Bone Mineral Density Disturbances and Fractures: Loss of bone mass after kidney transplantation occurs primarily in the first 12 months, predominantly in cortical bone. The most rapid decrease in bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) occurs in the first six months post-transplant, and seems to slow thereafter, possibly reflecting a decreasing use of corticosteroids. Rojas et al. showed that osteoid volume, osteoid thickness, osteoid resorption surface, and osteoclast surface were above the normal range before transplant and remained increased approximately 35 days after transplantation.12

However, osteoid and osteoblast surfaces, which also were increased before transplantation, significantly decreased within approximately 35 days post-transplant.12 There also was inhibition of bone formation and mineralization and apoptosis, which was associated with dose of glucocorticoids, also appeared after transplantation.12 BMD has been reported to decrease a mean of 5.5-19.5% during the first six months,13 but only 2.6%-8.2% between months 6 and 12 after transplantation,14 and only 0.4%-4.5% thereafter.15

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The overall fracture risk after renal transplantation is 3.6-3.8-fold higher than in healthy individuals,16,17 and is 30% higher during the first three years after transplantation than in patients on dialysis.16 In a retrospective study with follow-up time up to 33 years, the age and diabetic nephropathy were independent predictors of fracture risk generally, while higher activity status was protective.17

Additional risk factors for fracture that have been identified are female gender and combined kidney-pancreas transplantation. Similarly to the mortality risk curve of transplant patients compared with waitlisted dialysis patients, the relative risk of hip fracture associated with transplantation was 1.34-fold greater when compared with dialysis but then decreased by 1% per month until the estimated risk became equal for dialysis and transplant recipients approximately 630 days after transplantation.16 Renal transplant recipients are at particular risk of vertebral fracture; this risk is greater than their risk of lower extremity fractures.17

Contributors to MBD

There are several contributing factors, but the three main factors are pre-existing renal osteodystrophy at time of renal transplantation; transplantation-specific therapies; and reduced renal function.

Pretransplant Renal Osteodystrophy: Almost all patients undergoing 
kidney transplantation suffer from pre-existing bone disorders caused by chronic renal insufficiency and concomitant diseases. Consequently, post-transplant renal osteopathy cannot be considered as a separate entity; rather, its course is significantly conditioned by changes in bone structure and mineral metabolism that existed before engraftment. 

In the past several years, the spectrum of renal osteodystrophy in dialysis patients has changed considerably. The incidence and prevalence of low bone turnover, particularly adynamic bone disease, has increased steadily, becoming the main type of bone alteration in many centers.

To help clarify the interpretation of the bone biopsy, a 2006 National Kidney Foundation (NKF) working group on renal osteodystrophy published a position paper suggesting that renal bone disease should be characterized by three key histologic descriptors: turnover, mineralization, and volume. Using this new system, a survey of 544 bone biopsy samples from patients with CKD stage 5 on dialysis, found that bone turnover was 
low in 52% of samples, normal 
in 21%, and high in 27%. Defective mineralization was found in only 3%.18

Cancellous bone volume was low in 32%, normal in 30%, and high in 38%.19 In the assessment of bone volume abnormalities, it is important to differentiate between cortical and cancellous bone. Loss of cortical bone occurs mainly in patients with high turnover bone disease, while loss of cancellous bone is often seen in patients with low bone turnover.18

The mechanical function of bone is served mainly by cortical bone, whereas the metabolic function is primarily served by cancellous bone. The clinical outcome of decreased bone strength is fracture, while abnormal metabolic activity results in the inability to maintain mineral homeostasis, which is associated with vascular and soft tissue calcifications. 

Effect of Transplantation-Specific Therapies: Several studies suggest that post-transplantation immunosuppressive therapy constitutes a major factor in the pathogenesis of post-transplantation bone disease.20 During the first six months after transplantation, rapid bone loss secondary to glucocorticoid-induced acceleration in bone remodeling occurs in cancellous bone.6

A study that involved serial bone biopsies at 22 days and 160 days after transplantation reported impaired osteoblastogenesis and early osteoblast apoptosis.12 The etiology of glucocorticoid-induced bone disorder is multi-factorial. Steroids are directly toxic to osteoblasts and lead to increased osteoclast activity.21 They also have other effects that promote calcium loss and the development of osteopenia. These include decreased calcium absorption in the gut, reduced gonadal hormone production, diminished insulin-like growth factor-1 production, decreased sensitivity to PTH, increased in receptor activator of NF-kappa beta ligand (RANKL), and increased osteoclastogenesis. 

Both cyclosporin and tacrolimus use have been linked to osteoporosis in clinical studies,22,23 but population-based studies that have focused on fracture risk could not establish an association between use of calcineurin 
inhibitors and fracture risk.17,24 Although mycophenolate mofetil, sirolimus, 
and azathioprine did not affect bone volume in rodents, a recent in vitro study suggests sirolimus might interfere with the proliferation and differentiation of osteoblasts,25 and everolimus reduced cancellous bone loss in ovarectomized rats by decreasing osteoclast-mediated bone resorption.26

Effects of Reduced Renal Function: It has been postulated that patients
with post-transplantation CKD stage 3-5 are at increased risk for the persistent or de novo development of hyperparathyroidism.27 A study with more than 900 transplant patients, intact PTH showed negative correlation with estimated GFR in CKD stages 3-5 
(rho = -0.289, P < 0.001).27 Additionally, high PTH values correlated with significant bone loss at the hip.28