Hypercalcemia of Malignancy: Mechanisms and Therapeutic Implications of Concurrently Elevated PTHrP and Calcitriol.

Hypercalcemia of malignancy (HCM), the most common cause of hypercalcemia in hospitalized patients [ 1 ], has been well described in both solid and hematologic malignancies [ 1-3 ] and is predictive of poor prognosis [ 2-5 ]. Patients classically present with confusion, nausea, vomiting, and dehydration in the context of markedly elevated serum calcium levels, and these symptoms are often the first recognized manifestations of their underlying malignancy [ 5 ]. Classically, HCM has been attributed either to focal osteolysis associated with bone metastases or multiple myeloma or to paraneoplastic secretion of PTH-related peptide (PTHrP), 1,25-dihydroxyvitamin D (calcitriol), or extremely rarely PTH [ 1 , 2 , 6 , 7 ]. Although early literature identified PTHrP-associated (humoral) HCM as the most common paraneoplastic etiology in solid tumors and calcitriol-mediated HCM as the most common etiology in hematologic malignancies [ 1 ], emerging data challenge these assumptions [ 2 ]. Furthermore, HCM with PTHrP and calcitriol cosecretion has been increasingly detected in both solid and hematologic malignancies [ 3 , 4 , 8-23 ]. However, although often refractory to standard treatments [ 3 , 8 , 10 , 12 , 15 , 16 , 18 , 20 , 21 , 23 ], PTHrP and calcitriol co-mediated HCM is poorly understood. In this review, we discuss the prevalence and pathophysiology of PTHrP and calcitriol co-mediated HCM and reevaluate the diagnostic, prognostic, and therapeutic implications of concurrent elevations in PTHrP and calcitriol.

Methods of Evidence Acquisition

After searching PubMed using multiple combinations of the terms “hypercalcemia of malignancy,” PTHrP,” “calcitriol,” “combined causes,” and “concurrent etiologies” and cross-referencing citations from retrieved articles, we identified 2 retrospective chart reviews and 17 cases of HCM associated with concurrent elevations in PTHrP and calcitriol ( Tables 1 and 2 ). Given the scarcity of relevant articles, we did not exclude any studies or case reports. We also surveyed the literature regarding isolated humoral or calcitriol-mediated HCM to augment our understanding of the pathophysiology, diagnosis, and treatment of co-mediated cases.

Prevalence

Early studies in the 1980s and 1990s reported that HCM develops in 10% to 30% of patients with malignancy [ 1 , 25 ], with 80% of cases driven by PTHrP, 20% associated with osteolytic metastases, and <1% secondary to elevated calcitriol [ 1 , 25 ]. However, these estimates were derived from cohorts that underwent incomplete diagnostic evaluations of hypercalcemia and are limited by small sample sizes [ 25 , 26 ]. More recent literature suggests that HCM develops in 0.67% to 2% of cancer patients [ 27-29 ], but controversy persists regarding the prevalence of specific etiologies.

Long recognized as the leading paraneoplastic etiology of hypercalcemia in solid tumors [ 1 , 22 , 30 ], PTHrP-mediated (humoral) HCM is well characterized in squamous cell carcinomas of the head and neck, esophagus, cervix, lung, and breast and in adenocarcinomas of the ovary, kidney, and gallbladder [ 1 , 8 , 14 ]. Although less common than calcitriol-mediated HCM in most hematologic malignancies [ 1 ], elevated PTHrP occurs in up to 80% of patients with human T-lymphotrophic virus type 1 (HTLV-1) associated adult T-cell leukemia [ 31-34 ], and has been detected in patients with non-Hodgkin lymphoma (NHL) [ 4 ]. Moreover, although classically associated with lymphomas, elevated calcitriol has been increasingly identified in solid tumors.

A study evaluating 242 HCM patients between 2002 and 2013 found that 38% of cases were associated with elevated PTHrP, 27% with osteolytic metastases, and 40% with indeterminate etiology [ 35 ]. Since calcitriol was seldom measured in these patients, this study offers limited information regarding the prevalence of calcitriol-mediated HCM. However, after reviewing PTH, PTHrP, and calcitriol measurements in 101 patients with PTH-independent HCM associated with solid tumors between 2008 and 2017, Chukir et al noted elevated PTHrP in 62.8%, elevated calcitriol in 45%, and concomitant elevations in PTHrP and calcitriol in 34.2% of cases [ 23 ]. Although Chukir et al did not evaluate patients with hematologic malignancies, Sheehan et al reviewed similar diagnostic data between 2000 and 2019 in a cohort that included both solid and hematologic malignancies.

In 95 patients with solid tumors, Sheehan et al identified elevated PTHrP in 42.1%, elevated calcitriol in 31.5%, and concurrent elevations in PTHrP and calcitriol in 13.1% [ 4 ]. They found higher proportions of calcitriol and lower proportions of PTHrP and combined PTHrP and calcitriol-associated HCM cases in 58 patients with hematologic malignancies, but these proportions varied considerably between lymphoma and multiple myeloma [ 4 ]. Thirteen percent of the 36 lymphoma patients demonstrated elevated PTHrP, 60.8% demonstrated elevated calcitriol, and 4.3% demonstrated concomitant elevations in PTHrP and calcitriol [ 4 ]. In contrast, most cases of HCM in multiple myeloma patients were associated with osteolytic metastases, with only 11.1% demonstrating elevated calcitriol and none with elevated PTHrP [ 4 ]. This data challenges the long-held assumptions that concurrent PTHrP and calcitriol hypersecretion is rare and confirms that co-mediated cases may be associated with both solid and hematologic malignancies.

Overview of Case Reports Involving Concurrent Elevations in PTHrP and Calcitriol

We identified 17 cases of PTHrP and calcitriol co-mediated HCM [ 3 , 8-22 ] ( Table 1 ). Median patient age was 60 years (range 26-81 years), and approximately 59% were male. Thirteen patients had solid tumors [ 3 , 8-19 ], and 4 had hematologic malignancies [ 20-22 , 24 ]. The solid tumors included 5 squamous cell carcinomas of the lung, anus, esophagus, or thymus [ 8-12 ]; 5 adenocarcinomas of the kidney, gallbladder, or ovary [ 3 , 14-17 ]; 1 mixed adeno/squamous cell carcinoma of the lung [ 13 ]; 1 neuroendocrine tumor of the pancreas [ 18 ]; and 1 germ cell tumor [ 19 ]. Seven patients with solid tumors had distant metastases [ 3 , 8 , 9 , 12-14 , 19 ], 4 had local invasion or lymph node involvement [ 10 , 11 , 15 , 16 ], and 2 had no metastatic disease [ 17 , 18 ]. The hematologic malignancies included 3 cases of NHL [ 20 , 21 , 24 ] and 1 case of HTLV-1-associated adult T-cell leukemia [ 22 ]. In 3 of these hematologic cases, the workup of hypercalcemia led to new cancer diagnoses [ 21 , 22 , 24 ]. However, 1 case involved recurrent NHL that had proven refractory to multiple prior chemotherapeutic regimens [ 20 ].

Pathophysiology

Elevated PTHrP

Biochemically characterized in 1987 [ 1 , 36 ], PTHrP is a polypeptide with a 13 amino acid N-terminal segment that bears 70% sequence homology to PTH [ 1 , 37 ]. Its close resemblance to PTH enables PTHrP to selectively bind and activate PTH receptor-1, which stimulates osteoclastic bone resorption, renal calcium reabsorption, and renal phosphorus excretion [ 18 , 36 , 38 ]. Similar to patients with primary hyperparathyroidism, patients with humoral HCM experience hypercalcemia, reduced renal calcium clearance, and increased osteoclastic activity [ 39 ]. However, PTHrP and PTH also differ markedly in their effects on vitamin D metabolism. While calcitriol is either normal or increased in primary hyperparathyroidism [ 40 ], it is usually suppressed in humoral HCM [ 1 , 41-43 ].

The reason for these discordant effects remains unclear. PTH and PTHrP have comparable affinities for the PTH receptor-1 [ 1 , 3 , 44 ], and both promote calcitriol production in rodents [ 3 , 45-48 ]. However, in vitro models involving human cells suggest that PTHrP stimulates renal calcitriol production less effectively than PTH [ 42 ]. Moreover, PTHrP has not been found to stimulate calcitriol production in human patients [ 39 , 49 ], and Horwitz et al demonstrated that low doses of PTHrP decrease calcitriol levels in healthy controls [ 50 ].

It is possible that marked hypercalcemia in humoral HCM patients suppresses or impairs the function of renal 1-α hydroxylase, overcoming any stimulatory effects of PTHrP [ 51 ]. This hypothesis is supported by the observation that PTH and calcitriol levels often increase following the normalization of serum calcium in patients with HCM, even in the presence of persistently elevated PTHrP [ 51 ]. Since only the N-terminus of PTHrP shares strong homology with PTH, the polypeptides may also regulate 1-α hydroxylase through different signaling pathways [ 1 , 39 , 52-54 ]. Alternatively, discrepancies between rodent models and humans may be explained by interspecies variation in response to PTHrP [ 15 ] or by the concomitant presence of a tumor factor distinct from PTHrP that directly suppresses renal calcitriol production in patients with HCM [ 54 ].

The presence of elevated PTHrP in several normocalcemic patients with solid tumors [ 55 ] has also led some to conjecture that HCM manifests only after PTHrP exceeds a certain threshold [ 17 ]. However, no study to date has identified a consistent correlation between serum calcium and PTHrP level. Moreover, the development of hypercalcemia in patients with benign tumors [ 56 ] and early-stage carcinomas [ 17 ] reinforces that humoral HCM is not always associated with advanced malignancy.

Elevated calcitriol

Calcitriol, the active form of vitamin D, increases gastrointestinal calcium absorption and stimulates osteoclast-mediated bone resorption [ 3 , 57 ]. Physiologically, direct suppression of PTH production by calcitriol (via the vitamin D receptor in parathyroid cells) and indirect suppression by circulating calcium (mediated by the calcium-sensing receptor in parathyroid cells) maintain calcium homeostasis. Regulation occurs at the level of renal 1-α hydroxylase, the enzyme that catalyzes the conversion of inactive 25-hydroxyvitamin D to calcitriol [ 57 ]. In healthy controls, renal 1-α hydroxylase is stimulated by PTH and hypophosphatemia and inhibited by fibroblast growth factor 23 [ 16 , 57 ]. The failure of these negative feedback mechanisms to regulate calcitriol and calcium levels in calcitriol-mediated HCM suggests that extrarenal calcitriol production precipitates pathophysiologic hypercalcemia.

However, the source of elevated calcitriol in HCM remains controversial. The enzyme 1-α hydroxylase has been isolated in tissue-associated macrophages in both malignant and nonmalignant granulomatous diseases [ 58 , 59 ]. In patients with NHL, 1-α hydroxylase has been detected in surrounding macrophages but not in stained sections of malignant lymphoid tissue [ 59 ], suggesting that calcitriol is produced in macrophages rather than in malignant cells [ 60 , 61 ]. However, it is unclear whether this holds true for nonhematologic malignancies. Although high levels of 1-α hydroxylase have been measured in macrophages associated with lung cancer relative to healthy controls [ 62 ], extrarenal 1-α hydroxylase has also been detected in malignant cells associated with prostate, breast, renal, lung, and colonic tumors [ 3 , 63-66 ] and in nonmalignant tissue associated with the gastrointestinal tract, epidermis, testes, central nervous system, bone, and placenta [ 67 ]. Notably, 1-α hydroxylase levels are higher in malignant colonic cells than in healthy colonic tissue [ 64 ], and 1-α hydroxylase mRNA expression was found to be 222-fold higher in dysgerminoma cells than in nonovarian tissues [ 68 ].

Concomitant elevations in PTHrP and calcitriol

Although most agree that PTHrP is secreted by malignant tissue in patients with PTHrP and calcitriol co-mediated HCM, the secretory source of calcitriol and its connection to PTHrP remain unclear. In the cases of PTHrP and calcitriol co-mediated HCM that we reviewed, PTHrP expression was detected in malignant tissue associated with NHL and in a neuroendocrine tumor [ 18 , 21 ], and 1-α hydroxylase expression was detected in a hepatic metastasis associated with renal cell carcinoma [ 3 ]. However, none of these cases tested malignant tissue for expression of both PTHrP and 1-α hydroxylase. Moreover, since renal tissue expresses 1-α hydroxylase physiologically, it is unclear whether the 1-α hydroxylase detected in the hepatic metastasis [ 3 ] was the source of calcitriol hypersecretion or whether expression of this enzyme was associated with the tissue's nephrogenic origin.

Since PTHrP has not been shown to stimulate significant calcitriol secretion in humans, many propose that PTHrP and calcitriol are secreted independently [ 10 , 58 , 59 ]. This theory is supported by an analysis of 101 solid tumor patients with HCM, which did not detect a significant correlation between calcitriol level and PTHrP [ 23 ]. However, other studies suggest that calcitriol production is stimulated by PTHrP, and that secretion occurs in nonmalignant tissue [ 8 , 17 ]. In a case of combined PTHrP and calcitriol-mediated HCM associated with nonmetastatic ovarian carcinoma, Benit et al noted a higher concentration of PTHrP in the ovarian vein than in peripheral venous blood but no difference in the concentration of calcitriol [ 17 ]. These concentration gradients suggest that PTHrP alone was secreted by the tumor [ 17 ]. The normalization of PTHrP, serum calcium, and calcitriol levels almost immediately after surgical excision of malignant tissue producing PTHrP further suggests that PTHrP mediated calcitriol production in this case [ 17 ].

It is also unclear why calcitriol levels vary in HCM patients with elevated PTHrP. Panvelker et al propose that variation in serum calcitriol may be secondary to renal damage derived from longstanding hypercalcemia and that higher calcitriol levels are reflective of earlier stages of disease [ 20 ]. This argument is supported by the positive correlation between 1-α hydroxylase activity and stage of malignancy noted in a cohort of lung cancer patients [ 62 ]. However, case reports associated with severe hypercalcemia and early-stage or nonmetastatic disease are inconsistent with this hypothesis [ 17 , 18 ].

Approach to Diagnosis

Most current diagnostic algorithms recommend first testing for PTHrP after confirming PTH-independent hypercalcemia in patients with malignancy [ 69 ]. After detecting elevated PTHrP, additional testing is rarely performed [ 23 , 70 ]. Furthermore, given its historic association with hematologic malignancies, calcitriol is not routinely measured when evaluating patients with solid tumors unless their hypercalcemia proves refractory to standard treatments [ 4 , 71 ].

A retrospective analysis of 11 589 cancer patients with hypercalcemia over a 20-year period highlights the limitations of the current diagnostic approach. In this study, PTH was only measured in 25.4% of patients [ 4 ]. Furthermore, of the 907 patients with PTH-independent HCM, only 31.6% underwent further biochemical evaluation of PTHrP and/or calcitriol, and only 7.7% underwent sufficient workup to determine whether their hypercalcemia was associated with PTHrP, calcitriol, or osteolytic metastases [ 4 ].

Without measuring both PTHrP and calcitriol simultaneously when evaluating PTH-independent hypercalcemia, it will be nearly impossible to identify and determine the true prevalence of co-mediated cases. Although some authors advocate for revising our diagnostic algorithm to measure PTHrP and calcitriol concurrently after detecting PTH-independent hypercalcemia [ 1 ] ( Fig. 1 ), there is insufficient information to support this as a systematic recommendation. Since humoral, calcitriol-mediated, and combined cases occur in a wide variety of hematologic malignancies and solid tumors ( Table 3 ), it is unclear whether specific patients or tumor types would benefit from this revised diagnostic approach. Moreover, there is limited information regarding the economic, prognostic, and therapeutic implications of routinely measuring both biomarkers in all patients with HCM, and these implications must be considered carefully before incorporating this approach into standard practice.

Approach to Treatment

Treatment of isolated humoral HCM

Since elevated serum calcium induces diuresis and volume depletion, saline hydration is often indicated, especially since patients with malignancies frequently present with reduced oral intake [ 1 , 2 , 8 , 72 , 73 ]. Infusing normal saline inhibits tubular calcium reabsorption by both expanding intravascular volume and delivering sodium to the proximal tubule. Calcitonin causes a rapid, but transient, reduction in serum calcium levels, and loop diuretics may be administered with IV fluids to enhance renal calcium excretion in hypervolemic patients [ 1 , 2 ]. Following fluid resuscitation, antiresorptive therapy is the standard of care [ 2 , 25 , 72-74 ]. Although zoledronic acid is more efficacious [ 75-77 ] and potent [ 72 ] than pamidronate, both bisphosphonates are first-line therapies for HCM [ 1 , 2 , 72 ]. By inhibiting osteoclast activity in areas of bone remodeling, bisphosphonates reduce PTHrP-mediated bone resorption [ 1 , 2 , 16 , 76 , 77 ]. Denosumab, which prevents osteoclast activation by inhibiting the receptor activator of nuclear factor kappa-b ligand, has also proven effective in humoral HCM [ 1 , 2 , 78 ]. However, it is more expensive than zoledronic acid or pamidronate [ 79 ] and is usually reserved for cases that are refractory to bisphosphonates [ 1 ] or for patients with severe renal dysfunction that precludes bisphosphonate therapy.

Treatment of isolated calcitriol-mediated HCM

Treatment of calcitriol-mediated HCM also initially involves fluid resuscitation (with or without loop diuretics) and calcitonin to restore euvolemia and rapidly reduce serum calcium levels, but definitive treatment usually incorporates glucocorticoids rather than bisphosphonates [ 1 , 10 , 57 , 73 ]. By inhibiting transcription of extra-renal 1-α hydroxylase, glucocorticoids decrease calcitriol and consequently serum and urinary calcium [ 1 , 14 , 25 , 60 , 61 , 80 , 81 ]. The efficacy of glucocorticoids may also be associated with their anti-inflammatory and leukotoxic effects [ 8 , 57 ].

Glucocorticoid therapy is the standard of care when treating calcitriol-mediated HCM in hematologic malignancies [ 1 , 2 ]. However, many physicians continue to prescribe IV bisphosphonates as frontline therapy in patients with solid tumors who present with calcitriol-mediated HCM, with limited success [ 3 , 8-10 , 12-16 , 18 , 23 ] ( Table 2 ). The Endocrine Society also recommends antiresorptive therapy with IV bisphosphonates or denosumab in calcitriol-mediated HCM cases that prove refractory to glucocorticoids [ 74 ].

Treatment of HCM cases associated with concurrent elevations in PTHrP and calcitriol

Although bisphosphonates are highly effective in humoral HCM [ 23 , 72 , 75 , 76 ], cases involving concurrent elevations in PTHrP and calcitriol often prove refractory to antiresorptive therapy [ 3 , 8 , 10 , 12 , 15 , 16 , 18 , 20 , 21 , 23 ]. In a retrospective study at Memorial Sloan Kettering, 80% of solid tumor patients with HCM secondary to PTHrP and calcitriol cosecretion demonstrated an incomplete response to bisphosphonate therapy (vs 12% of patients with isolated humoral HCM, P < .001) [ 23 ]. The authors did not evaluate the efficacy of glucocorticoid therapy or hematologic malignancies in that series. However, the high response rate in patients with humoral HCM suggests that the low efficacy of bisphosphonates in PTHrP/ calcitriol co-mediated cases may be due to mechanisms other than bone resorption, such as calcitriol-mediated intestinal calcium absorption.

The therapeutic and prognostic implications of PTHrP and calcitriol co-mediated HCM can otherwise be inferred from published case reports ( Table 2 ). Treatment regimens usually incorporated bisphosphonates or glucocorticoids, and tumors' histologic origin did not correlate with the efficacy of any specific treatment. Of the 13 patients treated with IV bisphosphonates, 4 patients' hypercalcemia resolved without documented recurrence [ 9 , 13 , 14 , 22 ], 6 demonstrated a decrease in or normalization of serum calcium levels followed by a recurrence of hypercalcemia [ 8 , 10 , 12 , 15 , 16 , 21 ], and 3 did not respond [ 3 , 18 , 21 ]. Those who experienced resolution without documented recurrence included 1 patient with esophageal squamous cell carcinoma [ 9 ], 1 patient with cholangiocarcinoma [ 14 ], 1 patient with mixed adeno/squamous cell carcinoma of the lung [ 13 ], and 1 patient with HTLV-1-associated adult T-cell leukemia [ 22 ].

Only 2 of the 7 patients treated with glucocorticoids outside of a chemotherapeutic regimen experienced resolution without documented recurrence [ 3 , 11 ], including 1 patient with renal cell adenocarcinoma previously refractory to bisphosphonates [ 3 ] and 1 patient with lung squamous cell carcinoma [ 12 ]. Three experienced a moderate decrease in or transient normalization of serum calcium levels followed by a rapid recurrence of hypercalcemia [ 8 , 12 , 24 ], and 2 did not respond [ 15 , 20 ]. Of the 4 other cases treated with both antiresorptive therapies and glucocorticoids, 2 cases demonstrated transient normalization of serum calcium levels in response to both [ 8 , 12 ], 1 case demonstrated transient normalization of serum calcium following bisphosphonates but did not respond to glucocorticoids [ 15 ], and 1 case responded to neither treatment [ 20 ].

Less common treatments included denosumab, hydroxychloroquine, and interferon-α. Denosumab was only utilized following unsuccessful bisphosphonate therapy and normalized serum calcium levels transiently in 1 of the 2 patients who received it [ 12 , 20 ]. Hydroxychloroquine precipitated resolution of hypercalcemia in 1 patient with NHL who had previously failed to respond to prednisone [ 20 ], and interferon-α normalized serum calcium levels in 1 patient with a pancreatic neuroendocrine tumor with hypercalcemia that was refractory to bisphosphonates [ 18 ].

Case reports offered limited information regarding the duration of serum calcium normalization following pharmacological interventions. In patients who experienced transient normalization of serum calcium levels, hypercalcemia was usually documented within days to weeks. However, in patients who responded to therapy without recurrence, the duration of normocalcemia is more difficult to ascertain. The duration of documented follow-up after treatment in these patients ranged from no reported follow-up to 24 months (median 3 months). Although it is uncertain whether hypercalcemia would have recurred in these patients with more extensive follow-up, most entered hospice and/or died of other malignancy-associated complications within 1 month of treatment unless remission of their underlying malignancy was achieved.

Attaining remission of patients' underlying malignancy proved integral to resolve and prevent recurrence of hypercalcemia. In 7 of the 10 patients who received definitive cancer treatments [ 15-19 , 21 , 24 ], serum calcium levels normalized and remained within normal limits for the duration of follow-up (which ranged from <1 month to 24 months, median 7 months). All 3 patients with persistent hypercalcemia had metastatic malignancies that did not respond to chemotherapy [ 8 , 10 , 12 ], but serum calcium levels did decrease in 1 of these patients despite prior refractoriness to multiple bisphosphonates and glucocorticoids [ 8 ]. Notably, 2 patients with NHL who demonstrated either no response or transient improvement in serum calcium levels following isolated glucocorticoid therapy experienced complete resolution of hypercalcemia after receiving their first cycle of R-CHOP (prednisone followed by a combination of rituximab, cyclophosphamide, doxorubicin, and vincristine) [ 21 , 24 ]. Moreover, serum calcium, PTH, PTHrP, and calcitriol levels all normalized within days to weeks postoperatively in all 4 of the patients who underwent surgical excision or debulking of their solid tumors [ 15-18 ], including the patient whose hypercalcemia previously recurred 35 months after successful treatment with interferon-α [ 18 ]. Another patient who had not undergone prior treatment of hypercalcemia experienced normalization of serum calcium levels following his first cycle of bleomycin, etoposide, and cisplatin chemotherapy [ 19 ].

Of patients who received treatments without concomitant cancer-specific therapy, only the patient treated with interferon-α experienced longstanding normalization of serum calcium levels. However, this patient's hypercalcemia recurred after 35 months despite continued treatment with interferon-α during that period and remained elevated until his tumor was resected.

Discussion and Conclusions

Although initially considered rare [ 2 , 20 , 23 ], more recent data suggest that PTHrP and calcitriol co-mediated HCM occurs in up to 34.2% of patients with solid tumors [ 23 ] and in up to 4.3% of patients with lymphoma [ 4 ]. However, the prevalence, pathophysiology, secretory source(s) of PTHrP and calcitriol, and optimal therapy in co-mediated HCM remain controversial. Premature diagnostic closure and the preferential selection of refractory cases for more thorough laboratory evaluation [ 4 , 69 , 71 ] limit our understanding of combined cases. Larger-scale registry-based studies involving HCM patients who have undergone thorough diagnostic evaluations, studies that stain a wider variety of malignant tissues for PTHrP and calcitriol, and cost analyses are indicated to elucidate the prevalence, pathophysiology, and diagnostic implications of PTHrP and calcitriol co-mediated HCM. Until additional data is available, we suggest selectively measuring PTHrP and calcitriol simultaneously in cases of HCM refractory to first-line therapy (ie, patients thought to have humoral HCM who are refractory to antiresorptive agents and patients thought to have isolated calcitriol-mediated HCM who are refractory to glucocorticoids). However, in the research setting, we recommend testing for PTHrP and calcitriol concurrently in all cases of PTH-independent hypercalcemia ( Fig. 1 ) to clarify the frequency and pathophysiology of PTHrP and calcitriol co-mediated HCM.

Hypercalcemia often proves refractory to standard therapies in co-mediated cases ( Table 2 ). PTHrP and calcitriol co-mediated HCM has been found to be less likely to respond to bisphosphonates relative to humoral HCM [ 23 ], and the response to glucocorticoids was variable in the small number of cases where they were utilized ( Table 2 ) [ 3 , 8 , 11 , 12 , 15 , 20 , 36 ].

However, the absence of a control group in these studies makes it difficult to evaluate causation, and the paucity of large-scale studies and bias inherent in case reports further limit the generalizability of these results. Moreover, since less than half of the documented case reports [ 3 , 8 , 11 , 12 , 15 , 20 , 36 ] and only 38% of the cases treated with antiresorptive agents [ 3 , 8 , 12 , 15 , 20 ] utilize glucocorticoids, additional studies are necessary to compare the efficacy of IV bisphosphonates and glucocorticoids. If glucocorticoids prove beneficial in cases that are refractory to bisphosphonates, measuring calcitriol during the initial diagnostic evaluation would identify patients who may benefit from these therapies.

Although bisphosphonates or glucocorticoids should be utilized as temporizing measures while determining the optimal cancer treatment regimen, and in patients unable to tolerate surgery or chemotherapy, the association between anticancer therapy and increased survival in HCM patients [ 5 ] underscores the importance of targeted cancer treatment. Notably, the most enduring improvements in serum calcium levels are associated with remission of patients' underlying malignancies [ 15-19 , 21 , 24 ]. The rapid normalization of serum calcium, PTHrP, and calcitriol following surgery or chemotherapy further suggests that reducing tumor burden is essential for source control [ 15-18 ].

Since HCM usually occurs in advanced, metastatic malignancies [ 3 , 8-10 , 12-14 , 19 ], it remains unclear whether the poor prognosis associated with co-mediated cases is secondary to concurrent elevations in PTHrP and calcitriol, to hypercalcemia itself, or to the severity of patients' underlying malignancy. It is also unknown whether elevated PTHrP, calcitriol, or serum calcium levels consistently recur with cancer relapse. Additional studies with more extensive follow-up are necessary to clarify the prognostic and therapeutic implications of PTHrP and calcitriol co-mediated HCM. Moreover, if rising PTHrP and calcitriol are predictive of cancer recurrence, future randomized controlled trials and cost-based analyses should be considered to investigate the value of monitoring these levels serially during remission.

Disclosures

The authors have no conflict of interest to disclose.

Data Availability

Original data generated and analyzed during this study are included in this published article or in the data repositories listed in References.

References

1 Asonitis N , Angelousi A , Zafeiris C , Lambrou GI , Dontas I , Kassi E . Diagnosis, pathophysiology and management of hypercalcemia in malignancy: a review of the literature . Horm Metab Res . 2019 ; 51 ( 12 ): 770 ‐ 778 . 31826272 10.1055/a-1049-0647

2 Guise TA , Wysolmerski JJ . Cancer-associated hypercalcemia . N Engl J Med . 2022 ; 386 ( 15 ): 1443 ‐ 1451 . 35417639 10.1056/NEJMcp2113128

3 Shivnani SB , Shelton JM , Richardson JA , Maalouf NM . Hypercalcemia of malignancy with simultaneous elevation in serum parathyroid hormone--related peptide and 1,25-dihydroxyvitamin D in a patient with metastatic renal cell carcinoma . Endocr Pract . 2009 ; 15 ( 3 ): 234 ‐ 239 . 19364692 10.4158/EP.15.3.234 PMC4237065

4 Sheehan MT , Li YH , Doi SA , Onitilo AA . Evaluation of diagnostic workup and etiology of hypercalcemia of malignancy in a cohort of 167 551 patients over 20 years . J Endocr Soc . 2021 ; 5 ( 11 ): bvab157 . 34703961 10.1210/jendso/bvab157 PMC8533987

5 Ralston SH , Gallacher SJ , Patel U , Campbell J , Boyle IT . Cancer-associated hypercalcemia: morbidity and mortality. Clinical experience in 126 treated patients . Ann Intern Med . 1990 ; 112 ( 7 ): 499 ‐ 504 . 2138442 10.7326/0003-4819-112-7-499

6 Wendt R , Heller M , Härtwig D , et al Case report: ectopic production of intact parathyroid hormone (iPTH) by malignoma mimicking primary hyperparathyroidism . Front Oncol . 2024 ; 14 : 1422131 . 39703837 10.3389/fonc.2024.1422131 PMC11655464

7 VanHouten JN , Yu N , Rimm D , et al Hypercalcemia of malignancy due to ectopic transactivation of the parathyroid hormone gene . J Clin Endocrinol Metab . 2006 ; 91 ( 2 ): 580 ‐ 583 . 16263810 10.1210/jc.2005-2095

8 Galindo RJ , Romao I , Valsamis A , Weinerman S , Harris YT . Hypercalcemia of malignancy and colorectal cancer . World J Oncol . 2016 ; 7 ( 1 ): 5 ‐ 12 . 26998187 10.14740/wjon953w PMC4797652

9 Song R , Bijay Y , Rizk SH , Cao S . Hypercalcemia of malignancy in metastatic esophageal squamous cell carcinoma with simultaneous PTHrP and calcitriol overproduction: a case report with literature review . Ann Med Surg (Lond) . 2021 ; 68 : 102667 . 34401137 10.1016/j.amsu.2021.102667 PMC8358632

10 Nemr S , Alluri S , Sundaramurthy D , Landry D , Braden G . Hypercalcemia in lung cancer due to simultaneously elevated PTHrP and ectopic calcitriol production: first case report . Case Rep Oncol Med . 2017 ; 2017 : 2583217 . 28751994 10.1155/2017/2583217 PMC5511685

11 Ogawa T , Miyata J , Fukunaga K , Kawana A , Inoue T . Successful treatment for hypercalcemia due to cosecretion of parathyroid hormone-related protein and 1,25-dihydroxyvitamin D(3) in non-small-cell lung cancer: a case report and literature review . Case Rep Pulmonol . 2020 ; 2020 : 2475725 . 31976112 10.1155/2020/2475725 PMC6961606

12 Cheng C , Kuzhively J , Baim S . Hypercalcemia of malignancy in thymic carcinoma: evolving mechanisms of hypercalcemia and targeted therapies . Case Rep Endocrinol . 2017 ; 2017 : 2608392 . 28168064 10.1155/2017/2608392 PMC5266834

13 Yu R . Simultaneous PTHrp- and calcitriol-mediated hypercalcemia associated with probable spontaneous transformation of lung adenocarcinoma to squamous cell carcinoma: a case report . Curr Probl Cancer Case Rep . 2024 ; 14 : 100289 .

14 Yu R . Concurrent PTHrp- and calcitriol-mediated hypercalcemia associated with cholangiocarcinoma . Endocrinol Diabetes Nutr (Engl Ed) . 2018 ; 65 ( 4 ): 241 ‐ 243 . 29366826 10.1016/j.endinu.2017.11.011

15 Hoekman K , Tjandra YI , Papapoulos SE . The role of 1,25-dihydroxyvitamin D in the maintenance of hypercalcemia in a patient with an ovarian carcinoma producing parathyroid hormone-related protein . Cancer . 1991 ; 68 ( 3 ): 642 ‐ 647 . 2065286 10.1002/1097-0142(19910801)68:3<642::aid-cncr2820680334>3.0.co;2-a

16 Taniguchi F , Kigawa J , Kitazawa R , Terakawa N . Successful management of humoral hypercalcemia of malignancy in A patient with ovarian cancer . Yonago Acta Med . 2000 ; 43 : 81 ‐ 86 .

17 Benit A , Allard J , Rimailho J , et al Persistent and moderate hypercalcemia related to an ovarian clear cell adenocarcinoma: pre- and postoperative parathyroid hormone related-peptide and 1,25-dihydroxyvitamin D3 levels . J Endocrinol Invest . 2006 ; 29 ( 5 ): 443 ‐ 449 . 16794368 10.1007/BF03344128

18 Van den Eynden GG , Neyret A , Fumey G , et al PTHrP, calcitonin and calcitriol in a case of severe, protracted and refractory hypercalcemia due to a pancreatic neuroendocrine tumor . Bone . 2007 ; 40 ( 4 ): 1166 ‐ 1171 . 17188588 10.1016/j.bone.2006.11.009

19 Rodriguez-Gutierrez R , Zapata-Rivera MA , Quintanilla-Flores DL , et al 1,25-dihydroxyvitamin D and PTHrP mediated malignant hypercalcemia in a seminoma . BMC Endocr Disord . 2014 ; 14 ( 1 ): 32 . 24721620 10.1186/1472-6823-14-32 PMC3991903

20 Panvelker S , Khan A . SAT-346 Hypercalcemia secondary to calcitriol and PTHrP cosecretion only responsive to hydroxychloroquine . J Endocr Soc . 2020 ; 4 ( Suppl 1 ): SAT-346 .

21 Gonciulea AR , Wang Y , Bikle DD , Sellmeyer DE . Hypercalcemia in non-Hodgkin's lymphoma due to cosecretion of PTHrP and 1,25-dihydroxyvitamin D . Osteoporos Int . 2021 ; 32 ( 12 ): 2587 ‐ 2592 . 34230999 10.1007/s00198-021-06054-7

22 Johnston SR , Hammond PJ . Elevated serum parathyroid hormone related protein and 1,25-dihydroxycholecalciferol in hypercalcaemia associated with adult T-cell leukaemia-lymphoma . Postgrad Med J . 1992 ; 68 ( 803 ): 753 ‐ 755 . 1480540 10.1136/pgmj.68.803.753 PMC2399449

23 Chukir T , Liu Y , Hoffman K , Bilezikian JP , Farooki A . Calcitriol elevation is associated with a higher risk of refractory hypercalcemia of malignancy in solid tumors . J Clin Endocrinol Metab . 2020 ; 105 ( 4 ): e1115 ‐ e1123 . 31841590 10.1210/clinem/dgz278 PMC7067545

24 Carias E , Ferreira H , Chuva T , Paiva A , Maximino J . Hypercalcemia of malignancy with simultaneous production of parathyroid hormone-related peptide and 1,25-dihydroxyvitamin D by non-hodgkin lymphoma: case report & brief review . Journal of Onco-Nephrology . 2023 ; 7 ( 2 ): 70 ‐ 73 .

25 Stewart AF . Clinical practice. Hypercalcemia associated with cancer . N Engl J Med . 2005 ; 352 ( 4 ): 373 ‐ 379 . 15673803 10.1056/NEJMcp042806

26 Burtis WJ , Brady TG , Orloff JJ , et al Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer . N Engl J Med . 1990 ; 322 ( 16 ): 1106 ‐ 1112 . 2320080 10.1056/NEJM199004193221603

27 Jick S , Li L , Gastanaga VM , Liede A . Prevalence of hypercalcemia of malignancy among cancer patients in the UK: analysis of the clinical practice research datalink database . Cancer Epidemiol . 2015 ; 39 ( 6 ): 901 ‐ 907 . 26520619 10.1016/j.canep.2015.10.012

28 Gastanaga VM , Schwartzberg LS , Jain RK , et al Prevalence of hypercalcemia among cancer patients in the United States . Cancer Med . 2016 ; 5 ( 8 ): 2091 ‐ 2100 . 27263488 10.1002/cam4.749 PMC4899051

29 Taylor CD . In response to “cancer-related hypercalcemia” . J Oncol Pract . 2016 ; 12 ( 12 ): 1275 ‐ 1276 . 27875071 10.1200/JOP.2016.016980

30 Budayr AA , Nissenson RA , Klein RF , et al Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia . Ann Intern Med . 1989 ; 111 ( 10 ): 807 ‐ 812 . 2817628 10.7326/0003-4819-111-10-807

31 Moseley JM , Danks JA , Grill V , Lister TA , Horton MA . Immunocytochemical demonstration of PTHrP protein in neoplastic tissue of HTLV-1 positive human adult T cell leukaemia/lymphoma: implications for the mechanism of hypercalcaemia . Br J Cancer . 1991 ; 64 ( 4 ): 745 ‐ 748 . 1911223 10.1038/bjc.1991.391 PMC1977688

32 Watanabe T , Yamaguchi K , Takatsuki K , Osame M , Yoshida M . Constitutive expression of parathyroid hormone-related protein gene in human T cell leukemia virus type 1 (HTLV-1) carriers and adult T cell leukemia patients that can be trans-activated by HTLV-1 tax gene . J Exp Med . 1990 ; 172 ( 3 ): 759 ‐ 765 . 2388034 10.1084/jem.172.3.759 PMC2188541

33 Motokura T , Fukumoto S , Takahashi S , et al Expression of parathyroid hormone-related protein in a human T cell lymphotrophic virus type I-infected T cell line . Biochem Biophys Res Commun . 1988 ; 154 ( 3 ): 1182 ‐ 1188 . 2457368 10.1016/0006-291x(88)90265-3

34 Motokura T , Fukumoto S , Matsumoto T , et al Parathyroid hormone-related protein in adult T-cell leukemia-lymphoma . Ann Intern Med . 1989 ; 111 ( 6 ): 484 ‐ 488 . 2549824 10.7326/0003-4819-111-6-484

35 Szymanski JJ , Otrock ZK , Patel KK , Scott MG . Incidence of humoral hypercalcemia of malignancy among hypercalcemic patients with cancer . Clin Chim Acta . 2016 ; 453 : 190 ‐ 193 . 26706788 10.1016/j.cca.2015.12.017

36 Wysolmerski JJ . Parathyroid hormone-related protein . In: Rosen CJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism . Wiley Online Library; 2013. Accessed March 10, 2025 . 10.1002/9781118453926.ch27

37 Suva LJ , Winslow GA , Wettenhall RE , et al A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression . Science . 1987 ; 237 ( 4817 ): 893 ‐ 896 . 3616618 10.1126/science.3616618

38 Nakayama K , Fukumoto S , Takeda S , et al Differences in bone and vitamin D metabolism between primary hyperparathyroidism and malignancy-associated hypercalcemia . J Clin Endocrinol Metab . 1996 ; 81 ( 2 ): 607 ‐ 611 . 8636276 10.1210/jcem.81.2.8636276

39 Horwitz MJ , Tedesco MB , Sereika SM , et al Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2 vitamin D . J Bone Miner Res . 2005 ; 20 ( 10 ): 1792 ‐ 1803 . 16160737 10.1359/JBMR.050602

40 Moosgaard B , Vestergaard P , Heickendorff L , Mosekilde L . Plasma 1,25-dihydroxyvitamin D levels in primary hyperparathyroidism depend on sex, body mass index, plasma phosphate and renal function . Clin Endocrinol (Oxf) . 2007 ; 66 ( 1 ): 35 ‐ 42 . 17201799 10.1111/j.1365-2265.2006.02680.x

41 Soki FN , Park SI , McCauley LK . The multifaceted actions of PTHrP in skeletal metastasis . Future Oncol . 2012 ; 8 ( 7 ): 803 ‐ 817 . 22830401 10.2217/fon.12.76 PMC3566558

42 Schilling T , Pecherstorfer M , Blind E , Leidig G , Ziegler R , Raue F . Parathyroid hormone-related protein (PTHrP) does not regulate 1,25-dihydroxyvitamin D serum levels in hypercalcemia of malignancy . J Clin Endocrinol Metab . 1993 ; 76 ( 3 ): 801 ‐ 803 . 8445039 10.1210/jcem.76.3.8445039

43 Stewart AF , Vignery A , Silverglate A , et al Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: uncoupling of bone cell activity . J Clin Endocrinol Metab . 1982 ; 55 ( 2 ): 219 ‐ 227 . 7085851 10.1210/jcem-55-2-219

44 Horiuchi N , Caulfield MP , Fisher JE , et al Similarity of synthetic peptide from human tumor to parathyroid hormone in vivo and in vitro . Science . 1987 ; 238 ( 4833 ): 1566 ‐ 1568 . 3685994 10.1126/science.3685994

45 Mundy GR , Edwards JR . PTH-related peptide (PTHrP) in hypercalcemia . J Am Soc Nephrol . 2008 ; 19 ( 4 ): 672 ‐ 675 . 18256357 10.1681/ASN.2007090981

46 Insogna KL , Stewart AF , Vignery AM , et al Biochemical and histomorphometric characterization of a rat model for humoral hypercalcemia of malignancy . Endocrinology . 1984 ; 114 ( 3 ): 888 ‐ 896 . 6546543 10.1210/endo-114-3-888

47 Strewler GJ , Wronski TJ , Halloran BP , et al Pathogenesis of hypercalcemia in nude mice bearing a human renal carcinoma . Endocrinology . 1986 ; 119 ( 1 ): 303 ‐ 310 . 3013591 10.1210/endo-119-1-303

48 Walker AT , Stewart AF , Korn EA , Shiratori T , Mitnick MA , Carpenter TO . Effect of parathyroid hormone-like peptides on 25-hydroxyvitamin D-1 alpha-hydroxylase activity in rodents . Am J Physiol . 1990 ; 258 ( 2 Pt 1 ): E297 ‐ E303 . 2305877 10.1152/ajpendo.1990.258.2.E297

49 Horwitz MJ , Tedesco MB , Sereika SM , Hollis BW , Garcia-Ocaña A , Stewart AF . Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1–36) [hPTHrP-(1–36)] versus hPTH-(1–34) on serum calcium, plasma 1,25-dihydroxyvitamin D concentrations, and fractional calcium excretion in healthy human volunteers . J Clin Endocrinol Metab . 2003 ; 88 ( 4 ): 1603 ‐ 1609 . 12679445 10.1210/jc.2002-020773

50 Horwitz MJ , Tedesco MB , Sereika SM , et al A 7-day continuous infusion of PTH or PTHrP suppresses bone formation and uncouples bone turnover . J Bone Miner Res . 2011 ; 26 ( 9 ): 2287 ‐ 2297 . 21544866 10.1002/jbmr.415 PMC3304443

51 Budayr AA , Zysset E , Jenzer A , et al Effects of treatment of malignancy-associated hypercalcemia on serum parathyroid hormone-related protein . J Bone Miner Res . 1994 ; 9 ( 4 ): 521 ‐ 526 . 8030440 10.1002/jbmr.5650090412

52 Dean T , Vilardaga JP , Potts JT Jr , Gardella TJ . Altered selectivity of parathyroid hormone (PTH) and PTH-related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor . Mol Endocrinol . 2008 ; 22 ( 1 ): 156 ‐ 166 . 17872377 10.1210/me.2007-0274 PMC2194631

53 Pioszak AA , Parker NR , Gardella TJ , Xu HE . Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides . J Biol Chem . 2009 ; 284 ( 41 ): 28382 ‐ 28391 . 19674967 10.1074/jbc.M109.022905 PMC2788887

54 Fukumoto S , Matsumoto T , Yamoto H , et al Suppression of serum 1,25-dihydroxyvitamin D in humoral hypercalcemia of malignancy is caused by elaboration of a factor that inhibits renal 1,25-dihydroxyvitamin D3 production . Endocrinology . 1989 ; 124 ( 5 ): 2057 ‐ 2062 . 2539966 10.1210/endo-124-5-2057

55 Bundred NJ , Ratcliffe WA , Walker RA , Coley S , Morrison JM , Ratcliffe JG . Parathyroid hormone related protein and hypercalcaemia in breast cancer . BMJ . 1991 ; 303 ( 6816 ): 1506 ‐ 1509 . 1782489 10.1136/bmj.303.6816.1506 PMC1671803

56 Knecht TP , Behling CA , Burton DW , Glass CK , Deftos LJ . Humoral hypercalcaemia of “benignancy” . Lancet . 1995 ; 346 ( 8976 ): 711 ‐ 712 . 7658859 10.1016/s0140-6736(95)92328-4

57 Tebben PJ , Singh RJ , Kumar R . Vitamin D-mediated hypercalcemia: mechanisms, diagnosis, and treatment . Endocr Rev . 2016 ; 37 ( 5 ): 521 ‐ 547 . 27588937 10.1210/er.2016-1070 PMC5045493

58 Davies M , Hayes ME , Yin JA , Berry JL , Mawer EB . Abnormal synthesis of 1,25-dihydroxyvitamin D in patients with malignant lymphoma . J Clin Endocrinol Metab . 1994 ; 78 ( 5 ): 1202 ‐ 1207 . 8175979 10.1210/jcem.78.5.8175979

59 Hewison M , Kantorovich V , Liker HR , et al Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by tumor-adjacent macrophages . J Bone Miner Res . 2003 ; 18 ( 3 ): 579 ‐ 582 . 12619944 10.1359/jbmr.2003.18.3.579

60 Seymour JF , Gagel RF , Hagemeister FB , Dimopoulos MA , Cabanillas F . Calcitriol production in hypercalcemic and normocalcemic patients with non-hodgkin lymphoma . Ann Intern Med . 1994 ; 121 ( 9 ): 633 ‐ 640 . 7944070 10.7326/0003-4819-121-9-199411010-00001

61 Seymour JF , Gagel RF . Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas . Blood . 1993 ; 82 ( 5 ): 1383 ‐ 1394 . 8364192

62 Yokomura K , Suda T , Sasaki S , Inui N , Chida K , Nakamura H . Increased expression of the 25-hydroxyvitamin D(3)-1alpha-hydroxylase gene in alveolar macrophages of patients with lung cancer . J Clin Endocrinol Metab . 2003 ; 88 ( 12 ): 5704 ‐ 5709 . 14671156 10.1210/jc.2003-030537

63 Mawer EB , Hayes ME , Heys SE , et al Constitutive synthesis of 1,25-dihydroxyvitamin D3 by a human small cell lung cancer cell line . J Clin Endocrinol Metab . 1994 ; 79 ( 2 ): 554 ‐ 560 . 8045976 10.1210/jcem.79.2.8045976

64 Tangpricha V , Flanagan JN , Whitlatch LW , et al 25-hydroxyvitamin D-1alpha-hydroxylase in normal and malignant colon tissue . Lancet . 2001 ; 357 ( 9269 ): 1673 ‐ 1674 . 11425375 10.1016/S0140-6736(00)04831-5

65 Segersten U , Holm PK , Björklund P , et al 25-Hydroxyvitamin d3 1alpha-hydroxylase expression in breast cancer and use of non-1alpha-hydroxylated vitamin D analogue . Breast Cancer Res . 2005 ; 7 ( 6 ): R980 ‐ R986 . 16280049 10.1186/bcr1332 PMC1410765

66 Young MV , Schwartz GG , Wang L , et al The prostate 25-hydroxyvitamin D-1 alpha-hydroxylase is not influenced by parathyroid hormone and calcium: implications for prostate cancer chemoprevention by vitamin D . Carcinogenesis . 2004 ; 25 ( 6 ): 967 ‐ 971 . 14729578 10.1093/carcin/bgh082

67 Bikle DD . Extra renal synthesis of 1,25-dihydroxyvitamin D and its health implications . Clin Rev Bone Miner Metab . 2009 ; 7 ( 2 ): 114 ‐ 125 .

68 Evans KN , Taylor H , Zehnder D , et al Increased expression of 25-hydroxyvitamin D-1alpha-hydroxylase in dysgerminomas: a novel form of humoral hypercalcemia of malignancy . Am J Pathol . 2004 ; 165 ( 3 ): 807 ‐ 813 . 15331405 10.1016/s0002-9440(10)63343-3 PMC1618616

69 Shane E . Diagnostic approach to hypercalcemia. October 10, 2022. Updated March 1, 2025. Accessed March 15, 2025. https://www.uptodate.com/contents/diagnostic-approach-to-hypercalcemia?search=hypercalcemia20workup&source=search_result&selectedTitle=17E150&usage_type=default&display_rank=1H4

70 Goltzman D . Approach to hypercalcemia . In Feingold KR, Ahmed SF, Anawalt B, et al . eds. Endotext [Internet] . MDText.com, Inc.; 2000. Updated April 17, 2023. Accessed March 15, 2025. http://www.ncbi.nlm.nih.gov/books/NBK279129/

71 Carroll MF , Schade DS . A practical approach to hypercalcemia . Am Fam Physician . 2003 ; 67 ( 9 ): 1959 ‐ 1196 . 12751658

72 Rosner MH , Dalkin AC . Onco-nephrology: the pathophysiology and treatment of malignancy-associated hypercalcemia . Clin J Am Soc Nephrol . 2012 ; 7 ( 10 ): 1722 ‐ 1729 . 22879438 10.2215/CJN.02470312

73 Mc Donald D , Drake MT , Crowley RK . Treatment of hypercalcaemia of malignancy in adults . Clin Med (Lond) . 2023 ; 23 ( 5 ): 503 ‐ 507 . 37775175 10.7861/clinmed.2023-0227 PMC10541286

74 El-Hajj Fuleihan G , Clines GA , Hu MI , et al Treatment of hypercalcemia of malignancy in adults: an endocrine society clinical practice guideline . J Clin Endocrinol Metab . 2023 ; 108 ( 3 ): 507 ‐ 528 . 36545746 10.1210/clinem/dgac621

75 Cheer SM , Noble S . Zoledronic acid . Drugs . 2001 ; 61 ( 6 ): 799 ‐ 805 . 11398911 10.2165/00003495-200161060-00010

76 Major P . The use of zoledronic acid, a novel, highly potent bisphosphonate, for the treatment of hypercalcemia of malignancy . Oncologist . 2002 ; 7 ( 6 ): 481 ‐ 491 . 12490736 10.1634/theoncologist.7-6-481

77 Major P , Lortholary A , Hon J , et al Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials . J Clin Oncol . 2001 ; 19 ( 2 ): 558 ‐ 567 . 11208851 10.1200/JCO.2001.19.2.558

78 Hu MI , Glezerman IG , Leboulleux S , et al Denosumab for treatment of hypercalcemia of malignancy . J Clin Endocrinol Metab . 2014 ; 99 ( 9 ): 3144 ‐ 3152 . 24915117 10.1210/jc.2014-1001 PMC4154084

79 Set C: Medicare Single Drug Pricing . Centers for Medicare & Medicaid Services. Published April, 27 2024. Accessed March 10, 2025. https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice

80 Sandler LM , Winearls CG , Fraher LJ , Clemens TL , Smith R , O'Riordan JL . Studies of the hypercalcaemia of sarcoidosis: effect of steroids and exogenous vitamin D3 on the circulating concentrations of 1,25-dihydroxy vitamin D3 . Q J Med . 1984 ; 53 ( 210 ): 165 ‐ 180 . 6087399

81 Adams JS , Gacad MA . Characterization of 1 alpha-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis . J Exp Med . 1985 ; 161 ( 4 ): 755 ‐ 765 . 3838552 10.1084/jem.161.4.755 PMC2189055