Pathophysiology and management of hypercalcemia in malignancy

Humoral hypercalcemia

Humoral hypercalcemia occurs in 80% of tumor patients having hypercalcemia. This hypercalcemia usually arises in solid tumors such as squamous cell carcinoma of the head and neck; esophageal, lung, cervix, colon, ovarian, breast, bladder, endometrial cancer; and renal cell carcinoma.^[2,4,8] Despite the above, hematological malignancies such as non-Hodgkin lymphoma, the blast phase of chronic granulocytic leukemia, or T-cell lymphoma can also bring about humoral hypercalcemia.^[4,8] Humoral hypercalcemia theory, established in 1941 by Fuller Albright, involves PTHrP.^[7,10] PTHrP is produced by the parathyroid hormone-like hormone (PTHLH) gene located on the short arm of chromosome 12, while PTH is produced by chromosomes 11.^[7,10,14,15]

PTHrP is a gene product commonly expressed by certain tissues such as mesodermal, epithelial, neuroendocrine, and breast tissues. Under normal conditions, PTHrP is steadily secreted and responsible for calcium transport, both transplacental and into the breast milk.^[7,8,10,14] PTHrP regulates osteoblast, osteoclast, chondrocyte differentiation, brain development, skin, hair follicle, teeth, hematopoiesis, and vascular smoothness muscle.^[7] Nevertheless, PTHrP plays a role in tumor formation in breast cancer.^[14]

Structurally, PTHrP is similar to PTH, making PTHrP able to bind to the PTH-1 receptor just like PTH. It activates cyclic adenosine monophosphatase (cAMP), protein kinase A and C, inositol phosphate, and phospholipase C.^[4,7,15] In bones, these PTH-1 receptors are located in osteocytes, chondrocytes, and osteoblasts.^[15] Bone resorption is then activated, alongside an increase in calcium reabsorption in the distal convoluted tubule and Henle loop of the kidney and an increase in phosphate excretion. In osteoblast, PTHrP increases RANKL synthesis.^[2,4,8] Beside that, PTH and PTHrP have other similarities, which are their activities with the calcium-sensing receptor (CaSR). The activity of these receptors located on the surface of the parathyroid gland will be inhibited in hypercalcemia, halting the production of PTH. However, the relationship between PTHrP with CaSR is still a subject under more investigation.^[10]

The first 13 amino acids at the aminoterminal end of PTHrP have structural similarities to PTH (Val2, Ser3, Glx4, Gln6, Leu7, His9, Gly12, Lys13), while other parts are distinct from each other.^[4,7,15] In this regard, PTHrP does not increase the amount of 1,25(OH)2D (calcitriol), thus not affecting calcium absorption in the intestines. Different than PTH, PTHrP also cannot activate PTH2R.^[15] Consequently, humoral hypercalcemia in malignancies contributes to hypercalcemia caused by PTHrP activation on kidneys and bones.^[2,4,7,8] In cell T lymphoma, PTHrP production is also triggered by TNF-β activation.^[2,4,8] In humoral hypercalcemia, these changes in laboratory parameters could be seen: normal or low calcitriol, intact PTH suppression due to the presence of PTHrP, and an increase in PTHrP. PTHrP can therefore be utilized as a marker to evaluate the response of cancer and antiresorptive treatment.^[4]

Local osteolytic metastasis

Hypercalcemia caused by local osteolysis generally accounts for 20% of all hypercalcemia in malignancies. It is usually due to extensive bone metastasis. This condition mainly occurs in tumors such as multiple myeloma, breast cancer with bone metastasis, and leukemia and lymphoma, although with a much rarer mechanism.^[2,4] The primary mechanism of hypercalcemia is indirect bone destruction caused by metastatic cancer cells producing factors that affect osteoclast formation. Generally, these factors are local cytokines such as interleukin (IL)-1, IL-3, IL-6, tumor necrosis factor (TNF)-α, prostaglandin E, lymphotoxin, tumor growth factor (TGF)-α, and TGF-β. These local cytokines caused an increase in RANK/RANKL binding, leading to an increase in the number of osteoclasts and bone resorption.^[2,7] Changes in laboratory parameters that could be observed include low to low-normal PTHrP or calcitriol levels, low or intact PTH suppression, and extensive bone infiltration.^[4]

In breast cancer, bone metastasis has a very high incidence of 70%.^[16] PTHLH and PTHrP play a role in the osteolytic process, mainly locally but also systemically.^[4,14,15] An increase of PTHrP leads to an increase in RANKL expression, which binds to RANK and, therefore, promotes fusion, activation, differentiation, and migration of hematopoietic cells involved in osteoclast formation. Excessive bone resorption then commences and will cause hypercalcemia. Besides that, breast cancer cells also increase proinflammatory cytokines such as IL-1, IL-6, IL-8, and vascular endothelial growth factor (VEGF), increasing PTHrP. The risk of hypercalcemia also increases with antiestrogen and aromatase inhibitor usage. The mechanism behind it is probably due to an increase in bone resorption factor when using these drugs.^[4]

Besides PTHrP, another essential factor in bone metastasis in patients with breast cancer is CaSR. CaSR is a class C G protein-coupled receptor expressed in the parathyroid gland, bone, kidney, normal breast epithelial cells, and breast tumor cells, including those which metastasize to bones. In normal conditions, CaSR activation by the chief cells of the parathyroid gland is suppressed. This, in turn, causes PTH to be secreted. In breast cancer, however, calcium, which is high in number, will bind to CaSR, thereby increasing the secretion of PTHrP. After that, PTHrP will increase tumor proliferation by acting as an intracrine tumor, causing the tumor cycle to be continued.^[16,17] Picture two explains the activation of CaSR and its relationship to PTHrP in inducing hypercalcemia in breast cancer patients with bone metastases.^[16]

In multiple myeloma and some types of lymphoma, the cancer cells infiltrating bone marrow will trigger the release of factors activating osteoclast, coinciding with the absence of bone formation by osteoblast. In this condition, osteoblast differentiation from bone marrow stromal cells is inhibited by paracrine factors. The resulting bone resorption causes extensive loss of bone mass.^[4] Another cause of the rise in calcium levels in this regard is the increase of paraprotein secretion, which also increases the number of calcium binding to these paraproteins.^[8]

Extrarenal production of calcitriol

Increasing extrarenal production of 1,25(OH)₂D is observed in 1% of all hypercalcemia in malignancies. This mechanism mainly occurs in Hodgkin and non-Hodgkin lymphoma, ovarian dysgerminoma, and other nonmalignancy conditions such as sarcoidosis, tuberculosis, and other inflammatory conditions.^[2,4,8,10] This mechanism is the prime cause of hypercalcemia in Hodgkin lymphoma and is found in one-third of non-Hodgkin lymphoma patients with hypercalcemia. However, Shallis et al. reported that hypercalcemia in non-Hodgkin lymphoma is not mediated by increased extrarenal 1,25(OH)₂D and PTHrP. Therefore, the precise mechanism behind hypercalcemia in this type of lymphoma has not yet been revealed.^[7,18]

The increase of extrarenal 1,25(OH)₂D production in lymphoma is independent of PTH and mediated by the presence of malignant macrophages or lymphocytes. It will cause an increase in calcium absorption and bone resorption. The changes reflected on laboratory parameters are normal or low 25(OH)D levels, increasing calcitriol, and low or suppressed PTH. Hypercalcemia caused by an increase of calcitriol showed a good response when treated with glucocorticoids.^[4]

Primary or ectopic secretion of PTH

An increase in PTH secretion could be due to primary or ectopic origin. Hypercalcemia in malignancies due to PTH increase accounts for < 1% of all cases. This condition frequently happens on parathyroid adenoma or hyperplasia, causing hyperparathyroidism. Its incidence peaked at age > 45 years, with female preponderance and risk factors of receiving long-term lithium therapy or head and neck radiation. Hyperparathyroid syndrome could also be caused by tumors such as type 1 and type 2 multiple endocrine neoplasias or primitive neuroectodermal tumors.^[2,10] Some other malignancies that have been reported to secrete PTH are lung squamous cell carcinoma, thyroid papillary carcinoma, ovarian carcinoma, gastric carcinoma, pancreas tumor, or metastasizing rhabdomyosarcoma. Hypercalcemia due to primary hyperparathyroidism should be suspected in patients with high PTH and low or normal PTHrP.^[4]

Volume expansion

Volume expansion target is to increase urinary calcium excretion and fluid restoration to lower volume depletion triggered by nephrogenic diabetes insipidus and low fluid intake due to nausea and vomiting. Hypovolemia will exacerbate hypercalcemia by disturbing calcium clearance through the kidneys. This expansion volume can be done through intravenous delivery of isotonic saline, firstly with 1–2 liters as a bolus and is continued with 150–300 mL/hour for the next 2–3 days as maintenance. Other literature suggests the initial fluid delivery to be 200–300 mL/hour in patients without edema.^[2,20] In this condition, the urine output target is 100–150 mL/hour, necessitating the need for tight monitoring of urine output, central vein pressure (CVP), and fluid balance.^[2,19,20] However, a study found that volume expansion did not provide enough reduction of calcium levels when compared to the administration of calcitonin or bisphosphonate, which directly decreases bone resorption.^[19]

Additional caution should be exercised, especially in patients prone to fluid overloads, such as those with decreased kidney function, anuria, or heart failure. In such conditions, furosemide can be considered while maintaining electrolyte levels like phosphor and potassium. Strong diuretics, for example, 80–100 mg of furosemide every 1–2 hours, were previously given in patients rehydrated with saline solution reaching 10 liters/day.^[2,9,19] Furosemide exerts its effect by inhibiting sodium-potassium-chloride transporter (NKCC2) in the ascending Henle loop, thereby augmenting calcium excretion.^[21] Nevertheless, strong diuretics are not recommended for patients not fulfilling the above criteria due to the risk of volume depletion and electrolyte imbalance like hypomagnesemia or hypokalemia.^[2,9,12,21]

Calcitonin

Calcitonin is a hormone with amino acid 32, which is intrinsically produced by parafollicular C cells of the thyroid. Calcitonin is reported to have the ability to lower calcium levels up to 2 mg/dl in 72 hours.^[9] Calcitonin is beneficial in increasing calcium excretion and abating bone resorption as it hinders osteoclast function. Extrinsically, calcitonin could be obtained from salmon fish as its preparation. Calcitonin is given subcutaneously or intramuscularly with a dose of 4–8 units/kg bodyweight every 6–12 hours. After calcitonin administration, the calcium-lowering effect could happen rapidly, as much as 1–2 mg/dl in the first 4 to 6 hours. However, the tachyphylaxis effect of calcitonin should be observed as it appears mainly in the first 24 to 48 hours. Therefore, calcitonin can only be administered for the first 24–48 hours because afterward, the downregulation of its receptor ensures.^[2,19]

Calcitonin provides a satisfactory effect when given together with bisphosphonate. In addition, a simultaneous glucocorticoid administration with calcitonin could enhance the response to calcitonin as it increases the number of receptors in the osteoclast. Calcitonin has side effects, although they rarely happen, such as hypersensitivity and mild nausea.^[2] An adjustment for calcitonin dose is not needed in patients with kidney function disorder.^[19]

Bisphosphonate

Bisphosphonate is the mainstay of treatment for hypercalcemia in malignancies.^[1] Bisphosphonate is a nonhydrolyzed analog of inorganic pyrophosphate, which could absorb the hydroxyapatite surface of the bone and hamper the release of calcium from the bone by inhibiting osteoclast action.^[8,19] An induction of osteoclast apoptosis and RANKL stimulation neutralization are how bisphosphonate exerts its bone resorption lowering effect. Bisphosphonate also plays a role in osteoblast differentiation and proliferation and prevents its apoptosis. Besides its ability to lower calcium levels, bisphosphonate can also lower SRE incidence in patients with bone metastasis.^[2] In fact, bisphosphonate is more potent in reversing hypercalcemia when compared to fluid expansion and calcitonin administration.^[19] Its upper hand is demonstrated in a study by Mousseaux et al. that showed bisphosphonate to be the most effective treatment in hypercalcemia. It can lower calcium serum levels until < 12 mg/dl (HR 0,42; 95% CI 0,27–0,67; p < 0,001). This study found no significant difference between different types of bisphosphonate such as zoledronic acid, pamidronate, and ibandronate.^[6]

Bisphosphonate is recommended to be administered quickly in the first 48 hours of hypercalcemia as its effect will only be seen in 2–4 days after its first administration. Bisphosphonate is also nephrotoxic, making dose adjustments in patients with kidney disorders and tight monitoring of kidney function mandatory.^[2] Some bisphosphonate options and doses in hypercalcemia conditions are 4 mg IV zoledronic acid for 15–30 minutes, 60–90 mg of IV pamidronate for 4 hours, or 2–6 mg of IV ibandronate. Zoledronic acid is preferred in lowering calcium levels in malignancies.^[19] A repeated dose of bisphosphonate is advised to be given 1 week after the first dose.^[8]

There are two generations of bisphosphonate. The first generation, such as clodronate and etidronate, does not contain nitrogen. The second generation, like zoledronic acid, risedronate, alendronate, pamidronate, and ibandronate, contains nitrogen.^[8] Ibandronate and etidronate are only available in intravenous form, risedronate and alendronate only in oral form, while clodronate is available both in intravenous and oral form. The administration of oral risedronate and alendronate is not recommended for the acute management of hypercalcemia. Other options that are available in Indonesia are ibandronate and clodronate. In one study, ibandronate was beneficial in treating hypercalcemia in malignancies and could be given at a dose of 2 mg within 1 hour of administration. Clodronate in oral form is more recommended for maintenance to prevent hypercalcemia and SRE in bone metastasis, while its intravenous form is more suitable for acute hypercalcemia.^[19]

One side effect that could happen in long-term use (6 months or 2–3 years) of high-dose bisphosphonate is an increased risk of osteonecrosis of the jaw (ONJ) in breast cancer patients with bone metastases or multiple myeloma. However, it rarely happens (1%). The same applies to patients with risk factors such as a history of dental procedures, bad dental and oral hygiene, and smoking. Other rarer adverse effects are uveitis (0.5%), hypophosphatemia, hypocalcemia, femur fractures, and flu-like symptoms.^[8,9,19,21]

A decline in kidney function is observed due to acute tubular necrosis caused by zoledronic acid or focal segmental glomerulonecrosis (FSGS) and minimal change disease in pamidronate use.^[8,9,19,21] The risk of acute tubular necrosis in zoledronic acid use increases in those with a history of NSAID and bisphosphonate use or advanced-stage cancers.^[21] In an attempt to decrease the risk of a further decrease in kidney function among patients with kidney diseases (serum creatinine > 4.5 mg/dl for zoledronic acid and creatinine clearance < 30 mL/minutes for pamidronate or ibandronate) requiring bisphosphonate, longer duration or a lower dose could be given (4 mg zoledronic acid in 30–60 minutes, 30–45 mg pamidronate in 4 hours, and 2 mg ibandronate in 1 hour).^[8,9,19] Other studies have not yet recommended the use of ibandronate in those with declining kidney function as there are still not enough studies supporting that. Albuminuria examinations like urinary albumin excretion rate (UAER) every 3–6 months are recommended for the above population. The treatment should be terminated if albuminuria happens. Table 4 shows the dose adjustment for bisphosphonates in patients with declining kidney function.^[21]

Denosumab

Denosumab is a monoclonal against RANKL, so its administration could decrease the activation, maturation, and function of osteoclast, leading to a diminished bone resorption. Denosumab could be given in hypercalcemia patients who are refractory to bisphosphonate or with contraindications such as a severe decline in kidney function. Denosumab administration is given in 7–30 days, usually in a subcutaneous dose of 120 mg on day-1, -8, -15, -29, and 4 weeks afterward (an initial dose of 60 mg could be given subcutaneously). The effect of denosumab is observed 2–4 days after the first administration. The denosumab effect is more potent in patients with a decline in kidney function, making the need for dose adjustment according to the glomerular filtration rate. Initially, a dose of 0.3 mg/kg bodyweight is given to decrease the hypocalcemic effect. Adverse effects include osteonecrosis of the lower jaw and a much rare atypical fracture.^[2,19] More frequent side effects include dyspnea, diarrhea, nausea, or bone tenderness.^[8]

Glucocorticoids

Glucocorticoids are given in hypercalcemia caused by increased extrarenal 1,25(OH)₂D (commonly occurs in lymphoma or ovarian dysgerminoma) or in multiple myeloma patients. Glucocorticoids can hamper bone resorption by osteoclast by lowering the cytokines produced by tumors, specifically 1α-hydroxylase that converts 25(OH)D (calcidiol) into 1,25(OH) ₂D (calcitriol). Another expected effect of glucocorticoids is to obstruct calcium absorption from the intestines.^[2,9]

Glucocorticoids are usually given to patients with granulomatous diseases, such as sarcoidosis or lymphoma, in which calcitriol increases. The recommended regimen is 200–400 mg/day of hydrocortisone for 3–4 days, continued with 10–20 mg/day of prednisone for 7 days, or 40–60 mg/day of prednisone for 10 days. Glucocorticoids are reported to lower serum calcium by > 3 mg/dl after 1 week of treatment.^[2,9] Side effects that need to be observed are hypertension, hyperglycemia, peptic ulcer disease, psychiatric disorder, and muscle weakness.^[8]

Hemodialysis

Hemodialysis is the treatment of choice in severe hypercalcemia presenting with symptoms such as a decrease in consciousness. This usually happens when calcium level is severely low, reaching 18–20 mg/dl, in heart failure or oliguric end-stage renal disease patients who did not receive adequate hydration.^[6,22] Hemodialysis can also be done in severe hypercalcemia unresponsive to conservative treatments like hydration and bisphosphonate.^[9] Hemodialysis could be performed with low or no-calcium dialysate solution (dialysate calcium levels of ≤ 1 mmol/l).^[1,19,21] Hemodialysis could decrease calcium levels by 3–5 mg/dl in 3–4 hours.^[9]

Calcimimetic

Calcimimetics, such as cinacalcet, lowers high serum calcium levels usually experienced in patients with secondary hyperparathyroidism undergoing hemodialysis or parathyroid malignancies. It acts through the CaSR allosteric modulator mechanism in parathyroid cells, leading to a decrease in PTH productions and effects.^[9,16,19] Because of that, cinacalcet is believed to be beneficial in the management of hypercalcemia in malignancies where PTH production increases ectopically.^[10] Meanwhile, its effect on hypercalcemia in malignancies with osteolytic metastases is unknown.^[16] CaSR is also present in kidney and bone tissues, involved in osteoblast differentiation and bone resorption by osteoclast.^[9] Cinacalcet is usually given with a starting dose of 60–360 mg/day orally, with possible side effects like headache, nausea, and vomiting.^[8]

Other managements

Another treatment for hypercalcemia in malignancies, which is currently still under research, is the antibody against PTHrP. Studies on this PTHrP antibody are still limited to animals (in this case, rats) and are reported to have calcium-lowering effects while suppressing cytokines produced by cancer cells.^[9,22] Administration of intermittent PTH (teriparatide) or PTHrP analog (abaloparatide) has also been thought to reduce the effect of hypercalcemia caused by osteolytic metastasis. However, their use is not yet recommended due to their narrow safety profile.^[16]

Previously, intravenous gallium nitric administration with a dose of 200 mg/m² for 5 days could lower calcium levels by inhibiting osteoclast activity and increasing calcium secretion into the urine. Nevertheless, gallium nitric has been withdrawn from the market as it has severe adverse effects such as anemia, hypophosphatemia, and acute tubular necrosis.^[7,8,20-22] Another proposed medication is mithramycin, a cytotoxic antibiotic that can lower calcium by inhibiting bone resorption by osteoclast. This drug is given intravenously with a 25 mcg/kg bodyweight dose for 4–6 hours. It will exert its effect within 12 hours and can be repeated once every 3–4 days. Nonetheless, mithramycin is not recommended due to its side effects such as thrombocytopenia, stomatitis, nausea, vomiting, hepatotoxicity, and nephrotoxicity.^[20]