Denosumab for Management of Hypercalcemia in Primary Hyperparathyroidism

Abstract

Denosumab is a completely human monoclonal high-affinity antibody that binds to the nuclear factor kappa-B ligand (RANKL) and is widely used to treat osteoporosis. Furthermore, it can potentially lower serum calcium levels by inhibiting osteoclast activation and preventing bone calcium from being released into the blood. This review aimed to provide evidence of the efficacy and safety of denosumab in treating hypercalcemia in primary hyperparathyroidism (PHPT). PubMed and the Cochrane Library were searched for published studies that described denosumab for hypercalcemia management in PHPT. Data were extracted by two independent investigators and analyzed using SPSS 23. The risk of bias was assessed by NIH Quality Assessment Tool. In total, 161 patients with PHPT from 18 studies were included in this review. The average age was 61 (47–72) years and the highest serum calcium was 3.76 (3.11–4.20) mmol/l. We found that denosumab can effectively reduce the serum calcium level by a median reduction of 0.5 mmol/l within 3 days. Significant reduction was maintained for 14 days. The serum calcium-lowering effect weakened after one month. In conclusion, denosumab has a potential clinical value in treating hypercalcemia in patients with PHPT.

 

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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.

 

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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.

 

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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).

 

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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.

 

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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).

 

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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.

 

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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)

 

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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]

 

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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.

 

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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.

 

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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.

 

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Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgement

We thank the doctors, nurses and technicians in the Endocrinology and Metabolism department for their help during this study.

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Publikationsverlauf

Eingereicht: 02. Juli 2024

Angenommen nach Revision: 01. September 2024

Artikel online veröffentlicht:
11. Oktober 2024