This document discusses the case of a 56-year-old woman with metastatic breast cancer and hypercalcemia that was refractory to treatment with zoledronic acid and calcitonin. She was started on cinacalcet and dexamethasone, and then administered denosumab injections to further lower her calcium levels. Denosumab binds to RANK ligand to inhibit bone resorption and reduce calcium levels. After receiving denosumab injections on days 1, 8, 15, 29 and 60, the patient's total calcium levels decreased from 13.9 to 7.7 mg/dl. The document discusses how denosumab has been used off-label for persistent hypercalcemia of malignancy.

1. Persistent Hypercalcemia of
Malignancy - Novel Therapeutic
Strategy
Dr Sudhir Ranjan Dash
Dr Vishal Ramteke

2. Case summary
Mrs VDA
56 yrs , Female
k/c/o Metastatic adenocarcinoma right breast
(lung , liver, peritoneal,omental mets) diagnosed
in Oct - 2012
Undergone Modified Radical Mastectomy +
Chemotherapy (Paclitaxel,Eribulin,Cisplastin based)

3. Admitted under oncology services in Dec 2013
with –
• Drowsiness
• Poor oral intake
On evaluation – no focal neurodeficit noted
Neuroimaging ruled out cerebral mets.
• Serum Calcium - 13.9 mg/dl,
• Serum Albumin – 1.8 gm%,
• Albumin Corrected Calcium- 15.8 mg/dl

4. Her previous admissions in JHRC on multiple
occasions were marked by hypercalcemia which
were managed each time by oncology team with
Zolendronic Acid
Calcitonin
Nephrology consultation was sought on this
admission for management of hypercalcemia
refractory to Zolendronic acid.
 Normal Saline+ Lasix
 Dexamethasone

5. 4/3/2013 7/11/2013 4/12/2013 14/12/13
Sr.Calcium 14.2 17.2 11.2 13.9
ACC- 15.8
Ionised Ca 7.9 9.7 6.6 8.0
PTH 52.4 38.2 ------ 34.4
Vit D3 64.9 49.3 ------ 42.4
Total
Protein
6.4 5.4 5.2 5.0
Albumin 2.9 2.1 2.0 1.8
FIRST CONSULTATION ↑

6. • The cause for the hypercalcemia was attributed to
Humoral (PTHrP related ) Hypercalcemia of Malignancy.
• Since patient had received zolendronic acid 10 days
back, it was not repeated in this admission.
• Other measures (saline diuresis, calcitonin,
dexamethasone) were tried.
• She was started on tab Cinacalcet 30 mg Q12H .
• In/v/o hypercalcemia not responding to above measures
administration of inj. DENOSUMAB was planned.

7. Denosumab is a fully human monoclonal IgG2 antibody
that selectively binds to RANK ligand (RANKL) inhibiting
the osteoclast – “Development, Activation and Survival”
It thus reduces osteoclast mediated bone resorption

8. Hypercalcemia due to bone resorption
DENOSUMAB
Inj Denosumab 120 mg s.c was given on
day 1, day 8, day 15, day 29 and 60

9. DAY 0 DAY 3 DAY 7 DAY 30 DAY 60 DAY 90
T.Cal 13.9 12.1 10.8 10.2 9.1 7.7
i.Cal 8 6.9 6.0 5.3 5.1 4.8
0
2
4
6
8
10
12
14
16
0 3 7 30 60 90
Total calcium
DAYS

10. Denosumab was approved by US FDA in 2010 for
• Osteoporosis in post menopausal women
• Prevention of skeleton-related events (SRE) in
patients with bone metastasis from solid tumors
• Off label use for hypercalcemia of malignancy
have been tried recently

11. “Denosumab for patients with persistent or relapsed
hypercalcemia of malignancy despite recent
Bisphosphonate treatment”
Mimi I. Hu et al.
J Natl Cancer Inst; July 2013;105:1417–1420
• 15 patients(hematologic malignancies, solid organ tumor)
• Albumin corrected serum calcium > 12.5 mg/dl
• Who have received inj Zolendronic acid within 7-30 days
• Were given Inj Denosumab 120 mg on
day 1, 8, 15 and 29 followed by every 4 week.

12. • By day 10 –
 12 patients (80%) responded to achieve Albumin
corrected serum Calcium i.e. (ACSC) ≤11.5 mg/dL
 10 patients (67%) had complete responses
(ACSC) ≤10.8 mg/dL
• Median response duration for all patients was 26 days.
• Requires no renal dose adjustment
• Hypocalcemia , hypophosphatemia, osteonecrosis of
jaw may be noted.
• Hypersensitivity reactions may be seen
• Cost – 120 mg cost 28,000 INR

13. THANK YOU