Mangement of hypercalcemia

1. K A R I M E L M E D A N Y
Hypercalcemia In Malignancy

2. Agenda
 Introduction
 Normal Regulation of Calcium Metabolism
 Etiology and Pathobiology of Hypercalcemia
of Malignancy
 Clinical Presentation of Hypercalcemia
 Diagnostic Approach to Hypercalcemia
 Management of Hypercalcemia

3. Introduction
 Hypercalcaemia is defined as elevated calcium (Ca2+)
levels in the blood (normal levels are 8–10 mg/dl) , but
reference values may differ slightly between laboratories.
 Hypercalcaemia is a frequent metabolic complication of
both solid cancers and haematological malignancies,
with a reported incidence of 20%–30%.
 Patients suffering from breast cancer, multiple myeloma,
small cell lung cancer and renal cell carcinoma appear to
be most at risk for developing hypercalcaemia.
 Usually associated with poor prognosis

4. Normal Regulation of Calcium
Metabolism
 Calcium is an essential element that participates in
various biochemical reactions, including muscle
contraction, coagulation and bone development among
others.
 Calcium in the body is present in two major
compartments: Bone, and plasma
 In plasma, serum calcium is present in several forms
Free : 45% of serum calcium
Ionized calcium (active form) :65% of serum calcium
40% bound to albumin
15% bound to citric acid, sulfate, and phosphate

6. Vitamin D

7. Bone mineralization
 Bone mineralization is a well balanced constant cycle
of bone formation stimulated by osteoblasts and
bone breakdown (or resorption) stimulated through
osteoclasts
 Osteoclast precursor cells carry the receptor
activator of nuclear factor-κ B (RANK).
 Osteoblasts in turn secrete a ligand for RANK
(RANKL), which stimulates the maturation of
osteoclast precursors and the formation of mature
osteoclasts capable of bone remodeling and calcium
release

8.  Osteoprotegerin is secreted by osteoblasts and
strongly inhibits bone resorption by binding to
RANKL, thereby blocking the interaction between
RANK/RANKL
 If the interaction between RANK and RANKL is
disrupted or blocked, then the osteoclasts do not
mature
 If there is increased interaction between RANK and
RANKL, then there is more osteoclastic expression
and more bone resorption

10. Etiology and Pathobiology of Hypercalcemia of Malignancy
 Humoral hypercalcemia- PTHrP mediated
 Local osteolytic hypercalcemia
 1,25-dihydroxyvitamin D mediated
 Hyperparathyroidism

11. Humoral hypercalcemia of malignancy
 Is mediated by the production of PTHrP (80% of
malignancy-related hypercalcemia)
 PTHrP acts on osteoblasts, leading to enhanced synthesis of
RANKL, with subsequent activation of osteoclasts and bone
resorption with calcium release into the blood stream
 Increased renal calcium reabsorption is another
mechanism through which PTHrP leads to hypercalcemia
 Squamous cell cancers, urinary tract cancers (renal cancer
and bladder cancer), breast cancer, nonHodgkin’s
lymphoma, and ovarian cancer account for the majority of
malignancies leading to hypercalcemia via PTHrP

13. Local osteolytic hypercalcemia
 Accounts for 20% of cases and is usually associated with
extensive bone metastases and skeletal tumor burden.
 It commonly occurs in multiple myeloma and metastatic
breast cancer and less commonly in leukemia and
lymphoma.
 It is now thought to be because of the release of local
cytokines from the tumor, resulting in excess osteoclast
activation and enhanced bone resorption, often through
RANK/RANKL

14. 1.25-Dihydroxyvitamin D
 Elevated levels of 1.25-dihydroxyvitamin D (1.25-D)
is the most frequent cause of hypercalcaemia in
lymphoma, acting by increasing intestinal calcium
absorption.
 This is due to increase of 1-alpha hydroxylase activity
in tumour cells, causing accelerated transition from
25-hydroxyvitamin D (25-D) to 1.25-D.

15. Parathyroid Hormone
 Secretion of PTH by tumour cells other than
parathyroid carcinoma is extremely rare.
 Reports have been published on ovarian carcinoma,
small cell and squamous cell lung carcinoma

16. Etiobiology of hypercalcemia of malignancy

17. Clinical Presentation of Hypercalcemia
“stones, bones, abdominal moans, and psychic groans”
 clinically Presentation depend on degree of
hypercalcemia and the rapidity of its development.

18. Organ system Clinical features
Neurologic Fatigue, altered mental status
including coma
Gastrointestina Nausea, vomiting, constipation, peptic
ulcer disease, and pancreatitis
Cardiovascular Short QT interval on ECG, ST segment
abnormalities including ST segment
myocardial infarction mimic, malignant
ventricular arrhythmias, and
hypertension
Renal Nephrogenic diabetes insipidus, acute
kidney injury and in chronic cases
nephrolithiasis, and chronic renal
failure

19. Diagnostic Approach to Hypercalcemia
Laboratory Evaluation of Hypercalcemia
 Confirm hypercalcemia (recheck if only one
measurement)
 Serum total calcium is the sum of carrier-bound
calcium that is not physiologically active and ionized
calcium, which is the active form of serum calcium
Serum corrected calcium equation:
0.8 (4.0 - serum albumin) + serum calcium = Ionized
calcium

20. Approach to hypercalcaemia.

21. Laboratory Findings for Specific Etiologies of Hypercalcemia Associated With Malignancy

22. Management of Hypercalcemia
 Increasing Urinary Calcium Excretion
 Inhibition of Bone Resorption :
Bisphosphonates
Denosumab
Calcitonin
 Calcium Removal/Chelation
 Corticosteroids

23. Increasing Urinary Calcium Excretion
 Patients are generally volume depleted, and many
can have concurrent renal insufficiency as a result.
 Treatment with intravenous (IV) fluids, specifically
isotonic saline, is essential as initial therapy.
 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 replete
 The use of furosemide should be reserved for
patients who develop signs of fluid overload while
receiving IV hydration

24. Inhibition of Bone Resorption
 Bisphosphonates have direct mechanisms by
inducing osteoclast apoptosis, and through indirect
mechanisms acting on the osteoblasts reducing
osteoclastic bone resorption
 It should be remembered that their maximum effect
occurs only after 2–4 days
 Zoledronate , pamidronate are the most common
bisphosphonates used

25. Zoledronate
 has become the treatment of choice for cancer-
induced hypercalcaemia because of :
-Higher potency 88% and 70% of the patients achieve
normo calcaemia after single-dose treatment with
zoledronate and pamidronate, respectively
-Significantly shorter infusion period (15–30
minutes).

26. Denosumab
 The monoclonal antibody denosumab blocks RANKL,
which plays a pivotal role in in osteoclast activation.
 It is approved for hypercalcaemia refractory to
bisphosphonates.
 The compound has little toxicity (osteonecrosis), and is
safe to administer in patients with decreased renal
function.
 Denosumab administered at 120 mg subcutaneously on
days 1, 8, 15 and 29, and then every 4 weeks, to patients
with refractory hypercalcaemia
 resulted in normocalcaemia in 64% of patients

27. Calcitonin
 Decreases bone resorption and also increases the urinary
clearance of calcium.
 It should be administered intramuscularly or
subcutaneously every 12 hours.
 Its main advantage is that it acts rapidly (within 6 hours).
 Its effect is limited to the first 24 hours.
 It is the ideal treatment of choice immediately after the
diagnosis, to bridge the time of action of other agents
(e.g. bisphosphonates

28. Calcium Removal/Chelation
 Sodium EDTA (ethylene diamine tetra acetic acid)
and intravenous phosphate can form complexes with
ionized calcium, after which these are cleared from
circulation.
 Dialysis is the ultimate rescue treatment in patients
with uncontrollable or severe hypercalcaemia. It can
be considered when hypercalcaemia is accompanied
by renal failure.

29. Corticosteroids
 Corticosteroids inhibit osteoclast-mediated bone
resorption in vitro and decrease gastrointestinal
calcium uptake.
 These drugs should only be prescribed in patients
with malignancies susceptible to steroids (e.g.
myeloma, lymphoma, leukaemia and occasionally
breast cancer).
 Doses of methylprednisolone range from 15–30
mg/day in breast cancer and 40–100 mg/day in
haematological diseases.

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