogonadism [63]. When the disease is present during childhood or adolescence, as is the case with cystic fibrosis or congenital heart disease, peak bone mass, which is attained during adolescence, may be low. Therefore, in caring for organ transplant candidates, it is essential to consider the possibility that bone mass may be reduced before transplantation. Consideration of particular issues related to transplantation of specific organs follows.

Table 22.3 Osteoporosis , fractures, and bone loss in candidates for solid organ transplantation
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Kidney and Kidney-Pancreas Transplantation

Skeletal Status Before Transplantation

In patients with severe chronic kidney disease (CKD) or end-stage kidney disease (ESKD), disturbances in calcium and phosphate metabolism, decreased calcitriol synthesis, increased synthesis and secretion of PTH, metabolic acidosis, and defective bone mineralization, result in the complex form of bone disease known as renal osteodystrophy [64], now termed mineral and bone disorders of chronic kidney disease (CKD-MBD). Some form of CKD-MBD is almost universal in patients who undergo kidney transplantation. A given individual may have high bone turnover, due to hyperparathyroidism with or without osteitis fibrosa, low turnover or adynamic bone disease, osteomalacia, or “mixed” renal osteodystrophy, a combination of one or more of the aforementioned lesions. Type I diabetes, hypogonadism secondary to uremia, and diseases such as systemic lupus erythematosus, common in patients with CKD and ESKD, also adversely affect the skeleton. Several drugs used routinely in the management of patients with renal disease, such as loop diuretics and calcium-containing phosphate binders, can also affect bone and mineral metabolism. In addition, some kidney transplant candidates may have had previous exposure to GCs or CsA as therapy for immune complex nephritis or other diseases and thus may already have sustained significant bone loss prior to transplantation.

Measurement of BMD by dual energy X-ray absorptiometry (DXA) is of limited utility in patients with ESKD as it does not distinguish among the various types of renal osteodystrophy and more importantly, does not discriminate between patients with and without fractures [65]. That being said, several cross-sectional studies have documented that osteoporosis and low bone mass are present in a significant proportion of patients on chronic dialysis (Table 22.3) [66,67,68].

Not surprisingly, the risk of fracture in patients with ESKD is greatly elevated. Risk of all fractures has been estimated at 4.4–14 times greater than that of the general population [69, 70]. Vertebral fractures were present in 21% of Japanese hemodialysis patients [71]. In one study, 34% of 68 hemodialysis patients had a history of previous fracture [72]. In another prospective study, the incidence of fractures was 0.1 fractures per dialysis year in patients with osteitis fibrosa and 0.2 fractures per dialysis year in patients with adynamic bone disease [73]. Recently, we have appreciated that hip fractures are also twofold more common in patients with moderate-to-severe CKD, who do not yet require dialysis [74] than in those with normal kidney function.

Risk factors for low bone mineral density and fractures include female gender, Caucasian race, hyperparathyroidism, adynamic bone disease, secondary amenorrhea, type I diabetes, older age, duration of dialysis, peripheral vascular disease, prior kidney transplant [75], and diabetic nephropathy [61].

Prevalence of Osteoporosis in Kidney Transplant Recipients

Low BMD measurements have been reported in several cross-sectional studies of patients who have undergone kidney transplantation [2, 3, 76,77,78,79,80] (Table 22.4), although again the prognostic significance of low BMD is unclear in such patients. For example, lumbar spine (LS) BMD was below the fracture threshold in 23% of 65 renal transplant recipients studied an average of 4 years after transplantation [81]; female gender, postmenopausal status, and cumulative prednisone dose were independent predictors of low BMD. Similarly, LS BMD was more than two standard deviations below age- and sex-matched controls (Z score ≤ −2.0) in 41% of patients studied 6–195 months after renal transplantation [82], and was directly related to increasing time since transplantation and PTH concentrations. LS and femoral neck (FN) bone density were more than two standard deviations below age- and sex-matched controls in 29% and 11% of 70 kidney transplant recipients studied an average of 8 years after transplantation [83], and was particularly prevalent in women. In a study of male renal transplant recipients, only 17% had normal BMD, 30% had osteoporosis at the hip or LS, 41% including the one-third radius; bone resorption markers were elevated in 48% [84]. Other studies have shown similar results [47, 85, 86].

Table 22.4 Osteoporosis, fractures, and bone loss after solid organ and bone marrow transplantation
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Mineral Metabolism and Bone Turnover After Kidney Transplantation

The changes in biochemical indices of mineral metabolism and bone turnover after renal transplantation are fairly consistent [87, 88]. PTH levels, usually elevated before transplantation, frequently remain high for some time after transplantation and may never completely normalize [89]. Hypercalcemia and hypophosphatemia, related to persistent parathyroid hyperplasia and elevated PTH levels, occur commonly during the first few months. Persistent elevations in fibroblast growth factor-23 (FGF-23) after transplant have been hypothesized to be related to post-transplant hypophosphatemia [90]. In most patients, these biochemical abnormalities are mild and resolve within the first year. In long-term transplant recipients, persistent elevations in PTH may be associated with reduced hip BMD [89]. Calcitriol production by the transplanted kidney may be inadequate to suppress PTH secretion by hyperplastic parathyroid tissue [91], and treatment with calcitriol may prevent hyperparathyroidism after renal transplantation [92]. Vitamin D deficiency is common and severe in patients after kidney transplantation [93, 94]. In one study [94], the mean serum level of 25-hydroxyvitamin D (25OHD) was 10 ng/ml (25 nmol/L) and one-third of patients had undetectable levels; transplant recipients had significantly lower levels than age-matched controls [94].

Bone Loss After Kidney Transplantation

Prospective longitudinal studies have documented high rates of bone loss after kidney transplantation (Table 22.4), particularly during the first 6–18 months after grafting. Julian et al. were the first to report that LS BMD decreased by 6.8% at 6 months and by 8.8% at 18 months after transplantation [87]. At 18 months, BMD was below the “fracture threshold” in 10 of 17 patients. Several prospective studies have confirmed this pattern of bone loss [21, 95,96,97,98,99,100,101,102], in which the rate of bone loss is greatest during the first 6 months after transplantation and at sites where cancellous bone predominates, such as the LS. The rate of LS bone loss varies between 3 and 10%. There may be a gender difference in the site at which bone is lost [75, 95, 97]; men have been shown to lose more bone at the proximal femur than women in the first few months after transplantation.

The pathogenesis of bone loss after renal transplantation is complex. The majority of studies have found that glucocorticoid dose correlates directly with bone loss. Men and premenopausal women may be at lower, and postmenopausal women at higher risk. There is also some evidence in the literature to support a role for cyclosporine in the pathogenesis of the high turnover state often apparent in renal transplant recipients by 1 year after renal transplantation [103].

In recent years, many centers have stopped using glucocorticoids for immunosuppression in kidney transplant patients after hospital discharge. These steroid-free regimens may be associated with less bone loss. In one study of patients who did not receive GCs after discharge, spine BMD remained stable and there was a transient 1–2% decrease in BMD at the hip. However, progressive declines occurred at the forearm [104]. Further, high-resolution peripheral CT scans of these patients demonstrated cortical bone loss and a decrease in whole bone stiffness, a surrogate for strength. These findings suggest that even in the absence of glucocorticoids there are ongoing detrimental skeletal effects after renal transplant [104].

Bone Histology After Kidney Transplantation

Before transplantation, classic hyperparathyroid high-turnover lesions are most commonly seen on bone biopsy. However, by 6 months after transplantation, glucocorticoid effects predominate, with osteoblast dysfunction and decreased mineral apposition [87, 105]. In long-term kidney transplant recipients, many of whom had mild renal insufficiency, bone biopsy results were more heterogeneous and included osteoporosis, osteomalacia, and osteitis fibrosa. An increase in osteoblastic activity and mineralization defects were common [106].

Fracture After Kidney Transplantation

Fractures are very common after renal transplantation (Table 22.4), and affect appendicular sites (feet, ankles, long bones, hips) more commonly than axial sites (spine, ribs) [84]. One study determined that nonvertebral fractures are fivefold more common in males aged 25–64, and 18-fold and 34-fold more common in females aged 25–44 and 45–64, respectively, who have had a renal transplant than they are in the normal population [107]. Prevalent vertebral or appendicular fractures were identified in 24% of long-term kidney transplant subjects [78]. Vertebral fractures have been reported in 3–10% of nondiabetic patients after renal transplantation [47, 83]. A cohort study involving 101,039 subjects found that patients who underwent kidney transplant had a 34% greater risk of hip fracture than those who remained on dialysis [61].

Fractures are particularly common in patients who receive kidney or kidney-pancreas transplants for diabetic nephropathy [108,109,110,111]. In a retrospective study of 35 kidney-pancreas recipients, approximately half had sustained from one to three symptomatic, nonvertebral fractures by the end of the third post-transplant year [108]. In a nested case-control study, pre-transplant diabetes was associated with a significant increase in fracture after transplantation [112]. This relationship persisted after controlling for several potential confounders, including glucocorticoid use. Although subjects were predominantly kidney transplant recipients, this study also included heart, liver, lung, and heart and lung transplant recipients. Nikkel. et al. performed an analysis of data from the US Renal Data System investigating whether kidney transplant recipients placed on steroid-sparing immunosuppression had lower rates of fracture [113]. They found that fracture rates were 50% lower among patients who did not receive glucocorticoids after hospital discharge.

Cardiac Transplantation

Skeletal Status Before Transplantation

Risk factors common in patients with end-stage cardiac failure that may predispose to bone loss before transplantation include exposure to tobacco, alcohol, and loop diuretics; physical inactivity; hypogonadism; and anorexia that may contribute to dietary calcium deficiency. Hepatic congestion and prerenal azotemia may also affect mineral metabolism, causing mild secondary hyperparathyroidism. Although on average bone density of patients awaiting cardiac transplantation may not differ significantly from normal, it has been observed that approximately 4–10% fulfill World Health Organization criteria for osteoporosis (Table 22.3) [23, 60, 114,115,116,117].

Prevalence of Osteoporosis in Heart Transplant Recipients

Osteoporosis and fractures constitute a major cause of morbidity after cardiac transplantation. In cross-sectional studies, the prevalence rate of vertebral fractures in cardiac transplant recipients (Table 22.4) ranges between 18 and 50% and moderate-to-severe bone loss is present in a substantial proportion of subjects at both LS and the femoral neck [107, 114,115,116, 118,119,120,121,122,123,124,125,126,127,128]. In a cross-sectional study of long-term cardiac transplant recipients, osteopenia or osteoporosis (T score less than −1.0) were found in 66% at the femoral neck, and 26% at the LS [129]. Perhaps related to a failure to achieve peak bone mass, adults who receive cardiac transplants as adolescents have significantly lower BMD at LS, FN and one-third radius than age-matched controls [130].

Mineral Metabolism and Bone Turnover After Heart Transplantation

We reported that severe vitamin D deficiency was extremely common among heart and liver transplant recipients at the time of transplantation; 91% of patients had vitamin D insufficiency (25-OHD 20- < 32 ng/ml), 55% had deficiency (25-OHD 10- < 20 ng/ml), and 16% had severe deficiency (25-OHD 10 ng/ml) [131]. Biochemical changes after cardiac transplantation include sustained increases in serum creatinine [132,133,134] and decreases in 1,25 dihydroxyvitamin D concentrations [133]. Serum testosterone concentrations decrease in men, and may recover by the sixth post-transplant month [132,133,134,135]. In one study, testosterone levels were lowest in the first month following transplant, and reflected suppression of the hypothalamic pituitary gonadal axis by prednisone as well as peri-operative stressors [135]. Low total testosterone was also common at 1 and 2 years after transplantation. At these later time points, low testosterone may result from primary gonadal failure [135]. Serum osteocalcin falls precipitously and there is a sharp increase in markers of bone resorption (hydroxyproline and pyridinium crosslink excretion) during the first 3 months with return to baseline levels by the sixth month [132,133,134]. This biochemical pattern coincides with the period of most rapid bone loss and highest fracture incidence and suggests that the early post-transplant period is associated with uncoupling of formation from resorption, and restitution of coupling when glucocorticoid doses are lowered. There is also evidence for a high bone turnover state later in the post-transplant course perhaps due to cyclosporine, characterized by elevations in both serum osteocalcin and urinary excretion of resorption markers [116, 119, 120, 126, 127, 132, 134, 136]. The increased bone turnover may be due in part to secondary hyperparathyroidism related to renal impairment [120]. Thus, biochemical changes later in the post-transplant course may be mediated, at least in part, by cyclosporine A-induced renal insufficiency , although other etiologies cannot be excluded.

Bone Loss After Heart Transplantation

The pattern of bone loss after cardiac transplantation is similar to that observed after renal transplant. Prospective longitudinal studies have documented rates of bone loss ranging from 2.5% to 11%, predominantly during the first 3–12 months after transplantation (Table 22.4) [52, 133, 134, 136,137,138,139,140,141]. Although GCs affect the predominantly cancellous bone of the vertebrae to a greater extent than other sites, there is as much or more bone loss at the hip, a site with more cortical bone than the vertebral bodies [23, 133]. Moreover, while bone loss at the LS slows or stops after the first 6 months, femoral neck bone loss continues during the second half of the first year after transplantation [23, 133]. There are very few longitudinal data available on the pattern of bone loss after the first year. However, data suggest that the rate of bone loss slows or stops in the majority of patients, with some recovery at the LS noted during the third year of observation [23, 133]. Bone loss also slows at the hip after the first year; however, in contrast to the spine, there has been no significant recovery by the fourth post-transplant year. The results of a recent study suggest that there may be less bone loss than suggested in literature from the 1980s and early 1990s [23].

Fracture After Heart Transplantation

Fragility fractures are most common during the phase of rapid bone loss that characterizes the first post-transplant year (Table 22.3). In a prospective observational longitudinal study, 36% of patients (54% of the women and 29% of the men) suffered one or more fractures of the vertebrae, ribs, and hip in the first year despite daily supplementation with calcium (1000 mg) and vitamin D (400 IU) [142]. The mean time to first fracture was 4 months, with most patients sustaining their initial fracture during the first 6 months. Lower pre-transplant BMD and female gender were associated with a trend toward increased fracture risk. In men, however, it was the rate of bone loss after transplantation rather than the pre-transplant bone density that was associated with fracture risk. Many of the patients that fractured had normal pre-transplant BMD and thus it was not possible to predict who would fracture on the basis of pre-transplant BMD or any other demographic or biochemical parameter [142]. Two European studies of cardiac transplant recipients reported similar fracture incidence with approximately 30% to 33% sustaining vertebral fractures during the first 3 years [143]. The risk of a vertebral fracture was higher in those patients who had LS T scores below −1.0 (hazard ratio 3.1) [143].

In a more recent interventional study, the incidence of vertebral fractures during the first post-transplant year in patients who received only calcium and vitamin D was only 14% [23]. Similarly, in a prospective study of untreated patients only 12% had fractures [144], suggesting fracture rates may be lower than in the past. However, clinical experience suggests that fractures remain a very common and sometimes devastating complication of heart transplantation. A complete bone evaluation including BMD measurements before or immediately after transplantation, as well as aggressive intervention to prevent bone loss and fractures should be considered in all patients regardless of age, sex, or pre-transplant bone density.

Liver Transplantation

Skeletal Status Before Transplantation

Patients with liver failure have multiple risk factors that may predispose to low bone mineral density before transplantation and fracture after transplantation [145,146,147]. Many patients with end-stage liver disease who are listed for liver transplantation have prevalent osteoporosis (Table 22.3), as evidenced by low bone mineral density (BMD) and fragility fractures [148, 149]. Osteoporosis and abnormal mineral metabolism have been described in association with alcoholic liver disease, hemochromatosis, steroid-treated autoimmune chronic active hepatitis, post-necrotic cirrhosis, and particularly in chronic cholestatic liver diseases such as biliary cirrhosis [150,151,152,153]. A study of 58 patients with cirrhotic end-stage liver disease referred for liver transplantation [149], reported that 43% had osteoporosis (defined as Z score > 2 S.D. below age-matched controls or presence of vertebral fractures). Serum 25-OHD, 1,25(OH)2D, intact PTH, and osteocalcin (a marker of bone formation) were lower and urinary hydroxyproline excretion (a marker of bone resorption) was higher in cirrhotic patients than controls. Male patients had lower serum testosterone levels than controls. A study of 56 liver transplant recipients revealed that 23% had osteoporosis that antedated transplantation [154]. In a recent study of 360 liver transplant candidates, 38% had osteoporosis and 39% had osteopenia [155].

Histomorphometric studies have found that bone formation is decreased in patients with primary biliary cirrhosis, and reflected by low serum osteocalcin levels [156,157,158]. Another study found biochemical evidence of both decreased bone formation and increased bone resorption in patients with chronic liver disease [148]. However, while serum osteocalcin appears to be a valid marker of bone formation in cholestatic liver disease, the utility of collagen-related markers of bone turnover has recently been called into question. In fibrotic liver diseases, the synthesis of type I collagen is markedly increased. Guanabens et al. have found that collagen-related bone turnover markers appear influenced by liver, rather than bone, collagen metabolism and do not reflect skeletal turnover in patients with liver disease [156]. Serum osteocalcin and tartrate-resistant acid phosphatase (TRAP) may be more valid markers of bone remodeling activity in this clinical situation.

Mineral Metabolism and Bone Turnover After Liver Transplantation

Studies of calciotropic hormone levels and bone turnover markers after liver transplantation are limited. Compston et al. reported a significant rise in serum-intact PTH during the first 3 months after liver transplantation, although levels did not exceed the upper limit of the normal range [159]. Significant increases in PTH during the first 3–6 months after transplant have been observed by other authors as well [160, 161]. In contrast, intact PTH levels have been reported to be within the normal range in liver transplant recipients in other studies [162,163,164]. Our study that investigated 25-OHD at the time of transplantation found that liver transplant recipients had significantly lower vitamin D levels than heart transplant recipients. This finding likely relates to disease-specific factors such as malabsorption, and impaired hepatic 25-hydroxylation of vitamin D [131]. Moreover, reduced hepatic production of vitamin D binding protein may lead to an apparent decrease in total (bound and free) serum 25-OHD, but free levels may be normal.

With respect to bone turnover, markers of bone formation (osteocalcin and carboxyterminal peptide of type I collagen) and resorption are higher in liver transplant recipients than in normal controls in most [163,164,165,166], though not all, studies [167]. OPG and RANK-L levels are significantly elevated in the first 2 weeks following liver transplant [168]. The balance of the data thus suggests that low bone turnover observed in many patients with liver failure converts to a high turnover state that persists indefinitely after liver transplantation.

As is the case with renal and cardiac transplantation , the independent role of GCs and calcineurin inhibitors in the pathogenesis of bone disease in liver transplant patients is difficult to assess since single drug therapy is uncommon. The mechanism of bone loss after liver transplantation has been studied by transiliac crest bone biopsy after tetracycline labeling in 21 patients, evaluated before and 3 months after transplantation. Before transplantation, a low turnover state was observed, with decreased wall width and erosion depth. Postoperative biopsies showed high turnover with increased formation rates and activation frequency, and a trend toward increased indices of resorption [169], which may have been related to the concomitant increase in PTH concentrations [159] or alternatively to calcineurin inhibitors.

Bone Loss and Fracture After Liver Transplantation

Osteoporosis is also common after liver transplantation, as detailed in several recent reviews [62, 170]. The natural history of bone loss following liver and cardiac transplantation appears similar [143]. Rates of bone loss and fracture vary considerably after liver transplantation (Table 22.3), but were often extremely high, particularly in studies published before 1995 [143, 154, 162, 163, 171,172,173,174,175,176], in which LS BMD fell by 2–24%, primarily in the initial few months after liver transplantation. Bone loss appears to stop after 3–6 months with gradual improvement by the second and third post-transplant years. Eastell et al. reported that bone mass recovers and bone histology normalizes with increasing survival time after transplantation [171], and other investigators have shown that there is improvement in BMD in long-term liver transplant recipients [177]. This, however, has not been a uniform finding and other studies have found continued losses rather than recovery [162, 178].

More recent studies have found smaller amounts of bone loss. Keogh et al. reported that femoral neck BMD fell by 8% and LS BMD by 2% after liver transplantation [179]. Ninkovic et al. found only a 2.3% loss at the femoral neck, with preservation of LS BMD 1 year after liver transplant [22]. Floreani et al. found increases in BMD at 1 year [160]. Smallwood et al. reported in a cross-sectional study that lower bone mass following liver transplant was associated with older age, female gender, cholestatic liver disease, and higher prednisone dose [180]. A recent retrospective study found that women receiving cumulative glucocorticoid doses greater than 3500 mg had lower FN BMD at one and 2 years following liver transplant than other patients [181]. Guichelaar et al. followed 360 patients after liver transplant. Higher rates of LS bone loss occurred in patients with primary sclerosing cholangitis, current smokers, younger age, higher baseline BMD, shorter duration of liver disease, and ongoing cholestasis [155].

Fracture incidence is also highest in the first year and ranges from 24% to 65%, the latter in a group of women with primary biliary cirrhosis. The vertebrae and ribs are the most common fracture sites. Again, fracture rates appear to be considerably lower in more recent studies [22]. Whether type of liver disease at baseline predicts fractures is controversial. Some authors report more bone loss and fractures in patients with primary sclerosing cholangitis [155] and alcoholic cirrhosis [182]. Glucocorticoid exposure and markers of bone turnover do not reliably predict bone loss or fracture risk. Older age and pre-transplant BMD at the FN and LS were predictive of post-transplant fractures in recent prospective studies [22, 161]. Vertebral fractures prior to transplant have been shown to predict post-transplant vertebral fractures [143, 183]. In re-transplanted patients , those with primary biliary cirrhosis and those with previous fragility fractures are at increased risk. These patients may always be at risk for fractures as survival rates and duration increase. In a recent study of patients who survived more than 15 years after liver transplantation, 49% had osteoporosis and 30% had sustained vertebral fractures [184].

Lung Transplantation

Skeletal Status Before Lung Transplantation

Hypoxemia, tobacco use, and prior glucocorticoid therapy are frequent attributes of candidates for lung transplantation and may contribute to the pre-transplant bone loss (Table 22.3) particularly common in these patients [185, 186]. Cystic fibrosis (CF), a common reason for lung transplantation, is itself associated with osteoporosis and fractures due to pancreatic insufficiency, vitamin D deficiency and calcium malabsorption, and hypogonadism [187,188,189]. A greatly increased rate of all fractures and severe kyphosis has been reported in adults with cystic fibrosis [187]. Vitamin D deficiency is extremely common in CF patients, despite supplementation; bone density was significantly lower in D-deficient patients [188]. Two cross-sectional studies have found that low bone mass and osteoporosis are present in 45–75% of candidates for lung transplantation [185, 186]. In both , glucocorticoid exposure was inversely related to BMD. Vertebral fracture prevalence was 29% in patients with emphysema and 25% in patients with CF [185, 186]. Low bone mass is also common in patients with primary pulmonary hypertension prior to lung transplantation; in a retrospective study, 61% had osteopenia at the FN and 72% at the LS. BMD at the FN correlated with functional measures, walking distance, and pulmonary vascular resistance [190]. A cross-sectional study of patients with diffuse parenchymal lung disease presenting for lung transplantation found that 13% had osteoporosis, and 57% osteopenia. Low BMD was associated with lower body mass index , and Hispanic ethnicity [191].

Mineral Metabolism and Bone Turnover After Lung Transplantation

Bone turnover markers are elevated following lung transplant. Increased osteoclastic and decreased osteoblastic activity have been observed in post-transplant bone biopsies of CF patients [192].

Bone Loss and Fracture After Lung Transplantation

Few studies have prospectively evaluated patients after lung transplantation (Table 22.3). A study of 12 patients demonstrated an average 4% decrease in LS BMD during the first 6 months despite calcium and 400 IU of vitamin D [193]. Two men sustained multiple vertebral fractures. Another study documented decreases of approximately 5% in both LS and femoral neck BMD during the first 6–12 months after lung transplantation and fractures developed in 18% of 28 patients [194]. In a retrospective analysis of 33 lung transplant recipients who had survived at least 1 year after grafting, BMD was markedly decreased and 42% had vertebral fractures [195]. In a 10-year follow-up study of lung transplant recipients, of the 28 (29%) of patients who survived, 11% had prevalent osteoporotic fractures [196]. As many as 37% of lung transplant recipients suffer fragility fractures and significant bone loss during the first post-transplant year despite antiresorptive therapy [197].

Risk factors for fracture and bone loss include female gender, low pre-transplant LS BMD, pre-transplant glucocorticoid therapy, and higher bone turnover after transplantation. Some studies have found that bone loss correlates with GC dose [194], but others have not found this relationship [197].

Bone Marrow Transplantation (BMT)

BMT is performed with increasing frequency and for expanding indications. In preparation for transplantation, patients receive myeloablative therapy (alkylating agents and/or total body irradiation) and commonly develop profound and frequently permanent hypogonadism, which could certainly cause bone loss.

Mineral Metabolism and Bone Turnover After Bone Marrow Transplantation

Bone turnover markers are consistent with the pattern of decreased formation and increased resorption [198] observed in other forms of transplantation during the first 3 months, a pattern consistent with uncoupling of formation from resorption. After 3 months, there was recovery of bone formation markers and generally elevated turnover during the latter half of the year [198]. Similar elevations of bone turnover markers have also been observed by other investigators after BMT [199,200,201] [202, 203]. Rates of FN bone loss are lower after autologous BMT, about 4%. LS BMD returns to baseline, while FN bone loss persists for 2 years [204].

Cellular or cytokine-mediated abnormalities in bone marrow function after BMT may affect bone turnover and BMD [205]. Osteoblastic differentiation is reduced by damage from high-dose chemotherapy, total body irradiation and treatment with GCs and/or CsA. Colony forming units-fibroblasts (CFU-f) are reduced for up to 12 years following BMT [206, 207]. Long-term survivors have been shown to have persistent abnormalities in bone turnover and vitamin D [208].

Avascular necrosis (AVN) is common, occurring in 10–20% of allo-BMT survivors, at a median of 12 months following transplant [207, 209]. The most important risk factor for the development of avascular necrosis is GC treatment of chronic GVHD. AVN may be related to decreased numbers of bone marrow CFU-f in vitro, but does not appear to be related to BMD [210].

Bone Loss and Fracture After Bone Marrow Transplantation

After transplantation , patients may receive GCs, methotrexate, or cyclosporine A, alone or in combination. The pathogenesis of osteoporosis after allogenic BMT is complex, related to many factors including the effects of treatment and effects on the stromal cell compartment of the bone marrow [77, 202, 206]. Low BMD was first reported after BMT by Kelly et al. [211]. Since then, several cross-sectional studies have confirmed low total body BMD [212, 213] or bone mineral content (BMC) [214] (by DXA) and LS volumetric BMD (by computed tomography) [200] in bone marrow transplant recipients (Table 22.4). However, in one study, only those who were less than 18 years old at the time of transplantation were affected, perhaps because of a failure to achieve optimal bone mass and smaller bone size [212]. Two studies have documented that bone mass is low in hypogonadal women after bone marrrow transplantation [215, 216] and that hormone replacement therapy is associated with significant increases in BMD [215, 216].

With respect to natural history of bone loss after BMT, a study of 9 adults undergoing 6 months of high-dose glucocorticoid and CsA therapy for graft-versus-host disease (GVHD) observed significant LS bone loss [217]. Ebeling et al. found that low BMD antedates BMT, particularly in subjects with prior glucocorticoid exposure and that post-transplant bone loss is particularly severe in patients who undergo allogeneic BMT, probably because of their increased propensity for GVHD [209]. Another study followed a group of patients who had undergone allogeneic BMT for 6 months (n = 44) and 12 months (n = 36) after grafting. Although some received calcium and vitamin D and some received calcitonin, there was no discernable difference in rates of bone loss; therefore, the groups were combined. BMD decreased by approximately 6% at the LS and 7% at the FN [198]. In other studies, LS BMD decreased by 2.2–3.0% and FN BMD by 6.2–11.6% during the first 12–14 months [203, 218]. There appears to be little bone loss after the first year [200]. The significant bone loss that occurs in the femoral neck does not appear to be regained [219]. In a recent retrospective study, risk of fracture incidence was up to 9 times higher in bone marrow transplant recipients compared with an age- and sex-matched reference population [220].

Evaluation and Management of Candidates for Transplantation

Evaluation

There are now abundant data documenting the high prevalence of bone disease in candidates for all types of transplantation. Therefore, the possibility of significant bone disease should be considered before transplantation so that potentially treatable abnormalities of bone and mineral metabolism may be addressed and the skeletal condition of the patient optimized before transplantation (Table 22.5). Risk factors for osteoporosis should be assessed. These include a family history of osteoporosis, history of adult low-trauma fractures, medical conditions (thyrotoxicosis, renal disease, rheumatological, and intestinal disorders), unhealthy lifestyle choices (physical inactivity, dietary calcium and vitamin D deficiency, excessive caffeine and alcohol intake, tobacco use) and exposure to certain drugs (diphenylhydantoin, lithium, loop diuretics, glucocorticoids, prolonged, and large doses of heparin, thyroid hormone). In men, it is important to exclude hypogonadism. A physical examination should focus upon findings that suggest hypogonadism, thyrotoxicosis, and Cushing’s syndrome. Risk factors for falling (poor impaired vision, hearing, balance and muscle strength, psychotropic drugs) should also be assessed.

Table 22.5 Skeletal evaluation of the candidate for organ transplantation
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BMD of the spine and hip is the most important test to obtain before transplantation. Radiographs of the thoracic and lumbar spine are also important since risk of future fracture is greater in patients with prevalent vertebral fractures. A battery of biochemical tests is unnecessary if the BMD is normal and supplementation with calcium and vitamin D is planned. However, if the pre-transplant BMD is low, a thorough biochemical evaluation can alert the physician to the etiology of low bone mass and guide appropriate therapy, targeted to the cause. In such instances, the biochemical evaluation should include a chemistry panel (serum electrolytes, creatinine, calcium, phosphorus, alkaline phosphatase), thyroid function tests, intact PTH, and serum 25-OHD. In men, total and free testosterone should be obtained. Markers of bone formation (serum osteocalcin, bone specific alkaline phosphatase and procollagen type 1 amino-terminal propeptide (P1NP), and resorption (C- or N-telopeptide excretion) can also be measured to assess bone turnover status, although this is optional.

Although pre-transplant BMD does not reliably predict fracture in individual patients, low pre-transplant BMD probably increases fracture risk. Individuals awaiting transplantation who meet World Health Organization criteria for diagnosis of osteoporosis (T Score < −2.5), osteopenia or low bone mass (T score between −1.0 and −2.5) should be evaluated and treated similarly to others with, or at risk, for osteoporosis (Table 22.5).

While on the waiting list for transplantation, rehabilitation therapy should be prescribed as tolerated to maximize conditioning and physical fitness. All transplant candidates should receive the Recommended Daily Allowance of vitamin D (600–800 IU), or as necessary to maintain the serum 25-OHD level above 30 ng/ml (80 nmol/mL) and a daily calcium intake of 1000–1200 mg (depending on menopausal status). Patients should be encouraged to obtain as much of their calcium from diet as possible. Calcium citrate is preferred as a supplement. Many of these patients take proton pump inhibitors before or after transplantation, which can reduce intestinal calcium absorption. Hypogonadal men should also be offered testosterone replacement. Generally accepted guidelines for gonadal hormone replacement should apply to these patients.

Patients who are found to have osteoporosis before transplantation should begin antiresorptive therapy with a bisphosphonate. The pre-transplant waiting period is often long enough (1–2 years) for significant improvement in BMD before transplantation. Patients with CKD-MBD should be managed in accordance with accepted clinical guidelines [221]. A discussion of this topic is beyond the scope of this chapter.

After transplantation, monitoring serum and urine indices of mineral metabolism is less crucial, although it may be useful to detect developing conditions that may contribute to bone loss (vitamin D deficiency or renal insufficiency with secondary hyperparathyroidism. Serum (and urinary) calcium must be monitored frequently if pharmacologic doses of vitamin D or its active 1-hydroxylated metabolites are used, in order to detect hypercalciuria or hypercalcemia. Measurement of BMD should be performed annually for the first 2 years, particularly if the patient remains on GCs. Frequency of follow-up BMD measurement should be based upon whether the patient continues to require GCs and if they are using anti-osteoporotic therapy. Bone biopsy may be necessary in the kidney transplant recipient since many experts remain reluctant to use bisphosphonates in patients with adynamic bone disease. Although transiliac crest bone biopsy remains a research tool, more histomorphometric studies would be very helpful in confirming theories of the pathogenesis of transplantation osteoporosis.

Prevention of Transplantation Osteoporosis

The major principles, which have been demonstrated consistently after kidney, liver, heart, lung, and bone marrow transplantation, and which should guide therapy of transplantation osteoporosis are as follows:

  • Rates of bone loss are most rapid immediately after transplantation.

  • Fractures also occur very early after transplantation, sometimes within only a few weeks of grafting.

  • Fragility fractures develop both in patients with low and those with normal pre-transplant BMD.

  • Prevention of the rapid bone loss that during the first few months after transplantation is likely to be considerably more effective in reducing the morbidity from fractures than waiting for fractures to occur before initiating therapy.

  • Therefore, preventive strategies should be instituted immediately after transplantation both in patients with normal pre-transplant BMD and those with low BMD who are being treated with glucocorticoids (Table 22.6).

  • The long-term transplant recipient with established osteoporosis and/or fractures should not be neglected (Table 22.7).

Table 22.6 Primary prevention of bone loss in transplant recipients
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Table 22.7 Management of the long-term organ transplant recipient
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There are several prospective controlled randomized studies for prevention and treatment of transplantation osteoporosis in the literature, although the quality of these studies varies. The recommendations provided herein are also based upon experience with glucocorticoid-induced osteoporosis and recent guidelines from the American College of Rheumatology [222]. Available therapies of transplantation osteoporosis include antiresorptive drugs (bisphosphonates and denosumab), as well as analogs of vitamin D and gonadal hormone replacement. Since resorption markers increase after transplantation and correlate directly with rates of bone loss, [88] attempts to prevent post-transplantation bone loss, and hopefully fractures, by inhibition of bone resorption are a logical approach.

Bisphosphonates

Bisphosphonates act by inhibiting osteoclastic bone resorption. This class of drugs is most commonly used to treat osteoporosis in postmenopausal women and men. However, they have also been used successfully both to prevent and to prevent glucocorticoid-induced bone loss and bone loss in transplant recipients. Alendronate, risedronate, and zoledronic acid have been approved by the FDA for prevention and treatment of GC-induced osteoporosis. Since transplantation osteoporosis can be considered one form of glucocorticoid-induced osteoporosis and since cyclosporine and tacrolimus-induced bone loss are characterized experimentally by increases in both formation and resorption, bisphosphonates offer considerable hope for prevention of transplantation osteoporosis.

Several [164, 223,224,225,226,227,228,229,230,231,232,233,234,235] studies suggest that intravenous bisphosphonates can prevent bone loss and fractures after transplantation. Intravenous pamidronate administered in repeated doses has been shown to prevent bone loss at the LS and FN in kidney, [224, 235] heart, [228, 233] liver, [236] and lung [227, 232] transplant recipients. In a small, open but randomized clinical trial, intravenous pamidronate was administered to kidney transplant recipients at time of grafting and again 1 month later, [223] completely preventing LS and FN bone loss. In contrast, LS BMD fell by 6.4% and FN BMD by 9% in the control subjects. The benefits of this intervention were still apparent 4 years after transplantation, especially at the FN [224]. Coco et al. [235] compared kidney transplant recipients who received intravenous pamidronate at the time of transplantation and at 1, 2, 3, and 6 months afterward, along with calcium and calcitriol, to those treated with calcium and calcitriol alone. There was no bone loss in the patients who received pamidronate, while the other group sustained losses of 4–6%. Bone biopsies performed in a small number of patients after 6 months of therapy, however, revealed a high incidence of adynamic bone disease. Aris et al., in a randomized, controlled but nonblinded trial, demonstrated that intravenous pamidronate (30 mg every 3 months for 2 years) was associated with 8% increases in spine and hip BMD in patients who underwent lung transplantation for cystic fibrosis [227]. However, fracture rates were very high and did not differ between the two treatment groups. A retrospective study suggested that treatment with intravenous pamidronate before and every 3 months after liver transplantation prevented symptomatic vertebral fractures in liver transplant recipients who had osteoporosis before transplantation [237]. In contrast, a more recent prospective study in liver transplant patients found that bone loss at the FN was not prevented with pamidronate, which was given as a single infusion as long as 3 months before grafting. There was no LS bone loss in either group and fracture rates did not differ [236]. In two large prospective studies of patients after allogenic BMT, intravenous pamidronate prevented LS bone loss and reduced proximal femoral bone loss [238, 239]. About 3% of bone loss at the proximal femur still occurred, however, despite doses up to 90 mg one study [239]. The lack of efficacy may be related to a failure of pamidronate to inhibit matrix metalloproteinase (MMP)–mediated bone resorption or to reverse defects in osteoblast function after BMT [240].

Randomized trials with the more potent intravenous bisphosphonates, zoledronic acid and ibandronate, have shown significant protective effects on BMD at 6 and 12 months in recipients of heart, [241] liver, [229, 242, 243] and kidney [230, 234] transplants. Fahrleitner-Pammer et al. reported that in male heart transplant patients, ibandronate prevented bone loss and reduced the risk of vertebral fractures [241]. Crawford et al. administered repeated doses of zoledronic acid before and at 1, 3, and 6 months following liver transplantation, which prevented bone loss at the LS, FN, and total hip (TH), compared with placebo. One year after transplantation, the effects at the FN and TH persisted, but an increase in LS BMD in the placebo group abolished the significant difference at the spine [242]. Bodingbauer et al. investigated 4 mg of zoledronic acid given to a group of liver transplant patients monthly for the first 6 months and then at 9 and 12 monthly after transplantation. With treatment, BMD was stable at the LS and losses were reduced at the FN compared to controls. There was also a reduction in vertebral fractures with zoledronic acid treatment [243]. In another study, Kaemmerer and colleagues treated liver transplant patients treated with 2 mg of intravenous ibandronate every 3 months for 1 year also had stable spine BMD and attenuated hip bone loss compared to controls. Treated subjects had a significant reduction in total number of fractures [244]. Intravenous zoledronic acid (4 mg), given 12 months after BMT, prevented spinal and femoral bone loss [245]. Zoledronic acid has also been shown to increase ex vivo growth of bone marrow CFU-f, perhaps improving osteoblast recovery and increasing osteoblast numbers after BMT.

Clinical trials have also been performed with oral bisphosphonates. In terms of primary prevention of bone loss immediately after transplantation, several studies have compared alendronate with calcitriol. A randomized trial comparing alendronate (10 mg daily) with calcitriol (0.25 μg twice daily) treatment starting immediately after cardiac transplant found that both regimens prevented bone loss at the lumbar spine and hip 1 year after transplant, compared with a reference group receiving only calcium and vitamin D [23]. Although alendronate and calcitriol were discontinued during the second year after cardiac transplant, BMD remained stable [246]. Kidney transplant patients treated with alendronate (10 mg daily), calcitriol (0.25 μg daily), and calcium carbonate (2 g daily) had marked increases in LS BMD compared to decreases in those who received only calcium and calcitriol [247]. Two recent trials found similar improvements in LS BMD in patients treated with alendronate or risedronate following kidney transplant [248, 249].

Long-term cardiac transplant patients treated with clodronate also had improvements in BMD [250]. A trial of long-term kidney transplant patients who were started on alendronate, calcitriol, and calcium or only calcitriol and calcium approximately 5 years after transplantation, documented significant improvements in LS and FN BMD in the alendronate group. BMD in the other group was stable [251]. Similarly, a retrospective trial in long-term kidney transplant recipients found that bisphosphonate use was associated with preservation of FN BMD [252]. Three recent meta-analyses of bisphosphonate trials in kidney transplant recipients found that bisphosphonates effectively prevented bone loss at the LS and FN [253,254,255]. In addition, a meta-analysis also demonstrated bisphosphonates use reduced fracture in transplant recipients [255]. In a small randomized trial of long-term kidney transplant recipients that compared alendronate, alfacalcidiol, and alendronate for 1 year, BMD improved at the LS and FN in patients treated with alendronate and alendronate combined with alfacalcidiol. The increase was only significant in the combination alendronate-alfacalcidiol group likely because of inadequate power in this small study [256]. Alendronate has been shown to prevent bone loss after liver transplant as well [182]. In BMT recipients, risedronate given 12 months after BMT improved BMD at the spine and prevented loss at femoral neck [257].

Weekly or monthly dosing regimens [258] are very useful in transplant patients who have many gastrointestinal symptoms and take large numbers of medications. For such patients, the requirement to take oral bisphosphonates first thing in the morning and wait 30–60 min before eating or taking other medications is particularly inconvenient. In two recent studies, weekly alendronate (70 mg) has improved BMD in liver [259] and kidney transplant recipients [260]. Our randomized double-blind, double-dummy active comparator study compared single- dose zoledronic acid and weekly alendronate over 1 year in patients receiving liver or heart transplant. We found that both agents prevent bone loss at hip. In liver transplant patients, both medications increased LS BMD. In contrast, among heart transplant patients, those who received zoledronic acid had increased LS BMD but not those treated with oral alendronate [261].

Although fracture is the most important clinical outcome, very few treatment studies have had adequate statistical power to detect differences in fracture among treated and untreated patients. For this reason, we performed a meta-analysis of randomized controlled clinical trials to determine whether treatment with bisphosphonates or active vitamin D analogs reduced fracture risk in the first year following solid organ transplantation. Treatment with bisphosphonates or vitamin D analogs reduced the number of subjects with fracture (OR 0.50, 95% CI 0.29, 0.83) and number of vertebral fractures (OR 0.24, 95% CI 0.07, 0.78). When bisphosphonate trials were examined separately, there was a reduction in number of subjects with fractures (OR 0.53, 95% CI 0.30, 0.91), but no significant reduction in vertebral fractures (OR 0.34, 95% CI 0.09, 1.24) [255].

Prior to initiation of bisphosphonate treatment, particularly with intravenous agents, it is important to screen for and correct vitamin D deficiency. Bisphosphonates may not be optimally effective in the setting of severe vitamin D deficiency. More importantly, intravenous bisphosphonate treatment can precipitate symptomatic hypocalcemia in patients with severe, unrecognized vitamin D deficiency [262].

At present, bisphosphonates constitute the most promising approach to the prevention of transplantation osteoporosis. As with other forms of therapy, many issues remain to be resolved. These include whether or not they actually prevent fractures, since most studies have been under-powered to address this important issue, the optimal drug and route of administration, whether continuous or intermittent (cyclical) therapy should be used, at what level of renal impairment these drugs should be avoided, whether they are safe in renal transplant recipients with adynamic bone disease and whether they are beneficial in the setting of pediatric transplantation.

Vitamin D and Analogs

Administration of vitamin D or its analogs is often recommended after transplantation [263]. There are several potential mechanisms by which vitamin D and its analogs may influence post-transplantation bone loss. They may overcome GC-induced decreases in intestinal calcium absorption, reduce secondary hyperparathyroidism, promote differentiation of osteoblast precursors into mature cells, or influence the immune system and potentiate the immunosuppressive action of cyclosporine [264,265,266].

Since most of the observational studies of bone loss after organ transplantation have included at least 400 IU of parent vitamin D in the post-transplant regimen, it is clear that this amount is not sufficient to prevent transplantation osteoporosis. In two recent studies, parent vitamin D, in doses of 800 IU daily [267] or 25,000 IU monthly [24] also did not prevent bone loss after kidney transplantation.

Active forms of vitamin D may be more effective. Calcidiol (25-OHD) prevented bone loss and increased LS BMD after cardiac transplantation [268]. Alfacalcidiol (1-α-OHD) prevented or attenuated bone loss at the LS and FN when given immediately after kidney transplantation [269,270,271]. Several investigators have studied the effects of calcitriol in transplant recipients. The results have been contradictory, although some studies have found beneficial effects at doses greater than 0.5 μg per day. Sambrook et al. reported that calcitriol (0.5–0.75 mg/d) prevented spine and hip bone loss during the first 6 months after heart or lung transplantation and was as effective as cyclic etidronate [272]. Calcitriol given during the first year after kidney transplantation was associated with an increase in LS, FN, and forearm BMD [50]. In a stratified, placebo-controlled randomized study, heart and lung transplant recipients received calcitriol or placebo for 12 or 24 months after transplantation [273]. While LS bone loss was equivalent between groups, FN bone loss at 24 months was reduced only in the group that received calcitriol for the entire period. Although these results suggest that the protective effects of calcitriol are not sustained after cessation of treatment, we found no bone loss when we discontinued calcitriol after the first post-transplant year [246]. In another study of renal transplant recipients, intermittent calcitriol and calcium prevented TH but not LS bone loss [274]. In contrast, studies of long-term kidney [275] and heart transplant patients [276] have failed to find any benefit of calcitriol. Stempfle et al. found that the addition of a small dose to calcitriol (0.25 μg/d) to calcium supplementation and gonadal steroid replacement offered no benefit with regard to bone loss or fracture prevention after cardiac transplantation [128].

Hypercalcemia and hypercalciuria are the major side effects of therapy of these agents. Either may develop suddenly and at any time during the course of treatment. Thus, frequent urinary and serum monitoring may be required. If hypercalcemia occurs, it must be recognized and reversed promptly because of the adverse effects on renal function and the life-threatening potential of a severely elevated serum calcium concentration. Supplemental calcium and any vitamin D preparations should be discontinued until the calcium normalizes. Although one may be tempted to permanently discontinue pharmacologic doses of vitamin D or its metabolites in view of the necessary serial monitoring and potential dangers, one might also recommence therapy at a lower dose. However, given the requirement for serial monitoring and the narrow therapeutic window with respect to hypercalcemia and hypercalciuria, we regard pharmacologic doses of vitamin D and its analogs as adjunctive rather than primary therapy for the prevention and treatment of transplantation osteoporosis.

Denosumab

Denosumab is a monoclonal antibody to nuclear factor kappa B ligand that prevents bone resorption by impairing the development, activation, and survival of osteoclasts [277]. It is FDA approved for the treatment of glucocorticoid-induced osteoporosis. Previous studies have shown that denosumab is beneficial to prevent bone loss and lowers fracture risk in postmenopausal women and men with osteoporosis. In a recent randomized, controlled study that involved 795 patients with glucocorticoid-induced osteoporosis, denosumab (60 mg every 6 months) improved BMD at the LS to a greater extent than risedronate (35 mg weekly) at 12 months. Similarly, the improvement in BMD at the TH was greater for denosumab [278].

In another prospective randomized trial, 90 de novo kidney transplant patients were assigned to receive 2 doses, every 6 months, of either denosumab or placebo beginning at 2 weeks postoperatively. After 12 months, denosumab was associated with a 4.6% increase in LS BMD while the placebo group sustained a 0.5% loss in LS BMD [279]. In a subgroup analysis of these patients, denosumab also resulted in increased volumetric BMD and cortical thickness at tibia. With regard to bone strength, micro-finite element analysis showed that bone stiffness increased significantly at the tibia (median difference 5.6%) [280].

An increased risk of urinary tract infections was also reported in the kidney transplant patients who received denosumab treatment. The incidence of other infections was similar between patients treated with denosumab and controls [279]. Unlike bisphosphonates, denosumab is not cleared by the kidney and therefore dose adjustment is not required in CKD setting. However, hypocalcemia can be a serious side effect of denosumab, particularly in patients with CKD [281]. For this reason, serum calcium should be closely monitored in patients with CKD who receive denosumab.

Testosterone

Hypogonadism is common in men with chronic illness. Moreover, the suppressive effects of cyclosporine A and glucocorticoids on the hypothalamic-pituitary-gonadal axis often lower serum testosterone levels. Although testosterone usually normalizes by 6–12 months after transplantation, [132, 133] approximately 25% of men evaluated 1–2 years after transplantation will have biochemical evidence of hypogonadism. Hypogonadism is known to cause osteoporosis in men. Moreover, men with low serum testosterone concentrations have been shown to lose bone more rapidly after cardiac transplantation [132, 133]. Fahrleitner et al. found that hypogonadal men treated with intravenous ibandronate had improved BMD at 1 year if they were treated with testosterone compared with those who were not replaced [282].

In general, men who are truly hypogonadal, with testosterone levels below normal according to the laboratory assay utilized, should be treated with testosterone. Potential benefits of testosterone therapy include increased lean body mass and hemoglobin, and improved BMD. Potential risks include prostatic hypertrophy, abnormal liver enzymes, and acceleration of hyperlipidemia in patients already prone to atherosclerosis from hypertension, diabetes, glucocorticoid, and CsA therapy. Therefore, it is necessary to monitor serum lipids and liver enzymes, and perform regular prostate examinations in men receiving testosterone.

Resistance Exercise

A few small studies have examined the effects of resistance exercise on BMD following heart [283] and lung [284] transplantation. Resistance exercise led to significant improvements in LS BMD when used alone, and in combination with alendronate. The interpretation of these findings is limited, however, by the extremely small numbers of subjects enrolled and the method used to measure BMD (lateral spine), which is highly variable, leading to a percent change much greater than typically reported.

Summary and Conclusions

There has been tremendous progress in elucidating the natural history and pathogenesis of transplantation osteoporosis. It is now clear that a substantial proportion of candidates for solid organ and bone marrow transplantation already have osteoporosis. Prospective longitudinal studies have provided definitive evidence of rapid bone loss and a high incidence of fragility fractures, particularly during the first post-transplant year. Vertebral fractures occur both in patients with low and those with normal pre-transplant BMD, so that it is impossible to predict fracture risk in the individual patient. Early post-transplantation bone loss (before 6 months) is associated with biochemical evidence of uncoupled bone turnover, with increases in markers of resorption and decreases in markers of formation. Later in the post-transplantation course (after 6 months), concomitant with tapering of glucocorticoid doses, bone formation recovers and the biochemical pattern is more typical of a high-turnover osteoporosis. More recent studies suggest that rates of bone loss and fracture are lower than they were before 1995. However, the rates of bone loss and fracture following transplantation remain unacceptably high. Bisphosphonates are the most consistently effective agents for the prevention and treatment of bone loss in organ transplant recipients. Patients should be assessed before transplantation and receive treatment for prevalent osteoporosis, if present. Primary prevention therapy should be initiated immediately after transplantation, as the majority of bone loss occurs in the first few months after grafting. The lowest possible dosages of glucocorticoid and calcineurin phosphatase inhibitors should be used for immunosuppression. Long-term transplant recipients should be monitored and treated for bone disease as well. With proper vigilance, early diagnosis, and treatment, transplant osteoporosis is a preventable disease.