Continuing Education Activity

Transplantation has now become a standard treatment option for many end-stage disease processes. As the number of transplantations performed each year and the longevity of transplant recipients is steadily on the rise, it is crucial to identify transplant-related complications such as osteoporosis at an early stage and treat patients appropriately. This activity reviews in detail the pathophysiology, evaluation, and management of transplantation osteoporosis and highlights the role of early preventive therapy in reducing morbidity and improving quality of life in transplant recipients.

Objectives:

• Describe the pathophysiology of transplantation osteoporosis.
• Review the risk factors associated with an increased incidence of transplantation osteoporosis.
• Describe the management of treatment of transplantation osteoporosis.

Introduction

Organ transplantation has emerged as an established treatment option for patients with end-stage disease processes such as end-stage renal disease (ESRD), acute and chronic decompensated liver disease, end-stage cardiac and pulmonary diseases, diseases of the pancreas, intestines, hematological conditions, etc. The number of transplantations performed worldwide has steadily increased in the past three decades. The advent of newer immunosuppressive regimens and improved nutrition has significantly increased the survival rates among transplant recipients. Simultaneously, short and long-term complications of transplantation are increasingly recognized.[1] 

One such complication is the development of post-transplantation osteoporosis and fractures, both of which are associated with increased mortality and morbidity and decreased quality of life in transplant recipients.[2]

Etiology

The two principal factors that contribute to an increased rate of bone loss and fractures in transplant recipients are pre-transplant bone disease and post-transplant exposure to high-dose glucocorticoids and calcineurin inhibitors. Some of the non-modifiable factors associated with an increased risk of post-transplantation osteoporosis are advanced age, Caucasian race, female sex, and especially the post-menopausal period.[3]

Epidemiology

While some recent studies have shown comparatively lower rates of osteoporosis and fractures among transplant recipients, these rates continue to remain significantly higher than their age and sex-matched controls. The lower rates in recent studies are most likely the result of increased awareness, early diagnosis, and treatment of osteoporosis in addition to improved immunosuppressive regimens. A large cohort study in 2014 showed that the overall hazard ratio (HR) of osteoporosis after solid organ transplantation (SOT) was as high as 5.14, and HR of related fractures was 5.76 in comparison to age and sex-matched controls. The highest HR was observed in male patients (HR of 7.09) and patients aged 50 years or younger (HR of 7.38).[4]

The rate of bone loss after transplantation is found to be highest in the first 3 to 6 months[5] after heart, lung, liver, or bone marrow transplantations and the first 6 to 18 months after kidney transplantation. The reduction in bone mineral density (BMD) varies between 2% to 12% in the first post-transplant year in all transplantations.[6][7] The rate of osteoporosis ranges between 11 to 57 %, and the rate of fractures varies widely between 14% to 65 % in the first post-transplant year, depending on the organ transplanted and the duration of follow-up.[8][9][10][11]

The occurrence of fractures in the first post-transplant year was lower in kidney transplant recipients among all SOT recipients.[12] The highest incidence of osteoporosis and fractures have been recorded in lung transplant recipients.[4] While an improvement in BMD has been demonstrated in most SOT recipients after the first post-transplant year, BMD remains low up to several years after kidney transplantation.

Pathophysiology

The key factors that play a vital role in rapid bone loss in transplant recipients are as follows:

1. Their pre-existing bone disease
2. The effect of medications such as corticosteroids and calcineurin inhibitors on the skeleton.

Pre-transplantation Bone Disease

Several studies have shown that as high as 50 % of transplant candidates have a pre-existing bone disease, and the prevalence of fractures in this population is higher than that in the general population.[13][14] Hepatic osteodystrophy has been attributed to factors such as alcohol abuse, hypogonadism, vitamin D deficiency, and hyperbilirubinemia. Bone disease in congestive heart failure (CHF) patients is due to factors like vitamin D deficiency, renal insufficiency, and the use of loop diuretics. Among lung transplant candidates, chronic treatment with glucocorticoids and also smoking contributes to bone disease, and specifically in patients with cystic fibrosis, vitamin D deficiency due to intestinal malabsorption and hypogonadism play a vital role. Pre-transplant exposure to chemotherapeutic agents or whole-body irradiation, in addition to the underlying bone marrow pathology, are the major causes of bone disease in stem cell recipients.

Bone mineral disease in chronic kidney disease (CKD-BMD) is a prominent feature in ESRD patients, and based on the morphology seen on bone histomorphometry study, CKD-BMD can be classified into three distinct entities as follows:

1. Osteitis fibrosa, a result of secondary hyperparathyroidism and increased bone turnover
2. Osteomalacia, caused by decreased bone mineralization due to vitamin D deficiency.
3. Adynamic bone disease, that occurs due to parathormone (PTH) over-suppression and decreased bone remodeling.

Some of these entities can co-exist in the same patient. Bone histomorphometry is performed on biopsy samples from the iliac crest after tetracycline labeling. Differentiating between these entities is essential while considering therapy in patients with ESRD as bisphosphonates, which are the most commonly used drugs for transplantation osteoporosis treatment, are associated with worsening of adynamic bone disease.

Skeletal Effects of Corticosteroids (CS)

The main mechanisms by which CS induce bone loss are the direct inhibition of osteoblast functions, an increase in the apoptosis of osteoblasts, and the increased osteoclast activation by enhancing RANK ligand activity.[15][16] CS is also responsible for a multitude of other adverse effects that are detrimental to the bones. The most important of these is the effect of CS on calcium metabolism leading to a decrease in intestinal calcium absorption and an increase in calcium loss from the kidneys, which subsequently induce secondary hyperparathyroidism and increase bone loss. CS also induce hypogonadism by suppression of the hypothalamic-pituitary-gonadal axis and thereby lead to increased bone resorption.[17] Additionally, CS increases the risk of fractures by inducing severe myopathy leading to an increased risk of falls.

Skeletal Effects of Calcineurin Inhibitors (CNIs)

The lone effects of the CNI, such as cyclosporin and tacrolimus, on the human skeleton are unclear as patients treated with CNI are almost always concomitantly treated with CS. In murine models, though CNIs were seen to stimulate both osteoblasts and osteoclasts, the resorption rate was found to be much higher than the bone formation rate, thus leading to a net increase in bone resorption.[17]

History and Physical

Patients with transplantation osteoporosis may present with bone pain, low impact fractures, or bone deformities. Transplant recipients are usually not evaluated and treated for osteoporosis in current clinical practice. Hence when a history of transplantation is present, a high index of suspicion for osteoporosis and related fractures should be present that would potentially aid in the diagnosis.

Evaluation

As transplant candidates have an increased incidence of bone disease when compared to the general population, these patients should ideally be evaluated and managed appropriately before the transplantation.

The recommendations for evaluation of transplant candidates vary based on the underlying disease process and the organ transplanted. The AASLD (The American Association for the Study of Liver Diseases) and AST (American Society of Transplantation) 2013 guidelines recommend that all patients planned for liver transplantation undergo a bone density scan (DXA scan) and get treated if diagnosed with osteoporosis before the transplantation. The KDIGO (Kidney Disease Improving Global Outcomes) guidelines 2017 recommend checking calcium, phosphorus, vitamin D, and PTH levels at regular intervals after kidney transplantation until levels stabilize.[18][19]

Most authors recommend that all transplant candidates should undergo the following tests for evaluation:[20][21]

• DXA scan to evaluate for osteoporosis or osteopenia
• Radiographs of the thoracic and lumbar spine, or vertebral fracture assessment (VFA) by DXA scan to screen for vertebral fractures, and
• Screening for vitamin D deficiency and other secondary causes of osteoporosis such as hyperparathyroidism, alcohol abuse, chronic smoking, hypogonadism, and the use of offending medications such as heparin and loop diuretics.

The long waiting period for most of the transplantations should be utilized for identifying the secondary causes of osteoporosis and potentially treating them before the transplantation. In patients found to have osteoporosis or related fractures before transplantation, appropriate treatment should be initiated immediately. In patients with no osteoporosis or fractures before transplantation, preventive therapy after transplantation is most appropriate.[22]

Treatment / Management

The management of transplantation osteoporosis comprises of the following strategies:

• Preventive pharmacotherapy
• Treatment of established osteoporosis, and
• Treatment of the secondary causes of osteoporosis.

Preventive Pharmacotherapy

The ISHLT (International Society for Heart and Lung Transplantation) 2010 guidelines recommend preventive therapy for all heart transplant recipients throughout the first year after transplantation. The AASLD (The American Association for the Study of Liver Diseases) 2012 practice guidelines recommend therapy for all liver transplant patients with osteoporosis and patients with osteopenia and other risk factors for fractures.[23][24]

Since studies have failed to demonstrate an association between clinical indicators such as cumulative corticosteroid dose or the rate of change of BMD and fracture risk in transplant recipients, many authors recommend preventive pharmacologic therapy in all patients undergoing heart, liver, lung, and bone marrow transplantations.[22][25][26] In most of the prospective trials, preventive therapy has been initiated as soon as possible after transplantation and continued for at least twelve months.[27][28] Many authors recommend re-assessing the patient at one year to determine the need for continued therapy. Re-assessment can be based on repeat BMD measurement, current CS dose, etc.[10][29][10]

In kidney transplant recipients, there is no consensus regarding preventive pharmacologic therapy. Most authors recommend a comprehensive fracture risk assessment of these patients based on factors like BMD, vertebral fractures, PTH level, patient's age, sex, body weight, etc. and consider preventive therapy for high-risk patients. Some studies also suggest the measurement of bone turnover markers such as C-telopeptide crosslink (CTX) and bone-specific alkaline phosphatase to risk-stratify patients.[30]

Bisphosphonate Therapy

Bisphosphonate (antiresorptive) therapy is the initial choice of preventive therapy for transplantation osteoporosis as it directly counteracts the effects of CS. Several studies have proven their efficacy in decreasing bone loss and the number of vertebral fractures at one year after transplantation. Presently, there is no preference of one bisphosphonate over another, or of the route of administration. A study that compared the efficacies of intravenous zoledronic acid and oral alendronate for the prevention of bone loss in transplant recipients showed equal efficacy using either of these agents.[31][27][32] It is important to exercise caution while considering bisphosphonates in premenopausal women because their safety during pregnancy has not been sufficiently established. Due to their potential of worsening adynamic bone disease, bisphosphonates are not recommended in patients with glomerular filtration rate (GFR) less than 30 ml/minute.

Vitamin D Metabolites

Calcitriol, a vitamin D metabolite, can be used as preventive therapy when bisphosphonate therapy is contraindicated. It increases calcium absorption in the intestine and its reabsorption in the kidneys, and as a result, leads to negative feedback on PTH release. At a dose of 5 micrograms per day, calcitriol has shown efficacy in decreasing bone loss and vertebral fractures.[33][34][35] It is essential to screen all patients on calcitriol therapy for the development of hypercalcemia or hypercalciuria by periodically measuring serum and urinary calcium levels.

Hormone Replacement Therapy (HRT)

All transplant recipients with hypogonadism should be treated with HRT as it has been shown to slow bone loss in this population.[36] At present, HRT is used as sole preventive therapy only in select patients with hypogonadism, in whom bisphosphonates are contraindicated.

Denosumab

Denosumab, a humanized monoclonal antibody to the RANK ligand, is efficacious in the treatment of osteoporosis in kidney transplant recipients. It has also demonstrated efficacy in the treatment of osteoporosis in liver transplant recipients.[37] In a recent study where it was used as prophylactic therapy in kidney transplant recipients, denosumab has shown efficacy in increasing BMD in the first post-transplant year.[38] Of note, denosumab is associated with increased bone loss upon discontinuation, and in such cases, it may need to be switched to antiresorptive therapy with bisphosphonates.[39]

Teriparatide

Teriparatide, a recombinant human PTH, has shown efficacy in steroid-induced osteoporosis. A study that used teriparatide as preventive therapy in kidney transplant recipients did not show BMD improvement in the teriparatide group compared to the placebo group.[40] Hence, further studies are needed to delineate the role of this drug as preventive therapy for transplantation osteoporosis. As of now, no studies are available using abaloparatide, a parathyroid hormone-related peptide (PTHrP) analog, in transplant recipients.

Calcitonin

Calcitonin acts by directly inhibiting osteoclastic bone resorption. Its role in the prevention and treatment of post-transplantation osteoporosis has not been elucidated. An older study has illustrated the efficacy of combined preventive therapy with intranasal calcitonin and calcitriol in improving BMD at 18 months following heart transplantation. Nevertheless, newer studies are required to clarify the role of calcitonin in transplant recipients.[41]

Non-pharmacologic Measures

Non-pharmacologic measures that have been shown to decrease the risk of osteoporosis and fractures in the post-transplantation period are early mobilization, resistance training exercises, improved nutrition, and prevention of falls.[42]

Treatment of Transplantation Osteoporosis

Treatment of osteoporosis diagnosed in the post-transplantation period comprises of correction of secondary causes of osteoporosis and initiation of pharmacologic therapy. The preferred initial drug of choice is bisphosphonate therapy. Denosumab can be an alternative therapy for use in patients with poor renal function (GFR <30 mL/min). Teriparatide is another drug that can be utilized in patients with poor renal function where bisphosphonates are contraindicated. The anabolic effects of teriparatide are particularly useful in patients with low bone turnover, as seen with adynamic bone disease. Both denosumab and teriparatide are alternative drugs for the treatment of post-transplantation osteoporosis that is unresponsive to bisphosphonate therapy.

Treatment of Secondary Causes of Osteoporosis

All secondary causes of osteoporosis noted above under pre-transplantation bone disease should be identified and treated. Some of the common causes are hyperparathyroidism, vitamin D deficiency, hypogonadism, and CS exposure. Adequate supplementation of calcium and vitamin D is imperative for all transplant patients before and after transplantation. Appropriate lifestyle modifications such as smoking and alcohol cessation, improvement in nutritional status, and increased mobility are crucial as well. Patients should receive the lowest dose of CS necessary for avoiding rejection. Optimization of PTH and vitamin D levels are particularly effective for protecting against bone loss in kidney transplantation due to their high incidence in these patients.

Differential Diagnosis

Osteoporosis is diagnosed primarily by a DXA scan. Conditions such as osteomalacia that occurs in patients with cystic fibrosis and liver failure and adynamic bone disease that occurs in ESRD patients may present with a low BMD on the DXA scan. Since a precise diagnosis has specific implications on the treatment of these patients, caution must be exercised, and additional testing such as bone histomorphometry should be considered when necessary to arrive at an accurate diagnosis.

Prognosis

Despite the increasing knowledge and awareness about osteoporosis as a complication of transplantation, early evaluation and treatment of transplant candidates are not common in clinical practice. The resultant occurrence of osteoporosis, when left untreated, can cause increased fracture and hospitalization rates, ultimately leading to increased morbidity and mortality among transplant recipients.

Complications

The most serious complication of post-transplantation osteoporosis is the occurrence of fractures that includes vertebral compression fractures, which are the most common, and low impact fractures of the appendicular skeleton. These fractures can lead to bone deformities, which in turn result in decreased mobility and impaired quality of life for these patients.

Deterrence and Patient Education

Transplant candidates must be counseled early on about the potential for developing post-transplantation osteoporosis and needing special treatment. Patients should also be encouraged to make appropriate lifestyle modifications that comprise of smoking cessation, avoidance of alcohol abuse, and increase mobility in an effort to minimize their risk of developing osteoporosis. Early anticipatory counseling of patients is likely to improve patient follow-up rates and adherence to future therapy.

Enhancing Healthcare Team Outcomes

Healthcare providers are obligated to ensure that a patient who receives the gift of an organ has the best possible outcome. Efficient communication between the multi-disciplinary team consisting of the primary care physician, the consulting organ specialist, and the transplant surgeon is vital in providing comprehensive treatment to patients. Given the high complexity of treatment in these patients, consulting an endocrinologist early on for the evaluation and treatment of osteoporosis is likely to improve patient outcomes. Early preventive therapy for osteoporosis is associated with a decreased incidence of osteoporosis and fractures among transplant recipients.[33]