Prevention and treatment of bone disease after kidney transplantation

INTRODUCTION — 

The major bone diseases that affect kidney transplant recipients are osteoporosis and osteonecrosis (avascular necrosis), both of which cause significant long-term morbidity [1]. Osteoporosis increases the risk of fractures [1-3].

Due to longstanding history of chronic kidney disease (CKD), kidney transplant recipients are also vulnerable to persistent CKD-mineral and bone disorder (CKD-MBD). CKD-MBD complicates both the evaluation and treatment of osteoporosis.

This topic reviews the diagnosis, monitoring, and treatment of osteoporosis in kidney transplant recipients. Persistent hyperparathyroidism and other disorders of mineral metabolism are discussed elsewhere. (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation".)

Other bone diseases that affect kidney transplant patients, including dialysis-related amyloidosis and renal osteodystrophy associated with aluminum toxicity, are far less common and are discussed elsewhere. (See "Aluminum toxicity in chronic kidney disease" and "Dialysis-related amyloidosis".)

Osteoporosis in nonkidney transplant recipients is discussed elsewhere. (See "Prevention and treatment of osteoporosis after solid organ or stem cell transplantation".)

EPIDEMIOLOGY AND RISK FACTORS

Fracture incidence — Fracture risk may be highest early after kidney transplantation. Fractures can occur in either peripheral or central locations, and some evidence suggests that peripheral fractures (involving hands, ankles, and feet) may be more common [4-6]. A 2016 systematic review of 4,821 transplant recipients found an overall 5- and 10-year cumulative incidence of non-vertebral fractures of 2.7 percent and 5.5 percent, respectively [7]. Similar results were found in a cohort study in 3992 individuals who underwent kidney transplantation in Sweden (median age 53 years, 65 percent male); 7 percent of all transplant recipients sustained a fracture of the hip, spine, humerus, or forearm over a median follow-up of four years [8]. Of these fractures, half occurred at the forearm, with the remainder at the hip (25 percent), humerus (16 percent), or spine (9 percent). Fracture risk was highest during the first six months after kidney transplantation and higher in females than in males. Advanced chronic kidney disease (CKD) is associated with markedly elevated fracture risk, and posttransplant fracture risk may reflect both transplant-specific risk factors and underlying CKD.

Pattern of bone loss — Bone loss often occurs rapidly following kidney transplantation, but thereafter the trajectory of bone loss is highly variable and depends, in part, on the dose and duration of glucocorticoid treatment [9]. Bone loss may occur at both cortical and trabecular sites [1,3,10-12]. In a study of 47 kidney transplant recipients who were managed according to glucocorticoid-minimizing protocols, bone mass was preserved at the central skeleton during the first posttransplant year, whereas loss of both cortical and trabecular bone mass was evident at peripheral sites [11]. Persistent hyperparathyroidism was associated with preferential loss of cortical bone. Since the advent of glucocorticoid-minimizing protocols, studies suggest that after the first posttransplant year, bone mineral density generally remains stable [13-20].

Risk factors — After kidney transplantation, primary risk factors for bone loss include treatment with glucocorticoids and other immunosuppressive medications [1,3,10,13,18,21], as well as preexisting CKD-mineral and bone disorder (CKD-MBD), including persistent posttransplant hyperparathyroidism and posttransplant metabolic acidosis. Persistent hyperparathyroidism may contribute to the higher fracture risk in kidney transplant recipients compared with other solid organ recipients [22]. (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation".)

Additional risk factors include those present in the general population, including hypogonadism in males and premenopausal females (which may be induced by glucocorticoids and uremia), diabetes, inflammatory arthritis, family history of osteoporosis, and lifestyle factors (smoking, inadequate exercise, malnutrition, excessive alcohol use) [23]. In kidney transplant recipients, use of proton pump inhibitors has been associated with an increased risk of hip fracture, but a causal effect is uncertain [24,25]. (See "Pathogenesis of osteoporosis" and "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Calcium and fracture risk'.)

INITIAL EVALUATION OF FRACTURE RISK

Goals and timing of evaluation — In all kidney transplant recipients, we advocate for early assessment of osteoporosis and fracture risk. The goal of this evaluation is to identify patients who are at high risk for bone loss and fracture after transplantation. Such patients may benefit from more frequent monitoring as well as medical therapies intended to reduce bone loss and fracture risk. (See 'Identifying patients at high fracture risk' below and 'Monitoring bone mineral density' below.)

There is no consensus for optimal timing of this evaluation. Some transplant centers perform the initial evaluation prior to transplantation, whereas others perform the evaluation within the first few months after transplantation.  

Clinical assessment — In all kidney transplant recipients, we assess for clinical risk factors for bone loss and fracture. These include traditional risk factors for osteoporosis as well as pre- and posttransplant factors. (See 'Epidemiology and risk factors' above.)

If secondary causes of bone loss or other modifiable risk factors for fracture are identified, these should be addressed whenever possible. Such risk factors for bone loss and fracture include the following:

●Hypogonadism (males and premenopausal females) (See "Testosterone treatment of male hypogonadism" and "Evaluation and management of secondary amenorrhea".)

●Undernutrition and/or underweight (See "Pathogenesis and treatment of malnutrition in patients on maintenance hemodialysis".)

●Fall risk (See "Falls in older persons: Risk factors and patient evaluation".)

●Persistent hyperparathyroidism (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation".)

●Hypophosphatemia (See "Hypophosphatemia: Evaluation and treatment", section on 'Patients on kidney replacement therapy'.)

●Vitamin D deficiency (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

Laboratory testing — At two to four weeks after transplantation, or when kidney allograft function stabilizes, we measure serum calcium, phosphorus, parathyroid hormone (PTH), and 25-hydroxyvitamin D levels.

In addition, some authors obtain fasting morning serum concentrations of bone turnover markers (BTMs) before a treatment decision is made. These include C-telopeptide (CTX), which measures bone resorption, and bone-specific alkaline phosphatase (BSAP) or intact procollagen type I N-terminal propeptide (PINP), which measure bone formation [11,26,27]. These results may help predict posttransplant bone loss and can be used to guide treatment in patients who are candidates for pharmacotherapy. (See "Bone physiology and biochemical markers of bone turnover", section on 'Markers of bone turnover'.)

Serial rather than single measurement of non-renally cleared BTMs may be more helpful for predicting posttransplant changes in BMD. If BTMs are measured serially, measurements every three to six months are reasonable. As an example, in a prospective study of 209 kidney transplant recipients who underwent serial BMD testing, PTH, BSAP, and PINP were measured at the time of transplantation and three and 12 months posttransplant [9]. In participants who gained bone mass, baseline levels of PTH, BSAP, and PINP were higher than in those participants who did not gain bone mass. Furthermore, the proportion of participants who experienced bone loss at 12 months posttransplant was markedly higher among those in whom none of the BTMs decreased between baseline and 3 months compared with participants in whom at least one BTM decreased (69 versus 36 percent, respectively). These results suggest that baseline low bone turnover is a risk factor for fractures in this population.

Imaging studies — We obtain the following imaging studies either prior to transplantation or as soon as possible within the first three months after transplantation:

●Bone mineral density (BMD) measurement – We obtain a dual x-ray absorptiometry (DXA) scan of the hip, spine, and forearm to assess BMD. (See 'Bone mineral density (BMD) measurement' below.)

Results of DXA scans can be interpreted according to the World Health Organization (WHO) classification of osteoporosis. The WHO established a classification of BMD (by DXA) according to the standard deviation (SD) difference between a patient's BMD and that of a young-adult reference population (T-score) (table 1) [28]. (See "Overview of dual-energy x-ray absorptiometry", section on 'Diagnosis of osteoporosis'.)

●Imaging for vertebral fracture - We obtain imaging of the thoracic and lumbar spine, either with lateral radiographs or by performing vertebral fracture assessment (VFA) using DXA (if available), to assess for the presence of existing vertebral fractures. Prior fracture is a strong risk factor for future fracture, and most vertebral fractures are subclinical. (See "Overview of dual-energy x-ray absorptiometry", section on 'Vertebral fracture assessment'.)

PREVENTION OF POSTTRANSPLANT BONE LOSS

General measures for all transplant recipients — Many interventions to prevent bone loss and fracture in kidney transplant recipients are similar to those used in the general population (algorithm 1).

Lifestyle measures — We encourage all transplant recipients to perform regular weight-bearing exercises after transplant. Regular weight-bearing exercise may help to prevent and/or treat osteoporosis in the general population and in transplant recipients. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Exercise' and "Prevention and treatment of osteoporosis after solid organ or stem cell transplantation", section on 'General recommendations for all patients'.)

All patients should receive counseling regarding smoking cessation, good nutrition, limiting alcohol intake, early mobilization after transplantation, and fall prevention, which are beneficial for skeletal health and fracture risk reduction. (See "Prevention and treatment of osteoporosis after solid organ or stem cell transplantation", section on 'General recommendations for all patients'.)

Glucocorticoid dose minimization — For all patients, we use the lowest glucocorticoid dose compatible with graft survival. Significant osteoporosis has been observed with prednisone doses as low as 7.5 to 10 mg/day [4,23,29], and bone loss occurs even in patients on early glucocorticoid withdrawal protocols.

In an analysis of 77,430 kidney transplant recipients from the United States Renal Data System (USRDS), recipients discharged from the hospital without glucocorticoids had a lower incidence of fractures leading to hospitalization compared with those discharged with glucocorticoids (1.7 versus 3.3 percent, respectively) [30].

Calcium and vitamin D3

●Patients with normocalcemia – Patients with normal serum calcium should achieve adequate calcium intake, and most should receive vitamin D3 (cholecalciferol). We aim for a total calcium intake of 1000 mg/day, preferably from food, and we use calcium supplements as needed to achieve this goal. The optimal cholecalciferol dose has not been established; we give supplemental vitamin D3 as needed to target a serum 25-hydroxyvitamin D level of ≥30 to 50 ng/mL (75 to 125 mmol/L), although some clinicians target a range of >20 to 50 ng/mL (50 to 125 mmol/L). (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Calcium and vitamin D'.)

In the absence of hypercalcemia, vitamin D3 administration is relatively safe, and calcium ingested without vitamin D may be poorly absorbed, particularly in individuals who are taking glucocorticoids. Few data exist concerning the effectiveness of vitamin D3 alone in the prevention of posttransplant bone loss [31]. One randomized trial suggested that the addition of vitamin D3 to calcium provides no significant additional benefit to calcium alone [31]. In contrast, in a trial in 193 kidney transplant recipients (median baseline 25-hydroxyvitamin D level 10 ng/mL [25 mmol/L]) who were randomly assigned to treatment with cholecalciferol (4000 international units daily) or placebo for the first posttransplant year, cholecalciferol reduced bone loss at the lumbar spine [32]. In a separate trial designed to evaluate extraskeletal effects of vitamin D supplementation, 536 kidney transplant recipients without diabetes were randomly assigned to cholecalciferol treatment with a high-dose (100,000 international units) or low-dose (12,000 international units) regimen, both of which were administered every 2 weeks for 2 months and monthly thereafter [33]. After two years, fewer participants in the high-dose treatment group suffered a symptomatic fracture (3 versus 12 participants in the low-dose group, odds ratio [OR] 0.24, 95% CI 0.07-0.86]). (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Calcium and vitamin D'.)

Both vitamin D deficiency and excess may promote vascular calcification in patients with chronic kidney disease; this issue is reviewed in detail separately. (See "Vascular calcification in chronic kidney disease", section on 'Vitamin D deficiency and excess'.).

●Patients with hypercalcemia – We do not give calcium to patients who are hypercalcemic [34]. We give supplemental vitamin D only if levels are lower than the target range. Unlike with recipients of other solid organs, hypercalcemia is not uncommon among kidney transplant recipients, because of persistent hyperparathyroidism. This is discussed in detail separately. (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation", section on 'Hypercalcemia'.)

Treat persistent hyperparathyroidism — In all kidney transplant recipients, we monitor for persistent hyperparathyroidism and treat if present. If persistent hyperparathyroidism is evident posttransplant, we measure parathyroid hormone (PTH) levels every three months. Posttransplant hyperparathyroidism is discussed in more detail separately. (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation", section on 'Monitoring after transplant' and "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation", section on 'Treatment'.)

Identifying patients at high fracture risk — For patients with evidence of persistent hyperparathyroidism, hypophosphatemia, and/or vitamin D deficiency, we ensure that these conditions are adequately managed for 6 to 12 months before considering pharmacotherapy for patients at high fracture risk. Based on the initial evaluation, we consider the following patients to be at high risk of incident fracture:

●Patients with a history of low-trauma fracture (including radiologic evidence of vertebral fracture)

●Patients with osteoporosis by BMD criteria (T-score ≤-2.5 at hip, spine, or forearm) (See "Overview of dual-energy x-ray absorptiometry", section on 'Skeletal site selection' and "Overview of dual-energy x-ray absorptiometry", section on 'Diagnosis of osteoporosis'.)

●Patients with low bone mass (T-score between -1.0 and -2.5) who have one or more clinical risk factors for fracture or who receive glucocorticoids as part of their maintenance immunosuppression regimen

Fracture risk may be estimated using the Fracture Risk Assessment Tool (FRAX). Although not specifically validated in kidney transplant recipients, observational data support the utility of FRAX for predicting fracture risk in this population. Some UpToDate contributors do not use FRAX routinely in kidney transplant recipients, whereas other contributors use it in individuals with low bone mineral density to help guide treatment decisions. FRAX is reviewed in detail separately. (See "Osteoporotic fracture risk assessment", section on 'Fracture risk assessment tool'.)

Medical therapy for selected patients

Approach to pharmacotherapy — In kidney transplant recipients, the optimal approach to using pharmacotherapy for the prevention of bone loss and fractures is not well established. The approach below is based upon the clinical experience of the contributors, and little high-quality evidence exists to support one approach over the other.

In general, we do not use pharmacotherapy to prevent bone loss in kidney transplant recipients, regardless of fracture risk, until chronic kidney disease-mineral and bone disorder (CKD-MBD), including persistent hyperparathyroidism (if present), has been optimally managed for 6 to 12 months. This approach allows the remodeling bone sufficient time to reach a new steady state before osteoporosis pharmacotherapy is administered. (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation", section on 'Treatment'.)

Once persistent hyperparathyroidism has been addressed, we use pharmacotherapy to prevent bone loss in kidney transplant recipients who are at high risk of fracture, as defined above. (See 'Identifying patients at high fracture risk' above.)

●High risk of fracture – For transplant recipients who are at high risk for incident fracture, the choice of pharmacotherapy is guided by a posttransplant assessment of bone turnover biomarkers. (See 'Laboratory testing' above.)

•Evidence of low bone turnover – In high-risk patients with biochemical evidence of low bone turnover (ie, C-telopeptide [CTX] and bone-specific alkaline phosphatase [BSAP] concentrations in the lower one-third of the assay-specific reference range for premenopausal females or trending down over time), some authors would initiate treatment with an active vitamin D analog (eg, calcitriol) while others would select an anabolic agent (eg, teriparatide) during the first year after transplantation. (See 'Active vitamin D analogs' below and 'Anabolic agents' below.)

•No evidence of low bone turnover – In high-risk patients without biochemical evidence of low bone turnover, some authors would treat with an antiresorptive agent (oral bisphosphonate or denosumab) during the first posttransplant year. Some experts avoid denosumab given its association with increased risk of severe hypocalcemia in patients with impaired kidney function. (See 'Oral bisphosphonates' below and 'Denosumab' below and "Osteoporosis in patients with chronic kidney disease: Management", section on 'Pretreatment evaluation'.)

Some authors of this topic prefer oral bisphosphonates in this setting due to the risk of rapid bone loss and vertebral fracture after discontinuation of denosumab. (See "Denosumab for osteoporosis", section on 'Discontinuation or delay of denosumab'.)

●Low bone mass without high risk of fracture – For transplant recipients with low bone mass who are not at high risk for incident fracture and have no evidence of low bone turnover, some authors prefer nonpharmacologic measures alone to prevent bone loss. In such transplant recipients who are receiving >5 mg/day of prednisone (or its equivalent), other authors treat with an active vitamin D analog to counteract glucocorticoid-induced impairment of calcium absorption. (See 'Active vitamin D analogs' below and 'General measures for all transplant recipients' above.)

Choice of pharmacotherapy

Active vitamin D analogs — If an oral vitamin D analog is given (algorithm 1), available options include calcitriol, alfacalcidol, doxercalciferol, and paricalcitol. (See 'Approach to pharmacotherapy' above.)

Several studies have evaluated the effects of active vitamin D analogs on bone mass in kidney transplant recipients [35-40]. Collectively, these studies suggest that treatment with active vitamin D analogs may help to prevent bone loss after kidney transplantation during the first year after transplantation. However, these agents may also increase the risk of hypercalcemia and hypercalciuria, and therefore, frequent monitoring of serum calcium is necessary [35,41]. There are no studies showing that active vitamin D analogs reduce the risk of fracture in kidney transplant recipients.

Antiresorptive agents

Oral bisphosphonates — If an oral bisphosphonate is given (algorithm 1), available options include alendronate and risedronate. (See 'Approach to pharmacotherapy' above and "Bisphosphonate therapy for the treatment of osteoporosis".)

The effects of bisphosphonates on bone outcomes in kidney transplant recipients are unclear. Some [42-44], but not all [45], studies have found that bisphosphonate therapy within the first 6 to 12 months posttransplant improves bone mineral density (BMD), especially at the lumbar spine and femoral neck [45]. However, it is not clear whether bisphosphonates reduce the risk of fracture in this population [45].

Some experts do not use bisphosphonates to prevent bone loss among kidney transplant recipients due to concerns that they may worsen low bone turnover (ie, adynamic bone disease). Low bone turnover is a form of CKD-MBD that is associated with oversuppression of parathyroid hormone (PTH). However, in kidney transplant recipients, the risk of low bone turnover with bisphosphonates is unclear and remains an area of controversy [19,45,46]. (See "Adynamic bone disease associated with chronic kidney disease".)

Denosumab — Denosumab is a monoclonal antibody to the receptor activator of nuclear factor kappa-B ligand (RANKL), an osteoclast differentiating factor, that inhibits osteoclast formation, decreases bone resorption, and increases BMD. Like oral bisphosphonates, denosumab improves BMD in kidney transplant recipients but has not been shown to reduce fracture risk in this population. (See "Denosumab for osteoporosis".)

Discontinuation of denosumab has been associated with rebound increases in bone resorption and an associated increased risk of multiple vertebral fractures, particularly in patients with prevalent vertebral fractures prior to denosumab initiation. Thus, if denosumab is discontinued, an alternative therapy (typically a bisphosphonate) should be given to prevent rapid bone loss and increased risk of vertebral fractures. (See "Denosumab for osteoporosis", section on 'Sequential osteoporosis therapy'.)

Evidence supporting the use of denosumab in kidney transplant recipients comes primarily from one randomized controlled trial and four cohort studies [47,48]. In the randomized trial, 90 de novo kidney transplant patients were randomly assigned to denosumab (60 mg subcutaneously given up to 28 days posttransplant and at six months) or to no treatment, with all patients also receiving oral calcium and vitamin D [47]. Compared with the control group, denosumab improved 12-month BMD at the lumbar spine and total hip by 5.1 and 1.9 percent, respectively. This short-term study was not designed to assess fracture risk; however, an ancillary study showed improved bone microarchitecture and estimated bone strength with denosumab [49].

Raloxifene — In postmenopausal women without evidence of CKD-MBD, the selective estrogen receptor modulator (SERM) raloxifene is also an option, although no data are available for raloxifene specifically in kidney transplant recipients. Raloxifene modestly increases BMD in patients with advanced kidney disease and reduces risk of vertebral fracture in women with postmenopausal osteoporosis. However, raloxifene has not been shown to reduce risk of nonvertebral fractures. (See "Selective estrogen receptor modulators for prevention and treatment of osteoporosis", section on 'Raloxifene'.)

Anabolic agents — If an anabolic agent is given (algorithm 1), we typically use teriparatide. Abaloparatide is a reasonable alternative, although fewer data are available for abaloparatide use in kidney transplant recipients. We do not use romosozumab (a monoclonal anti-sclerostin antibody) given the lack of efficacy data in the transplant population. Upon completion of treatment with teriparatide, antiresorptive therapy should be considered, particularly if the patient’s bone turnover is expected to rebound.(See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Management after teriparatide'.)

In a double-blind, randomized trial, 26 kidney transplant patients were treated with daily subcutaneous injections of 20 mcg of teriparatide or placebo [50]. Femoral neck BMD remained stable over six months in the teriparatide group but decreased significantly in the placebo group. Lumbar spine and radial BMD, histomorphometric bone volume, and bone matrix mineralization remained unchanged in both the groups [50].

MONITORING BONE MINERAL DENSITY

Utility of monitoring — In individuals not taking pharmacotherapy to prevent posttransplant bone loss, serial measurement of bone mineral density (BMD) can detect accelerated bone loss that may warrant medical intervention (algorithm 2). In individuals who are taking pharmacotherapy to prevent bone loss, BMD monitoring is used to assess treatment effectiveness (algorithm 3).

Bone mineral density (BMD) measurement — A dual x-ray absorptiometry (DXA) scan provides an accurate, noninvasive, and cost-effective estimation of BMD and may help to predict fracture risk in kidney transplant recipients. The authors of this topic measure BMD of the spine, hip, and forearm and make treatment decisions based upon BMD assessments at all three skeletal sites. A more detailed discussion of DXA is presented separately. (See "Overview of dual-energy x-ray absorptiometry".)

Several studies in kidney transplant recipients have found an association between osteopenia or osteoporosis demonstrated at the hip and lumbar spine by DXA and an increased risk of fracture after transplantation [51-53]. No studies demonstrate that low BMD at other skeletal sites predicts fractures in transplant recipients. However, studies have shown that peripheral skeleton BMD decreases posttransplantation [11,19], and peripheral fractures are the most common type of fracture in transplant recipients [4-6,54].

Monitoring approach — The optimal frequency of monitoring BMD in kidney transplant recipients is not known. Our approach to monitoring BMD, which is based on our clinical experience, depends on whether the patient is receiving osteoporosis pharmacotherapy to prevent bone loss. A change in BMD is considered statistically significant only if it exceeds the least significant change (LSC) for the specific densitometer used. (See "Overview of dual-energy x-ray absorptiometry", section on 'Precision assessment'.)

Patients not taking pharmacotherapy — For individuals who are not taking osteoporosis pharmacotherapy to prevent posttransplant bone loss, the approach to monitoring depends on estimated fracture risk (algorithm 2). (See 'Identifying patients at high fracture risk' above.)

●With high fracture risk – In patients who are determined to be at high risk of incident fracture, we repeat BMD measurement with DXA one year posttransplant to assess the stability of BMD and the response to nonpharmacologic measures. (See 'General measures for all transplant recipients' above.)

●Without high fracture risk – In patients who are not determined to be at high risk of incident fracture, we repeat BMD measurement with DXA two years posttransplant and continue nonpharmacologic measures to prevent bone loss. (See 'General measures for all transplant recipients' above.)

Subsequent monitoring and management are guided by the results of the repeat DXA and development of interim fragility fracture:

●BMD stable or increased – In patients with stable or increased BMD (based on the least LSC for the instrument used), we continue nonpharmacologic measures and consider increasing the time interval between DXA scans.

●BMD decreased or interim fragility fracture – In patients with interim fracture and/or a significant decrease in BMD (based on the LSC for the instrument used), we assess for adherence to general measures for preventing bone loss. We also evaluate for the interim development of secondary causes of bone loss (eg, severe hyperparathyroidism, celiac disease, hyperthyroidism) (table 2). Such conditions, if identified, should be treated with the appropriate therapy. (See 'General measures for all transplant recipients' above.)

In patients in whom secondary causes of bone loss are excluded or cannot be mitigated, we typically initiate osteoporosis pharmacotherapy if any of the following apply:

•Continued glucocorticoid therapy of prednisone >5 mg daily (or equivalent)

•Severe bone loss is apparent (eg, T-score ≤-2.5) or

•Interim fragility fracture

For such patients, the choice of pharmacotherapy is based on the assessment of bone turnover and kidney allograft function. This assessment and the choice of pharmacotherapy are reviewed in detail below. (See 'Treatment of posttransplant osteoporosis' below.)

If the patient is on low-dose or no glucocorticoid therapy, has not sustained a fragility fracture, and has no evidence of severe bone loss, we continue to monitor and repeat BMD measurement in one to two years.

Patients taking pharmacotherapy — All patients taking osteoporosis pharmacotherapy should undergo repeat BMD measurement with DXA one year after initiation of pharmacotherapy to reassess BMD (algorithm 3).

Subsequent monitoring and management are guided by the results of the repeat DXA and development of interim fragility fracture:

●BMD stable or increased – In patients on osteoporosis pharmacotherapy, the decision to continue treatment is based primarily on the patient’s BMD. Regardless of BMD, however, if a patient has been taking bisphosphonates for five years they should discontinue the bisphosphonates, due to increased risk of atypical fractures.

•If the T-score is >-2.5 at all skeletal sites, we generally discontinue osteoporosis pharmacotherapy. However, the decision to discontinue osteoporosis pharmacotherapy should always be individualized based on estimated fracture risk, including non-BMD risk factors for fracture. In patients with major non-BMD risk factors for fracture (eg, continued glucocorticoid therapy >5 mg/day of oral prednisone), continued pharmacotherapy may be warranted. (See 'Risk factors' above.)

If pharmacotherapy is discontinued and the patient was on denosumab during the first posttransplantation year, consolidation therapy with an oral bisphosphonate should be initiated to prevent loss of accrued bone mass; consolidation therapy should be continued for at least 12 months. For patients treated with an anabolic agent (teriparatide or abaloparatide), UpToDate contributors have varying approaches. Some contributors uniformly follow treatment with consolidation therapy, whereas others follow patients with bone turnover markers and BMD measurement and initiate bisphosphonate therapy only if bone loss is evident. We typically remeasure BMD in one to two years. (See "Denosumab for osteoporosis", section on 'Sequential osteoporosis therapy' and "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Management after teriparatide'.)

•If the T-score is ≤-2.5 at any skeletal site, we continue osteoporosis pharmacotherapy and remeasure BMD in one year. There are no data in kidney transplant recipients on the optimal time to discontinue therapy. Our practice is to continue therapy until the T-score at all skeletal sites is >-2.5. For some patients with severe osteoporosis, it may take several years to reach an adequate T-score. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Duration of therapy'.)

●BMD decreased or interim fragility fracture – In patients taking osteoporosis pharmacotherapy for at least 12 months who have a significant loss of BMD (based on the LSC for the instrument used) and/or an interim fragility fracture, we assess treatment adherence and evaluate for the interim development of secondary causes of bone loss (eg, severe hyperparathyroidism, celiac disease, hyperthyroidism) (table 2).

•Treatment nonadherence and/or remediable secondary cause(s) of bone loss – Patients who have not been adherent to therapy or have been taking it incorrectly should continue current treatment for another 12 months if factors contributing to nonadherence or incorrect administration can be addressed. Any remediable cause(s) of bone loss should be addressed. A repeat DXA should be performed in one to two years to reassess BMD.

If treatment nonadherence or improper administration cannot be addressed, the patient should transition to an alternative regimen (eg, switching from an oral bisphosphonate to intravenous [IV] zoledronic acid).

•No remediable cause(s) of bone loss – In patients who have been adherent to therapy and do not have a remediable secondary cause of bone loss, the approach to management depends on BMD and the presence of fragility fracture(s).

-Fragility fracture or T-score ≤-2.5 – If the patient sustains a fragility fracture ≥12 months after pharmacotherapy initiation or has a T-score ≤-2.5 at any site, we switch to a more potent pharmacotherapy regimen. For patients taking oral bisphosphonates, we typically switch to an intravenous bisphosphonate (if there are concerns for poor gastrointestinal absorption of the oral bisphosphonate) or denosumab and repeat BMD measurement in one to two years. Anabolic therapy (eg, teriparatide, abaloparatide) is a reasonable alternative.

-No fragility fracture and T-score >-2.5 – In patients taking an oral bisphosphonate with apparent bone loss but without interim fragility fracture or T-score ≤-2.5 at any site, we measure bone turnover markers (BTMs; C-telopeptide [CTX] and bone-specific alkaline phosphatase [BSAP]) to assess medication absorption. Suppressed BTMs (ie, in the lower one-third of the reference range for premenopausal females) provide evidence of treatment effectiveness. In such cases, we generally continue current oral bisphosphonate treatment and remeasure BMD in one year.

If BTMs are not suppressed, we switch to an alternative regimen, usually IV zoledronic acid. Denosumab is a reasonable alternative. We remeasure BMD in one to two years.

TREATMENT OF POSTTRANSPLANT OSTEOPOROSIS — 

Posttransplant osteoporosis is defined as osteoporosis that is diagnosed at least 12 months after transplantation. In the first year posttransplant, there are dynamic changes in bone physiology including attenuation of prior chronic kidney disease-mineral bone disorder (CKD-MBD) that must be considered when making treatment decisions to prevent bone loss. After one year posttransplant, management decisions are similar to those made in nontransplant populations with and without chronic kidney disease and are informed primarily by the state of bone turnover and underlying kidney function.

The optimal approach to transplant recipients who are found to have osteoporosis after kidney transplantation is not known. We take the following approach (algorithm 4):

●General measures to prevent bone loss – All transplant recipients who have evidence of osteoporosis should receive general measures to prevent bone loss, as discussed elsewhere in this topic. (See 'General measures for all transplant recipients' above.)

●Address persistent hyperparathyroidism, vitamin D deficiency, and/or hypophosphatemia – Additional measures depend upon whether or not patients have persistent hyperparathyroidism, vitamin D deficiency, and/or hypophosphatemia, all of which may be observed after transplantation. These conditions should be treated before considering additional medical therapies for osteoporosis. (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation", section on 'Treatment'.)

If hyperparathyroidism, vitamin D deficiency, and/or hypophosphatemia are present, we wait at least 6 to 12 months after these conditions have been adequately managed to reassess bone mineral density (BMD) and fracture risk.  

●Assess risk of low-turnover bone disease – After persistent hyperparathyroidism and/or hypophosphatemia have been addressed, we assess the risk of underlying low-turnover bone disease (ie, adynamic bone disease). Antiresorptive agents should not be used in patients with low-turnover bone disease [55]. (See "Adynamic bone disease associated with chronic kidney disease".)

Bone biopsy with double-tetracycline labeling is the gold standard for the diagnosis of low-turnover bone disease. However, bone biopsies are not frequently performed, as few centers have the expertise to properly process and analyze bone biopsy specimens. Thus, to identify patients who have low-turnover bone disease, we use a combination of serum parathyroid hormone (PTH), C-telopeptide (CTX), and bone-specific alkaline phosphatase (BSAP) [56,57]. We identify patients as having low-turnover bone disease if the serum PTH and BSAP are at the lower limit or below the reference range for the premenopausal population as provided by the specific laboratory. In one study, the combination of PTH of <79 pg/mL and BSAP isoenzyme of <12.9 mcg/L was shown to have a predictive value for low-turnover bone disease of 88.9 percent [56].

Patients with indeterminate levels of PTH and BSAP may be considered for bone biopsy prior to treatment for osteoporosis if knowledge of the type of renal osteodystrophy will impact treatment decisions [58]. Patients who need bone biopsy should be referred to centers that have expertise in performing and interpreting bone biopsies. (See "Evaluation of renal osteodystrophy", section on 'Bone biopsy for selected patients'.)

●Approach to pharmacotherapy – Our approach to additional medical therapy for posttransplant osteoporosis depends on factors such as the presence or absence of low-turnover bone disease, the patient’s kidney allograft function, and whether the patient is receiving glucocorticoid therapy.

•Evidence of low-turnover bone disease – In patients with evidence of low-turnover bone disease, antiresorptive therapy (eg, bisphosphonates, denosumab) is contraindicated. For such patients, an anabolic agent (eg, teriparatide) is a potential alternative, but experience in transplant recipients is limited. Teriparatide exerts anabolic effects on the skeleton and has been shown to increase BMD and lower the risk of vertebral fractures in patients with glucocorticoid-induced osteoporosis [59]. (See "Osteoporosis in patients with chronic kidney disease: Management", section on 'Teriparatide'.)

Romosozumab prevents fractures in patients with osteoporosis but has not been studied in this population.  More data are needed about potential effects on vascular calcification and cardiovascular risk. (See "Osteoporosis in patients with chronic kidney disease: Management", section on 'Romosozumab' and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Romosozumab'.)

•No evidence of low-turnover bone disease – In patients without evidence of low-turnover bone disease, the approach to pharmacotherapy is guided by the patient’s allograft function (estimated glomerular filtration rate [eGFR]) and use of glucocorticoids.

-eGFR ≥30 mL/min/1.73 m² - If the eGFR is ≥30 mL/min/1.73 m², the choice of pharmacotherapy depends upon whether or not the patient is receiving glucocorticoids for maintenance immunosuppression. Patients receiving glucocorticoids should be treated similarly to patients with glucocorticoid-induced osteoporosis, as discussed separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Choice of therapy'.)

Patients not receiving glucocorticoids can be treated similarly to nontransplant patients with osteoporosis, as discussed separately. (See "Evaluation and treatment of premenopausal osteoporosis", section on 'Pharmacologic therapy for selected women' and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Choice of initial therapy' and "Treatment of osteoporosis in men", section on 'Choice of therapy'.)

-eGFR <30 mL/min/1.73 m² - If the eGFR is <30 mL/min/1.73 m², the choice of pharmacotherapy is the same as that for individuals with advanced chronic kidney disease (CKD) who have osteoporosis. In such patients, an oral bisphosphonate or denosumab is generally preferred. Some experts avoid denosumab given its association with increased risk of severe hypocalcemia in patients with impaired kidney function. This is discussed in more detail elsewhere. (See "Osteoporosis in patients with chronic kidney disease: Management", section on 'Estimated glomerular filtration rate <30 mL/min'.)

OTHER FORMS OF POSTTRANSPLANT BONE DISEASE

Osteonecrosis — Osteonecrosis (avascular or ischemic necrosis) is probably the most debilitating of the musculoskeletal complications following transplantation [60-63]. (See "Treatment of nontraumatic hip osteonecrosis (avascular necrosis of the femoral head) in adults".)

●Incidence – The risk of osteonecrosis is higher among transplant recipients compared with the nontransplant population, although the reported incidence has decreased over the past several decades. Previous studies suggested an incidence of approximately 15 percent within three years of transplantation [61-63]. However, in a historic cohort study of over 40,000 kidney transplant recipients, the incidence of hospitalization due to osteonecrosis was seven episodes per 1000 person-years [64].

●Risk factors – Among transplant recipients, factors that contribute to osteonecrosis include uremic-induced defects in mineral metabolism and immunosuppressive medications. Glucocorticoids play a central role. Some, though not all, studies have suggested an association between cyclosporine use and osteonecrosis [65,66]. Osteopenia and hyperparathyroidism may also contribute [60].

●Clinical presentation – Pain is the most common presentation of osteonecrosis. As in the nontransplant population, the weight-bearing long bones are most often affected, particularly the femoral head; however, among transplant recipients, osteonecrosis is commonly multifocal, with 50 to 70 percent of patients having more than one bone involved.

The clinical presentation, diagnosis, and treatment of osteonecrosis are discussed elsewhere. (See "Treatment of nontraumatic hip osteonecrosis (avascular necrosis of the femoral head) in adults", section on 'Introduction'.)

Bone pain and cyclosporine — In addition to osteopenia and osteonecrosis, a different bone pain syndrome has been described in patients receiving cyclosporine (and, perhaps, tacrolimus [67]) and is often temporally related to increased plasma cyclosporine levels [68]. The mechanism by which this occurs and its possible relation to the development of osteonecrosis are not clear, but intraosseous vasoconstriction and hypertension may play a role. There are characteristic magnetic resonance imaging (MRI) findings that are consistent with edema and subclinical trauma [69,70]. Administration of calcium channel blockers (such as sustained-release nifedipine, 30 to 60 mg before bedtime) and a reduction in the calcineurin inhibitor dose appear to relieve the symptoms in most patients [68].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease-mineral and bone disorder".)

SUMMARY AND RECOMMENDATIONS

●Bone loss after kidney transplantation – Bone loss often occurs rapidly following kidney transplantation, but thereafter the trajectory of bone loss is highly variable and depends, in part, on the dose and duration of glucocorticoid treatment. (See 'Epidemiology and risk factors' above.)

●Initial evaluation of fracture risk – In all kidney transplant recipients, we advocate for early assessment of osteoporosis and fracture risk. Some transplant centers perform the initial evaluation prior to transplantation, whereas others perform the evaluation within the first few months after transplantation. (See 'Initial evaluation of fracture risk' above.)

•Clinical assessments – In all transplant recipients, we assess for clinical risk factors for bone loss and fracture. (See 'Clinical assessment' above.)

•Laboratory tests – At two to four weeks after transplantation, or when kidney allograft function stabilizes, we measure serum calcium, phosphorus, parathyroid hormone (PTH), and 25-hydroxyvitamin D levels. In addition, some authors obtain fasting morning serum concentrations of bone turnover markers (BTMs), including C-telopeptide (CTX) and bone-specific alkaline phosphatase (BSAP). (See 'Laboratory testing' above.)

•Imaging – We obtain a dual x-ray absorptiometry (DXA) scan of the hip, spine, and forearm either prior to transplantation or as soon as possible within the first three months after transplantation to assess bone mineral density (BMD). We also obtain imaging of the lumbar and thoracic spine to evaluate for subclinical vertebral fracture(s). (See 'Imaging studies' above.)

●Prevention of posttransplant bone loss

•General measures – General measures to prevent posttransplant bone loss include the following (algorithm 1): (See 'General measures for all transplant recipients' above.)

-Lifestyle measures (eg, weight-bearing exercise, smoking cessation)

-Minimizing the glucocorticoid dose

-Ensuring adequate calcium intake and vitamin D sufficiency

-Treating persistent hyperparathyroidism

•Identifying patients at high risk for fracture – We consider the following patients to be at high risk of incident fracture: (See 'Identifying patients at high fracture risk' above.)

-Patients with a history of low-trauma fracture (including radiologic evidence of vertebral fracture)

-Patients with osteoporosis by BMD criteria (T-score ≤-2.5 at hip, spine, or forearm)

-Patients with low bone mass (T-score between -1.0 and -2.5) who have one or more clinical risk factors for fracture or who receive glucocorticoids as part of their maintenance immunosuppression regimen

Fracture risk may be estimated using the Fracture Risk Assessment Tool (FRAX). Although not specifically validated in kidney transplant recipients, observational data support the utility of FRAX for predicting fracture risk in this population.

•Pharmacotherapy for selected patients – In general, we do not use pharmacotherapy to prevent bone loss in kidney transplant recipients until chronic kidney disease-mineral and bone disorder (CKD-MBD), including persistent hyperparathyroidism (if present), has been optimally managed for 6 to 12 months. This approach allows the remodeling bone sufficient time to reach a new steady state before osteoporosis pharmacotherapy is administered.

For transplant recipients who are considered to be at high risk for incident fracture, the choice of pharmacotherapy depends on whether a state of high or low bone turnover is present (algorithm 1). (See 'Medical therapy for selected patients' above.)

●Monitoring BMD – In individuals not taking pharmacotherapy to prevent posttransplant bone loss, serial measurement of BMD can detect accelerated bone loss that may warrant medical intervention. In individuals who are taking pharmacotherapy to prevent bone loss, BMD monitoring is used to assess treatment effectiveness (algorithm 2 and algorithm 3). (See 'Monitoring bone mineral density' above.)

●Treatment of posttransplant osteoporosis – Posttransplant osteoporosis is defined as osteoporosis that is diagnosed at least 12 months after transplantation. In the first year posttransplant, there are dynamic changes in bone physiology including attenuation of prior CKD-MBD that must be considered when making treatment decisions to prevent bone loss. Persistent hyperparathyroidism, vitamin D deficiency, and/or hypophosphatemia should be treated before considering additional medical therapies for osteoporosis. After one year posttransplant, management decisions are similar to those made in nontransplant populations. (See 'Treatment of posttransplant osteoporosis' above.)

Our approach to additional medical therapy for posttransplant osteoporosis depends on factors such as the presence or absence of low-turnover bone disease, the patient’s kidney allograft function, and whether the patient is receiving glucocorticoid therapy (algorithm 4).

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges David W Butterly, MD, who contributed to earlier versions of this topic review.