Current Status of Mineral and Bone Disorders in Transplant Recipients

(1)

Transplantation ■ October 2023 ■ Volume 107 ■ Number 10 www.transplantjournal.com 2107 ISSN: 0041-1337/20/10710-2107

DOI: 10.1097/TP.0000000000004538

Received 12 August 2022. Revision received 22 November 2022.

Accepted 10 December 2022.

1 Department of Renal Medicine, Westmead Hospital, Sydney, Australia.

2 Skeletal Biology Program, Garvan Institute of Medical Research, Sydney, Australia.

3 School of Medicine, University of Notre Dame, Sydney, Australia.

The authors declare no funding or conflicts of interest.

Correspondence: Grahame J. Elder, MB, BS, PhD, Department of Renal Medicine, Westmead Hospital, Cnr of Darcy and Hawkesbury Rds, Westmead, NSW 2145, Australia. ([email protected]).

Current Status of Mineral and Bone Disorders in Transplant Recipients

Grahame J. Elder, MB, BS, PhD^1,2,3

Abstract. Most patients with end-stage kidney disease undergoing kidney transplantation are affected by the chronic kidney disease–mineral and bone disorder. This entity encompasses laboratory abnormalities, calcification of soft tissues, and the bone abnormalities of renal osteodystrophy that together result in an increased risk of fracture, cardiovascular events, and mortality. Although many biochemical disturbances associated with end-stage kidney disease improve in the first year after transplantation, hyperparathyroidism commonly persists, and residual changes of renal osteodystrophy are slow to resolve. When superimposed on common, traditional risk factors, post-transplant glucocorticoid treatment, the possibil- ity of tubular disturbances and post-transplant chronic kidney disease, rates of incident fracture remain high. This review examines hormonal and biochemical changes before and after kidney transplantation, fracture risk assessment tools and imaging modalities, a staged approach to management and concerns associated with antiresorptive and anabolic therapies.

A multidisciplinary approach is proposed as the best means to improve patient-level outcomes.

(Transplantation 2023;107: 2107–2119).

BACKGROUND TO POST-TRANSPLANT MINERAL AND BONE DISORDERS

The concept of chronic kidney disease–mineral and bone disorder (CKD-MBD) encompasses the intersection of laboratory measures, particularly those reflecting disturbances of bone and mineral metabolism, the calcification of soft tissues, and bone abnormalities that fall under the general heading of renal osteodystrophy.¹ Together, these abnormalities result in an increased risk for the patient- level outcomes of cardiovascular (CV) events, fracture, and mortality. This review will focus on CKD-MBD in patients about to undergo kidney transplantation, how changes in the post-transplant period affect laboratory measures, soft tissue calcification and bone outcomes, and means to evaluate and manage these changes, with the goal of improving patient wellbeing. This review is written in narrative style, which introduces potential for bias, but may, nevertheless, provide useful guidance. To focus on recent developments, a literature search using key words was conducted from

2018 to 2022 inclusive, with earlier references included as necessary background.

LABORATORY PARAMETERS IN CKD-MBD

Chronic kidney disease has diverse etiologies, but common pathways lead to complications of the CKD-MBD. Briefly summarized, a loss of estimated glomerular filtration rate (eGFR) leads to incremental rises in serum phosphate and positive phosphate balance. This stimulates release of the phosphaturic hormone fibroblast growth factor 23 (FGF23) from osteocytes within bone. FGF23 binds to FGF receptors and their α-klotho coreceptors in the proximal tubule, to downregulate sodium-phosphate cotransporters, and this reduces phosphate reabsorption and maintains phosphate balance. FGF23 also reduces 1,25(OH)₂D production and increases its breakdown, which reduces intestinal phosphate absorption. Although this is useful to maintain phosphate homeostasis, it also reduces intestinal calcium absorption, and the combined effects of reduced serum calcium and 1,25(OH)₂D, plus rising phosphate levels predispose to secondary hyperparathyroidism. Elevated levels of phosphaturic hormone (PTH) improve phosphate homeostasis and maintain calcium balance by increasing renal calcium reabsorption, and the release of calcium from bone.

Kidney damage reduces membrane bound α-klotho expression, and loss of this coreceptor for FGF23 renders FGF23 less effective. Rising phosphate and PTH levels, inflammation, and iron deficiency or functional iron deficiency² are among a number of factors that lead to increased FGF23 transcription, and a reduction in the cleavage of full- length FGF23 to its fragments.³ In patients with end-stage kidney disease (ESKD), this can result in extreme intact FGF23 values that aberrantly activate pathways leading to cardiac hypertrophy and increase CV risk.⁴

(2)

Renal damage also activates developmental programs of tissue repair, including the expression of activin A and Wnts. Activin A levels increase in the kidney in response to ischemia or other injury, triggering fibroblast proliferation.

However, activin A is also associated with many adverse effects of CKD-MBD, including the promotion of vascular calcification (VC), high-turnover bone disease, and possi- bly cardiac fibrosis. Levels increase as early as CKD stage 2 and the relationship to bone turnover abnormalities is as strong as those found with PTH and FGF23.⁵ Wnts are secreted glycoproteins that trigger multiple signaling cascades essential for tissue generation in the embryo, and for adult bone anabolism. Wnts act locally, and to maintain this local activity, their expression induces secretion of circulating Wnt inhibitory proteins, including dickkopf- related protein-1 and sclerostin, both of which can inhibit bone anabolism.

Sclerostin values rise early in CKD⁵ and by ESKD, reach levels 2–4-fold higher than in individuals with normal renal function.⁶ Because sclerostin is an inhibitor of the Wnt-β-Catenin signaling pathway that promotes osteoblast development, a rise in sclerostin reduces bone formation. Normal circadian surges in PTH suppress sclerostin and contribute to bone anabolism, whereas continuous elevations of PTH, as seen in patients with severe hyperparathyroidism on dialysis, are likely to result in bone resorption.⁷ Serum sclerostin values have been negatively correlated with parameters of osteoblast surface, osteoid volume and thickness, and the bone formation rate.^8,9 Higher sclerostin values may contribute to skeletal resistance to PTH and the early development of low bone turnover (or adynamic bone). On the other hand, a rise in sclerostin may also counteract the development of VC¹⁰ caused by the dedifferentiation of vascular smooth muscle cells (VSMCs) into cells with an osteoblast phenotype.

As CKD develops, these cumulative effects increase risks for calcification of soft tissues and CV events, abnormal

bone mineralization, turnover and volume, fracture, and mortality. Progressive changes to hormones involved in CKD-MBD development are illustrated in Figure 1.

LABORATORY CHANGES AFTER TRANSPLANTATION

After successful transplantation, tubular targets for PTH and FGF23 are restored, but hyperparathyroidism and elevated levels of FGf23 may persist at inappropriately raised levels for their new environment. Simultaneously, drugs used to suppress PTH, including calcimimetics, calcitriol, and its analogs and calcium-based phosphate binders, are often withdrawn, and most patients commence glucocorticoids. For patients with immediate graft function, PTH values measured by intact PTH assays fall immediately to around 50% of pretransplant values. However, it is important to recognize that this decrease reflects the removal of PTH fragments, particularly C-terminal PTH 7-84, by the functioning transplant, and the lower PTH does not rep- resent regression of hyperparathyroidism. In fact, despite lower PTH values, hypercalcemia may develop rapidly as PTH facilitates conversion of 25OHD to 1,25OH₂D by 1-alpha hydroxylase in now-functional proximal tubules, PTH causes reabsorption of filtered calcium, 1,25OH₂D increases gastrointestinal calcium uptake, and there is reduced skeletal resistance to the effects of PTH result- ing in osteoclastic resorption of bone. An exception to the usual reduction in PTH after kidney transplantation is when patients treated with a calcimimetic have the drug withdrawn, in which case, pre- and post-transplant values of PTH may be similar.

The recovery of renal function also influences values of commonly used bone turnover markers (BTMs), total (monomeric plus trimeric) procollagen type 1 N-terminal propeptide, and the C-terminal telopeptide of type 1 col- lagen. Values of these markers are often 3–5-fold the upper

FIGURE 1. Changes in hormones mediating CKD-MBD development.¹¹ Stars show the first CKD stage at which values differed from controls. Serum calcium and phosphate remained normal until CKD stage 4. Data were derived from Lima et al.⁵ CKD-MBD, chronic kidney disease–mineral and bone disorder; PTH, phosphaturic hormone.

(3)

range of their respective assay pretransplant, falling to a range that more likely reflects bone turnover by 1–3 mo post-transplant, in patients with a relatively normal eGFR.

However, bone alkaline phosphatase (BALP) (one of the liver, kidney, and bone “tissue nonspecific” ALPs), which reflects osteoblast activity, and (if available) tartrate resist- ant acid phosphatase-5b, which reflects osteoclast number, are not influenced by renal function and have good discrim- inatory ability for high and low bone turnover in patients with CKD and after transplantation.¹² Serum (total) ALP is also a useful indicator of osteoblast activity and bone turnover,¹³ providing liver function tests are normal and the patient does not have liver cysts associated with poly- cystic kidney disease.

Post-transplant, hyperparathyroidism is slow to regress once glandular nodularity has developed, because as parathyroid glands progress from initial diffuse hyper- plasia to early nodularity and finally, a single nodule of uniform parenchymal cells, calcium-sensing receptor, vitamin D receptor, and FGF23 receptor expression decreases, proliferative activity increases, and the rate of apoptosis appears to decrease.¹⁴ Rates of persistent hyperparathyroidism (PTH >65 pg/mL) 1 y after kidney transplantation are reported to be as high as 86.2% when patients remain untreated with cinacalcet, vitamin D sterols, or parathyroidectomy,¹⁵ and even 7 y post-transplant, only 27% of a Swiss cohort of 823 patients had normal PTH values.¹⁶ In the study of Wolf et al,¹⁵ patients were classi- fied based on their pretransplant PTH into lower (≤300 pg/mL) or higher (>300 pg/mL) PTH strata (Figure 2A).

At 8 wk, hypercalcemia was present in 48% of patients in the higher PTH stratum, and this was followed by a gradual decline in serum calcium (Figure 2B). Levels of intact FGF23 decreased rapidly during the first 3 mo in all patients (Figure 2C). However, elevated levels may persist in patients with high pretransplant FGF23, in whom osteocytes and osteoblasts may have developed resistance to suppression of FGF23 synthesis.

Hypophosphatemia (<2.5 mg/dL) is common in the early post-transplant period, after which phosphate levels gradually improve (Figure 2D). Nevertheless, a uri- nary phosphate leak may persist, and rates of persisting hypophosphatemia are reported in 13% of patients at 1 y¹⁷ and in 22% of patients 7 y post-transplant in another study.¹⁸ Causes of hypophosphatemia include persisting elevation of PTH and FGF23 production (so-called hyper- phosphatoninism), initially low levels of 1,25(OH)₂D, and use of calcineurin inhibitors and glucocorticoids. The mechanism for the calcineurin inhibitor effect may be to decrease type II Na/Pi gene expression in the proximal tubule, as demonstrated in a cell line and in vivo.¹⁹

Low values of 25OHD are common before kidney transplantation and post-transplant, persisting hyperparathyroidism causes conversion of 25OHD to 1,25(OH)₂D.

Consequently, values of 25OHD are often insufficient or deficient by 1–3 mo post-transplant, whereas 1,25(OH)₂D values may exceed the assay normal upper range by 3–12 mo post-transplant.

Sclerostin levels are reported to fall by 3 mo post-transplant but rise again by 12 mo. Because sclerostin is filtered

FIGURE 2. Biochemical changes following kidney transplantation. A–D, Changes to PTH, calcium, FGF23, and phosphate following kidney transplantation in patients with pretransplant high and low serum PTH levels.¹⁵ PTH, phosphaturic hormone.

(4)

and reabsorbed in the proximal tubule, this early reduction in sclerostin may reflect post-transplant proximal tubular dysfunction.²⁰

Sexual dysfunction is common in patients on dialysis, with abnormalities at all levels of the hypothalamic–pitui- tary–gonadal axis. Many older women undergoing transplantation are postmenopausal, and younger women may be amenorrheic and hypogonadal. In younger women, estradiol levels rise from the time of transplantation to 12 mo, and around 73% of younger women report the resumption of a regular menstrual cycle, with ~65%

of cycles ovulatory, which is comparable with healthy women.²¹ Men may also be hypogonadal, and in a study of 321 men with a mean age of 47 y who were awaiting transplantation, one third had values of total testosterone below the reference range, and 50% had calculated free testosterone values below the reference range.²² Male testosterone values generally reach a nadir around 1–3 mo post-transplant before returning toward the normal range.

BONE CHANGES ASSOCIATED WITH CKD-MBD Even based on this simplified background, it is not sur- prising that the histopathology of renal osteodystrophy is diverse. Using the turnover, mineralization, and volume classification, the main categories of renal osteodystrophy include low bone turnover (or adynamic bone), osteoma- lacia, and high-turnover (hyperparathyroid) bone disease, or so-called osteitis fibrosa. A recent report described static histomorphometry and micro-CT of 30 patients undergoing kidney transplantation.²³ Baseline changes were consistent with high bone turnover in 19% of patients, and low bone turnover in 22%, although without dynamic histomorphometry with tetracycline labeling these results are inferential.

In addition to bone changes that develop with progressive CKD, many patients have low bone volume and reduced bone mineral density (BMD), meeting criteria for osteopenia or osteoporosis, which predispose to fracture in the general community. Added to this, patients with ESKD seem to have “premature aging” of bone, with marked reductions in cortical thickness and increased cortical tun- neling, which appears in cross section as porosity.²⁴ These cortical changes have been assessed using high-resolution peripheral quantitative CT (HRpQCT),²⁵ micro-MRI,²⁶ dual-energy X-ray absorptiometry (DXA), using advanced hip analysis software²⁷ and on micro-CT of iliac crest bone biopsies.²⁴ Both the reduction in cortical thickness and increased cortical porosity reduce strength and fracture resistance.

In patients with ESKD undergoing transplantation, fracture risk reflects alterations to bone quantity, often measured by areal BMD in gm/cm², and bone quality.

Bone quantity assessment as DXA-derived BMD is now suggested in all stages of CKD and following transplantation if it is likely to influence therapy,²⁸ and in many set- tings, DXA has the advantage of being readily available and relatively inexpensive. However, DXA-derived BMD is not a good indicator of bone quality. Bone quality is altered by abnormal mineralization and high or low bone turnover, which are characteristic of renal osteodystrophy, and affect bone geometry, microarchitecture, and microcrack accumulation. Consequently, DXA-derived

BMD does not predict fracture risk in patients with CKD as effectively as in the general population, leading to an exploration of other tools. The trabecular bone score (TBS) is a DXA-derived measure that uses gray scale interpretation of pixels from the lumbar spine images.

TBS values correlate with parameters of trabecular micro- architectural integrity, including trabecular spacing, con- nectivity, and number, with higher TBS values indicative of better bone architecture. In the general population, the TBS is an independent predictor of fracture risk, leading to its incorporation into the multicomponent fracture risk assessment tool, FRAX^R. Use of the TBS for fracture prediction has also been studied over an average of 6.6 y in 327 kidney transplant recipients (KTRs), matched with individuals from the general population.²⁹ Transplant patients who fractured had significantly lower mean TBS values compared with those who did not (Figure 3). The TBS was associated with fractures independent of FRAX^R when used with the inclusion of BMD.

Using readily available DXA “advanced hip analysis”

software, DXA can also be used to estimate the cortical thickness of the femoral neck, the calcar, and the femoral shaft, with results that correlate closely to CT³⁰ but with minimal radiation. From those indices, a “buckling ratio” can be calculated, as the femoral neck radius/cortical thickness, with results >10 consistent with femoral neck instability. Similar to the results from high-resolution imaging, DXA advanced hip analysis indicates that patients with ESKD have significantly thinner hip cortices than age-matched members of the general population at all hip sites and higher buckling ratios.²⁷ Although these find- ings suggest that DXA-derived advanced hip analysis may be useful for fracture prediction in patients with ESKD and abnormal cortical parameters, longitudinal studies including fracture outcomes are required. Broadband ultrasound attenuation is used relatively infrequently but also assesses aspects of bone quality and fracture risk.³¹ Because of cost and availability, HRpQCT²⁵ and micro-MRI²⁶ are generally used only as research tools.

FRACTURE RATES AFTER TRANSPLANTATION For patients with CKD, rates of incident hip fracture increase with worsening kidney function across all age groups,³² and for patients on dialysis, rates are 4–5-fold that of the general population,³³ with greater post-fracture mortality.³⁴ However, rates on dialysis are reported to increase further during the first 2 y after kidney transplantation^35,36 and at 10 y post-transplant, have not returned to general population levels. A 2002 study examined the risk of hip fracture in KTRs and estimated the fracture rate at 3.3 events per 1000 person-years, versus 2.9 per 1000 patient years for similar patients waitlisted for transplantation and receiving dialysis.³⁶ Although the adjusted relative risk (RR) for transplant recipients was initially 34% higher than the waitlisted dialysis patients, the difference decreased progressively, becoming equiva- lent at approximately 360 d post-transplant (adjusted RR, 1.00; 95% confidence interval [CI], 0.87-1.15). Of course, transplant protocols have evolved since those studies, and current induction and maintenance glucocorticoids dos- ages are lower. A study based on patients transplanted from 2010 to 2016, suggested that contemporary kidney

(5)

transplantation has a limited impact on bone microarchitecture.²³ In that study, 30 patients with paired iliac crest bone biopsies were studied at the time of transplantation and 1 y later. At 12 mo, 4 patients had ceased prednisolone, 5 patients had received active vitamin D, and the mean eGFR was 48 ± 19 mL/min/1.73 m². Median biointact PTH values remained 2.1-times the upper range of the assay (95% Interquartile range [IQR]: 1.2-3.3) and elevated BALP at 24.3 µg/L (IQR: 17.8–32.9) had not reduced significantly. At 12 mo, histomorphometric bone turnover was low in 5 (17%) and normal in 25 (83%), and delayed mineralization was present in 5 (17%) of the 30 patients. By DXA, mean T scores at the lumbar spine and femoral neck did not change significantly over the year. Surprisingly, no correlation was found between 12-mo biointact PTH and bone microarchitecture, but higher ALP and BALP were directly correlated with increased cortical porosity, and ALP was inversely correlated with cortical thickness. The authors speculated that tighter pretransplant control of hyperparathyroidism and post-transplant normalization of bone turnover may have explained the limited changes in cortical bone microarchitecture. Although early glucocorticoid withdrawal may result in more stable axial (spine and hip) BMD by DXA, peripheral sites (1/3 radius and ultradistal radius) continue to show BMD reductions.³⁷ By HRpQCT at the dis- tal radius and tibia, reduced failure load with declines in cortical area, density, thickness and trabecular density and stiffness are reported over the first post-transplant year, with cortical losses directly related to levels of PTH.^37,38

Up to 90% of patients have hypophosphatemia soon after transplantation, and an ongoing phosphate leak, with or without hypophosphatemia, may be relatively common.

At 1 y post-transplant, lower phosphate levels are associated with delayed mineralization,¹⁷ and in a retrospective

cross sectional study, lower serum phosphate values at 5 y post-transplant were associated with fracture.³⁹

Although male hypogonadism is relatively common at the time of transplantation, higher sex hormone binding globulin values, rather than low serum testosterone or calculated free testosterone values, are associated with prevalent fracture in male patients.²²

As in the general population, the older a patient is at the time of transplant, the greater their fracture risk. The graph (Figure 4) shows the 5- and 10-y incidence of hip fracture in 47 815 US patients who received their first kidney transplant at age 55–75 y or over.⁴⁰ Patients in the study were predominantly male (63%), which would be expected to skew results toward fewer fractures, 28.0%

were Black, and 47.7% had diabetes. After accounting for competing risks, the cumulative 5-y hip fracture incidence for patients aged 75 y and older was 5.4 per 100 and for those aged 55–59, was 1.2 per 100. For perspective, in the Million Women Study, the 5-y incidence of hip fractures among postmenopausal women aged 70–73 y was 0.82 per 100 and for women aged 50–54 y, was 0.11 per 100.⁴¹

Patients with type 2 diabetes mellitus, who constitute over 50% of incident dialysis patients in many centers, are also more likely to have an increased post-transplant fracture risk, although data on this cohort are limited. In the general population, meta-analysis of clinical studies suggests T2DM imparts a 1.7-fold (1.3, 2.2) increased RR for hip fracture,⁴² and for T1DM, the risk for any fracture increases to 6.3-fold (2.6, 15.1),⁴² with vertebral fracture risk reported to be 1.2- fold (1.09, 1.31) that of the general population.⁴³ Comparing DXA parameters between patients with ESKD due to T1DM and other causes, BMD z-scores at the lumbar spine, femoral neck, and ultradistal radius are significantly lower in patients with T1DM, and cortical parameters assessed by advanced hip analysis are more abnormal in T1DM patients.⁴⁴

FIGURE 3. Kaplan–Meier estimator for fracture in kidney transplant recipients, stratified by median TBS (TBS below median <1.370;

TBS above median ≥1.370).²⁹ TBS, trabecular bone score.

(6)

During the first year following transplantation, the body mass index (BMI) of many patients increases. Body composition analysis by DXA indicates that the increase particularly affects visceral adipose tissue and increases the android to gynoid fat mass ratio. There is ongoing discussion regarding the relationship of body weight to BMD, but a recent study based on the US National Health and Nutrition Examination Survey reported a strong positive association between lean mass and BMD, whereas there was a negative association between fat mass and BMD.⁴⁵ This relationship did not differ between age groups and was most notable in men with high fat levels, in whom for every 1 kg/m² increase in BMI, there was a 0.13 lower BMD T score. Although there are no published data on the effect of increased fat mass on BMD following transplantation, this population data warn of a likely negative impact.

FRACTURE RISK CALCULATORS

Fracture risk calculators such as FRAX^R and the Garvan Fracture Risk Calculator are now widely used to estimate

“absolute fracture risk,” which is a means to determine treatment thresholds (and the cost benefit of treatment) for at-risk individuals. For example, a 50-y-old man with no known comorbidities and a T score of −2.4 at the femoral neck will have a lower absolute fracture risk, and less need to commence immediate treatment, than a 60-y-old woman with the same T score but a previous fracture and taking glucocorticoids. FRAX^R can be used with or without inclusion of the BMD or the TBS. To the authors knowledge, FRAX^R has not yet been assessed in a longitudinal study of patients following transplantation, but it has been evaluated in patients with CKD. In the Manitoba BMD database of 10 099 subjects aged 64 ± 13 y, 13%

were male, 2154 had an eGFR 30–60 mL/min/1.73 m² and 590 had an eGFR <30 mL/min/1.73 m².⁴⁶ Over 5 y of observation, there were 772 major osteoporotic fractures (MOFs) and 226 hip fractures. For patients with eGFR

<30 mL/min/1.73 m² (not on dialysis), for each SD increase in the FRAX^R score including BMD, the hazard ratio (HR) for hip fracture was 3.1 (1.8, 5.33) and for MOF 2.04

(1.58, 2.84). However, the observed MOF risk exceeded the predicted risk by 2.5% and inclusion of BMD (which is optional in calculating FRAX^R scores) did not improve accuracy. FRAX^R (without BMD) has also been utilized in patients on hemodialysis who were followed for 2 y or until fracture.⁴⁷ Due to underestimation of fracture risk in that Polish study, a FRAX^R “intervention threshold” of

>5% was proposed, rather than an intervention threshold of ≥10%, and used as the indication for pharmacological treatment for postmenopausal osteoporosis in Poland.

Although FRAX^R may underestimate absolute fracture risk in the post-kidney transplant setting, it is a useful addition when assessing the need for pharmacological intervention.

VASCULAR AND SOFT TISSUE CALCIFICATIONS Similar to the bone changes in CKD, blood vessel changes associated with CKD have been described as premature aging. VC typically affects the tunica media of large- and medium-sized arteries and may occur with or without intimal atherosclerosis. The consequent vascular stiffening contributes to systolic hypertension, increased pulse wave velocity, increased cardiac afterload and left ventricular hypertrophy, reduced coronary filling, suben- docardial ischemia, and CV mortality, the most common cause of death in ESKD. Patients with CKD share many traditional CV risk factors with the general population, and for elderly patients with CKD, these may be the major drivers of CV risk.⁴⁸ However, for younger patients, novel risk factors may play a greater role, in particular, the differ- entiation of VSMCs from a quiescent, contractile state to a

“synthetic” state. This phenotype switching is a naturally occurring repair process, but once the vascular damage is repaired, the cell should return to its former contractile state. However, the uremic milieu predisposes to dedifferentiation of VSMCs, and their maintenance in a synthetic, proliferative, osteogenic state.⁴⁹

As calcium and phosphate levels rise, calcium phosphate nanocrystals are normally removed from the cir- culation and recycled as primary calciprotein particles⁵⁰ but this recycling is impaired in CKD, and together with FIGURE 4. Fracture risk after kidney transplantation by age.⁴⁰

(7)

a reduction in powerful natural inhibitors of VC (particularly Fetuin A, matrix Gla protein, Gla Rich Protein and pyrophosphate), the result is an excess risk for soft tissue calcification.

Increased VC is associated with adverse consequences for patients with ESKD and following transplantation. A simple and reproducible way to assess VC is from a lateral abdominal X-ray using the Kauppila semiquantitative scoring method,⁵¹ which assigns an abdominal aorta calcification (AAC) score to the abdominal aortic segments opposite the first 4 lumbar vertebrae. A recent study of 626 patients with a mean age of 44 ± 12 y and followed over a median of 65 mo (29–107) from kidney or simulta- neous pancreas kidney transplantation⁵² reported that VC at the time of transplantation influenced the post-transplant course. Abdominal aortic calcification was identified at baseline in 44% of patients, of whom 59% had scores of 1–7/24 and 41% had scores ≥8/24 using the Kauppila scale. The risk of CV events and mortality increased with each point increase in the AAC (Figure 5), and for recipients with high scores versus absent AAC, the unadjusted and adjusted HRs were 5.90 (2.90,12.02) and 3.51 (1.54, 8.00) for CV events, 5.39 (3.00, 9.68) and 3.38 (1.71, 6.70)

for death, and 1.30 (0.75, 2.28) and 1.94 (1.04, 3.27) for graft loss after adjustment for age and smoking history.

GUIDELINES FOR POST-TRANSPLANT MANAGEMENT OF MBD

Kidney Disease Improving Global Outcomes CKD- MBD guidelines were updated in 2017¹³ and suggested BMD testing for all patients with CKD and in the post- transplant period, providing the results were likely to influence management. For patients with an eGFR >30 mL/

min/1.73 m² and low BMD, it was suggested that treatment with vitamin D, calcitriol/alfacalcidol, and/or antiresorptive agents be considered (evidence level 2D) in the first 12 mo after transplantation and that bone biopsy might also be considered.

Renal association clinical practice guidelines were also published in 2017.⁵³ They also suggested that KTRs on long-term steroids or at high risk for osteoporosis should undergo DXA scanning if the eGFR was >30 mL/min/1.73 m² (2D), and KTRs suffering from osteoporosis or at high potential risk should be considered for steroid avoid- ing immunosuppression (2D). They suggested that severe

FIGURE 5. Multivariable-adjusted restricted cubic spline regression for the association of abdominal aortic calcification with CV events and mortality and Kaplan–Meier survival plots by the presence or absence of abdominal aortic calcification for CV events and deaths.⁵² AAC, abdominal aorta calcification; CI, confidence interval; CVD, cardiovascular disease; CV, cardiovascular; HR, hazard ratio.

(8)

hyperparathyroidism should be treated before transplantation (2D), that cinacalcet can be used (2C), and treatment should be the same as for other patients with CKD (2D).

REFRAMING MANAGEMENT STRATEGIES FOR POST-TRANSPLANT MBD

Several recent publications have addressed factors associated with fracture following kidney transplantation and strategies for reducing risk.^54–56 Published algorithms can also be used to assist in the choice of pharmacological interventions, which, if followed, will likely improve outcomes and reduce adverse effects.^54,57 Recently published algorithms developed for patients with CKD stages 3–5 may also be relevant to patients following transplant with reduced kidney function.⁵⁸ Underlying most of these documents are 3 principles:

First, an assessment of background risk, including general risks for osteoporotic fractures. These include older age, female sex, prevalent (particularly recent) fracture, hypogonadism, a first-degree relative with osteoporosis, low BMI or elevated BMI with high fat mass, and secondary conditions such as celiac disease, diabetes mellitus, poor visual acuity, peripheral neuropathy, and falls risk.

Additional concerns for patients after transplant include persisting changes of renal osteodystrophy, post-transplant hyperparathyroidism, glucocorticoid exposure, and post- transplant CKD.

Second, there are general management principles that are applicable to most (but not all) patients, such as life- style modification and adequate dietary calcium, vitamin D supplementation for those patients who are vitamin D insufficient or deficient, consideration of menopausal hormonal therapy for women who have undergone premature menopause, and androgen replacement therapy for hypogonadal men, particularly if symptomatic.

The third step in most algorithms includes an assessment of fracture risk based on imaging and laboratory investigations. BMD evaluation together with the TBS, and consideration of advanced hip analysis, is generally acces- sible, and a lateral X-ray of the thoracic and lumbar spine, or vertebral fracture assessment by DXA, will indicate the presence of prevalent vertebral fracture and aortic calcification. Knowledge of the post-transplant serum PTH, 25OHD, sex hormone levels and BTMs, together with general biochemistry is necessary for targeted therapy.

Some important general principles relating to post- transplant CKD-MBD evaluation are discussed next, after which, the templates used in our clinic are included (Figure 6A and B). These investigation and management suggestions are a general guide, which can be modified according to local resources and practice.

Routine Evaluation

The optimal evaluation of bone and mineral disorders following kidney transplantation is through a dedicated clinic, with expertise in bone and mineral abnormalities associated with CKD, and osteoporosis treatment. Depending on the experience of the renal staff, endocrine or rheumatology input may be valuable in this setting. Multidisciplinary team management has already been proposed for the optimal treatment of heart failure and CKD,^59,60 and if resources are available, post-transplant bone fits well with a multidisciplinary team model. Our own Bone Clinic model is that

patients have investigations according to a standard local protocol and are seen by a clinic member within 3 mo of transplant. We interview all patients using a template ques- tionnaire, with fields that reflect our standard investigations, and a treatment algorithm that can then be used to gener- ate potential management options (Figure 6A and B). We evaluate absolute fracture risk using FRAX^R or the Garvan calculator but use a lower threshold for intervention than used in the general population. After the clinic review, management is discussed with the patient, and changes are com- municated to their treating physician. In general, follow-up 1-y post-transplant is recommended for repeat DXA and per-protocol investigations. Several Australian transplant centers follow similar protocols, and with discussion and some oversight, less experienced staff can safely manage patients after participation in just a few clinics.

GENERAL MANAGEMENT

At the time of transplant, many patients have low serum 25OHD values. Treatment may require relatively high doses of calciferol (cholecalciferol or ergocalciferol) to achieve 25OHD sufficiency, which should reduce the risk of worsening secondary hyperparathyroidism. In fact, a recent study of patients with CKD stages 1–5 observed an inverse association of PTH and values of 25OHD, that plateaued at 25OHD values of 42–48 ng/mL (105–120 nmol/L),⁶¹ which is considerably higher than general population guidelines suggest. However, some caution is required. Patients with hypercalcemia were excluded from that study, and in patients with more severe (tertiary) hyperparathyroidism and borderline calcium levels, aggressive supplementation with vitamin D may induce unaccepta- ble hypercalcemia, because of PTH-driven conversion of 25OHD to 1,25(OH)₂D in the transplant kidney.

Low serum phosphate levels are managed acutely with oral phosphate supplementation and longer term with dietary modification and calcitriol, although both phosphate supplementation and calcitriol may stimulate further FGF23 production.

Most men and premenopausal women with pretransplant hypogonadism recover during the first post-transplant year.

Because estrogen deficiency accelerates loss of BMD, for younger women who remain hypogonadal, we exclude hypothalamic hypogonadism and consider hormonal replacement therapy, keeping in mind possible risks. We also consider therapy for women who have undergone premature menopause or who have troubling menopausal symptoms. For men, we treat hypogonadism when BMD loss persists despite address- ing other causes, or for symptoms. In both cases, referral may be appropriate for specialized management.

When possible, we aim to lower glucocorticoid doses to ≤7.5 mg prednisolone to reduce skeletal risk. Lower doses, or glucocorticoid cessation, might be considered in patients at high fracture risk. Using the United States Renal Data System to follow 77 430 patients after a first kidney transplant over a median of 4 y, discharge without corticosteroids was associated with a 31% fracture risk reduction (HR, 0.69; 95% CI, 0.59-0.81), with significant differences by 24 mo.⁶²

We then consider the use of antiresorptive therapy, anabolic therapy, or calcitriol or its analogs in selected patients. A number of studies have reported that calcium,

(9)

vitamin D, calcitriol, or bisphosphonates reduce BMD loss after transplantation, and a 2007 meta-analysis reported that treatment with a bisphosphonate, vitamin D sterol or calcitonin after kidney transplantation may protect against reductions in BMD and fracture (RR, 0.51; 95%

CI, 0.27-0.99).⁶³ More recently, a network meta-analysis of 7 studies that included patients who had received kidney transplants reported that teriparatide and denosumab were likely to be the most effective treatments for reducing BMD loss and fracture risk.⁶⁴ Nevertheless, there was moderate to high risk of bias, and optimal treatment after kidney transplantation remains controversial.

Use of Antiresorptive Medications

A concern for the use of antiresorptive drugs has been to avoid causing or perpetuating low bone turnover or adynamic bone. To address this, we avoid using bisphosphonates or denosumab in patients with suppressed BTMs.

The rationale for this was presented in a recent editorial,⁶⁵ which emphasized that bone turnover is central to mineral balance and skeletal integrity and that bone turnover should be considered when starting a therapeutic regimen in patients with low bone density who are likely to have coexisting renal osteodystrophy. Disconcertingly, biochemical BTMs did not reflect bone formation and resorption at

FIGURE 6. Evaluation and management of post-transplant fracture risk. A, Template for bone assessment after transplantation. B, Guide to management options. The treatment algorithm is only a guide to be used in conjunction with discussion of each patient’s history and results.

(10)

the tissue level in a recent study of patients with untreated osteoporosis⁶⁶; however, more extreme values, often seen in transplant patients once renal function recovers, are likely to differentiate high from non-high and low from non-low bone turnover.^12,13 Extrapolating from the general population, in patients with low BMD recruited to the Fracture Intervention Trial and treated with an oral bisphosphonate, higher BTMs were associated with greater BMD responses and nonspine antifracture efficacy.⁶⁷ However, overall fracture risk was decreased, irrespective of BTMs status.

Recently, an association of bisphosphonate therapy with the risk of acute kidney injury (AKI) was reported in a large UK study of frail elderly patients, with a mean age

of 80 y and with complex health needs during exposure to bisphosphonate therapy.⁶⁸ However, there were several differences between those who were or were not exposed, including rates of prevalent fracture. By comparison, no differences in AKI, but some increase in stage worsening, was reported between bisphosphate users and nonusers in a multinational study of patients with moderate to severe CKD.⁶⁹ That study assessed records from the UK’s Clinical Practice Research Datalink and records from Catalonia’s Information System for the Development of Research in Primary Care. The primary outcome was CKD stage worsening, based on annual follow-up of eGFR measure- ments, and referral for dialysis or kidney transplant. The FIGURE 6. Continued

(11)

average age was 78–80 y, and propensity-score-matched patients receiving bisphosphonates in the UK’s Clinical Practice Research Datalink cohort had lower mortality (HR [95% CI]: 0.67 [0.62-0.73]). Those with a history of fracture were more likely to experience stage worsening (sub-HR [95% CI]: 1.36 [1.08-1.71]) than those without a history of fracture (1.10 [0.99-1.22]). However, based on combined propensity-score-matched results of both cohorts over a median of 3–4.4 y exposure, there was a 14% increase in stage worsening: sub-HR (95% CI) 1.14 (1.07-1.23) for bisphosphonate-treated patients. Although the risk from bisphosphonate therapy of worsening renal function or AKI appears low, these drugs do need to be used with caution and regular eGFR monitoring.

Unlike bisphosphonates, denosumab is hepatically metabolized, with no accumulation in CKD. Assessing data from postmenopausal women with osteoporosis and CKD stages 2 and 3 within the FREEDOM trial⁷⁰ and extension study, with follow-up to 10 y, most participants treated with denosumab remained within the same CKD subgroup; participants in all eGFR subgroups showed similar, persistent BMD gain; and the percentage of participants reporting serious AEs was similar among CKD subgroups.⁷¹ However, there is a risk of severe hypocalce- mia,⁷² particularly in patients with hyperparathyroidism, and cessation of denosumab results in an overshoot in bone turnover and the potential for rapid BMD loss and vertebral fracture.⁷³ Currently, the best means to transition from denosumab to a bisphosphonate remains unclear, and we therefore use denosumab less frequently than bisphos- phates, particularly in younger patients. When denosumab has been used for 12 mo or more, regimens used for tran- sitioning off denosumab include an intravenous infusion of zoledronic acid given 6 mo after the last denosumab dose and, depending on BTM responses, consideration of a further dose of zoledronic acid 6 mo later.

Anabolic Agents

Anabolic therapies, including teriparatide and romosozumab, the humanized monoclonal antibody to sclerostin, should be considered, particularly in patients with more severe BMD loss, prevalent fracture or fracture on other therapy, and in patients with low bone turnover, based on biochemical BTMs. Anabolics provide the greatest benefit when used as first-line therapy, but this is often determined by rules for access to subsidized medi- cation. However, they are also valuable second-line treatment after a bisphosphonate and can be used with caution following denosumab. At completion of treatment, they always require “consolidation therapy” with a bisphosphonate such as zoledronate, or with denosumab.

Any increase in CV risk is highly relevant to patients with CKD, and following the romosozumab versus alendronate for osteoporosis ARCH trial (Active-controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk) of postmenopausal women with osteoporosis,⁷⁴ concerns were raised regarding an increased risk of serious CV events in patients allocated to romosozumab, equat- ing to a 2.5% versus 1.9% risk in the first year of treatment. Although this risk cannot be neglected, differences between the drug regimens may have reflected a risk benefit for alendronate. No adverse CV signal was detected in the

large FRAME study (Fracture Study in Postmenopausal Women With Osteoporosis) of postmenopausal women with osteoporosis allocated to romosozumab versus placebo⁷⁵ but in the BRIDGE study (Placebo-controlled Study Evaluating the Efficacy and Safety of Romosozumab in Treating Men with Osteoporosis),⁷⁶ a difference in posi- tively adjudicated CV events was reported for men with osteoporosis treated with romosozumab versus placebo. Reassuringly, no increased risk with romosozumab was identified in a post-hoc analysis of the FRAME and BRIDGE studies that compared treatment effects in participants with CKD stages 1–3.⁷⁷

Parathyroidectomy in the Post-transplant Period Many patients have mild hypercalcemia, hypophosphatemia, and elevated PTH following transplantation, which can be monitored for the first 12 mo without aggressive intervention. However, for patients with ongoing hyperparathyroidism, the timing of parathyroidectomy or its avoidance by use of a calcimimetic is an important consideration.

Understanding the cause of deteriorating renal function is critical in the early post-transplant period, so we avoid parathyroidectomy during the first post-transplant year.

Nevertheless, patients with hyperparathyroidism, more severe hypercalcaemia and high bone turnover may require intervention. Although treatment with an antiresorptive agent can provide protection against PTH-induced loss of BMD, antiresorptive drugs do not reduce PTH values, and for patients with functioning transplants, persistently elevated PTH levels increase tubular reabsorption of calcium and often perpetuate hypercalcemia. In addition, hyperparathyroidism increases the conversion of 25OHD to 1,25(OH)₂D, which exacerbates hypercalcemia. In this situation, the off-label use of cinacalcet will generally ame- liorate hypercalcemia by reducing serum PTH. We would also accept lower values of 25OHD in this situation if supplementation with calciferol exacerbated hypercalcemia.

The question of course is how long to continue with calcimimetic therapy. One retrospective study reported a comparison of kidney transplant patients treated with cinacalcet (n = 30) or parathyroidectomy (utiliz- ing a historical cohort; n = 46).^78,79 Inclusion criteria were hyperparathyroidism and hypercalcemia a year after transplant, or severe hypercalcaemia at any time.

Hypocalcaemia requiring intravenous replacement was seen in 33% of patients following parathyroidectomy. At 12 mo from commencement of cinacalcet or parathyroidectomy, there was greater improvement in serum PTH, calcium, and phosphate values after parathyroidectomy, with 22% having PTH values above the normal range versus 96% in the cinacalcet group. However, at the 3-y follow-up, there was a further reduction in PTH for those treated with cinacalcet. Patients treated with cinacalcet had stable renal function, while those undergoing parathyroidectomy had a decrease in eGFR. Reductions in eGFR following parathyroidectomy are generally transient, with recovery by 12 mo,⁸⁰ and may reflect a hemodynamic effect of PTH on afferent and efferent glomerular arteriolar tone.⁸¹

In patients with significant hyperparathyroidism and hypercalcemia after the first year of transplantation, we

(12)

discuss the option of parathyroidectomy. Pending the outcome of those discussion, we continue antiresorptive therapy (generally using a bisphosphonate) to protect against loss of BMD. In our experience, this lessens the risk of postparathyroidectomy “hungry bone” if the patient proceeds to surgery. We may also continue cinacalcet to protect against severe hypercalcaemia. It is important to be aware that cinacalcet acts on tubular calcium-sensing receptors to increase calcium excretion, although this may be offset by a reduced serum calcium and a reduced filtered calcium load.

Evaluation of VC and body composition (derived from DXA examination) is also important in the post-transplant period, and should be considered as part of the overall management plan. For patients with a high Kauppila abdominal aortic calcification score, we address traditional CV risk factors, maintain normal serum magnesium and vitamin D sufficiency, avoid hypercalcaemia, and may suggest supplementation with vitamin K.

CONCLUSIONS

Patients undergoing kidney transplantation often have increased traditional risk factors for fracture and CV events, plus a legacy of bone abnormalities and soft tissue calcifications that result from CKD-MBD. After kidney transplantation, the risk for some outcomes such as fracture may initially increase, and pretransplant CKD-MBD influences hormonal and biochemical changes, which generally improve over the first post-transplant year. Improved renal function allows the implementation of treatments that reduce fracture risk effectively in the general population, and this requires familiarity with current osteoporosis management. When available, a multidisciplinary approach is valuable for treating these complex patients, in whom potential benefits of treatment should be balanced against the relatively low risk of adverse treatment effects on bone turnover, renal function, and CV health.

REFERENCES

1. Moe S, Drueke T, Cunningham J, et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int.

2006;6911:1945–1953.

2. Leifheit-Nestler M, Haffner D. How FGF23 shapes multiple organs in chronic kidney disease. Mol Cell Pediatr. 2021;8:12.

3. Edmonston D, Wolf M. FGF23 at the crossroads of phosphate, iron economy and erythropoiesis. Nat Rev Nephrol. 2020;16:7–19.

4. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121:4393–4408.

5. Lima F, Mawad H, El-Husseini AA, et al. Serum bone markers in ROD patients across the spectrum of decreases in GFR: Activin A increases before all other markers. Clin Nephrol. 2019;91:222–230.

6. Evenepoel P, D’Haese P, Brandenburg V. Sclerostin and DKK1:

new players in renal bone and vascular disease. Kidney Int.

2015;88:235–240.

7. Poole KE, Reeve J. Parathyroid hormone - a bone anabolic and cata- bolic agent. Curr Opin Pharmacol. 2005;5:612–617.

8. Boltenstal H, Qureshi AR, Behets GJ, et al. Association of serum sclerostin with bone sclerostin in chronic kidney disease is lost in glucocorticoid treated patients. Calcif Tissue Int. 2019;104:214–223.

9. de Oliveira RA, Barreto FC, Mendes M, et al. Peritoneal dialysis per se is a risk factor for sclerostin-associated adynamic bone disease.

Kidney Int. 2015;87:1039–1045.

10. Bisson SK, Ung RV, Picard S, et al. High calcium, phosphate and calcitriol supplementation leads to an osteocyte-like phenotype in

calcified vessels and bone mineralisation defect in uremic rats. J Bone Miner Metab. 2019;37:212–223.

11. Ott SM, Elder GJ. Osteoporosis associated with chronic kidney disease. In: Dempster Cauley, ed. Marcus and Feldman’s Osteoporosis.

Vol. 2. 5th ed. Academic Press; 2021.

12. Jorgensen HS, Behets G, Viaene L, et al. Diagnostic accuracy of non- invasive bone turnover markers in renal osteodystrophy. Am J Kidney Dis. 2022;795:667–676 e1.

13. Ketteler M, Block GA, Evenepoel P, et al. Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) guideline update: what’s changed and why it matters.

Kidney Int. 2017;92:26–36.

14. Wada Y, Kunimura T, Sato S, et al. Proliferating potential and apoptosis in the development of secondary hyperparathyroidism: a study based on Ki-67 immunohistochemical staining and the terminal dUTP nick-end labeling assay. Ther Apher Dial. 2008;12:319–328.

15. Wolf M, Weir MR, Kopyt N, et al. A prospective cohort study of mineral metabolism after kidney transplantation. Transplantation.

2016;100:184–193.

16. Yakupoglu HY, Corsenca A, Wahl P, et al. Posttransplant acidosis and associated disorders of mineral metabolism in patients with a renal graft. Transplantation. 2007;84:1151–1157.

17. Jorgensen HS, Behets G, Bammens B, et al. Patterns of renal osteodystrophy 1 year after kidney transplantation. Nephrol Dial Transplant.

2021;361:2130–2139.

18. Felsenfeld AJ, Gutman RA, Drezner M, et al. Hypophosphatemia in long-term renal transplant recipients: effects on bone histol- ogy and 1,25-dihydroxycholecalciferol. Miner Electrolyte Metab.

1986;125:333–341.

19. Moz Y, Levi R, Lavi-Moshayoff V, et al. Calcineurin Abeta is central to the expression of the renal type II Na/Pi co-transporter gene and to the regulation of renal phosphate transport. J Am Soc Nephrol.

2004;151:2972–2980.

20. Evenepoel P, Claes K, Viaene L, et al. Decreased circulating sclerostin levels in renal transplant recipients with persistent hyperparathyroidism. Transplantation. 2016;100:2188–2193.

21. Pietrzak B, Wielgos M, Kaminski P, et al. Menstrual cycle and sex hormone profile in kidney-transplanted women. Neuro Endocrinol Lett.

2006;271:198–202.

22. Aleksova J, Wong P, McLachlan R, et al. Sex hormone-binding globulin is a biomarker associated with nonvertebral fracture in men on dialysis therapy. Kidney Int. 2018;94:372–380.

23. Meng C, Jorgensen HS, Verlinden L, et al. Contemporary kidney transplantation has a limited impact on bone microarchitecture. Bone Rep. 2022;16:101172.

24. Sharma AK, Toussaint ND, Masterson R, et al. Deterioration of cortical bone microarchitecture: critical component of Renal Osteodystrophy evaluation. Am J Nephrol. 2018;47:376–384.

25. Nickolas TL, Stein EM, Dworakowski E, et al. Rapid cortical bone loss in patients with chronic kidney disease. J Bone Miner Res.

2013;28:1811–1820.

26. Sharma AK, Toussaint ND, Elder GJ, et al. Magnetic resonance imaging based assessment of bone microstructure as a non-invasive alter- native to histomorphometry in patients with chronic kidney disease.

Bone. 2018;114:14–21.

27. Aleksova J, Milat F, Kotowicz M, et al. Patients with end stage kidney disease have markedly abnormal cortical hip parameters by dual-energy X-ray absorptiometry. Nephrol Dial Transplant.

2021;36:543–550.

28. KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis.

Evaluation, Prevention, and Treatment of Chronic Kidney Disease–

Mineral and Bone Disorder (CKD-MBD). Kidney Inter Supplements.

2017;7:1–59.

29. Naylor KL, Lix LM, Hans D, et al. Trabecular bone score in kidney transplant recipients. Osteoporos Int. 2016;273:1115–1121.

30. Ohnaru K, Sone T, Tanaka K, et al. Hip structural analysis: a comparison of DXA with CT in postmenopausal Japanese women.

Springerplus. 2013;2:331.

31. Arici M, Erturk H, Altun B, et al. Bone mineral density in haemodi- alysis patients: a comparative study of dual-energy X-ray absorptiometry and quantitative ultrasound. Nephrol Dial Transplant.

2000;151:1847–1851.

32. Kim SM, Long J, Montez-Rath M, et al. Hip fracture in patients with non-dialysis-requiring chronic kidney disease. J Bone Miner Res.

2016;31:1803–1809.

(13)

33. Alem AM, Sherrard DJ, Gillen DL, et al. Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int.

2000;58:396–399.

34. Tentori F, McCullough K, Kilpatrick RD, et al. High rates of death and hospitalization follow bone fracture among hemodialysis patients.

Kidney Int. 2014;85:166–173.

35. Vautour LM, Melton LJ, 3rd, Clarke BL, et al. Long-term fracture risk following renal transplantation: a population-based study. Osteoporos Int. 2004;15:160–167.

36. Ball AM, Gillen DL, Sherrard D, et al. Risk of hip fracture among dialysis and renal transplant recipients. JAMA. 2002;288:3014–3018.

37. Iyer SP, Nikkel LE, Nishiyama KK, et al. Kidney transplantation with early corticosteroid withdrawal: paradoxical effects at the central and peripheral skeleton. J Am Soc Nephrol. 2014;25:1331–1341.

38. Marques IDB, Araujo M, Graciolli FG, et al. A randomized trial of zoledronic acid to prevent bone loss in the first year after kidney transplantation. J Am Soc Nephrol. 2019;30:355–365.

39. Aleksova J, Wong P, Mulley WR, et al. Serum phosphorus levels and fracture following renal transplantation. Clin Endocrinol (Oxf).

2017;87:141–148.

40. Salter ML, Liu X, Bae S, et al. Fractures and subsequent graft loss and mortality among older kidney transplant recipients. J Am Ger Soc.

2019;67:1680–1688.

41. Banks E, Reeves GK, Beral V, et al. Hip fracture incidence in relation to age, menopausal status, and age at menopause: prospective analysis. PLoS Med. 2009;61:e1000181.

42. Janghorbani M, Van Dam RM, Willett WC, et al. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidem.

2007;166:495–505.

43. Gao Y, Chai F. Risk of non-vertebral fractures in men with type 2 diabetes: a systematic review and meta-analysis of cohort studies. Exp Gerontol. 2021;150:111378.

44. Aleksova J, Ebeling PR, Milat F, et al. DXA-derived advanced hip analysis and the trabecular bone score in end stage kidney disease secondary to type 1 diabetes. Eur J Endocrinol. 2022;187:883–892.

45. Jain RK, Vokes T. Fat mass has negative effects on bone, especially in men: a cross-sectional analysis of NHANES 2011-2018. J Clin Endocrinol Metab. 2022;107:e2545–e2552.

46. Whitlock RH, Leslie WD, Shaw J, et al. The Fracture Risk Assessment Tool (FRAX(R)) predicts fracture risk in patients with chronic kidney disease. Kidney Int. 2019;95:447–454.

47. Przedlacki J, Buczynska-Chyl J, Kozminski P, et al. The utility of FRAX(R) in predicting bone fractures in patients with chronic kidney disease on hemodialysis: a two-year prospective multicenter cohort study. Osteoporos Int. 2018;29:1105–1115.

48. Shlipak MG, Fried LF, Cushman M, et al. Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. JAMA. 2005;293:1737–1745.

49. Chen NX, Kiattisunthorn K, O’Neill KD, et al. Decreased microRNA is involved in the vascular remodeling abnormalities in chronic kidney disease (CKD). PLoS One. 2013;8:e64558.

50. Viegas CSB, Santos L, Macedo AL, et al. Chronic kidney disease circulating calciprotein particles and extracellular vesicles promote vascular calcification: a role for GRP (Gla-Rich Protein). Arterioscler Thromb Vasc Biol. 2018;38:575–587.

51. Kauppila LI, Polak JF, Cupples LA, et al. New indices to classify loca- tion, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study. Atherosclerosis. 1997;132:245–250.

52. Lewis JR, Wong G, Taverniti A, et al. Association between aortic calcification, cardiovascular events, and mortality in kidney and pancreas- kidney transplant recipients. Am J Nephrol. 2019;50:177–186.

53. Baker RJ, Mark PB, Patel RK, et al. Renal association clinical practice guideline in post-operative care in the kidney transplant recipient.

BMC Nephrol. 2017;18:174.

54. Khairallah P, Nickolas TL. Bone and mineral disease in kidney transplant recipients. Clin J Am Soc Nephrol. 2022;17:121–130.

55. Kovvuru K, Kanduri SR, Vaitla P, et al. Risk factors and management of osteoporosis post-transplant. Medicina (Kaunas). 2020;56.

56. Vangala C, Pan J, Cotton RT, et al. Mineral and bone disorders after kidney transplantation. Front Med (Lausanne). 2018;5:1–16.

57. Mainra R, Elder GJ. Individualized therapy to prevent bone mineral density loss after kidney and kidney-pancreas transplantation. Clin J Am Soc Nephrol. 2010;5:117–124.

58. Hampson G, Elder GJ, Cohen-Solal M, et al. A review and perspective on the assessment, management and prevention of fragility fractures in patients with osteoporosis and chronic kidney disease. Endocrine.

2021;73:509–529.

59. Correale M, Paolillo S, Mercurio V, et al. Comorbidities in chronic heart failure: an update from Italian Society of Cardiology (SIC) Working Group on Heart Failure. Eur J Intern Med.

2020;71:23–31.

60. Rodríguez-Espinosa D, Guzman-Bofarull J, De La Fuente-Mancera JC, et al. Multimodal strategies for the diagnosis and management of refractory congestion. An integrated cardiorenal approach. Front Physiol. 2022;13:913580.

61. Dhillon-Jhattu S, McGill RL, Ennis JL, et al. Vitamin D and parathyroid hormone levels in CKD. Am J Kidney Dis. 2023;81:122–124.

62. Nikkel LE, Mohan S, Zhang A, et al. Reduced fracture risk with early corticosteroid withdrawal after kidney transplant. Am J Transplant.

2012;12:649–659.

63. Palmer SC, McGregor DO, Strippoli GF. Interventions for preventing bone disease in kidney transplant recipients. Cochrane Database Syst Rev. 2019;10:CD005015.

64. Chen CH, Lo WC, Hu PJ, et al. Efficacy of osteoporosis medications for patients with chronic kidney disease: an updated systematic review and network meta-analysis. Front Pharmacol. 2022;13:822178.

65. Ott SM, Malluche HH, Jorgetti V, et al. Importance of bone turnover for therapeutic decisions in patients with CKD-MBD. Kidney Int.

2021;100:502–505.

66. Malluche HH, Davenport DL, Lima F, et al. Prevalence of low bone formation in untreated patients with osteoporosis. PLoS One.

2022;17:e0271555.

67. Bauer DC, Garnero P, Hochberg MC, et al. Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res. 2006;219:292–299.

68. Oda T, Jodicke AM, Robinson DE, et al. Oral bisphosphonates are associated with increased risk of severe acute kidney injury in elderly patients with complex health needs: a self-controlled case series in the United Kingdom. J Bone Miner Res.

2022;37:1270–1278.

69. Robinson DE, Ali MS, Pallares N, et al. Safety of oral bisphosphonates in moderate-to-severe chronic kidney disease: a binational cohort analysis. J Bone Miner Res. 2021;36:820–832.

70. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis.

N Engl J Med. 2009;361:756–765.

71. Broadwell A, Chines A, Ebeling PR, et al. Denosumab safety and efficacy among participants in the FREEDOM extension study with mild to moderate chronic kidney disease. J Clin Endocrinol Metab.

2021;106:397–409.

72. Block GA, Bone HG, Fang L, et al. A single-dose study of denosumab in patients with various degrees of renal impairment. J Bone Miner Res. 2012;27:1471–1479.

73. Iseri K, Watanabe M, Yoshikawa H, et al. Effects of denosumab and alendronate on bone health and vascular function in hemodialysis patients: a randomized, controlled trial. J Bone Miner Res.

2019;34:1014–1024.

74. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med.

2017;377:1417–1427.

75. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med.

2016;375:1532–1543.

76. Lewiecki EM, Blicharski T, Goemaere S, et al. A phase III randomized placebo-controlled trial to evaluate efficacy and safety of romosozumab in men with osteoporosis. J Clin Endocrinol Metab.

2018;103:3183–3193.

77. Miller PD, Adachi JD, Albergaria BH, et al. Efficacy and safety of romosozumab among postmenopausal women with osteoporosis and mild-to-moderate chronic kidney disease. J Bone Miner Res.

2022;37:1437–1445.

78. Rivelli GG, Lima ML, Mazzali M. Therapy for persistent hypercalcemic hyperparathyroidism post-renal transplant: cinacalcet versus parathyroidectomy. J Bras Nefrol. 2020;42:315–322.

79. Rivelli GG, Lopes de Lima M, Mazzali M. Safety and efficacy of a 3-year therapy with cinacalcet in persistent hyperparathyroidism after renal transplant. Transplant Proc. 2020;52:1284–1286.

80. Parikh S, Nagaraja H, Agarwal A, et al. Impact of post-kidney transplant parathyroidectomy on allograft function. Clin Transplant.

2013;27:397–402.

81. Massfelder T, Parekh N, Endlich K, et al. Effect of intrarenally infused parathyroid hormone-related protein on renal blood flow and glomerular filtration rate in the anaesthetized rat. Br J Pharmacol.

1996;118:1995–2000.