Kidney transplantation in adults: 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].

Because of their longstanding history of chronic kidney disease (CKD), kidney transplant recipients are also vulnerable to persistent hyperparathyroidism and the mineral and bone disorders of chronic kidney disease (CKD-MBD). The evaluation and treatment of osteoporosis are made more complex because of CKD-MBD.

This topic reviews the diagnosis, monitoring, and treatment of osteoporosis and osteonecrosis among 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 non-kidney transplant recipients is discussed elsewhere. (See "Prevention and treatment of osteoporosis after solid organ or stem cell transplantation".)

PATHOGENESIS AND RISK FACTORS — Bone loss occurs rapidly following transplantation of the kidney and other organs. A study published in 2012 reported that recipients managed with glucocorticoids experienced a 2.9 percent bone loss at the spine over the first six months after kidney transplantation [4]. Following an initial period of rapid bone loss, bone loss may continue at a slower rate or stabilize. One longitudinal study of 70 kidney transplant recipients published in 1996 reported a mean rate of bone loss of 1.7 percent per year over a mean time of 8.1 years after transplantation [5]. However, more contemporary studies suggest that after the first posttransplant year, on average, bone density remains stable [6-13].

Bone loss is principally due to a reduction in trabecular bone mass, although cortical bone may also be affected [1,3,14-18]. Fractures can occur in either peripheral or central locations, although some evidence suggests that peripheral fractures (involving hands, ankles, and feet) may be more common [19-21].

Bone loss after kidney transplantation is primarily related to the use of glucocorticoids and other immunosuppressive medications [1,3,6,11,14,15,22,23] but may also reflect changes associated with prior renal osteodystrophy. Other risk factors include hyperparathyroidism, diabetes mellitus, posttransplant metabolic acidosis, and receiving a kidney/pancreas transplant [1,17,24-26]. Persistent hyperparathyroidism may contribute to the higher fracture risk in kidney transplant recipients compared with other solid organ recipients [27]. (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation".)

Additional risk factors include those present in the general population, including low testosterone levels in males (which may be induced by glucocorticoids and uremia), genetic predisposition, lifestyle factors (eg, smoking and lack of exercise), and impaired nutrition due, for example, to low dietary calcium intake or excess alcohol ingestion [28]. As in nontransplant patients, the use of proton pump inhibitors has also been associated with an increased risk of hip fracture among kidney transplant recipients [29], but their effects on bone density after kidney transplantation are unclear [29,30]. (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'.)

Major risk factors for osteoporosis are discussed here:

●Glucocorticoids – Among transplant recipients, glucocorticoid-induced suppression of bone formation is the most important risk factor for bone loss [5,24,31]. Glucocorticoids are directly toxic to osteoblasts and lead to increased osteoclast activity [32]. Glucocorticoids also have other effects that promote negative calcium balance and osteoporosis. These effects include decreased calcium absorption in the gut, reduced gonadal hormone production, diminished insulin-like growth factor 1 production, decreased sensitivity to parathyroid hormone (PTH), increased activity of nuclear factor kappa-beta ligand (RANKL), and increased osteoclastogenesis [1,24,32]. The lower rates of bone loss following kidney transplantation documented in recent years may reflect the lower doses of glucocorticoids used to treat these patients [4,12,15,17,22]. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

●Calcineurin inhibitors – Cyclosporine may contribute to bone loss among patients treated with glucocorticoids [1,33-35], although this may not occur in patients who are not treated with glucocorticoids [36]. (See "Drugs that affect bone metabolism", section on 'Cyclosporine'.)

The effect of tacrolimus on bone mineral density (BMD) in transplant patients is uncertain. Although one study suggested that tacrolimus had similar effects as cyclosporine on BMD [6], other studies have not shown this, possibly because the use of tacrolimus permitted lower doses of glucocorticoids [37,38]. However, one small study found that kidney transplant recipients with higher blood concentrations of tacrolimus (≥6 mg/mL) had lower BMD compared with those who had lower blood concentrations (<6 ng/mL), suggesting a possible dose-related effect of tacrolimus on bone loss [39].

●Persistent hyperparathyroidism – Persistent hyperparathyroidism occurs in approximately 15 to 50 percent of patients after transplantation and is associated with cortical bone loss and fractures [17,25]. In one retrospective study, PTH of >130 ng/L three months posttransplant was an independent risk factor for fractures [25]; however, another study found no association between PTH levels and posttransplant fracture risk [40]. Another retrospective study found that more intensive treatment of the mineral and bone disorders of chronic kidney disease (CKD-MBD) prior to transplantation was associated with lower rates of persistent hyperparathyroidism and fewer fractures in the first year after transplantation [41]. (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation".)

EVALUATION OF OSTEOPOROSIS AND FRACTURE RISK

Our approach to screening and monitoring kidney transplant candidates — We screen all kidney transplant candidates for osteoporosis and fracture risk prior to transplantation. Our approach is as follows:

●We measure serum parathyroid hormone (PTH) and 25-hydroxyvitamin D levels.

●We use dual-energy x-ray absorptiometry (DXA) to assess bone mineral density (BMD) of the hip, spine, and forearm. In deceased donor kidney transplant candidates, we perform the DXA scan at the time of initial transplant evaluation. In living donor kidney transplant candidates, we perform the DXA scan at the time of preoperative evaluation for surgery. Patients who have evidence of osteoporosis by DXA assessment (defined by a T-score of ≤-2.5) on the initial screen prior to transplantation are treated the same as nontransplant candidate chronic kidney disease (CKD) patients with osteoporosis. (See 'Bone mineral density (BMD) assessment' below and "Osteoporosis in patients with chronic kidney disease: Management".)

Among deceased donor kidney transplant candidates who do not have evidence of osteoporosis or osteopenia on the initial screen and do not develop a fracture while on the transplant waiting list, we repeat DXA every two years. In those patients who do not have a DXA scan in the year prior to transplant, we obtain a repeat DXA scan as soon as possible within the first three months after transplantation.

●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. (See "Overview of dual-energy x-ray absorptiometry", section on 'Vertebral fracture assessment'.)

●We assess for the presence of traditional clinical risk factors (table 1) as well as posttransplant risk factors for fracture [42]. Posttransplant risk factors include the following:

•Age of >50 years

•Female gender

•Low body weight (weight of <127 pounds or body mass index [BMI] of <20 kg/m²)

•Family history of osteoporosis

•Pretransplant low-trauma fracture (associated with trauma equivalent to a fall from standing height or less)

•Deceased donor transplantation

•Pretransplant diabetes or end-stage kidney disease caused by diabetic nephropathy

•Pretransplant dialysis

•Pretransplant glucocorticoid exposure

•Planned posttransplant glucocorticoid therapy

At two to four weeks after transplantation, or when kidney allograft function stabilizes, we measure serum calcium, phosphate, PTH, and 25-hydroxyvitamin D levels. In addition, some authors obtain fasting morning serum concentrations of bone turnover markers (BTMs), including C-telopeptide crosslink (CTX) and bone-specific alkaline phosphatase (BSAP) [17,43,44]. (See "Bone physiology and biochemical markers of bone turnover", section on 'Markers of bone turnover'.)

Based upon our initial pre- and posttransplant evaluations, we consider the following patients to be at high risk of incident fracture:

●Patients with a history of pretransplant low-trauma fracture or radiologic evidence of vertebral fracture

●Patients with osteoporosis (T-score of ≤-2.5)

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

In patients who are determined to be at high risk of incident fracture, we monitor DXA annually in order to assess the stability of BMD and the response to treatment. (See 'Prevention of osteoporosis' below and 'Treatment of osteoporosis' below.)

In patients who are not determined to be at high risk of incident fracture, we rescreen by DXA every two years and use preventive measures. (See 'Prevention of osteoporosis' below.)

Bone mineral density (BMD) assessment — A DXA scan provides an accurate, noninvasive, and cost-effective estimation of BMD and may help to predict fracture risk in kidney transplant recipients. 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 [40,45,46]. There are no studies demonstrating that low BMD at other skeletal sites predicts fractures in transplant recipients. However, studies have shown that peripheral skeleton BMD decreases posttransplantation [12,17], and peripheral fractures are the most common type of fracture in transplant recipients [19-21,47]. Thus, the authors of this topic make treatment decisions based upon BMD assessments at all skeletal sites.

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 2) [48]. (See "Overview of dual-energy x-ray absorptiometry", section on 'Diagnosis of osteoporosis'.)

A more detailed discussion of DXA is presented separately. (See "Overview of dual-energy x-ray absorptiometry".)

Role of bone biopsy — Bone biopsy with double-tetracycline labeling is the gold standard for the diagnosis of posttransplant bone disease in kidney transplant recipients. However, bone biopsies are not frequently performed, as few centers have the expertise to properly process and analyze bone biopsy specimens. The indications for performing a bone biopsy in kidney transplant recipients are not well established. If possible, a bone biopsy should be performed in patients with severe osteoporosis, frequent fractures, or persistent bone pain to rule out adynamic bone disease prior to initiating treatment with antiresorptive therapy. (See 'Treatment of osteoporosis' below.)

A more detailed discussion of bone biopsy is presented separately. (See "Evaluation of renal osteodystrophy".)

PREVENTION OF OSTEOPOROSIS

Our approach to the prevention of osteoporosis — The optimal approach to the prevention of bone loss and fractures among kidney transplant recipients is unknown. Many interventions are similar to those used in the general population to prevent osteoporosis.

Among all transplant recipients who have a normal bone mineral density (BMD) or osteopenia, we do the following:

●We encourage lifestyle changes. (See 'Lifestyle changes' below.)

●We maintain the lowest possible glucocorticoid dose. (See 'Glucocorticoid dose minimization' below.)

●Provided the serum calcium is normal, we treat with calcium and vitamin D3. (See 'Calcium and vitamin D3' below.)

●We treat persistent hyperparathyroidism. (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation", section on 'Treatment'.)

Among transplant recipients with osteopenia who are considered to be at high risk for incident fracture, as defined above (see 'Our approach to screening and monitoring kidney transplant candidates' above), some, but not all, contributors to this topic would treat with additional therapies to prevent bone loss, guided by a posttransplant assessment of bone turnover biomarkers:

●In high-risk patients with biochemical evidence of low bone turnover (ie, C-telopeptide crosslink [CTX] and bone-specific alkaline phosphatase [BSAP] concentrations in the lower one-third of the normal range for premenopausal women as provided by the specific laboratory), some authors would treat with an active vitamin D analog (eg, calcitriol) while others would treat with teriparatide for the first year after transplantation. (See 'Active vitamin D analogs' below.)

●In high-risk patients with biochemical evidence of normal or high bone turnover (ie, CTX and BSAP concentrations in the upper two-thirds of the normal range or above the normal range for premenopausal women as provided by the specific laboratory), some authors would treat with an oral bisphosphonate (either alendronate or risedronate) or denosumab during the first posttransplant year (see 'Bisphosphonates' below and 'Denosumab' below). After the first year, the subsequent approach is as follows:

•All patients who have received bisphosphonate therapy or denosumab should have a dual-energy x-ray absorptiometry (DXA) scan performed at 12 months posttransplantation to reassess BMD.

-In patients with stable BMD or in whom BMD increased, the decision to continue bisphosphonate or denosumab treatment is based upon whether glucocorticoids are being administered as maintenance immunosuppression and, if so, the dose of glucocorticoids. Patients who are on 5 mg/day or less of oral prednisone (or 4 mg/day or less of prednisolone) can discontinue bisphosphonate or denosumab therapy. If the patient was on denosumab during the first posttransplantation year, consolidation therapy with an oral bisphosphonate should be initiated to prevent loss of bone mass accrued on denosumab; bisphosphonates should be continued for at least 12 months. Those who are on more than 5 mg/day of oral prednisone (or more than 4 mg/day of prednisolone) can continue bisphosphonates or denosumab for another 12 months, and a repeat DXA scan should be performed at the completion of therapy to reassess BMD.

-In patients who have a significant loss of BMD (see "Overview of dual-energy x-ray absorptiometry", section on 'Precision assessment'), adherence to therapy should be assessed. Patients who have not been adherent to therapy or have been taking it incorrectly should continue treatment with bisphosphonates or denosumab for another 12 months, after factors contributing to nonadherence or incorrect administration have been addressed, and a repeat DXA should be performed at the completion of therapy to reassess BMD.

Patients who have been adherent to therapy should be evaluated for other causes of bone loss (eg, severe hyperparathyroidism, multiple myeloma, celiac disease, and hyperthyroidism). Such conditions, if identified, should be treated with the appropriate therapy. If no such conditions are identified, bisphosphonates or denosumab can be continued for another 12 months, and a repeat DXA should be performed at the completion of therapy to reassess BMD.

•In patients who develop a fragility fracture while receiving bisphosphonate or denosumab therapy (ie, prior to completing 12 months of treatment), adherence to therapy and mode of self-administration for oral bisphosphonates should be assessed. In addition, a DXA scan should be performed at the time of the fracture to evaluate BMD.

-Patients who have not been adherent to therapy should continue treatment with bisphosphonates or denosumab for another 12 months after factors contributing to nonadherence have been addressed, and a repeat DXA should be performed at the completion of therapy to reassess BMD.

-Patients who have been adherent to therapy should be evaluated for other causes of bone loss (eg, severe hyperparathyroidism, multiple myeloma, celiac disease, hyperthyroidism). Such conditions, if identified, should be treated with the appropriate therapy. If no such conditions are identified, subsequent treatment depends upon assessment of BMD. Patients with stable BMD can continue bisphosphonates or denosumab for another 12 months, and a repeat DXA should be performed at the completion of therapy to reassess BMD. Patients with a significant loss of BMD (see "Overview of dual-energy x-ray absorptiometry", section on 'Precision assessment') who are on an oral bisphosphonate should discontinue the bisphosphonate and initiate treatment with either an intravenous bisphosphonate (if prior treatment with an oral bisphosphonate was used), denosumab, or teriparatide if no contraindications to their use exist. Significant bone loss on denosumab is unusual, so if this occurs, patients should be reassessed for other causes of bone loss. (See 'Denosumab' below and 'Teriparatide' below and "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Contraindications/precautions'.)

Among transplant patients with osteopenia who are not considered to be at high risk for incident fracture and have evidence of normal or high bone turnover, some, but not all, contributors to this topic would treat with an active vitamin D analog.

However, other authors and editors of this topic do not use bisphosphonates, denosumab, teriparatide, or active vitamin D analogs to prevent bone loss in kidney transplant recipients, regardless of their fracture risk, until renal osteodystrophy has been optimally managed and persistent hyperparathyroidism (if present) has been treated. This approach allows the remodeling bone sufficient time to reach a new steady state before an antiresorptive agent is administered. Both of these approaches are based upon the clinical experience of the contributors, and there is little high-quality evidence to support one approach over the other.

Lifestyle changes — 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, early mobilization after transplantation, and fall prevention, which are beneficial for skeletal health. (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. However, we stress that significant osteoporosis has been observed with prednisone doses as low as 7.5 to 10 mg/day [19,28,49], and bone loss occurs even in patients on early corticosteroid withdrawal protocols. (See "Prevention and treatment of osteoporosis after solid organ or stem cell transplantation".)

Medical therapy

Calcium and vitamin D3 — Patients with normal serum calcium should receive calcium and vitamin D3 (cholecalciferol). The optimal dose is not known. We aim for a total calcium intake of 1000 mg/day, preferably from food, and we use calcium supplements in an additive manner to achieve this goal. We give vitamin D3 to target a serum 25-hydroxyvitamin D level of >30 ng/mL. (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Calcium and vitamin D'.)

There are few data concerning the effectiveness of vitamin D3 alone in the prevention of posttransplant bone loss [50]. One randomized trial suggested that the addition of vitamin D3 to calcium provides no significant additional benefit to calcium alone [50]. However, in the absence of hypercalcemia, vitamin D3 administration is relatively safe, and there is a concern that calcium given without vitamin D may be poorly absorbed among individuals who are taking glucocorticoids. (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Calcium and vitamin D'.)

We do not give calcium and vitamin D to patients who are hypercalcemic [51]. Unlike with recipients of other solid organs, hypercalcemia is not uncommon among kidney transplant recipients, because of persistent hyperparathyroidism. (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation", section on 'Hypercalcemia'.)

Active vitamin D analogs — The contributors to this topic do not agree on the use of active vitamin D analogs to prevent bone loss in kidney transplant recipients. Some authors would give an active vitamin D analog to patients who are at high risk of incident fracture and have low levels of bone turnover biomarkers. In addition, these authors would give an active vitamin D analog to patients who are not at high risk of fracture and have normal to high levels of bone turnover biomarkers. However, other authors would not give active vitamin D analogs, because of the concern that they will cause hypercalcemia or hypercalciuria. (See 'Our approach to the prevention of osteoporosis' above.)

Several studies have evaluated the effects of active vitamin D analogs on bone mass in kidney transplant recipients [52-57]. Collectively, these studies suggest that treatment with active vitamin D analogs may help to prevent bone loss after kidney transplantation. However, these agents may also increase the risk of hypercalcemia and hypercalciuria, and therefore, frequent monitoring of serum calcium is necessary [52,58].

Bisphosphonates — The benefit of bisphosphonates in the prevention of osteoporosis among kidney transplant recipients is unclear, and the authors and editors of this topic do not agree on the use of these agents in such patients. (See 'Our approach to the prevention of osteoporosis' above.)

Some experts do not use bisphosphonates to prevent bone loss among kidney transplant recipients due to concerns that they may worsen low-turnover (ie, adynamic) bone disease. Low-turnover bone disease is a mineral and bone disorder of chronic kidney disease (CKD-MBD) that is associated with oversuppression of parathyroid hormone (PTH). However, the risk of low-turnover bone disease with bisphosphonates is unclear and has not been consistently observed [12,59,60]. (See "Adynamic bone disease associated with chronic kidney disease".)

Some studies have suggested that bisphosphonates may provide a benefit [61-73]. These studies include the following:

●A 2017 systematic review and meta-analysis of 13 randomized, controlled trials (9850 patients) evaluated the efficacy and safety of bisphosphonates and other osteoporosis medications among patients with chronic kidney disease (CKD), including kidney transplant recipients (six trials, 541 patients) [74]. Treatment of kidney transplant recipients with bisphosphonates (pamidronate, ibandronate, or risedronate; four trials, 382 patients), compared with treatment without bisphosphonates or with placebo, reduced the loss of lumbar spine BMD but did not consistently reduce the loss of femoral neck BMD at 12 to 24 months. There was no significant difference in the risk of vertebral fractures between patients treated with or without bisphosphonate therapy, although the meta-analysis was not sufficiently powered to detect a difference in fracture risk in kidney transplant recipients. One trial that was included in the analysis compared treatment with ibandronate versus risedronate and found no significant differences in the change in lumbar spine or femoral neck BMD between these agents.

●Similar findings were reported by three separate meta-analyses of kidney transplant recipients treated with or without bisphosphonates [68,72,75]. These studies, which also included older trials that were not included in the systematic review discussed above, found that bisphosphonate therapy within the first six months posttransplant, compared with treatment without bisphosphonates, improved lumbar spine and femoral neck BMD. However, the risk of vertebral fractures was not different between the treatment groups.

●In a systematic review of 45 randomized, controlled trials and quasi-randomized, controlled trials (2698 patients), no individual intervention (including bisphosphonates, vitamin D compounds, teriparatide, denosumab, cinacalcet, parathyroidectomy, or calcitonin) reduced fracture risk compared with placebo [59]. However, there was a trend toward benefit with bisphosphonate therapy administered over 12 months, compared with placebo (relative risk [RR] 0.62, 95% CI 0.38-1.01).

The effect of bisphosphonates on BMD may be site specific. As an example, in a systematic review of 1209 patients, treatment with bisphosphonates increased BMD in the lumbar spine and femoral neck, but not the total hip [69].

Among transplant recipients, it is not clear whether antiresorptive therapy has an effect on the overall number of fractures [59]. However, trials that have evaluated bisphosphonates were not powered for fracture outcomes [69,76,77].

Denosumab — Some authors of this topic give denosumab as first-line therapy for patients at high fracture risk or who have progressive decreases in BMD despite management of posttransplant hyperparathyroidism, minimization of glucocorticoid use, and supplementation with calcium and vitamin D. Other authors reserve the use of denosumab for patients who do not respond to initial treatment with a bisphosphonate. (See 'Our approach to screening and monitoring kidney transplant candidates' above.)

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, as suggested for other forms of osteoporosis, 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 [77,78]. 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 [77]. 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 [79].

Teriparatide — Most authors of this topic do not routinely give patients teriparatide as first-line therapy to prevent bone loss in transplant recipients. However, some authors of this topic use teriparatide in patients who develop fragility fractures while receiving bisphosphonates or denosumab as preventive therapy or as first-line therapy in patients who are at high risk for fractures if bone turnover is demonstrated to be low by bone turnover markers or bone biopsy. After stopping teriparatide, antiresorptive therapy may be considered if the patient's bone turnover is expected to rebound. (See 'Our approach to the prevention of osteoporosis' above.)

In a double-blind, randomized trial, 26 kidney transplant patients were treated with daily subcutaneous injections of 20 mcg of teriparatide or placebo [80]. 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 [80].

TREATMENT OF OSTEOPOROSIS — The treatment of patients who are diagnosed with osteoporosis after transplantation (>12 months posttransplant) differs from that of patients who are diagnosed with osteoporosis prior to or at the time of transplantation.

Patients with osteoporosis before transplantation — The treatment of patients who are diagnosed with osteoporosis prior to or at the time of transplantation is the same as that of chronic kidney disease (CKD) patients with osteoporosis who are not transplant recipients. (See "Osteoporosis in patients with chronic kidney disease: Management".)

Patients with osteoporosis after transplantation — The optimal approach to transplant recipients who are found to have osteoporosis >12 months posttransplantation is not known [1,28]. We follow a stepwise approach:

●Step 1 – All transplant recipients who have evidence of osteoporosis are encouraged to follow the lifestyle changes. We administer calcium and vitamin D3 if there is no hypercalcemia. We use the lowest possible dose of glucocorticoids to prevent rejection. These measures are similar to those used for prevention in patients who do not have osteoporosis. (See 'Prevention of osteoporosis' above.)

●Step 2 – Additional measures depend upon whether or not patients have persistent hyperparathyroidism and/or hypophosphatemia, both of which may be observed after transplantation. Persistent hyperparathyroidism and severe hypophosphatemia should be treated before considering additional medical therapies for osteoporosis. (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation", section on 'Treatment'.)

We repeat bone density testing 12 months after treating hyperparathyroidism and severe hypophosphatemia.

●Step 3 – The treatment of patients who do not have or have been successfully treated for persistent hyperparathyroidism and/or hypophosphatemia depends upon whether or not patients are at risk for low-turnover bone disease (ie, adynamic bone disease). (See "Adynamic bone disease associated with chronic kidney disease".)

Antiresorptive agents are commonly used for patients with osteoporosis or fragility fractures. However, antiresorptive agents should not be used in patients with low-turnover bone disease [81].

It is difficult to identify patients with low-turnover bone disease. Dual-energy x-ray absorptiometry (DXA) cannot be used to identify such patients, since it is not a marker of bone turnover [45]. The gold-standard diagnostic method is by bone biopsy. Properly interpreted, a bone biopsy can unequivocally establish a diagnosis of low-turnover bone disease. However, there are very few centers with sufficient expertise to interpret bone biopsies. Thus, we, and many other experts, first attempt to establish a diagnosis of low-turnover bone disease using noninvasive methods. (See 'Role of bone biopsy' above.)

To identify patients who have low bone mineral density (BMD) and low-turnover bone disease, we use a combination of serum parathyroid hormone (PTH) and bone-specific alkaline phosphatase (BSAP) [82,83]. 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 [82].

Patients who have indeterminate levels of PTH and BSAP may be considered for bone biopsy prior to further treatment for osteoporosis if knowledge of the type of renal osteodystrophy will impact treatment decisions. This is consistent with the 2017 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, which acknowledge that there has been growing experience with osteoporosis medications in patients with CKD and that the inability to obtain a bone biopsy may not justify withholding osteoporosis treatment in a CKD patient at high risk of fracture [84]. Patients who need bone biopsy should be referred to centers that have expertise in performing and interpreting bone biopsies. (See 'Role of bone biopsy' above.)

For patients without evidence of low-turnover bone disease:

•We treat all patients who have osteoporosis and no evidence of low-turnover bone disease with antiresorptive therapies such as bisphosphonates. Alendronate, risedronate, ibandronate, pamidronate, and zoledronate have all been used in clinical trials in kidney transplant recipients. The selection of an optimal agent and initial doses is the same for transplant recipients as for CKD patients with a comparable glomerular filtration rate (GFR). (See "Osteoporosis in patients with chronic kidney disease: Management".)

•Denosumab is an alternative option in patients with osteoporosis. Some authors use denosumab as first-line therapy instead of a bisphosphonate. Patients with low GFR who are receiving denosumab should be monitored for the development of hypocalcemia (see "Denosumab for osteoporosis", section on 'Hypocalcemia'). In addition, discontinuation of denosumab may result in a rebound increase in bone resorption, rapid bone loss, and an increase in vertebral fractures [85,86]. There are no data supporting the use of denosumab in posttransplant patients with late-onset osteoporosis and no evidence of low-turnover bone disease.

For patients with evidence of low-turnover bone disease:

•For patients with low bone density and low-turnover bone disease, recombinant human PTH 1-34 (teriparatide) may be a potential option, but experience in kidney transplant patients is limited. Teriparatide exerts anabolic effects on the skeleton and has been shown to be effective at increasing BMD and lowering risk of vertebral fractures in patients with glucocorticoid-induced osteoporosis [87].

OTHER FORMS OF POSTTRANSPLANT BONE DISEASE

Osteonecrosis — Osteonecrosis (avascular or ischemic necrosis) is probably the most debilitating of the musculoskeletal complications following transplantation [88-91]. (See "Treatment of nontraumatic hip osteonecrosis (avascular necrosis of the femoral head) in adults".)

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 [89-91]. 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 [92].

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 [93,94]. Osteopenia and hyperparathyroidism may also contribute [88].

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 [95]) and is often temporally related to increased plasma cyclosporine levels [96]. 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 [97,98]. 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 [96].

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

●The major bone diseases that affect kidney transplant recipients are osteoporosis and osteonecrosis (avascular necrosis), both of which cause significant long-term morbidity. Osteoporosis increases the risk of fractures. (See 'Introduction' above.)

●Bone loss occurs rapidly following kidney transplantation and is primarily related to the use of glucocorticoids and other immunosuppressive medications. Other risk factors include hyperparathyroidism, diabetes mellitus, metabolic acidosis, and receiving a kidney/pancreas transplant. (See 'Pathogenesis and risk factors' above.)

●We screen all kidney transplant candidates for osteoporosis and fracture risk prior to transplantation. We use dual-energy x-ray absorptiometry (DXA) to assess bone mineral density (BMD) of the hip, spine, and forearm. In addition, we measure serum parathyroid hormone (PTH) and 25-hydroxyvitamin D levels, obtain imaging of the thoracic and lumbar spine to assess for existing vertebral fractures, and assess for the presence of traditional and posttransplant risk factors for fracture. (See 'Our approach to screening and monitoring kidney transplant candidates' above.)

At two to four weeks after transplantation, or when renal allograft function stabilizes, we measure serum calcium, phosphate, PTH, and 25-hydroxyvitamin D levels. In addition, we obtain fasting morning serum concentrations of bone turnover markers (BTMs), including C-telopeptide crosslink (CTX) and bone-specific alkaline phosphatase.

Based upon our initial pre- and posttransplant evaluations, we consider the following patients to be at high risk of incident fracture: patients with a history of pretransplant low-trauma fracture or radiologic evidence of vertebral fracture; patients with osteoporosis; and patients with osteopenia who have one or more clinical risk factors for fracture or will receive glucocorticoids as part of their maintenance immunosuppression regimen.

•In patients who are determined to be at high risk of incident fracture, we monitor DXA annually in order to assess the stability of BMD and the response to treatment.

•In patients who are not determined to be at high risk of incident fracture, we rescreen by DXA every two years and use preventive measures.

●The optimal approach to the prevention of bone loss and fractures among kidney transplant recipients is unknown. Among all transplant recipients who have a normal BMD or osteopenia, we encourage lifestyle changes, maintain the lowest possible glucocorticoid dose, and treat persistent hyperparathyroidism. Provided that serum calcium is normal, we treat with calcium and vitamin D3. (See 'Our approach to the prevention of osteoporosis' above.)

•Among transplant recipients with osteopenia who are considered to be at high risk for incident fracture, some, but not all, contributors to this topic would treat with additional prophylactic therapies (including bisphosphonates, active vitamin D analogs, denosumab, and teriparatide), guided by a posttransplant assessment of bone turnover biomarkers. (See 'Bisphosphonates' above and 'Active vitamin D analogs' above and 'Teriparatide' above.)

•Among transplant patients with osteopenia who are not considered to be at high risk for incident fracture and have evidence of normal or high bone turnover, some, but not all, contributors to this topic would treat with an active vitamin D analog.

However, other authors and editors of this topic do not use bisphosphonates or active vitamin D analogs to prevent bone loss in kidney transplant recipients, regardless of their fracture risk, until renal osteodystrophy has been optimally managed and persistent hyperparathyroidism (if present) has been treated. This approach allows the remodeling bone sufficient time to reach a new steady state before an antiresorptive agent is administered. Both of these approaches are based upon the clinical experience of the contributors, and there is little high-quality evidence to support one approach over the other.

●The treatment of patients who are diagnosed with osteoporosis prior to or at the time of transplantation is the same as that of nontransplant candidate chronic kidney disease (CKD) patients with osteoporosis. (See 'Patients with osteoporosis before transplantation' above.)

●The optimal approach to transplant recipients who develop osteoporosis after transplantation (>12 months posttransplant) is not known. Our approach is based upon our clinical experience rather than upon well-designed, randomized trials among transplant recipients. (See 'Patients with osteoporosis after transplantation' above.)

•Among all transplant recipients who have evidence of osteoporosis and are not hypercalcemic, we administer calcium and vitamin D3. We use the lowest possible dose of glucocorticoids to prevent rejection. We treat persistent hyperparathyroidism and severe hypophosphatemia before considering additional medical therapies for osteoporosis. We repeat bone density testing 12 months after treating hyperparathyroidism and severe hypophosphatemia.

•Patients who have low BMD and no evidence of hyperparathyroidism and hypophosphatemia may require additional medical therapy with antiresorptive therapies. We select patients for treatment with antiresorptive therapies based upon our assessment of the risk of low bone turnover (adynamic bone disease), using a combination of serum PTH and bone alkaline phosphatase. If low-turnover bone disease cannot be excluded biochemically, a bone biopsy may be necessary. (See 'Role of bone biopsy' above.)

•Among patients who have low-turnover bone disease excluded (by biochemical testing or bone biopsy), we give an antiresorptive agent (ie, bisphosphonate or denosumab). Alendronate, risedronate, ibandronate, pamidronate, and zoledronate have all been used in clinical trials in kidney transplant recipients. Denosumab is an alternative option for patients with osteoporosis and low glomerular filtration rate (GFR) who cannot receive bisphosphonates or for those who have not responded to vitamin D or bisphosphonate therapy. The selection of an optimal agent and initial doses is the same for transplant recipients as for CKD patients with a comparable GFR.

●Osteonecrosis (avascular or ischemic necrosis) is probably the most debilitating of the musculoskeletal complications following transplantation. Factors that contribute to osteonecrosis include defects in mineral metabolism (induced by uremia and immunosuppressive medications) and glucocorticoids. Osteopenia and preexisting hyperparathyroidism may also contribute. (See 'Osteonecrosis' above.)

●In addition to osteopenia and osteonecrosis, a different bone pain syndrome has been described in patients receiving cyclosporine (and, perhaps, tacrolimus) and is often temporally related to increased plasma cyclosporine levels. (See 'Bone pain and cyclosporine' above.)

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