eMedicine Specialties > Endocrinology > Metabolic Bone Disease

Osteoporosis in Solid Organ Transplantation

Author: Carmel M Fratianni, MD, FACE, Associate Professor of Clinical Medicine, Department of Internal Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Southern Illinois University School of Medicine
Contributor Information and Disclosures

Updated: May 20, 2009

Introduction

Background

Low bone mass is extremely common among patients awaiting solid organ transplantation. A large and rapid decrease in bone mineral density (BMD) occurs within the first year following virtually all forms of solid organ transplantation. This decrease in BMD is associated with increased fractures (see image below and Image 1). In a large series of abdominal organ and heart transplants from Northwestern University (1999), Ramsey-Goldman et al reported a fracture incidence 5-34 times higher than in historical controls.¹

Moreover, patients are often exposed to therapeutic agents such as steroids, heparin, or loop diuretics, which promote negative calcium balance and bone loss. Exposure to high-dose steroids and immunosuppression following transplantation further promotes bone loss and fracture development. To quote Elizabeth Shane, a recognized leader in this field, "Immunosuppression insults an already compromised skeleton."

Long-term survival following organ transplantation has improved considerably. Because patients often wait 2 or more years before transplantation, this represents an opportunity to protect bone mass, both to prevent further bone loss and to help restore what may already have been lost. The clinical focus should be to both optimize bone mass before transplantation and to prevent bone loss in the postoperative period.²

Pathophysiology

Lung transplantation

Osteoporosis is very common among patients awaiting lung transplantation. Shane and colleagues studied 70 patients awaiting transplant for end-stage lung disease and found osteoporosis in 30% at the lumbosacral (LS) spine and in 49% at the femur neck. Osteopenia (low bone mass) was noted in 35% and 31% at these same sites. In other words, only a minority of patients awaiting transplant had normal bone density. In a 1996 article, Ferrari et al also prospectively evaluated changes in bone mass in 21 consecutive lung transplant candidates and confirmed this increased osteoporosis prevalence. Prior to transplantation, BMD was decreased at all sites measured, and 35% of patients awaiting transplant had already established osteoporosis as defined by the World Health Organization (WHO).

Aris et al (1996) reported that nearly half (45%) of patients with end-stage lung disease awaiting transplant were at or below the fracture threshold. However, following lung transplantation, nearly three quarters (73%) of patients were at or below the fracture threshold.³ The prevalence rate of documented osteoporotic fractures was found to be 29% in patients with emphysema and 25% in patients with cystic fibrosis. Not surprisingly, the posttransplant BMD t- score was predicted by cumulative steroid dose.

Patients awaiting lung transplant are at increased risk for osteoporosis because of malnutrition, unrecognized vitamin D deficiency, tobacco use, decreased mobility, and, of course, glucocorticoid exposure. Cystic fibrosis, a common indication for transplantation, is itself associated with low bone mass and fragility fractures because of (1) delayed puberty and hypogonadism and (2) chronic malnutrition with pancreatic insufficiency causing calcium and vitamin D malabsorption. Despite the common practice of supplementing oral vitamin D in patients with cystic fibrosis, usual daily doses of 400-800 IU of vitamin D are often ineffective in maintaining normal vitamin D stores. Donovan et al found that 40% of patients with cystic fibrosis receiving 400-800 IU vitamin D daily were frankly vitamin D deficient.⁴ To ensure adequate vitamin D supplementation, measuring 25-hydroxyvitamin D levels should be included in the routine treatment of these patients. 

In Shane and colleagues' 1996 series, vitamin D deficiency was noted in 36% of patients with cystic fibrosis awaiting transplantation, although vitamin D deficiency was also very common among other patients with end-stage lung disease.⁵ In this same series, 20% of patients with chronic obstructive pulmonary disease awaiting transplant had vitamin D deficiency, which was associated with more severe demineralization at the LS spine and hip.

Significant glucocorticoid exposure is nearly universal in persons with end-stage lung disease. In 2001, Israel et al reported that even inhaled corticosteroids lead to a dose-related decline in bone density at the hip. Also in 2001, van Staa et al reported that vertebral, nonvertebral, and hip fractures occur with increased frequency in association with inhaled corticosteroids.⁶ Note that only very few patients receiving long-term glucocorticoid therapy in Shane and colleagues' 1996 study were simultaneously receiving an effective antiresorptive agent for osteoporosis prevention.^5,7

Similar to patients awaiting lung transplantation, only a minority of patients awaiting cardiac transplantation have normal bone density. Shane et al studied 101 patients with advanced congestive heart failure who were awaiting transplantation. Only 50% and 47% had normal BMD at the LS spine and total hip, respectively.⁸

The reasons for this are likely multifactorial. Patients with end-stage congestive heart failure are uniformly exposed to potent loop diuretics that promote negative calcium balance, and they often have coexisting renal disease and hepatic congestion from their low-flow state. Low serum concentrations of 25(OH) vitamin D and 1,25-dihydroxyvitamin D with secondary hyperparathyroidism are quite common. As the disease advances, patients are less mobile and have less sun exposure. Not surprisingly, Shane et al found that vitamin D deficiency was significantly more common in the patients with more severe heart failure.⁸ (Another study, by Iqbal et al, did not find significantly low BMD in the lumbar spine and hip, relative to age and sex, in ambulatory patients with heart failure who were waiting for cardiac transplantation.⁹ )

Vertebral fractures are highly prevalent among cardiac transplant recipients, with a fracture prevalence of 18-50% reported across various series.¹⁰ Among 47 patients monitored by Shane and colleagues postcardiac transplant, 17 sustained 34 fractures after 1 year, despite having adequate calcium and vitamin D. At least 1 fracture was experienced by 54% of the women and 29% of the men. The vast majority (85%) of fractures occurred in the initial 6 months’ posttransplant, with most fractures involving the spine. Women with low femur-neck density were significantly more likely to sustain posttransplant fractures.¹¹

Following cardiac transplantation, LS spine bone density typically declines 6-10% in the first 6 months, after which it stabilizes. Hip density similarly declines in the first year, dropping 10-15% below pretransplant levels. After the first year, bone loss usually slows, and LS spine density may actually increase slightly in the third year.¹⁰ In comparison, after the second and third years following cardiac transplant, the one third distal radius, a site enriched for cortical bone and susceptible to parathyroid hormone (PTH) action, shows evidence of continued bone loss.¹⁰

A cross-sectional case control study¹² examined 9 adolescent cardiac transplant recipients aged 12-16 years at the time of transplantation who were subsequently reevaluated 8-16 years posttransplant. Since most bone mass is accrued by the late teenage years, concern exists whether patients who undergo transplant during these critical years would fail to accrue normal bone mass or delay achievement of peak bone mass. Compared to people in control groups, transplant recipients had shorter stature than calculated midparental height would predict. Biochemical parameters suggested renal impairment with secondary hyperparathyroidism, without a difference in vitamin D levels between the groups.

The authors suggest a pathogenic role for PTH in the osteoporosis in this population. Most of the patients received glucocorticoids at the time of study, yet glucocorticoids are usually associated with low bone turnover and suppressed bone formation. High bone turnover was noted in the study with markedly lower BMD at the forearm. Whether the increased bone turnover observed would ultimately be associated with ongoing loss of bone or continued bone growth was not clear from this cross-sectional study.¹²

In a noncontrolled report, the incorporation of mycophenolate mofetil in the immunosuppressant regimen has successfully reduced steroid requirements in a subset of patients with symptomatic osteoporosis after cardiac transplantation. However, in the small number (12) of patients studied, this did not result in an improvement of bone mineral density after 1 year.¹³

Because both low BMD and low vitamin D concentrations are associated with higher rates of bone loss and fracture after cardiac transplantation, patients should receive appropriate evaluation and specific treatment for these conditions. Future treatment strategies should also address prevention and treatment of secondary hyperparathyroidism.

A minority of patients awaiting liver transplantation have normal bone density. In a large series of 243 consecutive patients undergoing evaluation for liver transplantation, only 15% had normal bone density.¹⁴ Moreover, vertebral fractures were present in 35% of patients prior to transplantation in this same population.¹⁵
 
End-stage liver disease (ESLD) itself is associated with osteoporosis. Vitamin D deficiency is extremely common among patients with cirrhosis who are awaiting transplant. Cirrhosis is associated with significantly depressed levels of 25-hydroxyvitamin D-3, 1,25-dihydroxyvitamin D, osteocalcin, and PTH.¹⁶ Cirrhosis is also associated with low osteocalcin levels and histomorphometric evidence of decreased bone formation. 

In chronic liver disease, low vitamin D levels predict bone loss.¹⁷ In one study of 27 patients awaiting orthotopic liver transplantation, 74% had subnormal 25-hydroxyvitamin D levels at baseline. Vitamin D levels were inversely associated with more advanced Child-Pugh classification, and more advanced Child-Pugh class is associated with increased bone loss at the LS spine.¹⁸

Chronic obstructive liver disease may interfere with the enterohepatic circulation of vitamin D metabolites. The cholestasis observed in persons with primary biliary cirrhosis (PBC) may inhibit normal osteoblast function by an uncertain mechanism, resulting in a low bone turnover osteoporosis. Although the specific pathophysiological mechanisms in PBC have not been defined, histomorphometry findings reveal depressed bone formation and inactive remodeling.^19,20

Polymorphism in the gene encoding collagen type I alpha1 (COLA1) Sp1 is a recently recognized genetic predictor of peak bone mass. Not surprisingly, COLA1 has been found to be a marker of bone mass in patients with PBC, although the degree of cholestasis remains the more important risk factor for osteoporosis.²¹

Along the same line, allelic polymorphism of the vitamin D receptor is also thought to be predictive of BMD in healthy patients and in patients with primary osteoporosis. The vitamin D receptor genotype influences bone loss after liver transplantation and also predicts lower BMD in patients with PBC. Specifically, the bb genotype is partially protective against posttransplant bone loss.^22,23

In general, more severe liver disease and more severe cholestasis are associated with more severe bone loss.²⁴ In fact, bone loss was predicted by the degree of hyperbilirubinemia in a recent Swedish study.¹⁸ Cholestasis-related osteopenia appears to be more severe than osteopenia associated with viral liver disease. In one cross-sectional study, BMD z scores were more than twice as depressed in cholestatic patients than in patients with viral liver disease, although viral liver disease is itself associated with significant osteopenia.²⁵

Gallego-Rojo et al studied bone metabolism in 32 consecutive viral cirrhotic patients in whom alcoholism had been excluded. These patients showed reduced BMD at all sites measured, and 53% had established osteoporosis. Serum immunoglobulin F-1 levels were lower in viral cirrhotic subjects than in control subjects, and levels differed significantly between cirrhotic patients with and without osteoporosis. Therefore, low immunoglobulin F-1 levels may play a role in osteopenia associated with viral cirrhosis.^25,26

Alcohol abuse is a well-known cause of cirrhosis, and alcohol is a well-known risk factor for osteoporosis, which is likely multifactorial in origin. Malnutrition and chronic pancreatitis are common in persons with alcoholism and are frequently associated with concomitant vitamin D and magnesium depletion.^27,28 In humans, magnesium deficiency is known to result in hypocalcemia, impaired PTH secretion, and low serum concentrations of 1,25-dihydroxyvitamin D.²⁹ Ultimately, alcohol itself may directly suppress bone formation, as evidenced by a direct correlation between bone GLA protein levels and days of abstinence from alcohol.³⁰

Hypogonadism is a known risk factor for osteopenia and occurs frequently in persons with alcoholism and ESLD. Both low testosterone and high sex hormone–binding globulin levels correlate with worsening Child-Pugh classification.

Monegal et al have documented osteoporosis in 43% of cirrhotic patients at the time of referral for liver transplantation. In the first year posttransplantation, bone mass declined further, with LS spine BMD falling 3.5-24%.^16,31 By 3 years after liver transplantation, a third of the patients developed fractures. In this cohort, age and low bone mass were identified as pretransplant risk factors for fracture.

Similar to cardiac transplantation, the highest fracture incidence rate occurs in the first year following liver transplantation. Estimates range from 24-65%, with the highest rate being reported in women with PBC. In a 1991 study of women with PBC by Eastell et al, BMD at the LS spine was inversely related to the severity of liver disease. The overall rate of bone loss in half the patients with PBC was twice that of healthy controls. Following liver transplantation, BMD in the LS spine fell at 3 months and was associated with atraumatic fractures in 13 of 20 women.²⁴

Histomorphometric analysis of transiliac bone biopsy specimens prior to and 3 months after liver transplantation in 21 patients with chronic liver disease demonstrates a highly significant and quantitatively large increase in bone turnover within the first 3 months after liver transplantation. The bone turnover rate was low preoperatively, with thinner walls and erosion depth. The bone formation rate increased after transplantation. A small increase in osteoid seam width was noted postoperatively, with a decrease in the mineralization lag time.³²

A high incidence of vertebral fracture in the first 3 months after liver transplantation is well recognized. As in other cohorts, prevalent vertebral fracture is an important risk factor for the subsequent development of fracture in the liver transplant population.¹⁵

Significant recovery of BMD following transplantation was noted in this population. By 12 months, the median BMD at the LS spine was similar to the pretransplantation BMD; by 24 months, BMD was actually 5% higher than the pretransplant baseline. Bone mass may be restored to normal within 2-3 years following liver transplant.²⁴

Several other studies have reported some long-term recovery of BMD in the liver transplant population. In a Dutch cohort treated with a prednisolone- and azathioprine-based immunosuppressant regimen and with follow-up care extending to 5-15 years, improvement in BMD was mainly observed in the second postoperative year, with stabilization thereafter.³³

Despite this interval improvement, approximately one third of patients were left with a BMD below the fracture threshold. In general, the outcome was less favorable in men than in women and in patients who received transplants for cholestatic liver disease, who may initially have had more severe bone disease.³³

Not all series have demonstrated recovery and stabilization of BMD following liver transplantation, and some show continued decline.²⁵

The most common sites to fracture in the liver transplant recipient are the vertebrae and ribs. A 2000 British study by Ninkovic et al looked prospectively at the incidence of vertebral fractures in 37 patients with ESLD before and 3 months after transplant. Before transplantation, vertebral fractures were evident in 35% of patients. New fractures developed by 3 months after transplantation in 27%. Although osteoporosis (defined as a t score <-2.5) was found in 39% of patients prior to transplantation, BMD did not reliably predict fracture risk. However, subsequent vertebral fractures were significantly more common in those with a prevalent vertebral fracture.

Nearly all cross-sectional studies of renal transplant recipients demonstrate that BMD is below normal levels. A fracture prevalence of 5-11% has previously been reported in cross-sectional studies, which is similar to or greater than rates observed in women with postmenopausal osteoporosis.^34,35 Hyperparathyroidism preceding renal transplantation accelerates trabecular bone loss at the spine in the early transplant period.³⁶

Most patients with end-stage renal disease (ESRD) are hypogonadal and have some degree of renal osteodystrophy. (For a comprehensive discussion of renal osteodystrophy, which is beyond the scope of this chapter, please see Goodman et al, 2003.³⁷ ) Most patients with ESRD have been exposed to drugs that negatively affect bone metabolism. In one large series of 250 such patients, risk factors for low bone mass included secondary amenorrhea, prior failed renal transplantation, chronic metabolic acidosis, and chronic heparin and aluminum exposure. Having had a prior failed renal transplant is probably associated with increased immunosuppressant exposure to prevent rejection and to hyperphosphatemia associated with osteomalacia and osteoporosis.³⁸

In recent years, continuous use of aluminum-containing phosphate binders has largely been abandoned; therefore, aluminum toxicity is not presently a significant problem in transplant-related bone disease.^39,40 However, adynamic bone disease has become increasingly prevalent in the chronic kidney disease population, evident in 27% of transiliac bone biopsy specimens⁴¹ and up to 50% of renal transplant patients prior to bisphosphonate treatment for osteoporosis.⁴²

After successful renal transplantation, secondary hyperparathyroidism usually resolves gradually, with normalized vitamin D metabolism and creatinine clearance (CrCl). PTH levels frequently normalize or improve by 1 month posttransplant because of immediate improvement in phosphate retention. Cortical bone density improves secondarily, with significantly better z scores at the distal radius occurring by 6 months after renal transplantation. However, in approximately a third of cases, persistent hyperparathyroidism and hypercalcemia are noted.⁴³

In cases of refractory hyperparathyroidism in which surgery is indicated, parathyroidectomy has been associated with a marked improvement in BMD.

With successful renal transplantation, improvement also occurs in aluminum bone disease and dialysis-associated amyloidosis.⁴⁴

Overall, the transplant-related bone disease in kidney recipients does not appear to be as severe as in other solid organ transplant recipients, with the possible exception of kidney recipients with type 1 diabetes.⁴⁵ This is perhaps because kidney transplant recipients are younger on average than other organ recipients at the time of transplantation and they may have had better recognition and management of pretransplant bone disease. Kidney transplant recipients may receive lower doses of immunosuppression overall. Rejection may also be more easily detected in renal recipients and, therefore, treated earlier than in other solid organ transplant recipients, resulting in lower total doses of immunosuppression. 

Simultaneous pancreas-kidney transplantation (SPKT) successfully restores euglycemia and insulin independence while reversing uremia in patients with ESRD due to diabetic nephropathy. While diabetic patients comprise approximately 20% of those receiving renal transplants, virtually all patients receiving both a pancreatic and renal transplant have type 1 diabetes mellitus. Because type 1 diabetes mellitus itself predisposes to cortical osteopenia and usually low bone turnover, patients with the condition are clearly at greater risk of transplant-associated bone disease and fracture.⁴⁵ The reasons for this are likely multifactorial.

Most patients with type 1 diabetes mellitus have not yet achieved peak bone mass before the onset of diabetes, and long-standing insulin deficiency may compromise bone mass. Multiple studies have documented that patients with type 1 diabetes have reduced BMD at all sites measured, with a high prevalence of osteoporosis. Munoz-Torres et al examined a cohort of 94 consecutive Spanish patients (aged 20-56 y) with type 1 diabetes of 1-35 years' duration presenting to a diabetes clinic for therapy. Reduced BMD was observed at all sites, and 19.1% of patients had osteoporosis.

Poor glycemic control, the presence of diabetic complications, and smoking are also associated with a lower BMD in multiple studies. In a study by Campos-Pastor, diabetic patients with retinopathy, for example, are much more likely to exhibit osteopenia or osteoporosis.⁴⁶ However, the presence of retinopathy and the degree of glycemic control are clearly not independent variables because the mean glycosylated hemoglobin value was significantly higher in the group with retinopathy (8.5% vs 7.1%; P = .05). BMD also correlates with body mass index, which is dependent upon the degree of insulinization and glycemic control.

Campos-Pastor et al observed 62 patients with type 1 diabetes before and after 7 years of intensive insulin therapy. With intensive insulin therapy, BMD stabilized at all sites. A significant fall in tartrate-resistant alkaline phosphatase (4.3 vs 2.7) and a significant rise in intact PTH (28 vs 40) were also observed.⁴⁶

Addesso et al and Shane et al studied bone density and fracture prevalence in a series of patients receiving SPKT.⁸ BMD measured by dual-energy x-ray absorptiometry (DEXA) scanning was compared before and after transplantation (6 ± 5 mo pretransplantation; 2 ± 0.5 mo posttransplantation). Twenty-five of 28 patients underwent SPKT and 3 patients received a solitary pancreas graft. The mean age of the patients was 39 years, with a mean duration of type 1 diabetes mellitus of 23 years. Among this type 1 diabetic cohort awaiting SPKT, osteoporosis and osteopenia were present in, respectively, 11% and 21% at the LS spine, 29% and 54% at the femur neck, 25% and 61% at the Ward triangle, and 14% and 64% at the trochanter. Of the 20 patients with available fracture data, 15 (75%) had already sustained a fracture while awaiting transplantation. In total, 12 extremity fractures and 3 rib fractures occurred.

Nisbeth and colleagues have followed a Swedish cohort of renal transplant recipients, looking specifically at the diabetic (type 1) subset. Symptomatic bone disease was examined in this cross-sectional study using questionnaires and hospital records in 193 renal transplant recipients with functional grafts 6 months to 23 years after transplantation.⁴⁵ Most fractures occurred within the first 3 years posttransplant. Patients with type 1 diabetes comprised 18% of the total population. While 17% of the group overall experienced a symptomatic osteoporotic fracture, 40% of diabetic patients experienced a similar fracture. Fractures in diabetic patients were often multiple and were located mostly in the appendicular skeleton, ankles, and feet. Only 11% of renal transplant recipients without diabetes experienced a symptomatic fracture.

Smets performed a cross-sectional study of fracture prevalence and bone metabolism in 31 Dutch patients at least 12 months following successful SPKT (mean 40 ± 23 mo). All were insulin independent with a mean CrCl level of 64 ± 21 mL/min. Secondary hyperparathyroidism was noted in 55% of patients. Increased osteocalcin, a marker of increased bone turnover, was present in 45%.⁴⁷ Osteocalcin, a bone turnover marker, is tricky and complex in the SPKT patient because the clearance of osteocalcin is reduced by a decreased CrCl and osteocalcin levels are raised by hyperglycemia.

In this Smets study, osteoporosis (t score <-2.5 standard deviation [SD]) was found in 23% of patients at the lumbar spine, a predominantly trabecular site, whereas osteoporosis was found in 58% patients at the femur neck, a predominantly cortical site. Fractures, which were primarily nonvertebral, were found in 45% of the SPKT patients studied.⁴⁷

Smets and colleagues subsequently prospectively followed 19 consecutive SPKT patients up to 4 years postengraftment. These patients had, on average, approximately 25 years of type 1 diabetes. None of the patients had osteoporosis at the lumbar spine prior to transplantation, although 7 (37%) had cortical osteoporosis with a femoral neck t-score of less than -2.5 SD pretransplant. The authors note that the cumulative prednisone dose was similar in most patients. At the end of the first posttransplantation year, all patients began the synthetic analog alfacalcidol at 0.25 mcg/d. Twelve patients ultimately had follow-up longer than 18 months. A significant increase in serum calcium (+0.08 ± 0.02 mmol/L, P =.002) was noted in the 6 months after alfacalcidol was begun, which was not associated with a significant decrease in PTH, so perhaps the dose was not sufficient to fully normalize PTH secretion.⁴⁷

Despite this, a small but significant increase in LS spine BMD was seen in the first 6 months following alfacalcidol (+1.7 ±2.1%, P =.028). The BMD at the femur neck increased insignificantly. This paper confirmed a pattern of heightened trabecular and cortical bone loss during the first 6 months after SPKT. In contrast to other studies,⁴⁴ however, which suggested continued bone loss up to 18 months postrenal transplant, this study in SPKT recipients suggested stabilization of BMD after the first 6 months posttransplant. Compared with their baseline, 9 patients, 47% had osteoporosis at the femoral neck, and only 1 patient developed osteoporosis at the lumbar spine (5%). In this cohort, all fractures occurred more than 1 year posttransplantation; about one third of patients experienced a fracture over a mean follow up period of approximately 3.3 years.⁴⁸

In conclusion, low bone mass is highly prevalent both prior to and following successful SPKT and is associated with a high fracture prevalence. Cortical bone loss is unusually prevalent in this specific transplant population, possibly due to both cortical osteopenia and persistent hyperparathyroidism.

Routinely administered posttransplant immunosuppressants play a central role in the pathogenesis of bone loss and fracture. Regimens typically include glucocorticoids (at high dose initially), cyclosporin A (CsA), tacrolimus FK506, azathioprine, or mycophenolate mofetil. Because they are always administered simultaneously, sorting out the independent effects of immunosuppressants from those of glucocorticoids is difficult, if not impossible. Immunosuppressant doses are typically higher in liver and heart transplantations compared with renal transplantation, contributing to the more advanced osteopenia seen in those groups.

• Glucocorticoids
  • While a detailed discussion on glucocorticoid-induced bone loss is beyond the scope of this article, glucocorticoids are known to induce osteoporosis. An increased risk of vertebral fracture has been associated with an oral dose of prednisolone of as low as 2.5 mg/d, which is approximately equipotent to prednisone at 2.5 mg/d. Glucocorticoids are commonly prescribed in high doses, up to 120 mg of prednisone or its equivalent daily during periods of acute rejection and immediately posttransplant.
  • Glucocorticoids promote bone loss through a variety of simultaneously operating mechanisms, as follows:
    • Reduce GI calcium absorption
    • Increase urinary calcium excretion
    • Induce secondary hyperparathyroidism
    • Decrease production of skeletal growth factors
    • Decrease the responsiveness of luteinizing hormone (LH) to gonadotropin-releasing hormone, thereby decreasing gonadal hormone production; may also directly decrease gonadal hormone production
    • Suppress corticotropin, thereby suppressing the adrenal production of androstenedione, a substrate for both testosterone and estrone production
    • Decrease osteoblast-mediated bone formation
    • Increase bone resorption
  • Glucocorticoids result in a disproportionate loss of cancellous or trabecular bone, possibly because trabecular bone has an inherently greater rate of turnover than cortical bone. Serum bone GLA protein, osteocalcin, is also inhibited. Thus, glucocorticoids induce a low-turnover osteopenia and disproportionately effect trabecular bone.⁴⁴ With the advent of the cyclosporines in the early 1980s, graft survival markedly improved owing to decreased organ rejection. The introduction of cyclosporines allowed steroid doses to be substantially reduced. At the time, the hope was that the harmful effects of immunosuppression on the skeleton would be ameliorated. Unfortunately, this was not the case. The lowest effective dose of glucocorticoids is recommended to minimize loss of bone mass and risk of osteonecrosis (a common complication in the first 2 years following transplant).
• Cyclosporin A
  • Similar to glucocorticoids, CsA causes severe and rapid trabecular bone loss. However, unlike glucocorticoids, accelerated bone turnover is observed, with both increased formation and resorption. The bone histomorphology resembles that of the oophorectomized female rat. Antiresorptive agents, such as estrogen, alendronate, and calcitonin, can largely prevent this bone loss. Alendronate specifically prevents CsA-induced osteopenia in rats, maintaining trabecular bone volume at the tibia. In contrast to glucocorticoids, CsA induces a high-turnover osteopenia of the trabecular skeleton.
  • Some investigators have speculated that this effect of cyclosporine may be mediated through testosterone because cyclosporine suppresses the hypothalamic-pituitary-gonadal axis and lowers serum testosterone levels in rats and in human transplant patients. Some evidence suggests that cyclosporine may have a direct testicular effect. Examination of rat testes after CsA exposure has revealed decreased LH-receptor numbers and dramatically decreased serum and intratesticular testosterone. Altered testicular cytochrome P-450 activity is reported due to suppressed heme formation and the steroidogenic activities that rely on it, such as 17-hydroxylase and side-chain cleavage enzymes.
  • Others have speculated that CsA may have a direct pituitary or hypothalamic effect, inducing hypogonadotrophic hypogonadism and a blunted response of LH/follicle-stimulating hormone (FSH) to gonadotropin-releasing hormone. While CsA may have both central and direct testicular effects, CsA-induced bone loss is not prevented by testosterone administration in the rat model and did not correlate with bone turnover or histomorphometry findings.
• Tacrolimus (FK506)
  • Tacrolimus is a fungal macrolide that is less nephrotoxic and more potently immunosuppressive than CsA. In rats, this has been reported to cause high-turnover bone loss of even greater magnitude than that caused by CsA.^49,50 Because tacrolimus is a more potent immunosuppressant, steroid doses may be reduced further with tacrolimus than with CsA.
  • A recent paper by Smallwood (2005) compared 137 liver transplant recipients receiving tacrolimus (n=112) compared with cyclosporine (n=25). Tacrolimus administration was associated with a nonsignificant tendency toward fewer patients with low bone density. Among the patients weaned from prednisone, the patients treated with tacrolimus were less likely to have low BMD (36.2% vs 68.8%, P =.02). Overall, rates of bone loss have been similar in heart, liver, and kidney transplant recipients receiving either tacrolimus or CsA.
• Sirolimus/rapamycin
  • Rapamycin inhibits downstream signaling from the mammalian target of rapamycin (mTOR) proteins, a signaling pathway promoting tumor growth. Rapamycin binds to the FK506 binding protein, and this complex then binds to mTOR and prevents interaction of mTOR with target proteins in the signaling pathway. Short-term administration of rapamycin causes no trabecular bone loss and potentially has bone-sparing effects.⁵¹
  • Two open-label, randomized, phase-2 studies comparing sirolimus versus cyclosporine examined bone metabolism with markers of bone turnover, osteocalcin, and urinary N-telopeptides measured over a 1-year period in 115 patients receiving CsA or sirolimus with azathioprine and glucocorticoids or mycophenolate with glucocorticoids. In the patients treated with CsA, serum osteocalcin and urine N-telopeptides were consistently higher compared with sirolimus.⁵²

Osteoprotegerin (OPG) is an antiresorptive cytokine and a potential mechanism for immunosuppressant osteopenia. A member of the tumor necrosis factor–receptor superfamily, OPG is a critical regulator of bone resorption. OPG inhibits terminal differentiation and activation of osteoclasts.⁵³ OPG deficiency causes osteoporosis in mice, and, when administered to ovariectomized rats, OPG decreases osteoclast activity and restores normal bone mass.

OPG is produced by osteoblasts and arterial cells, and inhibits osteoclast function by neutralizing receptor activator of NF-kappa B ligand (RANKL).

Injections of OPG are well tolerated and rapidly decrease markers of bone resorption, urine N -telopeptide, and bone alkaline phosphatase. CsA, rapamycin (sirolimus), and tacrolimus (FK506) significantly decrease OPG mRNA and protein levels in undifferentiated marrow stroma (44-68%). A reciprocal, significant increase in RANKL mRNA levels (60-120%) is also seen with these agents. In contrast, the potential bone-sparing effect of rapamycin may be explained by the increase in OPG-mRNA seen in mature osteoblasts.⁵⁴ Renal transplant recipients treated with intravenous zoledronate (a third-generation bisphosphonate) demonstrated significant elevations of OPG over the first 6 months of treatment, consistent with osteoclast inhibition.

Frequency

International

Kidney transplant patients generally experience less transplant-related bone disease than cardiac⁷ (50% vertebral fracture prevalence), lung, or liver transplant patients. This may be because renal transplant recipients are younger (on average) at the time of transplantation and may have better management and recognition of metabolic bone disease prior to transplantation; moreover, they may receive lower doses of immunosuppression overall. Kidney transplant patients with type 1 diabetes mellitus and SPKT recipients are probably an exception to this general statement because, for the reasons outlined above, they are predisposed by their type 1 diabetes to cortical osteopenia.

Sex

Women are at greater risk for all forms of osteoporosis. Women with small frames and low body weight (ie, <70 kg) are particularly at risk; white or Asian women are at highest risk. Postmenopausal women (particularly women with early spontaneous or surgical menopause) are at increased risk because of estrogen deficiency.⁵⁵ Women with a history of prolonged periods of amenorrhea and hypogonadism are also at increased risk.

Clinical

History

• The pretransplant bone evaluation should include a careful history with particular attention to risk factors for osteoporosis.
  • Any personal history of fracture is particularly relevant because prior fracture predicts future fracture.⁴⁹
  • Any family history of osteoporosis or fragility fractures is also relevant.
  • A history of loss of height suggests established osteoporosis and occult thoracic compression fracture.
• The review of systems should include a review of gonadal function because a history of amenorrhea, decreased libido, or erectile or orgasmic dysfunction could suggest underlying hypogonadism, predisposing to osteopenia.
• The review of systems should specifically inquire about bone pain, myalgias, or myopathic symptoms, which could suggest occult vitamin D deficiency or osteomalacia.
• Significant constitutional symptoms or symptomatic anemia could suggest occult multiple myeloma as a cause of osteopenia in the appropriate clinical context.
• Because immobility is known to promote negative bone balance, any history of periods of prolonged bed rest is also relevant.
• A careful medication history should be taken for past anticonvulsant use because these medications can derange vitamin D metabolism.
  • Heparin, loop diuretics, and steroids (both oral and inhaled) are associated with negative calcium balance.
  • Any history of tobacco or alcohol abuse is relevant because the use of these substances is an established risk factor for osteoporosis.
• A dietary history should be obtained.
  • This should include an estimate of daily calcium intake.
  • An overview of lifelong dairy intake or avoidance, lactose intolerance, malabsorption, or celiac disease,⁵⁰ which predispose the patient to vitamin D deficiency, is also relevant.
  • A history of sun avoidance is similarly important.
  • Overall nutritional status, including any prior periods of malnutrition or energy (caloric) restriction (eg, anorexia nervosa) should be assessed.
  • A history of dietary supplement intake is also relevant because recent observational data suggest that excess vitamin A intake (eg, as retinol) is associated with an increased hip fracture risk.⁵⁶

Physical

• Record height and weight, along with any loss of height or kyphosis, which could suggest occult compression fracture.
• The examiner should be alert for the presence of blue sclerae, which suggest underlying osteogenesis imperfecta. 
• Any scoliosis or other regions of bony deformity should be noted. These deformities have the potential to render bone density determinations inaccurate in these regions, and the physician or technician performing bone densitometry should be made specifically aware of them.
• Any areas of bone tenderness or pain, which could suggest occult fracture, avascular necrosis, or osteomalacia, should prompt further diagnostic evaluation. 
• Incapacitating pain or tenderness in the lower extremities or bones of the feet following organ transplantation could suggest the calcineurin-inhibitor–induced pain syndrome (CIPS), an unusual side effect of cyclosporine or tacrolimus. This may be accurately diagnosed by its typical presentation, negative inflammatory markers (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]), characteristic magnetic resonance imaging finding with altered bone marrow signal. The reduction of cyclosporine or tacrolimus trough levels and the administration of calcium channel blockers has led to relief of pain, although in some cases bone marrow edema on follow-up MRI and pain syndrome resolved over 3 months without specific therapy.^57,58

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• Understanding Osteoporosis Medications
• Heart and Lung Transplant Overview
• Bone Health Center