Bone Density Loss - 2

 January 23, 2004   Osteoporosis in Solid Organ Transplantation

Synonyms and related keywords: low bone mass, osteopenia, bone mineral density, BMD, liver transplantation, heart transplantation, lung transplantation, kidney transplantation, kidney/pancreas transplantation, simultaneous pancreas-kidney transplantation, SPKT, osteoporosis, glucocorticoid-induced osteoporosis, low body weight, estrogen deficiency, androgen deficiency, calcium deficiency, vitamin D deficiency, thyroid hormone excess, bone fractures, vertebral fractures, nonvertebral fractures, hip fractures, negative calcium balance, bone loss, osteoporotic fractures, fragility fractures, cystic fibrosis, primary biliary cirrhosis, PBC, osteogenesis imperfecta

Author: Carmel Fratianni, MD, Assistant Professor, Department of Clinical Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Southern Illinois University School of Medicine

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. 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. Traditionally recognized risk factors for osteoporosis include white race, low body weight, estrogen or androgen deficiency, calcium and/or vitamin D deficiency, and thyroid hormone excess. In addition to these traditional risk factors, pretransplant bone homeostasis is also influenced by the disease process or the diseased organ itself, eg, liver, lung, or kidney failure. 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." In recent years, 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.
Pathophysiology:  Lung transplantation
Osteoporosis is very common among patients awaiting lung transplantation. Elizabeth 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 transplant, 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 transpla ntation, nearly three quarters (73%) of patients were at or below the fracture threshold. 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. To ensure adequate vitamin D supplementation, measuring 25-hydroxy vitamin 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. 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. 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.
Cardiac transplantation
Similar to patients awaiting lung transplantation, only a minority of patients awaiting cardiac transplantation have normal bone density. Shane et al (Am J Med, 1997) 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.  The reasons for this are likely multifactorial. Patients with end-stage congestive heart failure are uniformly exposed to potent loop diuretics that promote a 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-dihydroxy vitamin D with secondary hyperparathyroidism are quite common. As the disease advances, patients are less mobile and have less sun exposure. Unsurprisingly, Shane et al (Am J Med, 1997) found that vitamin D deficiency was significantly more common in the patients with more severe heart failure. Vertebral fractures are highly prevalent among cardiac transplant recipients, with a fracture prevalence of 18-50% reported across various series (Shane, J Clin Endocrinol Metab, 1997). Among 47 patients followed by Shane and colleagues post–cardiac transplant, 17 sustained 34  fractures after 1 year, despite having adequate calcium and vitamin D.One or more fractures were 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 (Shane, 1993). Following cardiac transplantation, LS spine bone density typically declines 6-10% in the first 6 months, after which it stabilizes. Hip density declines through the first year, reaching 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 (Shane, J Clin Endocrinol Metab, 1997). 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.

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.   Posttransplant immunosuppression 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.
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 (Van Staa, 2000). Glucocorticoids are commonly prescribed in high doses, eg, 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 (Manelli, 2000):
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 (Julian, 1991). 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.
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 (Stein, 1991; Joffe, 1992; Sass, 1997). 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 (Krueger, 1991).  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 (Ramirez, 1991). 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 (Erben, 1998).
Tacrolimus FK506
Tacrolimus is a fungal macrolide that is 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 (Inoue, 2000; Stempfle, 2002). Because tacrolimus is a more potent immunosuppressant, steroid doses may be reduced further with tacrolimus than with CsA. Overall, rates of bone loss are similar in heart and liver transplant recipients receiving either tacrolimus or CsA. 

Sirolimus/rapamycin (Rapamune)
Short-term administration of rapamycin causes no trabecular bone loss and potentially has bone-sparing effects (Romero, 1995).  Osteoprotegerin (OPG), a potential mechanism for immunosuppressant osteopenia, is a member of the tumor necrosis factor–receptor superfamily and is a critical regulator of bone resorption. OPG inhibits terminal differentiation and activation of osteoclasts (Hofbauer, 2000). When administered to ovariectomized rats, OPG decreases osteoclast activity and restores normal bone mass.  Injections of OPG are well tolerated and rapidly decrease markers of bone resorption, urine N-telopeptide, and bone alkaline phosphatase. CsA, rapamycin, and tacrolimus FK506 significantly decrease OPG mRNA and protein levels in undifferentiated marrow stroma (44-68%). These agents also increase RANKL mRNA levels significantly (60-120%). In mature osteoblasts, rapamycin increased OPG mRNA and protein by 120%. This could explain the potential bone-sparing effect of rapamycin (Hofbauer, 2001).  Frequency: