3. INTRODUCTION
Hypercalcemia is a common metabolic complication of malignancy
Termed hypercalcemia of malignancy (HCM),
Tumour-induced hypercalcemia
Humoral HCM
Hypercalcemia is a metabolic emergency and the most common
paraneoplastic syndrome
4. EPIDEMIOLOGY
Hypercalcemia occurs in up to 30% of cancer patients
More frequently in advanced stages
HCM is more common in primary solid tumors of the lung, breast, head and
neck, kidney, and ovary.
Occurs preferentially in certain histology, such as squamous cell cancer of the
lung compared to adenocarcinomas or small cell lung cancer
Can also be manifested in prostate, colon, cervix, and uterus carcinomas
Hematological malignancies such as multiple myeloma ca also cause
hypercalcemia
5. PATHOPHYSIOLOGY
The regulation of calcium levels within the body is centered on three key
organ systems – gastrointestinal (GI) tract, kidneys, and bone
Hypercalcemia results from a combination of any of three main mechanisms,
particularly
(1) increased calcium absorption from the GI tract
(2) decreased excretion from the kidneys
(3) enhanced calcium resorption from bone
6. PATHOPHYSIOLOGY
Two mechanisms of hypercalcemia of malignancy are
(1) Secretion of parathyroid hormone-related protein (PTHrP),
which stimulates osteoclastic bone resorption and calcium
reabsorption through the kidneys
(2) Lytic bone metastases through cytokines released by tumour
cells
7. PATHOPHYSIOLOGY
PTHrP(parathyroid hormone-related protein)
16-kda peptide and shares a 61% sequence homology with PTH in the first 13 amino
acids at the n-terminal
It has four times the bioactivity of PTH and binds competitively to the PTH receptor
Predominant cause of hypercalcemia in patients with cancer.
At least 80% of patients with solid tumors and hypercalcemia have increased serum
concentrations of pthrp.
In addition to its humoral effects, pthrp can also induce local osteolysis around bone
metastases,
Important in the progression of bone metastases in patients with breast carcinoma
8. PATHOPHYSIOLOGY
The increased calcium level from pthrp-related secretion and
osteolysis diminishes the efficiency of renal elimination of excess
calcium.
In addition, decreased intravascular volume, secondary to
hypercalcemia-induced nausea and anorexia
These cause sodium and calcium resorption through the proximal
tubule.
9. Other factors secreted by tumos that cause hypercalcemia are
IL-1,
IL-6,
TNF-α
G-CSF
macrophage inflammatory protein-1α
tumor-induced 1,25(OH)2D3
10. CLINICAL MANIFESTATION
The signs and symptoms of hypercalcemia may be subtle
The severity of symptoms depends on the level of serum calcium and, more
importantly, the rate of increase in serum calcium level
Mild hypercalcemia may present with nonspecific symptoms, like fatigue,
lethargy, and vague-generalized discomforts, or may be asymptomatic
Sudden, rapid, severe elevations of calcium levels can present with acute
multi-organ effects, including neurocognitive dysfunctions such as delirium
and coma
12. • Not usually seen in
hypercalcemia of
malignancy
• Due to rapid elevation
of serum calcium
13. ASSESSEMENT
Laboratory evaluation
Serum calcium-Measurement of serum-ionized calcium should be preferred over total serum calcium
levels because hypoalbuminemia may be associated with low total calcium
If total calcium is ordered then serum albumin should be taken into account
14. ASSESSMENT
Calcium exists in three forms in plasma
1) bound to albumin and other proteins (∼40%)
2) chelated to serum anions (∼13%)
3) free ionized calcium (∼47%)
Assessing corrected calcium is important in management of hypercalcemia
15. ASSESSMENT
Based on the corrected total serum calcium level, hypercalcemia can be
classified as
Mild (10.5–11.9 mg/dl)
Moderate (12–13.9 mg/dl)
Severe (≥14 mg/dl).
16. ASSESSMENT
Other lab investigations-
serum electrolytes
phosphorus
Creatinine
alkaline phosphatase
albumin
PTH,
PTHrP
25(OH)D,
1,25(OH)2D3
creatinine clearance and serum
electrolytes are recommended to
monitor renal function
18. MANAGEMENT
Hydration
Bisphosphonates
I. Nitrogen-containing bisphosphonates
II. Non-nitrogen-containing bisphosphonates
Calcitonin
Corticosteroids
Gallium nitrate
RANKL inhibitors
Other treatments
19. HYDRATION
In severe hypercalcemia aggressive intravenous rehydration with isotonic saline and close
monitoring of volume status
This helps reverse the vicious cycle of decreased intravascular volume, decreased glomerular
filtration, and impaired calcium excretion
Hydration is started at a rate of 200–300 mL/h, which is then adjusted to 100–150 mL/h until
volume repletion
Mild hypercalcemia can usually be corrected with outpatient oral rehydration.
Patient with moderate hypercalcemia and with mild symptoms or asymptomatic may nor
require aggressive treatment
Monitoring of other electrolytes like potassium and magnesium should also be done as there
are usually concurrent electrolyte abnormalities present
20. BISPHOSPHONATES
Inhibit osteoclastic bone resorption through osteoclastic apoptosis.
Due to poor bioavailability of the oral route, parenteral administration is indicated.
It usually takes 2–6 days to achieve normal calcium levels
21. BISPHOSPHONATES
Adverse effects
Common
Hypocalcaemia and transient renal insufficiency
Rare side effects renal failure
Jaw osteonecrosis
Ocular reactions such as iritis, episcleritis, scleritis, and conjunctivitis.
Acute phase reactions include transient fever, malaise, myalgias, bone pain flare, and lymphocytopenia
22. NITROGEN CONTAINING BISPHOSPHONATES
Mechanism of action: inhibition of farnesyl diphosphate synthase, resulting in blockage of
protein isoprenylation, which is a vital process for osteoclast structural integrity, resulting in apoptosis
Renal function is a concern while administering as nephrotoxicity has been reported
PAMIDRONATE
ZOLEDRONATE- More potent in achieving normocalcemia.
IBANDRONATE- less nephrotoxicity
• ALENDRONATE
• RISEDRONATE
23. NITROGEN CONTAINING BISPHOSPHONATES
Theraputic Dosage
Pamidronate 60–90 mg IV over 2–24 h; wait at least 7 days before considering re-treatment
Ibandronate 2–6 mg IV over 1–2 h
Zoledronate 4 mg IV; wait at least 7 days before considering re-treatment
24. NON-NITROGEN-CONTAINING BISPHOSPHONATES
Mechanism of action:inhibit ATP-dependent intracellular enzymes by incorporating
into nonhydrolyzable adenosine triphosphate, which also results in apoptosis
• ETIDRONATE- earliest bisphosphonates used clinically
• TILUDRONATE
• CLODRONATE- similar efficacy to pamidronate
• can be administered subcutaneously, which is of particular advantage in palliative settings such as home
or hospice facility
1500 mg IV or SC single dose or 300 mg IV daily, not more than 7 days
25. CALCITONIN
Mechanism of action :Calcitonin inhibits bone resorption and renal tubular calcium
reabsorption. Physiologically, this hormone is secreted from parafollicular or C cells within the thyroid in
response to elevated serum calcium levels
Subcutaneous injections have a rapid onset of action, usually in 2–4 h, with a maximum reduction in
serum calcium of approximately 1–2 mg/dL.
However, effect diminishes after 48 h due to tachyphylaxis secondary to downregulation of osteoclastic
calcitonin receptors.
Calcitonin is useful when combined with bisphosphonates, life-threatening situations because of its
rapid effect while the bisphosphonates have a slower onset of action.
Adverse effects include nausea, flushing, abdominal pain, and local irritation at the injection site.
26. CORTICOSTEROIDS
Corticosteroids are more effective in treating HCM secondary to steroid-
responsive tumors such as lymphoma or myeloma
glucocorticoids prolonged the effective time of treatment with calcitonin by
upregulating cell surface calcitonin receptors and therefore may be an
effective adjunct to calcitonin administration
Dosages
Hydrocortisone 200–400 mg/day
Dexamethasone 4–12 mg/day
Prednisone 40–60 mg/day
27. GALLIUM NITRATE
Mechanism of action:
Gallium nitrate accumulates in metabolically active regions of bone where it
inhibits osteoclast-mediated bone resorption.
It prevents acidification and cell-mediated dissolution of bone material by
inhibiting an adenosine triphosphatase–dependent proton pump in the ruffled
membrane of the osteoclast
Gallium also inhibits PTH secretion from parathyroid cells in vitro.
It has been found to be effective in both PTHrP-mediated and non-PTHrP-
mediated hypercalcemia.
28. GALLIUM NITRATE
It has been shown to be at least or more effective than pamidronate,
etidronate, and calcitonin.
The main concerns with the use of gallium have been nephrotoxicity
Dosage
Gallium nitrate 100–200 mg/m2/day IV over 24 hours × 5 days
29. RANKL INHIBITORS
Mechanism of action
interfere with the receptor activator of nuclear factor-kB ligand (RANKL)
system, which is the molecular pathway that leads to osteoclast recruitment
and differentiation
These agents include recombinant osteoprotegerin and monoclonal
antibodies against RANKL, such as denosumab
30. RANKL INHIBITORS
Denosumab is a human monoclonal antibody that is administered subcutaneously every 4
weeks for prevention of skeletal-related events (e.g., fracture, spinal cord compression) in
patients with cancer metastatic to bone.
Its use in HCM is less well studied but promising.
The expense of denosumab may be prohibitive as it is more costly than the bisphosphonates.
31. OTHER NEWER TREATMENTS
anti-PTH-related protein antibodies with zoledronic acid have shown to be optimistic so far in decreasing
tumor-associated osteoclasts
Tyrosine kinase inhibitors focusing on IL-6 have also been shown in studies to be potential agents in
inhibiting osteoclast resorption and treating hypercalcemia
noncalcemic analogue of calcitriol (e.g., 22-oxacalcitriol) suggests its potential to suppress PTHrP gene
expression through binding to the vitamin D receptor in HTLV-1 infected cells
There have been case reports describing the use of long-acting octreotide in controlling hypercalcemia
in patients with neuroendocrine tumor and breast cancer
32. OTHER NEWER TREATMENTS
Ultrasound-guided percutaneous ethanol injection has been studied in patients with parathyroid
carcinoma for palliation, resulting in a transitory decrease in PTH and calcium levels
calcimemetics (e.g., cinacalcet) are used in patents with refractory hypercalcemia. Calcimemetics
attenuate calcium levels by decreasing PTH secretion through increase in calcium-receptor sensitivity
Patients with renal insufficiency or congestive heart failure where IV hydration is not possible , short-
term dialysis may be required until normocalcemia is achieved
33. TREATMENT OF UNDERLYING CAUSE
The treatments listed above are only temporizing measures.
The most effective long-term treatment is still treating the underlying cause
especially in the case of Hypercalcemia CM, which is effective antineoplastic
intervention
34. SUMMARY
Hypercalcemia is a common, treatable complication of malignant disease.
Secretion of PTHrP is the predominant cause of hypercalcemia in HCM, even without
overt bone metastasis.
Signs and symptoms may be subtle; a high index of suspicion is required.
The severity of symptoms depends on the rate of increase in serum calcium levels
more than the absolute serum calcium levels.
Treatment of HCM can result in improved overall palliation.
Rehydration is a key initial step in the management of HCM.
Intravenous bisphosphonates are the agents of choice in the treatment of HCM with
nitrogen-containing bisphosphonates being the more potent agents
