Factors which contribute to posttransplant bone disease. Posttransplant steroid use plays a major role in bone loss, although other metabolic derangements, especially in kidney transplant patients, may also contribute (Source: Bia )
Whereas patients with heart, lung, and liver disease tend to have preexisting osteoporosis, those with end-stage kidney diseases have what is termed renal osteodystrophy, which is an integral part of chronic kidney disease–metabolic bone syndrome (CKD–MBS) – also known as chronic kidney disease–mineral and bone disorder (CKD–MBD). This condition is marked by active vitamin D deficiency (low vitamin D-1.25-OH), hyperphosphatemia, secondary hyperparathyroidism, and excess aluminum levels—all of which may lead to reduced BMD and fractures but are distinct from osteoporosis as such . While the magnitude of many of these metabolic abnormalities is lessened by kidney transplantation, some aspects of the CKD-MBS such as parathyroid hyperplasia are likely to remain . Failure of enlarged parathyroid glands to involute means that PTH concentrations remain elevated after transplantation, a scenario true in 75 % of patients one year after renal transplant [62, 63]. In addition patients with end-stage kidney disease tend to be hypogonadal and thus could have already received treatment with immunosuppressive therapy (glucocorticoids or cyclosporine A) that will continue posttransplant . Finally, transplant patients frequently still have chronic kidney disease with its attendant complications.
Posttransplant Osteoporosis, Bone Loss, and Fractures
In addition to the standard risk factors for osteoporosis including age and female gender, kidney transplant patients face other challenges, ranging from time since transplantation to the immunosuppressive regimen and graft dysfunction. Ahmadpoor et al. reported an incidence of osteoporosis at 26 % (20 of 77 patients who had undergone transplantation in the previous 6 months–2 years), with the most common sites being the hip and spine . In a cohort of 44 patients followed up to 12 months posttransplant, Orzel et al. identified 43 % as osteopenic, 11 % as osteoporotic, and 46 % as normal, with younger age and high intact pretransplant parathyroid hormone levels as the principal risk factors .
As in the case of other transplants, improved results for BMD in kidney patients are evident in more recent studies. Whereas a 1991 investigation reported a BMD decline of 4–10 % in the first six months following transplant  due to the toxic effect of glucocorticoids, Bouquegneau et al. have pointed to newer trials that reveal a bone loss of only 0.1–5.7 % in the lumbar spine, reflecting reduced immunosuppressive therapy . In 2014, a large trial (n = 326) to assess long-term changes in BMD following kidney transplant used extensive DXA measurements to demonstrate that BMD typically improved or remained stable over a period of 8.2 years, with baseline values only slightly above average for age and sex. It should be noted, however, that baseline measurements did not begin until six months after transplantation, allowing for the well-established decline in BMD within the early posttransplant period. Over the long term, the single factor leading to a significant increase in mean BMD at all sites was osteoporosis treatment .
Similarly the results of later trials on fracture occurrence demonstrate improvement over earlier findings, mainly attributable to a reduction in the use of immunosuppressive agents; time after transplantation and the presence of diabetes are other contributing factors. Data from the US Renal Data System (USRDS) demonstrate that the demographic-adjusted incidence of hip fractures in kidney transplant recipients has declined significantly to the point where it is 45 % lower in patients transplanted in 2010 than in 1997 . Explanations for this decline include not only changes in immunosuppressive regimens but also an altered lifestyle (smoking cessation, reduced alcohol consumption, enhanced physical activity) and increased bisphosphonate use, which, as noted later, remains a matter of concern in kidney transplant patients.
In one of the largest studies of fracture incidence in kidney transplant patients yet undertaken (n = 4821) , Naylor et al. estimated the cumulative incidence of nonvertebral fractures at 3, 5, and 10 years in the period between 1994 and 2009 with the following results. The overall 3-year cumulative incidence of nonvertebral fractures was 1.6 %, with the number increasing over that time period; the hip fracture rate alone was 0.4 %. The overall 5- and 10-year cumulative incidence of nonvertebral fractures was 2.7 % and 5.5 %, respectively, with hip fractures alone at 1.7 % at the 10-year mark. The most common fracture site was the lower leg. These findings bear out the 2004 observation by Sprague et al. that “the more time since transplantation, the higher the reported fracture rate,” but with fracture occurrence at a much lower level than the rates of 5–44 % cited in this earlier study . To explain the lower fracture incidence now observed, Naylor et al.  cite the fact that earlier studies could not take into account patients transplanted after the year 2000 when decreased prednisone doses, as well as the use of bisphosphonates and vitamin D supplementation, came into play.
Another approach to reducing fracture risk in kidney transplant is early corticosteroid withdrawal. A study of 430 patients receiving transplants between 2000 and 2006 demonstrated that 31 % of patients discharged from the hospital without corticosteroids had a decreased risk of fracture compared with those discharged on a corticosteroid regimen – a finding that became significant at 24 months posttransplant . Despite these encouraging signs, kidney recipients still have a nonvertebral fracture rate of 1.6 % compared with 0.5 % for the comparable healthy population; women aged 50 and over sustain the highest cumulative 3-year increase of 3.1 % .
Is there an association between low BMD and fractures in kidney transplant? In a study conducted over 20 years ago, Grotz et al.  showed that many transplant recipients did not experience fractures, concluding that low BMD values at the lumbar spine could, at best, only partially explain fracture occurrence. DXA measurements at the femoral neck indicated no relation to fractures. Findings that BMD assessment does not discriminate between patients with fractures and those without have led to increasing interest in measurements of bone quality, achieved with newer three-dimensional imaging techniques such as quantitative computed tomography. Recent evidence that lower femoral neck BMD may be linked with increased fracture risk in chronic kidney disease  calls for increased efforts to develop simplified, less invasive, and more cost-effective ways to conduct bone biopsies .
Diabetes compounds the fracture risk for patients with kidney transplants. Epidemiologic studies show that pretransplantation diabetes can more than double the risk for fracture after a kidney transplant . Hypoinsulinemia, hyperglycemia, and other diabetic complications including peripheral neuropathy can all decrease bone strength. However, new research finds that a simultaneous pancreas–kidney transplant, as opposed to a kidney transplant alone, can result in lower fracture rates in kidney transplants, particularly in men . Apparent within three months of transplantation, overall fracture incidence was 31 % lower in men over a 5-year period but was not significantly different in women. Higher levels of circulating estrogen in women under the age of 50, less severe bone loss at the lumbar spine and femoral neck, and prior medication aimed at fracture prevention may, in part, account for this difference. As the authors emphasize, further studies to determine the mechanisms underlying coincident type 1 diabetes and chronic kidney disease are required to serve as the basis for new fracture prevention strategies that can be used in men, concurrently with the combined transplantation, as well as to advance other therapies that will help to prevent fractures in women.
Both nonpharmacologic and pharmacologic therapies have been employed to prevent bone loss posttransplant. In cases where the effect of these therapies have not been examined in kidney recipients directly, findings have been extrapolated from relevant trials involving other types of transplants, keeping in mind the special circumstances that define bone loss in the post-kidney transplant population. Given the sharp decline in bone loss that occurs in kidney as well as in other transplants immediately after surgery, therapeutic measures should be initiated at the earliest point.
Calcium and Vitamin D Supplementation
Hyperparathyroidism, abnormal vitamin D metabolism, and the use of prednisone all lead to reduced calcium absorption and further contribute to bone loss post kidney transplant. At the same time, calcium supplementation alone is ineffective in maintaining BMD or reducing fracture risk . A Cochrane Database Review of 24 trials found that no individual intervention with either vitamin D, calcitonin, or bisphosphonates was associated with reduced fracture risk but that when the results of all trials were combined, any one of these treatments proved effective against fracture risk and all had a beneficial effect on BMD at the lumbar spine . This study supports the concurrent use of vitamin D (with or without calcium) and bisphosphonates to reduce the deleterious effects of immunosuppressive therapy on bone density after transplant and indicates that any intervention to alter bone metabolism can reduce fracture risk in the year following surgery. With respect to calcium supplementation, Torres et al. report that intermittent-dose calcitriol during the first three months posttransplant, followed by oral calcium supplementation during the first year, decreased the rate of bone loss at the total hip compared with calcium supplementation alone, without any adverse effect on hypercalcemia levels .
The relation between vitamin D and hypercalciuria admits of mixed findings. A recent study reported that hypercalciuria occurred more frequently in a vitamin D supplementation group, leading to a reduction in the dosage or treatment discontinuation in 30 % of patients; calcium supplementation was also cited as a possible cause of hypercalciuria. It is clear that additional randomized controlled trials are required to determine the most effective dose and optimal duration of supplementation as well as to assess the specific impact on fracture risk . Until then, the level of calcium and vitamin D supplementation is determined on an individual basis taking into account regular screening results to determine the extent of bone damage, as well as the severity of the disease and existing comorbidities such as diabetes.
As in the case of dietary supplementation, exercise programs must be tailored to individual needs of the individual and, to the extent possible, should encompass mechanical loading, stretching, and strengthening regimens. Although the primary goal of exercise in the posttransplant phase is to reduce cardiovascular risk and improve graft function , the benefits of exercise extend to increasing BMD and preventing fractures by advancing motor fitness, improving balance, and decreasing fall risk. However, analyses of the efficacy and effectiveness of exercise post renal transplant are few in number, and the lack of evidence, in itself, represents one of the principal factors contributing to low exercise rates . Gordon et al. point to several other reasons underlying reduced physical activity: (1) lack of motivation and interest, coupled with fear of injuring the graft, (2) limited knowledge of the benefits of exercise on the part of healthcare professionals faced with what they consider to be more immediate and compelling concerns, and (3) inadequate reimbursement for physical activity programs and counseling on the part of insurance carriers. Exercise may be particularly difficult to initiate in older renal transplant recipients with reduced physical performance prior to transplant, as well as in younger patients who have been shown to be less physically active pretransplant by a measure of 25 % in comparison with healthy subjects .
The guidelines adopted by Kidney Disease: Improving Global Outcomes (KDIGO) recommend that at least 30 min of moderate-intensity exercise (walking, cycling, slow jogging) be undertaken on most, preferably all, days of the weeks, as adapted to the needs and capacity of the individual . In a highly cited randomized clinical trial, Painter et al. found that one year after transplant, an exercise intervention group increased its regular physical activity from 50 to 67 %, whereas the “usual care” group experienced a decline from 47 to 36 %; in addition the exercise group realized significantly greater gains in peak oxygen uptake (VO2), muscle strength, and physical functioning . Although guidelines and studies such as these have not directly addressed bone disease in renal transplant, they do raise awareness of the need to develop exercise regimens directed to individual needs as well as to conduct new empirical research on the safety and efficacy of specific exercise training programs with respect to the different outcomes of the transplant process including osteoporosis. Recent findings on the correlation between low physical activity and the risk of cardiovascular and all-cause mortality in renal transplant  may well stimulate further examinations of the impact of exercise on mineral and bone disorders as well as on fracture risk, leading to an improved quality of life.
As noted at the outset of this section, the value of bisphosphonates in kidney transplant is tempered by their potential to oversuppress bone metabolism. Given that concern, the general consensus is that bisphosphonates should not be used in kidney patients with low bone turnover that could be further exacerbated by these drugs, possibly increasing fracture risk. Studies of the effect of alendronate, pamidronate, and zoledronic acid have demonstrated benefits in terms of increased BMD.
In a 12-month analysis of kidney patients receiving 10 mg/day of alendronate plus calcitriol and calcium issued in 2001, BMD increased significantly by 5 % at the lumbar spine and 4 % at the femoral neck and bone turnover normalized; at the same time, bone continued to be lost due to prednisone treatment and persistent hyperparathyroidism . Two intravenous doses of pamidronate given to male patients at the time of transplantation and one month later prevented early rapid bone loss, with no significant reduction at the lumbar vertebrae and femoral neck . The regimen was well tolerated and easy to administer, with no detrimental effect on renal function and no discernible side effects. A subsequent study confirmed the efficacy of IV pamidronate in preserving bone mass but did observe an increased risk of low bone turnover .
A trial involving the third-generation bisphosphonate, zoledronic acid (ZA) reported that, at six months, two infusions of IV ZA increased trabecular calcium content significantly, with no change in BMD at the femoral neck. However, as Fratianni et al. have observed, the early bone-sparing effects of short-term ZA could not be sustained at three years after transplantation . In addition, FDA warnings concerning the deterioration of renal function and renal failure resulting from ZA must also be taken into account, with dose reduction as recommended.
Still in their infancy, comparative analyses of these medications are impaired by the small sample sizes and the heterogeneous nature of the research, particularly with respect to time duration following transplant. Based solely on randomized controlled trials, a recent meta-analysis of bisphosphonates posttransplant  concluded that they were beneficial to BMD at the lumbar spine but not at the femoral neck. Although changes in vertebral and nonvertebral fractures or in adverse events were not associated with their use; bisphosphonates were not found to reduce fracture incidence. As a result of this study, the largest database on the use of bisphosphonates in patients undergoing renal transplantation is now in place and can serve as the basis for further analyses of their efficacy and safety as new information is obtained.
In general, bisphosphonates which are renally excreted are not recommended for kidney transplant patients with moderate to severe renal insufficiency. As an alternative, denosumab, the fully human monoclonal antibody against RANKL, has recently been investigated to determine its effect on BMD in renal transplant, with results indicating that it significantly increased areal BMD at vertebral and nonvertebral sites . Unlike bisphosphonates it improved cortical volumetric BMD and thickness at the distal tibia and radius while decreasing levels of blood and urine biomarkers in bone turnover. Although associated with more frequent episodes of urinary tract infections, denosumab has the potential to improve bone health posttransplant and to sustain bone retention with long-term use. Synthetic parathyroid hormone (PTH) in the form of teriparatide does not improve BMD early after kidney transplantation, nor do histological analyses or bone markers provide evidence of improved bone turnover or mineralization .
The challenges of managing kidney recipients are many, emphasizing the importance of regular monitoring to determine the status of bone loss. Reduced doses of immunosuppressive therapy as well as early corticosteroid withdrawal, calcium and vitamin D supplementation as needed, increased physical activity, and the prudent use of bisphosphonates targeted at high-fracture risk recipients must be weighed carefully by an interdisciplinary team responsible for the care of transplant patients.
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