2008 JASN IMPACT FACTOR 7.505	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Torres, A. Articles by Salido, E. Search for Related Content PubMed PubMed Citation Articles by Torres, A. Articles by Salido, E.

Calcium Metabolism and Skeletal Problems after Transplantation

Nephrology Section and Research Unit, University Hospital of the Canary Islands, Instituto Reina Sofia de Investigación, Tenerife, Spain.

Correspondence to: Dr. Armando Torres, Unidad de Investigación, Hospital Universitario de Canarias, Ofra s/n, 38320 La Laguna, Tenerife, Spain. Phone: 34-922-67-83-81; Fax: 34-922-64-71-12; E-mail: atorres{at}ull.es

	Introduction

Top Introduction Persistent Hyperparathyroidism... Hypophosphatemia Posttransplantation Bone Loss Bone Fractures after Renal... Posttransplantation Bone... Prevention and Management of... Osteonecrosis Bone Pain References

 
Successful renal transplantation (RT) corrects the abnormalities of mineral metabolism that lead to renal osteodystrophy. This includes correction of uremia, normalization of serum calcium and phosphorus levels, and restoration of calcitriol production. However, the degree of renal function recovery is usually incomplete, and persistence of hyperparathyroidism is common. In addition, the immunosuppressive drugs used to prevent graft rejection exert profound effects on bone metabolism. Finally, persistent metabolic acidosis in patients with chronic impairment of graft function and the use of loop diuretics may also affect bone and mineral metabolism after RT. As a whole, detrimental factors predominate over beneficial factors, and disturbances of mineral metabolism and skeletal alterations are common causes of morbidity after RT. The major clinical problems include hypercalcemia and persistent hyperparathyroidism, hypophosphatemia, posttransplantation bone loss and fractures, osteonecrosis, and bone pain syndromes.

	Persistent Hyperparathyroidism and Hypercalcemia

Top Introduction Persistent Hyperparathyroidism... Hypophosphatemia Posttransplantation Bone Loss Bone Fractures after Renal... Posttransplantation Bone... Prevention and Management of... Osteonecrosis Bone Pain References

 
Serum parathyroid hormone (PTH) concentrations decrease progressively during the first 3 to 6 mo after grafting (1). However, 1 yr after transplantation, resolution of hyperparathyroidism is incomplete in 50% of recipients (2). Only 23% of long-term recipients with good renal function (serum creatinine <2 mg/dl) show PTH levels within the normal range, and 27% show a value more than twice the upper normal limit (3). Persistent hyperparathyroidism was detected in 43% of long-term renal transplant patients with a serum creatinine <1.5 mg/dl if a cutoff value for intact PTH of 90 pg/ml was taken, i.e., the mean value plus 2 SD observed in nontransplanted patients with mild chronic renal failure (4). Duration of dialysis, parathyroid gland size, and development of nodular and/or monoclonal hyperplasia of parathyroid glands are the most important factors responsible for persistent hyperparathyroidism (5). Although the reported improvement of parathyroid function observed between 3 and 6 mo after RT has been attributed to a reduction of the parathyroid functional mass (6), the process of involution may take from a few months to several years. The long lifespan of parathyroid cells (approximately 20 yr) with a cell renewal rate of approximately 5% per year (7) contributes to the very slow involution of the gland after renal transplantation. Additional factors that may contribute to maintain high PTH concentrations are incomplete normalization of renal function (3), suboptimal levels of calcitriol (2,8), and decreased intestinal calcium absorption induced by corticosteroids.

In recipients with serum creatinine <2 mg/dl and more than >1 yr after grafting, the prevailing PTH levels correlate with pretransplant PTH concentrations (3,9). Preliminary observations using receiver-operator curve analysis, have demonstrated that PTH concentrations above 230 pg/ml at the time of transplantation predict long-term persistent hyperparathyroidism (PTH >90 pg/ml) with a low sensitivity (45%) but a high specificity (85%) (4). Interestingly, this cutoff value is similar to the PTH concentration that is required to avoid significant hyperparathyroid bone lesions in dialysis patients (10,11).

Posttransplantation hypercalcemia is a common problem that results from the effect of increased PTH concentrations on different target tissues. High PTH concentrations stimulate the renal production of calcitriol that, in turn, increases intestinal calcium absorption and improves the skeletal mobilization of calcium. Correction of uremia and normalization of serum phosphorus levels are additional factors contributing to the resolution of the skeletal resistance to PTH, thus facilitating the release of calcium due to osteoclastic bone resorption (12). Finally, resorption of soft tissue calcifications can also contribute to posttransplantation hypercalcemia.

In a recent study, hypercalcemia (>10.5 mg/dl) developed after RT in 52% of 129 patients 3 mo after grafting (13). Subacute hypercalcemia develops within the first 3 mo, and calcium levels are in the range of 12 to 15 mg/dl; it usually causes graft dysfunction and, rarely, calciphylaxis. Typically, these patients suffer severe preexisting hyperparathyroidism with overt radiological bone erosions, and early posttransplantation parathyroid surgery is required (1). Fortunately, and due to the improved management of secondary hyperparathyroidism in dialysis patients, this form of hypercalcemia is currently rare. Transient posttransplantation hypercalcemia is more common, and spontaneous resolution occurs in most cases within 1 yr after grafting. However, in about 5 to 10% of recipients, hypercalcemia persists beyond the first year but resolves gradually within 2 to 5 additional years (1,14). Such persistent mild hypercalcemia is usually well tolerated and is not associated with graft dysfunction or other complications. Nevertheless, a small proportion of patients (<5% in our transplant clinic) maintain persistent hypercalcemia above 12 mg/dl. In this case, renal dysfunction, nephrocalcinosis, pancreatitis, and vascular calcifications become significant risks and elective parathyroidectomy is recommended.

	Hypophosphatemia

Top Introduction Persistent Hyperparathyroidism... Hypophosphatemia Posttransplantation Bone Loss Bone Fractures after Renal... Posttransplantation Bone... Prevention and Management of... Osteonecrosis Bone Pain References

 
The clinical significance of hypophosphatemia differs according to whether it occurs early or late after transplantation. During the first 4 mo, many transplanted patients, up to 93% in a recent study, develop moderate hypophosphatemia with serum phosphate concentrations between 0.9 and 2.25 mg/dl (15). Increased urinary loss due to primary tubular dysfunction of the allograft (16) and persistent hyperparathyroidism is the main cause, compounded by the effects of immunosuppressive and diuretic drugs. By ³¹P nuclear magnetic resonance, muscle phosphate concentration was estimated to be decreased by 25% during the early posttransplantation period (15). The correlation between serum phosphate concentration and muscle phosphate content was poor. When the plasma phosphate concentration is below 1.4 mg/dl, patients often present with muscle weakness and possibly osteomalacia. Severe phosphate depletion, with serum phosphate concentrations below 0.9 mg/dl is rare. It may lead to hemolytic anemia, rhabdomyolysis, decreased myocardial contractility, and respiratory failure.

Oral phosphate supplements have been shown to normalize serum phosphate concentration and muscle phosphate content after transplantation (15). Furthermore, the prolonged phosphaturia caused by the administration of neutral phosphate increases renal net acid excretion leading to faster recovery from the latent metabolic acidosis observed during the early posttransplantation period.

When the allograft functions well, the decrease in PTH concentration and improvements in tubular function lead to normalization of the serum phosphate concentrations within months after transplantation in most patients. Late after transplantation, mild hypophosphatemia is common in patients with persistent hyperparathyroidism. Phosphate is known to increase PTH synthesis and secretion and to decrease calcitriol concentrations; therefore, phosphate supplements convey the potential risk of worsening hyperparathyroidism. Early after transplantation, oral phosphate supplements do not seem to affect calcium and PTH metabolism (15), but a significant increase in PTH levels has been detected in patients with well-functioning renal allografts who received oral phosphorous supplements in the late posttransplantation period (mean transplantation time, 41 mo) (17).

	Posttransplantation Bone Loss

Top Introduction Persistent Hyperparathyroidism... Hypophosphatemia Posttransplantation Bone Loss Bone Fractures after Renal... Posttransplantation Bone... Prevention and Management of... Osteonecrosis Bone Pain References

 
Natural History of Posttransplantation Bone Loss
Prospective studies have demonstrated a rapid rate of bone loss during the first 6 mo after grafting, mainly affecting the trabecular bone compartment. Bone mass stabilizes or even tends to recover at 12 mo (18-21). The study by Horber et al. (20) in predominantly cadaveric renal transplant recipients demonstrated a rate of bone loss of 1.6%/mo at the lumbar spine during the first 5 mo after RT. In two studies, men experienced a substantial 3.6% bone loss at the proximal femur over 3 mo, whereas in women, there was only a tendency to decrease (19,20). The magnitude of such early bone loss can be best appreciated if compared with the average 1.7% annual loss demonstrated in postmenopausal women at the lumbar spine (22). These findings underscore the importance of starting prophylaxis immediately after kidney grafting.

Longitudinal studies in stable long-term recipients have demonstrated a slower but significant rate of bone loss of 1.7%/yr at the lumbar spine (23). However, Grotz et al. (24) demonstrated no change, or even a slight increase, in bone mineral density in a similar study. This apparent discrepancy between the two reports can be explained by differences in the mean daily dose of corticosteroids.

Pathogenesis of Posttransplantation Bone Loss
Role of Immunosuppressive Drugs.
The major cause of posttransplantation bone loss is corticosteroid treatment. This has been clearly shown in several reports comparing the evolution of bone mineral density (BMD) in patients on cyclosporine A (CsA) monotherapy versus those receiving CsA plus prednisone with or without azathioprine (25,26). Twelve to 18 mo after grafting, BMD remained unchanged or even increased both at the lumbar spine (25,26) and femoral neck (25) in the group without corticosteroids and significantly decreased in the corticosteroid-treated group. Furthermore, Julian et al. (18) observed that at the ilium, the mean wall thickness, a measure of the amount of bone replaced during a remodeling cycle, significantly decreased 6 mo after transplantation. Bone formation and mineralization lag times were prolonged; this association points to the presence of an osteoblastic dysfunction (18). In contrast, bone resorptive indices were normal, suggesting that progressive bone loss was due to an imbalance between bone formation and resorption (18). This picture fits with the known histologic effects of corticosteroids, suggesting that they are the predominant factor causing posttransplantation bone loss.

The pathogenesis of corticosteroid-induced bone loss is multifactorial and has been reviewed extensively (27). The main deleterious effect of corticosteroids is a direct and profound inhibition of bone formation. They inhibit osteoblast differentiation and induce apoptosis in mature osteoblasts as well as osteocytes (28). They also decrease gastrointestinal calcium absorption, resulting in a negative calcium balance and secondary hyperparathyroidism. In addition, corticosteroids directly suppress gonadotropins and may cause hypogonadism.

In vivo rat studies have shown that CsA induces high turnover osteoporosis with a transient rise in serum osteocalcin, which is exaggerated in the presence of estrogen deficiency (29). Interaction between the immune system and bone turnover seems to be important, as the effects of CsA seem to be dependent upon the presence of T lymphocytes (29). It has been suggested that CsA increases bone turnover by inhibiting the production of antiresorptive cytokine(s) by T cells (30). However, the clinical data in RT do not support an adverse effect of CsA on bone mass, because CsA monotherapy does not reduce BMD 12 to 18 mo after grafting (25,26). Furthermore, normocalcemic nondiabetic transplant patients on low-dose prednisone (10 mg/d) and CsA exhibited an increase in the lumbar spine BMD Z score (assessed by quantitative computed tomography) beyond 3 mo after transplantation (31). This increase in Z score was associated with lower prednisone and higher CsA dosages, and both higher plasma concentrations of bone formation and resorption markers at 6 mo. The increase in bone markers correlated with CsA concentrations, therefore, it has been suggested that CsA may counterbalance the depressive effect of low-dose prednisone on bone formation and BMD by stimulating bone remodeling (31). At an earlier posttransplantation period, when higher doses of corticosteroids are used, osteoblast dysfunction may be so severe that rapid bone loss ensues. However, these findings contrast with the reported bone histomorphometry data in long-term renal transplant patients on CsA monotherapy (32). Histomorphometry in 16 patients who were receiving CsA monotherapy was similar than in patients under CsA + prednisone or azathioprine + prednisone. Increased osteoclast activation, suppression of osteoblast function, and retardation of bone formation were noted, and these findings were independent of PTH levels (32). Obviously, additional studies are required to clarify the role of CsA in the genesis of posttransplantation bone disease.

In terms of producing osteopenia in the rat, the calcineurin inhibitor FK-506 seems to be as deleterious as CsA (29). FK-506 does differ from CsA in that the serum osteocalcin concentration does not increase significantly after FK-506 injection (29). Another study showed that FK-506 reduced femoral bone mineral density in normal rats, although the reduction was much less severe than with CsA (33). Clinical data in renal transplant recipients are needed to confirm this finding obtained in experimental animals.

Unpublished study results suggest that mycophenolate mofetil does not affect bone. Rapamycin has also not been shown to cause bone loss but may increase bone remodeling and decrease longitudinal growth (34).

Preexisting Hyperparathyroidism.
A direct correlation between the magnitude of early posttransplantation bone loss at the lumbar spine and pretransplantation PTH concentrations has been observed in two separate studies (19,21). Patients with a pretransplantation PTH level >250 pg/ml experienced a higher rate of bone loss after 3 mo of grafting than those with PTH values <250 pg/ml (21). In addition, the resolution of persistent hyperparathyroidism by parathyroidectomy has been associated with recovery of bone mineral density ranging between 1 and 8% at different sites (35). Higher cancellous bone volume is a known feature of patients with renal hyperparathyroidism. Consequently, early posttransplantation reduction in vertebral mineral density may in part be attributable to resolution of secondary hyperparathyroidism resulting from the loss of trophic effects of PTH on cancellous bone. The higher corticosteroid doses used early after transplantation adversely affect the osteoblast function and aggravate the imbalance between formation and resorption. However, cross-sectional studies in long-term graft recipients have not demonstrated a correlation between the prevailing PTH levels and BMD or different bone histomorphometry parameters (32,36,37).

Genetics and Posttransplantation Bone Loss.
Even among recipients with identical immunosuppressive treatments, a wide variation in the rate of bone loss can be observed. Thus, posttransplantation bone loss reflects variable individual susceptibility, resembling the polygenic determination of BMD in general (38). Family studies have shown that 60 to 80% of the variation in BMD observed in the general population is genetically determined (39). As in other complex diseases, elucidating the specific genes involved has been hampered by the limitations of linkage analysis in situations in which highly variable environmental factors are major determinants of the phenotype.

A few association studies have addressed the role of vitamin D receptor (VDR) polymorphism on BMD changes after transplantation. The VDR polymorphism has been shown to influence the rate of bone loss during the first year (21). Preliminary data, derived from 71 patients who received a renal transplant, confirm that this polymorphism is significantly associated with the rate of bone loss during the first year after transplantation, with patients carrying the ’bb’ genotype losing approximately half of the amount of BMD compared with non ‘bb’ individuals (40). Interestingly, similar findings have been reported during the first trimester after liver transplantation (41). Corticosteroids decrease intestinal calcium absorption and could provide an environmental setting in which the influence of VDR polymorphism becomes more evident.

The controversy on the relative role of the genetic polymorphisms reported to date on variability of BMD could be clarified in the near future, when the complete sequence of the human genome can be used to investigate other genetic variants that could be in linkage disequilibrium with the commonly tested polymorphisms. Alternative strategies for the study of genetic predisposition to complex diseases, such as family-based studies, should provide linkage information that is useful for the assessment of the relevance of findings in association studies. In addition, the contribution of the projects to tally the ethnic diversity of the human genome and to catalogue a large number of single-nucleotide polymorphisms will provide a better understanding of the genetic predisposition to BMD.

	Bone Fractures after Renal Transplantation

Top Introduction Persistent Hyperparathyroidism... Hypophosphatemia Posttransplantation Bone Loss Bone Fractures after Renal... Posttransplantation Bone... Prevention and Management of... Osteonecrosis Bone Pain References

 
The increased rate of bone loss places the renal transplant patient at increased risk of pathologic fractures. In fact, the yearly rate of fractures is much higher in this population than in age-matched control subjects. A similar estimate of 3 to 4% per year has been observed in two different studies (42,43). In terms of prevalence, fractures have been reported in approximately 7 to 21% of recipients, generally late in the posttransplantation period (42–44). Despite the preferential cancellous bone loss, most of the fractures involve the appendicular skeleton, particularly the feet and ankles (42–44). The patient with type 1 diabetes is at increased risk of fractures, and in a recent cross-sectional study, the 40% fracture prevalence in patients with diabetes contrasted with the 11% in the nondiabetic group (44). In addition, the fracture rate in simultaneous kidney/pancreas transplant patients may be as high as 12%/yr (43). Finally, postmenopausal women are also at increased risk of fractures after RT (42,43).

The genesis of fractures in type 1 diabetes after transplantation is probably multifactorial. Impaired vision and neuropathy may interfere with gait and postural stability. In addition, early onset of diabetes may decrease peak bone mass (44).

Some questions remain to be answered with respect to the value of BMD measurements with dual-energy x-ray absorptiometry (DEXA) in assessing the risk of fractures after renal transplantation. First, the peripheral distribution of fractures contrasts with the preferential cancellous bone loss demonstrated with densitometry. Furthermore, in one cross-sectional study, patients with fractures after minor trauma showed significantly lower BMD at the lumbar spine than those without fractures, although the broad overlap of BMD values limited the value of DEXA measurements to assess the fracture risk (42). It is important to note that no significant difference was observed at the femoral neck between patients with or without fractures. These findings suggest that BMD measurements may not have the same predictive power in the setting of RT as in postmenopausal osteoporosis. Thus, it is clear that additional information is needed regarding the utility of serial BMD measurements to assess the risk of fractures in transplant recipients. Finally, the pathogenetic role of other factors affecting bone architecture must be also investigated.

	Posttransplantation Bone Disease: Histologic Abnormalities

Top Introduction Persistent Hyperparathyroidism... Hypophosphatemia Posttransplantation Bone Loss Bone Fractures after Renal... Posttransplantation Bone... Prevention and Management of... Osteonecrosis Bone Pain References

 
To develop adequate prophylactic and therapeutic strategies for posttransplantation bone abnormalities, it is essential to understand the underlying histologic bone abnormalities and their evolution over time. Results from different publications are summarized in Table 1 (18,21,32,36,37,45–48). The predominant lesion in adult recipients is a decrease in bone turnover associated with normal/high bone resorption, i.e., uncoupling of bone resorption and formation. In two studies, the cumulative dose of corticosteroids was the main factor that influenced bone turnover (36,48). Therefore, the continuous use of corticosteroids late after transplantation is an important pathogenetic factor in the genesis of bone alterations after transplantation.

	Prevention and Management of Posttransplantion Bone Loss

Top Introduction Persistent Hyperparathyroidism... Hypophosphatemia Posttransplantation Bone Loss Bone Fractures after Renal... Posttransplantation Bone... Prevention and Management of... Osteonecrosis Bone Pain References

Prevention of Early Bone Loss
In the study of Fan et al. (49), 26 recipients who had immunosuppressive therapy comprising CsA, prednisone, and azathioprine, were randomized to receive placebo or the bisphosphonate pamidronate (0.5 mg/kg intravenously), at the time of grafting and 1 mo later. In the placebo group at 1 yr, the BMD had decreased by 6.4% and 9% at the lumbar spine and the femoral neck, respectively. In contrast, patients who received pamidronate experienced nonsignificant reduction of BMD at either site. The regimen of two intravenous doses of pamidronate was well tolerated, and apart from transient hypocalcemia in two patients, no discernible side effects were observed. Bisphosphonates improve bone density in corticosteroid-treated patients, and recent reports point to a reduction in the risk of vertebral fracture (50). However, in transplant patients fractures more typically involve the appendicular skeleton, and little information exists about the ability of bisphosphonates to reduce the fracture risk at this site in corticosteroid-treated patients. Thus, despite the beneficial effect on BMD, additional trials are needed to confirm that treatment with bisphosphonates reduces the number of fractures as well.

In a preliminary report, 85 patients were randomized to receive oral intermittent calcitriol (0.5 µg/48 h, at night) or placebo, during the first 3 mo after grafting; all patients received calcium supplementation. Calcitriol induced a more pronounced decrease in PTH levels after transplantation and a better preservation of the BMD at the proximal femur as compared with placebo (0.1 ± 0.6% versus -1.9 ± 07%, respectively; P < 0.05) (51). However, in another preliminary report, 62 patients were randomized to receive both calcium and calcitriol or double placebo, and at 12 mo, only a small therapeutic effect of calcium and calcitriol was observed at the lumbar spine (52).

Prevention of Late Bone Loss
In one study, 30 long-term renal transplant patients were randomized to receive placebo or calcitriol (0.25 µg/d) plus calcium (0.5 g/d). They were studied at baseline and 1 yr later by bone biopsy and densitometry (53). Osteoclast suppression and a trend to maintain trabecular bone volume and wall thickness were observed in the calcitriol group. It is possible that studies with longer follow-up are required to elucidate whether this therapy has a significant impact on bone status of long-term renal transplant recipients.

Grotz et al. (54) randomized 46 osteopenic recipients on average 57 mo after transplantation to supplemental calcium alone or in combination with cyclical clodronate or calcitonin during 12 mo. BMD at the lumbar spine increased by 4.6% in the clodronate group, by 3.2% in the calcitonin group, and by 1.8% in the calcium alone group. Although both clodronate and calcitonin treatments caused a statistically significant increase of BMD over baseline, no differences between the groups were found. BMD at the femoral neck did not change significantly in any of the groups.

Recommendations for Management
Before RT, intact PTH levels should be maintained in the range of 100 to 250 pg/ml to avoid low turnover or hyperparathyroid bone disease (Table 2) (10,11). In those recipients receiving corticosteroids in their immunosuppressive regimen, it is important to monitor BMD by DEXA at the lumbar spine and the hip in the first few days after grafting and 3 or 6 mo later. An effort should me made to use the lowest prednisone dose compatible with graft survival. With the new immunosuppressive regimens combining anticalcineurin agents with mycophenolate mofetil or rapamycin, the prednisone dose can be safely reduced to 10 mg/d by the first month in most recipients. Because significant osteopenia may be observed with doses as low as 7.5 mg/d of prednisone, the maintenance dose at long-term should not be above this value. In nonhypercalcemic patients, calcium supplementation to ensure a total daily calcium intake above 1.2 g/d is important because corticosteroids decrease intestinal calcium absorption. In addition, a daily intake of 400 IU of vitamin D should be recommended, in order to maintain 25OHD₃ levels above the 50^th percentile of the normal concentration. In one study, recipients with low 25OHD₃ concentrations had significantly higher PTH concentrations compared with recipients with higher 25OHD₃ concentrations irrespective of graft function (13). Lifestyle factors such as alcohol intake, smoking, and regular exercise have to be considered. Finally, recipients who show a rapid bone loss during the first 3 to 6 mo after grafting should be treated with an antiresorptive agent, such as a bisphosphonate. If not contraindicated, hormone replacement therapy can be an alternative in postmenopausal and premenopausal amenorrheic women.

	Osteonecrosis

Top Introduction Persistent Hyperparathyroidism... Hypophosphatemia Posttransplantation Bone Loss Bone Fractures after Renal... Posttransplantation Bone... Prevention and Management of... Osteonecrosis Bone Pain References

	Bone Pain

Top Introduction Persistent Hyperparathyroidism... Hypophosphatemia Posttransplantation Bone Loss Bone Fractures after Renal... Posttransplantation Bone... Prevention and Management of... Osteonecrosis Bone Pain References

 
Osteoporotic fracture and avascular bone necrosis (see above) are major causes of bone pain. In addition, some specific osteoarticular pain syndromes have been described in patients who have received a transplant.

Intraosseous vasoconstriction and hypertension have been proposed as the mechanism underlying a form of bone pain present in CsA-treated patients, usually during periods of high CsA levels (57). This form of bone pain characteristically responds to calcium channel blockers. In another CsA-related entity, sympathetic reflex dystrophy syndrome (58), bone pain appears together with a typical skin rash, and responds to a reduction in CsA levels or, eventually, calcitonin administration.

A severe osteoarticular pain syndrome, unrelated to CsA, has also been described in up to 10% of patients who have received a renal transplant. Detailed imaging analysis (59) suggests that bone impaction induces an inflammatory reaction in the epiphyseal medulla, with vasodilation and subsequent osteoblastic hyperactivity. Knees and ankles are mainly involved, often bilaterally, during the first 6 months after transplantation. The symptoms tend to be transient, and no modification of the immunosuppressive therapy is required (59).

	References

Top Introduction Persistent Hyperparathyroidism... Hypophosphatemia Posttransplantation Bone Loss Bone Fractures after Renal... Posttransplantation Bone... Prevention and Management of... Osteonecrosis Bone Pain References

 

1. Julian BA, Quarles LD, Nieman KM: Musculoskeletal complications after renal transplantation: Pathogenesis and treatment. Am J Kidney Dis 19: 99–120, 1992[Medline]
2. Lobo PI, Cortez MS, Stevenson W, Pruett TL: Normocalcemic hyperparathyroidism associated with relatively low 1:25 vitamin D levels post-renal transplant can be successfully treated with oral calcitriol. Clin Transplantation 9: 277–281, 1995[Medline]
3. Torres A, Rodríguez AP, Concepción MT, García S, Rufino M, Martín B, Perez L, Machado M, De Bonis E, Losada M, Hernández D, Lorenzo V: Parathyroid function in long-term renal transplant patients: Importance of pretransplant PTH levels. Nephrol Dial Transplant 13 (suppl 3): 94–97, 1998[Abstract/Free Full Text]
4. Torres A, Zarraga S, Rodríguez A, Gomez Ullate P, Concepción MT, Martínez I, Saracho R, Hernández D, Lorenzo V: Optimum PTH levels before renal transplantation to prevent persistent hyperparathyroidism [abstract]. J Am Soc Nephrol 9: 572A, 1998
5. Koch Nogueira PC, David L, Cochat P: Evolution of secondary hyperparathyroidism after renal transplantation. Pediatr Nephrol 14: 342–346, 2000[CrossRef][Medline]
6. Bonarek H, Merville P, Bonarek M, Moreau K, Morel D, Aparicio M, Potaux L: Reduced parathyroid functional mass after successful kidney transplantation. Kidney Int 56: 642–649, 1999[CrossRef][Medline]
7. Parfitt AM: The hyperparathyroidism of chronic renal failure: a disorder of growth. Kidney Int 52: 3–9, 1997[Medline]
8. Caravaca F, Fernández MA, Cubero J, Aparicio A, Jimenez F, García MC: Are plasma 1,25-dihydroxyvitamin D3 concentrations appropriate after successful kidney transplantation? Nephrol Dial Transplant 13 (suppl 3): 91–93, 1998[Abstract/Free Full Text]
9. Messa P, Sindici C, Cannella G, Miotti V, Risaliti A, Gropuzzo M, Di Loreto PL, Bresadola F, Mioni G: Persistent secondary hyperparathyroidism after renal transplantation. Kidney Int 54: 1704–1713, 1998[CrossRef][Medline]
10. Quarles DL, Lobaugh B, Murphy G: Intact parathyroid hormone overestimates the presence and severity of parathyroid-mediated osseous abnormailities in uremia. J Clin Endocrinol Metab 75: 145–150, 1992[Abstract]
11. Torres A, Lorenzo V, Hernández D, Rodríguez JC, Concepción MT, Rodríguez AP, Hernández A, De Bonis E, Darias E, González-Posada JM, Losada M, Rufino M, Felsenfeld AJ, Rodríguez M: Bone disease and intact PTH levels in predialysis, hemodialysis, and CAPD patients: Evidence of a better bone response to PTH in dialysis patients. Kidney Int 47: 1434–1442, 1995[Medline]
12. Rodriguez M, Martin-Malo A, Martinez ME, Torres A, Felsenfeld AJ, Llach F: Calcemic response to parathyroid hormone in renal failure: role of phosphorus and its effect on calcitriol. Kidney Int 40: 1055–1062, 1991[Medline]
13. Reinhardt W, Bartelworth H, Jockenhovel F, Schmidt-Gayk H, Witzke O, Wagner K, Heemann UW, Reinwein D, Philipp T, Mann K: Sequential changes of biochemical bone parameters after kidney transplantation. Nephrol Dial Transplant 13: 436–442, 1998
14. Massari P: Disorders of bone and mineral metabolism after renal transplantation. Kidney Int 52: 142–1421, 1997
15. Ambhul PM, Meier D, Wolf B, Dydak U, Boesiger P, Binswanger U: Metabolic aspects of phosphate replacement therapy for hypophosphatemia after renal transplantation: Impact on muscular phosphate content, mineral metabolism, and acid/base homeostasis. Am J Kidney Dis 34: 875–883, 1999[Medline]
16. Rosenbaum RW, Hruska KA, Korkor A, Anderson C, Slatopolsky E: Decreased phosphate reabsorption after renal transplantation: Evidence for a mechanism independent of calcium and parathyroid hormone. Kidney Int 19: 568–578, 1981[Medline]
17. Caravaca F, Fernandez MA, Ruiz-Calero R, Cubero J, Aparicio A, Jimenez F, Garcia MC: Effects of oral phosphorus supplementation on mineral metabolism of renal transplant recipients. Nephrol Dial Transplant 13: 2605–2611, 1998[Abstract/Free Full Text]
18. Julian BA, Laskow DA, Dubovsky J, Dubovsky EV, Curtis JJ, Quarles LD: Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 325: 544–550, 1991[Abstract]
19. Almond MK, Kwan JTC, Evans K, Cunningham J: Loss of regional bone mineral density in the first 12 months following renal transplantation. Nephron 66: 52–57, 1994[Medline]
20. Horber FF, Casez JP, Steiger U, Czerniak A, Montandon A, Jaeger P: Changes in bone mass early after kidney transplantation. J Bone Min Res 9: 1–9, 1994[Medline]
21. Torres A, Machado M, Concepción MT, Martin N, Lorenzo V, Hernández D, Rodríguez AP, Rodríguez A, De Bonis E, Hernández A, Salido E: Influence of vitamin D receptor genotype on bone mass changes after renal transplantation. Kidney Int 50: 1726–1733, 1996[Medline]
22. Hansen MA, Overgaard K, Riis BJ: Role of peak bone mass and bone loss in post-menopausal osteoporosis: 12 year study. Br Med J 303: 961–964, 1991
23. Pichette V, Bonnardeaux A, Prudhomme L, Gagne M, Cardinal J, Ouimet D: Long term bone loss in kidney transplant recipients: A cross-sectional and longitudinal study. Am J Kidney Dis 28: 105–114, 1996[Medline]
24. Grotz WH, Mundinger FA, Rasenack J, Speidel L, Olschewski M, Exner VM, Scollmeyer PJ: Bone loss after kidney transplantation: A longitudinal study in 115 graft recipients. Nephrol Dial Transplant 10: 2096–2100. 1995[Abstract/Free Full Text]
25. Torregrosa JV, Campistol JM, Montesinos M, Pons F, Martínez de Osaba MJ: Evolution of bone mineral density after renal transplantation. Nephrol Dial Transplant 10 (suppl 6): 111–113, 1995[Free Full Text]
26. Aroldi A, Tarantino A, Montagnino G, Cesana B, Cocucci C, Ponticelli C: Effects of three immunosuppressive regimens on vertebral bone density in renal transplant recipients. Transplantation 63: 380–386, 1997[CrossRef][Medline]
27. Canalis E: Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis. J Clin Endocrinol Metab 81: 3441–3447, 1996[CrossRef][Medline]
28. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC: Inhibition of osteoclastogenesis and promotion of apoptosis of osteoblasts and osteoclasts by glucocorticoids: Potential mechanisms of their deleterious effects on bone. J Clin Invest 102: 274–282, 1998[Medline]
29. Epstein S: Post-transplantation bone disease: The role of immunosuppressive agents on the skeleton. J Bone Min Res 11: 1–7, 1996[Medline]
30. Sprague SM: Mechanism of transplantation-associated bone loss. Pediatr Nephrol 14: 650–653, 2000[CrossRef][Medline]
31. Westeel FP, Mazouz H, Ezaitouni F, Hottelart C, Ivan C, Fardellone P, Brazier M, El Esper I, Petit J, Achard JM, Pruna A, Fournier A: Cyclosporine bone remodelling effect prevents steroid osteopenia after kidney trabsplantation. Kidney Int 58: 1788–1796, 2000[CrossRef][Medline]
32. Cueto-Manzano AM, Konel S, Hutchison AJ, Crowley V, France MW, Freemont AJ, Adams JE, Mawer B, Gokal R: Bone loss in long-term renal transplantation: Histopathology and densitometry analysis. Kidney Int 55: 2021–2029, 1999[CrossRef][Medline]
33. Inoue T, Kawamura I, Matsuo M, Aketa M, Mabuchi M, Seki J, Goto T: Lesser reduction in bone mineral density by the immunosuppressant FK-506, compared with cyclosporine in rats. Transplantation 70: 774–749, 2000[CrossRef][Medline]
34. Joffe I, KAtz I, Sehgal S, Bex F, Kharode Y, Tamasi J, Epstein S..: Lack of change of cancellous bone volume with short term use of the new immunosuppressant rapamycin in rats. Calcif Tissue Int 53: 45–52, 1993[CrossRef][Medline]
35. Abdelhadi M, Nordenstrom J: Bone mineral recovery after parathyroidectomy in patients with primary and renal hyperparathyroidism. J Clin Endocrinol Metab 83: 3845–3851, 1998[Abstract/Free Full Text]
36. Faugere MC, Mawad H, Qi Q, Friedler RM, Malluche HH: High prevalence of low bone turnover and occurrence of osteomalacia after kidney transplantation. J Am Soc Nephrol 11: 1093–1099, 2000[Abstract/Free Full Text]
37. Carlini RG, Rojas E, Weisinger JR, Lopez M, Martinis R, Arminio A, Bellorin-Font E: Bone disease in patients with long-term renal transplantation and normal renal function. Am J Kidney Dis 36: 160–165, 2000[Medline]
38. Nguyen TV, Blangero J, Eisman JA: Genetic epidemiological approaches to the search for osteoporosis genes. J Bone Miner Res 15: 392–401, 2000[CrossRef][Medline]
39. Howard GM, Nguyen TV, Harris M, Kelly PJ, Eisman JA: Genetic and environmental contributions to the association between quantitative ultrasound and bone mineral density measurements: a twin study. J Bone Miner Res 13: 1318–27, 1998[CrossRef][Medline]
40. Torregrosa V, Barrios Y, Campistol JM, García S, Oppenheimer F, Concepción MT, Miquel R, Marrero D, Machado M, Hernández D, Lorenzo V, Salido E, Torres A: Vitamin D receptor (VDR) and collagen I-aI polymorphisms and the rate of bone loss during the first year after renal transplantation (RT) [abstract]. Transplant Bone Disease Meeting, Barcelona 2000, Book of Abstracts, P19
41. Guardiola J, Xiol X, Sallie R, Nolla JM, Roig-Escofet D, Jaurrieta E, Casais L: Influence of the vitamin D receptor gene polymorphism on bone loss in men after liver transplantation. Ann Int Med 131: 752–755, 1999[Abstract/Free Full Text]
42. Grotz W.H., Mundinger F.A., Gugel B., Exner V., Kirste G., Schollmeyer P.J.: Bone fracture and osteodensitometry with dual energy X-ray absorptiometry in kidney transplant recipients. Transplantation 58: 912–915, 1994[Medline]
43. Ramsey-Goldman R, Dunn JE, Dunlop DD, Stuart FP, Abecassis MM, Kaufman DB, Langman CB, Salinger MH, Sprague SM: Increased risk of fracture in patients receiving solid organ transplants. J Bone Miner Res 14: 456–463, 1999[CrossRef][Medline]
44. Nisbeth U, Lindh E, Ljungall S, Backman U, Fellstrom B: Increased fracture rate in diabetes mellitus and females after renal transplantation. Transplantation 67: 1218–1222, 1999[CrossRef][Medline]
45. Briner VA, Thiel G, Monier-Faugere MC, Bognar B, Landmann J, Kamber V, Malluche H: Prevention of cancellous bone loss but persistence of renal bone disease despite normal 1,25 vitamin D levels two years after kidney transplantation. Transplantation 59: 1393–1400, 1995[Medline]
46. Velasquez-Forero F, Mondragón A, Herrero B, Peña JC: Adynamic bone lesion in renal transplant recipients with normal renal function. Nephrol Dial Transplant 11: 58–64, 1996
47. Sanchez CP, Salusky IB, Kuizon BD, Ramirez JA, Gales B, Ettenger R, Goodman WG: Bone disease in children and adolescents undergoing successful renal transplantation. Kidney Int 53: 1358–1364, 1998[CrossRef][Medline]
48. Parker CR, Freemont AJ, Blackwell PJ, Grainge MJ, Hosking DJ: Cross-sectional analysis of transplantation osteoporosis. J Bone Min Res 14: 1943–1951, 1999[CrossRef][Medline]
49. Fan SLS, Almond MK, Ball E, Evans K, Cunningham J: Pamidronate therapy as prevention of bone loss following renal transplantation. Kidney Int 57: 684–690, 2000[Medline]
50. Wallach S, Cohen S, Reid DM, Hughes RA, Hosking DJ, Laan RF, Doherty SM, Maricic M, Rosen C, Brown J, Barton I, Chines AA: Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int 67: 277–285, 2000[CrossRef][Medline]
51. García S, Barrios Y, González A, Concepción MT, Checa MD, Lorenzo V, Hernández D, Rufino M, Salido E, Torres A: Oral calcitriol prevents early bone loss after renal transplantation (RT): Double blind placebo controlled study [abstract]. J Am Soc Nephrol, 11: 575A, 2000
52. Josephson MA, Schumm LP, Chiu MY, Marshall C, Sprague SM: Calcium and calcitriol prophylaxis agains post-transplant bone loss [abstract]. J Am Soc Nephrol, 11: 720A, 2000.
53. Cueto-Manzano AM, Konel S, Freemont AJ, Adams JE, Mawer B, Gokal R, Hutchison AJ: Effect of 1,25-Dihydroxyvitamin D3 and calcium carbonate on bone loss associated with long-term renal transplantation. Am J Kidney Dis 35: 227–236, 2000[Medline]
54. Grotz WH, Rump LC, Niessen A, Schmidt-Gayk H, Reichelt A, Kirste G, Olschewski M, Schollmeyer PJ: Treatment of osteopenia and osteoporosis after kidney transplantation. Transplantation 66: 1004–1008, 1998[Medline]
55. Lausten GS, Lemser T, Jensen PK, Egfjord M: Necrosis of the femoral head after kidney transplantation. Clin Transplant 12: 572–574, 1998[Medline]
56. Bozic KJ, Zurakowski D, Thornhill TS: Survivorship analysis of hips treated with core decompression for nontraumatic osteonecrosis of the femoral head. J Bone Joint Surg Am 81: 200–209, 1999.[Abstract/Free Full Text]
57. Gauthier VJ, Barbosa LM: Bone pain in transplant recipients responsive to calcium channel blockers. Ann Intern Med 121: 863–865, 1994[Free Full Text]
58. Munoz-Gomez J, Collado A, Gratacos J, Campistol JM, Lomena F, Llena J, Andreu J: Reflex sympathetic dystrophy syndrome of the lower limbs in renal transplant patients treated with cyclosporin A. Arthritis Rheum 34: 625–630, 1991[Medline]
59. Goffin E, Vande Berg B, Pirson Y, Malghem J, Maldague B, Van Ypersele de Strihou C: Epiphyseal impaction as a cause of severe osteoarticular pain of lower limbs after renal transplantation. Kidney Int 44: 98–106, 1993[Medline]

This article has been cited by other articles:

				N. Y. Park, Y. S. Jung, and H. Rim Post-renal transplant calciphylaxis: treatment of hyperparathyroidism by percutaneous ethanol injection therapy and parathyroidectomy NDT Plus, February 1, 2010; 3(1): 93 - 94. [Full Text] [PDF]

				N. Kamar, I. Gennero, L. Spataru, L. Esposito, J. Guitard, L. Lavayssiere, O. Cointault, P. Gandia, D. Durand, and L. Rostaing Pharmacodynamic effects of cinacalcet after kidney transplantation: once- versus twice-daily dose Nephrol. Dial. Transplant., November 1, 2008; 23(11): 3720 - 3726. [Abstract] [Full Text] [PDF]

				P. Falck, N. T. Vethe, A. Asberg, K. Midtvedt, S. Bergan, J. L. E. Reubsaet, and H. Holdaas Cinacalcet's effect on the pharmacokinetics of tacrolimus, cyclosporine and mycophenolate in renal transplant recipients Nephrol. Dial. Transplant., March 1, 2008; 23(3): 1048 - 1053. [Abstract] [Full Text] [PDF]

				E. Lewin and K. Olgaard Parathyroidectomy vs calcimimetics for treatment of persistent hyperparathyroidism after kidney transplantation Nephrol. Dial. Transplant., July 1, 2006; 21(7): 1766 - 1769. [Full Text] [PDF]

				E. Goffin, G. Baertz, and J.-J. Rombouts Long-term survivorship analysis of cemented total hip replacement (THR) after avascular necrosis of the femoral head in renal transplant recipients Nephrol. Dial. Transplant., March 1, 2006; 21(3): 784 - 788. [Abstract] [Full Text] [PDF]

				T. R. Srinivas, J. D. Schold, K. L. Womer, B. Kaplan, R. J. Howard, C. M. Bucci, and H.-U. Meier-Kriesche Improvement in Hypercalcemia with Cinacalcet after Kidney Transplantation Clin. J. Am. Soc. Nephrol., March 1, 2006; 1(2): 323 - 326. [Abstract] [Full Text] [PDF]

				L. S. Nayagam, S. G. Rajan, N. Khandelwal, R. Sen, H. S. Kohli, K. Sud, K. L. Gupta, V. Sakhuja, and V. Jha Bilateral femoral capital avascular necrosis in a renal transplant recipient on tacrolimus-based immunosuppression Nephrol. Dial. Transplant., October 1, 2005; 20(10): 2262 - 2264. [Full Text] [PDF]

				A. E. Kruse, U. Eisenberger, F. J. Frey, and M. G. Mohaupt The calcimimetic cinacalcet normalizes serum calcium in renal transplant patients with persistent hyperparathyroidism Nephrol. Dial. Transplant., July 1, 2005; 20(7): 1311 - 1314. [Abstract] [Full Text] [PDF]

				N. M. Maalouf and E. Shane Osteoporosis after Solid Organ Transplantation J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2456 - 2465. [Abstract] [Full Text] [PDF]

				C. C. Magee and M. Pascual Update in Renal Transplantation Arch Intern Med, July 12, 2004; 164(13): 1373 - 1388. [Abstract] [Full Text] [PDF]

				H. Sperschneider and G. Stein Bone disease after renal transplantation Nephrol. Dial. Transplant., May 1, 2003; 18(5): 874 - 877. [Full Text] [PDF]

				J.-P. Casez, K. Lippuner, F. F. Horber, A. Montandon, and P. Jaeger Changes in bone mineral density over 18 months following kidney transplantation: the respective roles of prednisone and parathyroid hormone Nephrol. Dial. Transplant., July 1, 2002; 17(7): 1318 - 1326. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Torres, A. Articles by Salido, E. Search for Related Content PubMed PubMed Citation Articles by Torres, A. Articles by Salido, E.