The Journal of Clinical Endocrinology & Metabolism, 2022, 00, 1–7

https://doi.org/10.1210/clinem/dgac631

Clinical Practice Guideline Systematic Review

A Systematic Review Supporting the Endocrine Society

Clinical Practice Guideline on the Treatment of

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Hypercalcemia of Malignancy in Adults
Mohamed O. Seisa,1 Tarek Nayfeh,1 Bashar Hasan,1 Mohammed Firwana,1 Samer Saadi,1
Ahmed Mushannen,1 Sahrish H. Shah,1 Noora S. Rajjoub,1 Magdoleen H. Farah,1 Larry J. Prokop,2
Zhen Wang,1 Ghada El-Hajj Fuleihan,3 Matthew T. Drake,4 and Mohammad Hassan Murad1
1
Mayo Clinic Evidence-Based Practice Center, Rochester, MN 55902, USA
2
Mayo Clinic Libraries, Rochester, MN 55902, USA
3
Calcium Metabolism and Osteoporosis Program, American University of Beirut, Beirut, Lebanon
4
Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, Rochester, MN 55902, USA
Correspondence: Mohamed O. Seisa, MD, Mayo Clinic, 200 1st street SW, Rochester, MN 55902, USA
Email: seisa.mohamed@mayo.edu.

Abstract
Context: Hypercalcemia is a common complication of malignancy that is associated with high morbidity and mortality.
Objective: To support development of the Endocrine Society Clinical Practice Guideline for the treatment of hypercalcemia of malignancy in
adults.
Methods: We searched multiple databases for studies that addressed 8 clinical questions prioritized by a guideline panel from the Endocrine
Society. Quantitative and qualitative synthesis was performed. The Grading of Recommendations Assessment, Development and Evaluation
(GRADE) approach was used to assess certainty of evidence.
Results: We reviewed 1949 citations, from which we included 21 studies. The risk of bias for most of the included studies was moderate. A
higher proportion of patients who received bisphosphonate achieved resolution of hypercalcemia when compared to placebo. The incidence
rate of adverse events was significantly higher in the bisphosphonate group. Comparing denosumab to bisphosphonate, there was no
significant difference in the rate of patients who achieved resolution of hypercalcemia. Two-thirds of patients with refractory/recurrent
hypercalcemia of malignancy who received denosumab following bisphosphonate therapy achieved resolution of hypercalcemia. Addition of
calcitonin to bisphosphonate therapy did not affect the resolution of hypercalcemia, time to normocalcemia, or hypocalcemia. Only indirect
evidence was available to address questions on the management of hypercalcemia in tumors associated with high calcitriol levels, refractory/
recurrent hypercalcemia of malignancy following the use of bisphosphonates, and the use of calcimimetics in the treatment of hypercalcemia
associated with parathyroid carcinoma. The certainty of the evidence to address all 8 clinical questions was low to very low.
Conclusion: The evidence summarized in this systematic review addresses the benefits and harms of treatments of hypercalcemia of
malignancy. Additional information about patients’ values and preferences, and other important decisional and contextual factors is needed to
facilitate the development of clinical recommendations.
Key Words: hypercalcemia of malignancy, Endocrine Society, bisphosphonate, denosumab, skeletal-related events
Abbreviations: BP, bisphosphonate; CPG, clinical practice guideline; Dmab, denosumab; FDA, US Food and Drug Administration; GRADE, Grading of
Recommendations, Assessment, Development and Evaluation; HCM, hypercalcemia of malignancy; HR, hazard ratio; IRR, incidence rate ratio; IV,
intravenous; PICO, patient, intervention, comparison, outcomes; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT,
randomized controlled trial; RR, relative risk; SRE, skeletal-related event.

Hypercalcemia of malignancy (HCM) is the most common
metabolic complication of malignancies (1-6). It is most com-
monly associated with squamous cell carcinomas, breast and
renal carcinomas, and multiple myeloma and other hemato-
logic malignancies. HCM may affect up to 30% of patients
during the course of their disease (4, 7). Its presence confers
a poor prognosis, and, if left untreated, it can be life threaten-
ing (8). HCM treatment substantially and rapidly alleviates
symptoms; improves quality of life; and, importantly, pro-
vides an opportunity to administer therapies to target the
primary malignancy. The underlying pathophysiology of
HCM is most often through stimulation of parathyroid hor-
mone–related peptide (PTHrP)-mediated osteoclastic bone re-
sorption. Treatment is directed at hydration to enhance renal
calcium excretion and at decreasing bone resorption via the
use of potent antiresorptive medications. These include intra-
venous (IV) bisphosphonates (BPs) as the cornerstone therapy
for HCM, with denosumab (Dmab) more commonly used in
patients with refractory HCM and in those with renal failure.
In tumors secreting calcitriol, glucocorticoids are used, while

Received: 19 October 2022. Editorial Decision: 21 October 2022. Corrected and Typeset: 21 December 2022
Published by Oxford University Press on behalf of the Endocrine Society 2022.
This work is written by (a) US Government employee(s) and is in the public domain in the US.
2 The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0
calcimimetics are indicated in parathyroid hormone (PTH)–
secreting tumors (1, 3, 9).
While several published clinical practice guidelines (CPGs)
target the treatment of cancer patients with bone metastases,
multiple myeloma, parathyroid carcinoma, and small cell car-
cinoma of the ovary (10-19), we are unaware of any guidelines
that are specific for the treatment of HCM. In this context, the
Endocrine Society gathered a multidisciplinary panel of clinic-
al experts, together with experts in systematic literature re-
view, to develop CPGs for the treatment of HCM. These
CPGs apply to adults with HCM from humoral hypercalce-
mia of malignancy, local osteolytic hypercalcemia, calcitriol-
mediated hypercalcemia, and parathyroid carcinoma. The
CPGs apply to inpatient and outpatient settings alike and pro-
vide a framework to guide endocrinologists, oncologists, and
primary care and palliative care experts as well as other con-
cerned stakeholders. The writing panel identified several clin-
ical scenarios frequently faced by health care providers who
manage patients with HCM of various underlying pathophy-
siologic mechanisms. The writing panel also identified import-
ant clinical outcomes that would determine the selection of
specific treatment strategies for each clinical scenario. To sup-
port the guideline development process and summarize the
evidence base for the CPGs, we conducted this systematic re-
view and meta-analysis.
Methods
This report was written in accordance with the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) Statement (20). The 8 questions of this review
and the inclusion and exclusion criteria were developed by a
guideline panel from the Endocrine Society.
Eligibility Criteria
The guideline panel members prioritized 8 questions address-
ing the treatment of HCM. The questions are presented using
the PICO format (patient, intervention, comparison, out-
comes) along with the eligibility criteria in Supplementary
Table S1 (21).
Data Sources and Search Strategies
Five comprehensive searches of several databases from each
database’s inception to April 6, 2022, any language, were con-
ducted. The databases included Ovid MEDLINE, Epub Ahead
of Print, In-Process, In-Data-Review & Other Non-Indexed
Citations, Daily; Ovid EMBASE; Ovid Cochrane Central
Register of Controlled Trials; Ovid Cochrane Database of
Systematic Reviews; and Scopus. The search strategy was de-
signed and conducted by a medical reference librarian.
Additional references identified by the guideline panel mem-
bers were reviewed for eligibility. The strategy listing all
search terms used and how they were combined is available
in the appendix (Supplementary Table S2) (21).
Study Selection
Abstracts and titles were screened for eligibility by pairs of in-
dependent reviewers using the inclusion and exclusion cri-
teria. Full-text articles were screened if deemed eligible by at
least one reviewer at the abstract level. At the level of full-text
screening, any disagreements between the 2 reviewers (M.S.
and T.N.) were resolved by a third reviewer (H.M.).
Data Extraction
Data from the included studies were extracted by pairs of in-
dependent reviewers. Data included patient characteristics
(number of patients, mean age, female percentage, and details
of intervention) and outcomes of interest (resolution of hyper-
calcemia, duration of normocalcemia, time to normocalce-
mia, decrease in skeletal-related events [SREs], ability to
receive chemotherapy, and quality of life).
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Methodologic Quality and Certainty of the Evidence
The risk of bias in the included studies was assessed by 2 inde-
pendent reviewers. The risk of bias was assessed using the
Newcastle-Ottawa scale (22) for nonrandomized studies
assessing selection, comparability, and outcome measurements.
The Cochrane Risk of Bias Tool version 2 (23) was used to
access the risk of bias of randomized controlled trials
(RCTs) assessing randomization, deviation from intended
interventions, missing outcome data, measurement of out-
comes, andselection of the reported results. The Grading of
Recommendations, Assessment, Development and Evaluation
(GRADE) approach was used to rate the certainty of evidence
for each outcome. RCTs start at high certainty, and observa-
tional studies start at low certainty. Certainty of evidence is
then downrated according to risk of bias, inconsistency, indir-
ectness, imprecision, and publication bias.
Data Synthesis and Analysis
For binary outcomes, relative risks (RR) and incidence rate ra-
tios (IRR) were estimated along with 95% CIs. For continu-
ous outcomes, the mean deviation was calculated, and the
95% CI was estimated. For single-arm (noncomparative)
studies, proportions were estimated along with 95% CI.
Due to anticipated heterogeneity, meta-analysis using the re-
stricted maximum likelihood random effects model was
used. The I2 index and Cochrane Q test were used to evaluate
heterogeneity. All statistical analyses were conducted using
R version 4.2.0 (R Foundation for Statistical Computing).
When meta-analysis was not feasible, data were presented
narratively.
Results
Study Selection
We reviewed 1949 citations, from which we finally included
21 studies (question 1, 4 studies; question 2, 7 studies; ques-
tion 3, 1 study; question 4, 3 studies; question 5, 4 studies;
question 6, 5 studies; question 7, 1 study; and question 8, 2
studies). Some of these studies were included in more than
one question. The description of study selection is depicted
in the PRISMA flow diagram (24, 25) in Supplementary
Fig. S1 (21). The characteristics of included studies, details
of the interventions reported in each study, and the risk of
bias assessment tables are provided in Supplementary Tables
S3 and S4, respectively (21).
1. Should a bisphosphonate or denosumab vs no treatment
with a bisphosphonate or denosumab be used for adults
with hypercalcemia of malignancy?
We identified 4 RCTs (26-29) that reported on 301 patients
with HCM. The included studies compared the efficacy of BP
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0
to placebo. All the included studies had a moderate risk of bias
(Supplementary Table S4) (21). No studies comparing the ef-
ficacy of Dmab to placebo were identified. A higher propor-
tion of patients who received BP achieved resolution of
hypercalcemia when compared with placebo (4 studies, RR
= 2.22; 95% CI, 1.57-3.14; low certainty). The incidence
rate of the adverse events was significantly higher in the BP
group (3 studies, IRR = 2.33; 95% CI, 1.16-4.69; low cer-
tainty). The results of meta-analyses of the outcomes and ad-
verse events are summarized in Supplementary Table S5 and
in Supplementary Fig. S2 (21).
2. Should denosumab vs a bisphosphonate be used for
adults with hypercalcemia of malignancy?
We identified 1 observational study (30) with 40 patients.
The study evaluates the efficacy of Dmab vs BP in hypercalce-
mia of multiple myeloma patients. There was no significant
difference in the rate of patients who achieved resolution of
hypercalcemia (RR = 1.03; 95% CI, 0.53-2.00; low certainty).
Hypocalcemia rates also did not differ significantly. There was
no significant difference in hypocalcemia events rate.
Certainty of evidence was low.
Due to lack of direct evidence for this question, data were
retrieved from 6 studies (31-36) with 14 391 patients who re-
ceived either BP or Dmab for indications other than treatment
of HCM (ie, prevention of SREs, treatment of bone metasta-
sis, effect on calcium levels). Only 1 of these 6 studies (31)
evaluated prevention of hypercalcemia as the primary end-
point. Diel et al reported that Dmab delayed the time to first
on-study HCM compared with zoledronic acid (hazard ratio
[HR] = 0.63; 95% CI, 0.41-0.98; P = 0.042). Also, the study
reported that patients who received Dmab had a lower risk
of developing HCM than those receiving zoledronic acid
(1.7% vs 2.7%; P = 0.028). Another study (36) found that
the incidence of hypercalcemia was lower in patients who re-
ceived Dmab (1.7%) compared with patients who were treated
with zoledronic acid (3.5%). Three studies (32, 34, 36) eval-
uated the SREs. The Dmab group was associated with fewer
SREs (2 studies (32, 36), HR = 0.83; 95% CI, 0.77-0.89; low
certainty). As for hypocalcemia, the patients who received
Dmab had higher rates of hypocalcemic events than those
who received BP (3 studies (32, 34, 36), IRR = 1.73; 95% CI,
1.30-2.30; very low certainty). The survival rate was not differ-
ent between the 2 treatment groups (4 studies (31, 32, 34, 35),
RR = 1.00; 95% CI, 0.94-1.06; low certainty). The results of
meta-analyses of the outcomes and adverse events are summar-
ized in Supplementary Table S5 and in Supplementary Fig. S2.
3. Should addition of calcitonin vs no calcitonin be used for
adults with hypercalcemia of malignancy who will be
started on a bisphosphonate or denosumab?
We included 1 observational study (37) that reported on
140 patients with moderate or severe HCM who were treated
with BP therapy with or without calcitonin. The study had a
low risk of bias (Supplementary Table S2) (21). The mortality
rate was significantly lower in the BP group (RR = 0.45; 95%
CI, 0.22-0.91; very low certainty). There was no significant
difference in the resolution of hypercalcemia, time to normo-
calcemia, and hypocalcemia. The results of the outcomes and
3
adverse events are summarized in Supplementary Table S5
(21).
4. Should denosumab vs no denosumab be used for adults
with refractory/recurrent hypercalcemia of malignancy
on a bisphosphonate?
We did not identify any direct evidence evaluating Dmab
used to treat HCM refractory to BP therapy. Indirect evidence
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was retrieved from 3 single-arm studies (38-40) that reported
on 44 patients. All the included studies had a moderate risk of
bias (Supplementary Table S2) (21). Two-thirds of the pa-
tients achieved resolution of hypercalcemia after adding
Dmab to their BP regimen (3 studies, proportion 67%; 95%
CI, 51%-82%; very low certainty). Adverse events reported
with Dmab therapy in these studies included hypocalcemia,
hypophosphatemia, and nausea. The results of meta-analyses
of the outcomes and adverse events are summarized in
Supplementary Table S5 and in Supplementary Fig. S2 (21).
5. Should a bisphosphonate or denosumab vs no bisphosph-
onate or denosumab be used for adults with hypercalce-
mia resulting from tumors associated with high
calcitriol levels who are already treated with a
glucocorticoid?
We were unable to identify any study that directly evaluated
the use of BP or Dmab in patients with calcitriol-mediated hy-
percalcemia who were already receiving glucocorticoid ther-
apy but continued to have severe or symptomatic
hypercalcemia. Due to lack of direct evidence for this ques-
tion, indirect evidence was retrieved from 4 RCTs (26-29)
that reported on 301 patients with HCM (results summarized
in question 1).
6. Should a calcimimetic vs a bisphosphonate or denosumab
be used for adults with hypercalcemia due to parathyroid
carcinoma?
We were unable to identify any study that directly evaluated
the efficacy of calcimimetic therapy compared to BP or Dmab
for the treatment of hypercalcemia due to parathyroid carcin-
oma. Due to lack of direct evidence for this question, indirect
evidence was retrieved from 5 studies (41-45) with 125 pa-
tients (2 studies (41, 43) had different comparators, and the
other 3 studies had single-arm designs (42, 44, 45)). The in-
cluded studies had a low to moderate risk of bias
(Supplementary Table S4) (21).
Two RCTs (41, 43) comparing the oral BP alendronate vs
placebo in patients with primary hyperparathyroidism
showed no significant difference in the resolution of hypercal-
cemia between the 2 groups (odds ratio = 1.13; 95% CI,
0.07-18.75; very low certainty). In the other 3 observational
studies (42, 44, 45), patients received cinacalcet for the treat-
ment of intractable primary hyperparathyroidism or parathy-
roid carcinoma, and the proportion of patients who achieved
resolution of hypercalcemia was 33% (95% CI, 0%-87%;
very low certainty). Treatment-related adverse events with ci-
nacalcet therapy were reported in 27 of 53 patients (nausea in
14 patients, vomiting in 9 patients, paresthesia in 3 patients,
gastroesophageal reflux disease in 2 patients, hives in 1
patient, and hypercalcemia in 1 patient). The results of
4 The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0
meta-analyses of the outcomes and adverse events are sum-
marized in Supplementary Table S5 and in Supplementary
Fig. S2 (21).
7. Should addition of a bisphosphonate or denosumab vs no
addition of a bisphosphonate or denosumab be used for
adults with hypercalcemia due to parathyroid carcinoma
in patients not adequately controlled with a
calcimimetic?
We were unable to identify any study that directly addresses
this question. Indirect evidence was retrieved from 1 single-arm
study (46) by Eremkina et al. The study included 10 patients
with severe or symptomatic hypercalcemia due to primary
hyperparathyroidism, including 2 who had parathyroid carcin-
oma. Duration of use of Dmab and cinacalcet was not reported.
Resolution of hypercalcemia was achieved in 4 patients. This
study had a moderate risk of bias (Supplementary Table S4).
The results of the outcomes and adverse events are summarized
in Supplementary Table S5.
8. Should a calcimimetic vs no calcimimetic be used for
adults with hypercalcemia due to parathyroid carcinoma
who are not adequately controlled with a bisphosphonate
or denosumab?
We did not identify any studies that directly examined the
efficacy of a calcimimetic compared to placebo in patients
with HCM due to parathyroid carcinoma who have already
received treatment with BP or Dmab. Indirect evidence was re-
trieved from 2 single-arm studies (44, 45) that reported on 36
patients who received cinacalcet for the treatment of intract-
able primary hyperparathyroidism or parathyroid carcinoma.
These studies are reported narratively, and certainty of evi-
dence was very low. The study (44) of Silverberg et al included
29 patients with parathyroid carcinoma who underwent para-
thyroid surgery (23 previously treated with BP). The study re-
ported that no patient became normocalcemic at the end of the
titration phase of cinacalcet therapy. Treatment-related ad-
verse events were reported in 5 of 29 patients (vomiting in 2
patients, nausea in 1 patient, hives in 1 patient, and hypercal-
cemia in 1 patient). Another study (45) by Takeuchi et al re-
ported on 7 patients, (5 of whom had prior parathyroid
surgery and 4 who had been previously treated with BPs)
and noted that cinacalcet decreased serum calcium levels to
the normocalcemic range in 3 of 5 patients with parathyroid
carcinoma and 2 of 2 patients with intractable primary hyper-
parathyroidism. All 7 patients reported treatment-related ad-
verse events (nausea in 4 patients, vomiting in 3 patients, and
gastroesophageal reflux disease in 2 patients). The 2 studies
had a low risk of bias (Supplementary Table S4).
Discussion
This technical report provides the evidence that informed
the formulation of the “Treatment of Hypercalcemia of
Malignancy in Adults” CPG by the Endocrine Society.
Hydration combined with potent antiresorptive agents, name-
ly IV BPs and Dmab, are cornerstone therapies regardless of
disease pathophysiology. Clinical strategies can be further
modified, using calcimimetics in the case of parathyroid car-
cinoma, or glucocorticoids in the case of calcitriol-secreting
tumors. However, selection of the optimal therapy, and its
use either sequentially or in combination with other medica-
tions, remains unclear. The systematic reviews and meta-
analyses conducted were therefore framed by questions that
illustrate 8 clinical scenarios encountered during the care of
patients with HCM in an effort to provide needed evidence
to fill these knowledge gaps. The certainty of the available evi-
dence was low to very low for all recommendations, and indir-
ect evidence was used for several clinical scenarios.
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Importantly, regardless of the clinical scenario, treatment of
the primary malignancy is instrumental in controlling hyper-
calcemia and preventing its recurrence.
One clinical question focused on the value associated with
treatment using potent antiresorptive agents, namely, either
IV BP or Dmab, compared to placebo in patients with
HCM. The systematic review identified 4 studies (26-29)
that compared IV BP vs placebo for the treatment of HCM, al-
though it is notable that 3 of the studies were performed with
early non–nitrogen-containing BPs (etidronate and clodro-
nate), which are considerably less potent at inhibiting
osteoclast activity than the more recently developed nitrogen-
containing BPs (pamidronate and zoledronic acid). Notably,
no studies were identified that compared Dmab to placebo
for the treatment of HCM. Reasons for this are unknown
but may reflect accumulated evidence that treatment with
antiresorptive IV BP therapy was associated with increased
rates of HCM resolution and therefore that treatment with
placebo in future studies would be unethical.
The systematic review also evaluated Dmab vs IV BP ther-
apy for the treatment of HCM. In this context, only 1 small
observational study in patients with HCM due to multiple
myeloma was identified, which did not identify differences be-
tween the interventions (30). However, indirect evidence (ie,
use of Dmab or IV BP for indications other than HCM) dem-
onstrated that Dmab was more effective for prevention, rather
than treatment, of HCM compared to IV zoledronic acid
(31, 36). Given this slight evidence of efficacy, Dmab rather
than IV BP may be preferable for treatment of adults with
HCM. However, given reports that Dmab discontinuation
can be associated with an increased risk for hypercalcemia
in patients with malignancy (47), presumably due to rebound
osteoclastogenesis, Dmab therapy for treatment of HCM
should likely be used judiciously given the potential for com-
plications associated with therapy discontinuation.
One observational study that evaluated adding calcitonin to
IV BP therapy in patients with moderate-to-severe HCM was
identified in the systematic review. In this study, calcitonin
addition failed to show additional benefit (37). However, giv-
en the rapidity of onset of action for calcitonin (4-6 hours)
relative to that of IV BP (48-72 hours), calcitonin addition
may be appropriate in patients with severe hypercalcemia,
particularly when the HCM is refractory to provision of IV
hydration. Notably, tachyphylaxis is common with calcitonin
therapy, with effectiveness typically waning within 48 to
72 hours, the timeframe during which IV BP therapy has its
onset of action.
A common clinical scenario is HCM that is either recurrent
or refractory to medical therapy. In this context, the systemat-
ic review did not identify any direct evidence regarding the se-
quencing of IV BP and Dmab. However, indirect evidence
from 3 single-arm studies demonstrated that the addition of
Dmab in patients with HCM refractory to IV BP therapy re-
sulted in HCM resolution in some patients. It is noteworthy
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0
that Dmab has been approved by the US Food and Drug
Administration (FDA) for the treatment of HCM refractory
to IV BP. The absence of studies comparing the converse (ie,
provision of IV BP to patients with HCM refractory to
Dmab) is a limitation of the existing studies.
One clinical question addressed therapy in patients with
HCM due to calcitriol-secreting tumors (3, 48). In this setting,
glucocorticoid therapy is used to limit conversion of
25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol)
via glucocorticoid-mediated inhibition of the 1-alpha-
hydroxylase enzyme to ultimately limit intestinal calcium ab-
sorption (49, 50). The systematic review was unable to identify
any studies assessing the addition of IV BP or Dmab in patients
with calcitriol-mediated hypercalcemia who were already re-
ceiving glucocorticoid therapy but who continued to have se-
vere or symptomatic hypercalcemia. Accordingly, the
guideline committee used indirect, very low–certainty evidence
derived from 4 RCTs, each with a moderate risk of bias. The
studies included 2 RCTs of etidronate vs control (27, 29), 1
study with clodronate (28), and 1 with pamidronate (26).
Patients randomized to IV BPs were more like to have reso-
lution of hypercalcemia but were also more likely to suffer ad-
verse events (Supplementary Fig. S2.1) (21). Importantly, only
1 study included subjects with lymphatic tumors, the popula-
tion of interest in terms of pathophysiology of hypercalcemia.
Although IV BPs (such as pamidronate and zoledronic acid)
and Dmab would be expected to further decrease serum cal-
cium in patients with calcitriol-mediated hypercalcemia
treated with glucocorticoids, such evidence remains lacking.
Three clinical questions investigated the optimal approach
for patients with HCM from parathyroid carcinoma. The
questions aimed to address disease management regarding ini-
tial medication (calcimimetic vs BP or Dmab) and the sequence
of use of these medications (ie, starting with a calcimimetic fol-
lowed by either antiresorptive agent or starting with an antire-
sorptive drug followed by a calcimimetic). The systematic
review was unable to identify any direct evidence to support
recommendations for any of the 3 clinical questions. A total
of 6 studies (Supplementary Tables S3 and S4) were evaluated,
which included patient follow-up from 4 to 24 months. Two
studies included patients with primary hyperparathyroidism
randomized to alendronate vs placebo (41, 43). Three observa-
tional studies followed patients with intractable primary
hyperparathyroidism or parathyroid carcinoma treated with
cinacalcet (42, 44, 45). One case series included patients
with parathyroid carcinoma treated with Dmab (46).
Although the risk of bias was low for all studies (except for
the case series, for which it was moderate), the certainty of evi-
dence was very low regarding the outcome of HCM resolution
in both the alendronate and cinacalcet studies.
Strengths and Limitations
Strengths of the systematic review reflect a comprehensive lit-
erature search to identify and review the evidence available to
date as well as rigorous adherence to a structured methodo-
logic approach for evidence review. Evidence was gathered
by interrogating 7 medical databases, current through April
6, 2022, with additional relevant studies brought forward
by the Endocrine Society writing committee of the ensuing
CPGs. This report was written in accordance with the
PRISMA Statement (20). Study selection and abstract title
screening were performed by 2 independent reviewers, as
5
was data extraction. Risk of bias was assessed by well-
established tools, the Newcastle-Ottawa scale for observa-
tional studies (22), and the Cochrane Risk of Bias Tool 2 for
randomized trials (23). Finally, the GRADE approach was
used to rate the certainty of evidence for all outcomes (51).
Challenges and limitations encountered reflect the limited
evidence available, the low to very low certainty of the evi-
dence, reflecting a lack of comparative studies to assess the
relative efficacy of medications of interest, and the inclusion
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of studies of patients without parathyroid carcinoma (ie, pa-
tients with primary hyperparathyroidism and intractable
hyperparathyroidism) due to the lack of relevant studies
(Supplementary Tables S3 and S4.1 and S4.2) (21).
Furthermore, for some clinical scenarios, both the population
of interest and outcomes reported were different than specified
in the clinical question. Indeed, for the second clinical question
for example, we used evidence from patients with cancer and
bone metastases, rather than exclusively with HCM, and the
selected outcome was prevention of skeletal-related events, ra-
ther than some of the preselected outcomes such as resolution
of hypercalcemia and time to normocalcemia (see
Supplementary Table S3 for population characteristics in the
various studies and Supplementary Table S5 for the outcomes
reported) (21). Indirectness of the evidence was also because
we considered prevention of hypercalcemia as a surrogate
for treatment of hypercalcemia. Finally, most evidence in this
report was based on relatively small studies, with modest sam-
ple sizes and relatively short follow-up periods for outcomes of
interest. The evidence that enabled regulatory agency approval
of the antiresorptive zoledronic acid was based on 2 pivotal
studies that compared zoledronic acid and pamidronate with
less than 300 participants (52). The FDA has approved
Dmab for the treatment of HCM refractory to BP therapy.
The approval of Dmab is based on positive results from an
open-label, single-arm study that enrolled patients with ad-
vanced cancer and persistent hypercalcemia after recent BP
treatment (40, 53).The approval of cinacalcet for the manage-
ment of HCM in parathyroid carcinoma is based on the obser-
vational studies captured in this report (44).
Conclusion
This systematic review summarizes the best available evidence
regarding medical treatment of HCM in adults, regardless of
locale (outpatient, hospital, or hospice settings), with current-
ly available medications approved for such use to date. The
certainty of available evidence to support the recommenda-
tions to address 8 clinical scenarios formulated by the
Endocrine Society Guideline panel was low to very low,
underscoring the importance of shared decision making to ac-
count for the relevant contextual and decisional factors in-
volved in the selection of care pathways. These include
patient values and preferences, acceptability, feasibility,
cost, and equity, which will vary accordingly to local health
care settings and across countries (54). These factors were
carefully considered during the development of the
Endocrine Society Clinical Practice Guidelines on the
Management of Adult Patients with Hypercalcemia of
Malignancy (55).
Funding
This work was funded by the Endocrine Society.
6 The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0
Disclosures
The authors have nothing to disclose.
Data Availability
Original data generated and analyzed during this study are in-
cluded in the repository listed in references. The data that sup-
port the findings of this study are openly available in the
figshare data repository.
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