Mechanisms and treatment of hypercalcemia of malignancy

Mechanisms and treatment of hypercalcemia of malignancy 

Gregory A. Clines a,b 

a Division of Endocrinology, Diabetes, and Metabolism, 

Department of Medicine, University of Alabama at 

Birmingham and b Veterans Affairs Medical Center, 

Birmingham, Alabama, USA 

Correspondence to Gregory A. Clines, MD, PhD, 

Assistant Professor of Medicine and Cell Biology, 

Division of Endocrinology, Diabetes, and Metabolism, 

Department of Medicine, University of Alabama at 

Birmingham, 1808 7th Avenue South, BDB 730 

Birmingham, AL 35294-0012, USA 

Tel: +1 205 934 4187; fax: +1 205 975 9372; 

e-mail: clines@uab.edu 

Current Opinion in Endocrinology, Diabetes & 

Obesity 2011, 18:339–346 

Purpose of review 

Hypercalcemia of malignancy is a common paraneoplastic syndrome and a frequent 

complication of advanced breast and lung cancer, and multiple myeloma. The 

development of this malignancy complication often purports a poor prognosis. 

Thorough evaluation to establish the cause of hypercalcemia is essential because some 

patients may actually have undiagnosed primary hyperparathyroidism. 

Recent findings 

Production of humoral factors by the primary tumor, collectively known as humoral 

hypercalcemia of malignancy (HHM), is the mechanism responsible for 80% of cases. 

The vast majority of HHM is caused by tumor-produced parathyroid hormone-related 

protein followed by infrequent tumor production of 1,25-dihydroxyvitamin D and 

parathyroid hormone. The remaining 20% of cases are caused by bone metastasis with 

consequent bone osteolysis and release of skeletal calcium. Key therapies are saline 

hydration to promote calciuresis and bisphosphonates to reduce pathologic 

osteoclastic bone resorption. Calcitonin and glucocorticoids, especially in 1,25- 

dihydroxyvitamin D-mediated HHM, also have calcium-lowering effects. 

Summary 

Recent discoveries on mechanisms of malignancy-associated hypercalcemia highlight 

the critical role of the osteoclast. Bisphosphonates and other novel therapies being 

evaluated in clinical trial target this bone-resorbing cell type and provide effective 

and durable serum calcium reduction. 

Keywords 

bisphosphonate, bone metastasis, hypercalcemia, malignancy, parathyroid hormonerelated 

protein 

Curr Opin Endocrinol Diabetes Obes 18:339–346 

ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins 

1752-296X 

Introduction 

Malignancy-associated hypercalcemia is a common paraneoplastic 

syndrome occurring in up to 20% of cancer 

patients. The development of hypercalcemia in a cancer 

patient often translates to a poor prognosis [1]. Despite 

strategies to lower serum calcium and treat the hypercalcemic 

symptoms, median survival after discovery of 

hypercalcemia is approximately 30 days [2]. The poor 

prognosis is not necessarily due to the hypercalcemia 

itself but reflects correlation of this condition with an 

advanced cancer stage. Although hypercalcemia can 

occur with many types of malignancy, it is most often 

associated with breast cancer, lung cancer and multiple 

myeloma [3,4]. 

Signs and symptoms 

Symptoms of hypercalcemia vary in individual patients 

and are related to both the absolute concentration and the 

rate of rise of serum calcium [1,5]. Hypercalcemia associated 

with malignancy is likely to be more severe and rapid 

in onset, and therefore such patients are more likely to 

present with symptoms associated with acute onset. 

Gastrointestinal complaints that include nausea, vomiting, 

anorexia, abdominal pain and constipation are common. 

Pancreatitis is a less common but serious complication 

[6]. Neurologic manifestations range from fatigue 

to coma especially with very high calcium excursion. 

Psychiatric conditions such as depression, anxiety and 

cognitive dysfunction can occur. Shortening of the electrocardiogram 

QT interval and cardiac arrhythmia are 

associated with acute and markedly elevated serum 

calcium [7,8]. Muscular weakness is a common complaint 

with hypercalcemia. Nephrogenic diabetes insipidus is an 

incompletely understood complication of hypercalcemia 

and is likely to be related to downregulation of aquaporin- 

2 water channels in the collecting ducts resulting in a 

renal concentrating defect [9,10]. As a result, dehydration 

and intravascular volume contraction is further exacerbated 

by anorexia, nausea and vomiting leading to 

worsening hypercalcemia. 

1752-296X ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MED.0b013e32834b4401 

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

340 Parathyroids, bone and mineral metabolism 

Pathogenesis 

Four distinct mechanisms are responsible for hypercalcemia 

of malignancy. Three of these involve secretion of an 

endocrine factor and are collectively described as humoral 

hypercalcemia of malignancy (HHM). The last is the 

result of bone metastasis and massive osteolysis (Fig. 1). 

Parathyroid hormone-related protein and humoral 

hypercalcemia of malignancy 

Before the discovery of parathyroid hormone-related 

protein (PTHrP), the presence of a parathyroid hormone 

(PTH)-like factor was proposed that possessed similar 

hypercalcemic and phosphaturic actions of PTH. In 1987, 

PTHrP was purified from human cancer cells [11,12] by 

independent groups and cloned shortly thereafter [13]. 

PTHrP was subsequently found to have important biological 

roles in mammary gland development [14], lactation 

[15], endochondral bone formation [16] and islet 

beta-cell function [17]. 

The PTHrP gene encodes a 141 amino acid protein that 

shares a 60% sequence homology with PTH over the first 

13 amino acids at the N terminus [13]. Beyond the initial 

amino-terminal sequence, the two proteins are unique 

and show no further sequence homology. Other PTHrP 

endoproteolytic fragment species have been identified, 

with the PTHrP (1–36) fragment having similar activity 

as the full-length protein. PTHrP (38–94) may have 

antitumorigenic properties [18,19 ] and PTHrP (107– 

139), also known as osteostatin, may inhibit osteoclastic 

bone resorption [20,21]. 

Despite differences between PTH and PTHrP protein 

structure, both bind to a common PTH/PTHrP receptor 

(PTH1R) [22,23]. Three mechanisms of PTH1R activation 

by PTH that increase serum calcium and alter 

phosphate homeostasis are well described: PTH activates 

osteoclastic bone resorption and release of skeletal 

calcium and phosphate through increased osteoblast 

receptor activator of nuclear factor kB ligand (RANKL) 

expression leading to activation of the receptor activator 

of nuclear factor kB (RANK) located on osteoclast precursors 

[24]. PTH increases calcium reabsorption in the 

loop of Henle ascending limb and distal convoluted 

tubule [25] and inhibits phosphate reabsorption in the 

proximal convoluted tubule [26]. PTH increases renal 

1a-hydroxylase with production of 1,25-dihydroxyvitamin 

D [1,25-(OH) 2 D], the active form of vitamin D, in 

the proximal convoluted tubule resulting in targeted 

intestinal absorption of calcium and phosphate [27]. 

PTHrP has equivalent actions as PTH in regulating bone 

resorption and renal calcium/phosphorus. However, 

unlike PTH, PTHrP does not increase 1a-hydroxylase 

activity and 1,25-(OH) 2 D production. This is illustrated 

Key points 

Hypercalcemia of malignancy is associated with a 

poor prognosis. 

PTHrP is a common mediator of humoral hypercalcemia 

of malignancy. 

Local production of PTHrP and other factors mediate 

local bone osteolysis and hypercalcemia during 

bone metastasis. 

Saline hydration and bisphosphonates are the key 

therapies for hypercalcemia of malignancy. 

in patients with primary hyperparathyroidism who generally 

have an elevated circulating 1,25-(OH) 2 D, which is 

reflective of heightened PTH activity. Such an increase is 

not seen in patients with PTHrP-dependent HHM, even 

though stores of the vitamin D precursor may be normal 

[28]. Differences between PTH and PTHrP ligand– 

receptor binding kinetics and activation of PTH1R 

downstream signaling pathways are the likely mechanisms 

responsible for this difference [23,29]. The discordant 

effects between PTH and PTHrP on 1,25-(OH) 2 D 

production were confirmed in human controlled trials 

studying PTH (1–34) versus PTHrP (1–36) infusion 

[30]. 

Normally, PTHrP circulates at a concentration of less 

than 2.0 pmol/l. Approximately 80% of the hypercalcemic 

patients with solid tumors have plasma PTHrP concentration 

above this value [31,32]. Hypercalcemia ensues 

only when PTHrP reaches a threshold concentration that 

replaces and surpasses the analogous actions of PTH. 

Hypercalcemia attributed to elevated concentrations 

of humoral PTHrP has been estimated to occur in 33– 

84% of breast cancers [33–38], 46–76% of lung cancers 

[35,36,38], 21–63% of non-Hodgkin’s lymphomas 

(NHLs) [38–40] and 92% of adult T-cell leukemia/ 

lymphomas due to the human T-lymphotropic virus 

type 1 (HTLV-1) infection [39]. Infrequently, PTHrPmediated 

hypercalcemia occurs in head and neck tumors 

[41,42], renal cell carcinoma [43,44], bladder cancer [45], 

pancreatic carcinoma [46], hepatocellular carcinoma [47], 

carcinoid tumors [48] and melanoma [49]. 

Parathyroid hormone and humoral hypercalcemia of 

malignancy 

PTHrP is responsible for the vast majority of cases HHM. 

However, rare cases have been reported of ectopic PTH 

secretion by tumors, which is often clinically indistinguishable 

from primary hyperparathyroidism. Suspicion 

of malignancy-associated ectopic PTH should arise in a 

patient with a known malignancy that has an elevated 

calcium and PTH, and when a standard technetium 

( 99m Tc) sestamibi scan does not identify a parathyroid 

adenoma in the neck. Ectopic PTH production has been 


Mechanisms and treatment of hypercalcemia of malignancy Clines 341 

Figure 1 Production of a humoral factor by the primary tumor comprises 80% of cases of hypercalcemia of malignancy, collectively 

known as humoral hypercalcemia of malignancy 

PTHrP is by far the most common factor implicated in HHM, especially in cases of breast and lung cancer. PTH is a rare cause of HHM. PTHrP and PTH 

activate a common PTH1R receptor located on osteoblasts precursors resulting in RANKL expression, osteoclast activation and bone resorption. 

Tumor-produced 1,25-(OH) 2 D by hematologic malignancies is an uncommon mechanism of HHM. The principal action of tumor-produced 1,25- 

(OH) 2 D is to promote excessive calcium gut absorption. Approximately 20% of hypercalcemia of malignancy cases is the result of bone metastasis and 

local production of tumor factors in the bone microenvironment. Breast and lung cancer bone metastasis primarily produce PTHrP. Osteolytic lesions of 

multiple myeloma are the result of a complement of other bone-resorbing factors. 1,25-(OH) 2 D, 1,25-dihydroxyvitamin D; ATLL, adult T-cell leukemia/ 

lymphoma; HHM, humoral hypercalcemia of malignancy; HL, Hodgkin’s lymphoma; NHL, non-Hodgkin’s lymphoma; PTHrP, parathyroid hormonerelated 

protein; RANKL, receptor activator of nuclear factor kB ligand. 



documented in a small cell carcinoma of the lung [50], a 

squamous cell carcinoma of the lung [51], an ovarian 

cancer [52], a widely metastatic primitive neuroectodermal 

tumor [53], a papillary adenocarcinoma of the thyroid 

[54], a thymoma [55], a rhabdomyosarcoma [56] and a 

pancreatic cancer [57]. 

1,25-Dihydroxyvitamin D and humoral hypercalcemia of 

malignancy 

Another mechanism of HHM is overproduction of 1,25- 

(OH) 2 D, a cause of hypercalcemia of malignancy in less 

than 1% of cases [32]. Analogous to granulomatous 

diseases such as sarcoidosis, certain cancers possess 1ahydroxylase 

activity that produce 1,25-(OH) 2 D from the 

available 25-(OH) 2 D precursor [58,59]. Activated tissue 

macrophages adjacent to tumor tissue may be another 

source of 1,25-(OH) 2 D [60]. 

Most patients with 1,25-(OH) 2 D-mediated HHM have 

Hodgkin’s lymphoma and NHL [61]. In one report, 

4.1% of the patients with newly diagnosed NHL were 

hypercalcemic and the likelihood of hypercalcemia 

increased with the higher grade of disease [61,62]. The 

incidence of hypercalcemia with Hodgkin’s lymphoma is 

similar to NHL with 5.4% of patients diagnosed with this 

complication [62]. Hypercalcemia from production of 1,25- 

(OH) 2 D in acute lymphoblastic leukemia and dysgerminomas 

are a rare complication of these malignancies 

[63,64]. 

Bone metastasis and skeletal osteolysis 

Extensive bone metastasis and local osteolysis accounts 

for approximately 20% of cases of malignancy-associated 

hypercalcemia [32]. During massive osteolysis, the amount 

of calcium released from bone is greater than the renal 

calcium excretion capacity resulting in a net increase in 

serum calcium. Hypercalcemia-related nausea, anorexia, 

nephrogenic diabetes insipidus and volume depletion further 

impair renal function and exacerbate hypercalcemia. 

The most common malignancy associated with this mechanism 

of hypercalcemia is breast cancer metastasis to bone, 

a complication that occurs in 70% of patients with 

advanced disease. The formation of bone metastasis 

begins with a series of sequential steps starting with cancer 

cell escape from the primary tumor site, embolization in 

the circulation followed by cancer cell adherence to bone 

vascular endothelium and extravasation into the bone 

microenvironment [65]. With the arrival of cancer cells 

to bone, a unique synergetic interaction between cancer 

and bone was first recognized by Stephen Paget [66] in 

1889 and formed the basis for the ‘seed and soil’ 

hypothesis. 

Humoral PTHrP is responsible for most cases of hypercalcemia 

in lung cancer, but 30–40% of the patients with 

advanced disease develop bone metastasis and hypercalcemia 

with localized osteolysis [67]. Multiple myeloma is 

far less common than breast or lung cancer, but osteolytic 

bone lesions are a nearly universal feature in advanced 

cases. Although not typically characterized as a metastatic 

malignancy, multiple myeloma shares many of the molecular 

mechanisms of pathologic bone resorption with 

breast cancer bone metastasis [65]. Other malignancies 

rarely causing hypercalcemia and osteolytic bone disease 

include melanoma [68], acute lymphoblastic leukemia 

[69–71] and NHL [72,73]. 

PTHrP secretion into the metastatic bone microenvironment 

is the principal mechanism of pathogenic osteoclast 

activation and osteolysis from breast and lung cancer 

bone metastasis [74–77]. PTHrP also plays a significant 

role in the process of metastasis to bone, as evidenced by 

clinical studies indicating that PTHrP expression by 

primary breast cancer is more commonly associated with 

the development of bone metastasis and hypercalcemia 

[78]. In the case of breast and lung cancer, HHM and 

skeletal osteolysis share PTHrP as the principal factor 

leading to hypercalcemia; in one situation, it is a local 

mediator, whereas in another, it is a humoral mediator. 

Multiple myeloma secretes a complement of osteoclast 

activating factors that include macrophage inflammatory 

protein-1a [79], receptor activator of nuclear factor kB 

ligand (RANKL) [80], interleukin-3 and interleukin-6 

[81,82]. 

Differential diagnosis 

Hypercalcemia, especially in the hospital setting and 

when the serum calcium is above 13 mg/dl, is likely 

due to malignancy. In the outpatient setting, primary 

hyperparathyroidism is a more likely cause of hypercalcemia. 

Therefore, hypercalcemia in a patient with a 

known malignancy may not necessarily indicate an 

advanced disease stage or even be linked to the malignancy 

itself [83]. In one study, seven out of 47 patients 

with hypercalcemia and a malignancy had coexisting 

primary hyperparathyroidism [84]. Differentiating 

between the two has prognostic value because the likelihood 

of survival past 100 days is likely with primary 

hyperparathyroidism, whereas an elevated PTHrP was 

associated with a high mortality within 100 days [84]. 

Other conditions associated with hypercalcemia including 

excessive calcium intake, vitamin D toxicity and 

thiazide diuretics may also coexist in malignancy. It is 

therefore critical to fully evaluate the cause of hypercalcemia 

in all the patients with malignancy, even in those 

with advanced disease. 

Assessing circulating intact PTH concentration is the 

initial step in determining the cause of hypercalcemia 

in all patients. During hypercalcemia of malignancy and 



in the absence of parathyroid disease, hypercalcemia will 

overactivate the calcium-sensing receptor of the parathyroid 

glands resulting in suppressed PTH production. In 

patients without a known malignancy, PTHrP testing is 

generally not necessary in the initial diagnostic workup of 

hypercalcemia. In patients with a malignancy and hypercalcemia, 

both PTH and PTHrP should be measured. 

Treatment 

The principal goals are two-fold: restore and promote 

renal calciuresis and inhibit pathologic osteoclastic bone 

resorption. 

Hydration 

Volume resuscitation is a critical early treatment to 

restore renal perfusion and calciuresis [85]. The rate of 

hydration depends on the severity of hypercalcemia, the 

age of the patient and comorbidities such as congestive 

heart failure, which may limit the rate of saline infusion. 

A 1-liter normal saline bolus followed by 200–300 ml/h is 

a reasonable approach. Once euvolemia is established, 

either oral or maintenance intravenous fluids is continued 

to maintain a reasonable urine output. The addition of 

furosemide to promote calciuresis is generally not recommended 

given the paucity of clinical evidence supporting 

its use in this setting [86]. 

Calcitonin 

Calcitonin is a useful adjunctive initial therapy that inhibits 

osteoclastic bone resorption and renal calcium reabsorption. 

A disadvantage of calcitonin is the development 

of tachyphylaxis within 48 h of initiation. The effectiveness 

of this medication can be extended with the combination 

of glucocorticoids [87]. Calcitonin is administered 

either intramuscularly or subcutaneously at a dose of 4 U/ 

kg every 12 h up to 8 U/kg every 6 h if the initial dose is not 

satisfactory. Intranasal administration of calcitonin has 

shown not to be effective [88]. Few studies have examined 

the efficacy of calcitonin alone in the acute management of 

hypercalcemia of malignancy [87,89]. 

Bisphosphonates 

Pamidronate and zoledronic acid are the two bisphosphonates 

approved by the US Food and Drug Administration 

for treatment of hypercalcemia of malignancy. 

These nitrogen-containing bisphosphonates have a high 

affinity for hydroxyapatite and are rapidly deposited 

within bone after administration. Bisphosphonate 

released during bone resorption becomes internalized 

within the osteoclast, blocking prenylation of small 

GTP-binding proteins important for structural integrity 

of the osteoclast resulting in apoptosis [90 ]. 

Clinical trials have demonstrated efficacy of both 60 and 

90 mg doses of pamidronate administered intravenously 

over 4 h [91,92]. The higher 90 mg dose can be used in 

patients with more severe hypercalcemia. With the 90 mg 

infusion of pamidronate, the mean time to normocalcemia 

was approximately 4 days, whereas the mean 

duration of normocalcemia was 28 days in one study 

[93]. An effective method for achieving a rapid and 

sustained reduction in serum calcium concentration is 

to use pamidronate in combination with calcitonin. The 

combination of the durable action of a bisphosphonate 

with rapid-acting calcitonin lowers serum calcium levels 

more rapidly and effectively than either alone [94]. 

Zoledronic acid, a more potent bisphosphonate, is administered 

at a dose of 4 mg intravenously over 15 min. 

Compared with pamidronate, zoledronic acid was 

superior in respect to response rates, time to calcium 

normalization and response duration [95]. Therefore, 

many clinicians consider zoledronic acid the bisphosphonate 

of choice. The bisphosphonate ibandronate, currently 

approved in the USA for osteoporosis treatment, 

has similar efficacy as pamidronate but is not yet 

approved by the FDA for this indication [96]. Etidronate 

and clodronate have been studied in hypercalcemia of 

malignancy, but the availability of more potent bisphosphonates 

has supplanted the use of these low-potency 

first-generation bisphosphonates. Disadvantages of 

bisphosphonates are renal toxicity that can be minimized 

with a dose adjustment and risk of osteonecrosis of the 

jaw especially in patients who receive multiple doses and 

those with poor dentition [97 ]. 

Glucocorticoids 

Glucocorticoids are the preferred therapy for patients 

with 1,25-(OH) 2 D-mediated hypercalcemia and operate 

by reducing extrarenal vitamin D 1a-hydroxylase 

activity. Glucocorticoids also inhibit osteoclastic bone 

resorption by decreasing tumor production of locally 

active cytokines and maybe used in conjunction with 

other standard therapies in patients with other forms of 

hypercalcemia of malignancy [87,98]. Prednisone at dose 

of 40–60 mg administered daily is typically effective. If 

no appreciable response is observed within 10 days, then 

glucocorticoid therapy should be discontinued. 

Other therapies 

Plicamycin and gallium nitrate are two antineoplastic 

agents that have calcium-lowering abilities. However, 

these medications are no longer recommended for treating 

hypercalcemia of malignancy due to poor side-effect 

profiles and inconvenient dosing schedules. Hemodialysis 

using a calcium-free dialysate effectively lowers 

calcium in case reports [99,100]. This mode of therapy 

should be reserved only for the most severe cases of 

hypercalcemia when rapid normalization of calcium is 

required. Denosumab is a RANKL-targeted monoclonal 

antibody currently approved for treating osteoporosis and 



preventing skeletal-related events in bone metastasis 

[101,102 ]. The efficacy of denosumab for treating hypercalcemia 

of malignancy is currently being evaluated in a 

phase II clinical trial. 

Conclusion 

Hypercalcemia is a common complication of malignancy 

caused by a heterogeneous group of tumor-derived 

factors that disrupt normal calcium homeostasis. PTHrP, 

either acting as endocrine factor or locally in cancer 

metastasis to bone, is a central mediator of this paraneoplastic 

complication in breast and lung cancer. A complement 

of other factors is the foundation for hypercalcemia 

associated with multiple myeloma. Rarely, tumorproduced 

PTH and 1,25-(OH) 2 D are implicated. The 

standard of care for hypercalcemia of malignancy in most 

cases is bisphosphonate treatment combined with saline 

hydration. Alternative therapies with potential benefit 

include inhibitors of RANKL and neutralizing antibodies 

to PTHrP. Clinical trials, in progress, should determine 

whether these modalities would be as effective or complementary 

to bisphosphonate treatment. 

Acknowledgements 

The author receives funding from the National Institutes of Health 

(CA118428 and AR056826) and the Department of Defense 

(W81XWH-08-1-0030). 

Conflicts of interest 

There are no conflicts of interest. 

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Papers of particular interest, published within the annual period of review, have 

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102 

 

Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic 

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This report demonstrated that RANKL inhibition is an effective strategy to reduce 

skeletal-related events in bone metastasis.

Mechanisms and treatment of hypercalcemia of malignancy

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