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Hypercalcemia of malignancy: Mechanisms

Hypercalcemia of malignancy: Mechanisms
Author:
Mara J Horwitz, MD
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jun 2022. | This topic last updated: May 26, 2022.

INTRODUCTION — Hypercalcemia is relatively common in patients with cancer, occurring in approximately 20 to 30 percent of cases [1]. It is the most common cause of hypercalcemia in the inpatient setting. It occurs in patients with both solid tumors and hematologic malignancies. The most common cancers associated with hypercalcemia in the United States are breast, renal, lung, and squamous cell cancers and multiple myeloma [2]. Malignancy is usually evident clinically by the time it causes hypercalcemia, and patients with hypercalcemia of malignancy often have a poor prognosis. The mechanisms of hypercalcemia will be reviewed here. The clinical manifestations, diagnosis, and treatment of hypercalcemia are reviewed in detail separately.

(See "Clinical manifestations of hypercalcemia".)

(See "Diagnostic approach to hypercalcemia".)

(See "Treatment of hypercalcemia".)

MECHANISMS OF HYPERCALCEMIA — There are three major mechanisms by which hypercalcemia of malignancy can occur (table 1) [3-5]:

Tumor secretion of parathyroid hormone-related protein (PTHrP)

Osteolytic metastases with local release of cytokines (including osteoclast activating factors)

Tumor production of 1,25-dihydroxyvitamin D (calcitriol)

Ectopic tumoral secretion of parathyroid hormone (PTH) can also cause hypercalcemia, but it is rare.

PTH-related protein — The most common cause of hypercalcemia in patients with nonmetastatic solid tumors and in some patients with non-Hodgkin lymphoma is secretion of parathyroid hormone (PTH)-related protein (PTHrP); this condition, also called humoral hypercalcemia of malignancy (HHM), accounts for up to 80 percent of patients with hypercalcemia of malignancy [6-9]. Patients with HHM most often have squamous cell carcinomas (lung, head, and neck), renal, bladder, breast, or ovarian carcinomas (table 1). They typically have advanced disease and a poor prognosis [10-12].

PTHrP is a normal gene product expressed in a wide variety of neuroendocrine, epithelial, and mesoderm-derived tissues. Thus, in addition to patients with solid tumors, those with non-Hodgkin lymphoma [6,7,13], chronic myeloid leukemia (blast phase) [14], and adult T cell leukemia lymphoma may have PTHrP-induced hypercalcemia [7,15,16]. Tumor necrosis factor-beta also may contribute in some patients with adult T cell leukemia lymphoma [17]. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma", section on 'Pathogenesis'.)

Purification of PTHrP has revealed some homology with PTH, particularly at the amino-terminal end, at which the first 13 amino acids are almost identical [18]. As a result of this close homology with PTH, PTHrP binds to the same PTH-1 receptor as does PTH and thus activates similar postreceptor pathways. This accounts for the ability of PTHrP to simulate some of the actions of PTH, including increases in bone resorption and distal tubular calcium reabsorption and inhibition of proximal tubular phosphate transport [8,19-21]. (See "Regulation of calcium and phosphate balance".)

Structural divergence after the first 13 amino acids of the molecule accounts for its immunologic distinctiveness from PTH. PTHrP is less likely than PTH to stimulate 1,25-dihydroxyvitamin D production [8,22-25], although 1,25-dihydroxyvitamin D measurement in patients with PTHrP-mediated hypercalcemia may be variable [5]. In patients with HHM, there is an uncoupling of bone resorption and formation, which results in a large flux of calcium from bone into the circulation. In combination with the reduced ability of the kidney to clear calcium, this results in the striking hypercalcemia that occurs in HHM. Thus, hypercalcemia in HHM is predominantly due to the combined effects of PTHrP on kidney and bone [8,19,26].

Typical laboratory findings in patients with HHM include the following [1,8,27]:

Elevated serum PTHrP

Very low or suppressed serum intact PTH (secretion of endogenous PTH is suppressed by PTHrP-mediated hypercalcemia)

Variable serum 1,25-dihydroxyvitamin D

Serum PTHrP levels in patients with tumor-induced hypercalcemia can provide information regarding prognosis:

It is a useful tumor marker for assessing the response to treatment of the tumor.

It may predict the response to antiresorptive agents. Serum PTHrP concentrations above 12 pmol/L are frequently associated with both a smaller reduction in hypercalcemia and with recurrence of hypercalcemia within 14 days of therapy [10,28,29]. While the prognosis of cancer-associated hypercalcemia is generally poor, those who become normocalcemic with bisphosphonate therapy have a significantly better, although still short, survival (53 versus 19 days in one study) [29]. (See "Treatment of hypercalcemia", section on 'Bisphosphonates'.)

Osteolytic metastases — Osteolytic metastases account for approximately 20 percent of cases of hypercalcemia of malignancy [9]. Induction of local osteolysis by tumor cells is common with some solid tumors that are metastatic to bone and with multiple myeloma, but it is less common with lymphoma and leukemia (table 1) [4,5]. The solid tumor that most often produces hypercalcemia by this mechanism is breast cancer.

The bone destruction observed in osteolytic metastases is primarily mediated by osteoclasts and is not a direct effect of tumor cells [30]. Instead, tumors produce many factors that stimulate osteoclast production and action locally, resulting in increased skeletal resorption and hypercalcemia. (See "Mechanisms of bone metastases", section on 'Osteolytic versus osteoblastic bone metastases'.)

Typical findings in patients with osteolytic metastases include:

Low or suppressed serum intact PTH

Low or low-normal serum 1,25-dihydroxyvitamin D

Low or low-normal serum PTHrP (although tumor metastases in bone may secrete PTHrP locally, it is not usually measurable in a serum assay)

Extensive skeletal metastases or marrow infiltration

Breast cancer — Breast cancer cells in bone express PTHrP more frequently than those in soft tissue sites or in the primary tumor. PTHrP produced by metastatic tumor cells in the bone microenvironment acts as a local (rather than systemic) factor to cause osteolysis [27]. This occurs in the absence of high serum PTHrP concentrations. However, in other patients with breast cancer, bone metastases, and hypercalcemia, serum PTHrP is elevated, suggesting a systemic effect as well [31]. (See 'PTH-related protein' above.)

Locally produced PTHrP increases expression of receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL) in bone. RANKL contributes to the development of hypercalcemia by binding to RANK on the surface of osteoclast precursors. The RANKL/RANK interaction results in activation, migration, differentiation, and fusion of hematopoietic cells of the osteoclast lineage to begin the process of resorption. In addition, cytokines such as interleukin (IL)-6, IL-8, IL-1, and vascular endothelial growth factor (VEGF) are secreted by breast cancer cells and may contribute to the effects of PTHrP on bone resorption. (See "Mechanisms of bone metastases", section on 'Osteolytic versus osteoblastic bone metastases'.)

Among patients with breast cancer and extensive skeletal metastases, the administration of an antiestrogen (such as tamoxifen) can lead to hypercalcemia [32,33]. The presumed mechanism is release of bone resorbing factors from the tumor cells [34]. In addition, there have been case reports of flare hypercalcemia with aromatase inhibitors [35,36].

Multiple myeloma — Hypercalcemia in multiple myeloma and in some cases of lymphoma where there is bone marrow infiltration by tumor has been ascribed to the release of osteoclast-activating factors by the tumor cells [37,38]. Osteoclast-induced bone resorption may occur in discrete focal areas (lytic lesions) or throughout the skeleton. The high rate of bone resorption is associated with an absence of osteoblast-mediated bone formation, resulting in diffuse bone loss. The uncoupling of bone resorption and formation results from paracrine factors, which enhance osteoclast formation and activity and inhibit the capacity for marrow stromal cells to differentiate into osteoblasts [37,38]. In multiple myeloma, various studies have implicated cytokine release, pro-osteoclastogenic factors, an increase in RANKL production by osteocytes and inhibition of osteoblasts as factors contributing to the development of lytic bone disease and hypercalcemia [39]. (See "Mechanisms of bone metastases", section on 'Osteolytic versus osteoblastic bone metastases'.)

1,25-dihydroxyvitamin D — Increased production of 1,25-dihydroxyvitamin D (calcitriol) is the cause of almost all cases of hypercalcemia in Hodgkin lymphoma and approximately one-third of cases in non-Hodgkin lymphoma (table 1) [13,38,40]. An occasional patient with Hodgkin lymphoma, however, has hypercalcemia due to PTHrP, as do some with non-Hodgkin lymphoma, as stated above [6,13,41]. Additionally, there are rare cases of calcitriol mediated hypercalcemia in patients with solid tumors [42]. 1,25-dihydroxyvitamin D-induced hypercalcemia has also been described in patients with ovarian dysgerminoma [43] and lymphomatoid granulomatosis/angiocentric lymphoma [44]; the latter finding is consistent with the frequent association of hypercalcemia with chronic granulomatous diseases, such as sarcoidosis and tuberculosis. (See "Hypercalcemia in granulomatous diseases".)

In normal individuals, the conversion of 25-hydroxyvitamin D (calcidiol) to 1,25-dihydroxyvitamin D (calcitriol, the most active metabolite of vitamin D) occurs via a 1-hydroxylase in the kidney that is under the physiologic control of PTH and inhibited by high serum phosphate via fibroblast growth factor 23 (FGF-23) (see "Overview of vitamin D", section on 'Metabolism'). Hypercalcemia should suppress the release of PTH and therefore the production of 1,25-dihydroxyvitamin D. The lack of suppression of 1,25-dihydroxyvitamin D production in lymphoma is due to PTH-independent extrarenal production of 1,25-dihydroxyvitamin D from 25-hydroxyvitamin D by malignant lymphocytes, macrophages, or both.

Increased intestinal calcium absorption induced by high serum 1,25-dihydroxyvitamin D concentrations is the primary abnormality, although a 1,25-dihydroxyvitamin D-induced increase in bone resorption may play a contributory role. Patients with increased production of 1,25-dihydroxyvitamin D typically have low or suppressed serum intact PTH and elevated 1,25-dihydroxyvitamin D. In case reports, some patients have elevations of both 1,25-dihydroxyvitamin D and PTHrP [45]. Hypercalcemia induced by 1,25-dihydroxyvitamin D (but not PTHRP) usually responds to glucocorticoid therapy. (See "Treatment of hypercalcemia", section on 'Disease-specific approach'.)

Ectopic PTH secretion — A few patients with ectopic secretion of parathyroid hormone (PTH) have been described; among the tumors were an ovarian carcinoma, small cell and squamous cell lung carcinomas, a primitive neuroectodermal tumor, thyroid papillary carcinoma, metastatic rhabdomyosarcoma, pancreatic malignancy, and gastric carcinoma (table 1) [46-54]. In these case reports, serum intact PTH was elevated, and some patients were diagnosed after neck exploration failed to identify a parathyroid adenoma.

COEXISTING PRIMARY HYPERPARATHYROIDISM — There is a higher incidence of cancer in patients with primary hyperparathyroidism and of primary hyperparathyroidism in patients with cancer [55,56]. Thus, serum parathyroid hormone (PTH) should be measured in hypercalcemic patients with cancer [57]. If serum parathyroid hormone-related protein (PTHrP) and PTH concentrations are both high, then coexisting primary hyperparathyroidism is probably present as well. However, there have been rare reports of tumors simultaneously secreting both PTH and PTHrP [58].

Mild hypercalcemia due to primary hyperparathyroidism often precedes the acute and more severe hypercalcemia that is seen with hypercalcemia of malignancy. If serum PTH is elevated and PTHrP is not elevated, then primary hyperparathyroidism is probably the sole cause for the hypercalcemia [6]. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

DETERMINING THE MECHANISM — Most patients with hypercalcemia of malignancy have clinical evidence of malignancy at the time of hypercalcemia diagnosis. Humoral hypercalcemia is likely the cause of hypercalcemia in any patient with a solid tumor in the absence of bony metastases. Local release of cytokines from osteolytic metastases is the likely cause of hypercalcemia in patients with extensive skeletal metastases or marrow infiltration. Hypercalcemia induced by 1,25-dihydroxyvitamin D should be suspected in patients with lymphoma.

Hypercalcemia of malignancy should also be suspected in patients with otherwise unexplained hypercalcemia and a low serum parathyroid hormone (PTH) concentration. (See "Etiology of hypercalcemia".)

The approach to determining the mechanism of hypercalcemia is reviewed briefly below and in more detail separately (algorithm 1) (see "Diagnostic approach to hypercalcemia"):

Once hypercalcemia is confirmed, we measure concomitantly serum PTH and calcium. An elevated or mid- to upper-normal value with persistent hypercalcemia generally indicates primary hyperparathyroidism.

In the presence of low-normal or low serum PTH concentrations (eg, <20 pg/mL), PTH-related protein (PTHrP) and vitamin D metabolites should be measured to assess for hypercalcemia of malignancy and vitamin D intoxication.

Elevated PTHrP is consistent with humoral hypercalcemia of malignancy.

Increased levels of 1,25-dihydroxyvitamin D may be induced by direct intake of this metabolite, extrarenal production in granulomatous diseases or lymphoma, or increased renal production that can be induced by primary hyperparathyroidism or ectopic PTH secretion but not by PTHrP.

Markedly elevated 25-hydroxyvitamin D is consistent with vitamin D intoxication. Although the serum concentration of 25(OH)D at which hypercalcemia typically occurs is undefined, many experts define vitamin D intoxication as a value >150 ng/mL (374 nmol/L) [59].

If PTHrP and vitamin D metabolites are not elevated, another source for the hypercalcemia must be considered. Additional laboratory data (including serum and urine protein electrophoresis and serum free light chain assay for possible multiple myeloma, thyroid-stimulating hormone [TSH], and vitamin A) will often lead to the correct diagnosis. Some patients may require imaging (eg, skeletal radiographs) for diagnosis of osteolytic metastases if the diagnosis is not clear from history. (See "Diagnostic approach to hypercalcemia", section on 'Other tests'.)

TREATMENT — The treatment of hypercalcemia is reviewed separately. (See "Treatment of hypercalcemia", section on 'Preferred approach'.)

SUMMARY AND RECOMMENDATIONS

Cancers associated with hypercalcemia – Hypercalcemia is relatively common in patients with cancer, occurring in approximately 20 to 30 percent of cases, and it is associated with a poor prognosis. The most common tumors that cause hypercalcemia are breast cancer, renal cancer, lung cancer, multiple myeloma, lymphoma, and squamous cell cancers (table 1). (See 'Introduction' above.)

Pathophysiology of hypercalcemia of malignancy – There are three major mechanisms by which hypercalcemia of malignancy can occur:

Tumor secretion of parathyroid hormone-related protein (PTHrP) – Hypercalcemia is due to both increased bone resorption and increased distal renal tubular calcium reabsorption. (See 'PTH-related protein' above.)

Osteolytic metastases with local release of cytokines – Hypercalcemia is primarily due to increased bone resorption and release of calcium from bone. (See 'Osteolytic metastases' above.)

Tumor production of 1,25-dihydroxyvitamin D – Hypercalcemia is the result of a combination of increased intestinal calcium absorption and bone resorption. (See '1,25-dihydroxyvitamin D' above.)

Determining the etiology of hypercalcemia

Measure concomitantly repeat calcium and parathyroid hormone (PTH) – An elevated or mid- to upper-normal value with persistent hypercalcemia generally indicates primary hyperparathyroidism (algorithm 1). (See 'Determining the mechanism' above and "Diagnostic approach to hypercalcemia".)

Measure PTHrP and vitamin D metabolites – In the presence of low-normal or low serum PTH concentrations (eg, <20 pg/mL), PTHrP and vitamin D metabolites should be measured to assess for hypercalcemia of malignancy and vitamin D intoxication. (See 'Determining the mechanism' above and "Diagnostic approach to hypercalcemia".)

Additional testing – If PTHrP and vitamin D metabolites are not elevated, another source for the hypercalcemia must be considered. Additional laboratory data (including serum and urine protein electrophoresis and serum free light chain assay for possible multiple myeloma, thyroid-stimulating hormone [TSH], and vitamin A) will often lead to the correct diagnosis. (See 'Determining the mechanism' above and "Diagnostic approach to hypercalcemia", section on 'Other tests'.)

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Topic 842 Version 16.0

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