ckd bmd in tx
TRANSCRIPT
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In Practice
CKDMineral and Bone Disorder Management in KidneyTransplant Recipients
Hala M. Alshayeb, MD,1 Michelle A. Josephson, MD,1 and Stuart M. Sprague, DO2
Kidney transplantation, the most effective treatment for the metabolic abnormalities of chronic kidney
disease (CKD), only partially corrects CKDmineral and bone disorders. Posttransplantation bone
disease, one of the major complications of kidney transplantation, is characterized by accelerated loss of
bone mineral density and increased risk of fractures and osteonecrosis. The pathogenesis of posttransplan-
tation bone disease is multifactorial and includes the persistent manifestations of pretransplantation
CKDmineral and bone disorder, peritransplantation changes in the fibroblast growth factor 23
parathyroid hormonevitamin D axis, metabolic perturbations such as persistent hypophosphatemia and
hypercalcemia, and the effects of immunosuppressive therapies. Posttransplantation fractures occur more
commonly at peripheral than central sites. Although there is significant loss of bone density after
transplantation, the evidence linking posttransplantation bone loss and subsequent fracture risk is
circumstantial. Presently, there are no prospective clinical trials that define the optimal therapy for
posttransplantation bone disease. Combined pharmacologic therapy that targets multiple components of
the disordered pathways has been used. Although bisphosphonate or calcitriol therapy can preserve bone
mineral density after transplantation, there is no evidence that these agents decrease fracture risk.Moreover, bisphosphonates pose potential risks for adynamic bone disease.
Am J Kidney Dis. 61(2):310-325. 2013 by the National Kidney Foundation, Inc.
INDEX WORDS: Posttransplantation bone disease; epidemiology; pathogenesis; screening; diagnosis;
management.
CASEPRESENTATION
A 68-year-old white woman with a 37-year history of membra-
nous glomerulonephritis and progressive chronic kidney disease
(CKD) was found to have decreasing bone mineral density (BMD)
2 years after a pre-emptive living unrelated kidney transplantation.
Dual-energy x-ray absorptiometry (DEXA) showed T scores of
3.1 and 1.9 at the lumbar spine and femoral neck, respec-
tively. These values represented a decrease of 6% and 12.2%,
respectively, compared with the study performed at the time of
transplantation. Her induction immunosuppression therapy in-
cluded high-dose prednisone and polyclonal antithymocyte
globulin followed by maintenance therapy with cyclosporine,
75 mg, twice a day; azathioprine, 100 mg; and prednisone, 5 mg
daily. Other pertinent medications included alendronate, 70
mg/wk, that was started 4 years prior to transplantation, and
ergocalciferol, 50,000 U/wk. She was a nonsmoker. Age of
menarche was 13 years, with spontaneous menopause in her late
40s. Skeletal history was significant for 3 foot fractures in
childhood, one traumatic fracture 5 years prior to transplanta-
tion, and avascular necrosis of the left hip with a total hip
replacement 8 months posttransplantation. She had 3 cellular
rejection episodes during the first 10 months posttransplanta-
tion, all requiring intensified steroid dosing. OKT3 and poly-
clonal antithymocyte globulin also were used for the first and
third rejection episodes, respectively. Physical examination
showed a short frail-appearing woman with body mass index of22 kg/m2. Musculoskeletal examination was significant for a
1-inch left hip elevation. Pertinent laboratory data showed estimated
glomerular filtration rate (eGFR) of 40 mL/min/1.73 m2 and normal
serum calcium, phosphorus, calcidiol, and calcitriol concentrations.
Intact parathyroid hormone (PTH) level was elevated at 206 pg/mL,
and other values were for bone-specific alkaline phosphatase (16;
reference range, 9.1-27.5 U/L), osteocalcin (11.3; reference range,
0.4-8.7 ng/mL), and urine telopeptide (38; reference range, 65
nmol/mmoL).
INTRODUCTION
Posttransplantation bone disease is a complex
disorder and may lead not only to reduced bonequality or bone loss, which may result in fractures,
but also to changes in mineral metabolism. Al-
though considered to be within the spectrum of
CKDmineral bone disease,1,2 posttransplantation
bone disease is markedly different from the mineral
and bone disorders often seen in patients with CKD
and end-stage kidney disease and is influenced by
factors such as immunosuppressive therapy, kidney
transplant function, hypophosphatemia, and distur-
bances in the fibroblastic growth factor 23 (FGF-23)-
PTHvitamin D axis.
From the 1Department of Medicine, Section of Nephrology,University of Chicago, Chicago; and 2Department of Medicine,Section of Nephrology, NorthShore University HealthSystem, Evan-ston, IL.
Received March 5, 2012. Accepted in revised form July 9, 2012.Originally published online October 29, 2012.
Address correspondence to Stuart M. Sprague, DO, Departmentof Medicine, Section of Nephrology and Hypertension, NorthShoreUniversity Health System, 2650 Ridge Ave, Evanston, IL 60201.E-mail: [email protected]
2013 by the National Kidney Foundation, Inc.0272-6386/$36.00http://dx.doi.org/10.1053/j.ajkd.2012.07.022
Am J Kidney Dis. 2013;61(2):310-325310
mailto:[email protected]:[email protected]://dx.doi.org/10.1053/j.ajkd.2012.07.022http://dx.doi.org/10.1053/j.ajkd.2012.07.022http://dx.doi.org/10.1053/j.ajkd.2012.07.022mailto:[email protected] -
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EPIDEMIOLOGYOF POSTTRANSPLANTATION
BONEDISEASE
Posttransplantation osteoporosis is a common prob-
lem, with a prevalence of 11%-56% in long-term
kidney transplant recipients.3-5 Bone loss is acceler-
ated in the first 6-12 months after transplantation3-13
and predominantly involves trabecular bone. The re-
ported rate of bone loss in the first 6 months ranges
from 0.05%-14.5%; after 6 months, the rate varies
from 0.01%-7.9%; and after 12 months, bone loss
rates are reported to be 0.8%-9%. Bone loss in cortical
bone, which is predominant in the femoral neck, is
less pronounced. Almond et al14 found femoral neck
bone loss to be 3.9% at 3 months in male transplant
recipients. In contrast Mikuls et al15 found minimal or
no significant loss in the femoral neck during the first
6 months posttransplantation, and Smets et al16 showed
that femoral BMD is stable after 6 months. Data
regarding bone loss in long-term kidney transplantrecipients (ie, 12 months posttransplantation) are
conflicting, with some studies showing either less
pronounced loss of bone or even a late increase in
BMD, and others indicating ongoing bone loss.7,17,18
Fracture rates after kidney transplantation have
been reported to range from 5%-44%,3-5,19-31 with
fracture episodes increasing over time after transplan-
tation.32 Although posttransplantation fractures occur
both peripherally and centrally,33 most studies demon-
strate more fractures occurring at peripheral
sites.18,34-36 Compared with dialysis patients on the
waiting list, the relative risk of hip fracture in trans-plant recipients is 34% higher during the first 6
months posttransplantation and decreases by 1%
each month thereafter.37 Diabetes is an important risk
factor for posttransplantation fractures because dia-
betic patients receiving a kidney-pancreas transplant
have fracture rates up to 49%.38 Posttransplantation
fractures are associated with decreased survival, in-
creased morbidity, and higher hospitalization rates
compared with the general population.39 Risk factors
for posttransplantation bone loss and fractures are
summarized in Box 1.23,34-36,40-47 Decreased BMD
posttransplantation does not necessarily predict therisk of fracture.25,27
PATHOGENESISOF POSTTRANSPLANTATION
BONEDISEASE
RenalOsteodystrophy
Renal osteodystrophy is common, with 90%-100%
of kidney transplant recipients having histologic evi-
dence of osteodystrophy and osteopenia.48-50 High-
turnover bone disease as a result of persistent hyper-
parathyroidism has been reported in 25%-50% of
bone biopsies in kidney transplant recipients with
varying degree of severity.50 Adynamic bone disease
(characterized by decreased numbers of osteoblasts
and osteoclasts and reduced bone turnover) is a much
more common problem and accounts for 5%-50% of
the bone pathology observed in kidney transplant
recipients prior to the introduction of bisphosphonate
treatment.3,50,51
Adynamic bone disease may be exac-erbated further by the use of bisphosphonates after
transplantation.52 Mixed uremic bone disease (charac-
terized by a mixture of elements of both high and low
bone turnover with a mineralization defect) accounts
for12% of bone pathology after kidney transplanta-
tion.50 Osteomalacia (characterized by prolonged min-
eralization lag time and increased volume of osteoid
in association with low osteoclast and osteoblast activi-
ties) is uncommon bone pathology in kidney trans-
plant recipients, with a prevalence 5% even when
hypophosphatemia is present.50
Box 1. Factors Associated With Posttransplantation Bone Loss
and Fracture
Factors associated with increased risk of posttransplanta-
tion bone loss
Duration of dialysis prior to transplantation
Cumulative dose of glucocorticoid
Younger age at transplantation Vitamin D deficiency
Functionally different alleles of the VDR genea
High and low pretransplantation PTH levelsb
BMI23 kg/m2
High serum FGF-23 level
Risk factors for posttransplantation fractures (presence of
3 risk factors indicates high fracture risk)
Duration of dialysis prior to transplantation
Cumulative dose of glucocorticoid use
Time since transplantation
Female sex
Hypogonadal state
BMI23 kg/m2
Lumbar osteoporosis or nonvertebral fractures
Postural instability,decreased visual acuity, peripheral vascu-
lar disease, peripheral neuropathy, frequent falls
Diabetes
Age45 y
Pretransplantation high or low PTH levels or presence of
osteitis fibrosa cystica
Abbreviations: BMI, body mass index; FGF-23, fibroblast
growth factor 23; PTH, parathyroid hormone; VDR, vitamin D
receptor.aBMD levels posttransplantation are lower in the Bb and BB
genotype groups than the bb group.bHigh pretransplantation PTH level,500 pg/mL; low pretrans-
plantation PTH level,195 pg/mL.
Based on data from Ramsey-Goldman et al,23 Van Staa etal,34 Unal et al,35 Ozel et al,36 Nikkel et al,40 Kanaan et al,41
Dolgos et al,42 Braga et al,43 Marcen et al,44 Opelz and Dohler,45
Stehman-Breen et al,46 and Mainra et al.47
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ImmunosuppressiveAgents
Glucocorticoids are a main contributor to boneloss posttransplantation, particularly to the rapid
loss occurring in the first 6-12 months, because they
inhibit bone formation and enhance bone resorp-
tion.53-57 Table 1 lists the multifactorial effects of
glucocorticoids and other immunosuppressant agents
on bone.14,53-66
Changes inBoneRemodelingPosttransplantation
The primary changes to bone remodeling after
kidney transplantation are a decrease in bone forma-
tion and mineralization as a consequence of altera-tions in osteoblast function, decreased osteoblastogen-
esis, and increased osteoblast apoptosis coupled with
persistent bone resorption, resulting in bone loss.
Rojas et al48 prospectively studied 20 kidney allo-
graft recipients, performing bone biopsies on the
day of transplantation and within 21-120 days after
transplantation. They showed that osteoid and osteo-
blast surfaces decreased within 35 days of transplan-
tation, with prolongation of mineralization lag time,
consistent with decreased bone turnover. Resorp-
tive and osteoclast surfaces remained above nor-
mal. Forty-five percent of patients showed earlyosteoblast apoptosis and a decrease in osteoblast
surface and number. Osteoblast apoptosis was ob-
served more often in patients with both low turn-
over and mixed bone disease than in patients with
high turnover. The few bone biopsy studies that
evaluated patients with long-term relatively normal
functioning kidney transplants showed either a
purely adynamic lesion as the predominant pathol-
ogy67 or decreased bone formation with prolonged
mineralization lag time (low turnover) with fea-
tures of persistent bone resorption.68,69
Changes inMineralMetabolism
PostKidneyTransplantationCalcidiol deficiency and insufficiency are common
in kidney transplant recipients, with reported preva-
lences of 30% and 81%, respectively.70 The cause is
multifactorial and may be secondary to nutritional
deficiency, malabsorption, and decreased sun expo-
sure. Moreover, the regaining of functioning nephron
mass and subsequent increase in CYP27b (1-
hydroxylase) activity results in increased metabolism
of calcidiol to calcitriol, which subsequently causes a
gradual decrease in PTH concentrations during the
first 3-6 months posttransplantation.15,71 However,
persistent hyperparathyroidism still exists in 33%and 20% of patients at 6 and 12 months posttransplan-
tation, respectively.72 Contributory factors include the
degree of parathyroid gland hyperplasia and/or nodu-
larity coupled with downregulation of both the vita-
min D receptor (VDR) and calcium-sensing receptor
pretransplantation, as well as persistent CKD after
transplantation. Concentrations of the phosphaturic
hormone FGF-23 decrease immediately posttransplan-
tation, although they remain inappropriately elevated
in respect to the prevailing serum phosphate concen-
tration.73 By about 3 months posttransplantation,
FGF-23 concentrations are decreased by 89%,74
andby 12 months, FGF-23 concentrations are appropriate
for the CKD stage of the transplant.75 Elevated FGF-23
level results in an inhibition of CYP27b1 and likely
contributes to the low levels of calcitriol in the early
posttransplantation period, which may contribute to the
persistent hyperparathyroidism seen after transplanta-
tion. The elevated FGF-23 and PTH and low calcitriol
concentrations likely contribute to the hypophosphatemia
observed in many patients after transplantation.76 Cal-
cium levels typically decrease in the very early post-
transplantation period as a result of cessation of VDR
Table 1. Effects of Immunosuppressive Agents on Bone
Immunosuppressive Agent Effect on Bone
Glucocorticoids53-57 Effect on osteoblasts: decreases bone formation by inducing apopotosis, inhibiting function,
and decreasing collagen synthesis. Effect on osteoclasts: increases bone resorption
through osteoclast activation by upregulation of RANKL/OPG; systemic effects include
decreased gastrointestinal absorption of calcium, increased renal calcium wasting,increased PTH, hypogonadism, myopathy, avascular necrosis
Calcineurin inhibitors: cyclosporine58-63
and tacrolimus14,58,60,64,66,Controversial effect: in vitro appears to inhibit bone resorption; in vivo appears to increase
bone resorption, leading to bone formation
Mycophenolate mofetil6 No effect
Azathioprine6 No effect
Sirolimus65 Controversial effect; in vitro appears to inhibit osteoclast differentiation
Evirolimus66 Controversial effect; in vitro appears to inhibit osteoclast formation, activity, and
differentiation
Abbreviations: OPG, osteoprotegerin; PTH, parathyroid hormone; RANKL, receptor activator of nuclear factor-B ligand.
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activators (VDRAs) and calcium-containing phos-
phate binders. However, after that initial decrease,
calcium concentrations progressively increase, with
hypercalcemia developing in a substantial number ofpatients during the first to third months posttransplan-
tation.77,78 Hypercalcemia can be transient, resolving
by 6-8 months posttransplantation in some patients,79
but lasting for many years in others.80 Hypercalcemia
typically is associated with hyperparathyroidism and
results from enhanced renal tubular reabsorption of
calcium under the influence of PTH in the functioning
transplant, the effects of calcitriol on the gastrointesti-
nal absorption of calcium, and potentially by a direct
effect of PTH in causing calcium efflux from the
bone. Low bone turnover with relatively low PTH
levels also may result in hypercalcemia because thebone is not able to act as a buffer for the circulating
calcium pool.
RelationshipBetweenBoneLossand
VascularCalcifications
In CKD, observational studies have shown a strong
inverse correlation between BMD and cardiovascular
morbidity, cardiovascular mortality, as well as vascu-
lar calcification.81,82 Moreover, calcium apatite forms
the crystal component of bone and has been found to
accumulate in calcified blood vessels of many patientswith CKD, and calcified plaques also were shown to
express several bone matrix proteins that stimulate
vascular smooth muscle cells to differentiate to osteo-
blasts. These findings support an important interaction
of bone disorders and calcification of soft tissues.83,84
In the early postkidney transplantation period, obser-
vational studies have shown progression of both coro-
nary and aortic vascular calcifications,50,85 a finding
that possibly is linked to the accelerated bone loss in
the same period and should be evaluated further in
prospective studies.
SCREENINGANDDIAGNOSIS OF
POSTTRANSPLANTATION BONE DISEASE
Biochemical
Posttransplantation monitoring for alternations inbone and mineral metabolism is helpful to targettreatment more effectively. In the immediate posttrans-plantation period (up to 8 weeks), KDIGO (KidneyDisease: Improving Global Outcomes) guidelines rec-
ommend weekly monitoring of serum calcium andphosphorus concentrations until levels normalize.86
After the immediate posttransplantation period (8weeks), serum calcium, phosphorus, and PTH levelsshould be followed up according to KDIGO CKDMineral and Bone Disorders 2009 guidelines (Table2).86 Additionally, serum vitamin D levels should bechecked in the early posttransplantation period.86 Mea-surement of PTH and biomarkers of bone formation
(bone-specific alkaline phosphatase and osteocalcin)and bone resorption (urinary collagen breakdown prod-ucts and TRAP5b) does not correlate with bone lossor predict bone histology.87 However, monitoring thetrends of biomarkers over time may be suggestive ofthe bone turnover rate because they typically respondwithin days or weeks after initiation of antiresorptivetherapy, with a faster response rate in biomarkers ofbone resorption than of bone formation.88 Therefore,
they may provide some guidance about whether
therapy should be focused on increasing or decreasingbone turnover in the absence of a biopsy.
Radiographic
DEXA scans are a relatively accurate noninvasivecost-effective screening method of estimating bonemass with low exposure of radiation.89 Results ofDEXA scans are interpreted according to the World
Health Organization (WHO) classification of osteopo-rosis.90 It is important to note that the WHO classifica-tion was developed to predict fracture risk based ondata extrapolated from white postmenopausal women.
Table 2. KDIGO CKD-MBD 2009 Guidelines for Frequency of Measurements of Serum Calcium, Phosphorus, and Intact PTH After
8 Weeks Posttransplantation
CKD
Stage
GFR Range
(mL/min/1.73 m2)
Measurement
of PTH (pg/mL)
Measurement of Alkaline
Phosphatase (U/L)
Measurement of Calcium
and Phosphorus (mg/dL)
1T 90 Every 12 mo Not recommended Every 6-12 mo
2T 60-90 Every 12 mo Not recommended Every 6-12 mo3T 30-59 Every 12 mo Every 12 mo Every 6-12 mo
4T 15-29 Every 6-12 mo Every 12 mo Every 3-6 mo
5T 15 Every 3-6 mo Every 12 mo Every 1-3 mo
Note:Conversion factors for units: serum calcium in mg/dL to mmol/L,0.2495; serum phosphorus in mg/dL to mmol/L,0.323.
Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate; PTH, intact parathyroid hormone; MBD, Mineral and
Bone Disorder.
Based on data from Kidney Disease: Improving Global Outcomes Transplant Work Group.86
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This initial standardization of DEXA limits its applica-bility to many populations, including the transplanta-tion population, as shown by the poor correlationbetween BMD and fracture risk in posttransplantationpatients. Furthermore, BMD provides no informationregarding bone quality or turnover27 and measure-
ments may be skewed because of extraskeletal calcifi-cations, osteosclerosis, and osteomalacia.27 Thus, theindication for DEXA scanning after transplantation isunclear. Nevertheless, it has been recommended thatwhen patients have GFR30 mL/min/1.73 m2, DEXAscans may be obtained at the time of transplanta-tion47,86,91 or within the first 3 months after transplan-tation,86 particularly if patients are receiving glucocor-ticoids or have other risk factors for rapid bone loss.
DEXA scans can be repeated at 12-month intervals ifBMD decreases by5% or otherwise every 2 years32
to determine response to therapy and make decisionsabout whether therapy can be discontinued. BMDtesting is of no proven benefit in predicting fracturerisk in patients with eGFR30 mL/min/1.73 m2 andshould not be performed routinely in this patientpopulation.86 Results of a DEXA scan should beinterpreted in the setting of clinical history, risk fac-
tors, bone biomarkers, and a bone biopsy, if possible.When fractures are suspected, lateral spine radio-graphs can be obtained to screen for spinal fragilityfractures, either with or instead of DEXA scans.
BoneBiopsy
Bone biopsy is the gold standard for the identifica-tion and classification of posttransplantation bone
disease. It involves histologic examination of undecal-cified sections of bone from iliac crest with doubletetracycline labeling.92 Biopsy is helpful to classifybone as having increased or decreased turnover, in-creased or decreased volume, or normal versus abnor-mal mineralization. Unfortunately, a biopsy is rarelyobtained because of its invasive nature and the require-ment of special expertise in obtaining and analyzingbiopsy specimens. However, this should not prevent
the use of bone biopsies. Bone biopsy should beconsidered to assist in the assessment and treatment of
patients with multiple fractures or unexplained hyper-calcemia. Furthermore, a biopsy may be helpful torule out low turnover prior to the initiation of bisphos-phonate therapy.86,93
MANAGEMENT OF POSTTRANSPLANTATION
BONEDISEASE
GeneralMeasures
Preventive measures for osteoporosis in the generalpopulation also apply to transplant recipients, includ-ing smoking cessation, decreased alcohol consump-
tion, early mobilization after transplantation, fall risk
reduction, and weight-bearing exercise. Cautious use
of gonadal hormone replacement therapy for short
periods in men and postmenopausal women with
hypogonadism who do not have contraindications to
hormone replacement therapy has been shown to slow
the rate of bone loss in solid-organ transplant recipi-ents.94,95 However, these therapies should not be
considered first-line therapy because of increased risks
of thrombotic events, cancer, and coronary artery
disease. Various therapeutic strategies are listed in
Tables 3 and 4, with the key therapeutic studies
summarized in Tables 5 and 6.
SteroidSparingandSteroidWithdrawal
The increasing use of steroid-sparing and steroid-
withdrawal protocols has been associated with de-
creased bone loss, but with limited information for
fracture risk.96-99 In a study of 57 simultaneous kidney-
pancreas recipients who received steroid-sparing im-
munosuppression protocols, BMD measurements at 1
year showed improvement at the lumbar spine with
stable BMD at the femoral neck.At 4 years, BMD had
increased at both the lumbar spine and femoral neck.96
Steroid withdrawal 3 months after kidney transplanta-
tion was associated with decreased risk of osteoporo-
sis,97 and steroid withdrawal 1 year after kidney
transplantation was associated with improved BMD at
the femoral neck, total hip, and lumbar spine.98 Unfor-
tunately, there is no information about whether preser-vation of BMD results in fewer fractures, and data
from observational studies for whether early cortico-
steroid withdrawal decreases fracture risk are conflict-
ing.96,99,100 An observational study of 77,430 kidney
transplant recipients with a median follow-up of 3.9
(range, 2.2-5.6) years showed that steroid withdrawal
was associated with a 31% fracture risk reduction
(hazard ratio, 0.69; 95% confidence interval, 0.59-
0.81). Fracture incidence rates were significantly lower
in recipients discharged without versus with steroid
therapy (0.0058 vs 0.008 event/patient-year, respec-
tively).100
However, in 175 solid-organ recipientswith limited steroid exposure during the first 2-6
months after transplantation, Edwards et al99 found
that 27% (32% kidney-pancreas recipients) developed
fractures within 6 years. This fracture rate is similar to
that previously reported in kidney-pancreas recipients
who received steroids.29 The differences between
these studies may be related to differences in the
timing of steroid withdrawal. Further prospective com-
parative analyses are required to determine the impact
of steroid-sparing regimens on subsequent fracture
risk.
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CalciumandVitaminDSupplementation
Calcidiol deficiency is a prevalent problem in trans-plant patients. The effects of correcting calcidiol defi-ciency on BMD in transplant recipients remain con-troversial. Wissing et al101 showed that althoughcholecalciferol supplementation (25,000 IU/mo) con-
tributed to normalization of PTH levels, it did notprevent posttransplantation bone loss, whereas Sahinet al102 showed that oral administration of 400 IU/d ofcholecalciferol with 600 mg/d of calcium for 1 yearresulted in improved PTH levels and a significantincrease in femoral neck BMD. Thus, treatment ofcalcidiol deficiency with either cholecalciferol or ergo-calciferol appears reasonable given the effects onimproving calcium balance, decreasing PTH levels,
and potential beneficial effects on immune and endo-crine functions.103
VDRActivatorsVDRAs may influence posttransplantation min-
eral bone disease by several mechanisms. VDRAadministration reverses the glucocorticoid-induceddecrease in intestinal calcium absorption, directlysuppresses PTH secretion, promotes differentiationof osteoblast precursors into mature cells, and in-creases the intestinal absorption of calcium and
phosphorus.104 Several studies have shown thatoral calcitriol decreases PTH concentrations in theposttransplantation period.105-107 Other studies showthat calcitriol and other VDRAs improve BMD
after kidney transplantation.62,104,107,110,111,143 How-ever, these studies did not evaluate clinically impor-
tant outcomes such as mortality, hospitalizations, orfractures. However, VDRA use has been associatedwith prolongation of transplant survival.144 We recom-mend the use of VDRAs to prevent bone loss in
patients with osteopenia (T score, 1 to 2.5) orosteoporosis (T score less than 2.5) who have evi-dence of low turnover as confirmed by bone biopsy orsuggested by bone biomarkers because bisphospho-nate use should be avoided. VDRA use in this
patient population has been shown to preserveBMD for up to 12 months.47 Furthermore, VDRAsshould be considered in patients with normal BMDand no history of fragility fractures because boneloss is accelerated in the early posttransplantationperiod. In addition, the use of VDRAs to potentiallyprevent bone loss in patients with eGFR 30 mL/
min and secondary hyperparathyroidism withouthypercalcemia appears to be reasonable (Table 4).
Frequent monitoring of serum calcium, phosphate,and PTH levels are warranted with the use ofVDRAs.
TreatmentofHypophosphatemia
Hypophosphatemia and hyperphosphaturia are com-
mon in the early postkidney transplantation course,secondary to persistently elevated FGF-23 and PTHlevels, calcitriol deficiency, and use of corticoster-oids.76,145 Hypophosphatemia can affect bone miner-
Table 3. Therapies for Posttransplantation Bone Disease
Therapy Mechanism of Action
Effect on
PTH Effect on BMD
Steroid sparing/withdrawal96-99 Improve bone formation; improve calcium absorption;
improve vitamin D metabolism
Possible
decrease
Decreased loss
Vitamin D99-103
Nutritional vitamin D replacement; improve calciumabsorption
Decrease Possible decreasedloss
Calcitriol and VDRA62,103-107 Directly decreases PTH synthesis and increases
intestinal absorption of calcium
Decrease Decreased loss
Phosphorus replacement108,109 Increase serum phosphorus Unclear None
Bisphosphonates9,12,52,53,110-119 Inhibit osteoclastic bone resorption Possible
increase
Decreased loss and
possible net
increase
Calcitonin110 Inhibit osteoclastic bone resorption None Decreased trabecular
bone loss
Calcimimetics119-131 Allosterically modify CaSR, increasing sensitivity to
extracellular calcium
Decrease Decreased loss
Teriparatide132-135 Recombinant human PTH with anabolic bone effects Unclear May increase cortical
bone
Denosumab136 Humanized monoclonal antibody that blocks RANKL Increase Decreased loss; may
increase
Parathyroidectomy137-140 Surgical removal of parathyroid gland Decrease Decreased loss
Abbreviations: BMD, bone mineral density; CaSR, calcium sensing receptor; PTH, parathyroid hormone; RANKL, receptor activator
of nuclear factor-B ligand; VDRA, vitamin D receptor activator.
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Table 4. Therapeutic Options for Posttransplantation Bone Disease, Indications, and Effect on BMD and Frac
Therapy Indications Effect on BMD
Level of Evidence for
Effect on BMD
Bisphosphonates52,110-118,141,142 Kidney transplant recipients with eGFR30 mL/min/1.73 m2
who have osteopenia or osteoporosis in first 12 mo
posttranplantation, after excluding low-turnover bone
disease; kidney transplant recipients with eGFR 30 mL/
min/1.73 m2 who have normal BMD and are at high risk of
fractures (Box 1), after excluding low bone turnover
Improves femoral neck
and lumbar spine
BMD
Level I/A; validated
from randomized
trials
VDRA62,104,107,110,111,115,142,143 Persistent posttransplantation hyperparathyroidism with low
calcium levels that cannot be treated with cinacalcet;
prevention of bone loss in kidney transplant recipients with
eGFR30 mL/min/1.73 m2 who have
hyperparathyroidism without hypercalcemia; kidneytransplant recipients with eGFR30 mL/min/1.73 m2 who
have osteopenia or osteoporosis in first 12 mo
posttranplantation, and have low-turnover bone disease
confirmed by biopsy or suggested by trend of bone
biomarkers
Improves femoral neck
and lumbar spine
BMD
Level I/A; validated
from randomized
trials
Cinacalcet119-131 Persistent posttransplantation hyperparathyroidism with
hypercalcemia (off-label use)
Improves BMD Level III/B; based on
observational
descriptive study
Parathyroidectomy137-140 Persistent posttransplantation hyperparathyroidism with (1)
parathyroid hyperplasia, (2) hypercalcemia, (3)
unexplained or worsening transplant function, (4)
symptomatic bone disease or spontaneous fracture,
vascular calcification, calciphylaxis
Improves BMD Level III/C; based on
observational
descriptive study
Note:Conversion factors for units: eGFR in mL/min/1.73 m2 to mL/s/1.73 m2,0.01667.Abbreviations: BMD, bone mineral density; eGFR, estimated glomerular filtration rate; NA, not applicable; VDRA, vitamin D receptor activator.
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alization by increasing osteoblast apoptosis, impair-ing osteoblast activity, and inhibiting osteoblast prolif-eration.108 Therapy for hypophosphatemia should notbe overaggressive because phosphate replacement can
result in hypocalcemia by physiochemical binding,
persistent hyperparathyroidism,
146
hyperphos-phatemia, and calcitriol deficiency and increase therisk of nephrocalcinosis147,148 and acute phosphatenephropathy.149 Until more data become available re-garding the risks and/or benefits, we recommend cau-tious phosphate repletion when serum levels are lessthan 1-1.5 mg/dLor patients are symptomatic.
Bisphosphonates
Bisphosphonates induce osteoclastic apoptosis, re-duce osteoclastic activity, and result in decreasedbone resorption. Studies have shown that oral (risedro-nate, alendronate, and ibandronate) and intravenous
(ibandronate, zoledronic acid, and pamidronate) bis-
phosphonates preserve BMD in the lumbar spine and
femoral neck in the early posttransplantation period
(Table 5).12,52,110-118,141 However, there is a lack of
evidence that bisphosphonates decrease fracture risk
in kidney transplant recipients.115
This may be second-ary to the unpowered nature of these studies. Further-
more, because bone biopsies are not performed rou-
tinely after kidney transplantation and levels of PTH
and bone turnover biomarkers are not reflective of
bone histology, it is clinically challenging to avoid
bisphosphonate use in patients with pre-existing ady-
namic bone disease. This inadvertent use of bisphos-
phonates could be detrimental and partially respon-
sible for the lack of decrease in the incidence of
fractures after bisphosphonate treatment. A small ret-
rospective cohort study of self-reported fractures in
Table 5. Studies Reporting Effects of Bisphosphonate Use in Prevention and Treatment of Posttransplantation
Osteopenia/Osteoporosis
Study
No. of
Patients Design Outcome
Grotz et al12
(2001)
80 Prospective placebo controlled; kidney recipients
received either ibandronate or placebo at 3, 6,and 9 mo posttransplantation vs control group
Less bone loss, spinal deformation, and loss of body
height in the ibandronate group during first yposttransplantation
Fan et al112,113
(2000, 2003)
26 Prospective placebo controlled; kidney recipients
received either IV pamidronate or placebo at
time of transplantation and 1 mo later; 17
patients had second DEXA at 4 y
Preserved BMD at lumbar spine and femoral neck in
pamidronate group vs increased loss of BMD in
placebo group during first y posttransplantation;
preserved BMD at femoral neck in 4 y in
pamidronate-treated group
Haas et al116
(2003)
43 Prospective placebo controlled; kidney recipients
received either zoledronic acid or placebo at
baseline and within 3-6 mo after
transplantation
Improved BMD in lumbar spine, stable BMD in
femoral neck, no increased risk of adynamic bone
disease in the zoledronic acidtreated group
Coco et al52 (2003) 20 Prospective, controlled; kidney recipients
received either pamidronate at 1, 2, 3, 6 mo
plus daily vitamin D/Ca2 vs vitamin D/Ca2
Preserved BMD in vertebral spine at 6 and 12 mo
with increased risk of adynamic bone disease in
pamidronate-treated group (all patients in
pamidronate group vs 50% in control group)
Jeffery et al111
(2003)
117 Prospective, controlled; kidney recipients with
osteopenia at baseline received either daily
alendronate and Ca2 vs calcitriol and Ca2
Improved BMD in lumbar spine and femoral neck in
both groups, superior effect of alendronate on
spine BMD
El-Agroudy et al110
(2005)
60 Prospective, controlled; kidney recipients with
osteopenia or osteoporosis at baseline
received either alendronate or alfacalcidol or
calcitonin vs control
Alfacalcidol and alendronate improved BMD at both
lumbar spine and femoral neck, while calcitonin
improved BMD in lumbar spine only
Nowacka-Cieciura
et al114 (2006)
66 Prospective, controlled; kidney recipients with
osteopenia or osteoporosis at baseline
received either alendronate or risendronate or
were drug free
Improved BMD in femoral neck in bisphosphonate-
treated group at 12 mo
Torregrosa et al118
(2007)
84 Prospective, controlled; kidney recipients with
osteopenia at baseline received either weekly
risendronate daily vitamin D/Ca2 or vitamin
D/Ca2 only
Increased BMD in lumbar spine at 1 y in
risendronate-treated group
Abediazar &
Nakhjavani117
(2011)
43 Prospective, controlled; kidney recipients with
osteopenia at baseline were randomly
assigned to either weekly alendronate daily
vitamin D or daily vitamin D only
Alendronate increased BMD in distal radius and
lumbar spine at 1 y
Abbreviations: BMD, bone mineral density; Ca2, calcium; DEXA, dual-energy x-ray absorptiometry; IV, intravenous.
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bone loss in both the femoral neck and lumbar spinein comparison to control, whereas calcitonin did notimprove femoral neck BMD.110,115 Stein et al142 per-formed a meta-analysis of 11 trials evaluating 780
solid-organ transplant recipients (42% kidney recipi-ents) who received either bisphosphonates or VDRAs
within the first 12 months posttransplantation. Thisanalysis showed that use of bisphosphonates or
VDRAs was associated with reduced fractures. Differ-ences in the outcomes between Palmer et al115 and theStein et al142 meta-analyses are related to differencesin the methodology, study populations, timing oftherapy, and most importantly, frequency of reportedfractures in both analyses because in the Palmer et
al115 review, only 11 of 24 studies (34/514 patients)had reported fracture data, whereas in the Stein etal142 study, 134 fracture incidents were reported.These data support the notion that preventive therapywith either bisphosphonates or VDRAs likely is better
than no therapy in terms of preventing posttransplan-tation bone loss and possibly fractures.
In our opinion, bisphosphonates are well tolerated,reasonably safe, and effective for the prevention andmanagement of posttransplantation bone loss when
dosed appropriately and used for limited periods afterexcluding low bone turnover. There have not beendirect studies comparing the antiresorptive efficacy ofdifferent bisphosphonates or intravenous versus oralbisphosphonates in the posttransplantation period. In-
travenous bisphosphonates can be used as an alterna-tive in patients who cannot tolerate the oral regimen
or who are nonadherent. It should be noted thatstudies of bisphosphonate use in the posttransplanta-tion period have not been powered to detect fracture
risk reduction. Bisphosphonates should be avoided inpatients with eGFR 30 mL/min/1.73 m2 secondaryto the prolonged half-life, potential risk of adynamicbone disease52 and subsequently increased fracturerisk,151 or the possibility of acute worsening in kidney
function.152 In patients with eGFR 30-35 mL/min/1.73 m2, bisphosphonates can be used cautiously inthe first 12 months posttransplantation for patientswith osteopenia or osteoporosis or patients with nor-
mal BMD who are at high risk of fractures (Table 4),especially if on a steroid-based immunosuppressionprotocol, after excluding low bone turnover. There isno consensus about duration of therapy. Because boneloss is pronounced mainly in the first year posttrans-plantation and BMD begins to recover in many pa-tients after the first year,7,17,18 12-18 months of therapyshould be sufficient for most patients.
Calcimimetics
Calcimimetics allosterically increase sensitivity ofthe calcium-sensing receptor in the parathyroid gland
to calcium and suppress PTH. Cinacalcet has been
shown to be beneficial in correcting hypercalcemia
and hyperparathyroidism in multiple trials in kidney
transplant recipients (Table 6).119-131 In a multicenterretrospective analysis of transplant recipients with
secondary hyperparathyroidism, Copley et al130
showed that cinacalcet use was associated with a21.8% decrease in PTH level, 6.8% decrease in serum
calcium level, and 10% increase in serum phosphorus
level. Findings in all the other studies are consistent
with this observation.119-131 However, none of thesestudies had a control group or was able to differentiate
between persistent secondary hyperparathyroidism or
autonomous tertiary hyperparathyroidism; none pro-
vided measures of parathyroid gland size or informa-tion about whether these patients were resistant to
VDRA therapy. In a study that discontinued cinacalcet
therapy after 6 months, both calcium and PTH concen-
trations rebounded to elevated levels after with-drawal, whereas in another study in which cinacalcet
therapy was stopped after 12 months, most patients
maintained lower concentrations of calcium and
PTH.123,153 This raises questions about whether the
persistent hyperparathyroidism would resolve without
intervention in some patients, as well as how longcalcimimetic intervention is necessary. Cho et al131
demonstrated that cinacalcet therapy also was associ-
ated with improved BMD 36 months postkidney
transplantation, with a significant reduction in cal-
cium levels in patients with persistent secondary hy-perparathyroidism. Observations regarding the effects
of calcimimetics on kidney transplant function are
contradictory. Some studies120 indicate that it may be
associated with a slight decrease in kidney function,
whereas others show no difference in serum creatinine
levels.127 There have been 3 case reports in theliterature in which cinacalcet may be associated with
nephrocalcinosis and transplant failure.154-156 How-
ever Courbebaisse et al157 evaluated 71 kidney recipi-
ents with hypercalcemic hyperparathyroidism in which
34 patients received cinacalcet between months 3 and12 after kidney transplantation. Cinacalcet use was
associated with more significant reductions in PTH
level, hypocalcemia, increased serum phosphoruslevel, hypercalciuria, and hypophosphaturia in com-parison to the noncinacalcet group, with no adverse
effects on GFR or kidney transplant calcium phos-
phate deposition.
Prospective studies, such as the 2 ongoing studies(Treatment ofAutonomous Hyperparathyroidism in Post
Renal Transplant Recipients [ClinicalTrials.gov number
NCT00975000] and A Prospective, Randomized
Trial to Compare Subtotal Parathyroidectomy Ver-sus Cinacalcet in the Treatment of Persistent Second-
ary Hyperparathyroidism Post Renal Transplanta-
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tion [NCT01178450]), are required to evaluate therole of cinacalcet therapy and whether it is benefi-cial over parathyroidectomy.
Parathyroidectomy
On average, 0.5%-5% of transplant recipients with
persistent hyperparathyroidism ultimately will requireparathyroidectomy.137,138,158 Indications includesymptomatic or severe hypercalcemia, symptomatic
bone disease or spontaneous fracture, vascular calcifi-cation, calciphylaxis, or persistent hyperparathyroid-ism for more than 1 year after transplantation. Parathy-roidectomy results in an abrupt decrease in serumPTH and calcium concentrations and an increase inserum phosphorus level. In some studies, parathyroid-ectomy has been reported to be associated with wors-ening transplant function.138,159 However, at least onestudy showed that parathyroidectomy did not affect
transplant survival at 3 years.
139
In a retrospectiveanalysis of parathyroidectomy for tertiary hyperpara-thyroidism in kidney transplant recipients, BMD sig-nificantly improved in both the hip and spine.140 Theeffects of parathyroidectomy on fracture risk andwhether medical treatment with calcimimetics is anappropriate alternative to surgery await further clini-cal studies.
Teriparatide
Teriparatide is a recombinant human PTH (compa-rising amino acids 1-34) that has anabolic bone effects
when administered intermittently in the general popu-lation. Teriparatide is shown to reduce fracture risk inpostmenopausal women receiving glucocorticoids.132
One study showed that teriparatide administered for 6months was safe but did not alter BMD comparedwith the placebo group; however, the study was under-powered.133 In 2 reports, one a single case and theother a case series of 5 kidney transplant recipientswith a history of pretransplantation parathyroidec-
tomy who developed refractory hypocalcemia in theirearly posttransplantation course, teriparatide therapyled to faster normalization of calcium levels, permit-ted earlier suspension of intravenous calcium supple-
mentation, and reduced calcitriol requirements.134,135
PotentialNewTherapies
Denosumab is a fully humanized monoclonal anti-body that inhibits the formation, function, and sur-vival of osteoclasts, preventing interaction of RANKL(receptor activator of nuclear factor-B ligand) withRANK. The use of denosumab causes a reduction in
osteoclast formation and thus decreased bone resorp-tion and an increase in BMD. In a study of osteoporo-sis in postmenopausal women, denosumab was foundto be safe and was associated with improved BMD
and decreased fracture risk,136 even in a cohort ofpatients with varying degrees of kidney function.160
Odanacatib is a selective, potent, and reversible inhib-itor of cathepsin K that inhibits bone loss in mice.161
The antiresorptive properties of odanacatib have beenevaluated in phase 1 and 2 clinical trials, and phase 3
studies currently are underway. Both these agentshave the potential to prevent posttransplantation frac-tures. However, there presently are no studies evaluat-ing their use in the transplantation population.
CONCLUSIONS
In summary, complex abnormalities of mineralhomeostasis and bone remodeling in the posttransplan-tation period result in loss of BMD, with an increase
in bone fragility and fractures. Although decreases inBMD may predict fracture risk in many differentpatient populations, low BMD in kidney transplant
recipients does not appear to differentiate patients atrisk of fracture. Other metabolic factors influenceboth BMD and quality, resulting in decreased bonestrength, which predisposes the transplant recipient toincreased fracture risk. All transplant recipients should
be evaluated for metabolic disorders and monitoredfor ongoing bone loss. Management of posttransplan-tation bone disease is challenging, but initially shouldfocus on correcting metabolic disorders. The use ofbone biopsy may add important information to aid inthe choice of treatment. Although multiple studieshave shown that different interventions may slowbone loss and improve BMD, no therapy has yet been
shown to reduce fracture risk. With the lack of suffi-cient prospective studies evaluating currently avail-able therapies, clinical judgment must serve as theguiding principle to evaluate the risk-benefit of spe-cific therapies for preventing bone loss and fractures.
CASE REVIEW
The index case presented a common scenario en-countered in the transplant clinic. She was a postmeno-pausal kidney transplant recipient who had lumbarspine osteoporosis and worsening femoral osteopenia
with stage 3 CKD, mild hyperparathyroidism, and
prior vitamin D deficiency. She had multiple riskfactors that increased her risk of bone loss and frac-tures, including advanced age, female sex, early meno-pause, high cumulative dose of steroids, effects ofcyclosporine on osteogenesis, and persistent hyper-parathyroidism. A bone biopsy was performed (Fig 1),which was diagnostic for adynamic bone disease.
Pretransplantation osteodystrophy, in addition to ad-vanced CKD (eGFR, 40 mL/min/1.73 m2), long-termsteroid use, and long-term use of bisphosphonatetherapy (alendronate for 6 years), likely contributed toher adynamic bone disease. Based on biopsy results,
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alendronate therapy was discontinued, nutritional vita-min D treatment was continued, and low-dose cal-citriol therapy was initiated. Unfortunately, there is
little evidence to support the use of the other currentlyavailable therapies; thus, no other specific treatmentwas instituted.
ACKNOWLEDGEMENTS
Support: None.Financial Disclosure: The authors declare that they have no
relevant financial interests.
REFERENCES
1. Uhlig K, Berns JS,Kestenbaum B, et al. KDOQIUS commen-
tary on the 2009 KDIGO Clinical Practice Guideline for the
Diagnosis, Evaluation, and Treatment of CKD-Mineral and Bone
Disorder (CKD-MBD). Am J Kidney Dis. 2010;55(5):773-799.2. Moe S, Drueke T, Cunningham J, et al. Definition, evalua-
tion, and classification of renal osteodystrophy: a position state-
ment from Kidney Disease: Improving Global Outcomes (KDIGO).
Kidney Int. 2006;69(11):1945-1953.3. Brandenburg VM, Westenfeld R, Ketteler M. The fate of
bone after renal transplantation. J Nephrol. 2004;17(2):190-204.4. Stein E, Ebeling P, Shane E. Post-transplantation osteoporo-
sis. Endocrinol Metab Clin North Am. 2007;36(4):937-963.5. Malluche HH, Mawad HW, Monier-Faugere MC. Renal
osteodystrophy in the first decade of the new millennium
analysis of 630 bone biopsies in black and white patients. J BoneMiner Res. 2011;26(6):1368-1376.
6. Govindarajan S, Khandelwal N, Sakhuja V, Jha V. Bone
mineral density in patients with end-stage renal disease and its
evolution after kidney transplantation. Indian J Nephrol.
2011;21(2):85-89.
7. Brandenburg VM, Politt D, Ketteler M, et al. Early rapid loss
followed by long-term consolidation characterizes the develop-
ment of lumbar bone mineral density after kidney transplantation.
Transplantation. 2004;77(10):1566-1571.
8. Kodras K, Haas M. Effect of kidney transplantation on bone.
Eur J Clin Invest. 2006;36(7)(suppl 2):S63-S75.
9. Moreno A, Torregrosa JV, Pons F, Campistol JM, Martinez
de Osaba MJ, Oppenheimer F. Bone mineral density after renal
transplantation: long-term follow-up. Transplant Proc. 1999;31(6):
2322-2323.
10. Nam JH, Moon JI, Chung SS, et al. Pamidronate and
calcitriol trial for the prevention of early bone loss after renal
transplantation. Transplant Proc. 2000;32(7):1876.
11. Goffin E, Devogelaer JP, Lalaoui A, et al. Tacrolimus and
low-dose steroid immunosuppression preserves bone mass after
renal transplantation. Transpl Int. 2002;15(2-3):73-80.
12. Grotz W, Nagel C, Poeschel D, et al. Effect of ibandronateon bone loss and renal function after kidney transplantation. J Am
Soc Nephrol. 2001;12(7):1530-1537.
13. Grotz WH, Mundinger FA, Gugel B, Exner VM, Kirste
G, Schollmeyer PJ. Bone mineral density after kidney transplan-
tation. A cross-sectional study in 190 graft recipients up to 20
years after transplantation. Transplantation. 1995;59(7):982-
986.
14. Almond MK, Kwan JT, Evans K, Cunningham J. Loss of
regional bone mineral density in the first 12 months following
renal transplantation. Nephron. 1994;66(1):52-57.
15. Mikuls TR, Julian BA, Bartolucci A, Saag KG. Bone
mineral density changes within six months of renal transplantation.
Transplantation. 2003;75(1):49-54.
Figure 1. Bone biopsy in index case shows low bone turnover, defective mineralization, and decreased bone volume. Low-powerview shows (A) loss of connectivity, thinned trabeculae, and now marrow fibrosis; (B-D) minimal osteoid accumulation, markedlydecreased, osteoblasts, osteoclasts, or evidence of resorption; and (E, F) minimal tetracycline uptake; thus, a low bone formation rate.
Am J Kidney Dis. 2013;61(2):310-325 321
Management of CKD-MBD PostKidney Transplant
-
7/27/2019 ckd bmd in tx
13/16
16. Smets YF, de Fijter JW, Ringers J, Lemkes HH, Hamdy
NA. Long-term follow-up study on bone mineral density and
fractures after simultaneous pancreas-kidney transplantation. Kid-ney Int. 2004;66(5):2070-2076.
17. Brandenburg VM, Ketteler M, Heussen N, et al. Lumbar
bone mineral density in very long-term renal transplant recipients:
impact of circulating sex hormones. Osteoporos Int. 2005;16(12):
1611-1620.18. Pichette V, Bonnardeaux A, Prudhomme L, Gagne M,
Cardinal J, Ouimet D. Long-term bone loss in kidney transplant
recipients: a cross-sectional and longitudinal study. Am J KidneyDis. 1996;28(1):105-114.
19. Ebeling PR. Approach to the patient with transplantation-
related bone loss. J Clin Endocrinol Metab. 2009;94(5):1483-1490.
20. Kulak CA, Borba VZ, Kulak J Jr, Campos DJ, Shane E.
Post-transplantation osteoporosis. Arq Bras Endocrinol Metabol.
2010;54(2):143-149.
21. Elmstedt E, Svahn T. Skeletal complications following
renal transplantation. Acta Orthop Scand. 1981;52(3):279-286.22. Davidson JK, Tsakiris D, Briggs JD, Junor BJ. Osteonecro-
sis and fractures following renal transplantation. Clin Radiol.
1985;36(1):27-35.23. Ramsey-Goldman R, Dunn JE, Dunlop DD, et al. Increased
risk of fracture in patients receiving solid organ transplants. J Bone
Miner Res. 1999;14(3):456-463.24. OShaughnessy EA, Dahl DC, Smith CL, Kasiske BL. Risk
factors for fractures in kidney transplantation. Transplantation.2002;74(3):362-366.
25. Durieux S, Mercadal L, Orcel P, et al. Bone mineral density
and fracture prevalence in long-term kidney graft recipients. Trans-plantation. 2002;74(4):496-500.
26. Arlen DJ, Lambert K, Ioannidis G, Adachi JD. Treatment of
established bone loss after renal transplantation with etidronate.
Transplantation. 2001;71(5):669-673.27. Grotz WH, Mundinger FA, Gugel B, Exner V, Kirste G,
Schollmeyer PJ. Bone fracture and osteodensitometry with dual
energy x-ray absorptiometry in kidney transplant recipients. Trans-plantation. 1994;58(8):912-915.
28. Parker CR, Freemont AJ, Blackwell PJ, Grainge MJ, Hosk-
ing DJ. Cross-sectional analysis of renal transplantation osteoporo-
sis. J Bone Miner Res. 1999;14(11):1943-1951.
29. Patel S, Kwan JT, McCloskey E, et al. Prevalence and
causes of low bone density and fractures in kidney transplant
patients. J Bone Miner Res. 2001;16(10):1863-1870.
30. DAngelo A, Calo L, Giannini S, et al. Parathyroid hor-
mone and bone metabolism in kidney-transplanted patients. Clin
Nephrol. 2000;53(4)(suppl):19-22.31. Nam JH, Moon JI, Chung SS, et al. Prevalence and risk
factors for vertebral fractures in renal transplants. Transplant Proc.
2000;32(7):1877.
32. Sprague SM, Josephson MA. Bone disease after kidney
transplantation. Semin Nephrol. 2004;24(1):82-90.
33. Vautour LM, Melton LJ III, Clarke BL, Achenbach SJ,
Oberg AL, McCarthy JT. Long-term fracture risk following renal
transplantation: a population-based study. Osteoporos Int. 2004;
15(2):160-167.
34. Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper
C. Use of oral corticosteroids and risk of fractures. J Bone MinerRes. 2000;15(6):993-1000.
35. Unal A, Kocyigit I, Sipahioglu MH, et al. Loss of bone
mineral density in renal transplantation recipients. TransplantProc. 2010;42(9):3550-3553.
36. Ozel L, Ata P, Ozel MS, et al. Risk factors for osteoporosis
after renal transplantation and effect of vitamin D receptor Bsm I
polymorphism. Transplant Proc. 2011;43(3):858-862.
37. Ball AM, Gillen DL, Sherrard D, et al. Risk of hip fracture
among dialysis and renal transplant recipients. JAMA. 2002;288(23):3014-3018.
38. Nisbeth U, Lindh E, Ljunghall S, Backman U, Fellstrom B.
Increased fracture rate in diabetes mellitus and females after renal
transplantation. Transplantation. 1999;67(9):1218-1222.39. Abbott KC, Oglesby RJ, Hypolite IO, et al. Hospitalizations
for fractures after renal transplantation in the United States. AnnEpidemiol. 2001;11(7):450-457.
40. Nikkel LE, Hollenbeak CS, Fox EJ, Uemura T, Ghahramani
N. Risk of fractures after renal transplantation in the United States.
Transplantation. 2009;87(12):1846-1851.
41. Kanaan N, Claes K, Devogelaer JP, et al. Fibroblast growth
factor-23 and parathyroid hormone are associated with post-
transplant bone mineral density loss. Clin J Am Soc Nephrol.2010;5(10):1887-1892.
42. Dolgos S, Hartmann A, Bonsnes S, et al. Early changes in
bone mass, biochemical bone markers and fibroblast growth factor
23 after renal transplantation. Scand J Clin Lab Invest. 2009;69(2):161-167.
43. Braga JW Jr, Neves RM, Pinheiro MM, et al. Prevalence of
low trauma fractures in long-term kidney transplant patients with
preserved renal function. Braz J Med Biol Res. 2006;39(1):137-147.
44. Marcen R, Caballero C, Uriol O, et al. Prevalence of
osteoporosis, osteopenia, and vertebral fractures in long-term renal
transplant recipients. Transplant Proc. 2007;39(7):2256-2258.45. Opelz G, DohlerB. Association of mismatches forHLA-DR
with incidence of posttransplant hip fracture in kidney transplant
recipients. Transplantation. 2011;91(1):65-69.46. Stehman-Breen CO, Sherrard DJ, Alem AM, et al. Risk
factors for hip fracture among patients with end-stage renal dis-
ease. Kidney Int. 2000;58(5):2200-2205.47. Mainra R, Elder GJ. Individualized therapy to prevent bone
mineral density loss after kidney and kidney-pancreas transplanta-
tion. Clin J Am Soc Nephrol. 2010;5(1):117-124.48. Rojas E, Carlini RG, Clesca P, et al. The pathogenesis of
osteodystrophy after renal transplantation as detected by earlyalterations in bone remodeling. Kidney Int. 2003;63(5):1915-1923.
49. Bonomini V, Feletti C, Di Felice A, Buscaroli A. Bone
remodelling after renal transplantation (RT). Adv Exp Med Biol.1984;178:207-216.
50. Lehmann G, Ott U, Stein G, Steiner T, Wolf G. Renal
osteodystrophy after successful renal transplantation: a histomor-
phometric analysis in 57 patients. Transplant Proc. 2007;39(10):3153-3158.
51. Borchhardt K, Sulzbacher I, Benesch T, Fodinger M, Sunder-
Plassmann G, Haas M. Low-turnover bone disease in hypercalce-
mic hyperparathyroidism after kidney transplantation. Am J Trans-plant. 2007;7(11):2515-2521.
52. Coco M, Glicklich D, Faugere MC, et al. Prevention of
bone loss in renal transplant recipients: a prospective, randomized
trial of intravenous pamidronate. J Am Soc Nephrol. 2003;14(10):2669-2676.
53. Maalouf NM, Shane E. Osteoporosis after solid organ
transplantation. J Clin Endocrinol Metab. 2005;90(4):2456-2465.54. Adachi JD, Bensen WG, Hodsman AB. Corticosteroid-
induced osteoporosis. Semin Arthritis Rheum. 1993;22(6):375-384.
55. Monier-Faugere MC, Mawad H, Qi Q, Friedler RM, Mal-
luche HH. High prevalence of low bone turnover and occurrence
of osteomalacia after kidney transplantation. J Am Soc Nephrol.2000;11(6):1093-1099.
56. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibi-
tion of osteoblastogenesis and promotion of apoptosis of osteo-
blasts and osteocytes by glucocorticoids. Potential mechanisms of
Am J Kidney Dis. 2013;61(2):310-325322
Alshayeb, Josephson, and Sprague
-
7/27/2019 ckd bmd in tx
14/16
their deleterious effects on bone. J Clin Invest. 1998;102(2):274-282.
57. Khaleeli AA, Edwards RH, Gohil K, et al. Corticosteroid
myopathy: a clinical and pathological study. Clin Endocrinol
(Oxf). 1983;18(2):155-166.58. Stewart PJ, Stern PH. Cyclosporines: correlation of immu-
nosuppressive activity and inhibition of bone resorption. Calcif
Tissue Int. 1989;45(4):222-226.59. Schlosberg M, Movsowitz C, Epstein S, Ismail F, FallonMD, Thomas S. The effect of cyclosporin A administration and its
withdrawal on bone mineral metabolism in the rat. Endocrinology.
1989;124(5):2179-2184.
60. Moreira RO, Thiago LS, Oliveira FL, et al. Cyclosporine A,
but not tacrolimus, is associated with impaired proliferation and
differentiation of human osteoblast-like cells in vitro. Med SciMonit. 2009;15(3):BR65-BR70.
61. Movsowitz C, Epstein S, Fallon M, Ismail F, Thomas S.
Cyclosporin-Ain vivo produces severe osteopenia in the rat: effect
of dose andduration of administration.Endocrinology. 1988;123(5):
2571-2577.
62. Josephson MA, Schumm LP, Chiu MY, Marshall C, This-
tlethwaite JR, Sprague SM. Calcium and calcitriol prophylaxis
attenuates posttransplant bone loss. Transplantation. 2004;78(8):1233-1236.
63. Stewart PJ, Stern PH. Interaction of cyclosporine A and
calcitonin on bone resorption in vitro.Horm Metab Res. 1989;21(4):194-197.
64. NassarCA, Nassar PO, AndiaDC, Guimaraes MR, Spolido-
rio LC. Effects of long-term FK 506 therapy on the alveolar bone
and cementum of rats. Transplant Proc. 2009;41(5):1871-1874.
65. Westenfeld R, Schlieper G, Woltje M, et al. Impact of
sirolimus, tacrolimus and mycophenolate mofetil on osteoclasto-
genesisimplications for post-transplantation bone disease.Neph-rol Dial Transplant. 2011;26(12):4115-4123.
66. Kneissel M, Luong-Nguyen NH, Baptist M, et al. Everoli-
mus suppresses cancellous bone loss, bone resorption, and cathep-
sin K expression by osteoclasts. Bone. 2004;35(5):1144-1156.
67. Velasquez-Forero F, Mondragon A, Herrero B, Pena JC.Adynamic bone lesion in renal transplant recipients with normal
renal function. Nephrol Dial Transplant. 1996;1(suppl 3):58-64.68. Carlini RG, Rojas E, Arminio A, Weisinger JR, Bellorin-
Font E. What are the bone lesions in patients with more than four
years of a functioning renal transplant? Nephrol Dial Transplant.1998;13(21)(suppl 3):S103-S104.
69. Cueto-Manzano AM, Konel S, Hutchison AJ, et al. Bone
loss in long-term renal transplantation: histopathology and densi-
tometry analysis. Kidney Int. 1999;55(5):2021-2029.
70. Boudville NC, Hodsman AB. Renal function and 25-
hydroxyvitamin D concentrations predict parathyroid hormone
levels in renal transplant patients. Nephrol Dial Transplant. 2006;
21(9):2621-2624.
71. Messa P, Sindici C, Cannella G, et al. Persistent secondary
hyperparathyroidism after renal transplantation. Kidney Int. 1998;
54(5):1704-1713.
72. Bertoni E, Rosati A, Larti A, et al. Chronic kidney disease is
still present after renal transplantation with excellent function.
Transplant Proc. 2006;38(4):1024-1025.73. Pande S, Ritter CS, Rothstein M, et al. FGF-23 and sFRP-4
in chronic kidney disease and post-renal transplantation. NephronPhysiol. 2006;104(1):23-32.
74. Economidou D, Dovas S, PapagianniA, Pateinakis P, Mem-
mos D. FGF-23 levels before and after renal transplantation
[published online ahead of print May 17, 2009]. J Transplant.doi:10.1155/2009/379082.
75. Evenepoel P, Meijers BK, de Jonge H, et al. Recovery of
hyperphosphatoninism and renal phosphorus wasting one year
after successful renal transplantation. Clin J Am Soc Nephrol.
2008;3(6):1829-1836.
76. Trombetti A, Richert L, Hadaya K, et al. Early post-
transplantation hypophosphatemia is associated with elevated
FGF-23 levels. Eur J Endocrinol. 2011;164(5):839-847.
77. Cundy T, Kanis JA, Heynen G, Morris PJ, Oliver DO.
Calcium metabolism and hyperparathyroidism after renal transplan-
tation. Q J Med. 1983;52(205):67-78.78. Ramezani M, Einollahi B, Asl MA, et al. Calcium and
phosphorus metabolism disturbances after renal transplantation.
Transplant Proc. 2007;39(4):1033-1035.
79. Straffen AM, Carmichael DJ, Fairney A, Hulme B, Snell M.
Calcium metabolism following renal transplantation. Ann Clin
Biochem. 1994;31(pt 2):125-128.
80. Babarykin D, Adamsone I, Amerika D, Folkmane I, Rozen-
tal R. Disorders of calcium metabolism at various times after renal
transplantation. Ann Transplant. 1999;4(1):46-53.
81. London GM, Marty C, Marchais SJ, Guerin AP, Metivier F,
de Vernejoul MC. Arterial calcifications and bone histomorphom-
etryin end-stage renal disease.J Am Soc Nephrol. 2004;15(7):1943-
1951.
82. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E,
Luft FC. Electron beam computed tomography in the evaluation ofcardiac calcification in chronic dialysis patients. Am J Kidney Dis.
1996;27(3):394-401.
83. Moe SM, Chen NX. [Vascular calcification in end stage
renal disease]. Clin Calcium. 2002;12(10):1417-1422.
84. Marechal C, Coche E, Goffin E, et al. Progression of
coronary artery calcification and thoracic aorta calcification in
kidney transplant recipients. Am J Kidney Dis. 2012;59(2):258-
269.
85. Oschatz E, Benesch T, Kodras K, Hoffmann U, Haas M.
Changes of coronary calcification after kidney transplantation.
Am J Kidney Dis. 2006;48(2):307-313.
86. Kidney Disease: Improving Global Outcomes Transplant
Work Group. KDIGO clinical practice guideline for the care of
kidney transplant recipients. Am J Transplant. 2009;9(suppl 3):S1-S155.
87. Cruz EA, Lugon JR, Jorgetti V, Draibe SA, Carvalho AB.
Histologic evolution of bone disease 6 months after successful
kidney transplantation. Am J Kidney Dis. 2004;44(4):747-756.
88. Bergmann P, Body JJ, Boonen S, et al. Evidence-based
guidelines for the use of biochemical markers of bone turnover in
the selection and monitoring of bisphosphonate treatment in osteo-
porosis: a consensus document of the Belgian Bone Club. Int
J Clin Pract. 2009;63(1):19-26.
89. Bates DW, Black DM, Cummings SR. Clinical use of bone
densitometry: clinical applications. JAMA. 2002;288(15):1898-
1900.
90. Kanis JA. Assessment of fracture risk and its application to
screening for postmenopausal osteoporosis: synopsis of a WHO
report. WHO Study Group. Osteoporos Int. 1994;4(6):368-381.91. Huang M, Sprague SM. Bone disease in kidney transplant
patients. Semin Nephrol. 2009;29(2):166-173.
92. Sprague SM. The role of the bone biopsy in the diagnosis of
renal osteodystrophy. Semin Dial. 2000;13(3):152-155.
93. Kasiske BL, Zeier MG, Chapman JR, et al. KDIGO clinical
practice guideline for the care of kidney transplant recipients: a
summary. Kidney Int. 2010;77(4):299-311.
94. Isoniemi H, Appelberg J, Nilsson CG, Makela P, Risteli J,
Hockerstedt K. Transdermal oestrogen therapy protects postmeno-
pausal liver transplant women from osteoporosis. A 2-year fol-
low-up study. J Hepatol. 2001;34(2):299-305.
95. Stempfle HU, Werner C, Echtler S, et al. Prevention of
osteoporosis after cardiac transplantation: a prospective, longitudi-
Am J Kidney Dis. 2013;61(2):310-325 323
Management of CKD-MBD PostKidney Transplant
-
7/27/2019 ckd bmd in tx
15/16
nal, randomized, double-blind trial with calcitriol. Transplantation.1999;68(4):523-530.
96. Pereira S, Pedroso S, Martins L, et al. Bone mineral density
after simultaneous kidney-pancreas transplantation: four years
follow-up of 57 recipients. Transplant Proc. 2010;42(2):555-557.97. Hazzan M, Glowacki F, Lionet A, Provot F, Noel C.
[Weaning from corticosteroid therapy after kidney transplanta-
tion]. Nephrol Ther. 2009;5(suppl 6):S355-S358.98. Ing SW, Sinnott LT, Donepudi S, Davies EA, Pelletier RP,Lane NE. Change in bone mineral density at one year following
glucocorticoid withdrawal in kidney transplant recipients. ClinTransplant. 2011;25(2):E113-E123.
99. Edwards BJ, Desai A, Tsai J, et al. Elevated incidence of
fractures in solid-organ transplant recipients on glucocorticoidspar-
ing immunosuppressive regimens [published online ahead of print
September 12, 2011]. J Osteoporos. doi:10.4061/2011/591793.100. Nikkel LE, Mohan S, Zhang A, et al. Reduced fracture risk
with early corticosteroid withdrawal after kidney transplant. Am J
Transplant. 2012;12(3):649-659.
101. Wissing KM, Broeders N, Moreno-Reyes R, Gervy C,
Stallenberg B, Abramowicz D.A controlled study of vitamin D3 to
prevent bone loss in renal-transplant patients receiving low doses
of steroids. Transplantation. 2005;79(1):108-115.102. Sahin G, Yasar NS, Sirmagul B, Bal C, Yalcin AU. The
effect of low-dose cholecalciferol and calcium treatment on post-
transplant bone loss in renal transplant patients: a prospective
study. Ren Fail. 2008;30(10):992-999.
103. Rostand SG, Warnock DG. Introduction to Vitamin D
Symposium, March 14, 2008. Clin J Am Soc Nephrol. 2008;3(5):
1534.
104. Cueto-Manzano AM, Konel S, Freemont AJ, et al. Effect
of 1,25-dihydroxyvitamin D3 and calcium carbonate on bone loss
associated with long-term renal transplantation. Am J Kidney Dis.2000;35(2):227-236.
105. Lobo PI, Cortez MS, Stevenson W, Pruett TL. Normocal-
cemic hyperparathyroidism associated with relatively low 1:25
vitamin D levels post-renal transplant can be successfully treated
with oral calcitriol. Clin Transplant. 1995;9(4):277-281.106. Steiner RW, Ziegler M, Halasz NA, Catherwood BD,
Manolagas S, Deftos LJ. Effect of daily oral vitamin D and
calcium therapy, hypophosphatemia, and endogenous 1-25 dihy-
droxycholecalciferol on parathyroid hormone and phosphate wast-
ing in renal transplant recipients. Transplantation. 1993;56(4):843-846.
107. Torres A, Garcia S, Gomez A, et al. Treatment with
intermittent calcitriol and calcium reduces bone loss after renal
transplantation. Kidney Int. 2004;65(2):705-712.
108. Wilkins GE, Granleese S, Hegele RG, Holden J, Anderson
DW, Bondy GP. Oncogenic osteomalacia: evidence for a humoral
phosphaturic factor. J Clin Endocrinol Metab. 1995;80(5):1628-
1634.
109. Copley JB, Wuthrich RP. Therapeutic management of
post-kidney transplant hyperparathyroidism. Clin Transplant. 2011;
25(1):24-39.
110. El-Agroudy AE, El-Husseini AA, El-Sayed M, Mohsen T,
Ghoneim MA. A prospective randomized study for prevention of
postrenal transplantation bone loss. Kidney Int. 2005;67(5):2039-2045.
111. Jeffery JR, Leslie WD, Karpinski ME, Nickerson PW,
Rush DN. Prevalence and treatment of decreased bone density
in renal transplant recipients: a randomized prospective trial of
calcitriol versus alendronate. Transplantation. 2003;76(10):1498-1502.
112. Fan SL, Almond MK, Ball E, Evans K, Cunningham J.
Pamidronate therapy as prevention of bone loss following renal
transplantation. Kidney Int. 2000;57(2):684-690.
113. Fan SL, Kumar S, Cunningham J. Long-term effects on
bone mineral density of pamidronate given at the time of renal
transplantation. Kidney Int. 2003;63(6):2275-2279.
114. Nowacka-Cieciura E, Cieciura T, Baczkowska T, et al.
Bisphosphonates are effective prophylactic of early bone loss after
renal transplantation. Transplant Proc. 2006;38(1):165-167.
115. Palmer SC, McGregor DO, Strippoli GF. Interventions for
preventing bone disease in kidney transplant recipients. CochraneDatabase Syst Rev. 2007;3:CD005015.
116. Haas M, Leko-Mohr Z, Roschger P, et al. Zoledronic acid
to prevent bone loss in the first 6 months after renal transplanta-
tion. Kidney Int. 2003;63(3):1130-1136.
117. Abediazar S, Nakhjavani MR. Effect of alendronate on
early bone loss of renal transplant recipients. Transplant Proc.
2011;43(2):565-567.
118. Torregrosa JV, Fuster D, Pedroso S, et al. Weekly risedro-
nate in kidney transplant patients with osteopenia. Transpl Int.
2007;20(8):708-711.
119. Kruse AE, Eisenberger U, Frey FJ, Mohaupt MG. The
calcimimetic cinacalcet normalizes serum calcium in renal trans-
plant patients with persistent hyperparathyroidism. Nephrol Dial
Transplant. 2005;20(7):1311-1314.
120. Serra AL, Schwarz AA, Wick FH, Marti HP, Wuthrich RP.Successful treatment of hypercalcemia with cinacalcet in renal
transplant recipients with persistent hyperparathyroidism. Nephrol
Dial Transplant. 2005;20(7):1315-1319.
121. Srinivas TR, Schold JD, Womer KL, et al. Improvement in
hypercalcemia with cinacalcet after kidney transplantation. Clin
J Am Soc Nephrol. 2006;1(2):323-326.
122. Leonard N, Brown JH. Persistent and symptomatic post-
transplant hyperparathyroidism: a dramatic response to cinacalcet.
Nephrol Dial Transplant. 2006;21(6):1736.
123. Leca N, Laftavi M, Gundroo A, et al. Early and severe
hyperparathyroidism associated with hypercalcemia after renal
transplant treated with cinacalcet. Am J Transplant. 2006;6(10):
2391-2395.
124. Szwarc I, Argiles A, Garrigue V, et al. Cinacalcet chlorideis efficient and safe in renal transplant recipients with posttrans-
plant hyperparathyroidism. Transplantation. 2006;82(5):675-680.
125. Serra AL, Savoca R, Huber AR, et al. Effective control of
persistent hyperparathyroidism with cinacalcet in renal allograft
recipients. Nephrol Dial Transplant. 2007;22(2):577-583.
126. El-Amm JM, Doshi MD, Singh A, et al. Preliminary
experience with cinacalcet use in persistent secondary hyperpara-
thyroidism after kidney transplantation. Transplantation. 2007;
83(5):546-549.
127. Bergua C, Torregrosa JV, Fuster D, Gutierrez-Dalmau A,
Oppenheimer F, Campistol JM. Effect of cinacalcet on hypercalce-
mia and bone mineral density in renal transplanted patients with
secondary hyperparathyroidism. Transplantation. 2008;86(3):413-
417.
128. Serra AL, Wuhrmann C, Wuthrich RP. Phosphatemiceffect of cinacalcet in kidney transplant recipients with persistent
hyperparathyroidism.Am J Kidney Dis. 2008;52(6):1151-1157.
129. Gomez Marques G, Obrador Mulet A, Vilar Gimeno A, et
al. Treatment with cinacalcet of secondary hyperparathyroidism
after renal transplantation. Transplant Proc. 2009;41(6):2139-
2143.
130. Copley JB, Germain M, Stern L, et al. Evaluation of
cinacalcet HCl treatment after kidney transplantation. Transplant
Proc. 2010;42(7):2503-2508.
131. Cho ME, Duan Z, Chamberlain CE, Reynolds JC, Ring
MS, Mannon RB. Cinacalcet improves bone density in post-
kidney transplant hyperparathyroidism. Transplant Proc. 2010;
42(9):3554-3558.
Am J Kidney Dis. 2013;61(2):310-325324
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