Hypercalcemia of malignancy (HCM) is a common complication in advanced breast cancer. First line therapy for HCM involves intravenous bisphosphonates to reduce serum calcium levels. When hypercalcemia is refractory to bisphosphonates, denosumab can be used to reduce serum calcium levels [9]. Denosumab is a total human monoclonal antibody that selectively binds RANKL’s receptor activator, thus preventing bone resorption via inhibition of osteoclast-mediated bone destruction. In addition to the treatment of osteoporosis and the prevention of skeletal related events in patients with bone metastasis, denosumab is used to treat hypercalcemia of malignancy refractory to bisphosphonates [1,9]. Hypocalcemia is a known adverse effect of denosumab, affecting up to 10% of patients [1]. Severe symptomatic hypocalcemia affects <1%-3% of patients and can result in hospitalization or even death [1]. Therefore, denosumab should be used with caution in those with known hypocalcemia, osteoblastic metastatic disease, or severe renal dysfunction. The median half-life of denosumab ranges from 25 to 35 days, with risk of denosumab-induced hypocalcemia highest in the first two weeks and usually resolving within 30 days [11,12]. We discuss a case of ongoing refractory hypocalcemia requiring calcium supplementation for more than six weeks after denosumab treatment for hypercalcemia in a patient with breast cancer and osteoblastic metastatic disease without renal dysfunction.

A 58-year-old woman with a history of hypertension, prediabetes, metastatic estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, human epidermal growth

factor 2 (HER2)-negative (Immunohistochemistry 2+) stage IV invasive lobular breast cancer with diffuse bone metastasis, right orbit metastases, and liver metastases was receiving treatment with fourth line Enhertu. This patient had been followed by our Oncology service since presentation July 2023 with Stage IV metastatic hormone positive breast cancer with extensive bone metastases. Prior treatment regimens included Letrozole + Palbo (2023 -2025) followed by Capivasertib + Fulvestrant (2025) followed by Capecitabine (2025), and most recently Enhertu (October 2025 – present). During this period, she developed severe symptomatic hypercalcemia with albumin-adjusted calcium level of 16.8 mg/dL likely secondary to malignancy. At this time, parathyroid hormone related peptide (PTHrP) was 18 pg/mL (11-20 pg/mL) and phosphorus level was 3.1 mg/dL.The hypercalcemia was treated with an infusion of Zoledronic acid 4mg IV, along with Calcitonin 300 units a day subcutaneously for 7 days. A week after her first infusion of Zoledronic acid, her albumin-adjusted calcium level remained elevated at 12.1 mg/dL thus a second infusion of Zoledronic acid 4mg was given. A week after the second dose of Zoledronic acid, her albumin-adjusted calcium levels were still elevated at 11.5 mg/dL (8.5-10.3 mg/dL) as seen in Figure 1. The decision was then made to treat the patient refractory hypercalcemia with denosumab 120 mg based on recommendations from Endocrinology.

Figure 1: Serum Calcium Level During Initial Period Of Hypercalcemia Secondary To Malignancy Indicated. Timing Of Bisphosphonate And Denosumab Intervention, As Well As Resulting Serum Calcium Levels Noted. Serum Calcium Levels Dropped Below The Lower Limit Of Normal Just Prior To Admission.

One week after receiving denosumab, her albumin-adjusted calcium level was 8.5 mg/dL. Two weeks after receiving denosumab she presented to the emergency department for anxiety as well as perioral and peripheral paresthesia. At presentation she was found to have an albumin-adjusted serum calcium of 6.9 mg/dL (8.5-10.3 mg/dL) and ionized calcium of 3.6 mg/dL (4.7-5.5 mg/dL), both below the normal range. Other laboratory studies revealed normal levels of phosphorus, creatinine, and magnesium, as well as low albumin level, see Table 1.

 Table 1: Results of Initial Laboratory Studies on Admission. Reference Ranges Indicated.

Further evaluation showed her parathyroid hormone (PTH) was 29 pg/mL, vitamin D 38 ng/mL, and TSH 2.09mg/dL. Physical exam was unremarkable with negative Chvostek sign, though Trousseau sign was not tested. Electrocardiogram showed corrected QT prolongation of 514 ms and initial imaging with KUB x-ray showed stable diffuse osteoblastic lesions and stable T10 vertebral compression deformity.

Given the profound hypocalcemia on presentation, she was treated with both intravenous and continuous infusions of calcium gluconate for a total of ~60g in the first 5 days of admission. She was also given oral calcium carbonate-vitamin D 600mg-400 units two times a day (BID) and calcitriol 0.5mcg three times a day (TID) after consulting Endocrinology. After five days of aggressive calcium repletion, her serum calcium improved to 9.3 mg/dL and QTc improved to 355 ms. However, the patient’s symptoms of muscle spasms, perioral and distal extremity numbness persisted.

Though her calcium initially seemed to respond to intensive repletion, after the calcium drip was discontinued her serum calcium levels once again dropped below normal range, despite continued oral calcium supplementation. Over the next four weeks she required intermittent resumption of continue intravenous calcium infusions as seen in Figure 2.Calcium levels corrected for albumin were monitored as calcitriol was increased to 1mcg TID and calcium carbonate-vitamin D 600 mg-400 units was uptitrated to six tablets a day. The patient, however, continued to have symptomatic hypocalcemia, thus necessitating intermittent doses of IV calcium gluconate 10 g to supplement the high dose oral repletion to increase serum calcium levels as seen in Figure 2.

Figure 2: Dynamic Serum Calcium Level during Prolonged Hospitalization. The Patient Intermittently Received Calcium Supplementation Via Drip As Well As Intravenous Boluses Of Calcium Gluconate As Indicated. Date Of Discontinuation Of All Calcium Supplementation, Including High Dose Oral Regimen, Indicated By “STOP” After Which Calcium Levels Remained Stable.

Given ongoing paresthesia, additional workup was ordered and notable for thiamine <6 nmol/L (8-30 nmol/L), vitamin B6 4.1 ng/mL (2.1-21.7 ng/mL), vitamin B12 >2000 pg/mL (232-1245 pg/mL), methylmalonic acid 177 nmol/L (55-335 nmol/L), homocysteine 9.8 umol/L (<=15 umol/L), and ammonia 28 umol/L (11-51 umol/L). Neuroradiology also reviewed the patient’s MRI of brain and orbit given multiple metastatic lesions; however, the locations of her lesions were not able to explain her paresthesia. Venous blood gas additionally ruled out hypercapnia as cause of facial numbness and tingling. Further evaluation with MRI of her entire spine and lumbar puncture were suggestive of possible leptomeningeal disease.

Over the duration of the patient’s hospitalization the calcium repletion regimen underwent many iterations, frequently requiring continuous calcium infusions. Ultimately, more than 6 weeks after receiving denosumab, the patient’s serum calcium levels were stabilized in the low-normal range with calcium carbonate 3000 mg TID and calcitriol 1.5 mcg TID as seen in Figure 3. After three weeks on this regimen, we were able to titrate the patient off calcium carbonate and calcitriol altogether with serum calcium levels remaining stable at normal levels.

Figure 3: Trend of Serum Calcium Level Before, At Time of Admission and During Hospitalization. Initial Hypercalcemia And Timing Of Bisphosphonate And Denosumab Are Noted. Timing Of Calcium Drip As Well As IV Calcium Gluconate Are Indicated. The Patient Was Started On High Dose Oral Calcium and Calcitriol, After Discontinuation of Oral Regimen Serum Calcium Levels Remained Stable. Day 1 On The X-Axis Represents The Day Of Admission. The Red Interrupted Horizontal Lines Indicate The Upper And Lower Limits Of Normal Serum Calcium Levels.

Symptomatic hypocalcemia is an atypical feature of malignant breast cancer even with bone metastases but has been previously studied in men with prostate cancer and osteoblastic metastatic disease [2,3,5]. In our patient, the pathophysiology of her hypocalcemia can be attributed to denosumab treatment in the setting of osteoblastic metastasis. Osteoblastic disease allows for the rapid deposition of calcium into new abnormal bone formed by osteoblasts. However, when denosumab inhibits osteoclast bone resorption/release of calcium from the bone, the abnormal bone formation continues unopposed. Thus, resulting in sequestration of calcium within the abnormal bone and severe hypocalcemia [7,10]. Denosumab has a half-life of approximately 32 days and reaches its maximum concentration between 3 to 21 days [1]. Denosumab-induced hypocalcemia typically occurs 1-2 weeks after medication administration and is usually transient and asymptomatic. Risk of hypocalcemia is increased in patients with chronic kidney disease, which our patient did not have, where denosumab prevents osteoclasts from balancing low calcium absorption seen in renal dysfunction [2].Our patient received denosumab for severe hypercalcemia of malignancy (>14 mg/dL) deemed refractory to two Zoledronic acid infusions [10]. She was already at high risk for hypocalcemia prior to treatment due to high disease burden, elevated alkaline phosphatase 279 U/L (35-104 U/L), and vitamin D deficiency 26 ng/mL (30-100 ng/mL) [4].

 Though her case is unusual in that symptomatic hypocalcemia manifesting as perioral numbness, bilateral distal lower extremity tingling persisted >6 weeks after denosumab

administration and was refractory to intensive calcium repletion with both intravenous and continuous infusion of calcium, supplemented with high dose oral calcium and calcitriol. It is possible that the etiology of her paresthesia was multifactorial secondary to denosumab-induced hypocalcemia, vitamin B1 deficiency, leptomeningeal disease, and prior chemotherapy.

We considered vitamin D deficiency as a possible cause of the patient’s poor response to calcium repletion, as decreased vitamin D can impair calcium absorption from the gut [8].

However, despite the correction of vitamin D levels to normal range the patient’s serum calcium levels remained low. It is also possible that her progressive osteoblastic disease further exacerbated her hypocalcemia despite intense repletion [7]. Additionally effective repletion of calcium may have been limited due to ongoing nausea/vomiting and oral intake intolerance secondary to the patient’s disease burden. Thus, oral calcium and calcitriol doses were occasionally missed. Other risk factors for denosumab-induced hypocalcemia that were ruled out in our patient include chronic kidney disease, hypomagnesemia, and hypoparathyroidism [7].

It is likely that addressing risk factors like hypocalcemia and vitamin D deficiency prior to initiation of denosumab treatment in patients with osteoblastic metastatic disease would reduce the risk of severe hypocalcemia [2,3]. Regardless of whether mitigating steps are taken prior to treatment, close monitoring of calcium levels and early identification of symptoms due to hypocalcemia after denosumab initiation are critical to reduce sequelae of severe hypocalcemia [6,7].

Review of the literature revealed few case reports of cancer patients, mostly prostate cancer, who developed prolonged severe hypocalcemia lasting up to 111 days [13]. However, in all of these cases, serum calcium levels were normal at baseline and denosumab was given to treat skeletal events due to bone metastases and not for the treatment of malignancy-induced hypercalcemia as in our patient [13,14]. To the best of our knowledge, this is the first reported patient who developed prolonged and severe hypocalcemia after a single dose of denosumab for the treatment of malignancy-induced hypercalcemia.

This case highlights a rare but severe complication of denosumab therapy: prolonged, refractory symptomatic hypocalcemia lasting more than six weeks in a patient with extensive osteoblastic breast cancer metastases. The patient’s course underscores how denosumab, particularly when used for refractory hypercalcemia of malignancy in the setting of high osteoblastic burden, can possibly precipitate profound and persistent calcium sequestration that is difficult to correct despite aggressive intravenous and oral supplementation. This case emphasizes the importance of careful risk stratification, optimization of calcium and vitamin D status prior to denosumab initiation, and close posttreatment monitoring. Clinicians should maintain a high index of suspicion for prolonged hypocalcemia in similar patients and anticipate the potential need for extended hospitalization and intensive calcium repletion.

1. Hildebrand GK, Patel P, Kasi A. Denosumab In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025.
2. Body JJ, Bone HG, de Boer RH, Stopeck A, Van Poznak C, Damião R, et al. Hypocalcaemia in patients with metastatic bone disease treated with denosumab. Eur J Cancer. 2015; 51: 1812-21.
3. Lau LH, Cliff ERS, Wong V, Wong H, Torkamani N, Eer A, et al. Hypocalcaemia following denosumab in prostate cancer: A clinical review. Clin Endocrinol (Oxf). 2020; 92: 495-502.
4. Kanbayashi Y, Sakaguchi K, Hongo F, Ishikawa T, Tabuchi Y, Ukimura O, et al. Predictors for development of denosumab-induced hypocalcaemia in cancer patients with bone metastases determined by ordered logistic regression analysis. Sci Rep. 2021; 11: 978.
5. Darawshi S, Darawshi M, Daoud Naccache D. Unusual hypocalcaemia in breast cancer relapse with multiple bone metastasis. Endocrinol Diabetes Metab Case Rep. 2021; 2022: 20-0222.
6. Dadana S, Gundepalli S, Kondapalli A. Severe Refractory Hypocalcemia Caused by Denosumab. Cureus. 2023; 15: e39866.
7. Nizeyimana JD, Dreessen L, Andreescu C, Duhamel A, Lieten S, Balti E. Refractory Denosumab-induced Hypocalcemia in a High-risk Patient With Osteoblastic Metastatic Prostate Adenocarcinoma. JCEM Case Rep. 2025; 3: luaf121.
8. Ishikawa K, Nagai T, Sakamoto K, Ohara K, Eguro T, Ito H. High bone turnover elevates the risk of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis. Ther Clin Risk Manag. 2016; 12: 1831-1840.
9. Anastasopoulou C, Mewawalla P. Malignancy-Related Hypercalcemia. [Updated 2025 Mar 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025.
10. Zeng W, Swee DS. Severe and refractory hypocalcaemia secondary to osteoblastic bone metastases in bladder signet ring carcinoma: A case report and literature review. Medicine (Baltimore). 2022; 101: e29731.
11. Kc O, Dahal PH, Koirala M, Kothagundla CS, Al Zaghal E, Fahed R. A Case of Recurrent Severe Hypocalcemia with Prolonged Hospitalization and Readmissions after Single Dose of Denosumab in Metastatic Prostate Cancer Patient. J Community Hosp Intern Med Perspect. 2022; 12: 60-64.
12. Ikesue H, Tsuji T, Hata K, Watanab H, Mishima K, Uchida M, et al. Time Course of Calcium Concentrations and Risk Factors for Hypocalcemia in Patients Receiving Denosumab for the Treatment of Bone Metastases From Cancer. Annals of Pharmacotherapy. 2014; 48: 1159-1165.
13. McCaleb RV, Johnson JT. Severe, Prolonged, Denosumab-Induced Hypocalcemia with Recovery after 111 Days of High-Dose Calcium Supplementation. AACE Clin Case Rep. 2019; 5: e82-e85.
14. Uhm SJ, Hall JA, Herrington JD. Severe and prolonged hypocalcemia after a single dose of denosumab for metastatic breast cancer with diffuse bone involvement without prior calcium/vitamin D supplementations. J Oncol Pharm Pract. 2021; 27: 1287-1290.