Bone Disease after Kidney Transplantation

Evolution of Preexisting Renal Osteodystrophy

Preexisting renal osteodystrophy is a risk factor for fracture and adverse outcomes post-transplantation (14). The prevalence of histologic patterns of post–transplantation bone disease is not well defined, because there have been very few bone biopsy studies in kidney transplant recipients. Osteomalacia and adynamic bone disease (ABD) were the two most common types of renal osteodystrophy previously described (2); however, this may not represent the contemporary spectrum of renal osteodystrophy seen post-transplantation given the marked changes in both the management of CKD-MBD and immunosuppressive practice in recent years. In another cohort of 20 kidney transplant recipients, ABD was the most common lesion seen on bone biopsy 6 months post-transplantation (15), whereas in a different series of 57 kidney transplant recipients (biopsied at a mean interval of 53.5 months after transplantation), osteitis fibrosa (high–turnover bone disease) was the most common histomorphometric lesion seen, with ABD only affecting 5% of the kidney transplant recipients (16). This discrepancy in bone biopsy data may reflect the differing time after transplantation that the biopsy was taken, suggesting that bone disease continues to evolve for many years after transplantation.

Osteoporosis and Effect of Immunosuppression on Bone

Osteoporosis is defined as a reduction in bone mass with microarchitectural deterioration of bone tissue and subsequent increase in bone fragility and susceptibility to fracture. Osteoporosis has also been defined quantitatively using BMD and can be expressed as an SD score comparing an individual’s BMD with that of a reference population as measured by dual x-ray absorptiometry (DXA). A T-score that is ≤−2.5 (i.e., ≥2.5 SDs below the mean BMD of a normal young–adult reference population) is indicative of osteoporosis. Although GC use remains the key risk factor for the development of osteoporosis after transplantation, there are other factors (summarized in Table 1) that contribute to the marked bone loss seen after transplantation.

GCs induce a net loss of BMD by reduction in bone formation and bone density, especially in the trabecular bone of the axial skeleton (12), which is related to the cumulative dose exposure in kidney transplant recipients (17). GCs have a profound inhibitory effect on bone formation by targeting osteoblast proliferation and differentiation while stimulating apoptosis of both osteoblasts and osteocytes. GCs also have indirect effects on the skeleton by inhibiting the synthesis of testosterone, estrogen, and adrenal androgens.

However, the increased risk of bone loss post-transplantation persists even in a steroid-free era. For instance, in a recent study of 47 kidney transplant recipients where GCs were withdrawn 3 days after transplantation, BMD declined significantly at the distal radius at 12 months, although lumbar and hip BMDs did not decline (18). This discrepancy between central and peripheral skeleton seems to be associated with differentially catabolic effects of parathyroid hormone (PTH) rather than GC dosage. It is worth noting that, in immunologically high–risk recipients, steroid-free immunosuppression may be associated with an increased risk of rejection and therefore, paradoxically, increase the risk of high–dose pulsed GCs.

Calcineurin inhibitors have been shown to increase PTH and decrease magnesium. The increase in PTH results in an increase in osteoclastic activity, which may further increase the risk of osteoporosis (2).

Changes in Mineral Metabolism Post-Transplantation

A number of key changes in mineral metabolism occur in the post-transplant period, although it is important to recognize that the relationships between mineral abnormalities and graft/patient outcomes are, as yet, associative rather than causal, and one cannot assume that changes in mineral metabolism per se cause adverse outcomes. At present, the clinical utility of serum markers of bone turnover (PTH, bone–specific alkaline phosphatase [bALP], osteocalcin) is limited in terms of adequate sensitivity and specificity in predicting bone loss or bone structure and function.

PTH decreases by 50% 6 months after transplantation but remains high in nearly 45% of kidney transplant recipients 2 years post-transplantation (19) because of improvements in calcium, phosphorus, and 1,25–dihydroxy vitamin D [1,25(OH)₂D] levels associated with improving kidney function (20). High PTH values correlate with significant bone loss at the hip (21), with PTH preferentially catabolic toward cortical rather than trabecular bone. In a single-center study of >140 kidney transplant recipients, persistent hyperparathyroidism (PTH>130 ng/L) at 3 months was an independent risk factor for fracture, with a 7.5-fold increase in fracture risk (22). Furthermore, a recent analysis of 1609 kidney transplant recipients showed that persistent hyperparathyroidism was independently associated with worse graft survival (19). Despite this strong observational evidence linking high PTH levels to adverse outcomes, the optimal post–transplantation PTH level remains unknown.

Role of DXA and Other Imaging in Fracture Risk

A DXA scan is a relatively accurate, noninvasive, cost–effective screening method for estimating bone mass, and it seems to help predict fracture risk in kidney transplant recipients. In a Swedish study of 238 kidney transplant recipients, 19% of patients had a fracture over a 12-year follow-up, and those with osteopenia and osteoporosis at the hip had a significantly increased risk of fracture compared with those with normal BMD (relative risks of 2.7 [95% confidence interval, 1.6 to 4.6] and 3.5 [95% confidence interval, 1.8 to 6.4], respectively) (27).

DXA is unable to assess microarchitectural structure of the bone and provides only a two-dimensional measurement of bone density. In contrast, high–resolution peripheral quantitative computed tomography (HR-pQCT) of the distal tibia and radius provides microarchitectural information and is able to quantify volumetric density of cortical and trabecular bone (28). Iyer et al. (18) have used HR-pQCT to show significant reductions in both cortical and trabecular bone densities after transplantation, which resulted in reduced estimated bone strength. Presently, HR-pQCT is a promising research tool, but there have been no studies to show whether it is a better predictor of fracture than DXA in kidney transplant recipients.

Fracture Risk Assessment

The Fracture Risk Assessment Tool (FRAX) accurately estimates the 10-year probability of major osteoporotic fractures in the general population and generates recommendations for therapy in patients at high risk of fracture. The FRAX does not require bone densitometry data to predict fracture risk and therefore, is a potentially attractive clinical decision aid. Recently, the FRAX has been shown to modestly predict fracture risk in kidney transplant recipients at a single center (29), but additional validation is required before it can be used as a bedside tool.

Bone Biopsy

Bone biopsy with double-tetracycline labeling is the gold standard to accurately diagnose post–transplantation bone disease subtype, but it is not often performed. The Kidney Disease Improving Global Outcomes (KDIGO) CKD-MBD guideline (30) states that it is reasonable to consider bone biopsy to guide treatment in the first 12 months post-transplant, but this recommendation is not graded because of a lack of evidence. Ideally, kidney transplant recipients who have persistent bone pain, fragility fractures, or severe osteoporosis need a bone biopsy to exclude ABD before initiation of antiresorptive therapy, because PTH levels are poorly predictive of underlying bone turnover (30). However, it is important to recognize that many patients find this invasive procedure unacceptable, and the processing and analysis of bone biopsies require significant expertise that precludes its widespread use. Furthermore, there are no published studies looking at the predictive value of bone biopsies in identifying kidney transplant recipients at risk of fracture. More studies are needed to clarify the clinical utility of bone biopsy on the practical management of post–transplantation bone disease and the effect of antiresorptive therapy on bone histology in this population.

Minimizing GCs

Reducing steroid exposure can minimize bone loss and should be especially considered for patients with known pretransplant osteopenia or osteoporosis (30). In a study of 87 kidney transplant recipients, BMD improved at the lumbar spine (by 4.7%) and the total hip (by 2.4%) after GC withdrawal 1-year post-transplantation compared with those who remained on GCs (31), and even late GC withdrawal has been shown to improve BMD (32). A recent analysis of the USRDS data found that early steroid withdrawal at hospital discharge was associated with a 31% fracture risk reduction and lower fracture–related hospitalization (10) without an increased risk of rejection in the steroid withdrawal arm.

Vitamin D and Vitamin D Analogs

Supplementation with both active [1,25(OH)₂D] and native (25-OHD) vitamin D can reduce loss of BMD in both the femoral and lumbar regions, but these studies have not been sufficiently powered to determine whether there is a beneficial effect on fracture rate (23). Furthermore, vitamin D has well described pleiotropic effects on the renin-angiotensin-aldosterone system and proteinuria (23) and immune-modulatory effects on T cells and dendritic cells, which may affect graft function (25).

Paricalcitol, a synthetic metabolically active vitamin D analog of calcitriol, has been shown to suppress PTH post-transplantation but was associated with a higher risk of hypercalcemia (33). In the same study, moderate renal allograft fibrosis was reduced in the paricalcitol group compared with the control group. Another randomized, crossover study has shown that paricalcitol also reduced bone remodeling as reflected by reduction of bALP and osteocalcin together with improvements in lumbar spine BMD (34). Interestingly, there was a reduction in eGFR associated with paricalcitol therapy, but it is not clear whether this reflects changes in creatinine secretion and generation or a direct effect on GFR.

Calcimimetics

Cinacalcet is a calcimimetic agent that increases the sensitivity to calcium of the calcium-sensing receptor in the parathyroid gland and suppresses PTH. A recent RCT for the treatment of hypercalcemia and SHPT in 114 kidney transplant recipients (35) showed that cinacalcet significantly reduced PTH and calcium with an increase in serum phosphorus levels without any effect on graft function compared with placebo. Although PTH has a catabolic effect on bone, reducing PTH with cinacalcet, perhaps surprisingly, had no positive effect on BMD, possibly because of direct effects on a calcium-sensing receptor in bone that may offset any beneficial effects of lower PTH levels (36). Cinacalcet therapy does result in significant hypercalciuria and may cause nephrocalcinosis, although this was not seen in a cohort of 34 kidney transplant recipients who underwent an allograft biopsy at 3 and 12 months post-transplantation (37). The direct effect of cinacalcet on the bone histomorphometry in kidney transplant recipients has not been studied in detail. In a small study of kidney transplant recipients who underwent bone biopsy before and after starting cinacalcet, Borchhardt et al. (38) found that, although bone formation rates fell in seven of 10 patients, five of 10 patients had undetectable bone turnover after 18–24 months of cinacalcet therapy. Notwithstanding the risk of ABD associated with cinacalcet, one needs to recognize the risks associated with parathyroidectomy in kidney transplant recipients. These include irreversibly inducing ABD and a decline in eGFR after parathyroidectomy in the allograft, possibly as a result of the direct effects of PTH on renal hemodynamics (39).

Recombinant PTH

Recombinant PTH (teriparatide) is an anabolic agent, which can improve BMD in patients with GC-induced and postmenopausal osteoporosis. In a 6-month double–blind RCT of 26 kidney transplant recipients (40), patients who received daily teriparatide injection did not show an improvement of BMD in the lumbar spine or distal radius compared with those in the placebo group. However, there was stabilization of femoral neck BMD in the teriparatide-treated group. Teriparatide is expensive, and in view of the lack of supporting data from RCTs in kidney transplant recipients, its therapeutic role is unclear, although theoretically, it may be an attractive agent for those with severe osteoporosis who also have evidence of ABD.

Antiresorptive Agents

Bisphosphonates and denosumab are the two commonly used antiresorptive agents for osteoporosis. Both therapies can potentially induce low bone turnover, and therefore, it is important to consider a bone biopsy before initiating therapy in those at high risk of ABD, such as those who have had a previous parathyroidectomy (30).

Bisphosphonates accumulate at sites of active bone resorption, where they enter osteoclasts and inhibit farnesyl pyrophosphate synthase, which results in osteoclast apoptosis, thereby inhibiting bone resorption. They bind potently to mineralized bone, with a half-life of ≤10 years, and the fraction not taken up by bone (40%–60%) is excreted by a combination of glomerular filtration and active tubular transport. Therefore, impaired graft function can have a significant effect on the pharmacokinetics and half-life of bisphosphonates. However, treatment is well tolerated in kidney transplant recipients with a GFR>30 ml/min per 1.73 m², with no significant adverse effects compared with placebo/no treatment (30).

The key RCTs using bisphosphonates in kidney transplant recipients are summarized in Table 2 (41–52). Most of the studies show that bisphosphonate therapy preserves or increases BMD in the lumbar spine and femoral neck in the early post–transplantation period. It is worth noting that the risk of ABD as a result of bisphosphonate therapy has not been a consistently observed phenomenon. For example, Coco et al. (46) studied the effect of pamidronate combined with low‐dose calcium and calcitriol on preservation of bone mass at 6 and 12 months compared with placebo. Pamidronate was associated with preservation of vertebral BMD but an increased risk of low bone turnover on bone biopsy. In contrast, more recent data from the same group showed that risedronate did not affect BMD and that it was not associated with an increased risk of developing ABD in kidney transplant recipients (52). This difference between bisphosphonate effects could be related to differences in potency in their mechanisms of action or may reflect the difference in the enzyme-suppressive activity of second (pamidronate) and third generation (risedronate) bisphosphonates.

A recent study by Smerud et al. (51) showed no benefit with ibandronate compared with calcium and calcitriol supplementation alone on lumbar BMD, but ibandronate did modestly increase hip and forearm BMD. It also suppressed bone turnover markers, including procollagen type 1 N–terminal propeptide, osteocalcin, and bALP. This finding is in striking contrast to earlier studies, which seemed to show a beneficial effect of bisphosphonates on lumbar BMD. This is likely to be because of significantly less GC exposure in the study by Smerud et al. (51) as well as the fact that the control group received calcitriol and calcium supplementation. Indeed, a number of studies in which vitamin D therapy was part of standard care in the control group failed to show a benefit of bisphosphonates on BMD after kidney transplantation. This suggests that widespread bisphosphonate use may have less of an effect on BMD in the contemporary era of reduced rejection rates, reduced steroid exposure, and widespread use of vitamin D and that the value of bisphosphonate therapy will be targeted use in high-risk recipients.

Denosumab, a humanized monoclonal antibody against the receptor activator of NF-κB ligand, decreases bone resorption, significantly increases BMD, and decreases the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. It is also effective at reducing fracture risk in patients with impaired kidney function, including those with CKD stage 4 (53). Denosumab is not renally cleared, which makes it more attractive than bisphosphonates in patients with significant graft dysfunction, although there are little data of its use in the transplant population.