C H A P T E R
53
Management of Mineral and Bone
Disorders in Chronic Kidney Disease
Patients
Kristen L. Jablonski and Michel Chonchol
Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz
Medical Campus, Aurora, CO, USA
SCOPE OF THE PROBLEM AND PUBLIC
HEALTH IMPLICATIONS
With declining kidney function, mineral homeostasis
becomes progressively deregulated, including alterations
in serum concentrations of calcium, phosphorus, intact
parathyroid hormone (iPTH) and fibroblast growth fac-
tor-23 (FGF-23).1 These biochemical abnormalities are
tightly associated with cardiovascular mineralization
and paradoxical skeletal demineralization (Figure 53.1).2
In 2005, Kidney Disease: Improving Global Outcomes
(KDIGO), an international organization with the mission
of developing clinical practice guidelines in CKD, for-
mally classified this clinical syndrome as Chronic Kidney
Disease-Mineral and Bone Disorder (CKD-MBD).3 This
terminology replaced renal osteodystrophy in order to
better describe the broader consequences of CKD com-
plications on mineral metabolism, bone and the cardio-
vascular system.1 The term renal osteodystrophy is now
restricted specifically to the alterations in bone morphol-
ogy or pathology that can result from complications of
CKD, as CKD-MBD better reflects the systemic conse-
quences of kidney disease, beyond bone alone.1
CKD-MBD is a common complication in CKD,
occurs early in the disease, and both persists and pro-
gresses across all stages of CKD.1 The interactions
between abnormal mineral metabolism, extraskel-
etal calcification and skeletal demineralization may
increase morbidity and mortality in patients with
CKD.4 Thus, management of CKD-MBD may influence
important clinical outcomes in this patient population.
P. Kimmel & M. Rosenberg (Eds): Chronic Renal Disease.
DOI: http://dx.doi.org/10.1016/B978-0-12-411602-3.00053-6
However, much is still unknown, and there is an over-
all lack of large randomized controlled trials provid-
ing direction for clinical practice. The major basis of
the recommendations in this chapter are the KDIGO
CKD-MBD guidelines released in 2009,1 with select
updates included in the 2013 KDIGO guideline on
the Evaluation and Management of Chronic Kidney
Disease.4 The recommendations of the National Kidney
Foundations Kidney Disease Outcomes Quality
Initiative (KDOQI), released in 2010 to adapt the 2009
KDIGO guidelines for use in the US,5 are consistent
with the KDIGO guidelines, except where noted.
PATHOPHYSIOLOGY
Biochemical and hormonal abnormalities affect cal-
cium, phosphorus, vitamin D, iPTH and FGF-23 metabo-
lism and handling, and bone and vascular calcification
alterations occur in patients with CKD-MBD.
Calcium
CKD is characterized by moderate hypocalcemia,
although calcium remains relatively stable in most
patients with non-dialysis-dependent CKD (Figure
53.2).6,7 The mechanisms associated with the develop-
ment of modest hypocalcemia in CKD patients are multi-
factorial, but include decreased intestinal absorption and
reduced 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) levels
(Figure 53.3).8 An additional concern in patients with
646 2015 Elsevier Inc. All rights reserved.
2012

Biochemical
abnormalities
CKD-MBD
Skeletal
demineralization
FIGURE 53.1 Components of chronic kidney disease-mineral and
bone disorder (CKD-MBD). The clinical syndrome CKD-MBD was
formally classified by Kidney Disease: Improving Global Outcomes
(KDIGO) in 2005 to reflect the adverse consequences of CKD compli-
cations on mineral metabolism, skeletal demineralization and para-
doxical extraskeletal cardiovascular mineralization.
Pathophysiology 647
CKD, particularly those requiring dialysis, is increased
S[Ca] resulting from pharmacological agents such as
calcium-based phosphate binders. However, there are
currently no data to support an increased risk of either
fracture or mortality with increasing S[Ca] in patients
with stage 3 to 5 CKD,1 although observational stud-
ies suggest that hypercalcemia may increase the relative
risk of mortality in dialysis-dependent CKD.911 Based on
meta-analysis in the general population, calcium supple-
ments may increase the risk of cardiovascular events.12
Cardiovascular Although the applicability to patients with CKD is
mineralization
unclear, this is biologically plausible.
Phosphorus
In CKD stages 35, S[P] remains normal until eGFR
falls below 40mL/min/1.73m2 and is still relatively stable
until eGFR is <20mL/min/1.73m2 6,7 (Figure 53.2). S[P] is

(a) 100
90 Hyperphosphatemia, serum phosphate 4.6 mg/dl
80 Secondary hyperparathyroidism, PTH 65 pg/ml
70 FGF23 excess, FGF23 100 RU/ml
% of population

60
50
40
30
20
10
0
<20 2029 3039 4049 5059 6069 70
Estimated glomerular filtration rate, ml/min per 1.73 m2

(b) Median values of 1,25 dihydroxyvitamin D, (c) Median values of serum calcium, phosphorus,
25 hydroxyvitamin D, and intact PTH by GFR levels and intact PTH by GFR levels
50 1,25 Dihydroxyvitamin D3 (pg/ml) 150 45
Serum calcium (mg/dl) 150
45 25 Hydroxyvitamin D (ng/ml) 40 Serum phosphorus (mg/dl)
1,25 dihydroxyvitamin D (pg/ml),

Intact PTH (pg/ml) Intact PTH (mg/dl)

25 hydroxyvitamin D (ng/ml)

40 35
Serum calcium (mg/dl),
Intact PTH (pg/ml)

phosphorus (mg/dl)

35

Intact PTH (pg/ml)

100 30
100
30
25
25
20
20
50 15 50
15
10 10
5 5
0 0 0 0
>80 7970 6960 5950 4940 3930 2920 <20 >80 7970 6960 5950 4940 3930 2920 <20
GFR level (ml/min) GFR level (ml/min)

FIGURE 53.2 Alterations in biochemical and hormonal parameters with declining GFR in CKD. One of the earliest detectable changes in CKD-
MBD is rising fibroblast growth factor-23 (FGF-23) levels, which increases when GFR is approximately 70mL/min/1.73m2 and progressively rises
further as eGFR continues to decline (Panel A, right bars. Left bars indicate hyperphosphatemia; middle bars indicate secondary hyperparathyroid-
ism). Increasing FGF-23 contributes to a decline in calcitriol (1,25 dihydroxyvitamin D3) levels by inhibiting 1-hydroxylase activity and stimulating
24-hydroxylase, which is responsible for the degradation of calcitriol (Panel B). Intact parathyroid hormone (iPTH) also rises as GFR declines, although
not in a significant way until GFR falls below 45mL/min/1.73m2 (Panels B and C). In contrast, S[Ca] remains relatively stable in most patients with
non-dialysis-dependent CKD (Panel C). S[P] remains normal until GFR falls below 40mL/min/1.73m2 and is still relatively stable until GFR is
<20mL/min/1.73m2 (Panels A and C). Reprinted by permission from Macmillan Publishers Ltd: [Kidney International] (6), copyright (2011) [Panel A] and
Macmillan Publishers Ltd: [Kidney International] (13), copyright (2007) [Panels B and C].

VIII. THERAPEUTIC CONSIDERATIONS

648 53. Management of Mineral and Bone Disorders in Chronic Kidney Disease Patients
PTH secretion
Calcium FGF-23
absorption
production
Phosphorus
retention
1,25(OH)2D
production
FIGURE 53.3 Biochemical and hormonal abnormalities in CKD-
MBD. In CKD-MBD, production of fibroblast growth factor-23 (FGF-
23), the principal regulating hormone of phosphorus, is elevated
to counter a rise in S[P]. FGF-23 also inhibits synthesis of 1,25 dihy-
droxyvitamin D3 (1,25(OH)2D3), by decreasing renal 1-hydroxyase
expression and increasing 24-hydroxylase expression. FGF-23 also
initially suppresses parathyroid hormone (PTH) release and secre-
tion, although the parathyroid glands may become resistant and the
relationship may change with advancing kidney disease. PTH release
and secretion also increase in response to hypocalcemia, hyperphos-
phatemia and/or decreased 1,25(OH)2D3. Both decreased intestinal
absorption of calcium and reduced 1,25(OH)2D3 levels contribute to
the development of modest hypocalcemia.
maintained within the normal laboratory range until later
stages of CKD mainly by FGF-23, which increases phos-
phate excretion to maintain normal S[P].13 Increased S[P]
is a stimulus for secondary hyperparathyroidism1 and a
mediator of vascular calcification.14
Observational studies support that even in the nor-
mal range, increased S[P] is associated with increased
risk of all-cause mortality in patients without CKD,15,16
non-dialysis-dependent CKD,17,18 as well as consistently
in patients treated with chronic dialysis.18,19 In addition,
increased S[P] that is still in the normal range is also
associated with increased prevalence of vascular and val-
vular calcification in patients with CKD.20
Vitamin D
25-hydroxyvitamin D (25(OH)D3; calcidiol) is con-
sidered the best measure of vitamin D nutritional status
because of its long half-life in the circulation of approxi-
mately 3 weeks. 25(OH)D3 is converted in the kidney
by 1-hydroxylase to 1,25(OH)2D3 (calcitriol), the active
form of vitamin D, although extrarenal conversion can
also occur.1 1,25(OH)2D3 is an important regulator of
mineral homeostasis and musculoskeletal function, in
addition to having pleiotropic extracellular effects.
Most patients with CKD have low levels of
1,25(OH)2D3.1,21 This decline occurs early in the dis-
ease, and the severity increases as CKD progresses6,22
VIII. THERAPEUTIC CONSIDERATIONS
(Figure 53.2). Classic teaching was that the decline in
1,25(OH)2D3 was the result of loss of nephron mass.
It is now known that increases in serum FGF-23 in
the early stages of kidney disease is also an important
contributor by inhibiting 1-hydroxylase activity and
stimulating 24-hydroxylase, which is responsible for the
degradation of 1,25(OH)2D323 (Figure 53.3).
Several observational studies have shown inverse
associations between vitamin D metabolites and adverse
outcomes in patients with CKD, as well as in the general
population. Low serum 25(OH)D3 level is independently
associated with all-cause mortality in both non-dialysis-
and dialysis-dependent CKD patients,24,25 and in the
general population.26,27,28 1,25(OH)2D3 levels are also
inversely associated with mortality in non-dialysis-
dependent CKD patients. Low serum 25(OH)D3 and/or
1,25(OH)2D3 are also independently associated with car-
diovascular events and mortality in individuals with24
and without CKD.26,28,29 In addition, both 1,25(OH)2D330
and 25(OH)D327 levels are inversely associated with kid-
ney disease progression, and low 25(OH)D3 is associated
with increased risk of coronary artery disease progres-
sion in the general population.31
Parathyroid Hormone
Under physiological circumstances, PTH maintains
S[Ca], increases phosphate excretion, and stimulates pro-
duction of 1,25(OH)2D3. Production increases in response
to hypocalcemia, hyperphosphatemia and/or decreased
1,25(OH)2D3 (Figure 53.3).1 FGF-23 can also suppress
PTH, although the parathyroid glands may become resis-
tant and the relationship may change with advancing
kidney disease.23,32
iPTH rises as GFR declines, although not in a signifi-
cant way until eGFR falls below 45mL/min/1.73m2 6
(Figure 53.2). This is initially an adaptive response to
maintain calcium, phosphorus, and 1,25(OH)2D3 homeo-
stasis.1 Decreased S[Ca] was once thought to be central in
the development of secondary hyperparathyroidism. It is
now accepted that FGF-23 is a key player in this process,
initially inhibiting PTH, although this is compromised as
CKD progresses.13
Most observational evidence on the relationship
between PTH and clinical outcomes was generated from
chronic HD patients. When iPTH is elevated beyond an
inflection point ranging from 480 to 600pg/mL,10,33,34
there is an increased mortality risk, but this finding is
not consistent and the relationship may be U-shaped,
inverse, or non-significant.35,36,37 Increased iPTH may
also be associated with risk of cardiovascular events in
this population.1 In general, iPTH fails to correlate with
fracture risk, and the relationship of PTH levels with
bone formation rates vary greatly.1
 Diagnosis
FGF-23
FGF-23 was first identified in 2000,38 and the dis-
covery has led to a re-consideration of the mechanisms
driving secondary hyperparathyroidism.13 FGF-23 is
secreted by skeletal osteocytes in response to changes
in bone formation and S[P] (Figure 53.3). However, the
mechanisms underlying the direct regulation of FGF-23
production are largely unknown.39 FGF-23 is the princi-
pal regulating hormone of phosphorus, and also inhibits
synthesis of 1,25(OH)2D3 and suppresses PTH, at least
initially.23,32 These functions are accomplished by reduc-
ing the activity and/or expression of sodium-phosphate
co-transporters, possibly reducing intestinal phosphate
absorption, decreasing renal 1-hydroxyase expres-
sion, and increasing 24-hydroxylase expression absorp-
tion.23,32 FGF-23 acts by binding to receptors that are
part of the tyrosine kinase superfamily40 in the presence
of the membrane-bound co-receptor klotho,32 but animal
studies support that FGF-23 can also act independently
of klotho, at least in the heart.41
Increasing FGF-23 levels may be one of the earli-
est detectable changes in CKD-MBD. FGF-23 levels
begin to increase when eGFR is approximately 70mL/
min/1.73m2, and progressively rise as eGFR declines
further (Figure 53.2).13,42 Small elevations in FGF-23
are initially required, as this increases renal phosphate
excretion, thus maintaining S[P] within normal limits.
With CKD progression, circulating FGF-23 levels con-
tinue to rise, the phosphaturic response declines, and
eventually S[P] is increased. It is presently unknown
why FGF-23 rises early in CKD, before a rise in S[P].
In non-dialysis-dependent CKD patients, FGF-23 lev-
els are independently associated with mortality,43,44 car-
diovascular events,43,44,45 and CKD progression.43,44,46
Very large hazard ratios support the contention
that FGF-23 is a key outcome predictor. FGF-23 lev-
els are also independently associated with left ven-
tricular hypertrophy in non-dialysis-dependent CKD
patients,41,47 chronic HD patients,48 and in the general
population.49 Evidence in animals indicates that block-
ing FGF-23 can prevent the development of left ven-
tricular hypertrophy.41 One of the strongest working
hypotheses regarding why FGF-23 predicts of cardiovas-
cular events and mortality is its causal effect on left ven-
tricular hypertrophy.
Bone
Traditionally, renal osteodystophy has been charac-
terized based on bone turnover and mineralization. In
CKD-MBD, alterations in these parameters vary greatly.
The spectrum of bone turnover ranges from abnormally
low to very high, and mineralization may or may not be
present.
VIII. THERAPEUTIC CONSIDERATIONS
649
A systematic review of bone biopsies in patients
with CKD stages 3 to 5 showed 32% had osteitis fibrosa
(increased turnover and normal mineralization), 18%
adynamic (decreased turnover and acellularity), 16%
were normal, 8% had osteomalacia (decreased turnover
and abnormal mineralization), and 20% had mixed dis-
ease (increased turnover with abnormal mineralization).1
Alterations in bone are important, as this can lead
to increased bone fragility and fracture. Hip fractures
are 2 to 3 times more common in elderly patients with
stage 3 to 4 CKD.1 Although the risk in early stage CKD
is unclear, chronic dialysis patients with adynamic bone
disease and/or osteomalacia have an increased risk of
fracture.50,51
Vascular Calcification
Extraskeletal calcification of the vasculature increases
progressively with declining eGFR, and is more preva-
lent, severe, and accelerated in CKD compared to the
general population.14 Calcification can occur in both the
intimal and medial layers of the vasculature, but medial
calcification is considered the more common and major
form of calcification in CKD.52 Medial calcification is
characterized by diffuse mineral deposition through-
out the vascular tree53 and is associated with increased
large-elastic artery stiffness. This promotes increased
systolic blood pressure, reduced diastolic blood pressure,
increased cardiac afterload, compromised perfusion of
the coronary arteries and left ventricular remodeling.54,55
Accordingly, vascular calcification is a major contributor
to CVD in CKD patients, and observational data indicate
vascular calcification predicts of cardiovascular events
and mortality.14,52 However, it is presently unclear if
intervening to slow progression of vascular calcification
alters outcomes in CKD patients.1
DIAGNOSIS
The basis of these recommendations are primarily
the KDIGO guidelines,1,4 mentioning differences from
KDOQI5 when applicable. Traditionally, biochemical
parameters have been the primary indicators for the
basis of diagnosis, identifying therapeutic targets, and
managing CKD-MBD. When considering biochemical
values, it is recommended that all therapeutic decisions
are based on trends rather than a single value.
Clinically significant biochemical manifestations of
CKD-MBD may begin in stage 3 (a GFR of approxi-
mately 40 to 50 mL/min/1.73 m2),6 but the rate and
degree of changes are highly variable. Therefore the
frequency of assessment must consider the individual
patient.1 The most recent KDIGO guidelines recom-
mend measuring S[Ca], S[P], iPTH, as well as alkaline
650 53. Management of Mineral and Bone Disorders in Chronic Kidney Disease Patients
phosphatase (ALP), at least once in all adults with an
eGFR less than 45mL/min/1.73m2 in order to establish
a baseline.4 At least one of these biochemical abnormali-
ties must be present for the diagnosis of CKD-MBD.1
Most observational data on these parameters were gen-
erated in a HD population. Much less is known about
stage 3 to 5 CKD. This makes establishing diagnostic cri-
teria as well as treatment recommendations challenging.
Furthermore, there are no clear data available supporting
that routine measurement improves outcomes, but these
are the best recommendations based on the currently
available data.1
Calcium
KDIGO recommends monitoring S[Ca] beginning in
stage 3 CKD. While the frequency of monitoring should
consider the individual patient, a reasonable monitor-
ing schedule is every 6 to 12 months in stage 3, every 3
to 6 months in stage 4, and every 1 to 3 months in stage
5 (Table 53.1).1 Ideally, ionized calcium should be used,
as this is the physiologically active form. However, this
is not a routinely available, practical or cost effective
option, thus total calcium is most frequently measured.
Phosphorus
Recommendations for monitoring S[P] parallel those
for S[Ca] (Table 53.1).1 S[P] varies diurnally, although
this variation is less in patients with CKD.56
Vitamin D
25(OH)D3 is considered the best measure of vitamin
D nutritional status, as it has a long half-life (approxi-
mately 3 weeks). 1,25(OH)2D3 has a much shorter half-
life (approximately 4 to 6 hours).1 Epidemiological
studies have found both 25(OH)D3 and 1,25(OH)2D3
to be independent predictors of all-cause and cardio-
vascular mortality in both patients with CKD and in
the general population.2428 Vitamin D status refers to
whether or not circulating levels of 25(OH)D3 are con-
sidered adequate. While there is no consensus on what
is considered adequate levels, the most recent 2013
update from KDIGO recommended using the interna-
tional definition of <20ng/mL as a cut-off for vitamin D
deficiency.4 Serum 25(OH)D3 levels are inversely associ-
ated with serum PTH levels in CKD57 and non-CKD58,59
patients, until 25(OH)D3 increases to 30 to 40ng/mL, at
which point PTH level plateaus at its nadir.60 Such data
provide the basis for the term vitamin D status, which
refers generally to whether an individual has deficient,
insufficient or sufficient serum levels of 25(OH)D3.
KDIGO recommends considering monitoring 25(OH)D3
VIII. THERAPEUTIC CONSIDERATIONS
in CKD stages 3 to 5, with repeat testing intervals com-
mensurate with both baseline levels and current treat-
ment (Table 53.1).1 KDOQI also recommends periodic
testing of 25(OH)D3 and initiating treatment if levels are
low.5 However, there is still some debate in the nephrol-
ogy community regarding whether 25(OH)D3 levels
should be measured and monitored, as there is a lack
of evidence that vitamin D supplementation indeed
improves clinical outcomes. The assays used to measure
25(OH)D3 are not well standardized, with the DiaSorin
assay being most commonly used in clinical practice.1
PTH
KDIGO recommends monitoring serum iPTH lev-
els beginning in stage 3 and considering these levels
and progression in determining repeat testing inter-
vals. A reasonable monitoring schedule in stages 4
and 5 is every 6 to 12 and 3 to 6 months, respectively
(Table 53.1). An optimal level of iPTH in stages 3 to 5
CKD is currently unknown and difficult to establish
because the range of values widens as CKD progresses.
In addition, there are methodological challenges to
measurement associated with assay type, sample type,
methodology, and variability. The second generation
assay (iPTH) is most commonly used in clinical prac-
tice. There are also normally minute to minute oscilla-
tions in levels, although this is blunted in CKD. Thus,
KDIGO does not provide a specific target recommen-
dation, but instead recommends interpretation on the
basis of the specifics of each individual laboratory.
Guidance of therapy should be based on a persistent
rise in levels, rather than an absolute value.1
FGF-23
FGF-23 is not currently considered in the diagno-
sis of CKD-MBD, as it is still a relatively new, but very
important, component of CKD-MBD. Thus, FGF-23
is not discussed in the KDIGO or KDOQI guidelines,
and FGF-23 is currently more commonly assessed
in research. There are two enzyme-linked immuno-
asays that are used to measure FGF-23: the intact FGF-
23 assay (primarily serum) and the C-terminal FGF-23
assay (primarily plasma). Initial studies showed a good
correlation between the two, although this has been
questioned in more recent work.61,62 Values for FGF-23
are skewed to the right, therefore median levels are typ-
ically reported in research. Using the C-terminal assay,
typical levels in healthy adults are 17.8197.0 RU/mL
(median 76.5 RU/mL) (Table 53.1).63 In non-dialysis-
dependent CKD patients, the typical elevation is 25-
fold higher (63.65592 RU/mL; median 188 RU/mL),
and in dialysis patients, levels can reach an exponential
1000-fold increase (150115,000 RU/mL; median 4175
 Diagnosis 651
TABLE 53.1 Biochemical Diagnosis of CKD-MBD*

Physiological Triggers and KDIGO Monitoring

Parameter Normal Range (serum) Consequences Changes in CKD Recommendations

Calcium* 8.510.5mg/dL# Low 1,25(OH)2D3, decreased Most often moderate Stage 3: every 6 to 12
intestinal absorption and hypocalcemia, although months
phosphate retention hypercalcemia can occur (rare)
Stage 4: every 3 to 6 months

Favors the development of Remains normal until eGFR Stage 5: every 1 to 3 months
SHP <40mL/min/1.73m and stays
2

relatively stable until eGFR

Phosphorus* 2.54.5mg/dL
Vitamin D* Deficient = 25(OH)D3 <20ng/
mL
Insufficient = 2030ng/mL
Sufficient >30ng/mL
Impaired phosphate excretion
promotes a rise in S[P]
Increased levels stimulate SHP,
promote vascular calcification
1,25(OH)2D3 synthesis in the
kidney is compromised
May be an underlying cause of
elevated PTH
<20mL/min/1.73m2
Remains normal until eGFR Stage 3: every 6 to 12
<40mL/min/1.73m2 and stays months
relatively stable until eGFR
Stage 4: every 3 to 6 months
<20mL/min/1.73m2
Stage 5: every 1 to 3 months
Does not rise until later stages
because FGF-23 initially
maintains the normal range
by increasing renal phosphate
excretion
Insufficiency and deficiency Baseline testing in stages 3
are highly prevalent, possibly to 5, with repeat intervals
approximately 50% of CKD commensurate with baseline
patients levels and treatment

PTH* Abnormal if eGFR is <45mL/
min/1.73m2 and iPTH is
persistently above upper limit of
normal for the given assay and
progressively rising
FGF-23 In one small study: healthy
adults: 17.8197.0 RU/mL
(median 76.5 RU/mL)
Non-dialysis-dependent CKD:
63.65592.0 RU/mL (median
188.0 RU/mL)
Maintenance HD: 150115,000
RU/mL (median 4715.0 RU/
mL)
Increases in response
to hypocalcemia,
hyperphosphatemia and/or
decreased 1,25(OH)2D3
Hypercalcemia, high
1,25(OH)2D3 and FGF-23 can
suppress
Secreted by skeletal
osteocytes in response to
changes in bone formation
and S[P], principal
regulating hormone of
phosphorus
High FGF-23 inhibits
1,25(OH)2D3 and favors
increased PTH
Approximately 60% of Stage 3: based on baseline
patients with eGFR <60mL/ levels and CKD progression
min/1.73m2 have elevated
Stage 4: every 6 to 12
iPTH levels
months
Stage 5: every 3 to 6 months
Increases very early in CKD No recommendation given
(eGFR approximately 70mL/
min/1.73m2) and progressively
increases as GFR declines

All therapeutic decisions should be based on trends rather than a single laboratory value. 1,25(OH)2D3: 1,25D dihydroxyvitamin D3, SHP: secondary hyperparathyroidism, eGFR:
estimated glomerular filtration rate, S[P]: serum phosphorus concentration, 25(OH)D3: 25 hydroxyvitamin D3, iPTH: intact parathyroid hormone, FGF-23: fibroblast growth factor-23.
*
To make a diagnosis of CKD-MBD, one of more of these laboratory abnormalities must be present.
#
May vary by laboratory.

Frequency of monitoring should consider the presence and magnitude of abnormalities.

RU/mL).13,61,63 It is also important to consider the frac-
tional excretion of phosphate in the interpretation of
these values, as FGF-23 is the principal regulating hor-
mone of phosphorus.
Bone
Bone biopsy-based histology is considered the
gold standard technique for the diagnosis of the bone
component of CKD-MBD, as it provides information
regarding bone turnover, mineralization and volume.1
KDIGO asserts than bone biopsy is reasonable for cer-
tain settings in stage 3 to 5 CKD, including patients
with unexplained fractures, persistent bone pain, unex-
plained hypercalcemia or hyphophatemia, and before
starting therapy with biophosphonates in those with
known CKD-MBD.1 Routine bone mineral density
(BMD) testing using dual energy X-ray absorptiometry

VIII. THERAPEUTIC CONSIDERATIONS

652 53. Management of Mineral and Bone Disorders in Chronic Kidney Disease Patients
(DXA) scans is not recommended in patients with an
eGFR <45mL/min/1.73m2. BMD does not predict frac-
ture risk in these patients as in the general population,
and results may be either unhelpful or misleading.4,5
Vascular Calcification
While extraskeletal calcification is a component of
diagnosis of CKD-MBD, KDIGO does not recommend
indiscriminate screening of all patients with CKD-MBD
for vascular calcification, as it is unclear if intervention
will alter outcomes.1 KDOQI also does not recommend
screening asymptomatic patients with CKD for calcifica-
tion.5 At this time, there is consensus among the nephrol-
ogy community that screening for vascular calcification
will increase the costbenefit ratio, as there is a lack of
potential therapeutic interventions to reverse vascular
calcification. However, when vascular calcification is
detected, the patient should be considered to have high
cardiovascular risk.
TREATMENT
To date, the focus in the literature has been on the asso-
ciation between disordered mineral metabolism in CKD
and adverse outcomes, including mortality, cardiovascu-
lar disease, and fractures. This has led to targeting these
parameters in clinical practice to potentially improve
these outcomes, but large RCTs supporting clinical prac-
tice are presently very limited.1 Most of the available
literature consists of observational data or surrogate out-
comes, rather than therapeutic options associated with
hard outcomes. In general, therapy has typically focused
on correcting biochemical and hormonal abnormalities in
order to limit their potentially adverse consequences. This
section focuses largely on treatments targeting correction
of biochemical and hormonal abnormalities.
Calcium
There is little observational or interventional evi-
dence that targeting S[Ca] alters clinical outcomes in
CKD, although calcium supplementation may increase
risk of CVD in the general population.64 KDIGO recom-
mends maintaining S[Ca] in the normal range in stage
3 to 5 CKD patients (Table 53.2).1 KDOQI agrees with
this recommendation, with a preference towards the
lower end of the reference range in stage 5 patients (8.4
to 9.6mg/dL).5 However, most of the data supporting
this recommendation are observational, and there does
not appear to be any detriment to clinical outcomes to
maintaining S[Ca] within the normal laboratory range.
To achieve this goal, limiting the use of calcium-based
binders, calcitriol and/or its analogs in patients with
VIII. THERAPEUTIC CONSIDERATIONS
known hypercalcemia is recommended.1 Figure 53.4
provides an algorithmic approach to the treatment
of hypercalcemia and other abnormalities of mineral
metabolites in patients with CKD-MBD.
Recommendations suggest treatment for hypocal-
cemia should be initiated only when patients with
CKD present with symptoms of hypocalcemia, such as
numbness and tingling. In some cases, hypocalcemia
(defined as S[Ca] less than 7.5mg/dL) should war-
rant treatment. The initial treatment should include
oral calcium supplementation and/or active vitamin D
analogues to correct hypocalcemia. However, vitamin
D analogues should mainly be used only if the symp-
tomatic hypocalcemia is present with an elevated PTH.
In those patients who have hypocalcemia in the setting
of hyperphosphatemia, the high S[P] should be treated
with a phosphate binder before initiating any other
therapy for hypocalcemia.
Phosphorus
The data on normalizing S[P] in those patients with
CKD not requiring chronic dialysis are conflicting.65 The
recommendation in chronic dialysis patients is to achieve
at least a S[P] <5.5mg/dL. Figure 53.4 provides a sug-
gested approach to correcting S[P] abnormalities in non-
dialysis-dependent CKD patients.
Observational data suggest that phosphate binders
of any type may reduce mortality in both dialysis-66
and non-dialysis-dependent CKD patients.67 Most RCTs
have been completed in chronic HD populations, with
only one trial available in patients with stage 3 to 5
CKD.68 The phosphate binder sevelamer slowed vascu-
lar calcification in this study, which is largely consistent
with studies in dialysis patients,19,69 although not all
trials have been positive.70,71 The efficacy of phosphate
binders for reducing cardiovascular events or mortality
in non-dialysis-dependent CKD is currently unknown.
In dialysis patients, both a RCT72 and secondary anal-
ysis of an open label study73 showed no difference in
mortality based on allocation to sevelamer compared to
calcium-based binders. A third study performed in inci-
dent HD patients found increased mortality in calcium-
based binder compared to sevelamer group, although
the KDIGO work group1 raised a concern of a possibly
unsuccessful randomization.19 RCTs using phosphate
binders with cardiovascular end-points are also lack-
ing in the chronic dialysis population. The effects of
calcium-based binders compared to either sevelamer
or lanthanum on bone histology are unclear, with some
studies in chronic dialysis patients showing improve-
ments and some showing worsening.71,74,75
Sevelamer and calcium-based binders appear to be
equally effective at lowering S[P] in RCTs with stage 3 to
5 CKD patients.68 Lanthanum also appears to be effective

TABLE 53.2 Treatment of Biochemical Abnormalities in CKD-MBD
Parameter KDIGO/KDOQI Treatment Recommendations
Calcium Stage 3 to 4: maintain corrected S[Ca] in the
normal range
Stage 5: same as above, with a preference towards
the lower end of the reference range (8.49.6mg/dL)
Phosphorus If GFR <45mL/min/1.73m2, maintain S[P] in the
normal range
Choice of binder should consider other
components of CKD-MBD, other therapies and
side-effects
Maintain S[P] in the target range in stage 3 to 4,
lower in stage 5
Vitamin D Only indicated to correct 25(OH)D3 deficiency,
follow recommendations for general population
(10002000 IU/d cholecalciferol [D3])
Recommend using 50,000 IU/week or per month
ergocalciferol (D2) to correct deficiency to >30ng/mL
PTH Stages 3 to 5: optimal levels unknown
Suggest lowering PTH threshold in CKD stages 4
to 5 to prompt evaluation and possible treatment
FGF-23 Optimal levels unknown. KDIGO and KDOQI do
not make recommendations
S[Ca]: serum calcium concentration, 1,25(OH)2D3: 1,25D dihydroxyvitamin D, eGFR: estimated glomerular filtration rate, 25(OH)D3: 25 hydroxyvitamin D, S[P]: serum
phosphorus concentration, PTH: parathyroid hormone, HPT: hyperparathyroidism, FGF-23: fibroblast growth factor-23. See Figure 53.4 for an approach to treating biochemical
abnormalities in patients with CKD-MBD.
in chronic dialysis patients.76,77 A recent meta-analysis
concluded that all currently available phosphate bind-
ers effectively lower S[P] compared to placebo.78 Trials
have shown no difference in S[Ca] in stage 3 to 5 CKD
patients randomized to sevelamer or a calcium-based
phosphate binder,68 but lower S[Ca] in chronic dialysis
patients treated with sevelamer compared to calcium-
based binders.19,69,71,72
The most recent KDIGO guidelines recommend
maintaining S[P] in the normal range if eGFR <45mL/
min/1.73m2.4 KDOQI recommends lower than the
target range in stage 5 (Table 53.2).5 This is one of
the recommendations most widely accepted by the
nephrology community. Prospective RCTs, however, are
needed to prove that lowering S[P] below the recom-
mended target range indeed has any significant affect
VIII. THERAPEUTIC CONSIDERATIONS
Treatment 653
Therapeutic Options
Limit calcium-based binders and/or 1,25(OH)2D3 or active vitamin D
treatment if known hypercalcemia
Dietary phosphate restriction
Phosphate binders
Aluminum hydroxide (not recommended)
Calcium carbonate and calcium acetate
Magnesium hydroxide and magnesium carbonate
Sevelamer hydrochloride and sevelamer carbonate
Lanthanum carbonate
Nutritional vitamin D
Ergocalciferol (D2)
Cholecalciferol (D3)
First evaluate for hyperphosphatemia, hypocalcemia and vitamin D deficiency
Initial options
Limit dietary phosphate
Phosphate binders
Calcium supplements
Nutritional vitamin D (only if 25(OH)D3 deficient)
If PTH continues to rise and remains above upper limit of normal and the
patient is 25(OH)D3 deficient: calcitriol or vitamin D analogs
Cinacalcet not recommended by KDIGO in non-dialysis CKD patients
Severe HPT without response to other therapy: parathyriodectomy
KDIGO does not make a recommendation
Only therapeutic option at this time is dietary phosphate reduction
Sevelamer and lanthanum carbonate may lower FGF-23
on clinical outcomes. Overall, a phosphate-restricted
diet combined with oral phosphate binders is a well-
established recommendation for controlling hyper-
phosphatemia in patients with stage 3 to 5 CKD.1,5
The choice of phosphate binder should consider other
components of CKD-MBD, concomitant therapies, and
side-effects. There is currently insufficient evidence on
comparative clinical efficacy to recommend a specific
binder for all patients.1
Dietary phosphate restriction is important in the
treatment of CKD-MBD because 6070% of ingested
phosphate is absorbed.79 However, there are numer-
ous challenges to achieving treatment goals, includ-
ing patient compliance, issues with food labels, and
the presence of abundant food additives (Table 53.3).79
Consequently, there are not enough data on dietary
654 53. Management of Mineral and Bone Disorders in Chronic Kidney Disease Patients

Hypercalcemia Hyperphosphatemia 25(OH)D deficiency

(>10.2 mg/dl) (>4.5 mg/dl) (<20 ng/ml)

Oral calcium-based Dietary phosphorus 10002000 IU/d

phosphate binders? restriction cholecalciferol (D3)
yes
no
Discontinue
Active vitamin D or Persistent Re-check at
vitamin D analogs? hyperphosphatemia? 6 months

yes no
yes
no
Maintain
Discontinue Consider phosphate change Persistent
Check for other binders* 25(OH)D deficiency?
causes (e.g.
no
malignancy)
yes

Discontinue
Continue D3 or
increase dose

FIGURE 53.4 Algorithmic approach to treating biochemical and hormonal abnormalities in CKD-MBD. The first step in the treatment of
hypercalcemia is to check if the patient is taking oral calcium-based phosphate binders. If so, the binder should be discontinued. The same ques-
tion should be asked regarding therapy with active vitamin D or vitamin D analogs. If neither is a potential cause of hypercalcemia, other poten-
tial causes should be evaluated, such as malignancy. To treat hyperphosphatemia, dietary phosphorus restriction should first be attempted. If
hyperphosphatemia persists, phosphate binders should be considered. However, phosphate binders are not FDA-approved for the treatment of
hyperphosphatemia in non-dialysis-dependent CKD (indicated by *). Consistent with KDIGO recommendations, we recommend treatment of
25(OH)D3 deficiency with 10002000 IU/day of cholecalciferol (D3). Serum 25(OH)D3 should be re-checked after 6 months, with supplementa-
tion continued or increased according to repeat test levels.

modifications to strongly endorse phosphate restriction
alone as the primary or sole therapy to control hyper-
phosphatemia in patients with CKD-MBD.1
Phosphate binders available for the treatment of
CKD-MBD have particular advantages and disad-
vantages (Table 53.3). Aluminum hydroxide is not
recommended for use as there is a risk of serious hema-
tological, neurological and skeletal adverse events as a
consequence of aluminum toxicity.79 Calcium carbonate
and calcium acetate are both calcium-based phosphate
binders that are inexpensive and effective at lowering
S[P], but increase risk of calcium overload, which may
promote vascular calcification or adynamic bone dis-
ease (although there is less calcium exposure with cal-
cium acetate than calcium carbonate).79 Accordingly,
KDIGO does not recommend using calcium-based
phosphate binders in patients with known low bone
turnover, vascular calcification or hypercalcemia.1
Magnesium-based binders include magnesium hydrox-
ide and magnesium carbonate. Both magnesium-based
binders are associated with a lower calcium load than
pure calcium-based phosphate binders. However, they
have gastrointestinal side-effects, are not well studied,
and have lower efficacy, which may necessitate higher
doses that could induce hypermagnesemia in CKD
patients.79
Sevelamer hydrochloride is a non-calcium, non-metal,
non-absorbable phosphate binder. Sevelamer carbonate
is similar to sevelamer hydrochloride, and is assumed
to have equal efficacy and potentially improved acid
base balance and lower risk of acidosis.1,80 Both have the
advantages of avoiding calcium overload, metal expo-
sure and absorption, and have also been shown to lower
LDL cholesterol.79 Sevelamer also has potential benefits
on vascular calcification and mortality,68,72 and treat-
ment can lower FGF-23.81 Disadvantages of sevelamer
include high cost, gastrointestinal side-effects, a high pill
burden, and the risk of decreased bicarbonate levels with
sevelamer hydrochloride.79
Lanthanum carbonate is a non-calcium, naturally
occurring metal-based binder first approved for use
in 2004.82 Advantages include effective phosphate
lowering, avoidance of calcium overload, lesser pill
requirement than sevelamer, and chewable deliv-
ery. Lanthanum is eliminated by the liver, and there-
fore its handling is not dependent on renal function.79
Lanthanum may also have benefits beyond lowering
S[P], such as improving bone remodeling or lowering

VIII. THERAPEUTIC CONSIDERATIONS

 Treatment 655
TABLE 53.3 Advantages and Disadvantages of Available Therapies to Treat CKD-MBD-associated Biochemical Abnormalities

Therapeutic Options Pro Con

Dietary phosphate Important modulator of S[P] because 60 to 70% of all ingested Challenging to adhere to (food choices, food labeling,
restriction dietary phosphate is absorbed additives, etc.)
Not enough data available to strongly endorse as the sole
therapy for treatment hyperphosphatemia
Aluminum Very effective phosphate binding Not recommended due to risk of serious hematological,
hydroxide neurological and skeletal adverse events resulting from
aluminum toxicity
Calcium carbonate Inexpensive, effective and readily available Potential of hypercalcemia-associated risks (e.g. vascular
calcification, adynamic bone disease)
KDIGO does not recommend using in patients with
known low bone turnover, vascular calcification or
hypercalcemia
Calcium acetate Potentially less calcium exposure and better phosphate- Risk of hypercalcemia
binding capacity than calcium carbonate
More costly than calcium carbonate
KDIGO does not recommend using in patients with
known low bone turnover, vascular calcification or
hypercalcemia
Magnesium Potentially less calcium exposure than calcium-based binders Gastrointestinal side-effects
hydroxide and
Lower efficacy, which may necessitate higher doses and
magnesium
potentially hypermagnesemia
carbonate
Not well studied
Sevelamer Effective High cost
hydrochloride
Avoids calcium overload Gastrointestinal side-effects
Avoids metal exposure High pill burden
Not absorbed Potential for decreased serum bicarbonate levels
(acidosis)
May have benefits beyond lowering S[P] (such as lowering
LDL, slowing vascular calcification, and lowering FGF-23)
Sevelamer carbonate Assumed to have similar advantages to sevelamer High cost
hydrochloride with improved acidbase balance
Gastrointestinal side-effects
High pill burden
Lanthanum Effective High cost
carbonate
Avoids calcium overload Gastrointestinal side-effects
Chewable Long-term clinical consequences unknown
Eliminated by the liver thus metabolism not dependent on
renal function
May have benefits beyond lowering S[P] (such as improving
bone remodeling, lowering FGF-23 levels)
Nutritional vitamin Effective at raising 25(OH)D3 and 1,25(OH)2D3 levels Lack of RCTs in CKD patients
D (D2 and D3)
Extra-renal conversion to 1,25(OH)2D3 may confer extra-renal Less studied in CKD patients
benefits
Can also suppress PTH Some question as to whether it is adequate to raise
25(OH)D3 to sufficient levels in all CKD patients
Inexpensive
Incidence of hypercalcemia and hyperphosphatemia is low
(Continued)

VIII. THERAPEUTIC CONSIDERATIONS

656 53. Management of Mineral and Bone Disorders in Chronic Kidney Disease Patients
TABLE 53.3 Advantages and Disadvantages of Available Therapies to Treat CKD-MBD-Associated
CKD-MBD-associated Biochemical
Therapeutic Options Pro
Calcitriol (1,25D3) Effective at raising 1,25(OH)2D3 levels
Decreases PTH production by the parathyroid glands
Vitamin D Effective at raising 1,25(OH)2D3
receptor activators
Decreases PTH production by the parathyroid glands
(1,25(OH)2D3
analogs: e.g. Newer analogs are more selective for PTH suppression with
paricalcitol, fewer effects on S[Ca] and S[P]
doxercalciferol)
Cinacalcet Effectively lowers PTH
May also lower S[P]
Parathyroidectomy Generally reduces PTH, S[Ca] and S[P]
S[P]: serum phosphorus concentration, FGF-23: fibroblast growth factor-23, 1,25(OH)2D3: 1,25D dihydroxyvitamin D, 25(OH)D3: 25 hydroxvitamin D, PTH: parathyroid
hormone, S[Ca]: serum calcium concentration, RCT: randomized-controlled trial.
FGF-23.76,83 However, the cost of lanthanum carbonate
is high, gastrointestinal side-effects are common, and
the long-term clinical consequences of its use are still
largely unknown.1,79,84
Vitamin D
KDIGO recommends treating CKD patients with
low circulating levels of 25(OH)D3, with supplementa-
tion with 10002000 IU/d of cholecalciferol, consistent
with repletion recommendations for the general popula-
tion.4 KDOQI recommends using ergocalciferol (50,000
IU weekly or monthly) to correct 25(OH)D3 deficiency
if levels are lower than 30ng/mL.85 Both forms of vita-
min D supplementation have been shown to increase
serum 25(OH)D3 levels. However, there is a lack of data
regarding the impact of these nutritional vitamin D sup-
plements on clinical management issues, including pill
burden and the cost related to treatment and monitoring.
1,25(OH)2D3 levels are usually not monitored through-
out the course of CKD. Therefore, treatment should not
be administered in response to low 1,25(OH)2D3. Figure
53.4 provides an algorithmic approach to treating CKD
patients with low circulating levels of 25(OH)D3, with
the available evidence supporting this overall approach.
Observational data in chronic dialysis patients sup-
port increased survival with treatment with 1,25(OH)2D3
analogs,11,24 but this finding is likely confounded by indi-
cation and results are not consistent.86,87 Data are limited
in non-dialysis-dependent CKD patients, as well as for
nutritional vitamin D therapy. Observational data sug-
gest that active vitamin D therapy is also associated with
VIII. THERAPEUTIC CONSIDERATIONS
BiochemicalAbnormalities
Abnormalities (Continued)
Con
May promote hypercalcemia (risk of adynamic bone
disease, vascular calcification) and/or raise S[P]
May promote hypercalcemia (risk of adynamic bone
disease, vascular calcification) and/or raise S[P]
Did not reduce mortality in EVOLVE trial
Gastrointestinal side-effects
Risk of hypocalcemia
Not FDA approved for use in patients with CKD not
requiring dialysis
Last choice therapy
Lack of RCTs on the benefits and risks
reduced risk of progression to ESRD.88 In a meta-anal-
ysis of trials in non-CKD patients, nutritional vitamin
D supplementation was shown to decrease mortality.89
One small observational study in chronic HD patients
showed an association between cholecalciferol use and
reduced left ventricular mass index.90
There are currently no published large RCTs on the
effects of either active or nutritional vitamin D therapy
on mortality or cardiovascular events in patients with
CKD,1 or in the general population. The ongoing NIH-
funded Vitamin D and Omega-3 Trial (VITAL) will
provide insight into the effects of nutritional vitamin D
supplementation on hard outcomes in the general pop-
ulation. The PRIMO (Paricalcitol Capsule Benefits in
Renal Failure-Induced Cardiac Morbidity) trial showed
no change in left ventricular mass index in stage 3 to 4
CKD patients treated with 2 g/day paricalcitol for 48
weeks.91 This finding was in contrast to earlier evidence
that vitamin D analogs reduce LVH in rats.92 Studies
on vascular calcification are inconclusive, and mouse
models of CKD suggest that there is a balance needed
between high and low levels of 1,25(OH)2D3 to protect
against versus induce vascular calcification.93 It is cur-
rently unknown if vitamin D treatment reduces fracture
risk in patients with CKD, and the effects on bone are
inconclusive. Randomized trials have shown possible
improvements in osteitis fibrosa and mineralization, but
also reduced bone turnover, which could increase the
risk of developing adynamic bone disease.94,95
In stage 35 CKD patients, RCTs support that cal-
citriol and vitamin D analogs both lower serum iPTH
compared to placebo,9698 may increase S[Ca]9799 or
 Treatment
S[P],99 or may not change either.96 Additionally, vitamin
D analogs may reduce proteinuria100102 and lower the
inflammatory acute phase protein C-reactive protein.100
Nutritional vitamin D treatment may also lower iPTH in
this population, and the associated incidence of hyper-
calcemia and hyperphosphatemia is low.103
KDIGO currently recommends correcting 25(OH)
D3 deficiency to >30ng/mL using treatment strategies
similar to those used in the general population (Table
53.2).1,4 Use of calcitriol and vitamin D analogs should
be limited in the presence of hypercalcemia. KDIGO
acknowledges that the efficacy of this overall approach
is not well studied, but given that treatment is safe with
minimal risk of toxicity across all stages of CKD, this
strategy is recommended. KDOQI recommends using
vitamin D2 (ergocalciferol) to correct serum 25(OH)D3
levels that are <30ng/mL.5 Overall, there is no consen-
sus regarding the optimal treatment type, dose, or tar-
get levels of 25(OH)D3. More research is needed to help
answer these questions.
Nutritional options to treat 25(OH)D3 deficiency are
ergocalciferol (D2) and cholecalciferol (D3) (Table 53.3),
which must undergo conversion in the liver to 25(OH)
D3. Nutritional vitamin D is effective at raising both
serum 25(OH)D3 and 1,25(OH)2D3 levels in CKD patients
in both observational studies104,105 and RCTs.106,107 There
is currently debate regarding whether ergocalciferol
or cholecalciferol is better at raising and maintaining
serum 25(OH)D3 levels.108,109 There is overall a lack of
large observational cohort studies and RCTs using nutri-
tional vitamin D in CKD patients. However, there has
been greater interest in its use in addition to or instead
of active vitamin D in CKD patients more recently. There
is still some question regarding whether nutritional vita-
min D can adequately raise 25(OH)D3 to sufficient levels
in all CKD patients.104,105 Nutritional vitamin D is also
effective at lowering PTH,106,107 although the evidence is
not as strong as for active vitamin D therapy.110 An addi-
tional advantage of ergocalciferol and cholecalciferol is
that they are relatively inexpensive.
Active (1,25(OH)2D3) vitamin D and 1,25(OH)2D3
analogs have been more traditionally used as therapeu-
tic options in patients with CKD. Normalization of S[P]
should occur before initiation of active vitamin D or
vitamin D analogs. Calcitriol (1,25(OH)2D3) is effective
at raising serum 1,25(OH)2D3 levels, as well as decreas-
ing PTH production by the parathyroid glands. Calcitriol
also increases S[Ca], which further suppresses PTH
secretion.111 Observational evidence supports that cal-
citriol use may be associated with reduced risk of death
or dialysis in patients with secondary hyperparathyroid-
ism.88 However, there are concerns that calcitriol use may
lead to adynamic bone disease, hypercalcemia and/or
hyperphosphatemia, as well as vascular calcification.79,111
Paricalcitol (19-nor-1,25(OH)2D2) and doxercalciferol
VIII. THERAPEUTIC CONSIDERATIONS
657
(1,25(OH)D2) are analogs of 1,25(OH)2D3 that activate
the vitamin D receptor. Vitamin D analogs are also effec-
tive at raising serum 1,25(OH)2D3 levels, and newer ana-
logs are more selective for PTH suppression with less
effect on S[Ca] and S[P].96,112 Observational evidence sug-
gests that vitamin D analog use may improve survival
in dialysis patients11,24 and slow progression to ESRD in
earlier stages.88 However, negative results of the recent
PRIMO study on left ventricular mass index called the
utility of vitamin D analogs for treating CVD in CKD
into question.91
Parathyroid Hormone
The EVOLVE (Evaluation of Cinacalcet Hydrochloride
Therapy to Lower Cardiovascular Events) study raises
questions regarding the utility of lowering PTH for
improving cardiovascular outcomes in patients with
CKD.113 Prior to EVOLVE, observational data supported
notions that lowering PTH with cinacalcet is associated
with decreased all-cause and cardiovascular mortality
in chronic HD patients.9 RCTs with therapeutic agents
to lower PTH (testing calcium supplementation, phos-
phate binders, nutritional vitamin D, 1,25(OH)2D3 ana-
logs and calcimimetics) were mostly limited to the effects
on biochemical parameters and surrogate outcomes. In a
single trial in stage 3 to 5 CKD, calcium-binders did not
lower iPTH, but increased coronary calcification score.68
Treatment with active vitamin D and its analogs low-
ers serum iPTH, but may also increase S[Ca] or S[P].9698
Active vitamin D and vitamin D analogs have also been
shown to improve histological indices of bone turn-
over.98 No RCTs have prospectively aimed to evaluate
the efficacy of phosphate binders for lowering iPTH,68
though one study in stage 3 to 5 CKD patients showed a
decrease in iPTH with 8 weeks of treatment with lantha-
num.114 While most studies have been in chronic dialy-
sis populations,115,116 calcimimetics did lower iPTH in
prospective trials of stage 3 to 5 CKD patients, as well as
induce an asymptomatic decrease in S[Ca] and S[P].117,118
In the ADVANCE study, a randomized trial to evalu-
ate the effects of cinacalcet plus low-dose vitamin D on
vascular calcification in HD patients, cinacalcet, a calci-
mimetic, plus low-dose paricalcitol did not significantly
change the primary end-point, the Agatston coronary
calcification score.119
The EVOLVE study was a randomized, double-
blinded, placebo controlled study in 3883 chronic HD
patients with moderate to severe secondary hyperpara-
thyroidism.113 In the unadjusted intent to treat analysis,
there was no significant change in mortality or cardio-
vascular events with cinacalcet, despite effective lower-
ing of iPTH.
Optimal levels of iPTH for patients with stage 3 to 5
CKD are unknown, thus KDIGO does not recommend
658 53. Management of Mineral and Bone Disorders in Chronic Kidney Disease Patients
targeting a specific range (Table 53.2).1 KDOQI suggests
lowering the iPTH threshold in stage 4 to 5 CKD for
prompting evaluation and possible treatment of hyper-
parathyroidism.5 This is one of the most debated recom-
mendations, as there is a lack of studies relating serum
iPTH levels to bone disease. There is some consensus,
however, that trends in iPTH levels should be consid-
ered before initiating a therapeutic intervention. KDIGO
considers any of the following to be reasonable first-
line therapies for the treatment of hyperparathyroidism:
reduced phosphate intake, phosphate binders, calcium
supplements, and if the patient is also 25(OH)D3 defi-
cient, nutritional vitamin D.1,4 If these options are not
effective, iPTH is progressively rising and remains above
the upper limit of normal, and 25(OH)D3 deficiency is
present, then treatment with 1,25(OH)2D3 or 1,25(OH)2D3
analogs should be considered.
Calcimimetics are not currently recommended for
treatment of hyperparathyroidism in non-dialysis-
dependent CKD, as the work group felt more data were
still needed, nor are they approved by the FDA in this
population. In circumstances of severe hyperparathy-
roidism that fails to respond to other therapy, parathy-
roidectomy is recommended.
There are advantages and disadvantages associated
with calcimimetics compared to parathyroidectomy
for treatment of hyperparathyroidism in CKD patients
(Table 53.3). By mimicking an increase in extracellular cal-
cium, calcimimetics increase intracellular calcium, which
decreases PTH release.1 Cinacalcet, which acts as a posi-
tive allosteric modulator by inducing a conformational
change in the calcium sensing receptor to increase sensi-
tivity to extracellular calcium,79 is the only type II calcimi-
metic currently available for clinical use. While cinacalcet
is effective at lowering iPTH in both chronic dialysis
patients115,116 and non-dialysis CKD patients,117,118 its use
is associated with gastrointestinal side-effects.113 In the
EVOLVE study, there was also an increased occurrence of
hypocalcemia with use of cinacalcet, without any reduc-
tion in cardiovascular events or mortality.113
There is a lack of randomized controlled trials to
show either the benefits or risks associated with para-
thyroidectomy to treat secondary or autonomous
hyperparathyroidism, as well as studies specifically
comparing surgical to medical therapy for treatment of
secondary hyperparathroidism. However, it is gener-
ally accepted that a well-performed parathyroidectomy
reduces serum iPTH concentrations, S[Ca] and S[P] in
CKD patients with secondary or autonomous hyper-
parathyroidism. In addition to a last resort therapy
when patients fail to respond to medical therapy, para-
thyroidectomy could also be considered if the medical
management of hyperparathyroidism leads to an unac-
ceptable rise in S[Ca] and/or S[P], or if there are other
intolerable adverse events.1
VIII. THERAPEUTIC CONSIDERATIONS
FGF-23
The discovery of FGF-23 is relatively recent, and
thus its role in the treatment of CKD-MBD is not yet
well understood or targeted. There are some small diet
manipulation studies and observational evidence that
suggest that manipulating dietary phosphate intake can
alter FGF-23 levels.56,120,121 Several small studies have
also shown that phosphate lowering with the binders
sevelamer81,122 and lanthanum (plus a low phosphate
diet)83 can also reduce levels of FGF-23 in patients with
stage 3 to 4 CKD. However, the degree of change in FGF-
23 in response to phosphate binders or dietary phos-
phate restriction is minimal compared to the magnitude
of change seen with progression of CKD. Thus manipu-
lating phosphorus alone, either through dietary intake or
with phosphate binders, may not be enough to modify
FGF-23 levels in a meaningful way.
FGF-23 receptor blockers are currently being tested
in animal models to suppress FGF receptor signaling.123
There are also ongoing phase I/II oncology clinical trials
using FGF receptor (14) tyrosine kinase inhibitors. This
may represent a potential pharmacological target in the
treatment of CKD-MBD. However, there are potential
concerns of negative or unknown consequences of low-
ering FGF-23 that will need to be carefully considered.
Bone
KDIGO recommends that in patients with stage 1 to
2 CKD and osteoporosis or a high risk of fracture, and
patients with stage 3 CKD with osteoporosis or a high
risk of fracture and iPTH in the normal range, manage-
ment should be the same as in the general population. In
patients with stage 3 CKD and low bone mineral density
and/or fragility fractures, treatment should consider the
magnitude and reversibility of biochemical abnormali-
ties, as well as CKD progression, and performance of
bone biopsy should be considered. In patients with stage
45 CKD and low bone mineral density and/or fragil-
ity fractures, additional investigation with bone biopsy
is recommended prior to beginning an antiresorptive
agent, as they are likely only effective in patients with
increased bone resorption and could promote adynamic
bone disease. It is also recommended that secondary
hyperparathyroidism be corrected first.1
Biphosphonates are effective at decreasing fractures in
non-CKD patients with osteoporosis, and post-hoc anal-
ysis of RCTs supports they may be as effective in stage 3
CKD patients. While in theory therapy with bisphospho-
nates could benefit patients with stage 4 to 5 CKD and
low bone density and high turnover, KDIGO does not
recommend the use of bisphosphonates in patients with
an eGFR <30mL/min/1.73m2 unless there is a strong
clinical rationale.4 Teriparatide is an anabolic drug that
 REFERENCES
increases the formation of new bone. It is a recombinant
human 1-34 PTH, and therefore is contraindicated in
patients with hyperparathyroidism.1 Teriparatide does
not appear to be contraindicated in women with stage 2
to 3 CKD and normal biochemistry, based on a post-hoc
analysis.124
Raloxifene is a selective estrogen receptor modulator
approved for the treatment of post-menopausal osteo-
porosis. Raloxifene reduces vertebral fracture risk in
this population, although there are concerns common to
estrogen therapy, including increased risk of fatal stroke.1
A post-hoc analysis including participants from a trial
who had mild to moderate CKD and normal biochem-
istry suggests raloxifene may be as safe and effective for
these patients as the general population, although this
cohort in not likely representative of the typical CKD
population.125
Vascular Calcification
There is no clear evidence-based protocol established
for treatment given a positive calcification test. In gen-
eral, the KDIGO recommendations focus on strategies
to minimize the progression of vascular calcification in
patients with known calcification.1 Non-calcium-based
binders are recommended for the treatment of hyper-
phosphatemia in CKD patients with known vascular
calcification. There is currently a lack of intervention
data on the effects of calcimimetics, nutritional or active
vitamin D/analogs, or parathyroidectomy on vascular
calcification progression.
CONCLUSION
The pathophysiology of CKD-MBD, a common clini-
cal syndrome in patients with CKD with consequences
affecting mineral metabolism, bone mineralization and
extracellular calcification, is complex. Treatment of CKD-
MBD, especially in early stages of disease, with a focus on
the biochemical and hormonal factors, and calcium, phos-
phorus, vitamin D, iPTH and FGF-23 metabolism, as well
as consideration of bone and vascular calcification, is often
not evidence-based, because of the lack of information
from observational studies as well as RCTs performed in
specific patient populations. There is great need for well-
designed RCTs to further guide the diagnosis and com-
plex management of patients with CKD-MBD.
References
1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-
MBD Work Group. KDIGO clinical practice guideline for the diag-
nosis, evaluation, prevention, and treatment of Chronic Kidney
Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl
2009(113):S1130.
VIII. THERAPEUTIC CONSIDERATIONS
659
2. Demer L, Tintut Y. The bone-vascular axis in chronic kidney dis-
ease. Curr Opin Nephrol Hypertens 2010;19(4):34953.
3. Moe S, Drueke T, Cunningham J, Goodman W, Martin K,
Olgaard K, et al. Definition, evaluation, and classification
of renal osteodystrophy: a position statement from Kidney
Disease: Improving Global Outcomes (KDIGO). Kidney Int
2006;69(11):194553.
4. Kidney Disease: Improving Global Outcomes (KDIGO) CKD
Work Group KDIGO 2012 Clinical Practice Guideline for the
Evaluation and Management of Chronic Kidney Disease. Kidney
Int Suppl 2013;3:1962.
5. National Kidney Foundation. K/DOQI clinical practice guide-
lines for bone metabolism and disease in chronic kidney disease.
Am J Kidney Dis 2003;42(4 Suppl. 3):S1201.
6. Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams
LA, et al. Prevalence of abnormal serum vitamin D, PTH, cal-
cium, and phosphorus in patients with chronic kidney disease:
results of the study to evaluate early kidney disease. Kidney Int
2007;71(1):318.
7. Gal-Moscovici A, Sprague SM. Use of vitamin D in chronic kid-
ney disease patients. Kidney Int 2010;78(2):14651.
8. Hruska KA, Levi M, Slatopolsky E. Disorders of phospho-
rus, calcium and magnesium metabolism. In: Schrier RW,
editor. Diseases of the kidney and urinary tract 8th ed.
Philadelphia: Lippincott Williams and Wilkins; 2007.
9. Block GA, Zaun D, Smits G, Persky M, Brillhart S, Nieman K,
etal. Cinacalcet hydrochloride treatment significantly improves
all-cause and cardiovascular survival in a large cohort of hemo-
dialysis patients. Kidney Int 2010;78(6):57889.
10. Kimata N, Albert JM, Akiba T, Yamazaki S, Kawaguchi T,
Fukuhara S, et al. Association of mineral metabolism factors
with all-cause and cardiovascular mortality in hemodialysis
patients: the Japan Dialysis Outcomes and Practice Patterns
study. Hemodialysis Int 2007;11(3):3408.
11. Kalantar-Zadeh K, Kuwae N, Regidor DL, Kovesdy CP,
Kilpatrick RD, Shinaberger CS, et al. Survival predictability of
time-varying indicators of bone disease in maintenance hemodi-
alysis patients. Kidney Int 2006;70(4):77180.
12. Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS,
Gamble GD, etal. Effect of calcium supplements on risk of myo-
cardial infarction and cardiovascular events: meta-analysis. BMJ
2010;341:c3691.
13. Isakova T, Wahl P, Vargas GS, Gutierrez OM, Scialla J, Xie H,
etal. Fibroblast growth factor 23 is elevated before parathyroid
hormone and phosphate in chronic kidney disease. Kidney Int
2011;79(12):13708.
14. Kendrick J, Chonchol M. The role of phosphorus in the develop-
ment and progression of vascular calcification. Am J Kidney Dis
2011;58(5):82634.
15. Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G. Relation
between serum phosphate level and cardiovascular event rate in
people with coronary disease. Circulation 2005;112(17):262733.
16. Chonchol M, Dale R, Schrier RW, Estacio R. Serum phospho-
rus and cardiovascular mortality in type 2 diabetes. Am J Med
2009;122(4):3806.
17. Eddington H, Hoefield R, Sinha S, Chrysochou C, Lane B, Foley
RN, et al. Serum phosphate and mortality in patients with
chronic kidney disease. Clin J Am Soc Nephrol 2010;5(12):22517.
18. Kestenbaum B, Sampson JN, Rudser KD, Patterson DJ, Seliger
SL, Young B, et al. Serum phosphate levels and mortality risk
among people with chronic kidney disease. J Am Soc Nephrol
2005;16(2):5208.
19. Block GA, Spiegel DM, Ehrlich J, Mehta R, Lindbergh J,
Dreisbach A, etal. Effects of sevelamer and calcium on coronary
artery calcification in patients new to hemodialysis. Kidney Int
2005;68(4):181524.
660 53. Management of Mineral and Bone Disorders in Chronic Kidney Disease Patients
20. Adeney KL, Siscovick DS, Ix JH, Seliger SL, Shlipak MG, Jenny NS,
et al. Association of serum phosphate with vascular and valvular
calcification in moderate CKD. J Am Soc Nephrol 2009;20(2):3817.
21. Chonchol M, Kendrick J, Targher G. Extra-skeletal effects
of vitamin D deficiency in chronic kidney disease. Ann Med
2011;43(4):27382.
22. Levin A, Le Barbier M, Er L, Andress D, Sigrist MK, Djurdjev
O. Incident isolated 1,25(OH)(2)D(3) deficiency is more common
than 25(OH)D deficiency in CKD. J Nephrol 2012;25(2):20410.
23. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi
Y, et al. FGF-23 is a potent regulator of vitamin D metabolism
and phosphate homeostasis. J Bone Min Res 2004;19(3):42935.
24. Wolf M, Shah A, Gutierrez O, Ankers E, Monroy M, Tamez H,
et al. Vitamin D levels and early mortality among incident
hemodialysis patients. Kidney Int 2007;72(8):100413.
25. Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Jain A,
Schreiber Jr MJ, et al. Low 25-hydroxyvitamin D levels and
mortality in non-dialysis-dependent CKD. Am J Kidney Dis
2011;58(4):53643.
26. Ginde AA, Scragg R, Schwartz RS, Camargo Jr CA. Prospective
study of serum 25-hydroxyvitamin D level, cardiovascular dis-
ease mortality, and all-cause mortality in older U.S. adults. J Am
Geriatr Soc 2009;57(9):1595603.
27. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin
D levels and the risk of mortality in the general population. Arch
Intern Med 2008;168(15):162937.
28. Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz
B, et al. Independent association of low serum 25-hydroxyvita-
min D and 1,25-dihydroxyvitamin D levels with all-cause and
cardiovascular mortality. Arch Intern Med 2008;168(12):13409.
29. Kendrick J, Targher G, Smits G, Chonchol M.
25-Hydroxyvitamin D deficiency is independently associated
with cardiovascular disease in the Third National Health and
Nutrition Examination Survey. Atherosclerosis 2009;205(1):25560.
30. Kendall JM, Thomas SE, Spurlock G, Mir MA. An active sodium
transport inhibitor released from spontaneously hypertensive
and normotensive rat fetal hypothalamic cells in culture. Am J
Hypertens 1988;1(3 Pt 3):83S7S.
31. Dawson-Hughes B. Serum 25-hydroxyvitamin D and functional
outcomes in the elderly. Am J Clin Nutr 2008;88(2):537S540S.
32. Heine GH, Seiler S, Fliser D. FGF-23: the rise of a novel car-
diovascular risk marker in CKD. Nephrol Dial Transplant
2012;27(8):307281.
33. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG,
Chertow GM. Mineral metabolism, mortality, and morbidity in
maintenance hemodialysis. J Am Soc Nephrol 2004;15(8):220818.
34. Floege J, Kim J, Ireland E, Chazot C, Drueke T, de Francisco A,
etal. Serum iPTH, calcium and phosphate, and the risk of mor-
tality in a European haemodialysis population. Nephrol Dial
Transplant 2011;26(6):194855.
35. Avram MM, Mittman N, Myint MM, Fein P. Importance of low
serum intact parathyroid hormone as a predictor of mortality in
hemodialysis and peritoneal dialysis patients: 14 years of pro-
spective observation. Am J Kidney Dis 2001;38(6):13517.
36. Melamed ML, Eustace JA, Plantinga L, Jaar BG, Fink NE, Coresh
J, etal. Changes in serum calcium, phosphate, and PTH and the
risk of death in incident dialysis patients: a longitudinal study.
Kidney Int 2006;70(2):3517.
37. Drechsler C, Krane V, Grootendorst DC, Ritz E, Winkler K, Marz
W, et al. The association between parathyroid hormone and
mortality in dialysis patients is modified by wasting. Nephrol
Dial Transplant 2009;24(10):31517.
38. Yamashita T, Yoshioka M, Itoh N. Identification of a novel fibro-
blast growth factor, FGF-23, preferentially expressed in the
ventrolateral thalamic nucleus of the brain. Biochem Biophys Res
Commun 2000;277(2):4948.
VIII. THERAPEUTIC CONSIDERATIONS
39. Ohkido I, Yokoyama K, Kagami S, Hosoya T. The hypoth-
esis that bone turnover influences FGF23 secretion. Kidney Int
2010;77(8):7434.
40. Faul C. Fibroblast growth factor 23 and the heart. Curr Opin
Nephrol Hypertens 2012;21(4):36975.
41. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T,
et al. FGF23 induces left ventricular hypertrophy. J Clin Invest
2011;121(11):4393408.
42. Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G,
et al. Fibroblast growth factor-23 mitigates hyperphosphatemia
but accentuates calcitriol deficiency in chronic kidney disease.
J Am Soc Nephrol 2005;16(7):220515.
43. Kendrick J, Cheung AK, Kaufman JS, Greene T, Roberts WL, Smits
G, etal. FGF-23 associates with death, cardiovascular events, and
initiation of chronic dialysis. J Am Soc Nephrol 2011;22(10):191322.
44. Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J, etal.
Fibroblast growth factor 23 and risks of mortality and end-stage
renal disease in patients with chronic kidney disease. JAMA
2011;305(23):24329.
45. Seiler S, Reichart B, Roth D, Seibert E, Fliser D, Heine GH. FGF-
23 and future cardiovascular events in patients with chronic
kidney disease before initiation of dialysis treatment. Nephrol
Dial Transplant 2010;25(12):39839.
46. Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel
A, et al. Fibroblast growth factor 23 (FGF23) predicts progres-
sion of chronic kidney disease: the Mild to Moderate Kidney
Disease (MMKD) Study. J Am Soc Nephrol 2007;18(9):26008.
47. Gutierrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K,
Collerone G, et al. Fibroblast growth factor 23 and left ven-
tricular hypertrophy in chronic kidney disease. Circulation
2009;119(19):254552.
48. Kirkpantur A, Balci M, Gurbuz OA, Afsar B, Canbakan B,
Akdemir R, et al. Serum fibroblast growth factor-23 (FGF-23)
levels are independently associated with left ventricular mass
and myocardial performance index in maintenance haemodialy-
sis patients. Nephrol Dial Transplant 2011;26(4):134654.
49. Mirza MA, Larsson A, Melhus H, Lind L, Larsson TE. Serum intact
FGF23 associate with left ventricular mass, hypertrophy and geom-
etry in an elderly population. Atherosclerosis 2009;207(2):54651.
50. Piraino B, Chen T, Cooperstein L, Segre G, Puschett J. Fractures
and vertebral bone mineral density in patients with renal osteo-
dystrophy. Clin Nephrol 1988;30(2):5762.
51. Gerakis A, Hadjidakis D, Kokkinakis E, Apostolou T, Raptis S,
Billis A. Correlation of bone mineral density with the histologi-
cal findings of renal osteodystrophy in patients on hemodialy-
sis. J Nephrol 2000;13(6):43743.
52. Giachelli CM. The emerging role of phosphate in vascular calci-
fication. Kidney Int 2009;75(9):8907.
53. Covic A, Kanbay M, Voroneanu L, Turgut F, Serban DN, Serban
IL, etal. Vascular calcification in chronic kidney disease. Clin Sci
2010;119(3):11121.
54. Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London
GM. Impact of aortic stiffness attenuation on survival of
patients in end-stage renal failure. Circulation 2001;103(7):98792.
55. London GM. Alterations of arterial function in end-stage renal
disease. Nephron 2000;84(2):1118.
56. Moe SM, Zidehsarai MP, Chambers MA, Jackman LA, Radcliffe
JS, Trevino LL, et al. Vegetarian compared with meat dietary
protein source and phosphorus homeostasis in chronic kidney
disease. Clin J Am Soc Nephrol 2011;6(2):25764.
57. Gonzalez EA, Sachdeva A, Oliver DA, Martin KJ. Vitamin D
insufficiency and deficiency in chronic kidney disease. A single
center observational study. Am J Nephrol 2004;24(5):50310.
58. Chapuy MC, Preziosi P, Maamer M, Arnaud S, Galan P,
Hercberg S, et al. Prevalence of vitamin D insufficiency in an
adult normal population. Osteoporos Int 1997;7(5):43943.
 REFERENCES
59. Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska
DJ, Kitch BT, et al. Hypovitaminosis D in medical inpatients.
N Engl J Med 1998;338(12):77783.
60. Dawson-Hughes B, Harris SS, Dallal GE. Plasma calcidiol, sea-
son, and serum parathyroid hormone concentrations in healthy
elderly men and women. Am J Clin Nutr 1997;65(1):6771.
61. Shimada T, Urakawa I, Isakova T, Yamazaki Y, Epstein M,
Wesseling-Perry K, etal. Circulating fibroblast growth factor 23
in patients with end-stage renal disease treated by peritoneal
dialysis is intact and biologically active. J Clin Endocrinol Metab
2010;95(2):57885.
62. Smith ER, Cai MM, McMahon LP, Holt SG. Biological variabil-
ity of plasma intact and C-terminal FGF23 measurements. J Clin
Endocrinol Metab 2012;97(9):335765.
63. Imanishi Y, Inaba M, Nakatsuka K, Nagasue K, Okuno S,
Yoshihara A, etal. FGF-23 in patients with end-stage renal dis-
ease on hemodialysis. Kidney Int 2004;65(5):19436.
64. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium
supplements with or without vitamin D and risk of cardiovas-
cular events: reanalysis of the Womens Health Initiative limited
access dataset and meta-analysis. BMJ 2011;342:d2040.
65. Block GA, Wheeler DC, Persky MS, Kestenbaum B, Ketteler
M, Spiegel DM, etal. Effects of phosphate binders in moderate
CKD. J Am Soc Nephrol 2012;23(8):140715.
66. Isakova T, Gutierrez OM, Chang Y, Shah A, Tamez H, Smith K,
et al. Phosphorus binders and survival on hemodialysis. J Am
Soc Nephrol 2009;20(2):38896.
67. Kovesdy CP, Kuchmak O, Lu JL, Kalantar-Zadeh K. Outcomes
associated with phosphorus binders in men with non-dialysis-
dependent CKD. Am J Kidney Dis 2010;56(5):84251.
68. Russo D, Miranda I, Ruocco C, Battaglia Y, Buonanno E, Manzi
S, et al. The progression of coronary artery calcification in pre-
dialysis patients on calcium carbonate or sevelamer. Kidney Int
2007;72(10):125561.
69. Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the pro-
gression of coronary and aortic calcification in hemodialysis
patients. Kidney Int 2002;62(1):24552.
70. Qunibi W, Moustafa M, Muenz LR, He DY, Kessler PD, Diaz-
Buxo JA, et al. A 1-year randomized trial of calcium acetate
versus sevelamer on progression of coronary artery calcifica-
tion in hemodialysis patients with comparable lipid control: the
Calcium Acetate Renagel Evaluation-2 (CARE-2) study. Am J
Kidney Dis 2008;51(6):95265.
71. Barreto DV, Barreto Fde C, de Carvalho AB, Cuppari L, Draibe
SA, Dalboni MA, et al. Phosphate binder impact on bone
remodeling and coronary calcification results from the BRiC
study. Nephron Clin Pract 2008;110(4):c27383.
72. Suki WN, Zabaneh R, Cangiano JL, Reed J, Fischer D, Garrett L,
et al. Effects of sevelamer and calcium-based phosphate binders
on mortality in hemodialysis patients. Kidney Int 2007;72(9):11307.
73. St Peter WL, Liu J, Weinhandl E, Fan Q. A comparison of
sevelamer and calcium-based phosphate binders on mortality,
hospitalization, and morbidity in hemodialysis: a secondary anal-
ysis of the Dialysis Clinical Outcomes Revisited (DCOR) random-
ized trial using claims data. Am J Kidney Dis 2008;51(3):44554.
74. D'Haese PC, Spasovski GB, Sikole A, Hutchison A, Freemont TJ,
Sulkova S, etal. A multicenter study on the effects of lanthanum
carbonate (Fosrenol) and calcium carbonate on renal bone dis-
ease in dialysis patients. Kidney Int Suppl 2003;85:S738.
75. Ferreira A, Frazao JM, Monier-Faugere MC, Gil C, Galvao J,
Oliveira C, etal. Effects of sevelamer hydrochloride and calcium
carbonate on renal osteodystrophy in hemodialysis patients.
J Am Soc Nephrol 2008;19(2):40512.
76. Freemont AJ, Hoyland JA, Denton J. The effects of lanthanum car-
bonate and calcium carbonate on bone abnormalities in patients
with end-stage renal disease. Clin Nephrol 2005;64(6):42837.
VIII. THERAPEUTIC CONSIDERATIONS
661
77. Finn WF. Lanthanum carbonate versus standard therapy
for the treatment of hyperphosphatemia: safety and efficacy
in chronic maintenance hemodialysis patients. Clin Nephrol
2006;65(3):191202.
78. Navaneethan SD, Palmer SC, Vecchio M, Craig JC, Elder GJ,
Strippoli GF. Phosphate binders for preventing and treat-
ing bone disease in chronic kidney disease patients. Cochrane
Database Syst Rev 2011;(2):CD006023
79. Barreto FC, de Oliveira RA, Oliveira RB, Jorgetti V.
Pharmacotherapy of chronic kidney disease and mineral bone
disorder. Expert Opin Pharmacother 2011;12(17):262740.
80. Pai AB, Shepler BM. Comparison of sevelamer hydrochloride
and sevelamer carbonate: risk of metabolic acidosis and clinical
implications. Pharmacotherapy 2009;29(5):55461.
81. Oliveira RB, Cancela AL, Graciolli FG, Dos Reis LM, Draibe SA,
Cuppari L, etal. Early control of PTH and FGF23 in normophos-
phatemic CKD patients: a new target in CKD-MBD therapy?
Clin J Am Soc Nephrol 2010;5(2):28691.
82. Koizumi M, Komaba H, Nakanishi S, Fujimori A, Fukagawa M.
Cinacalcet treatment and serum FGF23 levels in haemodialy-
sis patients with secondary hyperparathyroidism. Nephrol Dial
Transplant 2012;27(2):78490.
83. Gonzalez-Parra E, Gonzalez-Casaus ML, Galan A, Martinez-
Calero A, Navas V, Rodriguez M, et al. Lanthanum carbon-
ate reduces FGF23 in chronic kidney disease Stage 3 patients.
Nephrol Dial Transplant 2011;26(8):256771.
84. Drueke TB. Lanthanum carbonate as a first-line phosphate
binder: the cons. Semin Dial 2007;20(4):32932.
85. Uhlig K, Berns JS, Kestenbaum B, Kumar R, Leonard MB,
Martin KJ, et al. KDOQI US commentary 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):77399.
86. Tentori F, Albert JM, Young EW, Blayney MJ, Robinson BM, Pisoni
RL, etal. The survival advantage for haemodialysis patients taking
vitamin D is questioned: findings from the Dialysis Outcomes and
Practice Patterns Study. Nephrol Dial Transplant 2009;24(3):96372.
87. St Peter WL, Li S, Liu J, Gilbertson DT, Arneson TJ, Collins
AJ. Effects of monthly dose and regular dosing of intravenous
active vitamin D use on mortality among patients undergoing
hemodialysis. Pharmacotherapy 2009;29(2):15464.
88. Shoben AB, Rudser KD, de Boer IH, Young B, Kestenbaum B.
Association of oral calcitriol with improved survival in nondia-
lyzed CKD. J Am Soc Nephrol 2008;19(8):16139.
89. Autier P, Gandini S. Vitamin D supplementation and total mor-
tality: a meta-analysis of randomized controlled trials. Arch
Intern Med 2007;167(16):17307.
90. Matias PJ, Jorge C, Ferreira C, Borges M, Aires I, Amaral T,
etal. Cholecalciferol supplementation in hemodialysis patients:
effects on mineral metabolism, inflammation, and cardiac
dimension parameters. Clin J Am Soc Nephrol 2010;5(5):90511.
91. Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J,
Tamez H, et al. Vitamin D therapy and cardiac structure and
function in patients with chronic kidney disease: the PRIMO
randomized controlled trial. JAMA 2012;307(7):67484.
92. Kong J, Kim GH, Wei M, Sun T, Li G, Liu SQ, etal. Therapeutic
effects of vitamin D analogs on cardiac hypertrophy in sponta-
neously hypertensive rats. Am J Pathol 2010;177(2):62231.
93. Mathew S, Lund RJ, Chaudhary LR, Geurs T, Hruska KA.
Vitamin D receptor activators can protect against vascular calci-
fication. J Am Soc Nephrol 2008;19(8):150919.
94. Baker LR, Muir JW, Sharman VL, Abrams SM, Greenwood RN,
Cattell WR, et al. Controlled trial of calcitriol in hemodialysis
patients. Clin Nephrol 1986;26(4):18591.
95. Salusky IB, Kuizon BD, Belin TR, Ramirez JA, Gales B,
Segre GV, et al. Intermittent calcitriol therapy in secondary
662 53. Management of Mineral and Bone Disorders in Chronic Kidney Disease Patients
hyperparathyroidism: a comparison between oral and intraperi-
toneal administration. Kidney Int 1998;54(3):90714.
96. Coburn JW, Maung HM, Elangovan L, Germain MJ, Lindberg
JS, Sprague SM, et al. Doxercalciferol safely suppresses PTH
levels in patients with secondary hyperparathyroidism associ-
ated with chronic kidney disease stages 3 and 4. Am J Kidney Dis
2004;43(5):87790.
97. Coyne D, Acharya M, Qiu P, Abboud H, Batlle D, Rosansky S, etal.
Paricalcitol capsule for the treatment of secondary hyperparathy-
roidism in stages 3 and 4 CKD. Am J Kidney Dis 2006;47(2):26376.
98. Nordal KP, Dahl E. Low dose calcitriol versus placebo in
patients with predialysis chronic renal failure. J Clin Endocrinol
Metab 1988;67(5):92936.
99. Coyle EF, Coggan AR, Hopper MK, Walters TJ. Determinants of
endurance in well-trained cyclists. J Appl Physiol 1988;64(6):262230.
100. Alborzi P, Patel NA, Peterson C, Bills JE, Bekele DM, Bunaye
Z, et al. Paricalcitol reduces albuminuria and inflammation in
chronic kidney disease: a randomized double-blind pilot trial.
Hypertension 2008;52(2):24955.
101. Fishbane S, Chittineni H, Packman M, Dutka P, Ali N, Durie N.
Oral paricalcitol in the treatment of patients with CKD and pro-
teinuria: a randomized trial. Am J Kidney Dis 2009;54(4):64752.
102. de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D,
Garimella T, et al. Selective vitamin D receptor activation with
paricalcitol for reduction of albuminuria in patients with type
2 diabetes (VITAL study): a randomised controlled trial. Lancet
2010;376(9752):154351.
103. Kandula P, Dobre M, Schold JD, Schreiber Jr MJ, Mehrotra R,
Navaneethan SD. Vitamin D supplementation in chronic kidney
disease: a systematic review and meta-analysis of observational
studies and randomized controlled trials. Clin J Am Soc Nephrol
2011;6(1):5062.
104. Al-Aly Z, Qazi RA, Gonzalez EA, Zeringue A, Martin KJ.
Changes in serum 25-hydroxyvitamin D and plasma intact PTH
levels following treatment with ergocalciferol in patients with
CKD. Am J Kidney Dis 2007;50(1):5968.
105. Zisman AL, Hristova M, Ho LT, Sprague SM. Impact of ergocal-
ciferol treatment of vitamin D deficiency on serum parathyroid
hormone concentrations in chronic kidney disease. Am J Nephrol
2007;27(1):3643.
106. Dogan E, Erkoc R, Sayarlioglu H, Soyoral Y, Dulger H. Effect of
depot oral cholecalciferol treatment on secondary hyperparathy-
roidism in stage 3 and stage 4 chronic kidney diseases patients.
Ren Fail 2008;30(4):40710.
107. Moe SM, Saifullah A, LaClair RE, Usman SA, Yu Z. A random-
ized trial of cholecalciferol versus doxercalciferol for lowering
parathyroid hormone in chronic kidney disease. Clin J Am Soc
Nephrol 2010;5(2):299306.
108. Holick MF, Biancuzzo RM, Chen TC, Klein EK, Young A, Bibuld
D, et al. Vitamin D2 is as effective as vitamin D3 in maintain-
ing circulating concentrations of 25-hydroxyvitamin D. J Clin
Endocrinol Metab 2008;93(3):67781.
109. Nigwekar SU, Bhan I, Thadhani R. Ergocalciferol and cholecal-
ciferol in CKD. Am J Kidney Dis 2012;60(1):13956.
110. Melamed ML, Thadhani RI. Vitamin D therapy in chronic kid-
ney disease and end stage renal disease. Clin J Am Soc Nephrol
2012;7(2):35865.
111. Palmer SC, McGregor DO, Craig JC, Elder G, Macaskill P,
Strippoli GF. Vitamin D compounds for people with chronic kid-
ney disease not requiring dialysis. Cochrane Database Syst Rev
2009;(4):CD008175.
VIII. THERAPEUTIC CONSIDERATIONS
112. Martin KJ, Gonzalez EA, Gellens M, Hamm LL, Abboud
H, Lindberg J. 19-Nor-1-alpha-25-dihydroxyvitamin D2
(Paricalcitol) safely and effectively reduces the levels of intact
parathyroid hormone in patients on hemodialysis. J Am Soc
Nephrol 1998;9(8):142732.
113. Chertow GM, Block GA, Correa-Rotter R, Drueke TB, Floege
J, Goodman WG, et al. Effect of cinacalcet on cardiovascu-
lar disease in patients undergoing dialysis. N Engl J Med
2012;367(26):248294.
114. Sprague SM, Abboud H, Qiu P, Dauphin M, Zhang P, Finn W.
Lanthanum carbonate reduces phosphorus burden in patients
with CKD stages 3 and 4: a randomized trial. Clin J Am Soc Nephrol
2009;4(1):17885.
115. Lindberg JS, Moe SM, Goodman WG, Coburn JW, Sprague SM,
Liu W, et al. The calcimimetic AMG 073 reduces parathyroid
hormone and calcium x phosphorus in secondary hyperpara-
thyroidism. Kidney Int 2003;63(1):24854.
116. Messa P, Macario F, Yaqoob M, Bouman K, Braun J, von
Albertini B, etal. The OPTIMA study: assessing a new cinacalcet
(Sensipar/Mimpara) treatment algorithm for secondary hyper-
parathyroidism. Clin J Am Soc Nephrol 2008;3(1):3645.
117. Chonchol M, Locatelli F, Abboud HE, Charytan C, de Francisco
AL, Jolly S, et al. A randomized, double-blind, placebo-
controlled study to assess the efficacy and safety of cinacal-
cet HCl in participants with CKD not receiving dialysis. Am J
Kidney Dis 2009;53(2):197207.
118. Charytan C, Coburn JW, Chonchol M, Herman J, Lien YH, Liu
W, et al. Cinacalcet hydrochloride is an effective treatment for
secondary hyperparathyroidism in patients with CKD not
receiving dialysis. Am J Kidney Dis 2005;46(1):5867.
119. Raggi P, Chertow GM, Torres PU, Csiky B, Naso A, Nossuli K,
et al. The ADVANCE study: a randomized study to evaluate
the effects of cinacalcet plus low-dose vitamin D on vascular cal-
cification in patients on hemodialysis. Nephrol Dial Transplant
2011;26(4):132739.
120. Burnett SM, Gunawardene SC, Bringhurst FR, Juppner H, Lee
H, Finkelstein JS. Regulation of C-terminal and intact FGF-
23 by dietary phosphate in men and women. J Bone Miner Res
2006;21(8):118796.
121. Gutierrez OM, Wolf M, Taylor EN. Fibroblast growth factor 23,
cardiovascular disease risk factors, and phosphorus intake in
the Health Professionals Follow-up Study. Clin J Am Soc Nephrol
2011;6(12):28718.
122. Yilmaz MI, Sonmez A, Saglam M, Yaman H, Kilic S, Eyileten T,
etal. Comparison of calcium acetate and sevelamer on vascular
function and fibroblast growth factor 23 in CKD patients: a ran-
domized clinical trial. Am J Kidney Dis 2012;59(2):17785.
123. Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K,
Beck S, etal. AZD4547: an orally bioavailable, potent, and selec-
tive inhibitor of the fibroblast growth factor receptor tyrosine
kinase family. Cancer Res 2012;72(8):204556.
124. Miller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE.
Safety and efficacy of risedronate in patients with age-related
reduced renal function as estimated by the Cockcroft and Gault
method: a pooled analysis of nine clinical trials. J Bone Miner Res
2005;20(12):210515.
125. Ishani A, Blackwell T, Jamal SA, Cummings SR, Ensrud KE. The
effect of raloxifene treatment in postmenopausal women with
CKD. J Am Soc Nephrol 2008;19(7):14308.