Evaluation and management of bone disease and fractures post transplant

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Abstract

Bone disease is common in recipients of kidney, liver, heart, and lung transplants and results in fractures in 20–40% of patients, a rate much higher than expected for age. Fractures occur because of the presence of bone disease as well as other factors such as neuropathy, poor balance, inactivity, and low body or muscle mass. Major contributors to bone disease include both preexisting bone disease and bone loss post transplant, which is greatest in the first 6–12 months when steroid doses are highest. Bone disease in kidney transplant recipients should be considered different from that which occurs in other solid organ transplant recipients for several reasons including the presence of renal osteodystrophy, which contributes to low bone mineral density in these patients; the location of fractures (more common in the legs and feet in these patients than in spine and hips as in other solid organ recipients); and the potential danger in using bisphosphonate therapy, which may cause more harm than good in kidney transplant recipients with low bone turnover.

Evaluation in all patients should preferably occur in the pretransplant period or early post transplant and should include assessment of fracture risk as well as metabolic factors that can contribute to bone disease. Bone mineral density measurement is recommended in all patients even if its predictive value for fracture risk in the transplant population is unproven.

Management of bone disease should be directed toward decreasing fracture risk as well as improving bone density. Pharmacologic and nonpharmacologic treatment strategies are discussed in this review. Although there have been many studies describing a beneficial effect of bisphosphonates and vitamin D analogues on bone density, none have been powered to detect a decrease in fracture rate.

Introduction

Despite advances in patient and graft survival of solid organ transplants, metabolic complications, resulting from the recipient's disease as well as the immunosuppressive agents, continue to be a major problem. Bone disease is one of the most common of these complications, affecting many transplant patients and incapacitating some of them with recurrent fractures. In this article, information pertaining to the cause, prevention, and treatment of post transplant bone disease and fractures will be reviewed. Although data on heart, liver, lung and kidney organ transplant recipients will be covered, emphasis will be on kidney transplant recipients.

Section snippets

Frequency of fractures

All recipients of solid organ transplants experience an increased frequency of fractures post transplant, but there are some differences between the groups. In kidney transplant recipients, fracture frequencies between 6% and 45% have been reported [1], [2], [3], [4], [5], [6]. A feature unique to fractures in these patients is the predominance of fracture in the appendicular skeleton, especially the feet. Although there is also an increased frequency of hip and vertebral fractures compared to

Reasons for fracture-bone disease is not the only factor

Although bone disease undoubtedly contributes to the high frequency of fracture post transplant, most studies in kidney transplant patients have been unable to correlate a relationship between bone mass as measured by bone mineral density (BMD) measurements and fracture frequency [2], [4], [12]. This is in marked contrast to the findings in women with postmenopausal osteoporosis in whom the predictive value of BMD measurement and fracture risk is well established [13]. However, even in women

Reasons for bone disease and bone loss: kidney transplant recipients are different

A schematic view showing all the factors that contribute to posttransplant bone disease is depicted in Fig 1. In most organ transplant patients, posttransplant bone disease is a result of both bone disease preexisting before transplant as well as post transplant bone loss. Patients with liver disease, end-stage pulmonary disease, and congestive heart failure experience osteoporosis and bone fractures before transplant for a variety of reasons, which have been well described elsewhere [16].

Most

Bone quality as important as bone density

In addition to bone density contributing to decreased bone strength, there is an increasing amount of interest in “bone quality.” Bone quality is based on the bone's architecture and, so far, can only be evaluated by bone biopsy. Both bone density (measured by a dual x-ray absorptiometry scan) and bone quality (estimated by bone biopsy) determines bone strength, which, in turn, determines fracture risk [28]. When performed post transplant, bone biopsies in kidney transplant recipients have

Role of steroids: is any steroid dose safe?

Although many studies have not been able to demonstrate a correlation between steroid dose and BMD, there is a significant amount of evidence that steroids are a major contributor to posttransplant bone loss, especially the rapid loss that occurs in the first 6–12 months. Firstly, steroids are known to contribute to osteoporosis and bone loss due to their effects inhibiting bone formation [36], [37], [38]. Secondly, most [39], [40], [41] but not all [42] transplant centers using steroid-free

Role of other immunosuppressive agents

Although original studies in rats demonstrated high turnover bone loss with the use of cyclosporine [43], a significant role for cyclosporine in bone disease has not been consistently defined. Studies examining this debate are summarized in a recent review [44]. When bone loss in patients on cyclosporine vs tacrolimus has been compared, bone loss is less with tacrolimus [45]. The effects of sirolimus, mycophenolate mofetil, and azathioprine on bone loss appear to be minimal, although studies of

Evaluation

Prevention and management of bone disease post transplant requires a multifactor approach that begins with identifying patients most at risk. When possible, evaluation of patients for bone disease should begin in the pretransplant period by identifying patients at risk and treating modifiable risk factors for fracture (Fig. 2). In patients at high risk for fracture, consideration should also be given to use a steroid avoidance protocol at the time of transplant. Patients most at risk for

Prevention of early posttransplant bone loss

One strategy to preserve bone post transplant and avoid the 4–10% loss expected in the first year post transplant is to use a steroid avoidance protocol because most [39], [40], [41] but not all [42] studies demonstrate bone sparing with steroid-free protocols. Fortunately, the patients most likely to benefit from skeletal advantages of steroid avoidance (older, white) are not those who may be at risk from the negative long-term sequelae of steroid-free protocols (African Americans). An

Treatment of established bone loss

Many patients do not get evaluated for bone disease pre transplant or receive preventative therapy in the early posttransplant period. When BMD is found to be low at any time post transplant, steps should be taken to improve bone mass and reduce fracture risk.

Nonpharmacologic maneuvers to prevent fractures

Prevention of fractures involves not only preventing or treating posttransplant bone disease but also preventing or improving other factors that contribute to bone fracture (Table 1). Although the studies in transplant recipients supporting nonpharmacologic maneuvers to reduce fracture risk are few in number and size, the results are encouraging and worth discussing. Poor mobility, balance, and strength are major contributors to fracture risk in all patients and should be addressed [2], [14],

Questions to be resolved

Although much progress has been made in our understanding of posttransplant bone disease, there are still many questions left to be resolved, especially in kidney transplant recipients. Important questions include the following:

  • Should all waitlisted patients receive a BMD?

  • Should all patients receive a steroid-free protocol post transplant to avoid bone loss?

  • If steroids are used, should bisphosphonates always be employed in the early transplant period to prevent steroid-induced bone loss?

  • Should

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