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

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

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

Associated Malignancies Lung-35% ( NSCL)- 15% occurrence Breast- 40-50% Multiple Myeloma-20-40% Head and Neck-6% Genitourinary-6% Other/Unknown primary-15%

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

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

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

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

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

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)

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

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

Clinical Manifestations Bone pain Pathologic fracture Weakness Lethargy Hyporeflexia Depression

Clinical Manifestations Stupor Coma Confusion Visual disturbances Apathy Restlessness

Clinical Manifestations Genitourinary Polyuria Polydipsia Nocturia Calcium nephropathy Hypercalciuria Nephrolithiasis

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

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

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

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

Medical Management Therapy Moderate to severe hypercalcemia Moderate 12-13 mg/dl Severe >13.5 mg/dl Therapy Rehydration Diuretics- Furosemide Discontinue thiazide diuretics

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

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

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. 1998. 1. Body JJ, Bartl R, Burckhardt P, et al. Current use of bisphosphonates in oncology. J Clin Oncol. 1998;16(12):3890-3899. 2. Rubens RD, Coleman RE. Bone metastases. In: Abeloff MD, Armitage JO, Lichter AS, et al, eds. Clinical Oncology. New York, NY: Churchill Livingstone; 1995:643-648. 3. Vinholes JJ, Guo CY, Purohit OP, et al. Metabolic effects of pamidronate in patients with metastatic bone disease. Br J Cancer. 1996;73:1089-1095. 4. Mundy GR. Bisphosphonates as anticancer drugs. N Engl J Med. 1998;339(6):398-400.

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. 1994. 2. Evans CE, Braidman IP. J Bone Miner Res. 1994. 3. Derenne S, et al. J Bone Miner Res. 1999. 4. Boissier S, et al. Cancer Res. 2000. 5. Marion G, et al. Bone. 1998. 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):745-751. 2. Evans CE, Braidman IP. Effects of two novel bisphosphonates on bone cells in vitro. J Bone Miner Res. 1994;26:95-107. 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;14:2048-2056. 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;60:2949-2954. 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;12:220-229. 7. Fromignè O, Siwek B, Body JJ. Bisphosphonates inhibit breast cancer cell proliferation. Acta Clinica. 1999. Abstract 54-2. 8. Fleisch H. Actions. In: Bisphosphonates in Bone Disease. San Diego, California: Academic Press; 2000:34-55.

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

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

Nursing Management Education Patient Significant others Rehydration Weights Activity Encourage ambulation

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

Nursing Management Decrease anxiety Education

References Jensen, G., “Hypercalcema of Malignancy” in Oncology Nursing Secrets, R Gates and R Fink (eds), Philadelphia: Hanley and Belfus, 2008,523-526 Paines, H., “How to manage metabolic emergencies”, Contemp Oncol, 3 (9), 54-57, 1993 2009 UpToDate, ‘Treatment of Hypercalcemia’ www.http://UPTODATE accessed 7/9/09