HypercalcemiaHypercalcemia

Carol S. Viele RN MSCarol S. Viele RN MSClinical Nurse SpecialistClinical Nurse Specialist

Hematology-Onc-BMTHematology-Onc-BMTUCSFUCSF

ObjectivesObjectives

At the completion of this presentation the At the completion of this presentation the participant will be able to:participant will be able to:– Describe 2 side effects of hypercalcemiaDescribe 2 side effects of hypercalcemia– Define 2 agents utilized to treat Define 2 agents utilized to treat

hypercalcemiahypercalcemia– Describe at least 2 nursing interventions for Describe at least 2 nursing interventions for

hypercalcemiahypercalcemia

PrevalencePrevalenceMost common metabolic complication of Most common metabolic complication of cancercancer

10-20% of all cancer patients per year will 10-20% of all cancer patients per year will be diagnosed with hypercalcemiabe diagnosed with hypercalcemia

Associated MalignanciesAssociated Malignancies

Lung-35% ( NSCL)- 15% occurrenceLung-35% ( NSCL)- 15% occurrence

Breast- 40-50%Breast- 40-50%

Multiple Myeloma-20-40%Multiple Myeloma-20-40%

Head and Neck-6%Head and Neck-6%

Genitourinary-6%Genitourinary-6%

Other/Unknown primary-15%Other/Unknown primary-15%

Mechanism of Calcium RegulationMechanism of Calcium Regulation

Bone formation and resorption (99%) in Bone formation and resorption (99%) in bonebone

GI absorptionGI absorption

Urinary excretionUrinary excretion

Hypercalcemia in CancerHypercalcemia in Cancer

Due to increased bone resorption and Due to increased bone resorption and release of calcium from bonerelease of calcium from bone

Three mechanismsThree mechanisms– Osteolytic metastases with local release of Osteolytic metastases with local release of

cytokinescytokines– Tumor secretion of parathyroid hormone-Tumor secretion of parathyroid hormone-

related proteinrelated protein– Tumor production of calcitriolTumor production of calcitriol

Hormonal ControlHormonal ControlParathyroid hormone- released from the Parathyroid hormone- released from the parathyroid in response to a drop in calcium, parathyroid in response to a drop in calcium, acts directly on bone by stimulating osteoclast acts directly on bone by stimulating osteoclast formation and inhibiting osteoblastsformation and inhibiting osteoblasts

Vitamin D (1,25-dihydroxycholecalciferol)-Vitamin D (1,25-dihydroxycholecalciferol)-increase calcium and phosphorous absorption increase calcium and phosphorous absorption from the intestinal mucosafrom the intestinal mucosa

Calcitonin-reduces calcium release into Calcitonin-reduces calcium release into circulation as a result of bone resorptioncirculation as a result of bone resorption

Pathogenesis of Skeletal Pathogenesis of Skeletal MetastasesMetastases

tumour cell

osteoblast

mineralized bone

Imunecell

IL-1, TNFGM-CSF

activatd TGFß IL-6

IL-1 IL-6 TNF TGF EGF

PGs PTHrPcathepsins

OIF / OAF

osteoclast

Osteolytic MetastasesOsteolytic Metastases

Osteolytic mets are the result of direct induction Osteolytic mets are the result of direct induction of local osteolysis by the tumor cellsof local osteolysis by the tumor cells

Breast and Non–small cell lungBreast and Non–small cell lung

In Breast cancer adminstration of estrogen and In Breast cancer adminstration of estrogen and antiestrogen Tamoxifen) can lead to antiestrogen Tamoxifen) can lead to hypercalcemiahypercalcemia

Cytokines play a major role Cytokines play a major role – Tumor necrosis factorTumor necrosis factor– Interleukin-1Interleukin-1

Osteoclast Activating FactorsOsteoclast Activating Factors

Multiple Myeloma can release these factors by Multiple Myeloma can release these factors by tumor cellstumor cellsCytokines active in osteoclastic activityCytokines active in osteoclastic activity– Interleukin-1-betaInterleukin-1-beta– LymphotoxinLymphotoxin– Tumor necrosis factorTumor necrosis factor– IL-6IL-6– Macrophage colony stimulating factorMacrophage colony stimulating factor– Macrophage inflammatory proteinMacrophage inflammatory protein– Vascular cell adhesion molecule-1Vascular cell adhesion molecule-1– Hepatocyte growth factor ( This is produced by Hepatocyte growth factor ( This is produced by

myeloma cells in culture)myeloma cells in culture)

Pathogenesis of Skeletal Pathogenesis of Skeletal MetastasesMetastases

tumour cell

osteoblast

mineralized bone

Imunecell

IL-1, TNFGM-CSF

activatd TGFß IL-6

IL-1 IL-6 TNF TGF EGF

PGs PTHrPcathepsins

OIF / OAF

osteoclast

Clinical ManifestationsClinical ManifestationsDehydrationDehydration

PolydipsiaPolydipsia

PolyuriaPolyuria

GastointestinalGastointestinal– AnorexiaAnorexia– Nausea/VomitingNausea/Vomiting– ConstipationConstipation– Abdominal painAbdominal pain

Clinical ManifestationsClinical Manifestations

Bone painBone pain

Pathologic fracturePathologic fracture

Weakness Weakness

LethargyLethargy

HyporeflexiaHyporeflexia

DepressionDepression

Clinical ManifestationsClinical Manifestations

StuporStupor

ComaComaConfusionConfusionVisual disturbancesVisual disturbancesApathyApathyRestlessnessRestlessness

Clinical ManifestationsClinical Manifestations

GenitourinaryGenitourinary–PolyuriaPolyuria–PolydipsiaPolydipsia–NocturiaNocturia–Calcium nephropathyCalcium nephropathy–HypercalciuriaHypercalciuria–NephrolithiasisNephrolithiasis

Clinical ManifestationsClinical Manifestations

CardiovascularCardiovascular– HypertensionHypertension

– BradycardiaBradycardia

– Cardiac arrhythmiasCardiac arrhythmias

– Cardiac arrestCardiac arrest

– Heart blockHeart block

– Digitalis sensitivityDigitalis sensitivity

DiagnosisDiagnosis

Laboratory testsLaboratory tests–Ionized calcium or free calcium is Ionized calcium or free calcium is

the physiologically active form of the physiologically active form of calcium circulating in the bloodcalcium circulating in the blood

–50% of serum calcium is ionized50% of serum calcium is ionized

–Results < 1.30Results < 1.30

DiagnosisDiagnosisNormal serum calcium 9-11mg/dl Normal serum calcium 9-11mg/dl

Hypercalcemia can be estimated via a Hypercalcemia can be estimated via a formula:formula:– Corrected Ca (mg/dl) = Ca divided by 4 minus Corrected Ca (mg/dl) = Ca divided by 4 minus

albumin(gm/dl) times ) 0.8albumin(gm/dl) times ) 0.8

Medical ManagementMedical Management

Mild hypercalcemiaMild hypercalcemia–Calcium < 12Calcium < 12

–AsymptomaticAsymptomatic

–TherapyTherapyActivityActivity

Avoid salt restrictionAvoid salt restriction

Discontinue thiazide diureticsDiscontinue thiazide diuretics

Medical ManagementMedical ManagementModerate to severe hypercalcemiaModerate to severe hypercalcemia– Moderate 12-13 mg/dlModerate 12-13 mg/dl– Severe >13.5 mg/dlSevere >13.5 mg/dl

TherapyTherapy– RehydrationRehydration– Diuretics- FurosemideDiuretics- Furosemide– Discontinue thiazide diureticsDiscontinue thiazide diuretics

Medical ManagementMedical Management

Antiresorptive therapyAntiresorptive therapy–CalcitoninCalcitonin

–BisphosphonatesBisphosphonatesEtidronate-DidronelEtidronate-Didronel

Pamidronate- ArediaPamidronate- Aredia

Zoledronic acid- ZometaZoledronic acid- Zometa

Ibandronate- BonivaIbandronate- Boniva

Risedronate- ActonelRisedronate- Actonel

Mechanism of action of Mechanism of action of BisphosphonatesBisphosphonates

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 Current Therapeutic Approaches for

Skeletal Complications ofSkeletal Complications of MalignanciesMalignanciesRadiotherapyRadiotherapy

Endocrine therapy Endocrine therapy

ChemotherapyChemotherapy

Orthopedic interventions Orthopedic interventions

AnalgesiaAnalgesia

BisphosphonatesBisphosphonates11

– Treatment of choice in hypercalcaemia of malignancy Treatment of choice in hypercalcaemia of malignancy (HCM)(HCM)

– Potent inhibitors of pathologic bone resorptionPotent inhibitors of pathologic bone resorption– Effective therapy for skeletal complications of bone Effective therapy for skeletal complications of bone

metastasesmetastases1. Body JJ, et al. J Clin Oncol. 1998.

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.

Zoledronic Acid—Mechanisms of Zoledronic Acid—Mechanisms of ActionAction

Zoledronic acid reduces bone resorption by Zoledronic acid reduces bone resorption by potently inhibiting osteoclast hyperactivitypotently inhibiting osteoclast hyperactivity

Proposed mechanisms of action include:Proposed mechanisms of action include:– Functional suppression of mature osteoclastFunctional suppression of mature osteoclast11

– Inhibition of osteoclast maturationInhibition of osteoclast maturation22

– Inhibition of osteoclast recruitment to the siteInhibition of osteoclast recruitment to the site22

– Reduction in the production of cytokines, eg, IL-Reduction in the production of cytokines, eg, IL-1, IL-61, IL-633

– Inhibition of tumour-cell invasion and adhesion Inhibition of tumour-cell invasion and adhesion to bone matrixto bone matrix4,54,5

Overall Safety ConclusionsOverall Safety Conclusions

ZOMETA ZOMETA (4 mg) via 15-minute infusion (4 mg) via 15-minute infusion is safe and is safe and well tolerated, with a safety profile comparable to well tolerated, with a safety profile comparable to that of pamidronate (90 mg) via 2-hour infusion, that of pamidronate (90 mg) via 2-hour infusion, including renal tolerability including renal tolerability

Similar overall safety profile to that of other Similar overall safety profile to that of other intravenous bisphosphonates intravenous bisphosphonates

Laboratory abnormalities (grade 3 and 4) were Laboratory abnormalities (grade 3 and 4) were similar for ZOMETA and placebosimilar for ZOMETA and placebo

EfficacyEfficacy

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

Nursing ManagementNursing ManagementEducationEducation– PatientPatient– Significant othersSignificant othersRehydrationRehydration– I&OI&O– WeightsWeightsActivityActivity– Encourage ambulationEncourage ambulation

Nursing ManagementNursing ManagementSafetySafety– Falls preventionFalls prevention– Do not allow patient to overstress bonesDo not allow patient to overstress bones– Do not pull on arms or legsDo not pull on arms or legs– Have patient report all bone painHave patient report all bone pain– Be very gentle when assisting patientBe very gentle when assisting patient– Use assistive devicesUse assistive devices– Safety assessment for home via Safety assessment for home via

PT/Home HealthPT/Home Health

Nursing ManagementNursing Management

Decrease anxietyDecrease anxietyEducationEducation

ReferencesReferencesJensen, G., “Hypercalcema of Malignancy” in Jensen, G., “Hypercalcema of Malignancy” in Oncology Nursing SecretsOncology Nursing Secrets, R Gates and R Fink , R Gates and R Fink (eds), Philadelphia: Hanley and Belfus, (eds), Philadelphia: Hanley and Belfus, 2008,523-5262008,523-526

Paines, H., “How to manage metabolic Paines, H., “How to manage metabolic emergencies”, emergencies”, Contemp OncolContemp Oncol, 3 (9), 54-57, , 3 (9), 54-57, 1993 1993

2009 UpToDate, ‘Treatment of Hypercalcemia’ 2009 UpToDate, ‘Treatment of Hypercalcemia’ www.http://UPTODATE accessed 7/9/09 accessed 7/9/09