The Pathophysiology and Treatment of Malignancy-Associated Hypercalcemia

Onco-Nephrology: The Pathophysiology and Treatment of Malignancy-Associated Hypercalcemia

Mitchell H. Rosner* and Alan C. Dalkin†

Summary Hypercalcemia complicates the course of 10%–30% of all patients with malignancies and can be a sign of very poor prognosis and advanced malignancy. Prompt recognition of the nonspecific signs and symptoms of hypercalcemia and institution of therapy can be lifesaving, affording the opportunity to address the *Division of Nephrology and underlying etiology. The mechanisms of malignancy-associated hypercalcemia generally fall into three cate- †Division of gories: humoral hypercalcemia due to secreted factors (such as parathyroid-related hormone), local osteolysis Endocrinology, due to tumor invasion of bone, and absorptive hypercalcemia due to excess vitamin D produced by malignancies. The University of Virginia mainstays of therapy for hypercalcemia are aggressive intravenous volume expansion with saline, bisphosphonate Health System, therapy, and perhaps loop diuretics. Adjunctive therapy may include calcitonin and corticosteroids. In refractory Charlottesville, Virginia cases, gallium nitrate and perhaps denosumab are alternatives. In patients presenting with severe AKI, Correspondence: Dr. hemodialysis with a low-calcium bath can be effective. In most cases, therapy normalizes calcium levels and Mitchell H. Rosner, allows for palliation or curative therapy of the malignancy. Division of Clin J Am Soc Nephrol 7: 1722–1729, 2012. doi: 10.2215/CJN.02470312 Nephrology, Box 800133, University of Virginia Health System, Introduction measurement is unclear. In at least one study, slightly Charlottesville, VA Hypercalcemia (defined as a serum calcium level increased ionized calcium levels did not predict the 22908. Email: mhr9r@ above the upper limit of the normal reference range development of frank hypercalcemia in patients virginia.edu of 10.5 mg/dl or 2.5 mmol/L, 40%–45% of which is with solid malignant tumors (8,9). Thus, evaluation ionized calcium) can complicate the course of 10%– of total calcium concentration in light of changes in 30% of all patients with cancer (1–4). The incidence of bound versus ionized calcium is essential in order to hypercalcemia is low at the initial presentation of can- obtain a complete patient assessment. cer (1%–5%) but increases dramatically in patients with advanced disease and a poor prognosis (5). In fact, the median duration of survival for patients with – Mechanisms of Malignancy-Associated malignancy-associated hypercalcemia is only 2 6 Hypercalcemia months from the onset of hypercalcemia (3,5). Perturbations of calcium regulation in patients with fi The symptoms of hypercalcemia are nonspeci c, hypercalcemia of malignancy fall into three general often develop gradually, and may resemble the symp- categories (Figure 1). First, most common are hu- toms of the underlying malignancy and its treatment. moral factors secreted in a paracrine or endocrine fi These nonspeci c symptoms may lead to a delay in fashion (humoral hypercalcemia of malignancy). Sec- diagnosis, with increased morbidity and mortality. ond, in patients with substantial tumor burden met- fl Clinical presentation is in uenced by the rate of onset astatic to bone, the local effects of tumor can directly as well as the severity of hypercalcemia. Typical symp- facilitate bone dissolution and calcium mobilization toms include nausea, vomiting, constipation, abdominal (local osteolysis). Third, less commonly, absorptive pain, anorexia, weight loss, bone pain, polyuria, fatigue, hypercalcemia results from excess vitamin D activa- and weakness. In patients with more severe degrees of tion by the neoplasm. The cellular basis for the former . hypercalcemia (serum calcium 14 mg/dl), neurologic two mechanisms includes changes in the activity and symptoms such as confusion and even coma may be- balance at the level of the bone-remodeling unit. come more apparent. These patients require hospitali- Bone turnover involves the highly coordinated zation and urgent therapeutic intervention (6). activity of two distinct types of cells (10). The osteo- Given the presence of concomitant cachexia and blast, or bone-forming cell, is derived from a mesen- malnutrition in this population, it is also critical to chymal stem cell and is closely related to adipocytes, correct the serum calcium for a low albumin level or chondrocyte, myocytes, and fibroblasts. In contrast, measure an ionized serum calcium level in order to the osteoclast, or bone-removing cell, is derived assess the true degree of hypercalcemia (7). Although from stems cells populating the monocyte and mac- ionized calcium is more sensitive than albumin- rophage lineage. Although the specifics remain in- corrected total calcium in the diagnosis of hypercal- completely understood, communication between cemia of malignancy, the clinical usefulness of this osteoblasts and osteoclasts primarily involves the

Figure 1. | Mechanism of malignancy-associated hypercalcemia. PTHrP, parathyroid hormone–related hormone. receptor activator of nuclear factor k B (RANK) ligand extensive in nature, can present with significant areas of os- (RANKL) signaling pathway (10–12). RANK is a receptor teolysis and hypercalcemia (23). Underlying the release of expressed on osteoclast precursor cells. The naturally oc- calcium from the bone microenvironment is increased oste- curring ligand, RANKL, is produced by osteoblasts and oclast activity, probably due to PTHrP and other factors that drives proliferation and differentiation of the osteoclasts can increase resorption. As a result of the paracrine nature of into mature, multinucleated units. In addition, the osteo- this condition, circulating levels of PTHrP may be “normal” blast cell produces osteoprotegerin (OPG), a decoy recep- or only slightly above normal, in contrast to levels in patients tor that binds to and inactivates RANKL. with humoral hypercalcemia due to PTHrP. The cellular regulation of RANK, RANKL, and OPG Vitamin D has numerous physiologic actions, including expression is incompletely understood, but the osteoblast is the enhancement of calcium and phosphate absorption the focal point for the integration of endocrine and paracrine from the intestinal tract. Stored vitamin D (25-[OH]D) is signals that alter bone remodeling. For example, osteoblast 1-hydroxylated in the kidney to the active compound 1,25- cells express estrogen receptors that when occupied with (OH)2D, which in turn acts via the vitamin D receptor. PTH ligand can reduce RANKL and increase OPG (13). Directly actively drives the 1-hydroxylase step at the kidney, and related to the hypercalcemia of malignancy, osteoblasts also states of hyperparathyroidism, including ectopic PTH from express the cell surface receptor for parathyroid hormone malignancies, are associated with elevated 1,25-(OH)2Dlev- (PTH) and parathyroid hormone–related hormone (PTHrP), els. Of note, despite its action through the common PTH1R, PTH1R (14). Both PTH and PTHrP stimulate PTH1R, which, PTHrP is a poor stimulus for 1a-hydroxylation compared in turn, increases osteoblast activity and RANKL signaling with PTH, and levels of active vitamin D are often low or to the osteoclast. OPG expression may decline as well. In normal in patients with humoral hypercalcemia of malig- sum, PTH/PTHrP signaling results in an increased bone nancy (24). Important for the understanding of hypercalce- turnover with a greater increase in bone resorption than for- mia, the 1-hydroxylase enzyme is expressed in tissues mation, resulting in a net efflux of calcium and hypercalce- outside of the kidney, including macrophages and some mia from the bone microenvironment. neoplastic tissues. Patients with Hodgkin lymphoma and Tumors that commonly produce PTHrP include squa- non-Hodgkin lymphoma, as well as multiple myeloma, mous cell carcinomas of the lung, cervix, and esophagus; have been described as having vitamin D–mediated hyper- certain lymphomas; renal cell carcinoma; and adenocarci- calcemia (25). In these individuals, 1,25-(OH)2D levels, along noma of the breast, prostate, and ovary (15–17). In addi- with calcium levels, are high while PTH is suppressed from tion, several case reports have documented PTHrP the negative feedback to the parathyroid cells. Similarly, secretion in other malignancies. Ectopic secretion of PTH measurements of bone turnover markers are low in vitamin secretion is less common than that of PTHrP. The number D–mediated hypercalcemia because the reduction in PTH of cases in which tumor-related production of PTH has results in a diminution of osteoblast and osteoclast activity. been verified are few but include pulmonary, thyroid, ovarian, and pancreatic malignancies (18–20). Laboratory Investigation Local osteolysis as the basis for hypercalcemia occurs Given that the malignancy is usually advanced by the most frequently in widely metastatic disease, and the degree time hypercalcemia develops, a thorough history and of hypercalcemia correlates with the extent of tumor burden. physical examination can often lead to the correct diagnosis Local osteolysis is most commonly seen in patients with with limited laboratory evaluation. Measurement of intact metastatic breast and lung cancers (21,22). Probably due to a PTH through an immunoradiometric or immunochemolu- common pathophysiology, multiple myeloma, usually minescent assay will confirm a PTH-independent process. 1724 Clinical Journal of the American Society of Nephrology

In this case, the PTH levels will be suppressed (often Volume expansion will lead to an increase in GFR and an ,20 pg/ml) and should prompt further testing to distin- increase in urine calcium excretion. The goal should be es- guish among the multiple possible causes in patients with tablishing an adequate urine output (.75 ml per hour). In malignancy. This would include measurement of PTHrP, milder cases of hypercalcemia, this therapy can be sufficient 1,25-(OH)2D levels, serum and urine protein electrophoresis, to restore normal calcium levels (30). However, the effect of assessment of serum free light chains, and possibly imaging repleting the extracellular volume is transient, and other ther- studies (such as a skeletal survey). Less common causes of apies are required. Careful monitoring of the patient’svital hypercalcemia in malignancy include drugs (e.g., retinoic signs and laboratory values must occur during the acute acid [26]) and, rarely, parathyroid carcinomas producing phase of volume repletion, along with vigilance for evidence excessive PTH. of volume overload. Hypernatremia may be seen during this phase of therapy because of hypercalcemia-induced nephrogenic diabetes insipidus and may require changing from iso- Therapy for Malignancy-Associated Hypercalcemia tonic to hypotonic fluid therapy (31). Patients presenting with acute and symptomatic hyper- A common practice is to add a loop diuretic to saline calcemia require prompt therapy that rapidly reduces the therapy in an effort to increase urine calcium excretion serum calcium level, restores the GFR, and leads to longer- term normalization of the serum calcium level. An algo- (forced saline diuresis). LeGrand and colleagues reviewed rithmic approach is shown in Figure 2. the evidence-base for this approach (32). By inhibiting the sodium-potassium-chloride (NKCC2) transporter in the thick ascending limb of the loop of Henle, a loop diuretic Intravenous Fluid and Diuretics Hypercalcemia leads to a decrease in the GFR through a decreases the lumen positive charge that normally drives combination of the natriuretic effects of high serum levels calcium reabsorption; thus, a loop diuretic increases urine of calcium and renal vasoconstriction (27). In fact, polyuria calcium excretion and theoretically should be useful in is the most common renal manifestation of hypercalcemia, therapy for hypercalcemia (33,34). However, LeGrand fi and it is thought that the impaired urinary concentrating et al. could nd only nine articles that documented the ability is due to activation of the calcium-sensing receptor use of furosemide in the treatment of hypercalcemia, the in the thick ascending limb of the loop of Henle (28). Ac- last of which was published in 1983. These studies tivation of the calcium-sensing receptor leads to decreased comprised a total of 37 patients. The average dosage of resorption of sodium and chloride in the loop of Henle, furosemide was 1120 mg given over 24 hours, and serum resulting in decreased countercurrent multiplication and calcium normalized in 14 of 39 episodes of hypercalcemia; , decreased ability to concentrate the urine. In addition, ac- however, normalization was rapid ( 12 hours) in only – tivation of the calcium-sensing receptor in the collecting two cases. Lower dosages of furosemide (40 60 mg/d) duct blunts the response of this segment to the actions of did not achieve normalization of the serum calcium. arginine vasopressin (29). Thus, patients presenting with Most important, monitoring in these patients was inten- hypercalcemia are usually profoundly volume depleted. sive and included aggressive replacement of hourly urine Furthermore, patients usually will present with poor oral output losses, and secondary electrolyte disorders, such as intake and may have had nausea and vomiting that further hypernatremia, hypophosphatemia, hypomagnesemia, worsen the volume depletion. The decrease in GFR leads to and metabolic acidosis, were seen. Thus, the routine use impaired calcium clearance and, thus, restoration of extra- of loop diuretics in the therapy for hypercalcemia cannot cellular fluid volume, and GFR is a key goal of therapy. be recommended, and their use should be restricted to Thus, initial therapy should begin with intravenous (IV) patients who develop fluid overload while receiving ag- volume expansion with 0.9% saline at 200–500 ml per hour. gressive volume resuscitation.

Figure 2. | Treatment algorithm for malignancy-associated hypercalcemia. IV, intravenous. Clin J Am Soc Nephrol 7: 1722–1729, October, 2012 Hypercalcemia of Malignancy, Rosner and Dalkin 1725

Bisphosphonates associated with a lower response rate) (47,48). The fact that High-potency IV bisphosphonates are effective agents patients with higher levels of PTHrP show less of a hypocal- for the treatment of malignancy-associated hypercalcemia. cemic response to bisphosphonates is probably due to the The three high-potency bisphosphonates are pamidronate, continued actions of PTHrP on the kidney to decrease cal- zoledronate, and ibandronate (dosing guidelines are cium excretion, an effect that is not modulated by bisphosph- shown in Table 1). Because the IV bisphosphonates are onates. excreted unchanged by the kidneys through glomerular Zoledronate is 100 times more potent than pamidronate, filtration, their dosing must be adjusted for impaired and two parallel randomized trials evaluated the efficacy of renal function to avoid toxicity (35,36). Mechanistically, 4 or 8 mg of zoledronate versus 90 mg of pamidronate in bisphosphonates decrease bone resorption through extra- restoring normocalcemia by day 10 after treatment (49). cellular and intracellular mechanisms (37–41). In the extra- Both doses of zoledronate were superior to pamidronate, cellular space, bisphosphonates bind to calcium phosphate with serum calcium normalizing by day 10 in 88%, 87%, and stabilize the bone matrix, while intracellularly these and 70% of patients receiving 4 and 8 mg of zoledronate agents inhibit osteoclast activity, in part through inhi- and 90 mg of pamidronate, respectively (49). Moreover, bition of the mevalonate pathway (37–39). Furthermore, the mean duration of complete response was 32, 43, bisphosphonates impair cellular adenosine triphosphate– and 18 days, respectively, in the three treatment dependent metabolic pathways, disrupt the osteoclast groups (49). cytoskeleton, and induce apoptosis (40,41). Ibandronate is also effective in treating malignancy- Randomized clinical trials with pamidronate, zoledronate, associated hypercalcemia (44,50). Doses of 2, 4, and 6 mg and ibandronate have all shown efficacy in the treatment of had success rates of 50%, 76%, and 77%, respectively hypercalcemia of malignancy (42–44). However, the three (44). Compared with pamidronate, the duration of re- bisphosphonates differ in terms of their potency and risk sponse is longer with ibandronate (50). However, for toxicity. Nussbaum et al. demonstrated a dose response ibandronate is not approved by the Food and Drug Ad- using pamidronate, with 40%, 61%, and 100% of patients ministration (FDA) to treat malignancy-associated hy- achieving normocalcemia with 30, 60, and 90 mg, respec- percalcemia. tively (45). Similar efficacy of pamidronate is seen over a The most common side effect associated with these agents dosing span ranging from 2 to 24 hours (46). Thus, a prac- is infusion-related fever, which is usually mild (51). How- tical approach is to administer pamidronate, 60–90 mg, over ever, bisphosphonate-associated nephrotoxicity affecting 2–6 hours, with the longer dosing time reserved for patients both glomerular and tubular structures has been described with lower GFRs and the higher doses for patients with in both case series and randomized clinical trials (35). In more severe hypercalcemia. The efficacy of pamidronate terms of glomerular toxicity, bisphosphonates (most com- (and probably other bisphosphonates) is influenced by the monly, pamidronate and, only rarely, zoledronate) have mechanism of hypercalcemia (more effective in cases of hy- been associated with collapsing focal segmental glomerulo- percalcemia associated with bone metastases); the level of sclerosis (FSGS), noncollapsing FSGS, and minimal-change hypercalcemia (higher doses required to treat more severe disease in several case series (52–56). The most common hypercalcemia); and, in patients with humoral hypercalce- lesion is collapsing FSGS, which is seen with high-dose IV mia, the level of PTHrP (higher levels of PTHrP are pamidronate often in patients with underlying multiple

Table 1. Dosing guidelines for intravenous bisphosphonates in the treatment of acute hypercalcemia

Bisphosphonate per CrCl Dose and Infusion Rate Dosing Interval

CrCl .60 ml/min pamidronate 90 mg over 2–3 hr Every 3–4wk zoledronate 4 mg over 15 min Every 3–4wk ibandronate Not FDA approved CrCl 30–60 ml/min pamidronate 60–90 mg over 2–3 hr Every 3–4wk Reserve higher doses for more severe hypercalcemia zoledronate Every 3–4wk CrCl 50–60 ml/min 3.5 mg CrCl 40–49 ml/min 3.3 mg CrCl 30–39 ml/min 3 mg ibandronate Not FDA approved CrCl , 30 ml/min pamidronate 60–90 mg over 4–6 hr Every 3–4wk Reserve higher doses for more severe hypercalcemia zoledronate Not recommended Not recommended ibandronate Not FDA approved

Data obtained from reference 61. CrCl, creatinine clearance; FDA, Food and Drug Administration. 1726 Clinical Journal of the American Society of Nephrology

myeloma and usually after repeated doses (35). In clinical addition, renal impairment has been reported, and hence trials, glomerular toxicity of the bisphosphonates was not gallium nitrate is not recommended for use when the se- reported (35). In some cases, the nephrotic syndrome re- rum creatinine concentration exceeds 2.5 mg/dl. Adequate solves after cessation of the drug, but some patients may fluid resuscitation is essential before initiation of treatment progress to ESRD, especially if the glomerular lesion is col- with gallium, and BUN and creatinine must be followed lapsing FSGS. closely during treatment. Patients receiving gallium have Tubular injury (nephrotoxic acute tubular necrosis) as- reported nausea, vomiting, lethargy, altered mental status, sociated with bisphosphonates (mainly, zoledronate) has and both diarrhea and constipation. also been described in both case reports and clinical trials – (57 59). In 2003, the FDA Adverse Event Reporting System Calcitonin experience with bisphosphonates and AKI revealed 72 Calcitonin is a peptide hormone secreted by the para- cases associated with IV zoledronate (60). In this cohort, follicular C cells of the thyroid gland. It inhibits osteoclast AKI developed approximately 2 months after initiation of bone resorption and increases urinary calcium excretion. therapy and after a mean of 2.4 doses of zoledronate. Risk Synthetic calcitonin (derived from salmon) is administered factors for AKI included advanced cancer, previous as 4–8 U/kg intramuscularly or subcutaneously every 6–8 bisphosphonate therapy, and use of nonsteroidal anti- hours. Calcitonin has a rapid onset of effect, leading to fl in ammatory agents. Most patients did not fully recover reductions in serum calcium within 2–6 hours after dosing. to baseline renal function, and 37.5% of patients required The calcium-lowering effects of calcitonin are modest and dialysis (60). transient, with a mean duration of effect of 2–4 days (76). On the basis of the renal toxicity of bisphosphonates, the Furthermore, repeated administration of calcitonin results American Society of Clinical Oncology developed dosing in downregulation of the calcitonin receptors on osteoclasts and monitoring guidelines (Table 1) and recommended and dimunition in effect (tachyphylaxis) (77). Overall, its that zoledronate be avoided in patients with a creatinine efficacy is poor, inducing normocalcemia in just one third , clearance 30 ml/min (61). Furthermore, serum creatinine of patients (78). Calcitonin’s major role may be as an adjunc- should be monitored before each dose of bisphosphonate tive agent with bisphosphonates in the treatment of severe, and the drug withheld in patients with worsening of renal symptomatic hypercalcemia when calcium levels must be function. Urine albumin excretion should be monitored at reduced rapidly (79). Side effects are minimal; nausea, vom- 3- to 6-month intervals, and the drug should be held if iting, and injection site pain are the most common. Overall, albuminuria develops (61). there is little evidence that calcitonin use has better efficacy Interestingly, ibandronate appears to have minimal to no over volume repletion and bisphosphonate therapy alone. renal toxicity, even in patients with underlying CKD (62– 64). However, more experience with this drug for the treatment of malignancy-associated hypercalcemia is needed Corticosteroids Corticosteroids are effective agents in the treatment of before firm conclusions on its renal safety can be made. hypercalcemia associated with malignancies that overpro- An increasingly recognized complication of bisphospho- duce calcitriol. This is due to their effect in inhibiting nate therapy is osteonecrosis of the jaw (ONJ) (65,66). The 1a-hydroxylase conversion of 25-hydroxyvitamin D to cal- precise etiology is not known, and the most common pre- citriol. Typically, these patients have underlying Hodgkin cipitating factors include dental extraction, long-term se- or non-Hodgkin lymphoma (80). The efficacy of cortico- quential use of IV pamidronate or zoledronate, smoking, steroids is based on case reports and thus the dosing and poor dental health (67). The absolute risk for ONJ is guidelines are uncertain; however, a reasonable regimen unknown, although it is estimated to occur in ,1:10,000 is IV hydrocortisone, 200–300 mg/d, for 3–5days(79). treated individuals and may be seen even less often in Typically, calcium levels are slow to decrease with corti- patients receiving shorter-term treatment. Diagnosis is based costeroid treatment alone. Patients who do respond with on clinical criteria that include pain and evidence of local normalization of their serum calcium can be transitioned infection. Management is largely supportive, with occa- to maintenance oral prednisone, 10–30 mg/d (81). sional need for surgical debridement. The condition can be prevented through good dental hygiene and avoidance of invasive dental procedures during bisphosphonate Hemodialysis fi therapy (68). For patients with acute hypercalcemia and signi cant AKI (especially in the setting of oliguria), saline-induced diuresis Gallium Nitrate may not be feasible and may lead to volume overload. In Gallium nitrate is approved for the treatment of cancer- these circumstances, hemodialysis using a very-low-calcium # related hypercalcemia. The cellular basis for this action is dialysate ( 1 mmol/L) is an option (82). For refractory unknown but appears to involve a reduction in osteoclast cases of hypercalcemia, several case reports describe the activity and bone remodeling (69–72). Clinically, gallium use of citrate anticoagulation to chelate calcium along with fi nitrate is administered by a continuous infusion at a dos- continuous venovenous hemodia ltration (83,84). age of 200 mg/m2 per day over 5 consecutive days. Re- ports comparing gallium to bisphosphonates (73,74) and Denosumab calcitonin (75) have shown equal or perhaps even superior Given the important role RANKL in the pathogenesis of efficacy in decreasing calcium levels. Adverse effects from bone metastases and secondarily in leading to hypercalcemia, treatment include hypocalcemia and hypophosphatemia, inhibition of this pathway is an attractive means of poten- the latter being observed in nearly 80% of patients. In tially treating forms of malignancy-associated hypercalcemia Clin J Am Soc Nephrol 7: 1722–1729, October, 2012 Hypercalcemia of Malignancy, Rosner and Dalkin 1727

due to bone calcium release. Denosumab is a fully human Disclosures monoclonal antibody that binds to RANKL and inhibits os- None. teoclast maturation, activation, and function (85). It is FDA approved for preventing skeletal-related events in patients with solid malignancy, as well preventing bone fractures in References 1. Sargent JTS, Smith OP: Haematological emergencies managing postmenopausal women with osteoporosis. In clinical trials, fi hypercalcaemia in adults and children with haematological denosumab has shown ef cacy in preventing skeletal-related disorders. Br J Haematol 149: 465–477, 2010 events (such as bone metastases) in patients with prostate, 2. Stewart AF: Clinical practice. Hypercalcemia associated with breast, and other solid-organ cancers, as well as multiple cancer. N Engl J Med 352: 373–379, 2005 myeloma (85). Denosumab is well tolerated, with arthralgias 3. 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