http://www.kidney-international.

org review
& 2008 International Society of Nephrology

Chronic kidney disease and bone fracture: a growing

concern
Thomas L. Nickolas1, Mary B. Leonard2 and Elizabeth Shane3
1
Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, New York, USA; 2Division of
Nephrology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA and 3Division of
Endocrinology, Department of Medicine, Columbia University Medical Center, New York, New York, USA

Susceptibility to fracture is increased across the spectrum of Kidney International (2008) 74, 721–731; doi:10.1038/ki.2008.264;
chronic kidney disease (CKD). Moreover, fracture in patients published online 18 June 2008
with end-stage kidney disease (ESKD) results in significant KEYWORDS: chronic kidney disease; renal osteodystrophy; fracture; bone
imaging
excess mortality. The incidence and prevalence of CKD and
ESKD are predicted to increase markedly over the coming
decades in conjunction with the aging of the population.
The worldwide population is aging. In the United States
Given the high prevalence of both osteoporosis and CKD in
alone, the number of persons aged 65 years and over is
older adults, it is of the utmost public health relevance to
expected to rise from 32 to 69 million between 1990 and
be able to assess fracture risk in this population. Dual-energy
2050, and the number over the age of 85 years will increase
X-ray absorptiometry (DXA), which provides an areal
from 3 to 15 million.1 The global population is demonstrat-
measurement of bone mineral density (aBMD), is the
ing similar trends as the number of persons aged 65 years and
clinical standard to predict fracture in individuals with
over is expected to rise from 323 to 1555 million between
postmenopausal or age-related osteoporosis. Unfortunately,
1990 and 2050.1 These demographic trends have raised great
DXA does not discriminate fracture status in patients with
concern about the burden of several common diseases
ESKD. This may be, in part, because excess parathyroid
associated with aging.
hormone (PTH) secretion may accompany declining kidney
Osteoporosis, defined by the World Health Organization
function. Chronic exposure to high PTH levels preferentially
as a disorder of bone resulting in decreased bone strength, is
causes cortical bone loss, which may be partially offset by
an extremely common disorder of aging that currently affects
periosteal expansion. DXA can neither reliably detect changes
10–12 million people in the United States alone.2 Future
in bone volume nor distinguish between trabecular and
projections, based on the aging of the United States
cortical bone. In addition, DXA measurements may be
population, indicate that the number of people with
low, normal, or high in each of the major forms of renal
osteoporosis will increase exponentially during the first half
osteodystrophy (ROD). Moreover, postmenopausal or
of this century.1 For example, the estimated 7.8 million
age-related osteoporosis may also affect patients with CKD
women and 2.3 million men affected with osteoporosis at the
and ESKD. Currently, transiliac crest bone biopsy is the
hip today is expected to increase to 10.5 and 3.3 million,
gold standard to diagnose ROD and osteoporosis in patients
respectively, by 2020.1
with significant kidney dysfunction. However, bone biopsy is
Fractures represent the main clinical manifestation of
an invasive procedure that requires time-consuming analyses.
osteoporosis. Half of all women over the age of 50 years will
Therefore, there is great interest in developing non-invasive
suffer an osteoporotic fracture during their lifetime.3 More-
high-resolution imaging techniques that can improve fracture
over, the increased prevalence of osteoporosis at the hip is
risk prediction for patients with CKD. In this paper, we review
expected to lead to a tripling of the number of hip fractures
studies of fracture risk in the setting of ESKD and CKD, the
worldwide by 2050.4 The medical and economic burden of
pathophysiology of increased fracture risk in patients with
fragility fracture is substantial. Burge and colleagues5 have
kidney dysfunction, the utility of various imaging modalities in
recently estimated that the incidence of osteoporotic fractures
predicting fracture across the spectrum of CKD, and studies
will increase by almost 50% from two million fractures
evaluating the use of bisphosphonates in patients with CKD.
in 2005 to three million fractures in 2025. The associated cost
of those fractures is estimated at $25.3 billion.5 When
Correspondence: Thomas L. Nickolas, Columbia University Medical Center,
Division of Nephrology, Department of Medicine, 622 West 168th Street,
the impact of hip fracture on the quality of life is considered
PH 4 Stem—Room 124, New York, New York 10032, USA. in disability-adjusted life years, the global burden of disease
E-mail: tln2001@columbia.edu has been estimated at 1.75 million years, with approximately
Received 19 November 2007; revised 19 February 2008; accepted 21 one-quarter occurring in China and India, and 50%
March 2008; published online 18 June 2008 occurring in Western countries alone.6

Kidney International (2008) 74, 721–731 721

review
Declining kidney function is another extremely common
disorder of aging. Over the past decade, there has been a
worldwide epidemic of chronic kidney disease (CKD).7,8 In a
recent analysis of the Third National Health and Nutrition
Examination Survey (NHANES III), Coresh et al.9 found
that the prevalence of significant kidney impairment was
remarkably high in the elderly US population. Of those aged
70 years and above, only 26% had normal kidney function,
whereas 49% had mildly and 25% had moderately decreased
kidney function. Notably, the short-term risk of osteoporotic
fracture increases dramatically after the age of 70 years.10
However, despite the fact that osteoporotic fracture and
mild-to-moderate CKD (Stages 1–4) are highly co-prevalent
in the elderly,11 relatively few studies have examined the
contribution of impaired kidney function to the risk of
fragility fracture.
Given the rapid worldwide growth of an elderly popula-
tion at risk for both osteoporosis and CKD, and the many
potential mechanisms by which CKD could decrease bone
strength12 and increase fracture risk, it is imperative that we
develop effective diagnostic strategies to identify patients
with CKD who are also at risk for fracture. It is also essential
that we develop effective therapeutic strategies that decrease
fracture risk in patients with CKD. This review will examine
the scope of the problem of osteoporotic fractures in patients
with end-stage kidney disease (ESKD) and CKD, the utility of
currently available methods to identify patients at risk for
fragility fracture, and what is known about the safety and
efficacy of available therapies for osteoporosis in patients
with CKD.
FRACTURE RISK IN END-STAGE KIDNEY DISEASE
The risk of fracture is greatly increased in patients with
ESKD.13 Using the United States Renal Data System, Alem
et al.14 demonstrated a four-fold increased risk of hip fracture
in men and women on hemodialysis. Although the risk
exceeded that of the normal population in all age groups of
patients with ESKD, for those less than 65 years old the
relative risk ranged between 10- and 100-fold higher, most
likely due to the generally low incidence of hip fracture
in normal men and women below the age of 65 years.14
Other studies of patients with ESKD have shown that yearly
incidence rates for fracture by site are about 1% per year for
hip fracture and about 2.6% for any fracture.14–16 This
compares with the incidence rates of 0.07–0.22% for fracture
at the hip in the general population.17–19 Risk factors for
fracture in patients with ESKD include, both traditional risk
factors for osteoporotic fracture (older age, female gender,
low body weight, postmenopausal status, osteoporosis
history, family history of osteoporosis, previous fracture,
propensity to fall, and the use of psychoactive medications,
such as benzodiazepines and selective serotonin reuptake
inhibitors) and also risk factors that are specific to patients
with ESKD,20 including the duration of kidney replacement
therapy, exposure to glucocorticoids, history of a kidney
transplant, and both low and high parathyroid hormone
722
TL Nickolas et al.: Chronic kidney disease and bone fracture
(PTH) levels.14,16,21,22 It is noteworthy that fracture rates in
patients with ESKD are similar to fracture incidence rates of
non-uremic individuals who are older by 10–20 years.16,22
FRACTURE RISK IN PRE-DIALYSIS CKD
A growing body of literature suggests that patients with CKD
who do not yet require renal replacement therapy are also at
an increased risk of fragility fracture (Table 1).23–27 In a cross-
sectional analysis of the NHANES III, we showed that
moderate-to-severe kidney disease was independently asso-
ciated with more than a 2-fold increase in history of hip
fracture. This association was stronger than several tradi-
tional risk factors for fracture including age, gender, race,
body weight, and bone mineral density (BMD) measured at
the hip by dual-energy X-ray absorptiometry (DXA).24 A
similar relationship was noted in an analysis of the
Cardiovascular Health Study. After multivariate adjustment
for risk factors associated with osteoporotic fracture, there
was a statistically significant 16% increased risk of incident
hip fracture for women per standard deviation increase
in cystatin C.27 Furthermore, in a case–control cohort study
that selected women with either hip (n ¼ 149) or vertebral
(n ¼ 150) fracture from the Study of Osteoporotic Fractures,
the risk of trochanteric fracture was significantly increased
by 5-fold and 3.5-fold with a glomerular filtration rate
(GFR) less than 45 ml/min and between 45 and 59 ml/min,
respectively.25 This study found no significant association
between kidney function and the risk of vertebral fracture. In
a cross-sectional study of elderly men and women treated for
osteoporosis,23 a creatinine clearance of less than 65 ml/min
was associated with a significant increase in the risk of hip,
spine, and wrist fractures. In summary, these studies are
consistent in demonstrating that fracture risk is increased in
patients with moderate-to-severe CKD.
RENAL OSTEODYSTROPHY: DEFINITION, CLASSIFICATION,
AND DIAGNOSIS
In 2004, the National Kidney Foundation defined renal
osteodystrophy (ROD) as a constellation of bone disorders,
present or exacerbated by CKD, that lead to bone fragility
and fractures, abnormal mineral metabolism, and extraske-
letal manifestations.28 However, this definition did not gain
international acceptance, in part, because of its lack of bone
specificity. The Kidney Disease: Improving Global Outcomes
(KDIGO) committee refined the definition of ROD, speci-
fically limiting the term to the various types of bone
pathology found in patients with CKD. Another term,
CKD-mineral and bone disorders (CKD-MBD), was chosen
to refer more broadly to the clinical, biochemical, and
imaging abnormalities that are associated with ROD. CKD-
MBD is defined as a systemic disorder of mineral and bone
metabolism due to CKD and manifested by either one or a
combination of (1) abnormalities of calcium, phosphorous,
PTH, or vitamin D metabolism; (2) abnormalities of bone
turnover, mineralization, volume, linear growth, or strength;
and (3) vascular or other soft tissue calcification. KDIGO
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TL Nickolas et al.: Chronic kidney disease and bone fracture review

Table 1 | Studies of fracture risk associated with CKD

Study Definition of kidney function Fracture site Fracture risk (95% CI)a
Dukas et al. (2005)23 o65 ml/min Hip OR 1.57 (1.18–2.09)
Wrist OR 1.79 (1.39–2.31)
Vertebral OR 1.31 (1.19–1.55)

Nickolas et al. (2006)24 o59 ml/min Hip OR 2.32 (1.13–4.74)

Ensrud et al. (2007)25 45–59 ml/min Hip HR 1.24 (0.60–2.56)

o45 ml/min HR 1.41 (0.59–3.36)
45–59 ml/min Trochanteric HR 3.69 (1.21–11.24)
o45 ml/min HR 5.04 (1.38–18.45)

Jamal et al. (2007)26 o45 ml/min Any fracture OR 1.3 (1.0–1.6)b

Vertebral OR 2.5 (1.6–3.9)b

Fried et al. (2007)27 o60 ml/min Hip HR 1.38 (0.99–1.94)b

Per s.d. increase in cystatin C Hip HR 1.16 (1.01–1.33)b
CI, confidence interval; CKD, chronic kidney disease; HR, hazard ratio; OR, odds ratio.
a
After multivariate adjustment.
b
Women only.

recommends that the initial evaluation of CKD-MBD
proceed with biochemical testing (PTH, calcium, phospho-
rous, alkaline phosphatase, bicarbonate, and imaging for soft
tissue calcification). Bone biopsy is recommended in cases
where there are inconsistencies in biochemical parameters,
unexplained bone pain, or unexplained bone fracture.
OSTEOPOROSIS: DEFINITION, PATHOGENESIS AND
DIAGNOSIS
Osteoporosis is generally considered to account for the
majority of fragility fractures. Osteoporosis is defined as a
skeletal disorder characterized by compromised bone
strength that leads to an increased risk of fracture.29
The amount of bone mineral present or the BMD is the
major determinant of the strength of bone in the general
population. Although BMD can be measured by a number
of different radiographic and ultrasonographic techniques,
the most widespread imaging modality in clinical use for
measurement of BMD is DXA of the spine and proximal
femur. However, the strength of bone is also influenced
by the quality of the bone that is present. Bone quality is, in
turn, determined by a number of material and structural
characteristics of bone, including architecture and micro-
architecture, bone remodeling activity or turnover,
mineralization, collagen properties, and accumulation of
microdamage.30,31 Histologically, osteoporosis is charac-
terized by a reduced quantity of normally mineralized bone.
In addition, the osteoporotic bone is structurally abnormal.
Microstructural studies reveal thinning and increased poros-
ity of the cortices and fewer, disconnected, widely spaced
bony trabeculae. The microarchitectural changes usually
result from an increase in the rate of bone remodeling and/
or an imbalance between the bone resorbing activity of
osteoclasts and the bone forming activity of osteoblasts. The
most common scenario leading to osteoporosis is one in
which bone resorption is increased and bone formation is
also increased, but insufficiently to compensate. However, the
histological changes of osteoporosis can also develop as a
result of a decrease in bone formation whereas resorption
proceeds at a normal pace. Measurement of biochemical
markers that reflect osteoclast and osteoblast activities can be
used to assess the rate of bone remodeling activity.32
In patients without kidney disease, the independent
contribution of bone microarchitecture to skeletal strength
is becoming increasingly recognized. Using a peripheral
quantitative computed tomography (QCT) machine with a
resolution (B80 mm) capable of imaging trabecular micro-
structure, Boutroy et al.33 investigated a group of post-
menopausal women with osteopenia, and reported that those
with a history of fracture had lower density of trabecular
bone and more heterogeneous trabecular distribution at the
radius than those without fracture, despite comparable
BMD measurements.
PATHOGENESIS OF DECREASED BONE STRENGTH IN
PATIENTS WITH KIDNEY DISEASE
Given the general definition of osteoporosis quoted above
and our increasing understanding of the contribution of
bone quality to bone strength, it is not surprising that
fracture risk increases in patients with ESKD at a younger age
than the typical individual with senile or postmenopausal
osteoporosis.16,22 ESKD is characterized by several metabolic
and hormonal abnormalities, including decreased renal
synthesis of 1,25(OH)2D3, hyperphosphatemia, hypo-
calcemia, increased secretion of PTH, chronic metabolic
acidosis, premature hypogonadism, and, more recently,
recognized 25(OH) vitamin D deficiency; all may adversely
affect the bone remodeling process in one or more of the
following ways—increasing bone resorption, decreasing bone
formation, or impairing mineralization of osteoid. These
changes in bone remodeling have the potential to accelerate
the deterioration of bone microstructure that accompanies
normal aging—trabecular thinning and perforation, dropout
of trabeculae, cortical thinning, and porosity—and therefore

Kidney International (2008) 74, 721–731 723

review
may prematurely decrease bone quality and strength and
increase susceptibility to fragility fracture.34,35 In this regard,
Amling et al.34 compared trabecular bone volume and
connectivity, trabecular thickness, and number in spine
autopsy specimens from 9 patients on hemodialysis and 26
normal controls. Although trabecular bone volume was
similar between cases and controls, trabecular connectivity
was reduced and more trabecular perforations were observed
in patients with ESKD. Schober et al.35 compared transiliac
bone biopsies from 40 men and women with ESKD and 142
healthy women. Endocortical resorption, cortical thinning,
and a 45% reduction in mineralized cortical bone were
common features, regardless of the histological classification
of ROD. In addition, cancellous bone mineralization was
significantly decreased by 36% in patients with osteitis fibrosa
and nonsignificantly reduced by 9% in patients with
osteomalacia. Thus, bone biopsy studies have demonstrated
that ESKD is associated with microstructural alterations at
both the cortical and trabecular levels.
The increased risk of fracture noted in patients with pre-
dialysis CKD may be related to the fact that abnormalities in
vitamin D metabolism, parathyroid function, and calcium–-
phosphate balance may result in full-blown ROD long
before kidney function deteriorates to the level of ESKD.
For example, in a large cross-sectional study of patients with
early CKD, serum 1,25(OH)2D declined in a linear fashion
as estimated GFRs (eGFR) decreased.36 Notably, 13% of
patients with eGFR X80 already had low serum concentra-
tions of 1,25(OH)2D and 12% patients had high serum
concentrations of PTH.36 Moreover, approximately 40% of
subjects with eGFR between 40 and 49 ml/min had elevated
serum PTH levels. As elevated PTH levels are catabolic for
cortical bone, these biochemical alterations could cause
deterioration in cortical architecture, leading to reduced
cortical density and increased cortical porosity37 much earlier
in the course of CKD than previously thought. As cortical
bone contributes substantially to bone mechanical compe-
tence,30,31 these architectural changes could account for the
increased fracture susceptibility noted in studies of patients
with CKD. In support of this notion, biopsy studies
performed early in the course of CKD already demonstrate
characteristics consistent with ROD, although routine
biochemical and radiographic studies may still be nor-
mal.38,39 In a study of the efficacy of alfacalcidiol in the
prevention and treatment of ROD, Hamdy et al.38 demon-
strated that 75% of subjects with pre-dialysis CKD had
abnormal bone histology (74% osteitis fibrosa, 19% mixed
bone disease, 1% osteomalacia, 1% aluminum bone disease,
and 5% adynamic bone disease). In this report, it was
noteworthy that the subjects’ creatinine clearances ranged
from 15 to 50 ml/min and that none had clinical, biochem-
ical, or radiographic evidence of bone disease.
PREDICTION OF FRACTURE RISK BY DXA IN ESKD AND CKD
In normal postmenopausal women and older men without
significant kidney dysfunction, the measurement of the
724
TL Nickolas et al.: Chronic kidney disease and bone fracture
amount of mineralized bone mass of certain areas of the
skeleton, particularly the spine and proximal femur, by DXA
is an established clinical tool for discriminating among those
with and without prevalent fractures and for identifying
those who are at an increased risk of incident fracture.40
However, DXA provides a two-dimensional areal view of a
three-dimensional structure and has very poor spatial
resolution. In recent years, it has become apparent that the
measurement of areal BMD (aBMD) by DXA has substantial
limitations as a measure of bone strength, and therefore as a
clinical technique.41 For example, studies in postmenopausal
women show that half of all fractures occur in women with
aBMD values above the World Health Organization’s
diagnostic threshold for osteoporosis (T-score p2.5).42,43
In addition, age and history of adult fracture predict future
fracture independent of BMD.44 The increase in spine BMD
associated with different therapies for osteoporosis varies
considerably (1–7%), underestimates the reduction in the risk
of vertebral fracture that accompanies such therapies
(35–60%), and explains only 4–30% of the reduction in
fracture risk.45,46 Reductions in the risk of fracture associated
with an institution of antiresorptive therapy also occur well
before maximum gains in BMD are achieved.47 Finally,
certain therapies (for example, sodium fluoride) are asso-
ciated with large gains in BMD, yet do not reduce and may
even be associated with increased risk of fracture.48 These
studies suggest that characteristics other than BMD are
related to fracture risk, characteristics not measured by DXA.
In this regard, the WHO is currently defining six risk factors
that are completely independent of BMD (age, weight, female
gender, Caucasian race, prior fracture, and glucocorticoid
use).
The limitations of measuring aBMD by DXA in men and
women without significant kidney dysfunction are magnified
in patients with ESKD and CKD. A number of studies have
reported that the prevalence of low BMD measurements is
higher than expected among patients with ESKD.49 However,
it is essential for nephrologists to recognize that the meaning
of low BMD measurements is unclear in patients with ESKD
and CKD, as DXA measurements can be low, normal, or high
in each of the three major forms of kidney bone disease—
hyperparathyroidism, adynamic bone disease, and osteoma-
lacia.50–52 In addition, postmenopausal and senile osteoporo-
sis may coexist with all the forms of bone disease seen in
patients with kidney dysfunction,53 who share multiple risk
factors for low BMD with the general population, including
old age, hypogonadism, and poor functional status. In this
regard, a recent analysis of NHANES III concluded that low
BMD in patients with CKD was attributable to traditionally
accepted risk factors for osteoporosis, rather than to CKD.54
Also important, most studies suggest that in patients with
ESKD and CKD, DXA measurements do not discriminate
between those with and without prevalent fractures.52
Although a recent meta-analysis by Jamal et al.55 demon-
strated a significant association between low BMD at the
lumbar spine and radius (mid, distal, and one-third) and
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TL Nickolas et al.: Chronic kidney disease and bone fracture review

Table 2 | Studies of imaging modalities to assess fracture status in patients with CKD that report test diagnostic characteristics
Kidney Imaging Area under the receiver
Study function modality Site imaged Fracture site operator curve Sensitivity Specificity
Jamal et al. ESRD DXA Total hip Any site 56 26 78
(2006)66
pQCT Radius (cortical density) Any site 89 NA NA
Radius (trabecular density) Any site 52 NA NA

Jamal et al. ESRD DXA Femoral neck Any site 47.3 26 78

(2002)65
Ultrasound Calcaneous Any site 56.2 29 78

Fontaine et al. ESRD DXA Femoral neck Any site 75.5 NA NA

(2000)85
Radius (mid) Any site 83.7 NA NA
Radius (one-third) Any site 78.0 NA NA
Lumbar Spine Any site 72.8 NA NA

Yamaguchi ESRD DXA Lumbar spine Vertebral 72.9 70 70

et al. (1996)52
Non-spine 69.3 63 63
Radius (one-third) Vertebral 75.2 69 69
Radius (ultradistal) Non-spine 86.9 82 82

Atsumi et al. ESRD DXA Total body Vertebral 55 NA NA

(1999)21
Lumbar spine Vertebral 60 NA NA
CKD, chronic kidney disease; DXA, dual-energy X-ray absorptiometry; ESRD, end-stage renal disease; NA, not applicable; pQCT, peripheral quantitative computed tomography.

fracture status in patients on dialysis, the studies used in
this meta-analysis did not permit adjustment for variables,
such as body weight, duration of dialysis, previous fragility
fracture, physical activity, and corticosteroid use, which
are all robustly associated with BMD. Finally, the site at
which BMD is measured in patients with CKD does not
consistently predict fracture at that particular site,52 in
contrast to patients without kidney dysfunction, in whom
BMD measured at any site can predict fracture risk for that
and other sites.56–59 Prospective studies that rigorously
control for factors associated with BMD are necessary to
identify non-invasive imaging technologies that predict
fracture in the CKD population.
The lack of predictive value of DXA for fracture in the
setting of kidney failure is likely because metabolic
abnormalities that accompany kidney disease differentially
affect the cortical and trabecular compartments of bone. In
particular, chronic excess PTH secretion is catabolic for
cortical bone, causing marked subperiosteal and intracortical
erosion. In contrast, chronic PTH excess may also cause
increased osteoblastic bone formation beneath the perio-
steum that may compensate for the loss of cortical bone
to some extent, as well as increased trabecular thickness
and increased trabecular number.37,60,61 The lumbar spine
and proximal femur comprise substantial amounts of both
cortical and trabecular bones. DXA provides a composite
measurement of the cortical and trabecular compartment,
and the resolution is not high enough to discriminate
between cortical and trabecular bone. Therefore, DXA cannot
detect the predominant cortical bone loss and periosteal
expansion that accompanies hyperparathyroidism. In addi-
tion, vertebral bodies of patients with kidney disease typically
develop the areas of endplate osteosclerosis (manifested
radiographically as ‘rugger jersey spine’), which may falsely
elevate DXA measurements and further complicate the
interpretation of the scans. Theoretically, DXA measurements
of the one-third radius site, which consists predominantly of
cortical bone, may be more useful in assessing the degree of
cortical versus trabecular bone loss. In the pre-dialysis
population, the prevalence of low BMD is much higher at
the one-third radius site (33%) than either the lumbar spine
(19%) or the femoral neck (26%).50,62–64 Perhaps for these
reasons, the International Society of Clinical Densitometry
recommends that BMD of the one-third radius, rather than
the hip or spine, be used to evaluate bone loss in disorders
of hyperparathyroidism (http://www.iscd.org/Visitors/
positions). However, despite the use of different anatomical
sites for BMD assessment, DXA does not provide an accurate
assessment of fracture risk in CKD.52,65,66 In Table 2, we
summarize studies that have determined diagnostic test
characteristics for DXA to discriminate fracture status in
cohorts of patients with ESKD. Notably, DXA is a poor test to
predict fracture status, no matter which site is imaged.
TRANSILIAC BONE BIOPSY TO ASSESS BONE QUALITY AND
STRENGTH IN PATIENTS WITH ESKD OR CKD
Currently, a transiliac crest bone biopsy, performed after
tetracycline labeling of bone-forming sites, is the gold

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review TL Nickolas et al.: Chronic kidney disease and bone fracture

standard for assessing the material and structural characteri- 10 mm 0.400 mm

stics that contribute to bone quality and hence to bone

strength. Specific analyses performed on bone biopsy samples
can assess the microarchitecture of cancellous and cortical
bone, the amount and location of past and ongoing
remodeling activity, and the accumulation of fatigue damage
or microcracks. Quantitative backscattered electron imaging
of bone biopsy sections provides additional information on
the amount and distribution of bone mineral across the bony
trabeculae and Fourier Transform Infrared Spectroscopy
provides information on the ratio of collagen cross-links
across trabeculae. Furthermore, micro-CT (resolution 20 mm)
can be applied to intact biopsy specimens to provide three-
dimensional images of trabecular microarchitecture, whereas
finite element analysis of the micro-CT scans can provide
estimates of mechanical strength. Transiliac bone biopsy is CKD
currently the best technique available for detecting micro-
10 mm 0.400 mm
structural alterations that occur in the setting of secondary
hyperparathyroidism, particularly thinning and trabecular-
ization of the cortex and increased bone volume of the
cancellous compartment. However, an invasive procedure
and time-consuming measurements are required. Further-
more, bone biopsies provide limited information on three-
dimensional trabecular connectivity and orientation. Thus,
there has been great interest in developing non-invasive
techniques that can provide an accurate assessment of bone
microarchitecture and strength without the necessity of a
biopsy.

NON-INVASIVE BONE IMAGING TECHNOLOGIES IN ESKD

AND CKD
Recently, several bone imaging modalities have been
developed that show promise in providing more accurate
estimates of bone quality and strength and that may prove
useful in assessing bone strength in patients with ESKD
and CKD.
Conventional central and peripheral QCT
QCT can be applied to peripheral sites (radius and tibia) and
central sites (lumbar spine and proximal femur). QCT
provides a true volumetric measurement of BMD of the
trabecular and cortical compartments, rather than the aBMD
measurement provided by DXA. Moreover, the resolution of
QCT is high enough to differentiate between the trabecular
and cortical compartments of bone, at least in the proximal
femur. Both central and peripheral QCT scans yield cortical
and trabecular measurements that correlate well with
comparable indices measured by micro-CT of bone biopsy
specimens in patients without CKD.67 Central QCT has been
used to evaluate BMD in patients with ESKD on dialysis and
in kidney transplant recipients.68,69 Torres et al. compared 17
ESKD patients with 29 healthy controls, and found that spine
BMD measured by central QCT was highly correlated with
trabecular bone volume measured by quantitative histomor-
phometry of the iliac crest. However, not surprisingly, the
type of ROD (high or low turnover) did not correlate with
Normal
Figure 1 | Example images from techniques to evaluate bone
structure. pQCT scans of the tibia mid-diaphysis in (a) 64-year-old
male with CKD Stage 4, and (b) 62-year-old male with normal
kidney function. In comparison with the cortex of the healthy
control, the cortex of the patient with CKD is noted to have
decreased cortical density and cortical thinning.
BMD, and normal, low, or high BMD was found in each type
of ROD. Grotz et al. compared 33 female kidney transplant
recipients with 74 women undergoing evaluation for
osteoporosis with mid-vertebral high-resolution CT. Women
in either group who had experienced a X15% reduction in
vertebral height demonstrated altered trabecular microstruc-
ture, including lower BMD, lower trabecular area, number,
thickness, and increased trabecular separation. Furthermore,
compared with controls of similar BMD, kidney allograft
recipients had significantly lower trabecular number and
increased trabecular separation.69 Peripheral QCT has also
been used to assess bone architecture in pre-dialysis patients,
hemodialysis patients, and in kidney transplant recipients
(Figure 1).70–73 Using peripheral QCT, Russo et al.72 demon-
strated selective loss of cortical bone in patients on
hemodialysis. In a study of kidney transplant recipients,
cortical bone loss was found to result from resorption of the

726 Kidney International (2008) 74, 721–731

TL Nickolas et al.: Chronic kidney disease and bone fracture
endosteal rather than the periosteal cortex.71 In a study of
dialysis patients, Jamal et al.66 found that peripheral QCT of
the distal radial cortical compartment was superior to DXA
measurements of hip BMD to predict prevalent fracture
(Table 2). In this same study, pQCT measurements of distal
radial trabecular BMD did not classify fracture status.
However, the resolution of conventional pQCT (350 mm) is
not sufficient to measure trabecular microstructure, which
may contribute substantially to bone strength and suscept-
ibility to fracture.
Micro-magnetic resonance imaging
Recent advances in micro-magnetic resonance imaging
(micro-MRI) have made it possible to obtain high-resolution
three-dimensional images of trabecular bone architecture in a
volume of interest selected from a set of contiguous slices
acquired in peripheral sites (distal radius, tibia, and
calcaneus) (Figure 2). The images can then be analyzed in
a manner analogous to a bone biopsy. Wehrli et al.74 used
micro-MRI to evaluate 17 subjects with ESKD under the age
of 50 years. They found that although there was substantial
variability among the patients, cortical thickness and cross-
sectional area were significantly lower than controls matched
for age, gender, and body mass index. In addition, they were
able to detect changes suggestive of trabecular disruption,
including reduced trabecular number and an increased
erosion index, which reflects disconnectivity; however, the
differences did not quite achieve statistical significance. Thus,
although larger studies are necessary, micro-MRI may have
the potential to assess fracture risk non-invasively in patients
with ESKD and CKD.
Ultra-high-resolution peripheral QCT
Recently, a newer technique, ultra-high-resolution peripheral
QCT (HRpQCT), has been developed. Similar to conven-
tional peripheral QCT methodology, the three-dimensional
datasets provided by HRpQCT permit separate analysis of
cancellous and cortical bone75,76 and can measure specific
geometric parameters that correlate with bone strength, such
as endosteal and periosteal circumferences, cortical area, and
thickness.76,77 As the resolution of HRpQCT is o100 mm
Normal ESKD
Figure 2 | Example images from techniques to evaluate bone
structure. Tibia micro-MRI from a healthy control (left) and a
patient with ESKD (right). Increased trabecular disconnectivity of
the tibia from the patient with ESKD is noted by decreased
trabecular density and loss of horizontal trabecular elements.
Kidney International (2008) 74, 721–731
review
(versus 350 mm for standard peripheral QCT machines),
HRpQCT technology yields scans that visualize the fine
ultrastructural detail of trabecular microarchitecture, includ-
ing trabecular thickness, number, and separation. HRpQCT
is not only more sensitive than DXA for detecting small
amounts of bone loss but can also localize that bone loss to
the trabecular or cortical compartments. Thus, this technique
may provide an improved method to assess microarchitec-
tural features of bone that contribute to the increased fracture
risk observed in patients with ESKD and CKD. Figure 3
shows representative HR-pQCT images from a healthy
individual and both HR-pQCT and DXA images from a
patient with ESKD. Cortical thinning and porosity and
trabecular disconnectivity are notable on the HR-pQCT
images. In addition, the DXA measurement of aBMD of the
same patient demonstrates that DXA does not permit
appreciation of the severity of the patient’s microstructural
abnormalities.
PREVENTION OF FRACTURE IN PATIENTS WITH ESKD
AND CKD
As awareness has increased that patients with ESKD and CKD
are at such high risk of fracture, so has the concern about
how best to prevent these debilitating events. Unfortunately,
we are a long way from knowing how to accomplish this goal,
especially in patients with ESKD.
Bisphosphonates, which inhibit osteoclast-mediated bone
resorption, are the mainstay for fracture risk reduction in
men and women with normal kidney function.78 However,
one cannot assume that a fracture in patient with ESKD
or severe CKD has osteoporosis secondary to the same
pathophysiologic etiologies as postmenopausal, senile, or
glucocorticoid-induced osteoporosis. Fractures develop in
kidney disease patients with hyperparathyroidism, osteo-
malacia, and adynamic bone disease. Without a bone biopsy,
it can be very difficult to determine precisely what type of
bone disease a fracturing patient with ESKD has. Moreover,
there are no prospective studies that address the safety or
efficacy of bisphosphonates in patients with ESKD. As
bisphosphonates are cleared by renal mechanisms, there is
also concern that they may accumulate in the skeleton to an
even greater extent than they do in patients with normal
kidney function. In general, most experts do not recommend
treating patients with ESKD with bisphosphonates. Similarly,
the only current anabolic therapy for osteoporosis, PTH
1-34 or teriparatide, is also not approved for use in this
population. Cunningham et al.,79 in a pooled analysis of
safety data from four randomized clinical trials of calcimi-
metics in 1184 patients with ESKD and severe hyper-
parathyroidism, found that cinacalcet was associated with a
significant 54% reduction in the risk of fracture. Although
active metabolites of vitamin D have not been demonstrated
to reduce fracture incidence in patients with ESKD, they have
been shown to reduce serum PTH levels80–82 and improve
BMD in patients with CKD,38,82 and also to improve bone
strength in animal studies.83 Thus, there is the hope that by
727
review
5.0 mm
1.0 mm
UD
MID
1/3
Figure 3 | Example images from techniques to evaluate bone
structure. Representative HR-pQCT images from a healthy patient
(a); a patient with ESKD (b); and a DXA image from the same
patient with ESRD (c). HR-pQCT of the radius of the patient with
ESKD demonstrates cortical thinning and extreme trabecular
dropout. In comparison with DXA imaging of the same bone, HR-
pQCT provides superior resolution with visualization of both
trabecular and cortical bone compartments.
addressing some of the mechanisms thought to lead to
increased bone fragility (hyperparathyroidism, mineraliza-
tion defects), judicious use of these agents will prevent or
arrest declining bone strength and lead to reduced fracture
risk in dialysis patients.
728
TL Nickolas et al.: Chronic kidney disease and bone fracture
Slightly more information is available on the safety and
efficacy of bisphosphonates in patients with milder degrees
of kidney dysfunction. The major registration clinical trials
investigating the efficacy of bisphosphonates to prevent
osteoporotic fractures generally excluded potential subjects
with significant kidney dysfunction. However, because
potential subjects were screened on the basis of elevated
serum creatinine concentrations rather than on the basis of
creatinine clearance or GFR, sizable populations of patients
with moderate-to-severe kidney disease were actually enrolled
in these studies. Recently, two studies have been published in
which Phase III clinical trials of risedronate and alendronate
have been reanalyzed with a view toward evaluating their
effects in the subjects with Stage 3 and 4 CKD, as assessed by
estimating creatinine clearance with the Cockcroft–Gault
formula (Table 3). Both studies addressed the efficacy of these
bisphosphonates in increasing BMD and preventing fracture
and their potential for nephrotoxicity in the subset of
patients with CKD.26,84 Miller et al.84 performed a retro-
spective analysis of the risedronate Phase III clinical trial
database that included pooled data from nine clinical trials of
postmenopausal women to evaluate the influence of baseline
kidney function on the safety and efficacy of risedronate
(5 mg/day). Approximately half of the subjects had moderate
(45%) or severe (7%) renal dysfunction, and were equally
distributed between the placebo and treatment groups. Mean
follow-up was 2 years and maximum duration of risedronate
treatment was 3 years. There were no differences between
groups in the rate of reported adverse renal events. Lumbar
spine and trochanteric BMD increased significantly in all
groups of kidney impairment. Femoral neck BMD increased
in the group with moderate kidney dysfunction but not in
the severe group. Importantly, fracture incidence was reduced
for all groups of kidney impairment. Pre- and post-treatment
bone biopsy samples were available for subjects with mild
(n ¼ 43) and moderate (n ¼ 14) CKD. Both mineralization
surface and activation frequency were decreased in treated
subjects. Jamal et al.26 recently published a retrospective
analysis of the Fracture Intervention Trial (FIT) evaluating
the use of alendronate in osteoporotic women with impaired
kidney function as estimated by the Cockcroft–Gault
formula. In this study population, 10% had severe CKD
(GFR o45 ml/min) and 37% had moderate CKD (eGFR
45–59 ml/min). They found no difference in outcomes among
subjects with an eGFR of 45–59 ml/min and those with
normal kidney function, defined as an eGFR X60 ml/min.
Thus, these groups were pooled and compared with the
women with severe CKD. Women with severe CKD were at
an increased risk of prevalent vertebral fractures and history
of non-spine fractures after the age of 45 years, compared
with women without CKD. Alendronate was associated with
an increase in BMD at the total hip, femoral neck, and spine
for subjects with and without severe CKD. Women with
reduced eGFR were at increased risk of sustaining incident
spine and non-spine fractures during the study. However,
compared with placebo-treated women, alendronate reduced
Kidney International (2008) 74, 721–731
TL Nickolas et al.: Chronic kidney disease and bone fracture
Table 3 | Studies of bisphosphonates in patients with CKD
Range of
kidney function Mean
(calculate by duration of Bone
Cockcroft–Gault follow-up histomor- normal kidney
Study Bisphosphonate formula) (years) phometry function group
Jamal et al. Alendronate 420 ml/min 3 No
(2007)26
Miller et al. Risedronate 413 ml/min 2 Yes
(2005)84
BMD, bone mineral density; CKD, chronic kidney disease.
the risk of non-vertebral and vertebral fractures to a similar
degree in subjects with and without kidney impairment.
Bone biopsies were not performed in FIT. There was a small
but significant increase in serum creatinine over the course of
the 3-year study, which did not differ between the groups
with severe CKD and those with eGFR X45 ml/min.
Similarly, the rate of other adverse events did not differ
according to the degree of renal impairment.
The results of these recent retrospective analyses of the
major oral bisphosphonate registration trials suggest that
2–3 years of therapy is efficacious in preventing fractures in
patients with moderate-to-severe CKD and provide some
reassurance that oral bisphosphonate use does not appear to
accelerate age-related declines in kidney function. However,
we do not advocate indiscriminate use of oral bisphos-
phonates in patients with severe CKD to prevent fractures. In
such patients, it is unclear whether a low BMD measurement
on a DXA scan or even fragility fractures are manifestations
of osteoporosis or one of the forms of ROD that should be
managed with phosphorous restriction and supplementation
with parent vitamin D and active vitamin D metabolites.
A careful clinical and biochemical evaluation that includes
measurement of serum calcium, phosphate, total, and
bone alkaline phosphatase, PTH, 25-hydroxyvitamin D, and
1,25-dihydroxyvitamin D is essential before committing such
patients to oral bisphosphonate therapy and a bone biopsy
should be strongly considered. Any decision to embark upon
oral bisphosphonate therapy in such patients should be
individualized and carefully considered. Although we can
expect increasing use of intravenous bisphosphonates, such
as zoledronic acid and ibandronate, for the management of
postmenopausal osteoporosis, the renal safety of intravenous
bisphosphonates is not well defined in patients with eGFR
o30 ml/min or in patients with diabetes or hypertension
who are at high risk for CKD.
FUTURE PERSPECTIVES
Fracture is an important complication of CKD that is
associated with excess morbidity and mortality. Given the
rapid growth of an elderly population at risk for both
Kidney International (2008) 74, 721–731
review
Comparison of
adverse event
rates in kidney
dysfunction to the
Clinical benefit
Equivalent Alendronate was equivalently effective at
increasing femoral neck and spine BMD in
patients with and without kidney dysfunction.
Spine and non-spine fractures were also reduced
to a similar degree
Equivalent Risedronate increased BMD at all sites (spine and
hip) and decreased fracture incidence for all
kidney failure groups (mild, moderate, and severe)
osteoporosis and CKD, and the many potential mechanisms
by which CKD could decrease bone strength and increase
fracture risk, it is imperative that we develop effective
diagnostic strategies to identify patients with CKD who
are also at risk for fracture. More studies incorporating
transiliac crest bone biopsy are urgently needed. Similarly,
studies are needed that assess the utility of novel imaging
technologies, such as micro-MRI and HR-pQCT, to provide
a more accurate assessments of bone strength and risk of
fracture.
It is also essential that we develop effective therapeutic
strategies that decrease fracture risk in patients with
CKD. Prospective treatment studies that specifically target
this population are urgently required. Such studies must
address fracture risk reduction, the potential for adverse
effects of bisphosphonates, and other agents on renal
function and should incorporate micro-MRI and HR-pQCT,
which may prove to be useful outcome measures for clinical
trials of interventions to reduce fractures. Also crucial are
prospective studies of the effects of bisphosphonates on bone
histomorphometry in patients with CKD, which specifically
address the concern that long-term use of these agents may
oversuppress bone remodeling and precipitate adynamic
bone disease. Similarly, more data are needed on the effects of
calcimimetics and active metabolites of vitamin D on fracture
risk reduction in patients with CKD. There remains a great
deal of work to do to deal with the burgeoning incidence of
fracture in older individuals with CKD.
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