review
org
Differentiating the causes of adynamic bone in
advanced chronic kidney disease informs see commentary on page 502
osteoporosis treatment OPEN
Mathias Haarhaus1,2 and Pieter Evenepoel3; on behalf of the European Renal Osteodystrophy (EUROD)
workgroup, an initiative of the Chronic Kidney Disease Mineral and Bone Disorder (CKD-MBD) working
group of the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA)
1
Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University
Hospital, Stockholm, Sweden; 2Diaverum Sweden AB, Malmö, Sweden; and 3Division of Nephrology, University Hospitals Leuven, Leuven,
Belgium
Patients with chronic kidney disease (CKD) have an
increased fracture risk because of impaired bone quality
and quantity. Low bone mineral density predicts fracture
risk in all CKD stages, including advanced CKD (CKD G4-5D).
Pharmacological therapy improves bone mineral density
and reduces fracture risk in moderate CKD. Its efficacy in
advanced CKD remains to be determined, although pilot
studies suggest a positive effect on bone mineral density.
Currently, antiresorptive agents are the most commonly
prescribed drugs for the prevention and therapy of
osteoporosis. Their use in advanced CKD has been limited
by the lack of large clinical trials and fear of causing kidney
dysfunction and adynamic bone disease. In recent decades,
adynamic bone disease has evolved as the most
predominant form of renal osteodystrophy, commonly
associated with poor outcomes, including premature
mortality and progression of vascular calcification. Evolving
evidence indicates that reduction of bone turnover by
parathyroidectomy or pharmacological therapies, such as
calcimimetics and antiresorptive agents, are not associated
with premature mortality or accelerated vascular
calcification in CKD. In contrast, chronic inflammation,
oxidative stress, malnutrition, and diabetes can induce low
bone turnover and associate with poor prognosis. Thus, the
conditions causing suppression of bone turnover rather
than the low bone turnover per se may account for the
perceived association with outcomes. Anabolic treatment,
in contrast, has been suggested to improve turnover and
bone mass in patients with advanced CKD and low bone
turnover; however, uncertainty about safety even exceeds
that of antiresorptive agents. Here, we critically review the
pathophysiological concept of adynamic bone disease and
discuss the effect of low bone turnover on the safety and
Correspondence: Mathias Haarhaus, Division of Renal Medicine, Depart-
ment of Clinical Science, Intervention and Technology, Karolinska Institutet,
Karolinska University Hospital, 141 86 Stockholm, Sweden. E-mail:
mathias.loberg-haarhaus@sll.se; or Pieter Evenepoel, Division of Nephrology,
University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail:
Pieter.Evenepoel@uzleuven.be
Received 27 June 2020; revised 15 April 2021; accepted 20 April 2021;
published online 5 June 2021
546
www.kidney-international.
efficacy of anti-osteoporosis pharmacotherapy in advanced
CKD.
Kidney International (2021) 100, 546–558; https://doi.org/10.1016/
j.kint.2021.04.043
KEYWORDS: adynamic bone disease; antiresorptive treatment; chronic kid-
ney disease; low bone turnover; osteoporosis
Copyright ª 2021, International Society of Nephrology. Published by
Elsevier Inc. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
O
steoporosis is a condition characterized by low bone
mass and/or qualitative bone deterioration that leads
to bone fragility and fracture susceptibility.1 Areal
bone mineral density (aBMD) is assessed in clinical practice
by dual-energy X-ray absorptiometry (DXA) as a proxy of
bone mass. Cross-sectional studies in the general population
and in patients with chronic kidney disease (CKD) not yet on
dialysis demonstrate an association of lower aBMD with more
severe CKD.2–6 Furthermore, aBMD was demonstrated to
predict fracture incidence in patients with advanced CKD,
including patients on dialysis, prompting the international
Kidney Disease: Improving Global Outcomes initiative to
suggest aBMD testing in all stages of CKD if results affect
treatment decisions.7 The consistency of the risk predicition
across stages of kidney disease, sexes, and degree of para-
thyroidism (PTH) control remains to be documented.8
The operational definition of osteoporosis is based on an
aBMD of #
2.5 SDs from the mean sex-matched aBMD in
young adults (T-score) assessed by DXA at the spine or hip.
Osteoporosis is subdivided by pathomechanism into primary
(postmenopausal and/or senile osteoporosis) and secondary
osteoporosis because of clinical disorders that affect bone
mass, for example, diabetes mellitus,9 rheumatic arthritis,10
or specific genetic diseases.11 A low bone mineral density
(BMD) is a common finding in patients with CKD.5,6,12
Historically, patients with advanced CKD, presenting with
T-score #
2.5 at the spine or hip were excluded from the
diagnostic label “osteoporosis,” mainly because renal osteo-
dystrophy (ROD) was thought to substantially modify the
relationship of BMD with fracture risk. Based on emerging
evidence for a prospective fracture risk prediction by DXA
Kidney International (2021) 100, 546–558
M Haarhaus and P Evenepoel: Differentiating causes of adynamic bone in CKD
and a positive effect of antiresorptive and anabolic osteopo-
rosis treatment on BMD in advanced CKD, an increasing
number of bone and kidney experts now stand for an in-
clusive definition.8
Fracture risk is excessively high in patients with CKD.13–15
For example, patients on hemodialysis show a fracture risk of
the hip that is 4-fold higher than the risk observed in age- and
sex-matched non-CKD counterparts.16 After kidney trans-
plantation, the risk further increases, at least transiently.17
Compared with patients without fractures, those with CKD
and fractures furthermore have a multifold increased risk of
mortality.18 Fragility fractures inflate the already impressive
economic and societal burden of advanced CKD.
During the last 2 decades, knowledge of the pathophysi-
ology of bone fragility in the setting of CKD has increased,
and the ability to predict patients with CKD at risk has
improved through the validation of fracture prediction tools
and an increasing understanding of imaging modalities.
Alongside, the armamentarium to tackle osteoporosis has
been continuously expanding. Against this background, the
existence of a huge treatment gap between those at risk of
fracture and those receiving treatment for the prevention of
fragility fractures is remarkable. The reluctance toward
pharmacological fracture prevention in general, and, more
specifically, toward the use of antiresorptive agents, in patients
with advanced CKD is largely driven by the lack of adequately
powered randomized controlled trials in this population and
the fear to induce or worsen adynamic bone. Adynamic bone,
overall, is perceived as being problematic and referred to as a
disease.
In the present review, we aimed to scrutinize the concept
of adynamic bone disease (ABD) and to discuss the effect of
low bone turnover on the management of osteoporosis in
advanced CKD.
Methods
This narrative review is endorsed by the board of the Euro-
pean Renal Osteodystrophy network, an initiative within the
Chronic Kidney Disease–Mineral and Bone Disorder Working
Group of the European Renal Association–European Dialysis
and Transplantation Association. European Renal Osteodys-
trophy network membership is based on experience with the
diagnosis and treatment of ROD, including bone biopsies.
The following questions were framed: (i) Is there consistency
in the use and definition of the term “adynamic bone disease”
or “aplastic bone disease” in CKD? (ii) Is there a link between
low bone turnover and clinical outcome, and if so, how is it
modified? (iii) Is the induction of low bone turnover by
osteoporosis medication associated with increased risks for
patients with advanced CKD? Both authors performed a
broad search of the literature, including the following search
terms—chronic kidney disease, dialysis, adynamic bone disease,
low bone turnover, fracture risk, cardiovascular disease, mor-
tality, vascular calcification, osteoporosis, antiresorptive treat-
ment, and anabolic treatment—among others in the literature
databases PubMed and EMBASE. The following search
Kidney International (2021) 100, 546–558
review
strategies were applied to identify studies on antiresorptive
agents in advanced CKD: (alendronate OR pamidronate OR
ibandronate OR zoledronic OR clodronate OR risedronate
OR zoledronate) AND ("renal failure" OR "kidney failure" OR
"renal disease" OR "kidney disease" OR dialysis) AND oste-
oporosis and denosumab AND ("renal failure" OR "kidney
failure" OR "renal disease" OR "kidney disease" OR dialysis)
AND osteoporosis. Reviews, case reports, nonhuman studies,
and non-English language articles were excluded.
Definition and epidemiology of ABD
The concept of ABD describes the histological picture of bone
with absent or reduced turnover in the presence of normal
mineralization (Figure 1). The diagnosis is based on the
histomorphometric analysis of a double-labeled bone biopsy,
usually taken from the anterior part of the iliac crest,
following the internationally established standards recom-
mended by the Histomorphometry Nomenclature Commit-
tee of the American Society of Bone and Mineral
Research.19,20 However, diagnostic criteria have been incon-
sistent with respect to parameters included and cutoff levels,
explaining at least partly the highly variable prevalence rate
reported in literature. Although originally described as min-
eral apposition rate (a parameter of bone formation) below
the lowest level observed in healthy individuals,21 Monier-
Faugere and Malluche defined ABD as dramatically reduced
bone turnover with a paucity of osteoid, bone cells, and
marked decrease in active remodeling sites and tetracycline
uptake, thereby including both formation and resorption
parameters and introducing the all-in evaluation of the biopsy
by the pathologist as a diagnostic criterion in addition to
quantifiable parameters recommended by the American So-
ciety of Bone and Mineral Research.22 Later studies used more
reproducible definitions of ABD, often based on a single
quantifiable parameter, exclusively describing some aspect of
bone formation (e.g., proportion of double-labeled bone
surface over total surface or bone formation rate). However,
the demarcation of ABD against other types of ROD became
more arbitrary, ranging from all individuals below the median
of the histomorphometric parameter of interest23 to patients
with values >1SD below the mean24 or even >1SD below the
normal range (i.e., by definition, 3SD below the mean of a
normal reference population).25 This large variation in the
definition of ABD may hamper unequivocal statements on
epidemiology and its association with outcomes.
In spite of the shortcomings in the definition of ABD, the
term has grown increasingly popular. ABD furthermore has
evolved as the most abundant form of ROD to date, according
to recent large retrospective bone biopsy studies, with a
prevalence of up to 60% in white patients on hemodialy-
sis.26,27 However, the actual prevalence of severely reduced
bone turnover in CKD is difficult to determine, as the bone
biopsy procedure is not readily available in large unselected
populations. Thus, the current perception of the prevalence of
ABD relies on the analysis of bone biopsy registries, which are
confounded by indication, or the analysis of biomarkers of
547
review
Figure 1 | Histomorphometry slides showing (a) normal and (b) low bone turnover. Compared to normal bone, conventional light
microscopy of Goldner-stained sections shows the almost complete absence of osteoblasts, osteoclasts, and osteoid deposition as well as the
absence of tetracycline labels as visualized by fluorescence microscopy. Courtesy Patrick D’Haese and Geert Behets.
bone turnover in large unselected populations, which, in
contrast, lack specificity and sensitivity to correctly diagnose
different forms of ROD.
Pathogenesis of low bone turnover in CKD
Patients with CKD and low bone turnover are characterized
by higher age and a high incidence of comorbidity, malnu-
trition, inflammation, and hypoalbuminemia.28 Several con-
ditions, including deficient PTH signaling, exposure to
aluminum, and diabetes mellitus may be involved in the
pathogenesis of low bone turnover in CKD (Figure 2).29–32
Inappropriately low PTH signaling. Secondary hyperpara-
thyroidism is an almost universal complication of advanced
CKD. Over the years, the armamentarium to control sec-
ondary hyperparathyroidism has expanded to include potent
drugs such as active vitamin D (analogues) and calcimimetics.
Also, exogenous calcium loading, either via calcium-
containing phosphate binders or via the dialysate, sup-
presses PTH. The striking increase in low bone turnover in
patients with advanced CKD in recent decades appears to
suggest an overtreatment of secondary hyperparathyroid-
ism.31,33 Importantly, bone responses to the action of PTH are
progressively blunted in CKD. This condition is referred to as
PTH “hyporesponsiveness” or resistance. Multiple factors are
involved including phosphate loading, calcitriol deficiency,
oxidative stress, magnesium deficiency, accumulation of PTH
fragments and uremic toxins, inducing deficiencies in trophic
factors, excesses of inhibitors, or postreceptor defects.12 PTH
hyporesponsiveness is as much an integral component of
chronic kidney disease–mineral and bone disorder as elevated
548
M Haarhaus and P Evenepoel: Differentiating causes of adynamic bone in CKD
circulating PTH levels and may partially explain the poor
performance of PTH as a biomarker for bone turnover.
Defining the optimal PTH level, especially at the individual
level, remains a challenge. A functional and readily available
assay quantifying PTH1 receptor activation would be a great
step forward. Parallel to the development of such an assay, the
performance of more specific bone turnover biomarkers (or a
panel of biomarkers) should be tested, if possible, against
bone histomorphometry, which is still considered the crite-
rion standard.34
Repressed WNT/b-catenin signaling. The expression of the
WNT inhibitor sclerostin in osteocytes increases early during
the course of CKD.35 Experimentally, repression of WNT/b-
catenin signaling by sclerostin inhibits bone formation
whereas it stimulates bone resorption.36 In an animal model,
sclerostin expression is induced by transforming growth fac-
tor b and activin A, members of the transforming growth
factor superfamily, and inhibited by PTH.37 Also, activin A
increases early in experimental CKD and activin A inhibition
stimulates bone formation and reduces bone resorption in
this setting.38 Moreover, fibroblast growth factor 23 increases
early in CKD and exerts inhibitory action on the WNT/b-
catenin pathway by activation of Dickkopf1 through the
interaction with soluble Klotho.39,40
Malnutrition/inflammation. Malnutrition is closely linked
to chronic inflammation, and the malnutrition/inflammation
syndrome has been associated with low bone turnover41 and
increased fracture risk.42 Low nutritional markers are a hall-
mark of low PTH states43,44 and are associated with the
development of low bone turnover.45 Experimentally,
Kidney International (2021) 100, 546–558
M Haarhaus and P Evenepoel: Differentiating causes of adynamic bone in CKD
Disease-related
Malnutrition Diabetes CKD
Oxidative stress
Hyperphosphatemia
Inflammation Calcitriol deficiency
AGEs Mg deficiency
Uremic toxins
PTH hyporesponsiveness
Negative bone
mineral balance
Figure 2 | Causes of low bone turnover: diseases and therapies may affect bone metabolism both indirectly by modifying
parathyroidism (PTH) signaling and directly. Diseases go along with PTH hyporesponsiveness and a negative bone mineral balance
(resorption > formation). Therapies, overall, can mediate a positive bone mineral balance, either directly or through PTH suppression. AGE,
advanced glycation end-products; CKD, chronic kidney disease.
inflammatory cytokines such as interleukin-1, interleukin-
6, and tumor necrosis factor-a stimulate bone resorption
and inhibit bone formation.46 Osteoblasts from patients on
dialysis with low bone turnover demonstrate a slower
growth in vitro and an increased interleukin-6 produc-
tion.47 In contrast, inflammatory cytokines suppress PTH
and may thereby indirectly contribute to a reduction of
bone turnover.48,49 Blocking of inflammatory cytokines has
a positive effect on BMD in clinical studies,50 which may be
mediated by inhibition of bone resorption and stimulation
of bone formation.51 An inhibitory effect on pro-
inflammatory cytokines has also been described for
bisphosphonates and may contribute to their positive effect
on bone mass.52
Diabetes mellitus. The skeleton is a target organ for in-
sulin. Insulin signaling in osteoblasts increases bone turnover
via upregulation of runt-related transcription factor 2 and
downregulation of osteoprotegerin, whereas systemic insulin
sensitivity is modulated through the release of under-
carboxylated osteocalcin. In several observational studies of
ROD, patients with diabetes mellitus are overrepresented in
the low turnover groups.9,24,53 The histomorphometric pic-
ture of diabetic osteodystrophy is characterized by low bone
turnover, low osteoblast and osteoclast activity, and reduced
bone volume.54 Hyperglycemia, insulin deficiency, insulin-
like growth factor I resistance, accumulation of advanced
glycation end products, inflammation, and oxidative stress are
among possible causes.55 However, a dissociation of bone
turnover with a stronger suppression of bone formation than
resorption has been suggested to contribute to bone loss in
both type 156 and type 257 diabetes mellitus.
Uremic toxins. Renally excreted compounds that accu-
mulate in CKD and exert toxic effects are commonly sum-
marized under the term uremic toxins. Among these, the
gut-derived toxin indoxyl sulfate has been extensively studied
Kidney International (2021) 100, 546–558
review
Therapy-related
• Ca loading
• Parathyroidectomy
• Vitamin D agonists
• Calcimimetics
Antiresorptive
PTH suppression
agents
PTH signaling
Positive bone
Low bone turnover mineral balance
and is associated with low bone turnover. Indoxyl sulfate
suppresses bone formation via PTH receptor down-
regulation58 and suppression of WNT signaling in osteo-
blasts.59 Reduction of uremic toxins via oral administration
of an intestinal adsorbent increased bone turnover in uremic
rats.60
Low bone turnover and osteoporosis in CKD
After a period of bone acquisition during adolescence, the
tightly coupled process of bone turnover reaches a balance
between bone resorption and formation during adulthood in
healthy individuals. Low mineralized bone mass can result
from impaired peak bone acquisition, impaired bone matu-
ration in high bone turnover states, an uncoupling of bone
turnover, where bone resorption exceeds bone formation, as
in postmenopausal primary osteoporosis, or combinations
thereof.61,62 A dissociation of bone turnover with a relative
predominance of resorption may also contribute to low BMD
in patients with CKD and low bone turnover, with chronic
inflammation and repressed WNT/b-catenin signaling rep-
resenting possible pathomechanisms.63 However, more
balanced states of low bone turnover may be associated with
better preservation of bone mass. Biomimicry studies have
suggested a balanced form of adynamic bone as the mecha-
nism of bone preservation in hibernating bears, in spite of
several months of immobilization and the transient devel-
opment of kidney failure.64–66
The clinical relevance of mechanisms leading to a low bone
mass in low bone turnover ROD is supported by 2 studies that
demonstrated a better fracture risk prediction by DXA in
patients with moderate to advanced CKD and biochemical
indication of a bone turnover in the lower range.67,68 Both
these cohorts were part of the basis for the Kidney Disease:
Improving Global Outcomes recommendation to use DXA
for fracture risk prediction in advanced CKD.7
549
review M Haarhaus and P Evenepoel: Differentiating causes of adynamic bone in CKD
Low bone turnover and outcomes in CKD
A low turnover state reduces the ability of bone to buffer
calcium fluxes from exogenous sources.69 Experimentally,
increased calcium concentrations induce vascular calcification
in vessels from patients on dialysis, but not healthy controls.70
Several studies in patients with CKD demonstrate associations
between reduced bone turnover23,71,72 or low PTH,73 inter-
preted as a surrogate marker of low bone turnover, and
arterial calcification, with significant interactions with path-
ogenetic factors, such as calcium load, inflammation, or
malnutrition. However, it is still a matter of discussion at
what doses and in which clinical context calcium supple-
mentation associates with negative outcomes in CKD.
Although a meta-analysis in 2013 demonstrated increased
mortality associated with the use of calcium-containing
phosphate binders,74 a recent large observational study
found no such association.75 Some data indicate that different
low bone turnover states may affect the association of calcium
supplementation with outcome differently. In a French
observational study, only patients with decreasing PTH and
high dialysate calcium demonstrated higher mortality,
whereas no such association was found in patients with
persistently low PTH. Remarkably, oral calcium supplemen-
tation was not associated with mortality in any subgroup.76 A
5-year observational study in patients on hemodialysis
demonstrated improved survival for patients with therapeu-
tically induced low PTH compared with patients with spon-
taneous PTH reduction or patients with unchanged PTH in
spite of an increased calcium dose via dialysate calcium in the
former group.77 To our knowledge, the only report to date of
accelerated vascular calcification after antiresorptive treat-
ment in CKD is in a patient with multiple myeloma who
received 120 mg of denosumab twice together with up to 4 g
of calcium phosphate and 1 mm of active vitamin D daily.78 In
contrast, a recent study of 1 year of antiresorptive treatment
with concurrent substitution of 1.5 g of calcium lactate and
0.25 mm of active vitamin D, tapered to control calcium levels
within normal limits, did not find any progression of vascular
disease.79
Suppressed bone turnover has been associated with
improved BMD in advanced CKD.80–83 Importantly, slow
remodeling allows more secondary mineralization so that the
bone becomes harder and probably stronger.84 However, in
the long term, hyper- or “overmineralization” may impair
toughening mechanisms, shift the bone to a condition often
referred to as “brittle bone,” and increase the risk of (atypical)
fractures.85–87 In addition, remodeling suppression may cause
the accumulation of microcracks.88 Taken together, the final
effect of a deep and/or long-term suppression of bone turn-
over on bone strength and fracture rates remains
undetermined.
In patients with CKD, some studies have demonstrated
associations of low PTH with an increased fracture risk.89,90
However, similar to studies investigating the link between
low PTH and vascular outcomes, no adjustments were made
for the presence of inflammation and malnutrition. This is an
550
important limitation because inflammation and malnutrition
are associated both with low PTH levels41,43,44 and with low
bone turnover.45 Prospective data on fracture risk in hypo-
parathyroidism do not exist. Case-control studies, however,
show no differences in overall fracture rate as compared with
the general population.91 In a study comprising 5918 patients
with end-stage renal disease without previous fractures, a first
parathyroidectomy was associated with >30% reduced frac-
ture incidence during long-term follow-up as compared with
matched controls. Fracture risk was lowest after total para-
thyroidectomy, suggesting a positive effect of a more pro-
nounced suppression of bone turnover on fracture
incidence.92 Others have found an increased fracture risk only
in patients with severely increased PTH,16 and in large bone
biopsy series, no difference in fracture prevalence was
observed between patients with adynamic bone and those
with other forms of ROD.22,93 Remarkably, although PTH
shows a U-shaped relationship with bone and vascular out-
comes,12 circulating alkaline phosphatase, as well as its bone
isoforms, which determines variations in total serum alkaline
phosphatase in the absence of liver disease,94 shows a linear
and direct relationship to these outcomes in CKD.95–97
Although this observation may add credit to the hypothesis
that residual confounding accounts for the association be-
tween low PTH and bone fragility or cardiovascular out-
comes, a word of caution is warranted. Circulating alkaline
phosphatase or bone alkaline phosphatase activities may
reflect not only bone turnover but also calcification burden
and propensity.94 Conflicting observations of a direct asso-
ciation of tartrate-resistant acid phosphatase 5b, another
nonrenally cleared bone turnover marker, with arterial stiff-
ness,98 but an inverse association with cardiovascular events99
in predialysis CKD, further fuels the controversy. It thus re-
mains a matter of debate whether severely reduced bone
turnover per se or the pathogenic mechanism inducing it to
occur underlies the association with poor outcomes. Data
from observational studies after parathyroidectomy and
interventional trials with antiresorptive agents may help to
resolve this conundrum. In patients with CKD, para-
thyroidectomy associates with improved survival100 and
vascular outcomes,101,102 despite PTH levels being below
target in many, implying a high prevalence of low bone
turnover. The regression of vascular calcification after para-
thyroidectomy is remarkable, as patients are often loaded with
calcium for weeks to cope with the hungry bone syndrome.103
Suppression of bone turnover is inherent to antiresorptive
agents, and most patients with osteoporosis who are treated
with antiresorptive agents also have a low bone formation
rate. In postmenopausal women treated with either
bisphosphonates or denosumab, while lowering fracture risk,
accelerated vascular calcification has not been reported.104,105
Moreover, vascular calcification progression did not differ
between treatment groups when analyzed by baseline esti-
mated glomerular filtration rate or by baseline vascular
calcification scores.104 It is reassuring that studies in patients
with (advanced) CKD did not detect any vascular safety
Kidney International (2021) 100, 546–558
M Haarhaus and P Evenepoel: Differentiating causes of adynamic bone in CKD
signals.79,106–108 Some caution is warranted because these
studies were characterized by either small sample size or short
follow-up. It is unlikely that the absence of detrimental effects
on calcification in bisphosphonate-treated individuals are
explained by the fact that bisphosphonates are analogues of
pyrophosphate, which is a potent vascular calcification in-
hibitor, as conventional doses of bisphosphonates fail to yield
circulating concentrations that are sufficient to exert direct
anticalcifying effects. With regard to bone health, there are
some concerns that long-term treatment or high doses with
certain bisphosphonates make the bone more brittle and less
tough, which may translate into reduced energy to fracture
and potentially a shorter bone fatigue life.109 Although no
reports from long-term studies in CKD exist, it is reassuring
that denosumab for up to 3, 5, and 10 years in post-
menopausal women was associated with normal histology,
low bone remodeling rate, increased matrix mineralization,
and lower mineralization heterogeneity compared with pla-
cebo while the benefit on fracture risk was maintained.110,111
Low bone turnover in CKD: is it always a disease?
Taken together, evolving evidence suggests that low bone
turnover is not always associated with an increased risk of
unfavorable outcomes in CKD. Thus, coexistence of addi-
tional modulating factors may explain the findings of an as-
sociation of low bone turnover with an increased risk of
cardiovascular complications rather than the low turnover per
se. Pathophysiologically, low bone turnover, associated with
processes linked to negative cardiovascular or skeletal out-
comes in CKD, such as diabetes mellitus, chronic inflam-
mation, or repressed WNT/b-catenin signaling, may be
paralleled by a dissociation of turnover with a relatively
stronger suppression of osteoblast function and bone for-
mation than that of osteoclast function and bone resorp-
tion.35,46,56,57 Whether such an imbalance in bone turnover
plays a causative role in the association of low bone turnover
with negative outcomes has yet to be determined. In contrast,
treatment with calcimimetics,112 long-term follow-up after
parathyroidectomy,113 adequate treatment with active vitamin
D,114 or antiresorptive agents115 may induce a more balanced
reduction of bone turnover, while clinical evidence to date
indicates an absence of negative cardiovascular effects in pa-
tients without CKD116,117 and in patients with advanced
CKD.79,100,108
Low bone turnover and efficacy of anti-osteoporosis
treatment
The validity of studies investigating the efficacy of denosu-
mab79,118–126 and bisphosphonates79,106,127–130 in patients
with advanced CKD, including those on dialysis, or in pa-
tients with earlier CKD stages presenting with biochemical
disturbances of mineral metabolism is limited by small
sample sizes. Although denosumab consistently improved
BMD, results regarding the effect of bisphosphonates on
Kidney International (2021) 100, 546–558
review
biochemical or BMD end points were less consistent
(Table 1).28,79,108,118–123,125–127,129–132
Importantly, none of the individual studies were powered
to inform on fracture risks. Advantages and disadvantages of
denosumab versus bisphosphonates in advanced CKD are
listed in Table 2. The present review focuses on the aspects of
osteoporosis in the presence of low bone turnover. For a more
thorough discussion of osteoporosis prevention and treat-
ment in advanced CKD, we refer to a recent consensus
statement by the European Renal Association–European
Dialysis and Transplantation Association and the Interna-
tional Osteoporosis Foundation.8
It may be hypothesized that the efficacy of antiresorptive
therapy is reduced in patients with already suppressed bone
turnover before treatment initiation. The observation of a
good bone response to antiresorptive treatment in diabetic
patients, despite the common finding of low bone turnover of
diabetic osteodystrophy133 and the continued effect of deno-
sumab on fracture risk and BMD for up to 10 years in
postmenopausal women, in spite of a sustained suppression
of bone turnover markers,110 refute this hypothesis. In
addition, denosumab had a greater effect on BMD gain if
initiated after bisphosphonate treatment than after selective
estrogen receptor modulators, in spite of a lower bone
turnover at treatment initiation in the former group.134 To
our knowledge, the effect of baseline bone turnover on the
efficacy of denosumab in advanced CKD has yet to be
determined. However, a recent study, demonstrating a posi-
tive effect of denosumab on BMD in advanced CKD, used an
upper limit for PTH of 240 pg/ml, thereby increasing the
probability of selecting patients with bone turnover in the
lower spectrum.79
As an alternative approach to antiresorptive agents,
anabolic agents have been suggested for osteoporosis
treatment in patients with CKD and low bone turnover.
Anabolic agents gain increasing interest as they provide a
faster and greater fracture risk reduction in post-
menopausal osteoporosis than do antiresorptive agents.135
Several small pilot studies of these PTH analogues in pa-
tients with advanced CKD and low bone turnover have
demonstrated positive effects on bone mass and turn-
over.128,136,137 However, there are uncertainties with
respect to dosing, and risks associated with long-term
treatment or discontinuation are still unclear. The sclero-
stin antagonist romosozumab also exerts an anabolic effect
on osteoblasts while inhibiting bone resorption.138
Although very promising from a bone perspective, con-
cerns with cardiovascular side effects139 warrant caution in
patients at high risk for cardiovascular disease, including
patients with advanced CKD.
Evidently, at all times, therapy should be personalized,
accounting for the individual medical and therapeutic history.
When considering off-label use of osteoporosis drugs, pa-
tients should be properly informed about potential risks,
551
 552
Table 1 | Studies on antiresorptive agents in advanced CKD
Study
Kunizawa et al.,122
prospective, observational,
safety and efficacy study
Chen et al.,108 non-
randomized safety and
efficacy study
Iseri et al.,79 randomized,
prospective, safety and
efficacy study
Takami et al.,123 retrospective
case-control study, efficacy
study
Cheng and Chen,119
retrospective efficacy study
Huynh et al.,28 retrospective
safety study
Festuccia et al.,120
retrospective efficacy study
Hiramatsu et al.,121
Kidney International (2021) 100, 546–558
prospective, single-arm,
open-label, efficacy study
Chen et al.,125 prospective,
single-arm, open-label,
efficacy study
Chen et al.,118 prospective,
single-arm, open-label,
efficacy study
Population Specific inclusion criteria
HD: 102 Any denosumab-treated
CKD 1–2: 144 patient with CKD and
CKD 3a: 44 osteoporosis
CKD 3b: 35
CKD 4–5: 20
Dialysis: 42 (21 Dmab, 21 PTH >800 pg/ml, low BMD,
control) ongoing treatment with Ca
and calcitriol
HD: 46 (22 denosumab, 24 Osteoporosis, age >20 yr,
alendronate) hemodialysis for >6 mo,
iPTH $60 and #240 pg/ml
HD: 37 male patients (Dmab Male patients with low BMD
17, control 20) (<70% of the young adult
mean)
CKD 1–5: 109 Any denosumab-treated
patient with CKD 1–5
CKD 1–3: 136 Any denosumab-treated
CKD 4–5: 19 patient at a single center
HD: 12 Any denosumab-treated
patient at a single center?
HD: 13 BMD <
2.5 SDs, well-
controlled mineral metabolism
HD/PD: 24 iPTH >800 pg/ml, DXA:
forearm or FN or LS <
2.5
SDs
HD/PD: 12 Dialysis treatment for >3 yr,
iPTH >1000 pg/ml Ca and
vitamin D supplement
according to KDOQI, DXA: FN
or LS T-score <
1 SD, stable
laboratory results for 6 mo
Specific exclusion criteria
Peritoneal dialysis, kidney
transplantation, history of
parathyroidectomy, hypo- or
hypercalcemia (Ca <8.5 or
>15 mg/dl)
Parathyroidectomy with
parathyromatosis, aluminum
levels >20 mg/l
Bisphosphonate or
denosumab in the preceding
6 mo, corr Ca <8.4 mg/dl,
poor oral condition
Conditions that influence
bone metabolism, treated
with bisphosphonates,
parathyroid hormone,
steroids, or selective estrogen
receptor modulators,
parathyroidectomy
No specific exclusion criteria
No specific exclusion criteria
No specific exclusion criteria
History of Ptx, anti-
osteoporotic drugs
Total Ptx, s-Al >50 g/l
No bone-specific exclusion
criteria
Intervention
Denosumab 60 mg s.c. every 6
mo, follow-up unclear
Single-dose denosumab 60
mg s.c. þ CaCO3 3 g/d þ
calcitriol 1 mg/d þ dialysate Ca
1.75 mmol/l for 2 wk, dialysate
Ca and CaCO3 tapered after 1
wk
Denosumab 60 mg s.c. every 6
mo or alendronate 900 mg i.v.
every 4 wk for 1 yr. All
received calcitriol 0.25 mg/
d and calcium lactate 1.5 g/
d during 2 wk after study drug
administration
Denosumab 60 mg every 6 mo
for 1 yr, control: no treatment
Any denosumab treatment
during 1 yr
Any denosumab treatment
Denosumab 60 mg every 6 mo
for 24 mo
Denosumab 60 mg 1 single
dose
Denosumab 60 mg 1 single
dose, CaCO3 3 g/d, calcitriol 2
mg/d, dialysate Ca 1.75 mmol/l
Denosumab 60 mg 1 single
dose, follow-up at 24 wk
review
Outcome
Annual DBMD HD: FN 4.3%, LS
6.7%
Annual DBMD CKD: FN 3.1%,
LS 7.5%
Hypocalcemia: HD 35.6%, CKD
5.4% (risk factors: high
TRAP5b, steroid Tx, no CaCO3
pretreatment)
CAC score unchanged in
Dmab, increased in controls
(P ¼ 0.004)
DBMD: FN 15.2%, LS 13.4%
Hypocalcemia: 38%
DBMD: Dmab: FN 1.5%, LS
5.6%, alendronate: FN <0%, LS
5.4%
CAC, CA-IMT, ABI, baPWV, and
FMD: no change from baseline
DBMD distal radius: control:
M Haarhaus and P Evenepoel: Differentiating causes of adynamic bone in CKD
–4.5%, Dmab: 2.6%
Hypocalcemia (<8.0 mg/dl):
29.4%
Best BMD effect in young
patients and patients with
advanced CKD
Hypocalcemia: CKD 3–4, 37%,
CKD 1–3, 11%
DBMD (QUS of fingers): 10%,
N.S.
Symptomatic hypocalcemia:
25%
DBMD: FN 4%, LS 37%
DBMD: FN: Sev HPT 27%, Mod
HPT 9%
DBMD: FN 23%, LS 17%
 Hiramatsu et al.,126
Kidney International (2021) 100, 546–558

M Haarhaus and P Evenepoel: Differentiating causes of adynamic bone in CKD

HD: 47 Any denosumab-treated No exclusion criteria specified Denosumab for osteoporosis Hypocalcemia: 25.5%
retrospective, observational, patient at a single center? treatment, dose not specified, DBMD: FN 4.2%, LS 5.9%
safety and efficacy study follow-up 2 yr
Dave et al.,131 retrospective CKD 4–5: 7, HD: 7 Any denosumab-treated No specific exclusion criteria Denosumab any dose, Hypocalcemia: 65%
safety study patient at a single center dialysate Ca 1.25 mmol/l, Severe (corr Ca <1.9 mmol/l):
vitamin D therapy 92%, oral Ca 57%
substitution 21%
Block et al.,132 randomized Normal: 12 CKD Ca $2.1 mmol/l (8.5 mg/dl), Ca <2.1 mmol/l (8.5 mg/dl), Denosumab 60 mg 1 single Hypocalcemia: 15%
controlled trial, Mild: 13 25-OH D $30 ng/ml, other 25-OH D <30 ng/ml dose Pain extremities: 15% (no
pharmacokinetic study, Moderate: 13 laboratory results were normal Later protocol amendment: After amendment: Ca daily up hypocalcemia after
safety (second end point) Severe: 9 or adequate for CKD stage severe CKD and to 1 g, cholecalciferol daily up amendment)
Dialysis: 8 Later protocol amendment: 1,25(OH)2D <30 pg/ml or to 800 IU
PTH <110 pg/ml (<300 pg/ml iPTH $110 pg/ml, kidney
for patients on dialysis), failure and iPTH $300 pg/ml
1,25(OH)2D $30 pg/ml
Amgen 20103161 CKD 4–5: 16 Patients on hemodialysis Ca, Mg, phosphate inadequate Denosumab 120 mg on day 1 Hypocalcemia: severe 9%
(ClinicalTrials.gov identifier Dialysis: 16 for the medical condition and day 29
NCT01464931), single-arm,
open-label, safety study
Wetmore et al.,130 randomized HD, postmenopausal women: Age >40 yr, HD for $3 mo, Ptx, previous hormone Alendronate 40 mg every DBMD: alendronate 0%,
controlled trial 31 (16 alendronate, 15 iPTH $100 and #300 pg/ml, replacement therapy for #2 week or placebo for 6 wk. All: placebo
3.6%
placebo) Ca  P < 70 mg2/dl2 yr, malnutrition calcitriol 0.25 or 0.50 mg once
a day and oral Ca substitution
Torregrosa et al.,129 HD: 13 iPTH >500 pg/ml, Ca >11 Previous Ptx, diabetes mellitus Pamidronate 60 mg i.v. every DBMD: FN and LS 33%
prospective, open-label, and <6.5 mg/dl, osteopenia 2 mo for 1 yr, dialysate Ca 1.5
single-arm study (T-score <
1 SD) mmol/l
Bergner et al.127 prospective, HD: 16 PTH >2 ULN, osteopenia (LS Normal or decreased PTH, Ibandronate 2 mg i.v. every 4 DBMD: 5%
open-label, single-arm study T-score <
1.0) previous Ptx or serum Ca < wk for 48 wk
normal range
1,25(OH)2D, 1,25 dihydroxy vitamin D; 25-OH D, 25 hydroxy vitamin D; DBMD, change of bone mineral density; ABI, ankle–brachial index; baPWV, brachial–ankle pulse wave velocity; BMD, bone mineral density; CA-IMT, carotid
artery intima-media thickness; CAC, coronary artery calcification; CKD, chronic kidney disease; corr Ca, albumin-corrected calcium; Dmab, denosumab; DXA, dual-energy X-ray absorptiometry; FMD, flow-mediated dilatation; FN,
femoral neck; HD, hemodialysis; iPTH, intact parathyroid hormone; KDOQI, Kidney Disease Outcomes Quality Initiative; LS, lumbar spine; Mod HPT, moderate hyperparathyroidism; N.S., not significant; PD, peritoneal dialysis; PTH,
parathyroid hormone, Ptx, parathyroidectomy; QUS, quantitative ultrasound; s-Al, serum aluminium; Sev HPT, severe hyperparathyroidism; TRAP5b, tartrate-resistant acid phosphatase 5b; tx, therapy; ULN, upper limit of normal.
A questionmark (?) indicates an assumption, as the population studied was not clearly described in the cited article.

review
553
review
Table 2 | Bisphosphonates vs. denosumab in advanced CKD (pros and cons)
Bisphosphonates
Pros Improves BMD in all CKD stages
Oral or i.v. dose (can be administered during dialysis)
Low risk of severe hypocalcemia
Can be stopped after limited treatment time
Cons Risk of kidney damage in CKD 4–5
Wear out after several years
Osteonecrosis of the jaw
Atypical femoral fractures
Acute phase reaction (i.v. bisphosphonates only)
Esophagitis
Uveitis
Atrial fibrillation
BMD, bone mineral density; CKD, chronic kideny disease.
benefits, and alternatives and notes should be taken in pa-
tients’ file.140 In many countries, clinical use of osteoporosis
drugs is limited by reimbursement restrictions, further
hampering optimal therapy.
Low bone turnover and safety of anti-osteoporosis treatment
in advanced CKD
A major safety concern with regard to the use of anti-
resorptive agents in patients with CKD is the induction or
worsening of low bone turnover. As outlined above, data on
skeletal and vascular risks in postmenopausal women are
reassuring. Extrapolation to patients with CKD, however,
warrants caution, as the uremic environment may represent
an important modifier. Clinical studies evaluating vascular
outcomes in patients with CKD are scanty. Although the first-
generation bisphosphonate etidronate markedly reduced the
progression of vascular calcification in patients with CKD,107
recent generation nitrogen-containing bisphosphonates
alendronate and ibandronate demonstrated either improved
or unchanged vascular outcomes.79,105,106 In a recent ran-
domized controlled trial, therapy with either alendronate or
denosumab for 1 year did not affect indices of vascular health
(including vascular calcification scores) in patients on
dialysis.79
Antiresorptive therapy associates with osteonecrosis of the
jaw and atypical femur fractures. Absolute risks are very low
during the first 1 to 2 years of treatment (in the order of 1–6
per 100,000 patient-years)141,142 but increase markedly with
the duration of exposure.142,143 Preexisting dental disease and
prior dental extraction are the highest risk factors for osteo-
necrosis of the jaw. Any dental disease that requires inter-
vention and poor oral hygiene should be addressed before
initiating antiresorptive therapy.141,144 Although a causal
relationship of osteonecrosis of the jaw with low bone turn-
over is still a matter of controversy,145 an association of
atypical femur fractures with a prolonged suppression of bone
turnover is more established.146 However, there is no evidence
that CKD confers an increased risk of atypical fractures.
Whereas bone turnover is permanently suppressed for the
duration of bisphosphonate therapy and even thereafter (long
skeletal half-life), bone turnover in denosumab-treated
554
M Haarhaus and P Evenepoel: Differentiating causes of adynamic bone in CKD
Denosumab
Improves BMD in all CKD stages
Subcutaneous dosing every 6 mo
Continued effectiveness for at least 10 yr (in patients without CKD)
Risk of severe hypocalcemia
Risk of fractures if stopped
Osteonecrosis of the jaw
Atypical femoral fractures
Risk of infections
patients shows an early and profound drop after each dose
and thereafter partly recovers up to the next administration.
Whether these differences in pharmacodynamics translate in
different risks of atypical fractures remains to be determined.
Another concern related to therapy with antiresorptive
agents is the induction of hypocalcemia. Hypocalcemia is
especially prominent in patients treated with denosumab and
is explained by a transient imbalance between bone resorp-
tion and formation. This risk is especially high in patients
with high bone turnover at baseline and can be reduced by
concomitant treatment with calcium and vitamin
D.126,131,132,147 Hypocalcemia after administration triggers a
transient reciprocal increase in PTH levels, which may be
sufficiently treated with maintenance of normocalcemia.
In denosumab-treated patients, the offset of the effect is
another major concern. Although bisphosphonates are
retained by the skeleton and only slowly released, guaran-
teeing a prolonged bone effect after treatment cessation, the
offset of the effect is almost instantaneous in denosumab-
treated patients and manifested by a rapid bone loss and a
significant increase in vertebral fracture rate.148 Hence,
denosumab should be either administered continuously or
followed by some alternative antiresorptive therapy. Bone
turnover markers may be useful to monitor the offset of the
effect in patients.149
Conclusions
Collectively, the evidence reviewed here demonstrates that
low bone turnover is not always associated with negative
outcomes. More specifically, although systemic factors such as
chronic inflammation, malnutrition, or diabetes mellitus may
induce low bone turnover and are commonly associated with
an increased cardiovascular risk, evidence to date does not
support an association of antiresorptive treatment with
increased vascular calcification and cardiovascular morbidity
or mortality in advanced CKD. We hypothesize that the cause
of bone turnover suppression determines clinical outcomes
rather than its mere presence. This insight may pave the way
for a more liberal attitude toward the use of antiresorptive
agents in patients with advanced CKD and osteoporosis. We
propose a reconsideration of the current use of the term
Kidney International (2021) 100, 546–558
M Haarhaus and P Evenepoel: Differentiating causes of adynamic bone in CKD
“adynamic bone disease” for a wide variety of low bone
turnover states, awaiting further clarification in which clinical
settings and at what levels reductions of bone resorption and
formation may lead to negative outcomes. There is an
imminent need for prospective, randomized, and controlled
studies of fracture prevention strategies in the setting of
advanced CKD.
DISCLOSURE
MH is a full-time employee of Diaverum Sverige AB. He has received
consultancy and lecture fees from Resverlogix and Amgen and is an
advisory board member at Resverlogix, all unrelated to the current
manuscript. PE reports grants from Amgen and Sanofi and personal
fees from Amgen. He is a member of speaker bureaus at Amgen and
Vifor and an advisory board member at MEDICE, all unrelated to the
submitted work.
European Renal Osteodystrophy (EUROD) workgroup members
Justine Bachetta has nothing to disclose. Jorge Cannata Andia re-
ports grants from Amgen, unrelated to the submitted work. Patrick
D’Haese has nothing to disclose. Anibal Ferreira reports personal
fees from Amgen, Astellas, NephroCare, and Mundipharma and
grants and personal fees from Vifor Pharma, all unrelated to the
submitted work. Marie-Hélène Lafage Proust reports grants and
nonfinancial support from Amgen, unrelated to the submitted
work. Sandro Mazzafero reports lecture fees from Amgen and Vifor
Fresenius, unrelated to the submitted work. Syazrah Salam reports
grants from Immuno Diagnostics, unrelated to the submitted work.
Goce Spasovski has nothing to disclose. Marc Vervloet reports
grants from the Dutch Kidney Foundation and from the Dutch
Ministry of Economic Affairs, grants and personal fees from Vifor,
Fresenius Medical Care, and Amgen, and personal fees from
MEDICE and Kyowa Kirin, all unrelated to the submitted work.
REFERENCES
1. NIH Consensus Development Panel on Osteoporosis Prevention,
Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and
therapy. JAMA. 2001;285:785–795.
2. Ambrus C, Almasi C, Berta K, et al. Bone mineral density and
parathyroid function in patients on maintenance hemodialysis. Int Urol
Nephrol. 2011;43:191–201.
3. Evenepoel P, Claes K, Meijers B, et al. Bone mineral density, bone
turnover markers, and incident fractures in de novo kidney transplant
recipients. Kidney Int. 2019;95:1461–1470.
4. Stein MS, Packham DK, Ebeling PR, et al. Prevalence and risk factors for
osteopenia in dialysis patients. Am J Kidney Dis. 1996;28:515–522.
5. Taal MW, Masud T, Green D, et al. Risk factors for reduced bone density
in haemodialysis patients. Nephrol Dial Transplant. 1999;14:1922–1928.
6. Ureña P, Bernard-Poenaru O, Ostertag A, et al. Bone mineral density,
biochemical markers and skeletal fractures in haemodialysis patients.
Nephrol Dial Transplant. 2003;18:2325–2331.
7. Ketteler M, Block GA, Evenepoel P, et al. Executive summary of the 2017
KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)
Guideline Update: what’s changed and why it matters. Kidney Int.
2017;92:26–36.
8. Evenepoel P, Cunningham J, Ferrari S, et al. European Consensus
Statement on the diagnosis and management of osteoporosis in
chronic kidney disease stages G4-G5D. Nephrol Dial Transplant. 2021;36:
42–59.
9. Hygum K, Starup-Linde J, Langdahl BL. Diabetes and bone. Osteoporos
Sarcopenia. 2019;5:29–37.
10. Adami G, Saag KG. Osteoporosis pathophysiology, epidemiology, and
screening in rheumatoid arthritis. Curr Rheumatol Rep. 2019;21:34.
11. Stein E, Shane E. Secondary osteoporosis. Endocrinol Metab Clin North
Am. 2003;32:115–134. vii.
Kidney International (2021) 100, 546–558
review
12. Evenepoel P, Bover J, Ureña Torres P. Parathyroid hormone metabolism
and signaling in health and chronic kidney disease. Kidney Int. 2016;90:
1184–1190.
13. Bucur RC, Panjwani DD, Turner L, et al. Low bone mineral density and
fractures in stages 3-5 CKD: an updated systematic review and meta-
analysis. Osteoporos Int. 2015;26:449–458.
14. Dukas L, Schacht E, Stähelin HB. In elderly men and women treated for
osteoporosis a low creatinine clearance of <65 ml/min is a risk factor
for falls and fractures. Osteoporos Int. 2005;16:1683–1690.
15. Moe SM, Nickolas TL. Fractures in patients with CKD: time for action.
Clin J Am Soc Nephrol. 2016;11:1929–1931.
16. Jadoul M, Albert JM, Akiba T, et al. Incidence and risk factors for hip or
other bone fractures among hemodialysis patients in the Dialysis
Outcomes and Practice Patterns Study. Kidney Int. 2006;70:1358–1366.
17. Ball AM, Gillen DL, Sherrard D, et al. Risk of hip fracture among dialysis
and renal transplant recipients. JAMA. 2002;288:3014–3018.
18. Tentori F, McCullough K, Kilpatrick RD, et al. High rates of death and
hospitalization follow bone fracture among hemodialysis patients.
Kidney Int. 2014;85:166–173.
19. Parfitt AM, Drezner MK, Glorieux FH, et al. Bone histomorphometry:
standardization of nomenclature, symbols, and units. Report of the
ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res.
1987;2:595–610.
20. Dempster DW, Compston JE, Drezner MK, et al. Standardized
nomenclature, symbols, and units for bone histomorphometry: a 2012
update of the report of the ASBMR Histomorphometry Nomenclature
Committee. J Bone Miner Res. 2013;28:2–17.
21. Ott SM, Maloney NA, Coburn JW, et al. The prevalence of bone
aluminum deposition in renal osteodystrophy and its relation to the
response to calcitriol therapy. N Engl J Med. 1982;307:709–713.
22. Monier-Faugere MC, Malluche HH. Trends in renal osteodystrophy: a
survey from 1983 to 1995 in a total of 2248 patients. Nephrol Dial
Transplant. 1996;11(suppl 3):111–120.
23. London GM, Marchais SJ, Guérin AP, et al. Association of bone activity,
calcium load, aortic stiffness, and calcifications in ESRD. J Am Soc
Nephrol. 2008;19:1827–1835.
24. Tomiyama C, Carvalho AB, Higa A, et al. Coronary calcification is
associated with lower bone formation rate in CKD patients not yet in
dialysis treatment. J Bone Miner Res. 2010;25:499–504.
25. Barreto DV, Barreto Fde C, Carvalho AB, et al. Association of changes in
bone remodeling and coronary calcification in hemodialysis patients: a
prospective study. Am J Kidney Dis. 2008;52:1139–1150.
26. Malluche HH, Mawad HW, Monier-Faugere MC. Renal osteodystrophy in
the first decade of the new millennium: analysis of 630 bone biopsies in
black and white patients. J Bone Miner Res. 2011;26:1368–1376.
27. Sprague SM, Bellorin-Font E, Jorgetti V, et al. Diagnostic accuracy of
bone turnover markers and bone histology in patients with CKD treated
by dialysis. Am J Kidney Dis. 2016;67:559–566.
28. Huynh AL, Baker ST, Stewardson AJ, et al. Denosumab-associated
hypocalcaemia: incidence, severity and patient characteristics in a tertiary
hospital setting. Pharmacoepidemiol Drug Saf. 2016;25:1274–1278.
29. Andress DL. Adynamic bone in patients with chronic kidney disease.
Kidney Int. 2008;73:1345–1354.
30. Bover J, Urena P, Brandenburg V, et al. Adynamic bone disease: from
bone to vessels in chronic kidney disease. Semin Nephrol. 2014;34:626–
640.
31. Drüeke TB, Massy ZA. Changing bone patterns with progression of
chronic kidney disease. Kidney Int. 2016;89:289–302.
32. Cannata-Andía JB. Hypokinetic azotemic osteodystrophy. Kidney Int.
1998;54:1000–1016.
33. Komaba H, Kakuta T, Fukagawa M. Management of secondary
hyperparathyroidism: how and why? Clin Exp Nephrol. 2017;21:37–45.
34. Covic A, Voroneanu L, Apetrii M. PTH and/or bone histology: are we still
waiting for a verdict from the CKD-MBD grand jury? Am J Kidney Dis.
2016;67:535–538.
35. Graciolli FG, Neves KR, Barreto F, et al. The complexity of chronic kidney
disease-mineral and bone disorder across stages of chronic kidney
disease. Kidney Int. 2017;91:1436–1446.
36. Sabbagh Y, Graciolli FG, O’Brien S, et al. Repression of osteocyte Wnt/b-
catenin signaling is an early event in the progression of renal
osteodystrophy. J Bone Miner Res. 2012;27:1757–1772.
37. Loots GG, Keller H, Leupin O, et al. TGF-b regulates sclerostin expression
via the ECR5 enhancer. Bone. 2012;50:663–669.
555
review M Haarhaus and P Evenepoel: Differentiating causes of adynamic bone in CKD
38. Williams MJ, Sugatani T, Agapova OA, et al. The activin receptor is
stimulated in the skeleton, vasculature, heart, and kidney during
chronic kidney disease. Kidney Int. 2018;93:147–158.
39. Carrillo-Lopez N, Panizo S, Alonso-Montes C, et al. Direct inhibition of
osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to
bone loss in chronic kidney disease. Kidney Int. 2016;90:77–89.
40. Carrillo-López N, Martínez-Arias L, Fernández-Villabrille S, et al.,
European Renal Osteodystrophy (EUROD) Workgroup. Role of the
RANK/RANKL/OPG and Wnt/b-catenin systems in CKD bone and
cardiovascular disorders. Calcif Tissue Int. 2021;108:439–451.
41. Feroze U, Molnar MZ, Dukkipati R, et al. Insights into nutritional and
inflammatory aspects of low parathyroid hormone in dialysis patients.
J Ren Nutr. 2011;21:100–104.
42. Gaipov A, Cseprekal O, Potukuchi PK, et al. Association between
malnutrition-inflammation score and risk of subsequent self-reported
bone fractures in prevalent kidney transplant recipients. Osteoporos Int.
2019;30:611–620.
43. Jean G, Lataillade D, Genet L, et al. Association between very low PTH
levels and poor survival rates in haemodialysis patients: results from the
French ARNOS cohort. Nephron Clin Pract. 2011;118:c211–c216.
44. Akizawa T, Fukagawa M. Modulation of parathyroid cell function by
calcium ion in health and uremia. Am J Med Sci. 1999;317:358–362.
45. Sánchez-González MC, López-Barea F, Bajo MA, et al. Serum albumin
levels, an additional factor implicated in hyperparathyroidism outcome
in peritoneal dialysis: a prospective study with paired bone biopsies.
Adv Perit Dial. 2006;22:198–202.
46. Monier-Faugere MC, Malluche HH. Role of cytokines in renal
osteodystrophy. Curr Opin Nephrol Hypertens. 1997;6:327–332.
47. Sánchez MC, Bajo MA, Selgas R, et al. Cultures of human osteoblastic
cells from dialysis patients: influence of bone turnover rate on in vitro
selection of interleukin-6 and osteoblastic cell makers. Am J Kidney Dis.
2001;37:30–37.
48. Carlstedt E, Ridefelt P, Lind L, et al. Interleukin-6 induced suppression of
bovine parathyroid hormone secretion. Biosci Rep. 1999;19:35–42.
49. Nielsen PK, Rasmussen AK, Butters R, et al. Inhibition of PTH secretion
by interleukin-1 beta in bovine parathyroid glands in vitro is associated
with an up-regulation of the calcium-sensing receptor mRNA. Biochem
Biophys Res Commun. 1997;238:880–885.
50. Zerbini CAF, Clark P, Mendez-Sanchez L, et al. Biologic therapies and
bone loss in rheumatoid arthritis. Osteoporos Int. 2017;28:429–446.
51. Karsdal MA, Schett G, Emery P, et al. IL-6 receptor inhibition positively
modulates bone balance in rheumatoid arthritis patients with an
inadequate response to anti-tumor necrosis factor therapy: biochemical
marker analysis of bone metabolism in the tocilizumab RADIATE study
(NCT00106522). Semin Arthritis Rheum. 2012;42:131–139.
52. Dundar U, Kavuncu V, Ciftci IH, et al. The effect of risedronate treatment
on serum cytokines in postmenopausal osteoporosis: a 6-month
randomized and controlled study. J Bone Miner Metab. 2009;27:464–
470.
53. Sherrard DJ, Hercz G, Pei Y, et al. The aplastic form of renal
osteodystrophy. Nephrol Dial Transplant. 1996;11(suppl 3):29–31.
54. Moreira CA, Dempster DW. Bone histomorphometry in diabetes
mellitus. Osteoporos Int. 2015;26:2559–2560.
55. Napoli N, Chandran M, Pierroz DD, et al. Mechanisms of diabetes
mellitus-induced bone fragility. Nat Rev Endocrinol. 2017;13:208–219.
56. Kalaitzoglou E, Popescu I, Bunn RC, et al. Effects of type 1 diabetes on
osteoblasts, osteocytes, and osteoclasts. Curr Osteoporos Rep. 2016;14:
310–319.
57. Sanches CP, Vianna AGD, Barreto FC. The impact of type 2 diabetes on
bone metabolism. Diabetol Metab Syndr. 2017;9:85.
58. Nii-Kono T, Iwasaki Y, Uchida M, et al. Indoxyl sulfate induces skeletal
resistance to parathyroid hormone in cultured osteoblastic cells. Kidney
Int. 2007;71:738–743.
59. Liu WC, Wu CC, Lim PS, et al. Effect of uremic toxin-indoxyl sulfate on
the skeletal system. Clin Chim Acta. 2018;484:197–206.
60. Iwasaki Y, Yamato H, Nii-Kono T, et al. Administration of oral charcoal
adsorbent (AST-120) suppresses low-turnover bone progression in
uraemic rats. Nephrol Dial Transplant. 2006;21:2768–2774.
61. Seeman E, Delmas PD. Bone quality—the material and structural basis
of bone strength and fragility. N Engl J Med. 2006;354:2250–2261.
62. Eriksen EF, Hodgson SF, Eastell R, et al. Cancellous bone remodeling in
type I (postmenopausal) osteoporosis: quantitative assessment of rates
of formation, resorption, and bone loss at tissue and cellular levels.
J Bone Miner Res. 1990;5:311–319.
556
63. Barreto FC, Barreto DV, Moyses RM, et al. Osteoporosis in hemodialysis
patients revisited by bone histomorphometry: a new insight into an old
problem. Kidney Int. 2006;69:1852–1857.
64. McGee ME, Maki AJ, Johnson SE, et al. Decreased bone turnover with
balanced resorption and formation prevent cortical bone loss during
disuse (hibernation) in grizzly bears (Ursus arctos horribilis). Bone.
2008;42:396–404.
65. McGee-Lawrence ME, Wojda SJ, Barlow LN, et al. Grizzly bears (Ursus
arctos horribilis) and black bears (Ursus americanus) prevent trabecular
bone loss during disuse (hibernation). Bone. 2009;45:1186–1191.
66. McGee-Lawrence M, Buckendahl P, Carpenter C, et al. Suppressed bone
remodeling in black bears conserves energy and bone mass during
hibernation. J Exp Biol. 2015;218:2067–2074.
67. Iimori S, Mori Y, Akita W, et al. Diagnostic usefulness of bone mineral
density and biochemical markers of bone turnover in predicting
fracture in CKD stage 5D patients—a single-center cohort study.
Nephrol Dial Transplant. 2012;27:345–351.
68. Hughes-Austin JM, Katz R, Semba RD, et al. Biomarkers of bone
turnover identify subsets of chronic kidney disease patients at
higher risk for fracture. J Clin Endocrinol Metab. 2020;105:e2903–
e2911.
69. Kurz P, Monier-Faugere MC, Bognar B, et al. Evidence for abnormal
calcium homeostasis in patients with adynamic bone disease. Kidney
Int. 1994;46:855–861.
70. Shroff RC, McNair R, Skepper JN, et al. Chronic mineral dysregulation
promotes vascular smooth muscle cell adaptation and extracellular
matrix calcification. J Am Soc Nephrol. 2010;21:103–112.
71. London GM, Marty C, Marchais SJ, et al. Arterial calcifications and bone
histomorphometry in end-stage renal disease. J Am Soc Nephrol.
2004;15:1943–1951.
72. Ok E, Asci G, Bayraktaroglu S, et al. Reduction of dialysate calcium level
reduces progression of coronary artery calcification and improves low
bone turnover in patients on hemodialysis. J Am Soc Nephrol. 2016;27:
2475–2486.
73. Asci G, Ok E, Savas R, et al. The link between bone and coronary
calcifications in CKD-5 patients on haemodialysis. Nephrol Dial
Transplant. 2011;26:1010–1015.
74. Jamal SA, Vandermeer B, Raggi P, et al. Effect of calcium-based versus
non-calcium-based phosphate binders on mortality in patients with
chronic kidney disease: an updated systematic review and meta-
analysis. Lancet. 2013;382:1268–1277.
75. Spoendlin J, Paik JM, Tsacogianis T, et al. Cardiovascular outcomes of
calcium-free vs calcium-based phosphate binders in patients 65 years
or older with end-stage renal disease requiring hemodialysis. JAMA
Intern Med. 2019;179:741–749.
76. Merle E, Roth H, London GM, et al. Low parathyroid hormone status
induced by high dialysate calcium is an independent risk factor for
cardiovascular death in hemodialysis patients. Kidney Int. 2016;89:666–674.
77. Jean G, Souberbielle JC, Zaoui E, et al. Analysis of the kinetics of the
parathyroid hormone, and of associated patient outcomes, in a cohort
of haemodialysis patients. BMC Nephrol. 2016;17:153.
78. Ueki K, Yamada S, Tsuchimoto A, et al. Rapid progression of vascular
and soft tissue calcification while being managed for severe and
persistent hypocalcemia induced by denosumab treatment in a patient
with multiple myeloma and chronic kidney disease. Intern Med.
2015;54:2637–2642.
79. Iseri K, Watanabe M, Yoshikawa H, et al. Effects of denosumab and
alendronate on bone health and vascular function in hemodialysis patients:
a randomized, controlled trial. J Bone Miner. Res. 2019;34:1014–1024.
80. Gerakis A, Hadjidakis D, Kokkinakis E, et al. Correlation of bone mineral
density with the histological findings of renal osteodystrophy in
patients on hemodialysis. J Nephrol. 2000;13:437–443.
81. Nakashima A, Yorioka N, Doi S, et al. Radial bone mineral density in
hemodialysis patients with adynamic bone disease. Int J Artif Organs.
2003;26:200–204.
82. Salam S, Gallagher O, Gossiel F, et al. Diagnostic accuracy of biomarkers
and imaging for bone turnover in renal osteodystrophy. J Am Soc
Nephrol. 2018;29:1557–1565.
83. Jørgensen HS, Winther S, Bøttcher M, et al. Bone turnover markers are
associated with bone density, but not with fracture in end stage kidney
disease: a cross-sectional study. BMC Nephrol. 2017;18:284.
84. Eastell R, Boonen S, Cosman F, et al. Relationship between pretreatment
rate of bone loss and bone density response to once-yearly ZOL:
HORIZON-PFT extension study. J Bone Miner Res. 2015;30:570–574.
Kidney International (2021) 100, 546–558
M Haarhaus and P Evenepoel: Differentiating causes of adynamic bone in CKD
85. Ng AH, Willett TL, Alman BA, et al. Development, validation and
characterization of a novel mouse model of adynamic bone disease
(ABD). Bone. 2014;68:57–66.
86. Lloyd AA, Gludovatz B, Riedel C, et al. Atypical fracture with long-term
bisphosphonate therapy is associated with altered cortical composition
and reduced fracture resistance. Proc Natl Acad Sci U S A. 2017;114:
8722–8727.
87. Ng AH, Omelon S, Variola F, et al. Adynamic bone decreases bone
toughness during aging by affecting mineral and matrix. J Bone Miner
Res. 2016;31:369–379.
88. Dong B, Endo I, Ohnishi Y, et al. Persistent activation of calcium-sensing
receptor suppresses bone turnover, increases microcracks, and
decreases bone strength. JBMR Plus. 2019;3:e10182.
89. Coco M, Rush H. Increased incidence of hip fractures in dialysis patients
with low serum parathyroid hormone. Am J Kidney Dis. 2000;36:1115–
1121.
90. Fishbane S, Hazzan AD, Jhaveri KD, et al. Bone parameters and risk of
hip and femur fractures in patients on hemodialysis. Clin J Am Soc
Nephrol. 2016;11:1063–1072.
91. Rubin MR. Skeletal manifestations of hypoparathyroidism. Bone.
2019;120:548–555.
92. Rudser KD, de Boer IH, Dooley A, et al. Fracture risk after
parathyroidectomy among chronic hemodialysis patients. J Am Soc
Nephrol. 2007;18:2401–2407.
93. Araújo SM, Ambrosoni P, Lobão RR, et al. The renal osteodystrophy
pattern in Brazil and Uruguay: an overview. Kidney Int Suppl. 2003;(85):
S54–S56.
94. Haarhaus M, Brandenburg V, Kalantar-Zadeh K, et al. Alkaline
phosphatase: a novel treatment target for cardiovascular disease in
CKD. Nat Rev Nephrol. 2017;13:429–442.
95. Maruyama Y, Taniguchi M, Kazama JJ, et al. A higher serum alkaline
phosphatase is associated with the incidence of hip fracture and
mortality among patients receiving hemodialysis in Japan. Nephrol Dial
Transplant. 2014;29:1532–1538.
96. Shantouf R, Kovesdy C, Kim Y, et al. Association of serum alkaline
phosphatase with coronary artery calcification in maintenance
hemodialysis patients. Clin J Am Soc Nephrol. 2009;4:1106–1114.
97. Regidor D, Kovesdy C, Mehrotra R, et al. Serum alkaline phosphatase
predicts mortality among maintenance hemodialysis patients. J Am Soc
Nephrol. 2008;19:2193–2203.
98. Manghat P, Souleimanova I, Cheung J, et al. Association of bone
turnover markers and arterial stiffness in pre-dialysis chronic kidney
disease (CKD). Bone. 2011;48:1127–1132.
99. Fahrleitner-Pammer A, Herberth J, Browning SR, et al. Bone markers
predict cardiovascular events in chronic kidney disease. J Bone Miner
Res. 2008;23:1850–1858.
100. Kestenbaum B, Andress D, Schwartz S, et al. Survival following
parathyroidectomy among United States dialysis patients. Kidney Int.
2004;66:2010–2016.
101. Bleyer AJ, Burkart J, Piazza M, et al. Changes in cardiovascular
calcification after parathyroidectomy in patients with ESRD. Am J Kidney
Dis. 2005;46:464–469.
102. Komaba H, Nakamura M, Fukagawa M. Resurgence of
parathyroidectomy: evidence and outcomes. Curr Opin Nephrol
Hypertens. 2017;26:243–249.
103. Viaene L, Evenepoel P, Bammens B, et al. Calcium requirements after
parathyroidectomy in patients with refractory secondary
hyperparathyroidism. Nephron Clin Pract. 2008;110:c80–c85.
104. Samelson EJ, Miller PD, Christiansen C, et al. RANKL inhibition with
denosumab does not influence 3-year progression of aortic calcification
or incidence of adverse cardiovascular events in postmenopausal
women with osteoporosis and high cardiovascular risk. J Bone Miner
Res. 2014;29:450–457.
105. Tankó LB, Qin G, Alexandersen P, et al. Effective doses of ibandronate
do not influence the 3-year progression of aortic calcification in elderly
osteoporotic women. Osteoporos Int. 2005;16:184–190.
106. Toussaint ND, Lau KK, Strauss BJ, et al. Effect of alendronate on vascular
calcification in CKD stages 3 and 4: a pilot randomized controlled trial.
Am J Kidney Dis. 2010;56:57–68.
107. Nitta K, Akiba T, Suzuki K, et al. Effects of cyclic intermittent etidronate
therapy on coronary artery calcification in patients receiving long-term
hemodialysis. Am J Kidney Dis. 2004;44:680–688.
108. Chen CL, Chen NC, Wu FZ, et al. Impact of denosumab on
cardiovascular calcification in patients with secondary
Kidney International (2021) 100, 546–558
review
hyperparathyroidism undergoing dialysis: a pilot study. Osteoporos Int.
2020;31:1507–1516.
109. Burr DB. Fifty years of bisphosphonates: what are their mechanical
effects on bone? Bone. 2020;138:115518.
110. Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab
treatment in postmenopausal women with osteoporosis: results from
the phase 3 randomised FREEDOM trial and open-label extension.
Lancet Diabetes Endocrinol. 2017;5:513–523.
111. Dempster DW, Brown JP, Fahrleitner-Pammer A, et al. Effects of long-
term denosumab on bone histomorphometry and mineralization in
women with postmenopausal osteoporosis. J Clin Endocrinol Metab.
2018;103:2498–2509.
112. Díaz-Tocados JM, Rodríguez-Ortiz ME, Almadén Y, et al. Calcimimetics
maintain bone turnover in uremic rats despite the concomitant
decrease in parathyroid hormone concentration. Kidney Int. 2019;95:
1064–1078.
113. Yajima A, Inaba M, Tominaga Y, et al. Bone formation by minimodeling
is more active than remodeling after parathyroidectomy. Kidney Int.
2008;74:775–781.
114. Lu CL, Shyu JF, Wu CC, et al. Association of anabolic effect of calcitriol
with osteoclast-derived Wnt 10b secretion. Nutrients. 2018;10:1164.
115. Pataki A, Müller K, Green JR, et al. Effects of short-term treatment with
the bisphosphonates zoledronate and pamidronate on rat bone: a
comparative histomorphometric study on the cancellous bone formed
before, during, and after treatment. Anat Rec. 1997;249:458–468.
116. Kranenburg G, Bartstra JW, Weijmans M, et al. Bisphosphonates for
cardiovascular risk reduction: a systematic review and meta-analysis.
Atherosclerosis. 2016;252:106–115.
117. Sing CW, Wong AY, Kiel DP, et al. Association of alendronate and risk of
cardiovascular events in patients with hip fracture. J Bone Miner Res.
2018;33:1422–1434.
118. Chen CL, Chen NC, Hsu CY, et al. An open-label, prospective pilot
clinical study of denosumab for severe hyperparathyroidism in patients
with low bone mass undergoing dialysis. J Clin Endocrinol Metab.
2014;99:2426–2432.
119. Cheng BC, Chen YC. Young patients and those with a low eGFR
benefitted more from denosumab therapy in femoral neck bone
mineral density. Clin Rheumatol. 2017;36:929–932.
120. Festuccia F, Jafari MT, Moioli A, et al. Safety and efficacy of denosumab
in osteoporotic hemodialysed patients. J Nephrol. 2017;30:271–279.
121. Hiramatsu R, Ubara Y, Sawa N, et al. Denosumab for low bone mass in
hemodialysis patients: a noncontrolled trial. Am J Kidney Dis. 2015;66:
175–177.
122. Kunizawa K, Hiramatsu R, Hoshino J, et al. Denosumab for dialysis
patients with osteoporosis: a cohort study. Sci Rep. 2020;10:2496.
123. Takami H, Washio K, Gotoh H. Denosumab for male hemodialysis
patients with low bone mineral density: a case-control study. Int J
Nephrol. 2017;2017:6218129.
124. Thongprayoon C, Acharya P, Acharya C, et al. Hypocalcemia and bone
mineral density changes following denosumab treatment in end-stage
renal disease patients: a meta-analysis of observational studies.
Osteoporos Int. 2018;29:1737–1745.
125. Chen CL, Chen NC, Liang HL, et al. Effects of denosumab and calcitriol
on severe secondary hyperparathyroidism in dialysis patients with low
bone mass. J Clin Endocrinol Metab. 2015;100:2784–2792.
126. Hiramatsu R, Ubara Y, Sawa N, Sakai A. Hypocalcemia and bone mineral
changes in hemodialysis patients with low bone mass treated with
denosumab: a 2-year observational study [e-pub ahead of print].
Nephrol Dial Transplant. https://doi.org/10.1093/ndt/gfaa359. Accessed
June 29, 2021.
127. Bergner R, Henrich D, Hoffmann M, et al. Treatment of reduced bone
density with ibandronate in dialysis patients. J Nephrol. 2008;21:510–516.
128. Mitsopoulos E, Ginikopoulou E, Economidou D, et al. Impact of long-
term cinacalcet, ibandronate or teriparatide therapy on bone mineral
density of hemodialysis patients: a pilot study. Am J Nephrol. 2012;36:
238–244.
129. Torregrosa JV, Moreno A, Mas M, et al. Usefulness of pamidronate in
severe secondary hyperparathyroidism in patients undergoing
hemodialysis. Kidney Int. Suppl. 2003;(85):S88–S90.
130. Wetmore JB, Benet LZ, Kleinstuck D, et al. Effects of short-term
alendronate on bone mineral density in haemodialysis patients.
Nephrology (Carlton). 2005;10:393–399.
131. Dave V, Chiang CY, Booth J, et al. Hypocalcemia post denosumab in patients
with chronic kidney disease stage 4-5. Am J Nephrol. 2015;41:129–137.
557
review M Haarhaus and P Evenepoel: Differentiating causes of adynamic bone in CKD
132. Block GA, Bone HG, Fang L, et al. A single-dose study of denosumab in
patients with various degrees of renal impairment. J Bone Miner Res.
2012;27:1471–1479.
133. Anagnostis P, Paschou SA, Gkekas NN, et al. Efficacy of anti-
osteoporotic medications in patients with type 1 and 2 diabetes
mellitus: a systematic review. Endocrine. 2018;60:373–383.
134. Nakatoh S. Bone turnover rate and bone formation/resorption balance
during the early stage after switching from a bone resorption inhibitor
to denosumab are predictive factors of bone mineral density change.
Osteoporos Sarcopenia. 2017;3:45–52.
135. Cosman F. The evolving role of anabolic therapy in the treatment of
osteoporosis. Curr Opin Rheumatol. 2019;31:376–380.
136. Cejka D, Kodras K, Bader T, et al. Treatment of hemodialysis-associated
adynamic bone disease with teriparatide (PTH1-34): a pilot study.
Kidney Blood Press Res. 2010;33:221–226.
137. Sumida K, Ubara Y, Hoshino J, et al. Once-weekly teriparatide in
hemodialysis patients with hypoparathyroidism and low bone mass: a
prospective study. Osteoporos Int. 2016;27:1441–1450.
138. Chavassieux P, Chapurlat R, Portero-Muzy N, et al. Bone-forming and
antiresorptive effects of romosozumab in postmenopausal women with
osteoporosis: bone histomorphometry and microcomputed
tomography analysis after 2 and 12 months of treatment. J Bone Miner
Res. 2019;34:1597–1608.
139. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for
fracture prevention in women with osteoporosis. N Engl J Med.
2017;377:1417–1427.
140. Vrancken I. Off-label prescription of medication. Eur J Health Law.
2015;22:165–186.
558
141. Khan A, Morrison A, Cheung A, et al. Osteonecrosis of the jaw (ONJ):
diagnosis and management in 2015. Osteoporos Int. 2016;27:853–
859.
142. Lo JC, Grimsrud CD, Ott SM, et al. Atypical femur fracture incidence in
women increases with duration of bisphosphonate exposure.
Osteoporos Int. 2019;30:2515–2520.
143. Dell RM, Adams AL, Greene DF, et al. Incidence of atypical
nontraumatic diaphyseal fractures of the femur. J Bone Miner Res.
2012;27:2544–2550.
144. Dennison EM, Cooper C, Kanis JA, et al. Fracture risk following
intermission of osteoporosis therapy. Osteoporos Int. 2019;30:1733–
1743.
145. Wat WZM. Current controversies on the pathogenesis of medication-
related osteonecrosis of the jaw. Dent J (Basel). 2016;4:38.
146. Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and
diaphyseal femoral fractures: second report of a task force of the
American Society for Bone and Mineral Research. J Bone Miner Res.
2014;29:1–23.
147. Larsson S, Fazzalari NL. Anti-osteoporosis therapy and fracture healing.
Arch Orthop Trauma Surg. 2014;134:291–297.
148. Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after
discontinuation of denosumab: a post hoc analysis of the randomized
placebo-controlled FREEDOM trial and its extension. J Bone Miner Res.
2018;33:190–198.
149. Naylor KE, McCloskey EV, Jacques RM, et al. Clinical utility of bone
turnover markers in monitoring the withdrawal of treatment with oral
bisphosphonates in postmenopausal osteoporosis. Osteoporos Int.
2019;30:917–922.
Kidney International (2021) 100, 546–558