Hypercalcemia is a common metabolic complication in cancer patients, linked with a poor prognosis and often caused by factors like parathyroid hormone-related peptide (PTHrP), cytokine production, and excess vitamin D. Clinical manifestations vary from mild symptoms like fatigue to severe complications requiring urgent management, including hydration and bisphosphonates for treatment. The document details the mechanisms, diagnosis, and treatments for hypercalcemia associated with malignancy, emphasizing the need for addressing the underlying cancer.

1. HYPERCALCEMIA
ASSOCIATED
WITH MALIGNANCY
Presented by – Dr Vijendra Patle
Moderator – Dr Sahil Attri MD

2. INTRODUCTION
 Hypercalcemia is a frequent metabolic complication of
both solid and hematological malignancies reported to
occur in up to 30% of patients.
 Usually associated with poor prognosis
 The most common causes include
1. humoral -mediated by parathyroid hormone–related
peptide (PTHrp),
2. osteolytic cytokine production
3. excess 1,25-dihydroxy vitamin D production.
4. primary hyperparathyroidism or granulomatous diseases.

3. Most common cancers are
lung cancer
multiple myeloma
renal cell carcinoma
breast cancer
colorectal cancers
prostate cancer

4. Calcium is present in the body in two compartments-
Bone and Plasma
In plasma, serum calcium is present in several forms –
Free – 45% of serum calcium
Ionized (active form)- 65% of serum calcium
40% bound to albumin
15% bound to citrate, sulfate and phosphate
Mild
• 10.5-11.9
mg/dl
Moderate
• 12-13.9
mg/dl
Severe
• ≥14
mg/dl

5. Clinical manifestation of
hypercalcemia:-
 Mild or indolent hypercalcemia - asymptomatic or
mild non specific symptoms such as constipation,
fatigue, lethargy, musculoskeletal pain and
depression.
 Moderate hypercalcemia- polyuria, polydipsia,
dehydration, anorexia, nausea, muscle weakness
and changes in sensorium.
 Severe, rapidly progressive hypercalcemia -
significant volume depletion and acute renal
insufficiency, dramatic neurocognitive symptoms

6. Other manifestation of hypercalcemia:-
Renal Polyuria,polydipsia,
nephrolithiasis,
Nephrocalcinosis
Distal renal tubular acidosis
Nephrogenic diabetes insipidus
Acute and chronic renal insufficiency
Gastrointestinal Anorexia, nausea, vomiting
Bowel hypo motility and constipation
Pancreatitis
Peptic ulcer disease
Musculoskeletal Muscle weakness
Bone pain
Osteopenia/osteoporosis
Neurogenic Decreased concentration
Confusion
Fatigue
Stupor, coma
Cardiovascular Shortening of the QT interval
Bradycardia
Hypertension

7. Mechanism of bone
Mineralisation
 Hypercalcemia is a result of abnormalities in the normal
bone formation and degradation cycle.
 During normal bone turnover, osteoclast activity is
regulated by the binding of RANK surface receptor on
the osteoclast to the receptor activator RANKL on the
osteoblast. This binding of RANK/RANKL regulates
osteoclastogenesis.
 Osteoprotegerin is secreted by osteoblasts and
strongly inhibits bone resorption binding to RANKL,
thereby blocking the interaction between

8. Mechanism of bone
Mineralisation

10. Calcium homeostasis is regulated
by following hormones-
parathyroid hormone (PTH)
1,25-dihydroxy vitamin D (1,25[OH]2D)
Calcitonin
serum calcium
serum phosphorus

11. Mechanism of Hypercalcemia
by Paratharmone-
 PTH is produced by the parathyroid glands. It
increases serum calcium and decreases serum
phosphorus via direct and indirect stimuli of
osteoclasts. It increases renal calcium absorption and
decreases renal phosphorus absorption.
 PTH also stimulates the conversion of 25-hydroxy
vitamin D (25[OH]D) to1,25(OH)2D in the kidneys
through 1-a-hydroxylase, which results in increased
intestinal absorption of both calcium and phosphate.

12.  In response to hypercalcemia, calcitonin is secreted
by the parafollicular C cells.
 Calcitonin lowers serum calcium by decreasing renal
calcium and phosphorus reabsorption and also by
decreasing bone reabsorption.

13. There have been several proposed
mechanisms for hypercalcemia associated
with malignancies which mainly include:
1. Humoral hypercalcemia of malignancy
2. local osteolytic hypercalcemia
3. excess extrarenal activated vitamin D (1,25[OH]2D)
4. PTH secretion- ectopic or primary

14. Humoral hypercalcemia of
malignancy
 It refers specifically to PTHrP- mediated
hypercalcemia. It accounts to almost for 80% of
hypercalcemia in cancer patients.
 Most commonly seen in squamous cell carcinomas
such as head and neck, esophageal, cervical, lung
and colon cancers in addition to renal cell, bladder,
breast, endometrial and ovarian cancers and it is
rarely seen in pancreatic neuroendocrine tumors.

15.  PTHrP is structurally similar to PTH and like PTH, it
enhances renal tubular reabsorption of calcium while
simultaneously increasing urinary phosphorus excretion.
The result is both hypercalcemia and hypophosphatemia
 However, unlike PTH, PTHrP does not increase
1,25(OH)2D and thus does not increase intestinal
absorption of calcium and phosphorus.
PTHrP acts on osteoblasts, leading to enhanced
synthesis of RANKL

16. Humoral hypercalcemia of
malignancy via PTHrP

17. Local Osteolytic
Hypercalcemia
 Local osteolytic hypercalcemia accounts for 20% of
cases and commonly occurs in multiple myeloma and
metastatic breast cancer and less commonly in
leukemia and lymphoma.
 Previously, the proposed mechanism was direct
destruction of bone by metastases or malignant cells.
 It is now because of the release of local cytokines
from the tumor resulting in excess osteoclast
activation and enhanced bone resorption.

18.  Humoral factors associated hypercalcemia include
interleukin 1 (IL-1), IL-3, IL-6, TNF a, TGF a and b,
lymphotoxin and E series prostaglandins.
 Macrophage inflammatory protein 1a is associated with
multiple myeloma. It stimulates osteoclastic formation in
human bone marrow cells.
 Local cytokines can also be released in metastatic
breast cancer bone lesions such as TGF b, which
stimulate local production of PTHrP.

19. Extra renal production of
1,25(OH)2D
 Extra renal production of 1,25(OH)2D by the tumor
accounts for approximately 1% of cases of
hypercalcemia in malignancy.
 In normal vitamin D metabolism, stored vitamin D
(25[OH]D) in the liver is converted to 1,25(OH)2D
under the influence of PTH by renal 1-a-hydroxylase
in the kidneys.
 1,25(OH)2D causes - increased intestinal absorption
of calcium and enhances osteolytic bone resorption,
resulting in increased serum calcium.

20.  Extrarenal production is most commonly seen with
Hodgkin and non-Hodgkin lymphoma and ovarian
dysgerminoma.
 Non malignant granulomatous diseases such as
sarcoidosis and other inflammatory conditions can also
produce hypercalcemia as a result of extrarenal
1,25(OH)2D production via autonomous 1-a-hydroxylase
activity in tissue macrophages.

21. Vitamin D intoxication
 Excess Vitamin D can result in intoxication and
hypercalcemia.
 In vitamin D intoxication, both 25(OH)D and
1,25(OH)2D are elevated with a suppressed PTH
whereas Extra renal production of 1,25(OH)2D can be
seen with low or normal 25(OH)D in addition to high
normal or high 1,25(OH)2D.

22. PTH secretion- ectopic or
primary
 Ectopic PTH production by the tumor itself is a rare cause
and occurs in less than 1% of cases.
 However, primary hyperparathyroidism as a result of
parathyroid adenoma(s) or hyperplasia can also occur in
patients with malignancy
 It is three times more common in women than in men,
especially after the age of 45, with a peak incidence in
the seventh decade
 It is also common in those having history of head and
neck irradiation and chronic lithium therapy.

23.  It is estimated that 5% to 10% of cases of primary
hyperparathyroidism are the result of hereditary
hyperparathyroid syndromes, including multiple
endocrine neoplasia types 1 and 2. Parathyroid
carcinoma is a rare cause of primary
hyperparathyroidism.

24. Etiobiology of Hypercalcemia in
Malignancy

25. Work Up
1. Serum Calcium- Serum calcium is the first step in the work-up
of suspected hypercalcemia.
2. Serum Albumin-Forty percent of calcium in serum is bound to
albumin, and calcium homeostasis is greatly affected by
albumin concentrations. If the albumin is abnormal, the serum
calcium should be corrected for the serum albumin using the
formula-
Serum corrected calcium equation:
0.8 (4.0 - serum albumin) + serum calcium = total estimated
calcium or
Ionized calcium (if total estimated calcium is believed to be
unreliable)

26. 3. pH-In respiratory alkalosis caused by hyperventilation,
the ionized calcium decreases acutely, and reductions in
pH can cause the ionized calcium to rise acutely, both
resulting in relatively rapid shifts.
4. Serum phosphorus - Hypercalcemia can be associated
with both hyper- and hypophosphatemia.
PTH and PTHrP are similar molecules therefore, both are
not concurrently elevated unless there are multiple
etiologies.

27. 5.Vit D
6.Serum Creatinine- A serum creatinine with estimated
glomerular filtration rate (GFR) measurement also has
an effect on the serum PTH level. Renal insufficiency
stimulates PTH production because it inhibits renal 1-a-
hydroxylase.
7. Vitamin A- Rarely, vitamin A toxicity can result in
hypercalcemia.
If the etiology is not clear with the above laboratory
tests then serum and urine protein electrophoresis or
immunofixation along with a skeletal survey is indicated
suspecting Multiple Myeloma

28. 8. 24-hour urine analysis for calcium and creatinine-
24-hour urine calcium clearance to creatinine clearance
ratio can be valuable to differentiate between primary
hyperparathyroidism and familial hypocalciuric
hypercalcemia.
 If the urine calcium clearance to creatinine clearance
ratio is low (0.01), then familial hypocalciuric
hypercalcemia should be suspected and definitive
evaluation can include testing for mutations in the
CASR, AP2S1, or GNA11 gene.

29. Laboratory Findings for Specific
Etiologies of Hypercalcemia
Associated With Malignancy
Etiology PTH PTHrP 1,25(OH)D 25(OH)D Phosphorus
PTHrP
mediated
Low High Low or
Normal
Any Value Low
1,25(OH)2D
mediated
Low Low High Low or
Normal
Low
PTH
mediated
High Low High Low or
Normal
Low
Vitamin D
intoxication
Low Low High High Normal/High

30. Treatment
 Treatment of the underlying malignancy is always the
primary goal of therapy.
 Mild asymptomatic hypercalcemia (calcium, 10.5-11.9
mg/dL) may not need to be treated until after the
work-up has been completed and a diagnosis has
been established.
 However, moderate to severe hypercalcemia (calcium
more than 12 mg/dL), especially when associated
with severe renal or neurologic symptoms, requires
prompt, often inpatient management.

31.  Medical therapy is aimed at inhibiting bone resorption
and promoting renal calcium excretion.
 Reducing intestinal calcium reabsorption is also
important in those with increased extrarenal
1,25(OH)2D production.

32. A treatment approach for
hypercalcemia of malignancy

33. Promoting Renal Calcium
Excretion
 Fluid replacement is first-line therapy for those with
acute renal insufficiency as a result of volume
depletion. Patients often require 1 to 2 L as an initial
bolus and then maintenance fluids of 150 to 300 mL/h
for the next 2 to 3 days or until they are volume
repleted.

34.  Furosemide therapy is often used as a means to
provide increased calciuresis. However, it can often
exacerbates dehydration and fluid loss.
 Furosemide should be reserved only for patients with
heart failure and those who need diuresis. If
furosemide is used, other electrolytes such as
potassium and phosphorus also need to be monitored
and replaced.

35. Reducing Bone Resorption
 Bisphosphonates are first-line therapy and also the mainstay for
long-term therapy. Through direct mechanisms they induce
osteoclast apoptosis, and through indirect mechanisms acting on
the osteoblasts they can reduce osteoclastic bone resorption.
 Bisphosphonates affect proliferation and differentiation of
osteoblasts and prevent their apoptosis, and they can also
neutralize the RANKL-mediated stimulation of osteoclasts.
 Bisphosphonates should be given within 48 hours of diagnosis,
because it takes approximately 2 to 4 days for them to have
effect.

36.  The two available preparations are pamidronate and
zoledronic acid. When compared directly, zoledronic
acid is more potent than pamidronate.
 The median response duration is 32 days with
zoledronic acid 4 mg IV while 18 days with
pamidronate 90 mg IV.
 Pamidronate is given at 60 to 90 mg IV over 4 to 24
hours. Zoledronic acid is given at 4 mg IV over 15 to
30 minutes.

37.  Bisphosphonates unfortunately, have been associated
with nephrotoxicity. Adequate hydration can enhance
renal protection and help preserve renal function.
 Dose adjustment- patients with mild to moderate renal
impairment before initiation of therapy (serum creatinine
< 4.5 mg) do not need dose adjustment.
However, it is not recommended in severe renal
impairment (serum creatinine > 4.5 mg/dL).

38.  Patients should be adequately hydrated, and a single
dose of 4 mg IV should be given over no less than 15
minutes. Retreatment with zoledronic acid 4 mg may
be considered for persistent hypercalcemia, but no
sooner than 7 days after the initial therapy.

39.  Dosing of zoledronic acid for multiple myeloma and
metastatic bone lesions recommends dose
reduction according to creatinine clearance:
GFR DOSE
> 60 ml/min 4 mg
50-60 ml/min 3.5 mg
40-49 ml/min 3.3 mg
30-39 ml/min 3.0 mg

40. Action of Calcitonin
 Calcitonin is used to acutely lower calcium levels. When
used with bisphosphonates, it can lower calcium more
rapidly than either agent alone. Unfortunately,
tachyphylaxis can occur within 48 hours as a result of
downregulation of the calcitonin receptors.
 Glucocorticoids can be used to enhance the effect of
calcitonin by upregulating the cell-surface calcitonin
receptors and creating new ones on the osteoclast.
Calcitonin is usually dosed at 4 to 8 IU/kg
subcutaneously every 6 to 12 hours.

41. Action of Steroid
 Glucocorticoids are also given to treat hypercalcemia
caused by excess extrarenal 1,25(OH)2D and multiple
myeloma. Steroids inhibit osteoclastic bone
resorption by decreasing tumor production of locally
active cytokines, in addition to having direct tumorolytic
effects.
 Steroids are usually given as hydrocortisone 200 to
400 mg/d for 3 to 4 days and then prednisone 10 to
20 mg/day for 7 days or prednisone 40 to 60 mg/d
for 10 days. If prednisone is not helpful after 10 days, it
should be discontinued.

42. Denosumab
 Denosumab is a human monoclonal antibody to
RANKL. It reduces the osteoclast activity and bone
resorption.
 Denosumab is more efficacious than zoledronic acid in
delaying or preventing hypercalcemia of malignancy in
patients with advanced cancer including breast cancer,
other solid tumors, and multiple myeloma.
 It is also effective in hypercalcemia refractory to
bisphosphonates.

43.  Denosumab is usually given to patients with serum
calcium more than 2.5 mg/dL and who had received
bisphosphonates for more than 7 days and less than 30
days before.
 Denosumab is dosed as 120 mg subcutaneously on
days 1, 8, 15, and 29 and every 4 weeks thereafter; it
lowered serum calcium within 10 days.

44.  Cinacalcet- It reduces PTH production and is
approved for use in secondary hyperparathyroidism
and refractory parathyroid carcinoma.
It has not been extensively studied in hypercalcemia
of malignancy. It has been approved only for use in
parathyroid carcinoma.
 Calcium Chelation- Sodium EDTA and intravenous
phosphate can form complexes with ionized calcium,
after which these are cleared from circulation.

45.  Dialysis or continuous renal replacement therapy is
usually reserved for hypercalcemia refractory to all of
the above therapies. It is the ultimate rescue treatment.
It can be considered when hypercalcemia is
accompanied by renal failure.