1. Carol S. Viele RN MS Clinical Nurse Specialist Hematology-Onc-BMT UCSF
Hypercalcemia
Carol S. Viele RN MS
Clinical Nurse Specialist
Hematology-Onc-BMT
UCSF

2. Objectives
At the completion of this presentation the participant will be able to:
Describe 2 side effects of hypercalcemia
Define 2 agents utilized to treat hypercalcemia
Describe at least 2 nursing interventions for hypercalcemia

3. Prevalence Most common metabolic complication of cancer
10-20% of all cancer patients per year will be diagnosed with hypercalcemia

4. Associated Malignancies
Lung-35% ( NSCL)- 15% occurrence
Breast %
Multiple Myeloma-20-40%
Head and Neck-6%
Genitourinary-6%
Other/Unknown primary-15%

5. Mechanism of Calcium Regulation
Bone formation and resorption (99%) in bone
GI absorption
Urinary excretion

7. Hypercalcemia in Cancer
Due to increased bone resorption and release of calcium from bone
Three mechanisms
Osteolytic metastases with local release of cytokines
Tumor secretion of parathyroid hormone-related protein
Tumor production of calcitriol

8. Hormonal Control
Parathyroid hormone- released from the parathyroid in response to a drop in calcium, acts directly on bone by stimulating osteoclast formation and inhibiting osteoblasts
Vitamin D (1,25-dihydroxycholecalciferol)-increase calcium and phosphorous absorption from the intestinal mucosa
Calcitonin-reduces calcium release into circulation as a result of bone resorption

9. Pathogenesis of Skeletal Metastases
tumour cell
osteoblast
mineralized bone
Imune
cell
IL-1, TNF
GM-CSF
activatd TGFß
IL-6
IL-1
TNF
TGF
EGF
PGs
PTHrP
cathepsins
OIF / OAF
osteoclast

10. Osteolytic Metastases
Osteolytic mets are the result of direct induction of local osteolysis by the tumor cells
Breast and Non–small cell lung
In Breast cancer adminstration of estrogen and antiestrogen Tamoxifen) can lead to hypercalcemia
Cytokines play a major role
Tumor necrosis factor
Interleukin-1

11. Osteoclast Activating Factors
Multiple Myeloma can release these factors by tumor cells
Cytokines active in osteoclastic activity
Interleukin-1-beta
Lymphotoxin
Tumor necrosis factor
IL-6
Macrophage colony stimulating factor
Macrophage inflammatory protein
Vascular cell adhesion molecule-1
Hepatocyte growth factor ( This is produced by myeloma cells in culture)

12. Pathogenesis of Skeletal Metastases
tumour cell
osteoblast
mineralized bone
Imune
cell
IL-1, TNF
GM-CSF
activatd TGFß
IL-6
IL-1
TNF
TGF
EGF
PGs
PTHrP
cathepsins
OIF / OAF
osteoclast

13. Clinical Manifestations
Dehydration
Polydipsia
Polyuria
Gastointestinal
Anorexia
Nausea/Vomiting
Constipation
Abdominal pain

14. Clinical Manifestations
Bone pain
Pathologic fracture
Weakness
Lethargy
Hyporeflexia
Depression

15. Clinical Manifestations
Stupor
Coma
Confusion
Visual disturbances
Apathy
Restlessness

16. Clinical Manifestations
Genitourinary
Polyuria
Polydipsia
Nocturia
Calcium nephropathy
Hypercalciuria
Nephrolithiasis

17. Clinical Manifestations
Cardiovascular
Hypertension
Bradycardia
Cardiac arrhythmias
Cardiac arrest
Heart block
Digitalis sensitivity

18. Diagnosis Laboratory tests
Ionized calcium or free calcium is the physiologically active form of calcium circulating in the blood
50% of serum calcium is ionized
Results < 1.30

19. Diagnosis Normal serum calcium 9-11mg/dl
Hypercalcemia can be estimated via a formula:
Corrected Ca (mg/dl) = Ca divided by 4 minus albumin(gm/dl) times ) 0.8

20. Medical Management Mild hypercalcemia Calcium < 12 Asymptomatic
Therapy
Activity
Avoid salt restriction
Discontinue thiazide diuretics

21. Medical Management Therapy Moderate to severe hypercalcemia
Moderate mg/dl
Severe >13.5 mg/dl
Therapy
Rehydration
Diuretics- Furosemide
Discontinue thiazide diuretics

22. Medical Management Antiresorptive therapy Calcitonin Bisphosphonates
Etidronate-Didronel
Pamidronate- Aredia
Zoledronic acid- Zometa
Ibandronate- Boniva
Risedronate- Actonel

23. Mechanism of action of Bisphosphonates
inhibit osteoclast formation, migration and osteolytic activity, promote apoptosis
local release during bone resorption
concentrated in newly mineralizing bone and under osteoclasts
modulate signalling from osteoblasts to osteoclasts

24. Current Therapeutic Approaches for Skeletal Complications of Malignancies
Radiotherapy
Endocrine therapy
Chemotherapy
Orthopedic interventions
Analgesia
Bisphosphonates1
Treatment of choice in hypercalcaemia of malignancy (HCM)
Potent inhibitors of pathologic bone resorption
Effective therapy for skeletal complications of bone metastases
Current Therapeutic Approaches for Skeletal Complications of Malignancies
Bisphosphonates play an integral role in therapy
In addition to pain management, which includes surgery and analgesics2:
Radiotherapy rapidly relieves pain from local tumour effects in 60% to 80% of patients
Chemotherapy is administered for rapidly progressive diseases or extensive visceral metastases
Hormonal therapy is administered for patients with hormone receptor- positive disease; bone, soft tissue only, or asymptomatic visceral disease; or ER/PR-positive tumours. Prostate cancer patients on hormonal therapy may have symptomatic pain responses
Bisphosphonates remain the treatment of choice for hypercalcaemia of malignancy (HCM), and have become an integral part of the current treatment of skeletal metastases, reducing the incidence of skeletal-related complications and delaying their onset.3 With bisphosphonate use, it is possible to reduce tumour burden by making the bone microenvironment a less- favourable site for the growth of tumour cells.4 Bisphosphonates may reduce bone pain, delay the onset of fractures, and reduce the fracture incidence in patients who already have osteolytic disease.
Bisphosphonates are potent inhibitors of both normal and pathologic bone resorption, and have been shown to significantly reduce skeletal morbidity in patients with osteolytic bone disease.1
1. Body JJ, et al. J Clin Oncol
1. Body JJ, Bartl R, Burckhardt P, et al. Current use of bisphosphonates in oncology. J Clin Oncol. 1998;16(12):
2. Rubens RD, Coleman RE. Bone metastases. In: Abeloff MD, Armitage JO, Lichter AS, et al, eds. Clinical Oncology. New York, NY: Churchill Livingstone; 1995:
3. Vinholes JJ, Guo CY, Purohit OP, et al. Metabolic effects of pamidronate in patients with metastatic bone disease. Br J Cancer. 1996;73:
4. Mundy GR. Bisphosphonates as anticancer drugs. N Engl J Med. 1998;339(6):

25. Zoledronic Acid—Mechanisms of Action
Zoledronic acid reduces bone resorption by potently inhibiting osteoclast hyperactivity
Proposed mechanisms of action include:
Functional suppression of mature osteoclast1
Inhibition of osteoclast maturation2
Inhibition of osteoclast recruitment to the site2
Reduction in the production of cytokines, eg, IL-1, IL-63
Inhibition of tumour-cell invasion and adhesion to bone matrix4,5
Zoledronic Acid—Mechanisms of Action
Potency inhibits osteoclast activity
Zoledronic acid inhibits the activity of osteoclasts, which play a major role in the development of complications of bone metastases.1 Proposed mechanisms of action include:
Functional suppression of mature osteoclast1
Inhibition of osteoclast maturation2
Inhibition of osteoclast recruitment to the site2
Reduction in the production of cytokines, eg, IL-1, IL-63
Inhibition of tumour-cell invasion and adhesion to bone matrix4,5
Preclinical data suggest that zoledronic acid also may have anti-tumour activity.6 In vitro studies indicate that zoledronic acid reduces human tumour-cell proliferation,7 induces apoptosis6 and inhibits angiogenesis. The anti- angiogenic effect has been confirmed by in vivo data.
These anti-osteoclastic and anti-cancer activities are believed to be related to the imidazole ring of the side chain of zoledronic acid, together with its core bisphosphonate structure. Consequently, an important biosynthetic pathway (protein prenylation) is inhibited, disrupting cell function and altering cell survival.8
The unique structural features of zoledronic acid distinguish it from other bisphosphonates. Preclinical studies have associated its unique structure with its increased potency and therapeutic ratio, in contrast to compounds without the imidazole ring.1
1. Green J, et al. J Bone Miner Res
2. Evans CE, Braidman IP. J Bone Miner Res
3. Derenne S, et al. J Bone Miner Res
4. Boissier S, et al. Cancer Res Marion G, et al. Bone
1. Green J, Muller K, Jaeggi KA. Preclinical pharmacology of CGP 42’446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res. 1994;9(5):
2. Evans CE, Braidman IP. Effects of two novel bisphosphonates on bone cells in vitro. J Bone Miner Res. 1994;26:
3. Derenne S, Amiot M, Barille S, et al. Zoledronate is a potent inhibitor of myeloma cell growth and secretion of IL-6 and MMP-1 by the tumoural environment. J Bone Miner Res. 1999;14:
4. Boissier S, Ferreras M, Peyruchaud O, et al. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res. 2000;60:
5. Marion G, Serre CM, Trzeciak MC, et al. Bisphosphonates inhibit the platelet-aggregating activity of tumor cells, a process involved during hematogenous dissemination of metastatic cells. (Abstract T330). Bone. 1998;23:S279.
6. Aparicio A, Gardner A, Tu Y, et al. In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia. 1998;12:
7. Fromignè O, Siwek B, Body JJ. Bisphosphonates inhibit breast cancer cell proliferation. Acta Clinica Abstract 54-2.
8. Fleisch H. Actions. In: Bisphosphonates in Bone Disease. San Diego, California: Academic Press; 2000:34-55.

26. Overall Safety Conclusions
ZOMETA (4 mg) via 15-minute infusion is safe and well tolerated, with a safety profile comparable to that of pamidronate (90 mg) via 2-hour infusion, including renal tolerability
Similar overall safety profile to that of other intravenous bisphosphonates
Laboratory abnormalities (grade 3 and 4) were similar for ZOMETA and placebo

27. Efficacy
Zoledronic acid is the only bisphosphonate to be proven effective across tumor types in patients with both lytic and blastic bone lesions

28. Nursing Management Education Patient Significant others Rehydration
Weights
Activity
Encourage ambulation

29. Nursing Management Safety Falls prevention
Do not allow patient to overstress bones
Do not pull on arms or legs
Have patient report all bone pain
Be very gentle when assisting patient
Use assistive devices
Safety assessment for home via PT/Home Health

30. Nursing Management
Decrease anxiety
Education

31. References
Jensen, G., “Hypercalcema of Malignancy” in Oncology Nursing Secrets, R Gates and R Fink (eds), Philadelphia: Hanley and Belfus, 2008,
Paines, H., “How to manage metabolic emergencies”, Contemp Oncol, 3 (9), 54-57, 1993
2009 UpToDate, ‘Treatment of Hypercalcemia’ www. accessed 7/9/09