Keywords
denosumab - calcium homeostasis - hypercalcemia - hyperparathyroidism
Introduction
Primary hyperparathyroidism (PHPT) occurs at all ages [1] and manifests as a mineral metabolism
disorder, urinary calculus, hypercalcemia, or even hypercalcemic crisis, an
extremely serious condition that needs to be treated immediately [2]. Parathyroidectomy is considered one of
the best treatments for hypercalcemia in patients with PHPT [3]. However, drug treatment of
hypercalcemia is crucial in clinical practice. Dealing with hypercalcemia by medical
management before the surgery it is important to keep the condition of the patient
stable and enhance the tolerance of patients to surgery [4]. Moreover, some patients do not meet the
surgical criteria or do not wish to undergo a parathyroidectomy.
Denosumab is a type of completely human monoclonal antibody that gained US approval
in 2010 for treating postmenopausal osteoporosis. It functions as an inhibitor of
receptor activator of nuclear factor kappa-B ligand (RANKL), thereby restraining
osteoclasts to reduce bone turnover. Thus, it has been used in males and
postmenopausal women with osteoporosis [5]
[6]. Furthermore, it has the
potential to reduce serum calcium levels as it can inhibit osteoclast activation and
prevent calcium in the bone from being released into the blood. Hence, denosumab can
be used for treating hypercalcemia in a new consensus on primary hyperparathyroidism
[7].
However, definitive evidence and clinical trials evaluating the effectiveness and
safety of denosumab in hypercalcemia management in PHPT remains insufficient.
Denosumab remains an off-label therapy for hypercalcemia in PHPT. Additionally, data
on the speed and extent of the effect of denosumab treatment on blood calcium levels
in patients with PHPT are lacking. To answer these important clinical questions,
this review summarized published studies on denosumab therapy for hypercalcemia in
PHPT. It provides clinical evidence of the efficacy and safety of denosumab in
hypercalcemia management.
Materials and Methods
Data sources and searches
We searched for related studies in PubMed and Cochrane, last updated on March
20th, 2024, using denosumab, hyperparathyroidism, and hypercalcemia as the major
search terms. Two independent investigators (Qian Ren and Xiaona Zhang)
conducted this search. No automated tools were used during this process.
Selection criteria
Observational studies, case reports, or case series describing patients with
hyperparathyroidism and hypercalcemia treated with denosumab were included.
Studies published in English were included, while reviews, comments, and
articles that only had abstracts were excluded. Duplicate studies were also
excluded. Two independent investigators evaluated and screened the abstracts and
titles of the retrieved studies (Qian Ren and Xiaona Zhang).
Data extraction
Data were extracted by two independent investigators (Qian Ren and Xiaona Zhang)
and included patient age, sex, complications (kidney stone, fracture),
histopathology, PTH level, and combined therapies (fluid resuscitation,
diuretics, cinacalcet, calcitonin, cinacalcet, and bisphosphonate). We extracted
the highest serum calcium levels at baseline and the value of serum calcium post
denosumab treatment. Disagreements were discussed and resolved by a third
investigator (Simin Zhang). No automated tools were used during this
process.
Statistical analysis
Continuous variables are expressed as medians and interquartile ranges. Data were
analyzed using SPSS version 23 for Windows. Study quality was evaluated using
the NIH Quality Assessment Tool (https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools).
The quality of each study was rated by two independent quality reviewers (Yihan
Zhao and Qian Ren).
Results
Study selection
The study selection process is illustrated in [Fig. 1]. A total of 75 potentially
eligible studies were identified using this search strategy. We excluded
undesirable studies based on their titles and abstracts. Meanwhile, studies that
could not be retrieved or passed the conformity assessment were excluded.
Finally, a total of 18 studies were included in this review. Moreover, the study
quality was assessed using the NIH Quality Assessment Tool, as depicted in
Table 1S and 2S.
Fig. 1 The study selection process.
Clinical characteristics of the patients
All included studies were conducted in 12 countries and their clinical
characteristics are summarized in [Table
1]. Among them, five were cohort studies [8]
[9]
[10]
[11]
[12], whereas the other 13 were case reports [13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]. In total, 161 patients with
primary hyperparathyroidism were enrolled in this study. The average age of the
patients was 61 (47–72) years and 26.7% were male. The highest level of serum
calcium was 3.76 (3.11–4.20) mmol/l and the average level of serum PTH was 703
(125–1547) pg/ml. Among the 161 patients, 40 (24.8%) had kidney stones and 66
(41.0%) had bone fractures. Ten patients (6.2%) were diagnosed with parathyroid
carcinoma, most of whom have been described in case reports. Bisphosphonates and
denosumab were the most common medicines used in combination therapy for
hypercalcemia in cohort studies. Over half of the patients in the case reports
received fluid resuscitation, calcitonin, cinacalcet, or bisphosphonate
therapy.
Table 1 Clinical characteristics of the
patients.
|
Clinical characteristics
|
Total
|
Cohort studies
|
Case reports
|
|
Number of Studies
|
18
|
5
|
13
|
|
Number of Patients
|
161
|
144
|
17
|
|
Age (years)
|
61 (47 –72)
|
67 (65–73)
|
57 (40–66)
|
|
Male (%)
|
43 (26.7)
|
32 (22.2)
|
11 (64.7)
|
|
Parathyroid carcinoma (%)
|
10 (6.2)
|
2 (1.4)
|
8 (47.1)
|
|
Kidney stone (%)
|
40 (24.8)
|
35 (24.3)
|
5 (29.4)
|
|
Fracture (%)
|
66 (41.0)
|
63 (43.5)
|
3 (17.6)
|
|
PTH (pg/ml)
|
703 (125–1547)
|
117.5 (94–131)
|
1168 (436–1708)
|
|
Highest serum calcium (mmol/l)
|
3.76 (3.11–4.20)
|
2.72 (2.68–3.30)
|
3.85 (3.65–4.38)
|
|
Combined therapy
|
Fluid resuscitation (%)
|
23 (14.3)
|
10 (6.9)
|
13 (76.5)
|
|
Diuretic (%)
|
5 (3.1)
|
–
|
5 (29.4)
|
|
Calcitonin (%)
|
10 (6.2)
|
–
|
10 (58.8)
|
|
Cinacalcet (%)
|
20 (12.4)
|
10 (6.9)
|
10 (58.8)
|
|
Bisphosphonate (%)
|
61 (37.9)
|
52 (36.1)
|
9 (52.9)
|
Short- and long-term efficacy of denosumab in hypercalcemia management in
PHPT
Herein, we defined short-term efficacy as the change in serum calcium levels
within 14 days post denosumab treatment. Twelve studies described the short-term
efficacy of denosumab in hypercalcemia management in PHPT. This included two
cohorts [9]
[12] and 10 case reports [14]
[15]
[16]
[17]
[18]
[19]
[21]
[22]
[24]
[25]. We observed that serum calcium of
the patients decreased from 3.50 (3.20–3.78) mmol/l to 3.00 (2.60–3.08) mmol/l
within 3 days, 3.38 (3.16–3.73) mmol/l to 2.72 (2.46–3.16) mmol/l in 3–7 days,
and 3.50 (3.15–3.74) mmol/l to 2.52 (2.23–2.65) mmol/l in 7–14 days. The median
reduction of serum calcium was 0.50 (0.47–0.75) mmol/l, 0.53 (0.21–0.61) mmol/l,
and 0.91 (0.50–1.45) mmol/l within 3, 3–7, and 7–14 days, respectively.
According to our findings, the most notable decline in serum calcium was
observed 7–14 d post denosumab administration. The percentage of serum calcium
reduction was 27 (16–39)%.
We defined long-term efficacy as a change in serum calcium post denosumab
treatment for one month and above. This included four cohorts [8]
[10]
[11]
[12] and three case reports [13]
[19]
[23]. We found that the
median reduction of serum calcium was 0.43 (0.18–0.60) mmol/l within one month.
After three months, the median decrease in serum calcium was only 0.16
(0.05–0.41) mmol/l. Regarding the long-term efficacy of denosumab, the reduction
in serum calcium levels of patients was attenuated after three months [6%
(2–13)]. The results are summarized in [Table 2].
Table 2 Short-term and long-term efficacy of Denosumab in
the management of serum calcium in PHPT.
|
Study types (No.)
|
Number of Patients
|
Baseline serum calcium
|
Serum calcium after denosumab treatment
|
Reduction (mmol/l)
|
Reduction (%)
|
Ref.
|
|
Within 3 days
|
Cohort (1), case report (3)
|
16
|
3.50 (3.20–3.78)
|
3.00 (2.60–3.08)
|
0.50 (0.47–0.75)
|
16 (14–20)
|
[9]
[15]
[18]
[21]
|
|
3–7 days
|
Cohort (2), case report (7)
|
36
|
3.38 (3.16–3.73)
|
2.72 (2.46–3.16)
|
0.53 (0.21–0.61)
|
15 (8–19)
|
[9]
[11]
[14]
[16]
[18]
[22]
[24]
[25]
|
|
7–14 days
|
Case report (5)
|
8
|
3.50 (3.15–3.74)
|
2.52 (2.23–2.65)
|
0.91 (0.50–1.45)
|
27 (16–39)
|
[19]
[21]
[22]
[23]
[24]
|
|
1 month
|
Cohort (1), case report (3)
|
33
|
3.10 (2.70–3.12)
|
2.60 (2.53–2.71)
|
0.43 (0.18–0.60)
|
14 (6–19)
|
[10]
[13]
[17]
[23]
|
|
≥3 months
|
Cohort (3), case report (2)
|
106
|
2.67 (2.59–3.10)
|
2.61 (2.49–2.69)
|
0.16 (0.05–0.41)
|
6 (2–13)
|
[8]
[11]
[12]
[13]
[17]
|
Denosumab for hypercalcemia management in parathyroid carcinoma and
adenoma
Among the included studies, 16 provided an etiological diagnosis, whereas the
other studies did not. Eight patients [57 (28–66) years old] had parathyroid
carcinoma. Their serum calcium decreased from 3.25 (3.10–3.50) mmol/l to 2.60
(1.95–2.69) mmol/l in a median of 7 days (2.5–13.8), with a reduction of 0.63
(0.50–1.30) mmol/l. The mean age of the eight patients with benign parathyroid
disease was 58 (47–71) years. Their serum calcium decreased from 3.38
(3.15–3.77) mmol/l to 2.73 (2.63–3.07) mmol/l in a median of 4 days (3.0–6.5),
with a reduction 0.49 (0.41–0.70) mmol/l.
Safety of denosumab for hypercalcemia management in PHPT
Hypocalcemia is the most common adverse reaction of denosumab . Regarding the
safety data of denosumab in hypercalcemia treatment in patients with PHPT, seven
studies dealt with the preoperative use of denosumab and surgery for
hyperparathyroidism, with a total of 16 patients. Among them, 11 patients
developed hypocalcemia post-surgery (68.75%). One patient developed
hypercalcemia after surgery. The lowest reported postoperative blood calcium
value was 1.52 mmol/l and the patient was diagnosed with metastatic parathyroid
carcinoma. The serum calcium levels of the other patients were normal.
Discussion
According to the five cohorts and 13 case reports included in our review, we found
that in patients with primary-hyperparathyroidism-associated hypercalcemia,
treatment with denosumab resulted in a significant decline in serum calcium levels
within 3 d compared to baseline. The significant reduction was maintained within 14
days. Subsequently, the serum calcium-lowering effect weakened after one month.
The effectiveness of denosumab in reducing blood calcium levels observed in this
review could be elucidated by the pathophysiological mechanisms of PHPT and the
pharmacodynamics of denosumab. Most patients with PHPT exhibit sustained high levels
of PTH, promoting osteoclast activation. This leads to increased bone resorption and
decreased bone density. Denosumab, a RANKL antagonist, can interrupt the action of
PTH on the bone by preventing osteoblasts from activating osteoclasts, thereby
reducing the release of calcium from the bones into the bloodstream. Additionally,
high-dose PTH can still promote the growth and activity of osteoblasts. This thereby
facilitates bone calcium deposition and reduces serum calcium levels.
The speed and duration of denosumab reduction in blood calcium observed in this
review depended on its pharmacokinetic characteristics. Denosumab reaches its
maximum concentration in the blood within an average of 10 days and a mean half-life
of 25.4 days. The concentration of denosumab decreases within 4–5 months [26]. Therefore, in this review, we found
that the optimal calcium-lowering effect was achieved within one month of denosumab
treatment.
In patients with PHPT, hypercalcemic crisis is a severe acute complication [27]. Therefore, the prompt correction of
hypercalcemia is essential. During anti-hypercalcemia treatment, bisphosphonates,
calcitonin, and cinacalcet were suggested in the guidelines [3]. Bisphosphonates directly inhibit
osteoclasts in PHPT [28], however, they
may have nephrotoxic side effects, such as focal segmental glomerulosclerosis
collapse and acute tubular necrosis [29].
They may even increase the kidney burden and uremia risk in patients with renal
dysfunction [30]. Calcitonin takes effect
rapidly; however, its effectiveness lasts only for a short period. Cinacalcet, a
positive regulator of the CaSR, reduces PTH secretion and increases urinary calcium
excretion [31]. Therefore, cinacalcet may
increase the risk of renal calcification, stone formation, and failure [32]. Furthermore, increasing urinary
calcium excretion aggravates total calcium loss in the human body in patients with
PHPT [33]. Therefore, compared to
bisphosphonates, calcitonin, and cinacalcet, we assumed that denosumab is a safer
choice for most patients with PHPT, especially those with renal insufficiency [34]. Furthermore, patients with PHPT and
hypercalcemia who received short-term use of denosumab had a rapid and significant
decline (0.5 mmol/l) in serum calcium levels in 3 days compared to the baseline.
Consequently, our study suggests that denosumab may have the potential to treat
hypercalcemia crisis.
Additionally, patients with PHPT-associated bone diseases are prone to osteoporotic
fractures due to bone resorption and decreased bone density [35]. Among the 161 patients included in
this study, 41.0% had fractures. We hypothesized that the inhibition of osteoclast
activation by denosumab might change the mode of action of PTH in PHPT instead of
reducing PTH secretion [8]
[12]. This thereby improves PHPT-associated
bone disease, increasing bone mineral density [9], preventing secondary osteoporosis in patients with PHPT, and reducing
the risk of fractures.
This study has several limitations. Randomized controlled trials on the safety and
efficacy of denosumab in managing hypercalcemia in PHPT were lacking. Therefore, our
study included most cohort and case reports and objectively assessed all studies and
reports. Although the quality of evidence provided by our study was lower than that
of the RCTs, it is currently the best evidence. It is best to evaluate the
therapeutic effect of a single-drug treatment with medication. However, in clinical
practice, denosumab is always used in combination with other drugs in patients with
severe hypercalcemia.
In conclusion, denosumab significantly decreased serum calcium levels. It has a
potential clinical value in hypercalcemia treatment in patients with PHPT,
especially those with renal dysfunction.
