C H A P T E R
58
Osteoporosis Associated with
Chronic Kidney Disease
Susan M. Ott1, Grahame Elder2
1University of Washington, Seattle, WA, USA, 2Department of Renal Medicine, Westmead Hospital; Osteoporosis and
Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia
INTRODUCTION
Since the kidney is essential for regulation of mineral
metabolism, bone disease is an inevitable consequence of
renal damage. Treatment is challenging due to the com-
plex physiology and the dearth of clinical data, and is
complicated by concern about vascular calcifications. A
newly defined term CKD-MBD (chronic kidney disease
mineral and bone disorder) highlights the connections
between the biochemical and hormonal abnormalities of
mineral metabolism, the vascular calcifications, and the
skeletal disease [1].
STAGES OF CHRONIC KIDNEY DISEASE
The stages of chronic kidney disease (CKD) are
defined by the presence of a reduced glomerular filtra-
tion rate (GFR), or when the GFR is normal, by other
indicators of renal disease. In clinical practice the GFR is
estimated (eGFR) using a Modification of Diet in Renal
Disease (MDRD) formula based on the serum creatinine,
the age, race, and gender of a person. CKD stages 1 and
2 refer to kidney diseases that are not associated with
FIGURE 58.1  Stages of chronic kidney disease.
Osteoporosis. http://dx.doi.org/10.1016/B978-0-12-415853-5.00058-3 1387
significant reductions in the eGFR; for example early
diabetes or conditions interfering with tubular transport,
such as Fanconi syndrome. These patients may have
bone disease, due to acidosis or hypophosphatemia, but
that is beyond the scope of this chapter. Here we will
consider the management of patients with CKD stages
3 to 5, defined as eGFR 30 to 59 mL/minute/1.73 m2
(CKD stage 3), eGFR 15 to 29 mL/minute/1.73 m2
(CKD stage 4), and eGFR less than 15 mL/minute/1.73
m2 (CKD stage 5) or on dialysis (5D) (Fig. 58.1). These
patients often show changes of CKD-MBD.
A systematic review of studies worldwide found the
median prevalence of CKD in adults (using the MDRD
formula) is 7.2%, and, in those older than 64 years of age,
this increases to about 30% [2]. Women had a higher rate
than men, African-Americans had a lower prevalence
than Caucasians, and Asian populations had a relatively
high prevalence. These estimated rates of prevalence
will vary depending on the method used to calculate
kidney function. For example, using the Cockcroft–Gault
equation, the prevalence of CKD is higher than when
using the MDRD equation, especially in older popula-
tions [2]. These methods both use serum creatinine,
which depends on the muscle mass. Cystatin C, another
Copyright © 2013 Elsevier Inc. All rights reserved.
1388 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE

marker used to determine GFR, is independent of mus-
cle mass and may, therefore, be a more sensitive method
for detecting CKD, particularly in elderly patients.
EPIDEMIOLOGY
Renal Osteodystrophy
The term renal osteodystrophy (ROD) encompasses
histologic changes in bone that develop as a consequence
of CKD [1]. Clearly these will vary in severity and pattern
with CKD duration and stage, together with factors such
as a patient’s age, sex, and racial background. Changes
of ROD will also be superimposed on, and coexist with,
underlying bone pathology such as postmenopausal
osteoporosis, and will be affected by drugs such as gluco-
corticoids. However, the predominant bone pathology of
patients with CKD stages 3 to 5 results from abnormali-
ties of mineral metabolism caused by CKD. Treatments
also impact bone histopathology, particularly the use of
vitamin D receptor activators (VDRAs), calcimimetics,
the choice of phosphate binder, the mode of dialysis, and
the dialysate used. Descriptively, these histologic find-
ings can be categorized by alterations in bone turnover,
mineralization, and volume (TMV). These are discussed

TABLE 58.1  Prevalence and Incidence of Fractures in Dialysis Patients

Prevalence (%) Incidence (%/year)

Author Year n Patients Any/hip Spine Any Hip

Pendras 1966 19 First HD patients 47 – – –

Rubini 1969 29 HD 27 – – –

Parfitt 1972 16 HD 44 25 – –

Piraino 1988 16 HD: fibrosis – – 4.8 –

Yamaguchi 1996 124 HD 10 11 – –

Atsumi 1999 187 HD – 21 – –

Gerakis 2000 62 HD 11 – – –

Alem 2000 182,493 Males – – – 0.74

Alem 2000 143,971 Females – – – 1.36

Coco 2000 1272 HD all in unit – – – 1.39

Stehman-Breen 2000 4952 HD – – – 0.69

Ball 2002 101,039 USRDS on tx list – – – 0.29

Jamal 2002 104 HD > 55 years 52 33 – –

Kaji 2002 183 HD 7.6 (hip) – – –

Urena 2003 70 HD 30 7 – –

Block 2004 40,538 HD, Fresenius – – 0.52 –

Inaba 2005 114 PD > 65 years – 18 – –

Danese 2006 9007 USRDS – – – 0.65

Elder 2006 242 Pre-Tx – 28 – –

Ersoy 2006 292 PD 10 – – –

Jadoul 2006 12,782 HD, DOPPS 2.6 (hip) – 2.56 0.89

Jamal 2006 52 HD > 50 years old 52 – – –

Kaneko 2006 7159 USRDS – – – 1

Mitterbauer 2007 1777 HD – – 4.1 –

Mares 2008 73 HD – 21 – –

Iimori 2012 485 HD – 6 1.9 –

DOPPS: Dialysis Outcomes and Practice Patterns Study; HD: hemodialysis; PD: peritoneal dialysis; tx: transplant; USRDS: United States Renal Data System.
Source: data from KDIGO (2009) [4] and Iimori et al. (2011) [123].

VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS

 Pathophysiology
in the section about skeletal manifestations of CKD later
in this chapter.
Fracture Rates
Abnormal bone quality or quantity resulting from
ROD can lead to increased fragility and an increased risk
of fracture. In 1966, Pendras and coworkers [3] report-
ing their experience with the first 22 patients to receive
long-term hemodialysis, found that bone and mineral
disorders emerged as one of the most troublesome com-
plications, with fractures occurring in 47%. Since then,
several studies of fracture prevalence and incidence have
been reported (Table 58.1) [4]. Prevalence rates have var-
ied from 10% to 40% in general dialysis populations and
the incidence of hip fracture for patients commencing
dialysis from 1989 to 1996 in the US was 4.4-fold that of
residents of Olmstead County [5]. Not surprisingly, frac-
tures occur more commonly in elderly patients, in women,
in diabetic patients, in those using g
­ lucocorticoids, and in
those with longer exposure to dialysis.
Fracture risk is also increased in earlier stages of CKD
[6]. In CKD stages 3 and 4, hip fractures occur two to
three times more commonly than among people without
CKD [4,7], and an increased risk has been reported in
both black and white women [8]. In elderly women [9]
and men [10] those with higher cystatin C levels have
significantly more fractures, and this may be a more
sensitive indicator of fracture risk than the creatinine,
because cystatin, as noted above, does not depend on
muscle mass [10]. For elderly patients, levels of eGFR
less than 45 mL/minute/1.73 m2 are also associated with
a near doubling of hip-fracture-related mortality both
before and after adjustment for confounding factors [11].
Coexistence of Osteoporosis and
Chronic Kidney Disease
Early stages of CKD are common in elderly people
who have low bone density because both osteoporosis
(defined as a T-score lower than –2.5) and CKD increase
with aging. In the Third National Health Assessment
and Nutritional Examination Survey (NHANES III),
84% of women with osteoporosis had CKD stage 3 to 4.
The survey also found that 26% of women and 17% of
men with CKD stages 3 to 5 had coexisting osteoporosis
[12]. These percentages varied with the age distribution
of the population sampled.
Clinical trials of postmenopausal osteoporosis therapy
have generally excluded patients with known kidney
disease based on serum creatinine levels. Consequently,
the proportion of patients with CKD in these trials is
lower than in the overall population. Nevertheless, 45%
of subjects in the pivotal teriparatide Fracture Preven-
tion Trial had eGFR levels less than 80 mL/minute/1.73 m2
[13] and 52% of subjects in the pooled risedronate trials
had eGFR levels lower than 50 mL/minute/1.73 m2 [14].
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
1389
In the alendronate Fracture Intervention Trial, 45% of
subjects had CKD stage 3 or 4 CKD [15] as did 37% of
patients in the denosumab study [16] and 62% in the ral-
oxifene study [17].
PATHOPHYSIOLOGY
Abnormal Mineral Metabolism
Overview
The pathophysiology of mineral metabolism in
renal failure is complex (Fig. 58.2). The kidney plays an
essential role in metabolism of calcium, phosphate, and
magnesium, not only by renal reabsorption and excre-
tion, but also by secretion of systemic hormones. These
changes result in a spectrum of bone disease that can
prove ­difficult to predict for an individual patient.
Calcium and phosphate balance are central to many
of these pathways, and bone and the kidney work
cooperatively to maintain mineral balance. To main-
tain homeostasis as GFR declines, the amount of a sub-
stance generated (or absorbed from the intestine) must
equal the amount excreted. Substances such as creati-
nine that are filtered with little tubular handling remain
in balance, because rising plasma levels increase their
filtration and excretion by each remaining nephron.
However potassium, calcium, and phosphate would
be lethal if their levels rose to maintain balance like cre-
atinine does. These solutes undergo both filtration and
tubular handling, so that with progressive nephron
loss, each intact nephron excretes a greater fraction of
its filtered load. For example, while each nephron may
need to excrete only 10% of its filtered phosphate load
to maintain homeostasis at normal GFR, 90% may need
to be excreted by residual nephrons at low GFR levels.
Despite these adaptations, as CKD progresses the abil-
ity of remaining nephrons to excrete the daily load of
phosphate is eventually exceeded, resulting in positive
balance. The intestinal absorption also contributes to the
balance of minerals, and with increasing kidney dam-
age the 1,25-dihydroxyvitamin D (1,25D) levels decrease
resulting in lower calcium and phosphate absorption.
The dietary intake is another important factor that will
contribute the overall mineral balance in these patients.
Phosphate
The phosphate bond is essential to life because it
allows cells to control energy. Phosphorylation is nec-
essary for enzyme activation, deoxyribonucleic acid
(DNA) replication, and glycolysis. Intracellular and
extracellular concentrations of phosphate and calcium
are tightly controlled by inter-related regulatory mecha-
nisms, in which the kidney plays a pivotal role. Phos-
phate is ubiquitous in foods, particularly those high
1390 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE

in protein. This makes it challenging to reduce dietary
phosphate. Its active gastrointestinal absorption is medi-
ated by 1,25D and its excretion is predominantly renal.
Excretion is regulated by parathyroid hormone (PTH)
and fibroblastic growth factor 23 (FGF23), both of which
cause internalization and degradation of the proximal
tubular sodium-dependent phosphate co-transporter
(NPT)2a. Klotho, another hormone secreted in the neph-
ron, is a coreceptor for FGF23, and is necessary for its
homing to target organs [18,19]. These hormones that
regulate phosphate homeostasis are further discussed in
Chapter 16 (Kumar and Tebben).
Positive phosphate balance resulting from progres-
sive CKD is often reflected by increased serum phos-
phate concentrations, which are directly associated with
cardiovascular risk and mortality [20]. Low phosphate
levels are much less common in CKD, although hypo-
phosphatemia may occur when patients undertake long
dialysis hours, such as with nocturnal hemodialysis.
Calcium
Like phosphate, serum calcium concentrations are
also maintained within strict limits. High extracellu-
lar calcium can change membrane potentials necessary
for cardiac, muscular, and neurological function. Low
extracellular calcium also predisposes to arrhythmias
and muscle dysfunction, and chronically low calcium
levels lead to osteoporosis or osteomalacia. Just as for
phosphate, 1,25D increases the intestinal absorption of
calcium, but unlike phosphate, calcium does not shift
into cells, and any excess must be excreted by the ­kidneys
or deposited in the skeleton or soft tissues.
Magnesium
To maintain normal serum magnesium levels, around
100 mg (4.1 mmol) must be excreted daily by the kid-
neys. The principal storage sites for magnesium are
muscle (20%) and bone (67%), where it is complexed
with apatite crystals at a calcium:magnesium ratio of
50:1. About 20% to 30% of total bone magnesium exists
as a surface-limited ion, which is freely exchangeable
with serum magnesium [21]. Like other intracellular
ions, serum magnesium levels do not necessarily reflect
total body balance.
Most disturbances of magnesium metabolism result
in renal or gastrointestinal magnesium losses, so CKD
is unusual for being a cause of positive magnesium bal-
ance. However, hypomagnesemia can occur in CKD,
related to drugs such as loop diuretics, calcineurin
inhibitors, aminoglycosides, cisplatin, amphotericin B,
and proton pump inhibitors, and following parathyroid-
ectomy or transplantation. Epidemiological studies sug-
gest that low levels may be a risk factor for osteoporosis.
Elevation of magnesium levels is generally caused
by the use of magnesium-containing antacids and
phosphate binders and by the dialysate magnesium
content. High magnesium levels may inhibit miner-
alization of bone and reduced dialysate magnesium

FIGURE 58.2  Complex effects of kidney disease on skeletal metabolism. The dashed lines represent “frustrated” feedback loops. For example,
higher phosphate levels increase parathyroid hormone (PTH) secretion, which normally decreases serum phosphate. However, chronic kidney
disease interrupts this feedback loop because kidney damage prevents a phosphaturic response to PTH. The resulting skeletal changes are shown
in the rectangles, and can vary from high to low bone formation and resorption rates. In addition, both high resorption and low formation could
contribute to vascular calcifications. BMP: bone morphogenetic protein; FGF: fibroblastic growth factor; IGF: insulin-like growth factor.

VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS

 Pathophysiology
concentrations have been associated with an improve-
ment in osteomalacia [22]. However, long-term con-
sequences of positive magnesium balance and the
abnormal magnesium to calcium ratio found in bone
biopsy studies [23] remains unclear. Magnesium com-
pounds are effective phosphate binders [24], which
may reduce the development of arrhythmias and in
observational studies of patients on dialysis, higher
serum levels may have improved survival [25] and
slow the progression of vascular calcification. How-
ever, the only prospective evaluation of vascular calci-
fication in magnesium-supplemented ­dialysis patients
was small and n­ onrandomized [26].
The Role of Bone Turnover
With progressive CKD and a reduced renal excretory
capacity for calcium and phosphate, bone is a key site
for mineral exchange and sequestration. Bone acts as
a “sink” to buffer the exchangeable mineral pool, with
hydrated osteoid covering the bone surfaces and chan-
nels acting as a potential site for immediate exchange.
The ability of bone to continue to perform the function
of mineral sequestration is predicated on normal bone
physiology. Low bone turnover results in quiescent bone
surfaces. The collagen matrix is more densely packed
with minerals and has lower water content, and thus is
more highly mineralized. This would make it more diffi-
cult to deposit further mineral into the bone. In addition,
the osteocytes are older, so that the ability of this bone
to exchange calcium and phosphate rapidly diminishes.
In contrast, high turnover often results in a net efflux
of mineral from bone. In both cases, loss of the bone
“sink” may increase the risk of vascular calcification,
1391
particularly when mineral balance is positive as occurs
in many patients on dialysis. Other factors involved with
­vascular calcification are described later in this chapter.
Parathyroid Hormone, Vitamin D and
FGF23 and Klotho
The three major circulating hormones that control
mineral metabolism are involved in complex feedback
networks, as shown in Figure 58.3. The direct conse-
quences of renal disease include an inability to excrete
phosphate and reduced production of 1,25D and Klotho.
This indirectly leads to increased concentrations of PTH
and FGF23.
Parathyroid Hormone
Secondary hyperparathyroidism is seen in many
patients with CKD 3 to 5, and PTH concentrations
increase as kidney function deteriorates. The “intact”
PTH (iPTH) assays measure not only PTH 1-84 but also
long C-terminal fragments, particularly PTH 7-84. These
fragments are normally metabolized by the kidney
and can contribute up to 50% of PTH measured by the
“intact” assay (as compared to the “biointact” assay) in
later stages of CKD [27]. Several factors contribute to sec-
ondary hyperparathyroidism, including low circulating
1,25D, low serum calcium, and high serum phosphate
[28]. These factors increase the PTH concentrations by
increasing the amount of PTH secreted per cell, and/or
by increasing parathyroid cell proliferation. This can lead
to diffuse glandular hypertrophy followed by the devel-
opment of nodules with similar gene profiles in each
nodule and finally a stage of uninodular hyperplasia,

FIGURE 58.3  A shows the feedback network for mineral-regulating hormones in normal persons and B indicates disruptions with chronic
kidney disease. Red lines indicate inhibition and blue arrows indicate stimulation. With kidney disease, the phosphate, parathyroid hormone
(PTH) and fibroblastic growth factor (FGF)23 increase but the calcium, 1,25D and Klotho decrease. Phosphate increases because the kidney can no
longer excrete it, and the kidney is no longer able to respond to the phosphaturic actions of increased FGF23 and PTH levels.

VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS

1392 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE
which is more resistant to medical treatments. Malignant
transformation is not common [29].
The progressive decline in levels of circulating 1,25D is
a major factor in these changes, because this hormone nor-
mally suppresses PTH levels by several mechanisms. 1,25D
directly inhibits transcription of the PTH gene [30] exerts
an antiproliferative effect on parathyroid cells through
induction of p21 gene expression and upregulates expres-
sion of the calcium-sensing receptor (CaR) [31], which sen-
sitizes parathyroid cells to the inhibiting effects of serum
calcium. 1,25D also indirectly reduces PTH ­secretion by
increasing gastrointestinal calcium absorption.
Low calcium levels also cause secondary hyperpara-
thyroidism by stimulating PTH secretion via the CaR.
With persistent hypocalcemia the expression of the PTH
gene is enhanced, due to greater stability of messenger
ribonucleic acid (mRNA) for PTH and when hypocal-
cemia is even more prolonged parathyroid hyperplasia
ensues [32]. Increased levels of serum phosphate also
result in hyperparathyroidism by stabilizing PTH mRNA
and when prolonged, hyperphosphatemia reduces p21
and contributes to parathyroid gland hypertrophy [33].
A further mechanism of parathyroid hypertrophy has
been identified. Reduced levels of 1,25D or high levels of
dietary phosphate induce translocation to the cell surface
of a tumor necrosis factor-α-converting enzyme (TACE),
which results in release of the growth promoter trans-
forming growth factor (TGF)-α [33,34]. In turn, TGF-α
binds to and activates the epidermal growth factor recep-
tor (EGFR). Activated EGFR then translocates to the
nucleus, where it functions as an autocrine signal for cell
growth. With phosphate restriction, parathyroid TGF-α
returns to normal levels rapidly, which suggests that low-
ering dietary phosphate may counteract uremia-induced
parathyroid hyperplasia by preventing parathyroid TGF-α
enhancement in addition to inducing expression of p21.
FGF23 reduces PTH by suppressing the PTH gene
[30], but in CKD the parathyroids are resistant to this
action, perhaps due to lower levels of Klotho [35].
Vitamin D
A decline in 25-hydroxyvitamin D (25(OH)D) levels
often accompanies progressive CKD [36,37], although
values may be similar to those in the general community.
In contrast, 1,25D levels decline progressively, due to an
early rise in FGF23 levels inhibiting 1 alpha-hydroxylase
(CYP27B1) activity as well as inducing 24-hydroxylase
activity (CYP24A1), resulting in 1,25D breakdown. With
worsening CKD, proximal tubular damage reduces the
ability of tubular cells to produce 1,25D and concen-
trations are generally low; this may be exacerbated by
poor sunlight exposure and reduced 25(OH)D levels in
patients who are not supplemented with cholecalciferol.
Low levels of 25(OH)D are inversely related to PTH
concentrations from CKD stage 1 to 4 [38] (Fig. 58.4) but
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
FIGURE 58.4  Vitamin D levels in chronic kidney disease (CKD)
stages with different parathyroid hormone (PTH) concentrations.
Source: reproduced from Patel et al. (2011) [38], with permission.
this relationship is not evident for patients on dialysis.
Reduced 1,25D exacerbates hypocalcemia, and together
these contribute to the development of secondary hyper-
parathyroidism. When used in management, calcitriol
and its analogs reduce bone turnover, improve miner-
alization, and stabilize or improve bone volume [39].
However, oversuppression of bone turnover is a major
concern. Less well studied are the effects of 1,25D on
blood vessel walls and vascular calcification, which vary
with 1,25D concentration and other factors [40,41].
FGF23 and Klotho
FGF23 is an endocrine hormone secreted by the osteo-
cytes that acts on the proximal tubule to increase phosphate
excretion, and on the parathyroid gland to reduce secretion
of PTH [42]. FGF23 also directly reduces 1-α-hydroxylation
of vitamin D [43] and increases the activity of the catabolic
24-hydroxylase enzyme (CYP 24A1). This latter action
enhances the conversion of 1,25D to 1,24,25(OH)3D and
reduces the availability of substrate to the 1-alpha hydrox-
ylase enzyme by converting 25(OH)D to 24,25(OH)2D
[44]. Klotho is a protein expressed in the kidneys and
­parathyroids that is ­necessary for the action of FGF23.
FACTORS THAT INCREASE CIRCULATING
FGF23 LEVELS
Multiple different factors modify FGF23 levels [45]
and some of these interact with each other (Fig. 58.5). One
driving factor for FGF23 production is a chronic increase
in phosphate load, although the mechanism is uncer-
tain, and some studies do not show an increased FGF23
immediately after increasing the serum phosphate [46].
Increased serum phosphate levels also stimulate the post
translational O-glycosylation of FGF23, which protects it
from cleavage and increases its stability [47]; the enzyme
involved being coded by the polypeptide N-acetylgalac-
tosaminyltransferase 3 (GALNT3) gene. FGF23 is also
 Pathophysiology
FIGURE 58.5  Interactions between mediators of fibroblastic
growth factor (FGF)23. Phosphate loading increases parathyroid hor-
mone (PTH) and inhibits 1,25D. Phosphate loading also increases
FGF23 but the action is indirect. PTH directly stimulates FGF23 and
1,25D, and also inhibits sclerostin and PHEX. 1,25D increases FGF23
directly. Sclerostin inhibits the PTH-stimulation of FGF-23, but also
inhibits PHEX. PHEX and Dmp1 both inhibit FGF23 through uncertain
mechanisms. Leptin and low iron both stimulate FGF23.
cleaved by the protein furin, so any factors that inhibit
furin would increase intact FGF23 levels [48]. FGF23 pro-
duction is decreased by both PHEX and Dmp1, through
uncertain mechanisms; mutations in either of these
­proteins cause hypophosphatemia and rickets.
FGF23 is upregulated by PTH and by 1,25D. 1,25D
acts through osteocyte vitamin D receptors to increase
FGF23 transcription [49,50], while PTH increases FGF23
both directly and indirectly [51,52]. The direct PTH effect
is via activation of the protein kinase A (PKA) pathway
in osteoblasts, which increases FGF23 mRNA levels and
the indirect PTH effect is by the conversion of 25(OH)D
to 1,25D as well as by decreasing PHEX. On a clinical
level, lowering PTH levels in hemodialysis patients with
cinacalcet also lowers levels of FGF23 [53] and FGF23
levels fall following parathyroidectomy [26]. The wnt
signaling pathway is also involved in FGF23 modula-
tion, through pathways with opposing effects; PTH-
stimulated increases in FGF23 expression are blocked
by sclerostin [54], but sclerostin also inhibits PHEX [55].
Studies also suggest that leptin increases FGF23 [45].
Iron deficiency increases FGF23 secretion in normal
people [56], but the protein is degraded so that the intact
molecule levels return toward normal while the frag-
ments remain increased. In CKD stage 1 to 4 a study
found that the serum iron was inversely correlated to
serum FGF23 using an assay that measured both intact
and C-terminal fragments [57]. However, iron infusions
also can increase FGF23 in dialysis patients [58]. It is pos-
sible that iron infusions inhibit furin, which stabilizes
the intact FGF23 levels [48].
FGF23 IN EARLY CHRONIC KIDNEY DISEASE
An increase in FGF23 levels is detected in very early
CKD, such as in otherwise healthy kidney donors who
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
1393
had lower serum phosphate levels and increased renal
tubular fractional excretion of phosphate compared to
controls [59]. This suggests that hyperphosphatemia
is not the only stimulus for FGF23 production. Simi-
lar results were seen in another study of 3879 patients
with CKD stage 2 to 4. The mean serum phosphate and
median PTH levels were still in the normal range, but
median FGF23 was markedly greater than in healthy
populations, and increased significantly with decreas-
ing eGFR [60]. In children with CKD, levels of FGF23
are also reported to increase prior to the development of
hyperphosphatemia [61,62].
In a mouse model of renal injury, the serum FGF23
levels were increased prior to elevations in blood urea
nitrogen (BUN) and serum creatinine, but the gene tran-
scription in osteoblasts was not increased until later
stages. The source of the early increase in FGF23 was not
clear, but the authors thought it could represent changes
in excretion or post-transcriptional processing of the
hormone [63]. Most of the FGF23 in patients with CKD
is intact [64], suggesting that there may be something in
uremic serum that inhibits the cleavage of FGF23 [48].
FGF23 LEVELS AND CLINICAL OUTCOMES
High FGF23 concentrations are associated with poor
clinical outcomes, including cardiovascular disease, both
in patients with renal disease [65–67] and in the general
population [68]. Compared with the lowest quartile of
FGF23, each subsequent quartile was associated with a
progressively higher risk for death. However, it is not
clear if these problems are caused by FGF23 or if it is a
surrogate marker for disease.
FGF23 LEVELS AND BONE DISEASE
Emerging evidence suggests that high levels of FGF23
could have negative effects on bone tissue. For exam-
ple, exogenous FGF23 applied to cultured osteoblastic
MC3T3.E1 cells in the presence of soluble Klotho inhib-
ited mineralization and proliferation [69]. In patients on
hemodialysis, FGF23 values did not correlate to bone
mass, or to serum levels of bone specific alkaline phos-
phatase or C-telopeptide [70]. However, in stage 1 to 4
CKD, FGF23 levels were inversely correlated with bone
mineral density at the hip [57]. A study of 105 Japanese
patients with CKD found that those with vertebral
­fractures had higher FGF23 levels [71].
KLOTHO
Klotho is a protein named after the first of the Moi-
rae, who were the three Greek goddesses controlling
man’s fate. Klotho spun the thread of life, so it was
appropriate to assign her name to a transgenic mouse
gene that conferred longevity above the wild type when
overexpressed, but upon deletion resulted in prema-
ture aging and a shortened life span [72,73]. Klotho is
1394 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE
a 130-kDa single-pass transmembrane protein expressed
in the nephron, the parathyroids, and the choroid plexus.
Although expression is higher in the distal nephron,
Klotho is also found in the proximal tubule [18]. Klotho
is necessary for the actions of FGF23, which does not
have a specific receptor in the proximal tubule, but acts
through a more general FGF23 receptor. Once Klotho
binds to this nonspecific FGF receptor, it converts to a
receptor that will bind FGF23 [74]. Klotho is also impor-
tant in the regulation of insulin-like growth factor (IGF)
and in tubular calcium transport.
Acid-Base
With acute metabolic acidosis, calcium and bicar-
bonate are released from bone in a chemical reaction
that does not depend on cellular activity, although with
chronic metabolic acidosis, osteoclastic bone resorp-
tion is increased as well [75]. The released bicarbonate
buffers excess acid, but at the expense of loss of bone
mineral. Respiratory acidosis does not cause these prob-
lems, suggesting that the bicarbonate concentration is
the key factor. Since diseased kidneys are less capable
of secreting an acid load, these mechanisms may cause
bone loss, even in early stages of CKD. In healthy elderly
patients a randomized clinical trial for 2 years showed
an increase in bone density as well as markers of bone
formation with potassium citrate supplementation [76].
Another study showed decreases in the urine calcium
excretion with potassium bicarbonate [77]. A Cochrane
review found that the evidence for benefits of acid cor-
rection is very limited in patients with CKD, but small
trials suggested there may be some beneficial effects on
bone metabolism [78].
Abnormal Endocrine Hormones
Gonadal Hormones
Patients with late stages of CKD frequently have
abnormalities in gonadal hormones, which can con-
tribute to bone disease [79]. Many premenopausal
women with stage 4 or 5 CKD have oligomenorrhea or
amenorrhea, and serum estrogen levels are decreased.
However, albumin and sex hormone binding globulin
(SHBG) may also be decreased, so free estradiol levels
can be higher than suggested by total estradiol concen-
trations [80]. Men may also have low total testosterone
levels.
In men with stage 3 CKD, estradiol levels are associ-
ated with a slight but significant decrease in the serum
phosphate, although the relationship is stronger in men
with normal kidney function [81]. This may be due to
an estrogen-induced increase in levels of FGF23 as
described in a rodent model [82]. However, in women
with heart disease and mild to moderate CKD, those
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
taking estrogen have lower phosphate and lower FGF23
levels then women not taking estrogen [83].
Insulin and Osteocalcin
In osteoblasts, insulin is anabolic, acting through the
osteoblast insulin receptor and stimulating proliferation
and differentiation [84]. Osteocalcin, long known to be
secreted by osteoblasts and an important bone protein, is
now known to also be a systemic hormone that increases
insulin sensitivity [85]. States of high bone turnover are
associated with higher uncarboxylated osteocalcin.
Diabetes is a common cause of CKD and a known risk
factor for osteoporosis and fractures (see also Chapter
55). Diabetic patients tend to have low bone formation,
which could exacerbate the diabetes because they will
have lower uncarboxylated osteocalcin. Osteoblasts also
mediate the adverse effects of glucocorticoids on fuel
metabolism [86].
A study of 189 hemodialysis patients found that under-
carboxylated osteocalcin (ucOC) correlated inversely
with the plasma glucose, hemoglobin A1C, and gly-
cated albumin. Diabetic patients had lower serum ucOC
levels [87].
Malnutrition, Insulin-Like Growth Factor
Patients with CKD usually have nutritional prob-
lems. Their diets must be restricted because they can-
not excrete excess phosphate or potassium or sodium.
Nausea and anorexia limit the intake of food. This mal-
nutrition would be expected to play a role in the devel-
opment of bone disease, but this has not been carefully
studied.
Serum levels of IGF-I must be interpreted with cau-
tion, because the bioavailability of IGF-I is altered in kid-
ney disease [88]. In the US population, serum IGF-I is
positively associated with estimated GFR [89]. However,
Jehle et al. [90] studied 319 patients with various stages
of kidney disease, including dialysis patients, and found
that total and free IGF-I levels remained constant in most
patients. The IGF-I was positively correlated with the
bone formation rate.
Studies report various levels in dialysis patients
[91,92]. The bioavailable levels of IGF may be low even
when total levels are increased because the binding pro-
teins are also increased. Han et al. [92] found lower IGF-I
levels in patients on dialysis than in normal subjects.
These patients also had abnormalities in their muscle
strength.
Wnt-Signaling Pathway
In 2001, identification of the high bone mass gene
as LRP-5, a coreceptor for the wnt-signaling path-
way, led to numerous studies which documented the
 Pathophysiology
importance of this pathway in skeletal metabolism [93]
(see also Chapter 18). Sclerostin and Dickkopf (Dkk-1)
are two soluble proteins which inhibit wnt signaling
by binding to LRP-5. Secreted frizzled-related proteins
(sFRPs) also inhibit the pathway. Sclerostin is secreted
almost exclusively by osteocytes and tonically inhibits
bone formation. When the bone is subjected to mechani-
cal forces, the affected osteocytes stop secreting scleros-
tin and bone formation commences at that location [94].
Dkk-1 is expressed by many kinds of cells, including
those in the marrow and vasculature.
Alterations to wnt signaling and levels of wnt inhibi-
tory proteins are seen in patients undergoing dialysis [95]
and in animal models of CKD [96]. In a mouse model, an
early increase in expression of SOST (the sclerostin gene)
led to reduced wnt signaling and consequently reduced
osteoprotegerin (OPG).
In bone biopsies from 60 patients with stage 5 CKD,
Cejka and colleagues [95] investigated the associations
between serum levels of sclerostin or Dkk-1 and histo-
morphometric parameters of bone turnover, mineraliza-
tion, and volume (TMV). Serum sclerostin levels were
higher in CKD patients than in normal women. Scleros-
tin correlated negatively with iPTH and with histomor-
phometric parameters of turnover, osteoblastic number,
and function in both unadjusted and adjusted analyses.
Furthermore, sclerostin was superior to PTH for positive
prediction of high bone turnover. Dkk-1, however, did
not show correlations with any of the parameters of bone
turnover measured on bone biopsies.
Although wnt signaling is beneficial to the skeleton,
it also acts in other systems, where it may play a nega-
tive role. For example, in the kidneys wnt signaling leads
to podocyte dysfunction, proteinuria [97], and increased
epithelial damage [98]. Wnt inhibition is involved with
vascular calcifications, as discussed later in this chapter.
Bone Morphogenetic Protein-7
Bone morphogenetic protein (BMP)-7 is an impor-
tant promoter of osteoblast differentiation that is
produced primarily by the kidneys, so that levels are
reduced in CKD [99]. This growth factor is necessary
for the differentiation of preosteoblasts into mature
osteoblasts. The accumulation of preosteoblasts in
the marrow had traditionally been termed “fibro-
sis” because the long spindle-shaped cells resembled
­fibrocytes [100].
BMP-7 has been used successfully to treat the ady-
namic bone disorder that developed in adult mice after
the induction of renal impairment [101]. Because BMP-7
upregulates the expression of osteoblast PTH receptors,
higher levels of PTH may be required for regulation of
stem cell niches when levels of BMP-7 are reduced by
renal damage [102].
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
1395
Accumulation of Substances
Aluminum
About a decade after long-term dialysis was first used,
some centers reported a unique syndrome of dementia.
The first symptom was stuttering during dialysis, and
this rapidly progressed to seizures, coma, and death
within 6 months. The patients also had osteomalacia.
The etiology was a mystery and the most likely cause
seemed to be a virus. Several centers had epidemics of
this disease, while others did not have any cases. Even-
tually these outbreaks were linked to the aluminum lev-
els in the water used for the dialysate. Municipal water
companies may add aluminum to deflocculate water,
and in several cities the dialysis centers started seeing
dementia soon after the water department began using
this form of water treatment. Meanwhile, investigators
had described two forms of osteomalacia in dialysis
patients: one responded well to calcitriol but the other
was resistant and caused by aluminum [103]. Thereaf-
ter, all dialysis centers began using methods to purify
the water, and the incidence of aluminum-related osteo-
malacia dropped dramatically. Currently only sporadic
cases are seen, with high doses of oral aluminum or
with accidental contamination of dialysate or parenteral
solutions.
Iron
Iron accumulation in the bone can also cause osteoma-
lacia in dialysis patients. On bone biopsies, iron deposi-
tion is seen along the surface of the bone, particularly
at the mineralizing front [23,104]. This can be seen in
patients with frequent blood transfusions. Osteoporosis
is seen in patients with hemochromatosis who have nor-
mal renal function [105]. The iron appears to be directly
toxic to the osteoblasts [106] (see also Chapter 48, Marcus
and Shane).
Strontium
Some animal studies suggest that accumulation of
strontium may also cause osteomalacia [107]. In rats,
the effects are complex and dose-dependent; some had
adynamic bone and others developed osteomalacia
[108]. Strontium levels are increased in bones of dialy-
sis patients who had osteomalacia [109,110]. This has
not been seen in osteoporotic patients who have been
treated with strontium, but they did not have kidney
disease [111]. There are no clinical trials using strontium
in patients with CKD. Use of strontium as a treatment for
osteoporosis is discussed in Chapter 84.
β2 Microglobulin (Amyloid)
β2 microglobulin is a byproduct of immunoglobulin
metabolism, and is normally excreted by the kidney. This
protein is too large to be efficiently dialyzed, and it may
1396 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE
accumulate in patients after many years of hemodialy-
sis. The protein aggregates form β-pleated sheets, which
results in dialysis-related amyloid, but the distribution
is different than that of other forms of amyloid. Deposits
are seen in the bone near the joints, where it binds to col-
lagen and stimulates osteoclastic bone resorption, form-
ing cystic lesions [112]. Amyloid also deposits around the
tendons of the wrist and causes carpal tunnel syndrome
(Fig. 58.6) [113]. High-flux dialysis membranes are more
efficient at removing the β2 microglobulin [114].
Low Activity and Poor Muscle Strength
Patients with CKD 4 or 5 have multiple medical
problems that may result in decreased physical activity.
Measurements of muscle strength by the timed get up
and go test, and by the 6-minute walk, predict fractures
in patients with CKD. In one study the area under the
receiver operating curve (ROC) with these muscle tests
was 0.90, which was higher than the area using high-
resolution peripheral quantitative computed tomogra-
phy (HRpQCT) at the radius (area under the ROC 0.80)
[115,116]. Muscle strength is just one factor that can lead
to falls, and 44% of dialysis patients older than 65 years
had more than one fall in the previous year [117]. In
elderly men and women treated for osteoporosis, CKD
is a risk factor for falls [6].
Muscle wasting (or sarcopenia) is highly preva-
lent among patients with CKD, and may not be sim-
ply responsive to protein feeding. In these patients
there are complex mechanisms that stimulate loss of
skeletal muscle, involving activation of mediators that
stimulate the adenosine triphosphate (ATP)-dependent
FIGURE 58.6  Dialysis amyloid. The radiograph demonstrates
cysts in the radius and carpal bones. Source: reprinted from Adams (2002)
[113], with permission.
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
ubiquitin-proteosome system. Abnormalities in insulin
/IGF-I signaling activate caspase-3, a protease that dis-
rupts the complex structure of muscle proteins [118].
In dialysis patients, grip strength is reduced compared
to normal controls, and is lower in dialysis patients
with higher serum myostatin levels [92]. Relationships
between nerve and bone are being discovered, and the
neuropathy associated with CKD may play a role in the
bone disease. Neuropathy also can be a factor in devel-
opment of stress fractures of the feet due to reduced
proprioception.
SKELETAL MANIFESTATIONS OF
CHRONIC KIDNEY DISEASE
Fractures
Fractures Predict Mortality and Further Fractures
Mortality in patients with CKD stage 5D who have
had a hip fracture is about twice as high as mortality in
patients of similar age and gender who have not had a
fracture. Coco et al. [119] followed 1272 hemodialysis
patients over 10 years and observed that the mortality
for CKD stage 5D patients with a hip fracture was 2.7
times higher than in fracture-free hemodialysis patients.
Mittalhenkle et al. [120] recorded hip fracture cases over
5.5 years, and the mortality incidence was 2.15 times
greater in the cases as in matched controls. Danese et al.
[121] evaluated 9007 patients and found that a history of
hip, vertebral, or pelvic fracture was associated with an
age- and sex-adjusted mortality rate that was 2.7 times
greater than for the other dialysis patients. Kaneko et al.
[122] found that the adjusted hazard ratio for mortal-
ity was 1.95 in patients with long-bone fractures, using
data from 7159 subjects in the Dialysis Morbidity and
­Mortality Study.
In the general population, previous fractures as an
adult are strongly associated with the risk of a subse-
quent fracture. In patients with CKD stage 5D, a ­vertebral
fracture identified on a radiograph increased the risk of a
new fracture by over seven-fold [121].
Relationship of Parathyroid Hormone and Alkaline
Phosphatase to Fractures
In patient with CKD stage 5D, several large prospec-
tive studies relating serum PTH to fractures have pro-
vided inconsistent results [4,123]. Cross-sectional studies
have also evaluated this relationship and in general were
negative (Table 58.2). However, a case controlled cohort
study did find a 31% (95% confidence interval (CI) 0.57
to 0.83, p < 0.001) reduction in global fracture risk follow-
ing parathyroidectomy [124].
An association between high serum alkaline phospha-
tase levels and the risk of fractures has been reported [125].
 Skeletal Manifestations Of Chronic Kidney Disease 1397

Bone Pain osteitis fibrosa (high bone turnover with “fibrosis”), and
mixed (high bone turnover with abnormal mineraliza-
Whereas ordinary osteoporosis does not cause pain tion). There is no consensus on the exact measurements
until the patient experiences a fracture, ROD is associ- to define these categories. A review of 2340 biopsies
ated with bone pain, especially when there is osteoma- performed on Brazilian patients for clinical indications
lacia. Severe secondary hyperparathyroidism may also found that the frequency of fractures was significantly
cause bone pain. higher in those with osteomalacia compared with other
forms [127]. Another study that followed 62 patients for
Bone Histology 5 years after bone biopsy found a higher rate of fractures
in those with adynamic bone disease [128].
Types of Renal Osteodystrophy Bone volume was not previously used to categorize
In ROD, bone formation rate varies from unmeasur- biopsies, but on average those with adynamic bone have
ably low to very high [126]. Superimposed upon this lower bone volume, and those with high turnover have
spectrum are variations in the degree of mineralization increased cancellous bone volume (Fig. 58.7).
of the bone matrix and variations in bone volume, which A comprehensive literature review of the prevalence
combine to determine the bone density. An international of types of bone disease in CKD in shown in Figure 58.8.
committee sponsored by Kidney Disease: Improving The review analyzed studies carried out between 1983
Global Outcomes (KDIGO) concurred that the most and 2006 [4]. Differing prevalences of bone disease types
important parameters to describe ROD are turnover, observed between studies are due to differing classifi-
mineralization, and volume (TMV) [1,4]. Thus, instead cation methods, in addition to differences related to
of a one-dimensional axis, the TMV system defines a geographical areas, genetic background, and treatment
more comprehensive three-dimensional space. modalities.
Most older studies of ROD have classified biopsies A report from 2011 shows that the patterns of ROD
based on the bone formation rate or presence of fibrosis, may be evolving. Malluche analyzed 630 bone biopsies
as well as the degree of mineralization. The six traditional performed in patients with CKD stage 5, from 2003 to
categories are: normal, adynamic (low bone turnover 2008, using the TMV system. About 58% of patients had
and normal mineralization), osteomalacia (low bone low bone turnover, which is a shift from older studies
turnover and abnormal mineralization), high turnover, showing a preponderance of high turnover related to
hyperparathyroidism. Only 3% of patients had abnormal
TABLE 58.2  Relationship between Fractures and Parathyroid mineralization. In addition, 73% of the white patients
Hormone with low bone volume had low bone turnover [129].
Author Year n Fractures
On bone biopsies, the bone volume in black dialysis
patients is higher than that in whites and the bone for-
Coco 2000 1272 High risk with low PTH mation rate is mostly normal or elevated in blacks but
Stehman- 2000 4952 No relation mostly low in whites. This is in contrast to black patients
Breen with normal renal function who have low bone forma-
Block 2004 40,538 Weak direct association, p = 0.035 tion. In the dialysis population the black patients had
higher PTH levels than white patients (661 vs. 274 pg/
Danese 2006 9007 Higher risk with low or high PTH mL), but at any level of PTH, bone turnover was lower in
Jadoul 2006 12,782 Relative risk = 1.7 if PTH > 900 blacks than in whites, indicating resistance to the resorp-
Mitterbauer 2007 1774 No relation
tive effects of PTH. The black patients were treated more
often with vitamin D or its metabolites. In addition,
Iimori 2012 485 Higher risk with low or high PTH black dialysis patients have a greater survival rate than
Urena 2003 70 No relation white patients [130].
Negri 2004 65 No relation
Parathyroid Hormone in Relation to Bone
Inaba 2005 114 No relation Histology
Elder 2006 242 More after PTX otherwise not related The classic findings of renal hyperparathyroidism
Ersoy 2006 292 No relation
(still termed “osteitis fibrosa”) are increased numbers
of multinucleated osteoclasts, woven bone, blurry tet-
Jamal 2006 52 No relation racycline labels, increased cancellous bone volume
Atsumi 1999 187 More with low PTH but decreased cortical thickness, and intratrabecular
­tunneling (Fig. 58.9).
PTH: parathyroid hormone. Studies above line are cohort studies and below the
line are cross-sectional. The classic term is a misnomer; there is no active
Source: data from KDIGO (2009) [4]. inflammation, the “fibrosis” is predominantly cellular

VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS

1398 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE

FIGURE 58.7  A, Categories of renal osteodystrophy according to turnover and mineralization. The bone volumes shown are typical values
but these results vary according to the population studied. B, Histological sections of bone from patients showing adynamic (upper left), high
bone turnover (upper right), osteomalacia (lower left) and mixed disease (lower right). The bones were stained with Goldner’s stain which colors
mineralized bone blue/green and unmineralized osteoid orange. (See color plate.) Source: A, From the KDIGO guidelines [4], with permission; B, from
Ott (2009) [126], with permission.

with some extracellular matrix, which can disappear
rapidly when PTH is lowered. The cells are not fibro-
blasts, but inchoate preosteoblasts that proliferated
under the influence of PTH but have not achieved
mature differentiation. This can be corrected by addi-
tion of BMP-7 [100,131–133]. However, the bone
response to PTH is not consistent, and there is evidence
for skeletal resistance to PTH in patients CKD-MBD.
This is why guidelines recommend that serum levels of
PTH should be higher than the range seen in normal
individuals [4].
Correlations between PTH and bone formation vary
widely (Fig. 58.10). The older studies tended to find
better correlations between PTH and bone formation

VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS

 Skeletal Manifestations Of Chronic Kidney Disease 1399

FIGURE 58.8  Chart showing percentage of patients with different categories of renal osteodystrophy, from studies reported between 1983 and
2006 [4]. AD: adynamic bone disease; OF: osteitis fibrosa; OM: osteomalacia. Source: from KDIGO (2009) [4], with permission.

(A)

(B)

FIGURE 58.9  Histological sections from patients with osteitis fibrosa. A shows intratrabecular tunneling, B shows multiple large osteoclasts.
(See color plate.)

rates, whereas more recent studies show poor corre-
lations. This follows a trend for findings of adynamic
bone disease with high PTH levels. The reasons for
the recent poor correlations between PTH and bone
formation are not clear, but could involve differences
in the assays for PTH, secular changes in the dialysis
population with more diabetic and elderly patients,
differences in therapies, and differences in racial com-
position of the studies [4].
Bone Biochemical Markers
Markers Studied in Chronic Kidney Disease
In patients with normal renal function, serum bio-
chemical markers correlate with bone formation or
resorption, and they predict fractures in elderly popula-
tions. The interpretation of these markers is altered with
decreasing renal function, particularly for those mark-
ers that are excreted by the kidneys, so that the elevated

VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS

1400 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE
concentrations merely represent accumulation instead of
increased activity of the bone cells.
Markers that have been studied in CKD include the
collagen-based measurements of bone formation and
resorption (procollagen type I N-terminal propeptice
(PINP) and N-terminal telopeptide (NTX) or C-terminal
telopeptide (CTX)), alkaline phosphatase, and bone alka-
line phosphatase (b-ALP), receptor activator of nuclear
factor kappaB ligand (RANKL), osteocalcin, OPG [134],
and tartrate-resistant acid phosphatase (TRAP). Serum
levels of alkaline and acid phosphatases are not altered
by renal dysfunction, but the collagen-based markers are
excreted by the kidney.
Relationship to Bone Histology
Figure 58.10 shows correlations between tetracycline-
based bone formation and several bone turnover mark-
ers. b-ALP has better correlation to bone formation rate
than PTH or osteocalcin. The b-ALP also has higher
predictive value for the diagnosis of high or low bone
turnover.
Markers of Bone Turnover and Clinical Outcomes
In cohorts of elderly women, most of whom have
early stages of CKD, serum biochemical markers of bone
turnover have been associated with fractures [135–137]
(see also Chapter 67).
In patients with CKD stages 4 or 5 there are limited
data that relate serum markers to fractures. Urena et al.
[138] found that cross-laps TM (CTx) and b-ALP were not
different between fracture and nonfracture cases in a sur-
vey of 70 dialysis patients. Limori followed 485 hemodi-
alysis patients and did not see a difference in fracture rate
according to the baseline b-ALP, but the b-ALP measure-
ments prior to the fracture date were higher than those at
the end of the study in patients without a fracture [123].
FIGURE 58.10  Graph showing correlation coefficients between
markers and the bone formation rate in various studies. The corre-
lation coefficients are on the y-axis, and the studies are arranged in
chronological order. Symbols connected by a line were from the same
study. Symbol size is proportional to number of subjects [4]. b-ALP:
bone alkaline phosphatase, OC: osteocalcin, X-link: N-telopeptide or
C-telopeptide. Source: from KDIGO (2009) [4], with permission.
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
One study evaluated CKD patients without known
cardiovascular disease and found that reduced TRAP-
5b and elevated b-ALP were both associated with an
increase in the relative risk of cardiovascular mortality
[139]. These somewhat paradoxical findings suggest that
much more work needs to be done to understand fully
the clinical utility of such biomarkers.
Bone Mineral Density
Bone Mineral Density in Dialysis Patients
Figure 58.11 shows the average values of BMD in
patients with CKD stage 5D [140]. These values are
expressed as z-scores, which compare BMD in the
patients to the BMD from the reference values of age-
and gender-matched people in the community. Most of
the studies found that spine BMD was close to normal
and relatively better than BMD at the hip or radius. This
is consistent with observations from bone biopsies that
show thin cortices but increased cancellous bone volume.
Studies Relating Bone Mineral Density to Fracture
in Chronic Kidney Disease Stage 5
BMD measurements using dual-energy X-ray absorp-
tiometry (DXA) measure only one aspect of bone
strength. This is particularly true in CKD, because fac-
tors in addition to bone density play a large role in deter-
mining the strength of the bone and the risk of a fracture.
The KDIGO report suggested that in patients with CKD
stages 3 to 5D with evidence of CKD-MBD, BMD test-
ing not be performed routinely, because BMD does not
predict fracture risk as it does in the general population,
and BMD does not predict the type of ROD [4]. Since
then a prospective study of dialysis patients from Japan
found that hip or whole body bone density at baseline
was associated with fracture incidence. At the total hip,
the adjusted hazard ratio for a fracture was 0.65 for each
standard deviation increase in the BMD [123].
Figure 58.12 shows results of studies assessing the
relationship of fracture to BMD in patients on dialysis.
The results of these studies are mixed and differences
are not as great as in similar studies of postmenopausal
women from the general population [141]. There are sev-
eral potential reasons for the poor performance of DXA
in patients with CKD stage 5. Vertebral measurements
may overestimate BMD due to arthritic conditions,
scoliosis, and aortic calcifications. CKD patients have
poor bone quality that cannot be measured by DXA.
Abnormal microarchitecture, mineralization density,
crystal deposition in the bone matrix, or abnormalities
in the matrix itself could all contribute to loss of bone
strength. Patients with CKD, especially those with high
serum PTH, have increased cancellous bone volume but
decreased cortical thickness [142]. Furthermore, patients
with CKD may experience more trauma to the skeleton if
 Skeletal Manifestations Of Chronic Kidney Disease
they have more frequent falls. A study of fall prevalence
in osteoporotic patients showed a greater risk in those
with eGFR less than 65 mL/minute/1.73 m2, especially
when they were taking glucocorticoids [6].
Increases in BMD do not always mean the bone
strength is improved, because there may be concomitant
worsening of the bone quality. In contrast, it is difficult
to imagine that a loss of bone density could be beneficial,
except in rare cases of osteosclerosis.
Cross-Sectional Studies in Chronic Kidney Disease
Stages 3 to 5
A Canadian study included 211 patients, age over
18 years, with stage 3 to 5 CKD. A history of fracture
since age 40 years, or a prevalent vertebral fracture,
was present in 74 patients. Bone density was measured
using DXA and HR-pQCT at the radius. The odds
ratio of fracture for each standard deviation decrease
in measurement was 1.56 for DXA of the ultradistal
radius and 1.45 for trabecular thickness by HR-pQCT
at the radius. The area under the ROC curve was 0.73
1401
to 0.80 for bone density tests, in comparison to 0.90
for neuromuscular tests in the same group of patients
[115,116].
Nickolas et al. [143] measured BMD by DXA and HR-
pQCT in 91 patients with CKD stages 2 to 5, one-third
of whom had a prevalent fracture. The BMD by DXA
was 7% to 10% lower in those with a fracture. By HR-
pQCT, measurements of cortical thickness at the radius
and tibia were also lower in patients who had a fracture,
whereas trabecular density was lower only at the radius.
The best areas under the ROC curves were 0.66 for femo-
ral neck DXA, the HR-pQCT at the radius and at the cor-
tical bone of the tibia. There was better discrimination
between those with and without a fracture in patients
with longer duration of CKD.
The studies of patients with early stages of CKD are
consistent with those in the general population (ROC
area 0.61 for the total hip for osteoporotic fractures [141]).
This is not surprising because there is a large overlap
between persons with osteoporosis and persons with
age-related decreases in GFR.

FIGURE 58.11  Plot of bone density in dialysis patients. Circles are studies in women, diamonds in men, and squares both. Size of points are
proportional to numbers of subjects. Source: from Ott (2009) [140], with permission.

VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS

1402 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE

FIGURE 58.12  Studies that measured bone density in patients with fractures. All but the Iimori study were cross-sectional [123,140]. * = results
adjusted for age. Fx: fracture; nr: not reported.

EXTRASKELETAL CALCIFICATIONS
Factors that Modify Mineralization
Extracellular fluids are normally supersaturated with
respect to calcium and phosphate, and inhibitors of calcifi-
cation are necessary to prevent deposition (see Fig. 58.13).
In general, patients with CKD have increased levels of
minerals and calcification promoters, but decreased lev-
els of inhibitors. An exception is OPG, which inhibits
calcification but is increased in CKD patients. OPG is a
calcification inhibitor, and transgenic mice lacking OPG
have severe vascular calcifications. It is likely that the
elevated levels in CKD are a reaction to this pro-calcific
milieu and as such they are a marker of disease, increas-
ing early in the course of CKD-MBD [144] and predicting
adverse cardiovascular events [145].
Tumoral Calcinosis
One of the earliest problems discovered when hemo-
dialysis was first able to prolong the life of patients
with end-stage renal failure was the development of
tumoral calcinosis [3]. Phosphate did not dialyze well,
and the hyperphosphatemia resulted in huge mineral
deposits. These are still seen in patients who are non-
compliant with their phosphate control (Fig. 58.14).
When concentrations of phosphate and calcium exceed
a solubility threshold, the product will precipitate in
soft tissues.
Calciphylaxis
An unusual calcification of the small cutaneous
arteries is seen in patients with CKD, termed calciphy-
laxis. Another term for this is calcific uremic arterio-
lopathy. This results in skin necrosis and can progress
to large areas of soft-tissue necrosis (Fig. 58.15). This
is a serious condition with high mortality. The exact
etiology is uncertain, but high PTH is often seen.
Some patients respond to parathyroidectomy or to
the antioxidant c­ation chelator sodium thiosulphate
[146–148].

VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS

 Extraskeletal Calcifications 1403

FIGURE 58.13  Factors that are involved with vascular calcifications. The promoters of vascular calcification are shown above and the inhibi-
tors below. The principal factors are highlighted by color. Those in ovals are decreased in chronic kidney disease, while those in flags are increased,
and those in boxes are variable or normal. ANK: transmembrane protein; BMP: bone morphogenetic protein; IGF-1: insulin-like growth factor-1;
NPP-1: pyrophosphatase/phosphodiesterase; PTH: parathyroid hormone; PTHrP, parathyroid hormone-related peptide; TGF-β: transforming
growth factor-beta [41,152–160].

FIGURE 58.15  Calciphylaxis. (See color plate.)

frequently seen in dialysis patients in soft tissues of the

FIGURE 58.14  Tumoral calcinosis in a noncompliant dialysis
­patient.
Metastatic Calcifications
Many tissues which have been damaged or inflamed
may develop calcifications. This happens in people with
normal renal function, for example, with tuberculosis or
tendonitis, and the exact mechanism is unknown. Dys-
trophic calcifications are not metabolically active, and
do not take up tracers on nuclear medicine bone scans
[149]. Other, more metabolically active calcifications are
internal organs, including lung and stomach, and their
pathology is not well defined [150]. They contain whit-
lockite crystal patterns, as opposed to the ­hydroxyapatite
seen in bones [151].
Vascular Calcifications
Vascular calcifications (Fig. 58.16) are associated
with high mortality. They are common in patients with
CKD, and by stage 5 the majority of patients exhibit
vascular calcifications. These can be intimal or medial.
The intimal calcifications represent calcium deposition

VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS

1404 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE
FIGURE 58.16  Vascular calcifications in a patient with chronic
­kidney disease.
into atherosclerotic plaques caused by high cholesterol,
which is another abnormality seen in late stages of
CKD.
The medial calcifications are actively formed by vas-
cular smooth muscle cells which have transformed into
osteoblast-like cells. This causes stiffness of the arter-
ies and abnormal pulse pressure waves, with increased
systolic and decreased diastolic pressures that may
lead to left heart failure and reduced coronary perfu-
sion. In tissue cultures, these vascular smooth muscle
cells spontaneously differentiate into cells that express
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
osteoblast markers, and secrete collagen and control
mineralization. Degradation of elastin also contributes
to the ­calcification [152,153].
The vascular smooth muscle cells release apoptotic
particles or matrix vesicles that can form a nidus for
mineralization [152,154]. In severe cases there is literally
bone inside the arteries.
Phosphate is an important signal causing smooth
muscle cells to differentiate into osteoblasts [154–158]. In
CKD, the serum phosphate levels are correlated to the
extent of vascular calcifications; furthermore, phosphate
control can retard the progression of these calcifications.
The phosphate activates Pit-1, a phosphate transporter
[152,157].
Calcitriol can have different effects on vascular cal-
cification, depending on its concentration and experi-
mental conditions [40,41]. Low concentrations can
retard the differentiation of smooth muscle cells into
osteoblasts, but at high concentrations the calcitriol,
by increasing serum calcium and phosphate, contrib-
utes to vascular calcifications. In phosphate-enriched
cultures of mouse smooth muscle cells, calcitriol or
paricalcitol altered expression of many genes that are
involved in mineralization. The changes were complex,
with increases in factors that promote calcifications as
well as inhibitors, and decreases in both promoters and
inhibitors [159].
The vascular cells express CaRs and experimental
studies show reduction in vascular calcifications when
these are activated with calcimimetics. A phase II ran-
domized clinical trial of cinacalcet combined with low
doses of paricalcitol showed a trend towards reduction in
coronary artery calcification score [160], but the phase III
study, which involved 3883 hemodialysis patients with
secondary hyperparathyroidism, found that although
the patients in the cinacalcet arm experienced numeri-
cally fewer composite primary events, the results were
not statistically significant [161].
The wnt-signaling pathway is also involved in vascu-
lar calcification. Microarrays of vascular smooth muscle
cells cultured with calcitriol, which caused transforma-
tion to osteoblastic cells, revealed over-expression of
Dkk-1 and reduced expression of Wnt5A [159]. In rats
with CKD who developed aortic calcifications, microar-
ray analysis of the aortic tissue showed increased sFRPs
[158]. It is possible that these could circulate to bone and
inhibit bone formation. In 77 patients with CKD stage
3 to 4, sclerostin (which inhibits wnt signaling) was
increased as GFR worsened. In addition, levels of Dkk-1
were inversely associated with the arterial s­tiffness
index [162].
Other mechanisms involved in vascular calcifications
include oxidative stress [163], hydrogen sulfide [164],
decreased Fetuin [165], decreased BMP7 [166], increased
BMP2, lower pyrophosphate, lower matrix gla protein,
 Treatment
abnormal serum lipids, and the hostile environment of
the uremic milieu [155].
Relationship to Bone Turnover
In bone biopsies from patients with CKD, the bone
formation rate is lower in those with arterial calcifica-
tions than in those without [167–169]. Both suppressed
bone formation and excess bone resorption and forma-
tion are seen with coronary artery calcification [170]. In
stage 1 to 4 CKD the biochemical markers of bone forma-
tion are inversely correlated with the arterial wall stiff-
ness, whereas markers of bone resorption are directly
correlated [171].
Underlying mechanisms include excess bone resorp-
tion releasing calcium and phosphate from the bones,
and thereby initiating the process of vascular smooth
muscle cell transformation. In contrast, low bone forma-
tion results in mineralizing bone surfaces being unable
to buffer the extracellular phosphate concentration.
Thus, phosphate loads cannot be deposited into the bone
and instead increase the serum concentration [172,173].
This can lead to a viscous cycle as shown in Figure 58.15,
which is one potential pathway in a network of factors
that regulate mineral metabolism. The phosphate stimu-
lates differentiation of the vascular smooth muscle cells
into osteoblasts. This is also promoted by wnt signal-
ing, and is inhibited by moderate levels of 1,25D. The
­osteoblasts then form bone inside the vascular walls.
Bisphosphonates reduce excess bone resorption,
but they reduce bone formation and could potentially
exacerbate extraskeletal calcification. Clinical studies
of bisphosphonates are described later in this chapter.
It will be important for future studies to clarify the role
of the wnt-signaling pathway in the vasculature because
medications which increase the activity of the pathway,
and which increase intracellular beta-catenin, are being
developed for treatment of osteoporosis.
TREATMENT
Correct Classic Abnormalities
The first therapeutic steps in a patient with fractures
or bone density in the “osteoporotic” range (hip T-score
lower than –2.5) are to correct the known associated
problems with the mineral and bone disorder seen in
CKD-MBD. It is difficult but important to treat abnor-
malities in serum calcium, phosphate, vitamin D, and
PTH simultaneously. The 2009 KDIGO guidelines have
extensively reviewed the evidence about medications
that can help achieve this [4] (Table 58.3). Many patients
with fractures have abnormalities that can be improved
with greater attention to phosphate control using diet,
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
1405
TABLE 58.3  Management of CKD-MBD from KDIGO
Guidelines [4]
Parathyroid hormone (PTH)
Monitor serum levels of calcium, phosphorus, PTH, and alkaline
phosphatase activity beginning in CKD stage 3
In patients with CKD stages 3–5 not on dialysis, correct high PTH
levels with any or all of the following: reducing dietary phosphate
intake and administering phosphate binders, calcium supplements,
and/or native vitamin D
In patients with CKD stage 5D, maintain iPTH levels in the range of
approximately two to nine times the upper normal limit for the assay
In patients with CKD stage 5D and elevated or rising PTH, use
calcitriol, or vitamin D analogs, or calcimimetics, or a combination of
calcimimetics and calcitriol or vitamin D analogs to lower PTH
In patients with CKD stages 3–5D with severe hyperparathyroidism
(HPT) who fail to respond to medical/pharmacological therapy,
perform. parathyroidectomy
Phosphate
In patients with CKD stages 3–5 maintain serum phosphorus in the
normal range (2C)
In patients with CKD stage 5D, lower elevated phosphorus levels
toward the normal range
Use phosphate-binding agents to treat hyperphosphatemia
Restrict the dose of calcium-based phosphate binders and/or the
dose of calcitriol or vitamin D analog in the presence of persistent or
recurrent hypercalcemia, arterial calcification, adynamic bone disease,
or persistently low PTH levels
Limit dietary phosphate intake in the treatment of
hyperphosphatemia
Calcium
Maintain serum calcium in the normal range
Vitamin D
Correct vitamin D deficiency using treatment strategies recommended
for the general population
dialysis, and medications. Although we would expect
the bones to become stronger when these abnormali-
ties are addressed, no clinical trials have had sufficient
power to prove that fractures can be prevented. Since
the KDIGO report, several large randomized trials have
shown disappointing results when evaluating clinical
outcomes.
Cholecalciferol is frequently lower than 20 ng/mL (50
nmol/L) in patients with CKD, but clinical trials have
not shown whether supplementation is beneficial [174].
One study in predominantly African-American patients
showed that 200,000 international units (IU) of chole-
calciferol given weekly for 3 weeks increased the serum
levels, but there was no change in the PTH levels [175].
Data from the large international Dialysis Outcomes and
Practice Patterns Study found that the positive associa-
tions between 25(OH)D levels and clinical mortality were
1406 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE
not significant when adjusted for comorbidities. This
suggests that patients who were prescribed vitamin D
were healthier [176]. The KDIGO guidelines also sug-
gested that cholecalciferol should be given according to
recommendations for the general population, because
there were not enough studies to provide evidence that
supplementation should be different in patients with
CKD [4].
There have been many studies of calcitriol or analogs
in patients with CKD, but most were not large enough to
determine patient-oriented outcomes. A meta-analysis of
controlled trials of active vitamin D compounds showed
they did not consistently reduce PTH levels or have ben-
eficial effects on patient-level outcomes. Hypercalcemia
and hyperphosphatemia were frequent complications
[177]. In a large, multinational randomized controlled
clinical trial that enrolled 227 patients with CKD 3 or
4, paricalcitol did not reduce left ventricular volume
compared with placebo. However, the group treated
with paracalcitol experienced more frequent episodes of
hypercalcemia [178]. The appropriate timing, types, and
doses of vitamin D, calcitriol, and active analogs in this
population is still uncertain. However, in patients with
CKD stage 3 to 5 with progressively rising PTH levels
despite correction of modifiable factors, treatment with
calcitriol or activated vitamin D analogs is suggested by
the KDIGO guidelines [4]. For patients with CKD stage
5D, the benefits of treatment with both cholecalciferol
and physiological levels of calcitriol or an active analog
remain unproven. Nevertheless, this approach appears
logical, providing clinicians carefully monitor levels of
serum calcium and phosphate.
When should clinicians start using phosphate bind-
ers? In earlier stages of CKD, a historical cohort study
suggested that phosphate binders were associated with
lower mortality [179]. However, a pilot study in patients
with CKD stages 3 to 5 produced unexpected results.
Patients were randomized to placebo, calcium acetate,
lanthanum, or sevelamer. After 9 months the serum phos-
phate levels were decreased with each of the phosphate
binders, but calcification of the coronary arteries and
abdominal aortas was increased [180]. Although there
is abundant evidence that high phosphate is associated
with cardiovascular disease, lowering the phosphate
using binders may not prevent disease progression.
In CKD stage 5D phosphate must be controlled to
avoid the problems identified with the first dialysis
patients; these were severe enough to make it unethical
to do a placebo-controlled trial [3]. To date, none of the
phosphate binders are clearly better than others in terms
of patient outcomes such as mortality or cardiovascular
adverse events [181].
Calcium supplements are routinely prescribed for
patients with postmenopausal osteoporosis, but in
patients with CKD-MBD calcium intake must be
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
individualized depending on the serum calcium, phos-
phate, PTH, and presence of arterial calcifications, and
the bone turnover rate [182]. Calcium citrate should be
avoided because it increases absorption of aluminum,
and patients with CKD are at increased risk of ­aluminum
toxicity [183].
Treatment with the calcimimetic cinacalcet, reduces
parathyroid gland size by about 50% in hemodialysis
patients [184]. Early clinical studies that were not large
enough to determine patient-level outcomes had posi-
tive results that were not found in a large randomized
clinical trial. First a randomized trial with 741 hemodi-
alysis patients found reduced PTH levels after 26 weeks
of treatment [185]. Then a cohort study of 19,186 patients
found lower cardiovascular and all-cause mortality in
patients who had been treated with cinacalcet [186]. A
pooled analysis of four trials suggested a reduced risk
of cardiovascular events and fracture [187]. Finally, the
EValuation Of Cinacalcet HCl Therapy to Lower Cardio-
Vascular Events (EVOLVE) investigators enrolled 3883
hemodialysis patients in a randomized clinical trial of
cinacalcet or placebo, with a mean study duration of 21
months in the cinacalcet group. There was a 12% reduc-
tion in the composite end point of death or cardiovascu-
lar event, but this was not statistically significant. There
was no reduction in fracture rates with cinacalcet [160].
In patients with earlier stages of CKD, cinacalcet also
reduces PTH but the studies did not evaluate cardio-
vascular end points. In a large clinical trial patients had
frequent episodes of hypocalcemia, and increased serum
phosphate [188], likely to be related to a reduction in
PTH-related phosphaturia.
Life-Style
Nutrition
Nutrition in the dialysis patient is challenging. The
standard nutritional recommendations for patients with
ordinary osteoporosis do not apply to patients with
CKD-MBD, who must avoid foods with excess phos-
phate. And while protein deficiency can be harmful and
cause malnutrition, extra protein contributes to acidosis,
hyperphosphatemia, uremia, and progression of renal
failure. Thus, high biologic value protein should be used.
Consumption of dairy products is often limited
because they contain high amounts of phosphate. Many
patients are prescribed calcium-based phosphate bind-
ers, which also act as calcium supplements. Calcium
citrate increases absorption of aluminum and should be
avoided in CKD stages 4 to 5D.
Fruits and vegetables, which appear to be associated
with better bone density in the general population, con-
tain high levels of potassium, which can be dangerous to
patients as CKD becomes more advanced, so these foods
must often be limited.
 Treatment
The Institute of Medicine recommends 600 IU/day of
vitamin D for adults younger than 70 years and 800 IU/
day for older adults in the general population. There are
no studies specifically in kidney patients that suggest the
dose should be different in those with CKD.
Exercise
Bones respond to mechanical forces, and many patients
with CKD-stage 4 or 5 do not get much weight-bearing
exercise. Walking, stair climbing, and dancing, as well as
back extension exercises, should be encouraged in these
patients. Exercise programs have not been shown to
reduce fractures in large trials, but they make a lot of sense
and can also improve cardiovascular and mental health.
Fall Prevention
Patients with chronic diseases are at higher risk for
falls [6,117,189], and fall prevention strategies are similar
in those with CKD as in those with ordinary osteoporosis.
Medications used for Osteoporosis
Osteoporosis is a disease of reduced bone mass and
reduced bone strength. There is overlap between “ordi-
nary” osteoporosis and CKD-MBD, but they are different
diseases—just as hemolytic anemia and iron-deficiency
anemia have similar manifestations but different physi-
ology (Table 58.4).
Although clinical trials have included thousands of
patients with osteoporosis, a small minority of the sub-
jects had CKD-MBD. The pivotal trials were designed to
exclude those with renal disease. Subjects had normal
serum PTH, alkaline phosphatase, calcium, and phos-
phate and thus did not have the biochemical abnormali-
ties that herald the advanced mineral and bone disorders
associated with CKD-MBD. Because they were excluded
based on creatinine, and not estimated GFR, and they
TABLE 58.4  Differences between CKD-MBD and
Postmenopausal Osteoporosis
CKD-MBD Postmenopausal osteoporosis
Increased PTH and alkaline Normal PTH and alkaline
phosphatase phosphatase
BMD weakly associated with BMD predicts fractures
fractures
Bone loss mostly in cortical bone Bone loss in cancellous and
cortical bone
High prevalence of adynamic or Bone formation generally
very high bone formation rates normal to slightly high
Abnormal calcium, phosphate, Laboratory results normal
FGF23, BMP7, Klotho, 1,25D, iron,
bicarbonate, and various cytokines
1,25D: 1,25-dihydroxyvitamin D; BMD: bone mineral density; PTH: parathyroid
hormone.
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
1407
were elderly, some of the patients did have CKD stage 3
or 4. These patients respond to osteoporosis medications
and can be treated the same as other elderly people with
osteoporosis. The KDIGO guidelines [4] recommend
that patients with early stages of CKD, who have normal
laboratory values and low bone density or high risk of
fracture, should be treated to prevent fractures as in the
general population.
Patients with stage 4 or 5 CKD, who are developing
CKD-MBD, may have low bone density, poor bone qual-
ity, and fractures that appear similar to those patients
with ordinary postmenopausal osteoporosis, but the
physiological differences must be considered before
starting medications [190]. Unfortunately, there are still
no large randomized trials of osteoporosis medications
in stage 4 or 5 CKD patients. The following review sum-
marizes available evidence in these late stage patients.
Estrogen
Many women with CKD have gonadal dysfunction and
thus it may seem logical to treat with estrogen. In post-
menopausal women from the general population, estro-
gen replacement therapy has been conclusively shown to
reduce the incidence of hip, vertebral, and nonvertebral
fractures [191]. However, the administration of combined
estrogen–progestin may also increase the risk of breast
cancer, thromboembolic events, and coronary and cerebro-
vascular disease, with risks dependent on age and years
since menopause [192]. A current theory is that estrogen
can help prevent coronary artery calcifications if given to
women who have normal coronary arteries, but can cause
plaque rupture and myocardial infarctions in women who
already have coronary artery disease (CAD) [193]. Because
older women with CKD frequently have CAD, estrogen
should not be initiated in late postmenopausal women.
Estrogen treatment increases BMD in premenopausal
women with CKD. Amenorrheic women receiving dialy-
sis treated with transdermal estradiol for 1 year had bet-
ter change in BMD than those not treated [194]. Because
of abnormalities in protein binding, the free estradiol
levels in CKD stage 5D women are twice as high as in
women with normal kidney function when given the
same dose [80], so if estrogen is used in this population
the dose should be lowered.
Testosterone
Similarly, men with advanced CKD may also have
reduced testosterone levels [195,196], which also may
contribute to abnormal bone. However, there are no
studies that have specifically evaluated the effect of
­testosterone therapy on bone in CKD patients.
Bisphosphonates
Bisphosphonates are effective medications that
are widely used to prevent fractures in patients with
1408 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE
“ordinary” postmenopausal osteoporosis, in whom the
fracture rates are decreased by about 50%. These medi-
cations decrease both the bone resorption rate and bone
formation rate by 70% to 90%. They increase the bone
density, but not the bone volume, and it is likely that they
prevent fractures because they prevent the microarchi-
tectural deterioration that occurs with untreated osteo-
porosis. Women with the highest tertile of baseline bone
turnover markers show significant reduction in fracture
rates with alendronate, but there is no difference in frac-
ture rate in those with baseline low markers of bone
turnover [197]. The safety and efficacy in patients with
CKD-MBD remain uncertain [198]. ­Bisphosphonates
decrease serum calcium and increase PTH.
PHARMACOKINETICS
Several features about bisphosphonate actions and
pharmacokinetics are important in the context of CKD.
They bind very tightly to mineral, with a half-life of over
10 years [199]. In patients with normal kidney function,
about half of the administered dose is bound to the bone
and the rest excreted within several hours by the kidney,
so most of the tissues have only brief exposure to the
drugs [199]. They are cleared by hemodialysis [200].
ACUTE RENAL FAILURE
Acute renal failure has been reported with intravenous
bisphosphonates, especially when given with rapid infu-
sion and frequent doses to patients with malignancy [201].
Annual infusions given to osteoporotic patients resulted
in modest changes in creatinine in 0.4% of placebo-
treated patients and 1.3% of patients treated with zole-
dronic acid [202]. In older patients with a hip fracture, an
increase in serum creatinine of greater than 0.5 mg/dL
was seen in a similar percentage of patients in both pla-
cebo (5.6%) and zoledronic acid (6.2%) groups [203]. Spo-
radic cases of acute kidney diseases have been reported,
and the kidney biopsies show tubular injury with low
Na+, K+-ATPase expression [204]. The mechanism of
toxicity is uncertain but may relate to known proper-
ties of the drugs. The proximal tubular cells internalize
bisphosphonates, as do the osteoclasts, and inhibition of
farnestyl pyrophosphate synthase results in inhibition
of prenylation of small GTPases which are necessary for
maintenance of the cytoskeleton and r­ uffled border. This
may lead to renal damage.
CARDIOVASCULAR CALCIFICATIONS
Other safety issues must be considered in CKD
patients. Soft tissue calcifications can also bind bisphos-
phonates, as seen with bone scanning agents containing
bisphosphonates. In patients with ordinary osteopo-
rosis, the nonskeletal tissues have short and low expo-
sure to the drugs. In patients with late stages of CKD
the bisphosphonates may concentrate within soft-tissue
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
calcifications. One important and unexplored ques-
tion is whether there are any adverse effects related to
­bisphosphonate deposition in these nonskeletal sites.
Etidronate reduces vascular calcifications in ani-
mal studies and in some case reports [205]. This first-
generation bisphosphonate inhibits mineralization because
it is an analog of pyrophosphate. The newer bisphos-
phonates are given at substantially lower doses which
do not inhibit mineralization. In women with ordinary
osteoporosis radiographic imaging studies of coronary
arteries have shown increases in calcifications with both
ibandronate and alendronate that were similar to the
increases seen in control subjects [206,207]. In a random-
ized, placebo-controlled clinical trial using alendronate
in 51 patients with CKD stage 3 to 5, alendronate did
not decrease the progression of vascular calcification
­compared with placebo [208].
A retrospective cohort study included 9604 women
with CKD stages 3 or 4 who did not have a previ-
ous serious cardiovascular event. They were followed
for 3.9 years to ascertain mortality and rate of serious
cardiac events. In the 3234 women who had been
exposed to bisphosphonates the all-cause mortality
was significantly better than in the patients who had
not taken bisphosphonates (adjusted hazard ratio 0.78).
However, there was no benefit for cardiovascular events
(hazard ratio 1.14). Of note, in those patients who ini-
tially had some cardiac disease, the hazard ratios were
1.20 for death and 1.24 for a serious cardiovascular end
point [209].
A theoretical concern about bisphosphonate toxicity
in CKD patients relates to the low bone turnover which
is a direct effect of the drugs. This could increase vascular
calcifications (see Fig. 58.17). In contrast, high turnover
can also increase serum phosphate by directly releasing
it from the bone, and in this case the bisphosphonates
could be helpful.
CLINICAL TRIALS IN CHRONIC KIDNEY DISEASE
STAGE 3
Miller et al. [14] reported a pooled analysis of nine tri-
als using risedronate for treatment of osteoporosis. The
primary trials were designed to exclude patients with
significant systemic disease, so subjects with serum cre-
atinine greater than 1.1 times the upper limit of normal
were excluded. There were 4643 women with an eGFR
below 60 mL/minute, most of whom had stage 3 CKD.
These women did not demonstrate the classical bone
abnormalities seen in later stages of kidney failure. They
were excluded if serum PTH or alkaline phosphatase
values were higher than normal. These patients showed
reduction in vertebral fracture rates and improvements
in bone density that were similar to those with normal
renal function, except that in those with the highest cre-
atinine, the femoral neck bone density did not respond
 Treatment 1409

Vascular smooth 1,25 (OH)2 vitamin D

muscle cells HO moderate levels

Osteoblasts

wnt
High PO4
sFRP
1,25 (OH)2 vitamin D
high levels
wnt
H Low bone turnover

HO

Bisphosphonate

FIGURE 58.17  Viscous cycle of bone inhibition and vascular calcifications. Vascular smooth muscle cells differentiate into osteoblasts under
the influence of vitamin D and Wnt signaling. The osteoblasts secrete frizzled-related protein (sFRP), which blocks the Wnt signaling but also
causes low bone formation. Bisphosphonates could exacerbate this. The low bone formation leads to increased serum phosphate, which stimulates
the changes in the smooth muscle cells. Source: from Ott (2012) [198], with permission.

to risedronate. An important limitation of this study is
that nonvertebral fracture rates were not mentioned.
A similar posthoc analysis of an alendronate trial
was reported by Jamal et al. [15]. In that study as well,
the intent of the original trial was to exclude women
with renal disease, but because of their age, many sub-
jects did have mild to moderate decreases in the eGFR.
Data extrapolated from a figure in the paper shows that
fewer than 20 subjects had CKD stage 4, and those with
abnormal serum calcium, PTH or alkaline phosphatase
values were excluded. This makes it unlikely that many
patients had CKD-MBD. The authors found that the
women with eGFR less than 45 mL/minute/1.73 m2 had
similar improvements in bone density and decreases in
relative fracture risk to those with higher eGFR.
USE IN LATER STAGES OF CHRONIC KIDNEY DISEASE
A report of 12 dialysis patients given a single dose
of pamidronate found reduced serum calcium and
increased PTH [210].
Pamidronate every 2 months for 1 year was given to
13 hemodialysis patients with high PTH in an open-label
observational study. The PTH initially increased and then
decreased when the calcitriol dose was increased. The
bone density increased [211]. A similar study used iban-
dronate for 1 year in 16 dialysis patients who had increased
PTH and low bone density. Eleven of them completed the
study, and they showed a 5% increase in spinal bone den-
sity. They also found that the PTH increased at first, but
after increasing the calcitriol dose the PTH returned to
values similar to baseline. There were no controls or bone
density measurements at cortical sites [212].
The largest randomized trial in later stages of CKD
enrolled 51 patients with CKD stage 3 or 4, and treated
with alendronate 70 mg/week or placebo for 18 months.
The lumbar spine BMD T-score was normal at baseline
(+0.40) and with treatment increased to +0.7. The femo-
ral neck T-score at baseline was –1.27 but the change in
femoral BMD was similar between groups. There was a
significant increase in PTH levels and decrease in alkaline
phosphatase with alendronate compared to placebo [208].
In patients without known renal disease the bisphos-
phonates lead to decreased bone formation. This also
occurs in patients with CKD. Bone biopsies from 13 CKD
patients (stages 2–4) who were referred to a nephrology
clinic and who had taken bisphosphonates all demon-
strated adynamic bone [213].
There is no physiological rationale to treat patients
who have low bone turnover with medications whose
mechanism of action is to inhibit bone resorption. How-
ever, the bisphosphonates could potentially be use-
ful in patients with low bone density and increased
bone resorption. Mitsopoulos and colleagues therefore
designed a pilot study to tailor the medicine to the type
of ROD and value of iPTH. They measured bone den-
sity in 102 hemodialysis patients and 66 of them had
osteoporosis. Of these, 38 consented to a bone biopsy.
The biopsy revealed high turnover in 22, and in 11 of

VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS

1410 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE
these the iPTH was less than 300 pg/mL. This group was
treated with ibandronate, and 1 year later the bone den-
sity had decreased by 3% at the spine and by 2.2% at the
hip. The other 11 patients with high turnover had iPTH
greater than 300 pg/mL and were treated with cina-
calcet, and their bone density decreased by 7.7% at the
spine and 4.2% at the hip. Five patients whose biopsies
showed only mild lesions were not treated and they lost
3% at the hip without change at the spine [214].
In summary, there is no definite evidence that bisphos-
phonates are helpful to patients with CKD stages 4 or
5. They are not as effective at improving bone density
as they are in patients with normal kidneys. Long-term
effects of low bone formation in these patients pose a
theoretical concern but clinical evidence is scarce.
Raloxifene
On a physiologic level, raloxifene is expected to be
beneficial to the bone in postmenopausal women with
CKD-MBD because it acts as an agonist to the estrogen
receptors in the skeleton. In women with normal renal
function there is approximately at 50% reduction in the
incidence of breast cancer, which is an important addi-
tional benefit. Raloxifene increases the risk of thrombo-
embolism, similar to estrogen. The drug is excreted via
hepatic metabolism, and drug concentrations are about
1.4 times higher in patients with CKD [215].
CLINICAL TRIAL IN CHRONIC KIDNEY DISEASE
STAGE 3
A posthoc study utilized data from the MORE trial
(Multiple Outcomes of Raloxifene Evaluation) to evalu-
ate the efficacy of raloxifene in patients with reduced
kidney function [17]. The original trial included 7705
postmenopausal women aged 31 to 80 years old. Women
were randomly assigned to receive placebo, raloxifene
60 mg/day or raloxifene 120 mg/day in addition to
daily calcium and vitamin D. Importantly, the study
excluded individuals with elevations in serum PTH, or
with vitamin D deficiency. The femoral neck and spine
BMD increased with raloxifene compared to placebo.
The odds ratio for vertebral fracture was 0.60 for those
with normal kidney function, 0.54 with eGFR 45–59
mL/minute/1.73 m2, and 0.74 if eGFR was less than
45 mL/minute/1.73 m2. There was no difference in the
nonvertebral fracture incidence. The adverse events
­ DISEASE
were not increased in raloxifene compared with placebo.
CLINICAL TRIALS IN LATER STAGES OF CHRONIC
KIDNEY DISEASE
Hernandez and colleagues [216] conducted a random-
ized trial in 50 dialysis patients who were at least 2 years
postmenopausal with a bone density T-score below –2.0.
After 1 year, raloxifene-treated patients had a significant
improvement in BMD at the lumbar spine, but not at
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
the hip. Levels of serum pyridinoline (a marker of bone
resorption) and of LDL cholesterol decreased after 6
months in the raloxifene-treated patients, compared to
placebo. There were no side effects noted.
A prospective study in 17 postmenopausal Japanese
women on dialysis found an increase in spine bone den-
sity after 1 year, compared with a decrease in nonran-
domized controls. At the radius, the loss was less than
in controls. The PTH concentrations increased with ral-
oxifene, and the authors suggested that calcium and/or
vitamin D should be added to treatment [217].
In another study from Japan, 22 women were treated
with raloxifene and 23 similar women were controls who
chose not to be on the medication. In those with PTH lev-
els lower than 250 pg/mL, the bone density was better
with raloxifene than control. Abdominal aortic calcifica-
tions increased to a similar extent in those taking or not
taking the raloxifene [215].
Teriparatide
It seems counterintuitive to administer the active part
of PTH to patients in whom hyperparathyroidism is a
prominent part of the skeletal pathology. However, daily
subcutaneous injections are strongly anabolic in women
with postmenopausal and glucocorticoid-associated
osteoporosis.
PATIENTS WITH STAGE 3 CHRONIC KIDNEY DISEASE
Miller et al. [13] reported a post hoc analysis which
utilized data from a clinical trial that excluded subjects
with a serum creatinine greater than 2 mg/dL. The study
excluded individuals with elevations in serum calcium,
phosphorus, or PTH, or with vitamin D deficiency. The
number of patients was small enough that none had non-
vertebral fractures during the study period. However, the
vertebral fracture incidence was reduced in those using
teriparatide. In addition, teriparatide improved lumbar
spine BMD, femoral neck BMD and PINP similarly in
patients with normal, mild, and moderately impaired
GFR. The treatment increased serum calcium and uric
acid in all subgroups, but the percentage of patients with
hypercalcemia and hyperuricemia was greater in the
moderately impaired GFR group.
PATIENTS WITH LATER STAGES OF CHRONIC KIDNEY
A pilot study in seven hemodialysis patients with low
bone density, low serum PTH, and bone biopsy evidence
of adynamic bone disease found that 6 months of terip-
aratide increased the bone density of the spine from a
mean of 0.88 ± 0.08 to 0.91 ± 0.09 g/cm (p < 0.02). The
femoral neck increased from 0.66 to 0.71, which was not
significant [218].
Mitsopoulos et al. treated nine patients with biopsy-
confirmed adynamic bone disease with teriparatide for
 Hypercalciuria
a mean of 16 months. Serum calcium and phosphate
were unchanged, alkaline phosphatase and serum PTH
increased. Bone density of the spine had decreased by
5.4% the year prior to treatment, but increased 4.9% at
the spine and 2.7% at the hip, which, given the limited
number of participants, did not quite achieve statistical
significance [214].
Denosumab
Denosumab is a new medication that works by inhib-
iting RANKL, thereby reducing the number of osteo-
clasts and substantially decreasing bone formation
rates. This monoclonal antibody is not metabolized by
the kidney.
In a randomized clinical trial of denosumab, 2890
of 7801 women had an estimated GFR below 59 mL/
minute/1.73 m2 of safety and efficacy after 3 years
showed that the subjects with CKD had a similar frac-
ture reduction to those with normal renal function, and
they did not have more adverse events. As in the other
studies, patients with hyperparathyroidism were not
included. Only 17 had stage 4 CKD and none had stage
5 [16]. A pilot study of patients with later stages of CKD
showed a higher incidence of severe hypocalcemia after
an ­injection of denosumab [219].
Calcitonin
Intranasal calcitonin has been considered a safe medi-
cation that is approved for treatment of osteoporosis. The
BMD does not show large increases on this drug, and the
fracture reduction is significant but modest compared to
other drugs. There is minimal information about using
this antiresorptive medication in patients with stage 4
or 5 CKD. One small study from Poland did show that
control patients lost bone density whereas those taking
calcitonin did not. There were no serious side effects or
changes in the phosphate or PTH [220]. Similar results
were seen in a study of 148 Chinese patients who
received subcutaneous calcitonin three times a week
for 1 year. Their bone density was stable, whereas the
­control patients lost bone [221].
One study in dogs given calcitonin for 16 weeks
found protection against bone loss but abnormalities
in the bone quality [222]. However, bone biopsies from
humans show decreased erosion depth without change
in the activation frequency, and no problems with
­mineralization lag time [223].
Recently, the European Union medical regulatory
agency, based on analyses showing that calcitonin is
associated with an increased risk for malignancy, rec-
ommended that calcitonin nasal spray preparations be
removed from the market. At the time of writing, the
US Food and Drug Administration (FDA) had not yet
released any statements or recommendations, and data
review is still ongoing.
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
1411
Summary
In patients with early stages of CKD, in whom kidney
disease has not been recognized and whose PTH and
alkaline phosphatase are normal, the drugs approved
for ordinary osteoporosis are effective and appear safe.
In selected patients with CKD stage 4 to 5, medica-
tions used in the standard management of osteoporosis
may be helpful, but they should be used cautiously. In
other cases, none of the current osteoporosis medications
are appropriate, even when patients are at high risk of
fracture. If we are uncertain about efficacy and safety, we
should follow the principle of primum non nocere (above
all, do no harm). Pilot studies of new medications, such
as sclerostin inhibitors, offer hope that in the future there
will be better choices for these patients. However, any
studies must also consider effects on cardiovascular
calcifications.
HYPERCALCIURIA
Pathophysiology
Hypercalciuria can be extrinsic to the kidney when
there is excess filtered calcium. This does not necessarily
mean there is hypercalcemia, because the kidneys will
excrete the excess load to prevent hypercalcemia from
occurring. Other causes of hypercalciuria are intrin-
sic to the kidney and can be found with abnormalities
throughout the nephron [224]. This allows an anatomic
organization of the etiology of hypercalciuria, from the
glomerulus to the collecting tubule (Fig. 58.18). Several
of these causes are genetic (Table 58.5 [225–227]).
Glomerulus: Filtered Load
INCREASED CALCIUM LOAD
The kidney filters about 8000 mg of calcium a day.
The filtered load depends on the serum ionized calcium
and the GFR. The causes of increased calcium load are
similar to the causes of hypercalcemia. Increased bone
resorption, caused by space flight [228], spinal cord
injury, strict bed rest, malignancy, hyperparathyroidism,
hyperthyroidism, vitamin A toxicity, and glucocorticoid
use can all cause an increased filtered load.
Increased intestinal absorption is directly related
to the dietary calcium intake and the vitamin D level.
In a clinical trial of calcitriol, hypercalciuria was seen
before a noticeable increase in the serum calcium [229].
High endogenous levels of 1,25D are also seen in sar-
coidosis, some lymphomas, granulomatous diseases,
and hyperparathyroidism. Some studies have found
an increased incidence of calcium-containing kidney
stones in patients with polymorphisms in the vitamin D
receptor which may lead to increased intestinal calcium
1412 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE
FIGURE 58.18  Calcium reabsorption through the nephron.
absorption [230]. A newly defined mutation in the
CYP24A1 gene also causes hypercalcemia, idiopathic
­hypercalciuria and elevated 1,25D [231,232].
It is worth noting here that low dietary calcium can
decrease the urine calcium but increase the risk of kid-
ney stones [233]. This seemingly paradoxical situation
is due to oxalate, which is less soluble when complexed
in the gastrointestinal tract to calcium than to sodium.
A low calcium intake, may increase the absorption of
sodium oxalate, which must be excreted by the kidney.
The increased urine oxalate may then form calcium oxa-
late kidney stones. In the past, physicians who did not
understand this instructed patients to decrease their
calcium intake, which only exacerbated the problem
of oxalate stones and potentially increased the risk of
osteoporosis.
Phosphate wasting can indirectly lead to hypercalci-
uria, because low phosphate stimulates renal produc-
tion of 1,25D. In turn, this increased vitamin D increases
intestinal calcium absorption and the filtered calcium
load. The PTH concentration may be low, which will
also contribute to hypercalciuria by an effect on tubular
reabsorption (discussed below). One study reported a
shift in the distribution of phosphate tubular resorption
in hypercalciuric patients with calcium nephrolithiasis,
all with normal PTH, and in some patients it was due to
a mutation in the sodium phosphate cotransporter [234].
However, another study did not find a similar high inci-
dence of ­hypophosphatemia [235].
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
INCREASED GLOMERULAR FILTRATION
Increased delivery of calcium to the renal tubules can
also be caused by increased GFR. This can cause mild
hypercalciuria, and is seen with caffeine, amino acids,
and pregnancy.
Proximal Tubular Reabsorption
Seventy percent of the filtered calcium is reabsorbed
in the proximal tubule. This is mainly by passive reab-
sorption and is paracellular. Normally the lumen has
a net positive charge which favors reabsorption. There
is also some cellular transport via calcium/hydrogen
exchangers, which require luminal bicarbonate [236].
This is one mechanism by which patients with acidosis
have decreased calcium reabsorption [237].
Sodium excess and mannitol increase calcium excre-
tion by increasing the flow and solvent drag.
Dent disease is an x-linked recessive disease caused
by a mutation in the gene for the chloride channel
(CLCN5), which leads to proximal tubular dysfunc-
tion. Patients have hypercalciuria, phosphaturia with
hypophosphatemia, normal to low serum PTH, micro-
globulinemia, rickets, and progressive renal failure.
The mechanism is probably decreased proximal tubular
CLCN5-dependent endocytosis of filtered PTH. This
increases the luminal PTH and activates PTH receptors
in the late proximal tubule, leading to increased levels of
1,25D and phosphaturia. Thiazide diuretics reduce the
urine calcium to normal [238].
 Hypercalciuria
TABLE 58.5 Some Genetic Causes of Hypercalciuria
Gene Name
CYP24A1 Vitamin D 24-hydroxylase
SLC34A3 Sodium-phosphate cotransporter
(hereditary hypophosphatemic rickets
with hypercalciuria)
CLCN5 Chloride channel (Dent disease)
ROMK1, NKCC2, Potassium channel or sodium chloride
ClC-Kb cotransporter or chloride channel (Bartter
syndrome type I, II, III)
CASR Calcium-sensing receptor (autosomal-
dominant hypocalcemia with
hypercalciuria)
Claudin-16 Familial hypomagnesemia
WNK-4 Pseudohypoaldosteronsim
ATP6B1, SLC4A1, Distal renal tubular acidosis
SLC4A1
1,25D: 1,25-dihydroxyvitamin D; PTH: parathyroid hormone.
Reabsorption from the Loop
There is no calcium transport in the descending loop
of Henle, but the thick ascending loop is an important
segment which reabsorbs 20% of the calcium. This
is also passive and paracellular and is driven by the
lumen-­positive voltage, which depends on the Na/K/Cl
triporter and associated potassium channel. This
­segment also has abundant CaRs [239,240].
LOOP DIURETICS
Loop diuretics increase calcium excretion by inhibi-
tion of the Na/K/Cl triporter. This triporter creates a
transepithelial voltage gradient that is positive in the
lumen, which drives paracellular calcium reabsorption.
ACTIVATING MUTATIONS OF CaRs
The CaRs, when activated by extracellular calcium,
signal intracellular inhibition of the potassium channels.
This inhibition of potassium recycling will inhibit the
ability of the Na/K/Cl triporter to maintain the voltage
gradient, and therefore calcium remains in the urine [239].
Patients can have either activating or inactivating muta-
tions of the CaR, with resulting mineral abnormalities that
are mirror images of each other. With activating mutations
(autosomal-dominant hypocalcemia with hypercalciuria),
they have hypercalciuria, hypocalcemia, and suppressed
PTH. Overtreatment with calcium or vitamin D leads to
nephrocalcinosis [241], and thiazides are beneficial [242].
In contrast, inactivating mutations cause hypocalciuria,
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
1413
Location Mechanism
Filtered load Mutated enzyme in proximal tubule causes
accumulation of 1,25D
Filtered load Mutated protein in the proximal tubule causes
phosphate loss which stimulates 1,25D and
increases gastrointestinal calcium absorption
Proximal tubule Abnormal proximal transport, excess PTH in
urine leads to calcium loss
Thick ascending Mutations block potassium recycling which
limb causes loss of voltage gradient
Thick ascending Activating mutation blocks potassium
limb recycling which causes loss of voltage gradient
Thick ascending Tight junction do not function properly, so
limb voltage dissipates
Distal tubule Loss of inhibition of sodium chloride
cotransporter which results in closed calcium
channels
Distal tubule Acidosis blocks calcium channels
hypercalcemia and elevated PTH, which is “benign” in
heterozygotes (familial hypocalciuric hypercalcemia).
Parathyroidectomy should be avoided in heterozygotes.
Homozygotes, however, have severe neonatal hyperpara-
thyroidism and need both parathyroidectomy and loop
diuretics. Rarely, these diseases are seen in patients who
develop autoantibodies to the calcium sensor, which can
be either activating [243] or inactivating [244].
MUTATIONS IN CLAUDIN-16
Claudin-16 (formerly called paracellin) is found in
the tight junctions. It allows sodium to pass through the
junction, but not chloride. This segment of the nephron
is impermeable to water, so the sodium concentration
in the tubule in much lower than in the extracellular
space; therefore, sodium will move down the concen-
tration gradient, leaving chloride behind, and keeps the
transepithelial voltage positive on the lumen side. With
homozygous mutations, the voltage dissipates and both
calcium and magnesium remain inside the tubule. Famil-
ial hypomagnesemia with hypercalciuria is an autoso-
mal-recessive disease, presents in children with urinary
tract infections, polyuria, hematuria and magnesium
and calcium wasting [245]. They develop nephrocalcino-
sis and renal failure, may have rickets, ocular abnormali-
ties and hearing impairment. Heterozygotes may have
hypercalciuria. Treatment with thiazide partially helps
the hypercalciuria, but definitive cure requires renal
transplantation [246].
1414 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE
Distal Tubular Reabsorption
The distal nephron provides the fine regulation of
electrolyte excretion or reabsorption [247]. About 5%
to 10% of the filtered load is reabsorbed, and this is an
active process that is transcellular, against both electrical
and concentration gradients. Epithelial calcium channels
on the luminal side (TRPV5; transient receptor potential
cation channel vanilloid 5) are induced by 1,25D and
activated by membrane hyperpolarization agents such
as PTH, amiloride, and calcitonin. These channels are
inhibited by acidosis. The calcium is carried through
the cell by calbinden (which is transcribed when vita-
min D receptors are activated), and then exported from
the basolateral side by magnesium-dependent calcium-
ATPase with cotransport of H+ or by a Na/Ca exchanger
which can be stimulated by PTH [248].
On the luminal cell membrane, the sodium-chloride
cotransporter regulates membrane polarization. When this
transporter is inhibited, the membrane becomes hyperpo-
larized and the voltage-sensitive calcium channels (TRPV5)
are opened. This transporter is sensitive to thiazide diuret-
ics. The cell membranes are also hyperpolarized with
amiloride, which also reduces urine calcium loss [249].
HYPOPARATHYROIDISM
Both hyperparathyroidism and hypoparathyroidism
cause hypercalciuria, but the mechanisms are different.
In hyperparathyroidism the serum calcium is elevated
and this causes the high urine calcium. In hypoparathy-
roidism there is increased tubular reabsorption of cal-
cium. If serum calcium is markedly low then patients
will not have hypercalciuria. However, if well-meaning
health care providers treat with calcium and vitamin D
in an attempt to “normalize” the serum calcium, then
serious hypercalciuria or nephrocalcinosis may develop
[250]. These patients should be maintained at a serum
calcium slightly below the normal range.
PTH acts to increase calcium passage into the cells by
the epithelial calcium channels. When the PTH receptor
is activated, intracellular signaling causes transcription of
TRPV5, hyperpolarization of cell membranes which opens
the TRPV5 channels, and inhibition of caveolae-mediated
endocytosis of the TRPV5. In addition PTH receptors are
on the basolateral side of the cells, and when activated
they probably activate the nearby Na/Ca exchanger [251].
ACIDOSIS
Hydrogen ions within the lumen will close the TRPV5
channels and reduce calcium reabsorption [237]. Sev-
eral hereditary forms of distal renal tubular acidosis are
­associated with hypercalciuria [227].
KLOTHO DEFICIENCY
Klotho is expressed in the distal tubules, and the
extracellular portion of the molecule is shed into blood
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
and urine. Klotho hydrolyzes sugar residues on TRPV5,
which traps this calcium channel in the membrane,
prolongs its activity and increases calcium reabsorp-
tion [252]. Klotho also contributes to the inhibition of
1-alpha hydroxylase and the synthesis of 1,25D. Mice
with Klotho knockout have hypercalciuria. A patient
with a missense mutation in the Klotho gene developed
tumoral calcinosis with high serum calcium, high 1,25D,
and hypercalciuria [253], but in other people with klotho
gene mutations, the urine calcium has not been elevated
[254,255].
PSEUDOHYPOALDOSTERONISM II
Pseudohypoaldosteronism type II is caused by
mutations in WNK-4 [256,257]. This is an autosomal-
dominant disease. WNK-4 normally inhibits the Na/
Cl cotransporter, so when it is mutated the transporter
is unregulated and patients develop hypercalciuria,
hypertension, hypermagnesemia, hyperkalemia, acido-
sis, and low bone mass. Thiazide diuretics correct all the
abnormalities.
The “mirror image” disease is an inactivating mutation
of the Na/Cl cotransporter (Gitelman’s syndrome) which
results in hypocalciuria, hypotension, hypomagnesemia,
hypokalemia, alkalosis, and high bone mass. These find-
ings could also be seen with overdoses of t­ hiazide diuretics.
Collecting Duct
There is not much calcium transport, but this seg-
ment plays an important role in regulating the concen-
tration of the urine, and CaRs are located here [239].
When activated by calcium, they block the message
from anti-diuretic hormone (on the basolateral side) and
inhibit aquaporin (on the luminal side) which makes the
urine more dilute. This mechanism is one of the body’s
defenses against kidney stones. It also contributes to
hypernatremia in patients with hypercalcemia.
Hypercalciuria and Relationship to Osteoporosis
Hypercalciuria as a Factor in Osteoporosis
Hypercalciuria is variably defined [258], but most
agree that urine calcium should be lower than 300
mg/day when the dietary intake is within the recom-
mended range (1200 mg/day). Fasting and postpran-
dial spot urinary calcium:creatinine ratios may not
detect hypercalciuria accurately, so a 24-hour urine is
the best test [259]. The prevalence of idiopathic hyper-
calciuria in patients with o
­ steoporosis varies from 10%
to 20% [258,260–262].
Osteoporosis in Stone Formers
Not only is hypercalciuria common in patients with
osteoporosis, but patients with hypercalciuria manifest
decreased bone density [224,263,264]. BMD is about one
 Hypercalciuria
standard deviation below expected in patients with idio-
pathic hypercalciuria [265]. The bone loss is seen par-
ticularly when patients also avoid dairy products [266].
Vertebral fracture risk was increased nearly fourfold in
patients with urolithiasis [267]. The NHANES study
also showed increased fracture incidence in patients
with kidney stones [266]. An analysis of multiple studies
showed bone loss at all skeletal sites [268].
Bone Biopsy Data
Three studies have measured bone biopsies in
patients with hypercalciuria. There is decreased bone
volume, increased eroded surfaces without fibrosis, and
decreased bone formation rates. Some mineralization
defects have been described as well [269–271].
1415
Treatment of Bone in Patients with
Hypercalciuria
Response to Alkali
Several studies have shown increase in BMD in patients
with kidney stones who have been treated with potas-
sium citrate [268], which also decreases the urine calcium.
Hydrochlorthiazide
It is important to remember that different diuretics
have opposite effects on urine calcium. Loop diuretics
such as furosimide will cause calcium loss, whereas thia-
zides and amiloride will reduce calcium loss. Studies of
bone density in thiazide users are shown in Table 58.6
[272]. Most show a positive effect on the bone density.

TABLE 58.6 Studies that Relate Thiazide to Bone Density

Author Year Design n Subjects BMD difference

Cauley 2005 xs 5995 Healthy men Hip 2.4% higher, spine 3.0% higher, not significant in
multivariate analysis

Bakhireva 2004 cohort 507 Elderly men No significant difference in bone loss during 4 years

Tanaka 2001 xs 325 Older men Higher in thiazide

Sigurdsson 2001 xs 248 Spine 9.6% higher, whole body 5.4% higher

LaCroix 2000 RCT 320 Healthy men and Better hip (0.8–0.9% difference) and spine
3 years women

Reid 2000 RCT 185 pm women Better at total body, arms (0.8% between groups),
2 years not spine or hip

Orwoll 1996 xs 7963 Women > 65 years Higher

Glynn 1995 xs 523 Men > 50 years Higher

Wasnich 1995 RCT 119 Hypertensive women Calcaneus, radius increased (+1.5%/year vs. –0.9%/year
2.6 years in placebo)

Morton 1994 xs 1696 Community > 44 years Higher with current use

Jergas 1994 xs 89 Hypertensive Spine BMD 10% higher in men, 19% higher in women

Cauley 1993 xs 9704 Women > 65 years Higher 7–10%, 4–5% adjusted

Bauer 1993 xs 9704 Women > 65 years Higher BMD about 6%

Sowers 1993 cohort 435 Women 55–80 years Loss less (5% vs. 7.4% in 5 years)

Ooms 1993 xs 348 Women > 70 years Thiazide not better

Dawson Hughes 1993 obs 246 pm women Bone loss during winter less in those on thiazide

Wasnich 1990 obs 1017 Japanese men Bone loss less with thiazide

Wasnich 1986 retro 993 Japanese women Higher

Sowers 1985 xs 324 pm women Higher

Adland-Davenport 1985 retro 54 pm women Not different than control

Wasnich 1983 xs 1368 Elderly men SPA 1.157 vs. 1.11 nonusers vs. 1.103 hypertensive nonusers

Transbol 1982 RCT 63 Early pm No loss in SPA for 6 months, then decline similar to placebo;
2 years after 3 years placebo –5.9%, thiazide –4.8%

pm: postmenopause; RCT: randomized controlled trial; SPA: single photon asorptiometry; xs: cross-sectional.
Source: table from Ott, SM. (2012) [272] “Hypercalciuria” Retrieved 12/12/12, from http://courses.washington.edu/bonephys/hypercalU/hypercal.html.

VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS

1416 58.  OSTEOPOROSIS ASSOCIATED WITH CHRONIC KIDNEY DISEASE
FIGURE 58.19  Forest plot of comparison: current thiazide users versus nonusers. Source: from Aung and Htay (2011) [281], with permission.
Hydrochlorthiazide (HCTZ) reduced bone resorption
in a bone histological study [273]. Pilot studies showed
increase in bone density in patients with hypercalciuria
[274]. A 1-year randomized clinical trial of thiazides in
24 men with hypercalciuria showed increased of 2.5% of
bone density at the radius in the treatment group com-
pared to a loss of 2.1% in the placebo group [275].
Several randomized trials in normal subjects have
shown a modest but significant benefit on BMD [276–
278]. One trial showed that HCTZ lowered urine cal-
cium, but in many people the effect waned, whereas
there was a consistent mild increase in bicarbonate,
which reverted to normal upon discontinuation of the
thiazide. Thus, thiazides also could act by reducing the
acid load [279].
A meta-analysis of fracture risk with thiazide use
found an overall benefit with a relative risk of 0.86 (95%
CI 0.81 to 0.92) [280]. A Cochrane review of thiazide
diuretic use and the risk of hip fracture showed a benefit
in the large cohort studies, with a summary relative risk
of 0.76 (95% CI 0.64 to 0.89) (Fig. 58.19) [281].
Summary
The renal handling of calcium is complex and abnor-
malities can occur in many steps along the way. These
often are associated with bone loss or osteomalacia. The
VII.  SPECTRUM OF SECONDARY OSTEOPOROSIS
treatment for the bone disease depends on the etiology
of the renal disease. In idiopathic hypercalciuria, thia-
zide diuretics are often helpful for both the kidney and
the bone.
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