Received: 22 November 2022 Revised: 25 April 2023 Accepted: 12 May 2023

DOI: 10.1111/hdi.13098

REVIEW ARTICLE
Mineral Bone Disorder

Effects of denosumab on bone mineral density and bone

metabolism in patients with end-stage renal disease:
A systematic review and meta-analysis

Zhaoyan Gu 1 | Xuhui Yang 2 | Yan Wang 3 | Jianjun Gao 4

1
Department of Endocrinology, The
Second Medical Center & National
Clinical Research Center for Geriatric
Diseases, Chinese PLA General Hospital,
Beijing, People’s Republic of China
2
Department of Oncology, The Fifth
Medical Center, Chinese PLA General
Hospital and Chinese PLA Medical
School, Beijing, People’s Republic of
China
3
Chaoyang 1st Sanitarium for Retired
Cadres of Beijing Garrison of the Chinese
PLA, Beijing, People’s Republic of China
4
Department of Nephrology, The Chinese
PLA Strategic Support Force
Characteristic Medical Center, Beijing,
People’s Republic of China
Correspondence
Jianjun Gao, Department of Nephrology,
The Chinese PLA Strategic Support Force
Characteristic Medical Center,
No 28 AnXiangBeiLi Road, Beijing
100101, People’s Republic of China.
Email: gao306kidney@126.com
Abstract
Introduction: The effects of denosumab on bone mineral density (BMD) and
metabolism in patients with end-stage renal disease (ESRD) remain controver-
sial. Hence, we performed a systematic review and meta-analysis of observa-
tional studies.
Methods: The MEDLINE, EMBASE, and Cochrane Library databases were
searched in June 2022 to identify studies that evaluated the risk of
denosumab-associated hypocalcemia and changes in bone metabolism,
changes in BMD from baseline to post-treatment in patients with ESRD.
Findings: Twelve studies with 348 participants were included. The pooled
incidence of hypocalcemia during denosumab treatment was 35.0% (95% confi-
dence interval [CI], 25%–46%; I2 = 63.6%). There were no significant changes
in either the serum calcium or phosphate levels from the baseline to post-
treatment period; the mean differences were 0.04 mg/dL (95% CI, 0.12 to
0.20 mg/dL) and 0.39 mg/dL (95% CI, 0.89 to 0.12 mg/dL). We found sig-
nificant changes in the alkaline phosphatase and parathyroid hormone levels;
the standardized mean differences were 2.98 (95% CI, 5.36 to –0.59) and
3.12 (95% CI: –4.94 to –1.29), respectively. Denosumab may increase BMD,
with mean differences of 9.10% (95% CI: 4.07%–14.13%) and 9.00% (95% CI:
5.93%–12.07%) for the femoral neck and lumbar spine, respectively.
Discussion: Denosumab increased the BMDs of the lumbar spine and femoral
neck in patients with ESRD. The onset of hypocalcemia must be carefully
monitored during denosumab administration.

KEYWORDS
bone metabolism, bone mineral density, denosumab, end-stage kidney disease

INTRODUCTION and mineral metabolism, anomalies in skeletal remodel-

Chronic kidney disease (CKD) is a major global public
health concern. Most patients with advanced CKD exhibit
abnormal mineral levels and bone metabolism. A wider
systemic disorder characterized by abnormalities in bone
ing, and extraskeletal calcification, is termed CKD–
mineral and bone disorder (CKD-MBD)1 and increases the
risks of cardiovascular morbidity and mortality.2
Osteoporosis is characterized by skeletal complica-
tions of CKD-MBD.3 Osteoporosis is a systemic skeletal

Hemodialysis International. 2023;1–12. wileyonlinelibrary.com/journal/hdi © 2023 International Society for Hemodialysis. 1


2 GU ET AL.
disease characterized by low bone mass and microarchi-
tectural bone degeneration, which increase bone fragility
and fracture risk.4,5 One independent risk factor for oste-
oporosis is a decreased glomerular filtration rate (GFR).6
With the progression of CKD, the risks of osteoporosis
and fragility-related fractures increase.7 Patients with
end-stage renal disease (ESRD) on maintenance dialysis
(CKD G5D) are at an increased risk of fracture, given
their suboptimal bone quantity and quality.8–11 The inci-
dence of non-vertebral fractures in patients with osteopo-
rosis is higher than that in control individual matched by
age and sex.12,13
Denosumab is an inhibitor of receptor activator of
nuclear factor kappa-B ligand (RANKL) which plays an
important role in osteoclast formation, function, and sur-
vival.14,15 Denosumab reduces the fracture risk and
increases the bone mineral density (BMD) in postmeno-
pausal women with osteoporosis.16 Although denosumab
is successfully used in patients with CKD owing to its
effectiveness for increasing BMD, the prevalence of hypo-
calcemia in such patients is considerable.17,18 Further
assessment of the efficacy and safety of denosumab in
patients with CKD is urgently needed.
In this systematic review, we evaluated the effects of
denosumab treatment in patients with ESRD. We evalu-
ated the prevalence of denosumab-associated hypocalce-
mia and the effects of denosumab on BMD and bone
metabolism in these patients.
METHODS
Protocol design and search strategy
Our protocol was registered in the International Prospec-
tive Register of Systematic Reviews (registration number:
CRD42022351080). We followed the guidelines of Pre-
ferred Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA) guidelines.19 We searched PubMed,
EMBASE, and the Cochrane Central Register of Con-
trolled Trials databases for articles published in August
2022. The search strategy is described in Online Supple-
mentary Data 1. The clinicaltrials. gov website was
searched for relevant studies that had been completed
but had not yet been published. We manually evaluated
all potentially relevant citations of the included articles.
Selection criteria
The inclusion criteria were: (1) English-language, con-
trolled clinical trials or observational studies (case–con-
trol, or cohort works, or case series); (2) the availability
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of data allowing calculation of mean differences,
standardized mean differences, relative risks, or hazard
ratios with 95% confidence intervals (CIs); (3) the inci-
dence of hypocalcemia during denosumab treatment and
changes in the levels of serum calcium, parathyroid hor-
mone (PTH), and phosphate, and the BMD from baseline
to post-treatment course of denosumab in patients with
ESRD. The post-treatment course referred to the follow-
up endpoints after denosumab treatment, which ranged
from 113 days to 24 months. The study sample size did
not affect inclusion.
Data abstraction and quality assessment
Two authors independently extracted the first author
names; years of publication; number of patients; baseline
patient characteristics; follow-up durations; interven-
tions; number of hypocalcemia patients; and calcium,
phosphate, alkaline phosphatase (ALP), PTH, 25-OH
vitamin D, and 1,25(OH)2 vitamin D levels. Hypocalce-
mia was defined as a serum calcium nadir <8.0 mg/dL
during follow-up. Laboratory tests were performed dur-
ing all follow-up visits (weekly or monthly). The follow-
up duration ranged from 1 week to 24 months after deno-
sumab commencement. One study (Iseri, et al.) was a
randomized controlled trial, the quality of which was
evaluated according to the Cochrane Handbook.20 Other
studies were evaluated using the validated methodologi-
cal index for non-randomized studies (MINORS) with a
quality score21 (Supplementary Table S1.2).
Statistical analysis
The hypocalcemia incidence rates with the 95% CIs were
analyzed using the DerSimonian-Laird random-effects
model, which weighted each study by variance.22 Sum-
mary statistics are the mean changes from baseline and
with the standard deviations (SDs). The mean differences
were preferred when comparing studies that used the
same continuous outcomes and units of measurement.
Otherwise, standardized mean differences with 95% CIs
were calculated to summarize the continuous data. The
SD of each mean change was computed by assuming a
conservative correlation coefficient of 0.5.23 Given the
high likelihood of inter-study variance, we used a
random-effects model rather than a fixed-effects model.
The heterogeneity of the among-study treatment effects
was investigated using the chi-squared test and I 2 statis-
tics. I 2 values of 25, 50%, and 75% reflected low, medium,
and high heterogeneities.24 Funnel plots, and Egger’s
regression symmetry test were used to assess publication

DENOSUMAB FOR PATIENTS WITH END-STAGE RENAL DISEASE
F I G U R E 1 Flow diagram of the
study design process. [Color figure can
be viewed at wileyonlinelibrary.com]
bias. A p-value < 0.05 was considered statistically signifi-
cant. All analyses employed Stata software (V.12.0; Stata-
Corp, College Station, TX).
RESULTS
Search results and the characteristics of
included studies
Initially, 1286 records were retrieved. After excluding
repetitive studies, 1159 remained. After excluding 1138
articles because their titles and abstracts did not meet the
inclusion criteria, 21 articles underwent a full-length
review. A further nine articles were excluded: four did
not report outcomes of interest, four were meeting
abstracts, and one article was not written in English
(Figure 1).
Twelve observational studies involving 348 patients
with ESRD were finally included.25–36 Of these, eight
were observational prospective studies, three were
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3
observational studies, and one was a randomized con-
trolled trial. The characteristics of the included studies
are summarized in Table 1. The mean age of the partici-
pants ranged from 53 to 72 years. The mean serum cal-
cium level (reported by eight studies) ranged from 8.8 to
10.1 mg/dL, the mean serum phosphorus level (seven
studies) from 3.8 to 5.9 mg/dL, and the mean PTH level
(eight studies) from 132.5 to 1702.1 pg/mL. Patients in
the three studies had a history of severe secondary hyper-
parathyroidism (PTH > 800 pg/mL). The femoral neck
and lumbar spine BMD scores were generally low at
baseline.
Incidence of hypocalcemia after
denosumab treatment
Of the 12 included studies, the incidence of hypocalcemia
in patients with ESRD during denosumab treatment was
assessed in 10 studies.25–28,30–32 The pooled estimated
incidence of hypocalcemia during denosumab treatment
 4

TABLE 1 Characteristics of studies included in meta-analysis.

Number of
Female/ hypocalcemia Phosphate 25(OH) Follow-
Study Year Study sample Research type Number Outcomes Control Denosumab male Age Ca (mg/dL) (<8.0 mg/dL) (mg/dL) D (ng/mL) iPTH (pg/mL) ALP (IU/L) up Supplement

Block 2012 HD patients Observational 8 Ca, pharmacokinetics No A single 60 mg 2/6 67 ± 15 9.1 ± 0.4 5 NA 39.2 ± 40.4 158.2 ± 125.1 NA 113 days Calcium (up to
prospective and subcutaneous 1000 mg/day)
pharmacodynamics of and vitamin
of denosumab denosumab D (up to
800 IU/day)

Chen 2014 HD/PD patients with Observational 12 Ca, PTH, BMD 8 controls A single 60 mg 5/7 53.5 ± 3.8 10.1 ± 0.4 6 5.3 ± 0.3 35.9 ± 4.1 1702.1 ± 181.9 449.8 ± 94.2 24 weeks Calcium (calcium
severe prospective subcutaneous carbonate
hyperparathyroidism of 3 g/day) and
(iPTH >1000 pg/mL) denosumab vitamin D
and low BMD (calcitriol
(forearm, femoral 1 μg/day)
neck, lumbar spine
T-score < 1.0 SD)

Chen 2015 HD/PD patients with Observational 24 Ca, PTH, BMD 8 controls A single 60 mg 19/5 58.4 ± 2.8 10.1 ± 0.2 8 5.7 ± 0.3 30.0 ± 3.1 1464.8 ± 93.2 331.7 ± 48.9 24 weeks Calcium (calcium
severe prospective subcutaneous carbonate
hyperparathyroidism of 3 g/day) and
(iPTH >800 pg/mL) denosumab vitamin D
and low BMD (calcitriol
(forearm, femoral 2 μg/day)
neck, lumbar spine
T-score < 2.5 SD)

Chen 2020 HD/PD patients with Observational 21 Ca, P, ALP, BMD, CAC 21 controls A single 60 mg 18/3 62.14 ± 2.50 9.96 ± 0.2 8 5.50 ± 0.32 27.01 ± 2.29 1310.50 ± 108.40 268.38 ± 30.43 6 months Calcium (calcium
severe prospective subcutaneous carboate 3 g/
hyperparathyroidism of day,
((iPTH >800 pg/mL) denosumab Vitamin D)
and low BMD
(forearm, femoral
neck, lumbar spine
T-score < 2.5 SD)

Festuccia 2016 HD patients with severe Observational 12 Ca, PTH, β-CrossLaps, No A single 60 mg 11/1 66.3 ± 9.4 9.08 ± 0.5 NA 5.91 ± 1.5 NA 655.9 ± 658.5 Bone ALP 33.5 ± 24 months Calcium,
osteoporosis or prior retrospective T-score subcutaneous 28.8 vitamin D,
history or high risk of cinacalcet,
of femoral and denosumab phosphate
vertebral fractures every binder
6 months

Han 2020 HD patients with Observational 25 Ca, P, PTH, BMD, ALP No A single 60 mg 14/11 69.88 ± 10.25 8.88 ± 0.81 NA 3.86 ± 0.99 NA 317.88 ± 207.40 Bone ALP 65.63 6 months Calcium, vitamin
osteoporosis (T-score retrospective subcutaneous ± 34.47 D, phosphate
was < 2.5) of binder
denosumab

Hiramatsu 2015 HD patients with low Observational 11 Ca, P, BMD, PTH, ALP No A single 60 mg 10/1 66 (60, 71) 9.7 (9.4, 10.5) 4 4.4 (3.5, 5.3) 15.0 (11.6, 19.3) 142.0 (125, 211) 295 (255, 412) 6 months Calcium (calcium
BMDs (T scores ≤ prospective subcutaneous carbone 1.42
2.5) of ± 1.8 g/day),
denosumab vitamin D
(alfacalcidol
0.25 ± 0.4 μg/
day),
cinacalcet
(0-75 mg/day)
GU ET AL.

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 TABLE 1 (Continued)
Number of
Female/ hypocalcemia Phosphate 25(OH) Follow-
Study Year Study sample Research type Number Outcomes Control Denosumab male Age Ca (mg/dL) (<8.0 mg/dL) (mg/dL) D (ng/mL) iPTH (pg/mL) ALP (IU/L) up Supplement

Hiramatsu 2021 HD patients with low Observational 47 Ca, BMD, P, PTH, bone No A single 60 mg 26/21 66.1 ± 11.1 9.79 ± 0.4 12 4.8 ± 1.0 16.0 (13.3, 18.7) 133.0 (70.0, 240.0) bone ALP 35.6 ± 24 months Calcium (calcium
BMDs (T scores ≤ prospective metabolic markers subcutaneous 72.5 carbone),
2.5, or T-score of of vitamin D
2.5 to 1.0 with denosumab
history of fragility
fractures)

Hori 2022 HD patients with Observational 28 BMD 56 controls A single 60 mg 15/13 67.6 ± 11.2 9.5 ± 0.4 16 4.9 ± 0.9 NA 132.5 (72.3, 178.3) 259 (201, 341.3) 6 months Calcium,
osteoporosis (having prospective subcutaneous vitamin D,
a prior fracture; of calcimimetics
BMD <80% of young denosumab
adult mean, or < 70% every
of the young adult 6 months
mean or T-score was
< 2.5)

Iseri 2019 HD patients with Randomized 22 Ca, P, BMD 24 controls A single 60 mg 9/13 71.3 ± 10.5 9.3 (8.9, 9.5) 7 4.9 ± 1.1 22.5 ± 9.5 142.0 (67.8, 172.8) 235.5 (210.8, 12 months Calcium
osteoporosis (having controlled (Alendronate) subcutaneous 287.5) (calcium
a prior fracture; study of lactate
BMD <80% of young denosumab 1.5 g/d),
DENOSUMAB FOR PATIENTS WITH END-STAGE RENAL DISEASE

adult mean, or < 70% every vitamin D

of the young adult 6 months (calcitriol
mean or T-score was 0.25 mg/d)
< 2.5)

Kunizawa 2020 HD patients with low Observational 121 BMD and bone No A single 60 mg 73/48 66.7 ± 10.6 9.9 ± 0.8 22 4.6 ± 1.2 NA 132 (56, 217) NA 24 months NA
BMDs (< 70% of the prospective metabolic markers subcutaneous
young adult mean or of
T-score was < 2.5) denosumab

Takami 2017 HD patients with low Observational 17 Ca, P, PTH, BMD, ALP 20 controls A single 60 mg 0/17 72.8 ± 9.5 9.2 ± 0.5 5 5.0 ± 1.3 NA 164 (58.5, 228) 276 ± 129 24 months Calcium carbonate
BMDs (< 70% of the retrospective subcutaneous mean
young adult mean) of 1.47 g/day,
denosumab alfacalcidol
every mean
6 months 0.31 μg/day,
calcitriol
mean
0.01 μg/day,
max acalcitol
mean 5 μg/
week,
cinacalcet
mean
2.94 mg/day,
phosphate
binder

Abbreviations: ALP, alkaline phosphatase; BMD, bone mineral density; Ca, calcium; HD, hemodialysis; P, phosphorus; PD, peritoneal dialysis; PTH, parathyroid hormone.
5

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6 GU ET AL.
F I G U R E 2 Forest plot of all included studies evaluating incidence of hypocalcemia during denosumab treatment. [Color figure can be
viewed at wileyonlinelibrary.com]
was 35.0% (95% CI: 25%–46%, I 2 = 63.6%, p < 0.001;
Figure 2); we employed a random-effects model. Funnel
plots for the incidence of hypocalcemia during denosu-
mab treatment were symmetrical (Supplementary
Figure S1). Egger’s regression asymmetry tests were per-
formed to assess publication bias. Significantly different
crossovers had a p-value of = 0.0026.
Hypocalcemia often develops between the first week
and second month of denosumab treatment.34,36 The inci-
dence of hypocalcemia during denosumab treatment in the
study by Block et al.25 was 62.5% (5/8), which was the high-
est among all reported studies. Some patients had symp-
tomatic hypocalcemia. Festuccia et al.29 reported that 25%
(3/12) of patients with ESRD treated with denosumab
developed symptomatic hypocalcemia, including paresthe-
sia and myalgia. However, none of the patients were hospi-
talized because of hypocalcemia. In a study by Hori et al.35
one patient reported temporary fatigue, which may have
been attributable to hypocalcemia. Only one patient devel-
oped severe asymptomatic hypocalcemia in the study by
Iseri et al.33 However, most of the patients required calcium
and vitamin D supplementation (Table 1).
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We performed a subgroup analysis to explore the
sources of heterogeneity in patients with (PTH > 800 pg/
mL) or without severe secondary hyperparathyroidism
(PTH < 800 pg/mL). In three studies that included
patients with severe secondary hyperparathyroidism, the
pooled estimated incidence of hypocalcemia was 38.0%.
In studies without severe secondary hyperparathyroidism
patients, the pooled estimated incidence of hypocalcemia
was 34.0%. There was no significant difference in the
incidence of hypocalcemia between the subgroups
(Supplementary Figure S2).
Changes in Ca levels, intact PTH levels,
and bone metabolism
Nine studies with 288 patients with ESRD evaluated
changes in serum calcium levels from baseline to post-
treatment. We used the last available values before the
end of the study and baseline values to calculate the
mean difference in serum calcium levels. Significant
heterogeneity was observed (I 2 = 86.5%, p = 0.000).

DENOSUMAB FOR PATIENTS WITH END-STAGE RENAL DISEASE
F I G U R E 3 Forest plot of all included studies evaluating changes in calcium (a), changes in phosphate (b), changes in ALP (c), changes
in PTH (d) after denosumab treatment. [Color figure can be viewed at wileyonlinelibrary.com]
Therefore, a random-effects model was used to evaluate
these changes. There was no significant change; the
mean difference was 0.04 mg/dL (95% CI, 0.12 to
0.20 mg/dL, Figure 3a). Seven studies reported changes
in the serum phosphate levels. On pooled analysis
using a random-effects model, the change from base-
line to post-treatment was not significant; the mean dif-
ference was 0.39 mg/dL (95% CI, 0.89 to 0.12 mg/
dL, I 2 = 94.6%, p = 0.00; Figure 3b).
After denosumab administration, the ALP levels
fell in four studies (standardized mean differences of
2.98, 95% CI: 5.36 to –0.59, I 2 = 95.0%, p = 0.00,
Figure 3c). Two studies enrolled patients with severe
secondary hyperparathyroidism. The pooled ALP
change in those groups (standardized mean
differences: –5.48, 95% CI: –7.80 to –3.16, I 2 = 76.6%)
was significantly more pronounced than two of groups
with moderate numbers of secondary hyperparathy-
roidism (standardized mean differences: –0.71, 95%
CI: –1.26 to 0.17, I 2 = 0.0%, Supplementary
Figure S3).
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7
Seven studies reported changes in PTH levels during
denosumab treatment. On pooled analysis, we found that
the PTH level decreased significantly with standardized
mean differences of –3.12 (95% CI: –4.94 to –1.29),
but with high inter-study heterogeneity (I 2 = 96.0%,
p = 0.00) (Figure 3D). Three studies enrolled patients
with severe secondary hyperparathyroidism. The pooled
PTH change in those groups (standardized mean differ-
ences: –6.99, 95% CI: –9.54 to –4.43, I 2 = 82.7%) was sig-
nificantly more pronounced than that of groups with
moderate numbers of secondary hyperparathyroidism
(standardized mean differences: –0.46, 95% CI: –1.11 to
0.18, I 2 = 66.1%). However, heterogeneity remained high
(Supplementary Figure S4).
Changes in the BMDs of the femoral neck
and lumbar spine
Nine studies evaluated the BMD changes during denosu-
mab treatment. The BMDs of the femoral neck and

8 GU ET AL.
F I G U R E 4 Forest plot of all included studies evaluating changes of BMD in femoral neck after denosumab treatment. [Color figure can
be viewed at wileyonlinelibrary.com]
lumbar spine increased significantly by 9.10% (eight stud-
ies, 95% CI: 4.07% to 14.13%, I 2 = 98.9%, p = 0.00,
Figure 4) and 9.00% (nine studies, 95% CI: 5.93%–12.07%,
I 2 = 97.5%, p = 0.00, Figure 5), respectively.
In three studies that included those with severe sec-
ondary hyperparathyroidism, significant increases in the
femoral neck and lumbar spine BMDs were apparent,
thus with mean differences of 18.80% (95% CI: 12.98%–
24.63%, I 2 = 95.5%, p = 0.00) and 14.54% (95% CI:
11.78%–17.30%, I 2 = 87.3%, p = 0.00), respectively. In
studies without severe secondary hyperparathyroidism
patients, significant increases in the femoral neck BMD
were evident in five studies (mean differences of 3.94%,
95% CI: 3.29%–4.59%, I 2 = 14.0%, p = 0.325) and lumbar
spine BMD in six studies (mean differences of 5.82%, 95%
CI: 5.40%–6.24%, I 2 = 0.0%, p = 0.549).
Evaluation of publication bias
Egger regression asymmetry tests were used to evaluate
publication bias in terms of changes in serum calcium,
phosphate, ALP, and PTH levels, as well as in BMD, from
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baseline to the post-treatment course of denosumab in
patients with ESRD. A publication bias was evident in
terms of changes in PTH levels (p = 0.001)
(Supplementary Table 3).
DISCUSSION
We found that denosumab treatment of dialysis-
dependent patients with ESRD increased the BMDs of
the lumbar spine and femoral neck, and decreased ALP
and PTH levels. The overall incidence of denosumab-
associated hypocalcemia was 35%. Serum calcium and
phosphate levels were not affected by denosumab treat-
ment, which is consistent with the data from an earlier
meta-analysis.37 Six new studies, involving 234 patients,
were included in this meta-analysis. We analyzed lumbar
spine and femoral neck BMD changes but not T-scores;
BMD data were more accurate.
Patients with CKD and osteoporosis show higher
fracture, morbidity, and mortality rates than the normal
populations.38 The rates of hip fracture are 7.5 and 13.6
per 1000 person-years in men and women on

DENOSUMAB FOR PATIENTS WITH END-STAGE RENAL DISEASE
F I G U R E 5 Forest plot of all included studies evaluating changes of BMD in lumbar spine after denosumab treatment. [Color figure can
be viewed at wileyonlinelibrary.com]
maintenance dialysis, respectively, which are much
higher than those in the general populations.11 In
patients with ESRD, hyperphosphatemia, 1,25(OH)2D3
deficiency, and hypocalcemia stimulate PTH synthesis
and secretion. PTH normalizes plasma calcium con-
centration by increasing bone turnover. All of
pro-inflammatory cytokines, tumor necrosis factor-α
(TNF-α), interleukin-1 (IL-1), and IL-6 also play impor-
tant roles in bone turnover.39
Denosumab is a fully humanized monoclonal immu-
noglobulin (Ig) G2 antibody that binds with high affinity
and specificity to the DE loop region of the receptor acti-
vator of NF-κB ligand (RANK-L).40 RANK-L promotes
osteoclastogenesis and osteoclast activation by binding to
RANK.41 Denosumab plays an antiresorptive role by inhi-
biting RANK signaling. Denosumab is used to treat osteo-
porosis in patients with advanced CKD; however, its risk
of renal toxicity is low.25–28,42 Hypocalcemia is a common
complication of denosumab treatment, particularly in
patients with ESRD. In our meta-analysis, the incidence
of symptomatic hypocalcemia ranged from 0 to 62.5%.
The pooled estimated incidence of denosumab-associated
hypocalcemia was 35%, similar to the 42% reported by
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9
Thongprayoon et al.37 Hypocalcemia is defined as a
serum calcium nadir <8.0 mg/dL, and usually occurs
from week 1 to month 2, especially in week 1–3, after
denosumab treatment commences. However, this compli-
cation can be prevented and corrected by using an appro-
priate high-calcium dialysate, adequate calcium, and
active vitamin D supplementation. In the included stud-
ies, hypocalcemia was adjusted for the drug dosage or
appropriate treatment. Therefore, there was no difference
in serum calcium levels compared to baseline levels at
the end of follow-up. Serum calcium levels should be fre-
quently monitored when denosumab is prescribed to
hemodialysis patients, at least during the first week, and
preferably during the first month. Aggressive denosumab
dose reduction or the addition of active vitamin D and
calcium supplementation may be required to prevent the
development of hypocalcemia. Although risk factors for
denosumab-induced hypocalcemia in hemodialysis
patients should be considered, only two studies have
addressed this issue. A correlation was found between
total ALP levels and the extent of denosumab-induced
hypocalcemia.43 Another study reported that tartrate-
resistant acid phosphatase-5b (TRACP-5b) levels most

10
accurately predicted denosumab-induced hypocalcemia
(area under the curve: 0.750).34
The mechanism of denosumab-induced hypocalcemia
in hemodialysis patients is believed to be similar to that
of Hunger Bone Syndrome that develops post-parathy-
roidectomy.25 In patients with ESRD, elevated iPTH
levels accelerate bone resorption to maintain calcium
homeostasis via calcium efflux from the bone to the
blood. The endogenous supply of calcium from the bone
is quickly reduced when denosumab prevents iPTH-
dependent bone resorption; however, bone matrix miner-
alization remains ongoing. Thus, hypocalcemia can
develop after denosumab treatment as a dose-dependent
Hunger Bone Syndrome following parathyroidectomy.34
Denosumab significantly improved BMD and reduced
ALP and PTH levels in patients undergoing hemodialysis.
The BMDs of the lumbar spine and femoral neck
increased from 6 months to 1 year in hemodialysis
patients receiving denosumab. Unlike bisphosphonates,
denosumab did not affect renal function. There is no
need to modify the dose of denosumab in patients with
impaired kidney function because denosumab is not
eliminated by the kidney, obviating concerns regarding
bone retention.44 The antiresorptive effects of denosumab
involves RANKL inhibition. Most denosumab-treated
dialysis patients show elevated PTH levels during the first
month of treatment. After the inhibition of bone resorp-
tion, a compensatory PTH increase in response to serum
calcium reduction medicated by denosumab is biologi-
cally plausible. However, in our meta-analysis, PTH and
ALP levels were much lower than before denosumab
commenced, probably due to appropriate calcium and
active vitamin D supplementation.
We found that the BMD was significantly higher in
patients with severe hyperparathyroidism than in those
without. In general, a high PTH level (>300 pg/mL) is
associated with high bone turnover, which is evident on
bone biopsy of CKD patients,45 and it is attributable to
increased osteoclast activity. Denosumab blocks bone
resorption by inhibiting osteoclast activity. Thus, denosu-
mab may be more effective in patients with severe sec-
ondary hyperparathyroidism.
Our study has several limitations. First, statistical het-
erogeneity was high. Various tests can explain this het-
erogeneity. Thus, we employed random-effects models.
Second, we analyzed observational studies and only one
randomized controlled trial. Large, high-quality random-
ized controlled trials are required to validate our conclu-
sions. Third, all the studies aimed to evaluate the effect of
denosumab on BMD and not on fracture risk. Although
BMD reflects bone density, volume, and fracture risk, it
is not informative in terms of bone turnover or minerali-
zation. In patients undergoing dialysis, BMD may be
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GU ET AL.
affected by many factors in patients on dialysis.46 Further
studies are needed to assess the effects of denosumab on
fragility fractures in these patients.
In conclusion, denosumab may improve BMD in
patients on hemodialysis. The incidence of denosumab-
associated hypocalcemia in these patients was 35%.
Systemic hypocalcemia can be prevented through care-
ful monitoring, sufficient calcium intake, and active
vitamin D supplementation. Denosumab is an alterna-
tive treatment option for osteoporosis in patients
with CKD.
C O N F L I C T O F I N T E R E S T S T A TE M E N T
The authors declare no conflicts of interest.
ORCID
Jianjun Gao https://orcid.org/0000-0001-9675-3071
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