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S U P P L E M E N TJNCCNVolume 7 Supplement 3Journal of the National Comprehensive Cancer NetworkNCCN Task Force Report: Bone Health inCancer CareJulie R. Gralow, MD; J. Sybil Biermann, MD; Azeez Farooki, MD;Monica N. Fornier, MD; Robert F. Gagel, MD; Rashmi N. Kumar, PhD;Charles L. Shapiro, MD; Andrew Shields, MD; Matthew R. Smith, MD, PhD;Sandy Srinivas, MD; and Catherine H. Van Poznak, MDCE Provided by NCCNNCCN appreciates that supporting companies recognizeNCCN’s need for autonomy in the development of the contentof NCCN resources. All NCCN content is produced completelyindependently. The distribution of this task force report issupported by an educational grant from Novartis Oncology.NCCN.org


JNCCNVolume 7 Supplement 3 Journal of the National Comprehensive Cancer NetworkMission StatementNCCN Member InstitutionsCity of Hope ComprehensiveCancer CenterLos Angeles, CaliforniaDana-Farber/Brigham andWomen’s Cancer Center|Massachusetts GeneralHospital Cancer CenterBoston, MassachusettsDuke Comprehensive Cancer CenterDurham, North CarolinaFox Chase Cancer CenterPhiladelphia, PennsylvaniaHuntsman Cancer Institute at theUniversity of UtahSalt Lake City, UtahFred Hutchinson CancerResearch Center/Seattle Cancer Care AllianceSeattle, WashingtonThe Sidney KimmelComprehensive Cancer Centerat Johns HopkinsBaltimore, MarylandRobert H. Lurie ComprehensiveCancer Center ofNorthwestern UniversityChicago, IllinoisMemorial Sloan-KetteringCancer CenterNew York, New YorkH. Lee Moffitt Cancer Center& Research InstituteTampa, FloridaThe Ohio State UniversityComprehensive CancerCenter – James Cancer Hospitaland Solove Research InstituteColumbus, OhioRoswell Park Cancer InstituteBuffalo, New YorkSiteman Cancer Center atBarnes-Jewish Hospital andWashington University Schoolof MedicineSt. Louis, MissouriSt. Jude Children’s ResearchHospital/University ofTennessee Cancer InstituteMemphis, TennesseeStanford ComprehensiveCancer CenterStanford, CaliforniaUniversity of Alabama atBirmingham ComprehensiveCancer CenterBirmingham, AlabamaUCSF Helen Diller FamilyComprehensive Cancer CenterSan Francisco, CaliforniaUniversity of MichiganComprehensive Cancer CenterAnn Arbor, MichiganUNMC Eppley Cancer Center atThe Nebraska Medical CenterOmaha, NebraskaThe University of TexasM. D. Anderson Cancer CenterHouston, TexasVanderbilt-Ingram Cancer CenterNashville, TennesseeFor more information, visitwww.nccn.orgJNCCN is dedicated to improving the quality of cancer care locally,nationally, and internationally while enhancing the collaborationbetween academic medicine and the community physician. JNCCNis further committed to disseminating information across the cancercare continuum by publishing clinical practice guidelines and reportingrigorous outcomes data collected and analyzed by experts from the world’sleading care centers. JNCCN also provides a forum for original researchand review papers focusing on clinical and translational research andapplications of the NCCN Guidelines in everyday practice, as well ascorrespondence and commentary.NCCN275 Commerce DriveSuite 300Fort Washington, PA 19034215–690–0300www.nccn.orgAbout the NCCNThe National Comprehensive Cancer Network (NCCN), a not-for-profit allianceof 21 of the world’s leading cancer centers, is dedicated to improving the quality andeffectiveness of care provided to patients with cancer. Through the leadership andexpertise of clinical professionals at NCCN Member Institutions, NCCN developsresources that present valuable information to the numerous stakeholders in thehealth care delivery system. As the arbiter of high-quality cancer care, NCCNpromotes the importance of continuous quality improvement and recognizes thesignificance of creating clinical practice guidelines appropriate for use by patients,clinicians, and other health care decision-makers. The primary goal of all NCCNinitiatives is to improve the quality, effectiveness, and efficiency of oncologypractice so patients can live better lives. For more information, visit www.nccn.org.


JNCCNVolume 7 Supplement 3Journal of the National Comprehensive Cancer NetworkNCCN Task Force: Bone Health in Cancer Care Panel Members* P Julie Gralow, MD†Fred Hutchinson CancerResearch Center* P J. Sybil Biermann, MDτUniversity of MichiganComprehensive Cancer Center* P Azeez Farooki, MDðMemorial Sloan-KetteringCancer Center* P Monica N. Fornier, MDÞ†Memorial Sloan-KetteringCancer Center* P Robert F. Gagel, MDðThe University of TexasM. D. Anderson Cancer Center*Rashmi N. Kumar, PhDNational ComprehensiveCancer Network* P Charles L. Shapiro, MD†The Ohio State UniversityComprehensive Cancer Center –James Cancer Hospital andSolove Research Institute* P Andrew Shields, MDφUniversity of WashingtonMedical Center* P Matthew R. Smith, MD, PhD†Massachusetts General HospitalCancer Center* P Sandy Srinivas, MD†Stanford ComprehensiveCancer Center* P Catherine H. Van Poznak, MD†University of MichiganComprehensive Cancer CenterKEY:*Writing Committee Member; P PresenterSpecialties: ‡Hematology/HematologyOncology; ÞInternal Medicine;τOrthopedics/Orthopedic Oncology;ðEndocrinology; †Medical Oncology;φNuclear MedicineDisclosure of Affiliations and Significant RelationshipsDr. Gralow has disclosed that she has financial interests, arrangements, or affiliations with the manufacturer of products anddevices discussed in this report or who may financially support the educational activity. She has received research support fromNovartis AG, Roche, and Amgen Inc.Dr. Biermann has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products anddevices discussed in this report or who may financially support the educational activity.Dr. Farooki has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devicesdiscussed in this report or who may financially support the educational activity. He is on the speakers’ bureau for Novartis AG andProctor & Gamble. He has also received honoraria from Novartis AG (that totals $10,000 or more).Dr. Fornier has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products anddevices discussed in this report or who may financially support the educational activity.Dr. Gagel has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devicesdiscussed in this report or who may financially support the educational activity. He is on the speakers’ bureau for Eli Lilly andCompany and Novartis AG.Dr. Kumar has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of productsand devices discussed in this report or who may financially support the educational activity. She is an employee of the NationalComprehensive Cancer Network.Dr. Shapiro has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devicesdiscussed in this report or who may financially support the educational activity. He receives research funding from Pfizer Inc. andGenentech, Inc. He is also a consultant for Genentech, Inc.Dr. Shields has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products anddevices discussed in this report or who may financially support the educational activity.Dr. Smith has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devicesdiscussed in this report or who may financially support the educational activity. He is a consultant for Amgen Inc., Novartis AG, andGTx, Inc.Dr. Srinivas has disclosed that she has financial interests, arrangements, or affiliations with the manufacturer of products anddevices discussed in this report or who may financially support the educational activity. She receives research funding from NovartisAG.Dr. Van Poznak has disclosed that she has financial interests, arrangements, or affiliations with the manufacturer of products anddevices discussed in this report or who may financially support the educational activity. She has received grant or research supportfrom Novartis AG and Amgen Inc.


JNCCNVolume 7 Supplement 3 Journal of the National Comprehensive Cancer NetworkCME AcceditationThe National Comprehensive CancerNetwork (NCCN) is accredited by theAccreditation Council for ContinuingMedical Education (ACCME) toprovide continuing medical educationfor physicians.The NCCN designates thiseducational activity for a maximum of1.25 AMA PRA Category 1 Credits.Physicians should only claim creditcommensurate with the extent of theirparticipation on the activity.This educational activity was plannedand produced in accordance withACCME Essential Areas and Policies.The NCCN adheres to the ACCMEStandards for Commercial Support ofContinuing Medical Education.This activity is approved for 1.25contact hours. NCCN is an approvedprovider of continuing nursingeducation by the PA State NursesAssociation, an accredited approverby the American Nurses CredentialingCenter’s Commission on Accreditation.Approval as a provider refers torecognition of educational activities onlyand does not imply ANCC CommissionAccreditation of PA Nurses approval orendorsement of any product. Kristina M.Gregory, RN, MSN, OCN, is our nurseplanner for this educational activity.Continuing Education InformationTarget AudienceThis educational program is designed to meet the needs of oncologists, advancedpractice nurses, and other clinical professionals who treat and manage patients withcancer.Educational ObjectivesAfter completion of this CME activity, participants should be able to:• Implement recommended techniques for screening and detection of osteoporosis.• Define biomarkers in bone health.• Describe the pathophysiology, imaging techniques, and surgical management ofbone metastases.• Summarize the skeletal complications that arise from direct effects of cytotoxicchemotherapy, including treatment-induced ovarian failure.• Choose the appropriate management strategy for treatment-induced bone loss andskeletal complications associated with breast and prostate cancer.The opinions expressed in this publication are those of the participating facultyand not those of the National Comprehensive Cancer Network, Novartis Oncology,or the manufacturers of any products mentioned herein.This publication may include the discussion of products for indications notapproved by the FDA.Participants are encouraged to consult the package inserts for updatedinformation and changes regarding indications, dosages, and contraindications. Thisrecommendation is particularly important with new or infrequently used products.Activity InstructionsParticipants will read all portions of this monograph, including all tables, figures, andreferences. A post-test and an evaluation form follow this activity, both of whichrequire completion. To receive your continuing education certificate, you will needa score of at least 70% on the post-test. The post-test and evaluation form must becompleted and returned by June 26, 2010. It should take approximately 1.25 hours tocomplete this activity as designed.There are no registration fees for this activity. Certificates will be mailed within 3to 4 weeks of receipt of the post-test.Copyright 2009, National Comprehensive Cancer Network (NCCN). All rightsreserved. No part of this publication may be reproduced or transmitted in any otherform or by any means, electronic or mechanical, without first obtaining writtenpermission from the NCCN.


S-1SupplementNCCN Task Force Report: Bone Health inCancer CareJulie R. Gralow, MD; J. Sybil Biermann, MD; Azeez Farooki, MD; Monica N. Fornier, MD; Robert F. Gagel, MD; Rashmi N. Kumar, PhD;Charles L. Shapiro, MD; Andrew Shields, MD; Matthew R. Smith, MD, PhD; Sandy Srinivas, MD; and Catherine H. Van Poznak, MDKey WordsNCCN Clinical Practice Guidelines, bone health, breast cancer,prostate cancer, dual x-ray absorptiometry, bone mineral density,FRAX TM analysis, osteopenia, osteoporosis, bisphosphonates, aromataseinhibitors, chemotherapy, imaging, bone metastasesAbstractBone health and maintenance of bone integrity are importantcomponents of comprehensive cancer care in both early and latestages of disease. Risk factors for osteoporosis are increased in patientswith cancer, including women with chemotherapy-inducedovarian failure, those treated with aromatase inhibitors for breastcancer, men receiving androgen-deprivation therapy for prostatecancer, and patients undergoing glucocorticoid therapy. Theskeleton is a common site of metastatic cancer recurrence, andskeletal-related events are the cause of significant morbidity. TheNational Comprehensive Cancer Network (NCCN) convened a multidisciplinarytask force on Bone Health in Cancer Care to discussthe progress made in identifying effective screening and therapeuticoptions for management of treatment-related bone loss; understandingthe factors that result in bone metastases; managingskeletal metastases; and evolving strategies to reduce bone recurrences.This report summarizes presentations made at the meeting.(JNCCN 2009;7[Suppl 3]:1–32)BackgroundBone health is emerging as an important issue amongclinicians who care for cancer patients. The most commonlydiagnosed cancers among women and men in theUnited States are breast and prostate. The AmericanCancer Society estimated that 184,450 new cases ofbreast cancer and 186,320 new cases of prostate cancerwere diagnosed in 2008. 1 Although most patients willnot experience bone metastases, those who do developmetastatic disease have a high likelihood of the tumorinvolving bone or bone marrow. The incidence of bonemetastases is 73% in patients with metastatic breastcancer, 68% in those with prostate cancer, and in nearlyall patients with myeloma. 2Complications of bone metastases include pain,hypercalcemia, nerve compression, and pathologic fractures,and significant morbidity and mortality are associatedwith bone metastases. In addition, bone health canbe significantly impacted by cancer treatments in patientswith early stage cancer. Treatment–related boneloss may lead to osteoporosis and its complications, includingfractures, pain, and diminished quality of life.Managing and maintaining bone health in patientswith cancer requires understanding normalbone metabolism and how it is affected by both bonemetastasis and the drugs used to treat cancer, includingthe effect of chemotherapy-induced menopauseand anti-estrogen therapies on bone loss; the role ofbone markers and imaging techniques to assess boneloss, bone metastases, and therapeutic strategies tomaintain bone health; treatment of bone metastases,including surgery and radiation therapy for pathologicfractures; and emerging data in preventing bone metastases.Since publication of a previous NCCN TaskForce Report in 2006, new data on bone health, treatment,and the role of bisphosphonates to prevent bonemetastases in cancer patients have emerged, promptingan update. This task force focuses on bone healthand bone metastases in solid tumors.Ten expert task force members were chosen, representingendocrinology, medical oncology, imaging, andorthopedic surgery. All task force members are affiliatedwith NCCN member institutions and were identifiedand invited solely by NCCN. During a day-longmeeting in December 2008, panel members provideddidactic presentations integrating expert judgment withkey literature review on screening, detection, and treatmentoptions for osteoporosis; cancer therapy–inducedbone loss; reducing risk of recurrences; pathophysiologyof bone metastases; and imaging, management,and treatment of bone metastases, particularly in breast© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


S-2SupplementNCCN Task Force ReportAccording to the National Osteoporosis Foundation(NOF) guidelines for preventing and treating osteoporosis,“all postmenopausal women and men age50 and older should be evaluated clinically for osteoporosisrisk to determine the need for bone mineraldensity (BMD) testing.” The NCCN Clinical PracticeGuidelines in Oncology: Breast Cancer and ProstateCancer (to view the most recent version of theseguidelines, visit the NCCN Web site at www.nccn.org)recommend that patients for whom planned therapyincludes medications that lower sex steroids shouldbe evaluated at baseline and with periodic follow-updual-energy x-ray absorptiometry (DEXA) scans toevaluate risk of fracture. 5,6 Osteoporosis risk factorsunique to or commonly found in cancer patients arechemotherapy-induced menopause, gonadotropinreleasinghormone (GnRH) suppression of gonadalfunction, anti-estrogen and anti-androgen therapies,glucocorticoids (used predominantly in treatment ofhematologic malignancies or as supportive agents insolid tumors), inadequate calcium intake, vitamin Ddeficiency, and inadequate exercise.Bone health is currently assessed using BMD levels.Bone strength is defined by BMD and bone quality.The U.S. Preventive Service Task Force clinicalguidelines recommend BMD screening for all women65 years and older and for women aged 60 to 64who are at high risk for bone loss. 7 ASCO guidelinesagree with those and further suggest BMD screeningfor women with breast cancer who have high risk factorssuch as family history of fractures, body weightless than 70 kg, and prior non-traumatic fracture, forpostmenopausal women of any age receiving aromataseinhibitor (AI) therapy, and for premenopausalwomen with therapy-induced ovarian failure. 8 Formen, the NOF recommends BMD testing for men70 years and older. The NCCN Clinical PracticeGuidelines recommend screening for osteoporosisin men on androgen-deprivation therapy (ADT) asoutlined in NOF guidelines. 5The WHO defines osteoporosis by BMD. Technologywidely used to confirm the diagnosis of osteoporosisis DEXA measurement of the hip and spine.DEXA is generally considered the “gold standard”method of measuring BMD for diagnosing osteoporosisand monitoring the effects of osteoporosis therapy.BMD may be expressed in absolute terms, in gramsper square centimeter (g/cm 2 ), and in relative termsas the difference in standard deviation (SD) from exandprostate cancer patients. This report summarizesthe NCCN Bone Health in Cancer Care TaskForce meeting.Screening for and Detecting OsteoporosisOsteoporosis and its associated increase in fracturerisk is a major health issue for cancer patients. Muchof the morbidity and mortality associated with boneloss can be prevented with appropriate screening,lifestyle interventions, and therapy. The hormonedeprivation state resulting from certain cancer therapiesenhances osteoclastic bone resorption, promotingbone loss. Glucocorticoids are commonly usedfor supportive therapy (e.g., premedications for taxanesor antiemetics) in the treatment of solid tumorsand are often used in hematologic malignancies aswell. These therapy-related affects can combine withother important clinical factors such as age, priorfracture history, and family history of fracture, furtherincreasing fracture risk. 3,4 Screening and modifyingrisk factors for development of osteoporosis is acritical issue for all cancer survivors and their healthcare providers.Bone is a dynamic tissue that undergoes formationand resorption throughout the life of an individualto maintain skeletal integrity. This homeostaticprocess involves a continuous cycle of bonematrix and mineral resorption (osteoclastic activity)and bone formation (osteoblastic activity). Inthe most common form of osteoporosis, resorptionexceeds formation, leading to low bone mass, deteriorationof bone tissue, and disruption of bone architecture.This leads to compromised bone strengthand an increased risk of fractures. Advancing ageand the onset of menopause further increase the rateof bone resorption, magnifying the impact of theremodeling imbalance.Many non-oncologic factors are associated withan increased risk of osteoporosis-related fracture.These include lifestyle factors such as smoking, excessalcohol intake, inadequate exercise, low calciumintake, and vitamin D deficiency; genetic factorssuch as parental history of hip-fractures; and the useof specific pharmacologic agents such as glucocorticoids,proton pump inhibitors, anticoagulants, certainantidepressants, and agents that lower sex steroidsor block their effects. In general, the more riskfactors present, the greater the risk of fracture.© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


SupplementS-3Bone Health in Cancer Carepected BMD for the patient’s age and sex (Z-score) orfrom that of “young normal” adults of the same sex (Tscore).In 1994, WHO established diagnostic criteriafor osteoporosis, based on T scores. 9 Under the WHOcriteria, BMD within 1 SD of a “young normal” adult(T-score of ≥ −1.0) is considered normal, 1.0 to 2.5SD below (T-score of −1.0 to −2.5) constitutes lowbone mass or osteopenia, and 2.5 SD or more below(T-score ≤ −2.5) constitutes osteoporosis.Although DEXA measurement is considered thegold standard, its limitations must also be recognized.For example, results can vary with the machine used,different underlying dual-energy methods used, differencesin calibration, different detectors used, differentreference standards, and also by anatomic site(e.g., hip vs. vertebrae). These factors support therecommendation that serial BMD monitoring shouldbe performed on the same piece of equipment usingthe same reference standards. In addition, osteoarthritisor calcification of the aorta, if present, maylead to falsely high BMD. DEXA scan exposes patientsto low levels of radiation, equal to one-tenthof a chest x-ray.WHO Fracture Risk AlgorithmRecently, WHO developed a fracture risk algorithm(FRAX), a risk assessment tool that combines bothbone density measurements and clinical factors inassessing fracture risk (available at www.shef.ac.uk/FRAX/). 10 This tool provides an estimate of the 10-year probability of hip fracture and major osteoporoticfracture based on age, sex, clinical risk factors,femoral neck BMD (T-score), and other information.FRAX models were developed from studying population-basedcohorts in Europe, North America, Asia,and Australia. It has separate calculation tools forU.S. white, black, Asian, and Hispanic populations.FRAX analysis is optimized for postmenopausalwomen and men aged 50 and older and is intendedto predict risk for patients previously untreated forbone loss. It includes a “secondary osteoporosis” riskmodifier that can be used to factor hypogonadismand premature menopause into the fracture risk. TheWHO FRAX tool provides an individualized 10-yearfracture risk estimate that can be used to guide interventionand therapy. An example of the analysisresults is shown in Figure 1. Current Medicareguidelines recommend therapeutic intervention forpatients with a 10-year FRAX risk of 3% for hip fracturesand more than 20% for all major fractures. TheNCCN Bone Health in Cancer Care Task Force recommendsusing the FRAX algorithm in the baselineassessment of all cancer patients at increased risk forbone loss and fracture because of cancer or -relatedtherapy. FRAX calculations can be performed withor without BMD data, making it useful in situationsin which bone density is unavailable.Other Techniques for Assessing Bone HealthBone Turnover Markers: Biochemical markers ofbone remodeling can be broadly subdivided intomarkers of bone formation and bone resorption. Boneformation markers include osteocalcin, bone-specificalkaline phosphatase (BAP), and N-terminal and C-terminal pro-peptides of type I procollagen (P1NP,P1CP). 11 Bone resorption markers include N-terminaland C-terminal cross-linking telopeptides of typeI collagen (NTX and CTX); both can be detected inserum or urine using enzyme-linked immunosorbentassay or chemiluminescence based techniques.Bone biomarkers can be used to assess risk of fractureindependent of age, BMD, and prior fracture.Several cohort studies have shown that bone markerssuch as CTX and BAP are predictive of vertebraland hip fractures, 12–14 and bone turnover markers mayimprove the diagnosis of women at high risk of fracture.However, bone metabolism markers cannot betranslated into a patient-specific estimate of fracturerisk. Therefore, bone markers are not widely usedclinically for assessing osteoporosis. In addition, manyphysiologic factors affect bone marker levels. For example,bone markers can vary with bed rest, seasonalchanges, menstrual cycle, and time of day, and are affectedby comorbid conditions such as kidney or liverdisease, leading to marked variability ranging from15% to 40%. Studies have shown that overnight fastingsignificantly reduces variation for CTX, and, forthe urinary NTX marker, obtaining a second morning-voidurine sample reduces variability caused bydiurnal changes in bone resorption. 15,16 Additionally,studies have shown lower physiologic variability forserum markers compared with urine markers. 17,18Vertebral Fractures: Vertebral fractures are themost common osteoporotic fractures. 19 Independentof BMD and other clinical risk factors, existing vertebralfractures are a strong predictor of future vertebraland other fractures. Studies by Black et al. 20 andMelton et al. 21 show that women with vertebral fractureshave a 5-fold increased risk of a new vertebralfracture and a 2-fold increased risk of hip fracture. 20,21© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


S-6SupplementNCCN Task Force ReportCancer patients at increased risk for boneloss and fracture due to therapy or ageHistory & physical examination,BMD screening, FRAX TM analysis *Lifestyle modifications, calcium, andvitamin D †T-score > –1T-score between–1.0 and –1.5T-score between–1.5 and –2.0T-score < –2.0 ORFRAX 10 year fracture risk> 20% for major fractureor > 3% for hip fractureConsider checking 25(OH) vitamin D level ‡Consider pharmacologictherapyStrongly considertreatment withpharmacologic therapyRepeat DEXA every 2 years §Figure 2 Algorithm for management of bone health of cancer patients in the United States.Abbreviations: 25(OH), serum hydroxy; BMD, bone mineral density; DEXA, dual-energy x-ray absorptiometry; FRAX TM , FractureRisk Assessment Algorithm.*See section on “Screening and Detection of Osteoporosis” for FRAX TM algorithm.†See section on “Update on Treatment Options for Osteoporosis” for lifestyle modifications and calcium and vitamin D repletion.‡See section on “Update on Treatment Options for Osteoporosis” to correct vitamin D deficiency.§In selected cases, longer or shorter intervals may be considered. If a major change in patient risk factors or a major interventionoccurs, repeating DEXA scan at one year is reasonable.Note: In addition to monitoring changes in BMD, the oncologist should obtain a lateral thoracic and lumbar x-ray of the spine to determineif vertebral compression deformities are present if there is: 1) a historical height loss > 4 cm (1.6 in) or a prospective height loss > 2cm (0.8 in), or 2) complaint of acute back pain. Consider referral to a bone health specialist if loss of vertebral height > 20% is present.tions of 25(OH) D associated with deficiency, adequacyfor bone health, and optimal overall health.For bone health, vitamin D should ideally be supplementedin amounts sufficient to bring serum 25(OH)D levels to 30 ng/ml (75 nmol/L) or higher. 40 Insupplements, vitamin D is available in 2 forms: D2(ergocalciferol) and D3 (cholecalciferol). These 2forms are metabolized differently, and vitamin D3could be more effective in raising 25(OH) D concentrationsand maintaining those levels for a longertime when longer dosing intervals are employed. 41,42No difference in maintaining 25(OH) D levels wasfound when daily dosing was studied. 43One common regimen for patients with serum25(OH) D levels below 30 ng/mL is prescriptionvitamin D (ergocalciferol) 50,000 IU weekly for 8weeks, followed by a recheck of the serum 25(OH) Dlevel, with subsequent dosing based on the results. 40For patients with 25(OH) D levels between 20 and30, an alternative suggested by the panel is adding1000 IU over the counter vitamin D2 or D3 per dayto the patient’s current intake and rechecking thelevel in 3 months. Vitamin D toxicity (hypercalcemia,hyperphosphatemia, and activation of boneresorption) is uncommon but may occur with dailydoses of more than 50,000 IU per day that produce25(OH) D levels larger than 150 ng/mL. 40Therefore, current expert opinion on supplementationfor adults older than age 50 is 1200 mgof calcium (from all sources) and 800 to 1000 IU ofvitamin D daily. The NCCN Bone Health in CancerCare Task Force also recommends these ranges for© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


SupplementS-7Bone Health in Cancer Careyounger patients at risk for cancer treatment–associatedbone loss. A caveat to the vitamin D intake recommendationis that many patients need more thanthe recommended amount and should be repletedbased on serum 25(OH) D level.Pharmacologic AgentsThe United States FDA–approved pharmacologicoptions for preventing or treating osteoporosis includebisphosphonates, SERMs, estrogen, calcitonin,and teriparatide (Table 1). For FDA approval,a drug must show that it reduces the risk of vertebralfractures; non-vertebral anti-fracture efficacy isnot a requirement. 44Bisphosphonates: Bisphosphonates decrease boneresorption and increase mineralization by inhibitingosteoclast activity. 45 Bisphosphonates approvedby the FDA for postmenopausal osteoporosis arealendronate, ibandronate, risedronate, and zoledronicacid. All except ibandronate are approvedin both men as well as women. Because complianceis a significant problem with daily oral bisphosphonatedosing, a trend toward less frequent oral dosingand intravenous options have emerged (Table1). Generally, oral formulations (alendronate,ibandronate, and risedronate) are considered firstline. Use of intravenous bisphosphonates (ibandronateor zoledronic acid) may be considered,particularly for patients who cannot tolerate theoral formulations.Several bisphosphonates were studied in thecontext of cancer treatment–induced bone loss.Some settings in which bisphosphonates have shownefficacy at preserving BMD changes during anti-cancertreatment include breast cancer patients receivingAIs or those with chemotherapy-induced menopauseor other forms of ovarian suppression, prostatecancer patients undergoing ADT, and hematologicmalignancy patients undergoing stem cell transplantation.46–49 Details of some of these trials are presentedin subsequent sections of this report.Because of potential gastrointestinal toxicities,oral bisphosphonates should be avoided in patientswith esophageal emptying disorders and those whocannot sit upright; these patients are at high risk forpill esophagitis. 50 Intravenous bisphosphonates aregenerally not recommended in patients with creatinineclearance less than 30 mL/min because theycan increase serum creatinine and may, rarely, causeacute renal failure. 51 The risk for renal insufficiencyappears related to dose, infusion rate, and hydration.Oral bisphosphonates appear to have better renalsafety in patients with lower creatinine clearance. 52Calcium intake and vitamin D status should be optimizedwhen starting any bisphosphonate. VitaminD deficiency should be corrected before treating withintravenous bisphosphonates because hypocalcemiahas been reported in patients with unrecognized vitaminD deficiency.Table 1 FDA Approved Medications for Osteoporosis Prevention and TreatmentDosingMechanism; ClassEstrogen See Kalantaridou et al. 221 Antiresorptive; steroid hormoneCalcitonin 200 IU intranasal daily Antiresorptive; peptide hormoneAlendronateRisedronateIbandronate35 mg orally weekly70 mg orally weekly; with or withoutvitamin D: 2800, 5600 IU35 mg orally weekly150 mg orally monthly150 mg orally monthly, or3 mg intravenous push every 3 monthsAntiresorptive; bisphosphonateAntiresorptive; bisphosphonateAntiresorptive; bisphosphonateZoledronic acid 5 mg intravenous yearly (over 15 minutes) Antiresorptive; bisphosphonateRaloxifene 60 mg orally daily Antiresorptive; selective estrogenreceptor modulatorTeriparatide (recombinantparathyroid hormone)20 mg subcutaneous daily for a maximumof 2 yearsAnabolic; peptide hormone fragment© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


S-8SupplementNCCN Task Force ReportOsteonecrosis of the jaw (ONJ) has emerged as acomplication of bisphosphonate treatment. The etiologyis unknown, and it occurs in 1% to 10% of patientswith intravenous bisphosphonate used at thehigher doses for treating metastatic bone disease. 53,54The incidence of ONJ with bisphosphonate to treatosteoporosis (or prevent cancer treatment–inducedbone loss) appears to be low (< 10,000–100,000), 53accounting for roughly 4% of reported ONJ cases,compared with 95% of cases reported with intravenousbisphosphonate in patients with bone metastases.53,54 In cancer therapy–induced bone lossprevention trials with zoledronic acid (4 mg every6 months), no cases of ONJ have been reported todate. However, the fact that no previous trial of oralbisphosphonates reported ONJ cases is important torecognize. This highlights the difficulty of identifyinglow frequency but serious effects in clinical trials.55,56 Risk factors associated with ONJ include dentalextractions. Therefore, dental examination andprophylactic measures should be considered beforestarting bisphosphonate therapy. Patients shouldalso be advised against unnecessary invasive oralsurgery while on bisphosphonate therapy. 57 The ongoingSWOG S0702 trial, involving 7000 patientswith metastatic bone disease treated with zoledronicacid, is designed to prospectively investigate risk factors,incidence, outcome, and mechanisms associatedwith ONJ.In a phase III fracture prevention trial of yearlyzoledronic acid in women with postmenopausal osteoporosis,Black et al. 20 reported a higher risk ofserious atrial fibrillation for patients receiving zoledronicacid 5 mg yearly when compared with placebo(1.3% vs. 0.4%). This serious adverse event wasnot more common in other studies of osteoporoticpatients in which zoledronic acid was dosed 5 mgyearly. 58 Additionally, in studies in which 4 mg ofzoledronic acid was administered every 3 to 4 weeksfor preventing skeletal-related events in patientswith skeletal malignant involvement, no increase inatrial fibrillation was seen. In response to concernsregarding atrial fibrillation, the FDA released an earlycommunication letter stating that evidence wasnot strong enough to associate atrial fibrillation withbisphosphonate use and that further investigation iswarranted before making any conclusions. 59During the past 2 years, a small but concerningnumber of cases of subtrochanteric hip fractures havedeveloped in patients on long-term bisphosphonatetherapy. Although a causal relationship has not beenestablished with certainty, the unusual nature of thehorizontal fractures that occur at angles perpendicularto the long axis of the femur have raised concernsabout long-term use of bisphosphonates. 60,61Patients treated with zoledronic acid mayalso experience acute phase reactions. This physiologicreaction is associated with fever and flu-likesymptoms including myalgia, arthralgias, fever, fatigue,and nausea. It occurs in roughly 30% of patientsafter the initial dose and may persist for a fewdays. Acute phase reaction is not common withsubsequent dosing. 62Estrogen/Hormonal Therapy: Estrogen is an antiresorptiveagent with proven anti-fracture efficacyas shown in the Women’s Health Initiative study.Estrogen therapy alone or combined estrogen andprogesterone were associated with a 33% to 34% reductionin hip fracture. 49 The same study reportedincreased risks of myocardial infarction, stroke, invasivebreast cancer, pulmonary emboli, and deep veinthrombosis in postmenopausal women. 49 Because ofthese risks, the FDA recommends that “estrogenswith or without progestins should be prescribed atthe lowest effective doses and for the shortest durationconsistent with treatment goals and risks for theindividual woman.” 59 Estrogen replacement therapyis highly controversial in women with a history ofbreast cancer, including those who had hormonereceptor negative disease, due to the increased riskof breast cancer recurrence. 63 In young patients withcancers other than breast cancer who experiencechemotherapy-induced premature menopause, estrogenmay be a treatment option both for menopausalsymptoms and bone health. Data in young womenwith spontaneous premature ovarian failure arguesagainst an increased risk of breast cancer or otheradverse events with full replacement doses. 64 Therefore,in women with chemotherapy-induced menopausewho are not at increased risk for breast cancer,replacement of estrogen/progesterone until thenormal age of menopause is not likely to produce ahigher risk for adverse events seen in the WHI studyand may be beneficial for bone health.SERMs: Although tamoxifen has shown favorableimpact on bone density in postmenopausal breastcancer patients, raloxifene is currently the onlySERM that is FDA approved for the prevention and© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


SupplementS-9Bone Health in Cancer Caretreatment of osteoporosis in postmenopausal women.Raloxifene is a less potent antiresorptive agentthan bisphosphonates. Raloxifene has been shownto decrease the incidence of vertebral fracture; however,randomized studies have failed to documentany benefit against non-vertebral or hip fractures. 65Raloxifene, unlike estrogen, is not associatedwith an increase in myocardial infarction. Raloxifenehas been associated with an increased risk offatal stroke (hazard ratio [HR], 1.49; absolute riskincrease, 0.7/1000), and venous thromboembolism(HR, 1.44; absolute risk increase, 1.3/1000) in theRUTH (Raloxifene Use for The Heart) trial ofpostmenopausal women with a history of coronaryartery disease or cardiovascular risk factors. 66 A decreasedrisk of invasive breast cancer was shown inthe RUTH trial, confirming previous findings froman osteoporosis treatment trial 67 and also from a trialof postmenopausal women at high risk for breastcancer. 68 Hot flushes, leg cramps, peripheral edema,and gall-bladder disease are more common withraloxifene than with placebo. 66,69–71 The hot flushesinduced by raloxifene may be accentuated in earlymenopause. Raloxifene use is not indicated in premenopausalwomen at high risk for breast cancer; ithas resulted in decreased BMD in clinical trials. 72The efficacy of raloxifene in combination withan AI for breast cancer remains unknown. In theAnastrozole, Tamoxifen, Alone or in Combination(ATAC) trial, the concurrent use of tamoxifen (aSERM) and anastrozole (an AI) had less anti-tumorefficacy than anastrozole alone. 73 Thus, combined AIand SERM should not be used outside a clinical trial.Newer SERMs may have potential for use concomitantwith AIs, although the effects on bone are unknown.74 For women with a history of breast cancer,bisphosphonates are probably the best choice for preventingbone loss or treating established osteoporosis.Parathyroid Hormone(1-34, Teriparatide): Recombinantparathyroid hormone (PTH) 1-34 orteriparatide is the first anabolic agent approved fortreatment of postmenopausal osteoporosis. It hasbeen shown to reduce the incidence of vertebral andnon-vertebral fractures. It is administered daily bysubcutaneous injection for 2 years. Because of thepotential increased risk for osteosarcoma, it is contraindicatedin patients with increased baseline riskof osteosarcoma such as those with Paget’s diseaseof bone, open epiphyses, or prior radiation therapyinvolving the skeleton (which includes many patientswith cancer). Furthermore, teriparatide is notindicated in patients with bone metastases, includingthose who may have micrometastatic or occultdisease. A recent study involving 200,000 patientsshows no significant difference in incidence of osteosarcomabetween the treated group and the generalpopulation. 75 Although no data in patients with cancerexist, teriparatide is best avoided in patients witha history of malignancy prone to metastasize to bone.The drug works to sequentially increase bone resorptionfollowed by bone formation. This markedincrease in bone turnover may be favorable to propagationof microscopic bone metastases 76 throughliberation of bone-derived growth factors and cytokines,and potentially through direct anabolic effectson tumor cells. However, in cases of severe osteoporosiswith fractures occurring on bisphosphonatetherapy, the benefits may outweigh these theoreticalrisks. In such patients with a remote history of cancer,teriparatide could be cautiously considered. 77Receptor Activator of Nuclear Factor kB LigandInhibition: Receptor activator of nuclear factor kBligand (RANK-L) is an essential cytokine expressedon the surface of preosteoblastic and osteoblasticcells. RANK-L activates its receptor RANK, whichis expressed on osteoclasts and their precursors, ultimatelypromoting osteoclast formation and activation.Denosumab is a human monoclonal antibodyto RANK-L that blocks osteoclast differentiation,proliferation, and function. A 3-year, phase III trialof 7868 postmenopausal women with osteoporosisrandomized participants to receive either 60 mg subcutaneousdenosumab or placebo every 6 months. 78At the end of 36 months, treatment with denosumabshowed a statistically significant reduction in the incidenceof new vertebral fractures, new non-vertebralfractures, and hip fractures compared with placebotreatment. No serious adverse events reportedwith denosumab were significantly increased relativeto placebo. A randomized phase III non-inferioritytrial compared denosumab with alendronate in 1189postmenopausal women. 79 At 12 months, denosumabproduced a significantly greater increase in BMDat the hip (3.5% vs. 2.6% for alendronate; P < .0001)and greater suppression of bone turnover markers(CTX-I and P1NP). Denosumab appears to be apromising new agent that may receive FDA approvalfor managing postmenopausal osteoporosis. Deno-© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


S-10SupplementNCCN Task Force Reportsumab is currently being evaluated in patients previouslytreated with bisphosphonates 80 and in patientswith cancer (both for prevention of cancer therapy–induced bone loss and skeletal-related events).Role of Bone BiomarkersBone biomarkers are useful for monitoring patient responseand effectiveness of antiresorptive therapies.Changes in bone turnover markers can reflect responseto antiresorptive therapy in weeks to monthsrather than the months to years required for changesin BMD. This may be helpful in avoiding the timeand expense of a potentially ineffective therapy ordetecting of nonadherence with therapy, permittingthe earlier start of potentially more-effective therapy.Chestnut et al. 81 compared changes in urinaryNTX levels and bone mass in 109 postmenopausalwomen undergoing hormone replacement therapy.Patients with the highest quartile for baseline levelsof NTX and those with decreasing levels over6 months also had the largest percentage gain inBMD. Ravn et al. 82 compared short-term changes (3to 12 months) in urine CTX and other biomarkersto changes in BMD measured after 2 years in postmenopausalpatients receiving alendronate. A 50%decrease in CTX showed an 87% positive predictivevalue for prevention of bone loss.Treatment DurationNo published guidelines are available on duration ofantiresorptive therapy and whether to institute drugholidays. Treatment with alendronate for 10 yearswas shown to be well tolerated and with a positiveimpact on bone density versus placebo. 83 The resultsof the Fracture Intervention Trial Long-term Extension(FLEX) study suggest that postmenopausal womenwith a history of alendronate use for 5 years whodiscontinued it for 5 subsequent years had a modestabsolute increase in clinical vertebral fractures (5.3%vs 2.4%) but no difference in morphometric vertebralfractures or non-vertebral fractures. 84 Patients at veryhigh fracture risk may benefit by continuing beyond5 years. 84 In the setting of continued risk for cancertreatment–induced bone loss, such as AI use formore than 5 years, no data on duration are available.Factors to consider for duration of anti-osteoporosistherapy include BMD, response to therapy, and riskfactors for continued bone loss or fracture.Impact of Therapy-Induced OvarianFailure on Bone HealthNearly all premenopausal women with breast cancerreceiving standard chemotherapy experience at leasttemporary amenorrhea, and 50% to more than 70%will have permanent ovarian failure or early menopause.85–87 Development of chemotherapy-inducedovarian failure is considered a high risk factor forbone loss. 8 The most important factor for predictingpremature menopause or ovarian failure is age attime of chemotherapy treatment; greater risk is seenwith increasing age. 88 Additional factors includecumulative dose and duration of alkylating agents,such as cyclophosphamide. 86,87 One of the challengesin studying this issue is the lack of standard definitionfor chemotherapy-induced ovarian failure inthe literature. For example, some studies define itas at least 3 to 6 months of amenorrhea. However,distinguishing between temporary amenorrhea thatwill reverse and permanent ovarian failure is important,because bone loss is of greatest magnitude withovarian failure. 88,89Several small studies have identified additionalrisk factors for ovarian failure independent of age:baseline BMD before adjuvant chemotherapy mightpredict individual risk of developing ovarian failure.In a multivariate analysis of 49 premenopausal patientsundergoing adjuvant chemotherapy, a higherbaseline BMD increased the risk of ovarian failure. 90Studies have also shown accelerated bone lossas a consequence of ovarian failure after adjuvantchemotherapy. 90–96 In a prospective study by Shapiroet al. 90 involving 49 young women with breastcancer receiving adjuvant chemotherapy, 35 womenexperienced chemotherapy-induced ovarian failure.In patients with ovarian failure, a highly significantbone loss was seen in the lumbar spine by6 months, but no significant change was seen inpatients who retained ovarian function. Bone lossassociated with chemotherapy-induced menopauseis several-fold higher than that seen with naturalmenopause or AI therapy-induced bone loss inpostmenopausal women. 91,97–99Several studies have reported that bisphosphonates,including clodronate and risedronate, attenuatethe bone loss associated with chemotherapy-relatedovarian failure. 53,93–95 Zoledronic acid was testedin the CALGB 79809 study, in which premenopausalpatients beginning adjuvant chemotherapy were© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


SupplementS-11Bone Health in Cancer Carerandomized between early zoledronic acid (4 mg,every 3 months) or delayed zoledronic acid (given 1year after adjuvant chemotherapy). The primary endpoint was change in lumbar spine BMD. Density waspreserved in patients treated with early zoledronicacid at 12 months, compared with a 6.6% loss reportedfor the control group (delayed group). Similarly,in a randomized placebo-controlled trial of 4mg of zoledronic every 3 months for 1 year, BMD waspreserved in the lumbar spine and hip. 100Bisphosphonates are also effective for minimizingloss of BMD in women receiving ovarian suppressionwith GnRH. 101,102 In the Austrian Breastand Colorectal Cancer Study Group (ABCSG)-12trial, premenopausal breast cancer patients receivingendocrine treatment including a GnRH agonist wererandomized to 4 mg of zoledronic acid treatment ornot every 6 months for 3 years. The addition of thebisphosphonate prevented bone loss in both thelumbar spine and hip. Additionally, a recent reportnoted fewer breast cancer recurrences with the additionof zoledronic acid. 102Although studies showing the ability of bisphosphonatesto preserve BMD in young women withcancer treatment–related ovarian failure are encouraging,no study to date has shown an impact on theclinically relevant endpoint of fractures.AI-Induced Bone LossAs reviewed in the NCCN Breast Cancer Guidelines(to view the most recent version of these guidelines,visit the NCCN Web site at www.nccn.org), 6AIs play an important role in the treatment of estrogenor progesterone receptor (PR)–positive breastcancers in postmenopausal women in both the adjuvantand metastatic settings. Randomized studies ofAIs compared with or after tamoxifen therapy haveled to the widespread use of AIs as adjuvant therapyin postmenopausal, estrogen receptor (ER)–positivebreast cancer. 102 AIs act by inhibiting aromatase enzymeinvolved in conversion of the androgen precursorsto estrogen. Lower estrogen levels are associatedwith increased bone resorption and fracture risk. AIscause a rapid decline of circulating estrogen levels,leading to bone loss, 103,104 and are divided into steroidal(exemestane) and non-steroidal (letrozole oranastrazole). Exemestane binds irreversibly to thecatalytic site of aromatase, whereas letrozole and anastrozolebind reversibly to the heme group of theenzyme. The NCCN Breast Cancer Guidelines Panelconsiders the 3 selective AIs (anastrozole, letrozole,exemestane) to be similar in antitumor activityand toxicity profiles.Several reviews of AIs and their impact on bonehealth were published recently. 98,105–108 In the ATACtrial, 109 the annual incidence of fractures was higherin women receiving anastrozole (2.93%) comparedwith tamoxifen (1.9%) throughout 5 years of treatment.After treatment, the fracture rates of bothgroups were similar, suggesting that AI-related fracturerates decrease after treatment.The Breast International Group (BIG) 1-98 trialcompared adjuvant therapy with tamoxifen to letrozole.110 As with the ATAC trial, increased incidenceof bone fracture was seen in patients on AI (8.6%vs. 5.8% at 51 months). The Intergroup ExemestaneStudy (IES) compared adjuvant tamoxifen for5 years with initial adjuvant tamoxifen followed byexemestane. 111 Because exemestane is a steroidal AIwith androgenic properties, researchers hypothesizedthat it might have less impact on bone loss and fracturesthan anastrozole and letrozole. However, theincidence of fracture at 58 months was significantlyhigher (7%) in the exemestane group than in thetamoxifen group (5%). 112The recently closed MA-27 trial randomizingpostmenopausal breast cancer patients to eitheradjuvant exemestane or anastrozole will hopefullyclarify whether the androgenic nature of exemestaneresults in less impact on bone density. 113 The MA-17 trial compared an additional 5 years of letrozoleversus placebo after an initial 5 years of adjuvanttamoxifen. 114 The design of this trial allowed for amore direct look at the effect of AIs on bone withoutthe confounding factor of tamoxifen present in thecomparator arm. The incidence of a new diagnosisof osteoporosis was 5.8% in the letrozole group comparedwith 4.5% in the placebo group (P = .07), withsimilar fracture rates in both groups. These resultssuggest that the difference in bone loss and fracturerates in the adjuvant studies may be primarily due toa bone protective effect of tamoxifen as opposed to abone destructive effect of the AIs.Several of the large adjuvant trials have evaluatedbone loss and fractures in more detailed breakout studiesof women receiving AI therapy. 98,106,115 The ATACstudy evaluated risk factors for fractures in patients on© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


S-12SupplementNCCN Task Force ReportAI. 109 Older age was associated with higher risk. Additionally,a prospective study of the ERs trial assessedBMD changes in postmenopausal women. Amonganastrozole-treated patients, median BMD decreasedfrom baseline to 5 years in lumbar spine (−6.08%)and total hip (−7.24%) compared with the tamoxifengroup (lumbar spine, +2.77%; total hip, +0.74%). Importantly,no patients with normal BMD at baselinebecame osteoporotic at 5 years.Role of BisphosphonatesSeveral studies have analyzed the impact of bisphosphonatetherapy on maintaining bone density inpatients on AI treatment. Two trials examined theeffects of oral bisphosphonates in patients receivinganastrozole therapy. The SABRE (Study of Anastrozolewith the Biophosphonate Risedronate) trial 116was an open-label intervention study in which allpatients received anastrozole and were assigned to abisphosphonate treatment group based on T-score.Patients with a low-risk T score (> −1) received nointervention; patients with a T score greater than−2 received risedronate; and patients with a T scorebetween −1 and −2 were randomized to risedronateor placebo. For patients at low risk, bone loss duringshort-term follow-up was minimal. For otherpatients, risedronate therapy at doses established forpreventing and treating osteoporosis resulted in favorableeffects on BMD over 24 months. 117The ARIBON study evaluated the impact ofibandronate on BMD in postmenopausal, early stagebreast cancer patients receiving anastrozole. 118 Patientswith a T score greater than −1 received nointervention; patients with a T score of −1.0 to −2.5were randomized to ibandronate or placebo; patientswith a T score less than −2.5 received ibandronatetreatment. The addition of ibandronate to anastrozoleled to a significant increase in BMD at thespine and hip after 1 year, which was maintainedfor 2 years.The Zometa-Femara Adjuvant Synergy Trials(Z-Fast and ZO-Fast) were designed to compare effectsof upfront versus “delayed” initiation of anintravenous bisphosphonate, zoledronic acid (4 mgintravenously every 6 months), in preventing AIassociatedbone loss. 119,120 All patients received adjuvantletrozole. The “delayed therapy” group receivedzoledronic acid only when bone loss became clinicallysignificant or a fragility fracture occurred (10% ofpatients in the study). A pooled analysis of approxi-mately 1600 patients was performed and showedthat upfront use of zoledronic acid was associatedwith preservation of BMD. 55 These studies suggestthat both oral and intravenous bisphosphonates canmitigate the bone loss effects of AIs, although noneof these trials have shown a reduction in fractures.No clinical trials have directly compared oral versusintravenous bisphosphonates in this setting. Importantly,health care professionals should recognizethat AIs do cause bone loss. However, bone densitymonitoring and intervention strategies should be individualizedfor patients on AIs, with drug therapyreserved for those at greatest risk.Role of RANK-L InhibitionEllis et al. 121 conducted a randomized, double-blind,placebo-controlled phase III trial evaluating the effectof denosumab in patients receiving adjuvant AItherapy. The primary end point was the percentagechange from baseline in lumbar spine BMD. Patientswith early stage (nonmetastatic), hormone receptor–positivebreast cancer were randomized to eitherdenosumab, 60 mg, or placebo every 6 monthsfor a total of 4 doses while receiving AI therapy. At12 and 24 months, lumbar spine BMD increasedby 5.5% and 7.6%, respectively, in the denosumabgroup compared with placebo (P < .0001). After 24months, the increase in BMD in the total hip, femoralneck, trochanter, and radius was 4.7%, 3.5%,5.9%, and 6.1%, respectively.Management of Bone Healthin Prostate CancerProstate cancer is the most commonly diagnosedmalignancy in American men. Because prostate cancergrowth is driven by androgen hormones, ADT,either by orchiectomy or using GnRH agonists, iscommonly used for treatment. According to theNCCN Clinical Practice Guidelines in Oncology:Prostate Cancer (available at www.nccn.org), longtermADT is used for locally advanced, recurrent,and metastatic prostate cancer. 5 Osteoporosis andgreater fracture risk have emerged as important longtermadverse events in ADT.The term ADT is used because the intendedtherapeutic effect is lower testosterone levels. Becauseestradiol is produced from testosterone byaromatase activity, ADT also reduces estradiol levels.122,123 A compelling body of data suggest that© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


SupplementS-13Bone Health in Cancer Careestradiol has important effects in men. 124 Selectivedeficiency of estradiol, caused by genetic deficiencyof aromatase or inactivation of the ER, produces profoundosteoporosis in the presence of normal testosteronelevels. Estrogen receptors are expressed in osteoclastsand osteoblasts. In population-based studiesof older men, low estradiol levels are associated withlow bone mass and greater fracture incidence. 125 Inthese studies, low estradiol levels are more closelyassociated with fracture incidence than low testosteronelevels.A number of studies have associated ADT withincreased fracture risk. A Medicare claims-basedstudy characterized the relationship between GnRHagonists and risk for clinical fractures. 126 Men (n =10,617) with nonmetastatic prostate cancer werematched for age, race, geographic location, and comorbidity;3887 men were treated with GnRH agonistand 7774 men were not. 126 GnRH agonist usewas associated with a faster time to fracture and asignificantly increased risk for any clinical fracture,hip/femur fractures, and vertebral fractures. Shorttermtreatment did not confer any greater fracturerisk, suggesting reversal of the hypogonadal effectson the bone.Another study used both SEER and Medicare databasesto evaluate the risk of fracture after ADT forprostate cancer. 127 Records of more than 50,000 menwith prostate cancer revealed that the frequency ofany fracture was significantly higher in those receivingADT. The relative risk of the occurrence of anyfracture or one resulting in hospitalization increasedwith increasing doses of GnRH agonist received duringthe first year after diagnosis. Many studies haveshown that GnRH agonist treatment is associatedwith accelerated bone loss. In one prospective analysis,for example, Mittan et al. 128 examined the effectsof GnRH analogue treatment on bone loss and boneresorption in men with prostate cancer comparedwith age-matched control subjects. After 12 monthsof GnRH therapy, a significant decrease was seen inBMD of the total hip and ultra-distal radius in menreceiving GnRH compared with the control group.Similar data on BMD loss in ADT have come fromseveral other clinical trials. 129–132Randomized studies have focused on bisphosphonatetherapy in hypogonadal men with prostatecancer using BMD end points. Intravenous pamidronateand zoledronic acid given once every 3 monthsprevented ADT-induced bone loss in the spine andhip compared with control groups. 133,134 In contrastto pamidronate, zoledronic acid increased BMD.Mean lumbar spine BMD was increased by 5.6% inmen receiving zoledronic acid (n = 42) but decreasedby 2.2% in the placebo group (n = 37). 133A second randomized controlled trial of zoledronicacid evaluated the efficacy of a single annualdose. 135 Mean BMD of the lumbar spine and hipincreased by 4.0% and 0.7%, respectively, in menreceiving zoledronic acid. In contrast, mean BMDdecreased 3.1% and 1.9% in the spine and hip, respectively,with placebo.Yearly dosing of zoledronic acid is effective ingeneral populations with osteoporosis and is FDAapproved. Whether more frequent dosing is indicatedin cancer patients with accelerated bone absorptionremains to be defined. Greenspan et al. 136 haveshown the efficacy of alendronate in preventingBMD loss in patients with nonmetastatic prostatecancer undergoing ADT. In a randomized, doubleblind,placebo-controlled trial in men treated withweekly oral doses of alendronate, BMD increasedover 1 year by 3.7%. Although long-term data onthe impact of bisphosphonates on fracture preventionis not available, these studies provide evidencethat bisphosphonates effectively reduce bone loss inmen receiving ADT. The NCCN Prostate CancerGuidelines (available at www.nccn.org) recommendcalcium and vitamin D supplementation for all patients,and consideration of bisphosphonate therapywith zoledronic acid (4 mg, annually) or alendronate(70 mg orally, weekly) as options in men receivingADT who are at substantial risk for fracture based onstandard risk assessment tools. 5Consistent with the important role of estradiol/ER signaling in bone metabolism in men, severalsmall randomized, controlled trials have shown thatSERMs increase BMD in men undergoing ADT forprostate cancer. In one study, raloxifene increasedBMD of the hip and tended to increase BMD of thelumbar spine. 137 Toremifene, a SERM approved forthe treatment of advanced breast cancer, increasedBMD of the hip and spine in men receiving ADTfor prostate cancer in another trial. 138 Two large randomized,placebo-controlled trials to prevent fracturesduring ADT were recently completed. In onemulticenter study with a primary end point of newvertebral fractures, 1389 men in the United States© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


S-14SupplementNCCN Task Force Reportand Mexico receiving ADT for prostate cancer wererandomly assigned to either toremifene or placebo.Secondary end points included BMD, serum lipids,vasomotor flushing, and breast symptoms. Interimanalyses reported that toremifene significantly increasedBMD of the lumbar spine, total hip, and femoralneck. 138 Toremifene also significantly improvedlipid profiles in men on ADT. 139In a recently completed global study, 1468 menreceiving ADT for prostate cancer were randomlyassigned to either the RANK-L inhibitor, denosumab,subcutaneously every 6 months or placebo. Theprimary study end points were BMD and new fractures.Complete results are expected this year. Twoother large studies to evaluate the role of denosumabfor preventing bone metastases and disease-relatedskeletal complications in men with prostate cancerare ongoing.In conclusion, ADT is associated with significantmorbidity, including osteoporosis and increasedincidence of clinical fractures. Strategies to reducemorbidity include educating patients about risks,encouraging healthy lifestyle modifications, supplementationwith calcium and vitamin D, screeningfor osteoporosis, and drug therapy in appropriateindividuals. The results of recently completed largerandomized controlled trials will help establish evidence-basedguidelines for fracture prevention inprostate cancer survivors.Role of Adjuvant Bisphosphonatesin Reducing RecurrenceBreast CancerPreclinical in vitro studies have shown that bisphosphonatesinhibit the adhesion of breast cancer cellsto extracellular bone matrix, inhibit tumor cell invasion,140–143 and induce apoptosis via the ras pathwayin human breast cancer cells. 144 In an animal study,pretreatment of nude mice with bisphosphonates beforeinoculation of tumor cells reduced the developmentof osteolytic lesions. 145 Taken together, thesestudies suggest that bisphosphonates may inhibitcritical steps in the development of bone metastasesin addition to inhibiting resorption.Three randomized trials in early stage breast cancerinvestigated whether oral clodronate can preventbone metastases and improve survival; 2 of the 3showed a survival benefit. In a large (n = 1069) pla-cebo-controlled trial, breast cancer patients receivingstandard systemic therapies were randomized toreceive oral clodronate (1600 mg, daily) or placebofor 2 years as adjuvant treatment. 146 This trial reporteda reduced risk of bone metastases with clodronateof 51 versus 73 events (HR, 0.69; P = .04) at 5 years,and 19 versus 35 events (HR, 0.55; P = .048) duringthe 2 years on treatment. Survival at 5 years, thepreplanned study end point, favored the clodronategroup with a hazard rate of uncertain significancebecause of multiple analyses (for all patients: HR, =0.77; P = 0.048). The most recent report includessurvival data with long-term follow-up that showed acontinued separation of the survival curves betweenyears 5 and 10. 146In a second smaller, randomized, open-labelstudy, 302 women with breast cancer and micrometastasesdetected in a bone marrow aspirate at diagnosiswere randomized to receive either clodronate(1,600 mg, daily) or no bisphosphonate for 2 years.Additionally, patients received standard adjuvantsystemic therapy. Patients who received clodronatehad a 50% reduction in the incidence of bone metastases(P = .003), and a significantly longer bonemetastasis-free survival (P < .001). Distant metastaseswere detected in 21 of 157 patients (13%)who received clodronate compared with 42 of 145patients (29%) in the control group (P < .001). 147A later analysis at 8.5 years’ follow-up continued toconfirm a significant improvement in overall survivalfor clodronate patients, although the significancein disease-free survival no longer persisted. 148In a third small randomized, open-label study investigating3 years of adjuvant clodronate therapy in299 patients with lymph node-positive breast cancer,the results showed no reduction in bone metastasesin the clodronate-treated arm, although bone as afirst site of relapse was less frequent in the clodronategroup than in the control arm (14% vs. 30%). However,a worrisome increase in visceral metastases andreduction in overall survival at 5 years was seen forpatients receiving clodronate. 149 A possible explanationfor these adverse outcomes is an imbalancein hormone-negative cases between the arms of thestudy, with significantly more PR-negative (45% vs.31%; P = .03) and a trend towards more ER-negative(35% vs. 23%) tumors in the clodronate group. Thisdifference was potentially exacerbated by the practicein this trial of assigning endocrine therapy alone© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


SupplementS-15Bone Health in Cancer Careto all postmenopausal women and chemotherapyalone to all premenopausal women, regardless of ER/PR status. The negative impact of clodronate onoverall survival appears to be neutralized when theimbalance in hormone receptor negativity is corrected.Even without correction, the survival detrimentno longer showed significance at 10 years.A meta-analysis using the 5-year data from these3 adjuvant clodronate trials did not show a statisticallysignificant difference in overall or bone metastasis-freesurvival when the data were pooled. 150 Amarked heterogeneity among the trials in part explainsthe wide confidence interval around the HR(HR, 0.75; 95% CI, 0.31–1.82).A recent study investigating the adjuvant useof zoledronic acid reported an improvement in disease-freesurvival, in addition to favorable effectson BMD. 102 The ABCSG-12 trial enrolled 1,800premenopausal women with ER-positive breast cancer.All patients received ovarian suppression for 3years with a luteinizing hormone-releasing hormoneanalogue, goserelin. Patients were randomized in a2 by 2 design to receive tamoxifen versus anastrozole,and zoledronic acid (4 mg, every 6 months)or not. At the first efficacy analysis, reported after137 events (70 distant relapses) with approximately60 months follow-up, no difference in outcome wasseen with respect to the endocrine therapy randomization.However, the authors found a statisticallysignificant improvement in disease-free survival forpatients who received zoledronic acid (HR, 0.64; P= .01), with a similar trend toward improved overallsurvival (HR, 0.60; P = .10). The absolute benefit indisease-free survival was 3.2%.Although ABCSG-12 clearly provides additionalsupport for the metastasis-suppressing potential ofadjuvant bisphosphonates, this study enrolled onlya narrow subset of breast cancer patients: premenopausalwomen with ER-positive tumors who didnot receive adjuvant chemotherapy. Although theresults are promising, caution must be taken not toover-extrapolate these findings, or this dose schedule,to all breast cancer patients.The Z-FAST and ZO-FAST trials enrolled ERpositivepostmenopausal women receiving letrozoleand randomized them to “upfront” versus “delayed”zoledronic acid therapy (4 mg, every 6 months for5 years) in an attempt to reduce bone loss–relatedmorbidity. 55,119,120 Time to recurrence was a secondaryend point. A recent combined analysis of these trialsshowed lower recurrence rates in the group receivingupfront zoledronic acid therapy (1.1% vs. 2.3%;P = .04). 55Two additional large trials of adjuvant bisphosphonateshave met their targeted accrual goals, withefficacy analysis pending. The National SurgicalAdjuvant Breast and Bowel Project (NSABP) B-34trial (closed to accrual in 2004) enrolled womenwith stage I or II breast cancer and compared 3 yearsof daily oral clodronate (1600 mg, daily) to placebo.The primary end point was disease-free survival. Anotherclinical trial asking “Does Adjuvant ZoledronicAcid Reduce Recurrence in Patients with High-RiskLocalized Breast Cancer?” (AZURE) enrolled stageII and III breast cancer patients, comparing standardadjuvant cancer therapy alone or given with “intensive”zoledronic acid for 5 years (4 mg monthly for 6months, followed by once every 3 months for 2 years,then once every 6 months through year 5). This trialclosed to accrual in 2006.The North American Breast Cancer Intergroup,in combination with the NSABP, is conductingSWOG S0307, a comparison of 3 different bisphosphonatesin the adjuvant breast cancer setting. Thistrial is randomizing 4500 women with stage I or IIIbreast cancer receiving standard adjuvant therapyto oral clodronate (1600 mg, daily) versus oral ibandronate(50 mg, daily) versus zoledronic acid (4 mgintravenously, monthly for 6 months, then every 3months), all for 3 years duration.These unreported trials include all patient andtumor subsets, including both pre- and postmenopausalwomen, ER-positive and -negative tumors,and patients who received a range of standard systemictherapy, including chemotherapy. The resultsof these trials will be critical in determining howbroadly applicable bisphosphonates are across thespectrum of breast cancer patients. Several additionalongoing early stage bisphosphonate trials are evaluatingvarious agents, doses, schedules, and adjuvantsettings, including residual disease after preoperativechemotherapy and in elderly populations.Prostate CancerIn prostate cancer, trials have yet to show any reductionin recurrence or death from the adjuvant use ofbisphosphonates. A randomized controlled trial toevaluate the effects of zoledronic acid on time to firstbone metastasis in men with prostate cancer, no bone© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


S-16SupplementNCCN Task Force Reportmetastases, and rising prostate-specific antigen despiteADT was terminated approximately halfway into accrualwhen interim analysis showed a lower-thanexpectedevent rate. 151 A randomized, double-blind,placebo-controlled trial of oral clodronate versus placeboin patients with nonmetastatic prostate cancerfound no difference in bone metastases–free survivalor overall survival after nearly 10 years of follow-up. 152Several trials evaluating the adjuvant use of osteoclast-targetedtherapy in prostate cancer are ongoing.One of the objectives of the Randomized AndrogenDeprivation and Radiotherapy (RADAR) trial isto determine whether 18 months of zoledronic acidwill reduce relapse risk by impeding the developmentof bony metastases. The ZEUS trial will assess the efficacyof zoledronic acid every 3 months versus bestsupportive care in preventing skeletal metastases inpatients with high-risk prostate cancer. Additionally,the RANK-L inhibitor denosumab is being tested inan ongoing large (1500 patients) international randomized,phase III, placebo-controlled trial in menwith hormone-refractory prostate cancer with the endpoint of bone metastasis–free survival.ConclusionsThe adjuvant bisphosphonate trials in breast cancerreported to date support the potential role of thesedrugs in impacting recurrence and survival in earlystage breast cancer. The data do not yet support theaddition of adjuvant bisphosphonates as standard ofcare for all patients. The promising, yet somewhatcontradictory, results of the 3 reported breast canceradjuvant clodronate studies suggest that bisphosphonatescan impact disease recurrence, but highlightthe need for further investigation. Extrapolation ofthe ABCSG-12 findings to postmenopausal women,ER-negative tumors, and women receiving chemotherapywill require data from ongoing clinical trials.These studies will aid in defining the optimal patientand tumor populations for the addition of adjuvantbisphosphonates, as well as optimal doses andschedules of administration, and long-term toxicities.Whether doses used in metastatic disease are requiredfor prevention or whether lower doses will suffice isunknown. It is unclear whether adjuvant bisphosphonatesshould be given continuously and orally, whetherintravenous therapy is preferable, and whether lessintensive intravenous regimens will be as effective asmore intensive regimens. The optimal duration of adjuvantbisphosphonate therapy is also unknown.Bone MetastasesPathophysiologyNormal bone homeostasis involves constant remodelingby the coordinated actions of osteoclasts and osteoblasts.In metastatic bone disease, as in osteoporosis,this balance is tipped to favor osteoclast-mediatedresorption. The interactions between the tumor andthe bone microenvironment shape the characteristicsof the bone metastases. Metastatic bone diseaseassociated with breast cancer is often predominantlyosteolytic, whereas lesions from prostate cancer arepredominantly osteoblastic on imaging. However,bone metastases are frequently heterogeneous, andhistological examination often shows evidence ofboth osteolytic and osteoblastic features. 153,154At the cellular level, evidence of reciprocalsignaling between the tumor and bone microenvironmentcan be seen. Cancer cells interact with osteoclasts,osteoblasts, and the bone matrix throughmultiple pathways. 155 Tumor cells in the bone microenvironmentmay produce factors such as interleukins,prostaglandins, and PTH–related protein(PTHrP) which directly and indirectly stimulatesbone resorption. Osteolysis releases cytokines andgrowth factors that were stored within the bone matrix,such as transforming growth factor (TGF)-beta,insulin-like growth factor (IGF)-1, and plateletderivedgrowth factor (PDGF). These factors mayinduce tumor cell proliferation, thereby generatinga vicious cycle of tumor growth and bone destruction.155 Understanding the biology of this processhas provided useful insights for developing therapyto prevent or reduce the morbidity of bone metastases.In addition, therapies that specifically target thebone microenvironment are being incorporated intoclinical practice.FrequencyThe frequency of bone metastases varies by cancertype and duration of advanced disease. The incidenceof bone metastases in patients with advanceddisease is 73% in breast, 68% in prostate, 42% inthyroid, 35% in kidney, and 36% in lung cancers.Bone metastases can cause significant morbidity. 156Patients with bone metastases are at risk forskeletal-related events, including fracture, need forradiation to bone, spinal cord compromise, and hypercalcemiaor need for surgery (Figure 3). The riskof experiencing an additional skeletal-related event© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


SupplementS-17Bone Health in Cancer Care60%50%40%52%43%33%37%34%Pathologic fractureRadiation therapySurgical interventionSpinal cord compression34%30%20%25%22%10%0%Breast24 mo11%3%4%Prostate24 mo8%Cancer TypeMultiple myeloma21 moNSCLC + othersolid tumors21 moFigure 3 Prevalence of skeletal-related events in patients with metastatic bone disease not treated with a bisphosphonate.The data are obtained from 4 major trials of placebo versus an intravenous bisphosphonate in different tumor types. 165,166,222,223Abbreviation: NSCLC, non–small cell lung cancer.5%3%5%4%within 1 year of a first event is substantial. In ananalysis performed in the United Kingdom, skeletalrelatedevents accounted for 63% of hospital costsfor patients with metastatic breast cancer. 157 Cancerpatients with bone involvement are at risk forpain, particularly with motion, and the effects ofbone metastases can negatively impact a patient’squality of life.TherapiesIn addressing bone metastases, the mainstay of oncologycare is attempting to control the tumor burden.This is typically addressed through antineoplastictherapies. Bone-specific interventions are oftenincorporated into the treatment plan and may belocalized or systemic. Surgery and radiation therapycan be used to address local control of specific lesions.Bone-directed systemic interventions includebisphosphonates and radiopharmaceutical therapy.Throughout the management of the patient, attentionmust be paid to pain control and minimizing therisk of potentially catastrophic events, such as fractureor spinal cord compromise.Bisphosphonates to Reduce Skeletal MorbidityLarge randomized clinical trials have shown that theaddition of bisphosphonate therapy to standard anticancertherapy can decrease the frequency of skeletal-relatedevents by approximately a third. 158–162Studies have also shown that bisphosphonate therapycan reduce pain and improve quality of life inpatients with bone metastases. 161,163–167 Bisphosphonateshave been incorporated into the routineclinical management of metastatic bone disease in anumber of tumor types. 8,161,168,169 In the Unites States,pamidronate and zoledronic acid are FDA approvedfor treating metastatic bone disease. Clodronate andibandronate are licensed for use in bone metastasesoutside the United States.Treatment of Bone Metastases in Breast CancerIn clinical trials, bisphosphonates have shown treatmentbenefits for breast cancer patients with bonemetastases. Pamidronate reduced the frequency ofskeletal morbidity in placebo-controlled trials involvingbreast cancer patients with bone lesionswho were receiving hormone or chemotherapy. 166The skeletal morbidity rate was 2.4 events per yearin the pamidronate arm and 3.7 in the placebo arm(P < .001). The median time to skeletal complicationwas 12.7 months in the pamidronate group and7 months in the placebo group (P < .001). In thepamidronate arm, 51% had skeletal complications atup to 24 months on treatment, compared with 64%in the placebo arm (P < .001).© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


S-18SupplementNCCN Task Force ReportIn preclinical testing, zoledronic acid appearedto be a more potent bisphosphonate than pamidronate,and clinically it showed superiority over pamidronatein treating hypercalcemia of malignancy. 170A randomized, phase III, multicenter trial was conductedto compare zoledronic acid to pamidronate inpatients with bone lesions secondary to breast canceror multiple myeloma, with the objective of determiningthe safety and efficacy of long-term therapywith these agents. 171 The 13-month core phase ofthe trial showed that zoledronic acid had an efficacyand safety profile comparable with pamidronate. In a25-month extension phase, the overall incidence ofskeletal-related events other than hypercalcemia ofmalignancy was similar between the zoledronic acidand pamidronate groups. The percentage of patientswho required radiotherapy to bone was 19% for zoledronicacid compared with 24% for pamidronate(P = .037). A comparable median time to first eventwas seen in both groups (376 days with zoledronicacid, 356 with pamidronate; P = .151). Zoledronicacid reduced the mean annual incidence of skeletalcomplications, or skeletal morbidity rate, by 25%compared with pamidronate, with 1.04 events peryear for zoledronic acid and 1.39 for pamidronate(P = .084). In the overall patient population, zoledronicacid reduced the risk of developing a skeletalcomplication by an additional 16% compared withpamidronate, with a risk ratio derived from the multiple-eventanalysis of 0.841 (P = .030).A randomized trial in Japan compared zoledronate,4 mg, to placebo every 4 weeks for 1 year in 228women with breast cancer with at least 1 osteolyticbone metastasis. 172 The placebo control was usedbecause no intravenous bisphosphonate is approvedfor this indication in Japan. In this trial, zoledronatereduced the rate of skeletal-related events by 39%(P = .027). The absolute reduction in the number ofpatients having an event was 20% (number neededto treat = 5). In addition, bone pain scores were significantlyimproved within 4 weeks of treatment andremained modestly reduced for 52 weeks. No serious(grade 3 or 4) toxicities or substantial declines in renalfunction were seen. This study corroborates thebenefit of zoledronate in reducing skeletal-relatedevents seen in previous studies.The ASCO clinical practice guidelines forbreast cancer suggest that patients in whom radiographicevidence of bone metastases exist should re-ceive therapy with either zoledronic acid, 4 mg over15 minutes, or pamidronate, 90 mg delivered over 2hours, both every 3 to 4 weeks. 8 Currently evidenceis insufficient to support superiority of one over theother, and, in countries where they are approved, clodronateor ibandronate are also therapeutic options.Due to increasing concerns over potential bisphosphonate-associatedtoxicities, all women shouldundergo dental examination with appropriate preventivedental care before starting bisphosphonatetherapy. Serum creatinine also should be monitoredbefore each dose of pamidronate or zoledronate.The optimal duration of bisphosphonate therapyhas not been well defined. The longest phase III clinicaltrials in patients with bone metastases examineda 3 to 4 week dosing of bisphosphonates for only 2years. Little data is available beyond 2 years of treatment.The unknown potential additional benefitfrom continuing bisphosphonates must be weighedagainst the potential toxicities of long-term administration.The ASCO bisphosphonate guidelines forbreast cancer recommend continuing bisphosphonatetherapy indefinitely or until the patient’s performancestatus declines substantially. The consensusof the NCCN Task Force is that continuation ofbisphosphonate therapy should be reconsidered at 2years. Continued bisphosphonate treatment shouldbe considered in patients with active cancer or anexisting focus of bone metastasis. Discontinuationshould be considered for patients with no active diseaseor who have experienced significant deteriorationof renal function. The presence of bisphosphonate-associatedONJ or sub-trochanteric hip fractureis not necessarily an indication for discontinuation.If a clear indication was seen for starting therapy(bone metastasis or active cancer known to metastasizeto bone) and those indications continue to exist,continued therapy may be appropriate. The developmentof low-frequency significant side effects shouldnot detract from the overall usefulness of the agents.If bisphosphonates are discontinued, an active bonesurveillance program should be initiated.The optimal dosing interval of bisphosphonatetherapy in bone metastases is also unknown. No dataare available to support lengthening intervals betweentreatments, although this is the subject of importantongoing investigations. The ongoing OPTI-MIZE 2 trial is studying breast cancer patients withbone metastases who received approximately 1 year© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


SupplementS-19Bone Health in Cancer Careof monthly zoledronic acid. Patients are randomizedin a double-blind fashion to continue monthly dosingfor an additional year versus changing dosing intervalsto every 3 months. The ongoing BISMARKtrial is a randomization between standard dosing—once every 4 weeks—of zoledronic acid and intervalsbased on markers of bone turnover, which areevaluated at 15- to 16-week intervals. For patientswith low bone turnover at the time of the markerevaluation, 1 dose of zoledronic acid is given every15 or 16 weeks. For patients with intermediate markersof bone turnover, 2 doses are given in this timeframe. For patients with high levels of bone turnover,one dose every 4 weeks is given. This protocoltherefore allows for changes in the dosing interval ofzoledronic acid based on current bone activity. TheCALGB 70604 trial randomizes patients with metastaticbreast or prostate cancer or multiple myelomainvolving the bone to receive zoledronic acid, 4 mgevery 4 or 12 weeks, and will investigate the rate ofSREs between the groups over 2 years.Pamidronate and zoledronic acid are FDA approvedfor use in patients with metastatic bone diseaseand have been shown to be efficacious in reducingor delaying the onset of skeletal-related eventsin patients with breast and solid tumors with documentedbone metastases. Bisphosphonates are effectivein reducing bone pain and improving qualityof life. Currently, questions remain on how to optimallyuse bisphosphonates. Ongoing clinical trialswill help identify optimal dosing schedules, duration,and the role of other novel agents in the treatmentof bone metastases.Treatment Bone Metastases in Prostate CancerAn estimated 65% to 75% of patients diagnosedwith advanced prostate cancer experience a skeletalrelatedevent. Their median 5-year survival is 25%,and almost all patients who die of prostate cancerhave skeletal involvement. 157Almost all men diagnosed with metastatic diseaseare initially offered hormonal therapy, and almostall show response to the treatment. Significantimprovement in pain relief, a decline in prostatespecificantigen levels, and improvement in qualityof life are seen. Unfortunately, in most cases, thedisease relapses after a median response of about 2years. Unlike in breast cancer, only 3 chemotherapydrugs have been approved for patients with prostatecancer. The NCCN Prostate Cancer Guidelines(available at www.nccn.org) recommend docetaxeladministered every 3 weeks in combination withprednisone as preferred first-line treatment for castration-recurrentdisseminated prostate cancer. 5 Alternateregimens included in these NCCN Guidelinesinclude 3-week docetaxel with estramustine,weekly docetaxel with prednisone, or mitoxantronewith prednisone.Bisphosphonates have been shown to be effectivein reducing bone complications in patientswith osteolytic bone metastases caused by a varietyof solid tumors. Because prostate cancer is primarilyosteoblastic, researchers initially thought thatbisphosphonates may not be as effective in thisdisease. However, studies have revealed that boneresorption in metastatic prostate cancer is high, reflectingsubstantial osteoclastic activity. Therefore,biologic rationale exists for the use of bisphosphonatesin prostate cancer.Effectiveness of clodronate treatment was evaluatedin symptomatic bone progression-free survivalin 2 studies. 173,174 In the first, 311 men with hormonesensitivemetastatic prostate cancer were randomlyassigned to receive oral clodronate or placebo for 3years. 173 The second trial used clodronate in conjunctionwith mitoxantrone and prednisone versusmitoxantrone and prednisone alone. 174 Clodronatetreatments resulted in no pain relief or improvementin quality of life in both studies.Similarly, a randomized placebo-controlledstudy of pamidronate (90 mg every 3 weeks) versusplacebo in 378 metastatic prostate cancer patientsfound no differences in pain control or reductionof skeletal-related events. 175 Zoledronic acid is theonly bisphosphonate with proven clinical benefitin reducing skeletal complications in patients withhormone-refractory prostate cancer. In a doubleblindphase III trial, patients with hormone-refractorydisease (rising prostate-specific antigen despitemedical or surgical castration) and a history of bonemetastases were randomized to zoledronic acid, 4mg (n = 214), zoledronic acid, 8 mg (n = 221), orplacebo (n = 208) every 3 weeks for 15 months. 176The primary end point was time to occurrence ofskeletal-related events. Risk of renal impairment waselevated with the 8-mg dose, and medication for thisarm was therefore reduced to 4 mg. Patients takingplacebo had significantly more events than those onzoledronic acid (44.2% vs. 33.2%; P = .021). Subse-© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


S-20SupplementNCCN Task Force Reportquently, of 122 patients who completed 24 monthson the study, fewer patients treated with zoledronicacid developed skeletal complications (38% vs. 49%for the placebo group; P = .028). 167 The delay in onsetto the first skeletal-related event was about 31%longer for those on zoledronic acid. Overall, the authorsnoted a decrease in fracture, spinal cord compression,need for antineoplastic therapy, and needfor radiation and surgery in patients receiving zoledronicacid compared with placebo.In conclusion, the main risk factor for skeletalcomplications is the presence of bone metastases inpatients with hormone-refractory prostate cancer.These patients should be considered for bisphosphonatetherapy. As with other tumors, insufficientdata are available to guide choice, dose, and route ofadministration of bisphosphonates in prostate cancerpatients. Bisphosphonates have no proven rolein hormone-naïve patients with advanced prostatecancer; currently, hormone therapy adequately controlsunderlying disease in this setting. Research intothe earlier use of bisphosphonates in these patientsis ongoing. 177 A phase III trial is currently recruitingpatients with hormone-refractory prostate cancer tocompare time to development of a skeletal event onzoledronic acid versus denosumab. 178 Better understandingof the role of bisphosphonates and othernovel bone-targeting agents in treatment-relatedbone loss, prevention and treatment of metastases,and antitumor effects, will probably expand the rolethey play in managing advanced prostate cancer.Investigational Targets for Treatment of BoneComplicationsNew classes of agents with anti-osteoclastic activityare in various stages of investigation for treatingand preventing bone metastases and osteoporosis.These include the RANK-L inhibitor, denosumab,the Src kinase inhibitor, dasatinib, and several versionsof cathepsin k inhibitors. The relative efficacyand toxicity profiles of these agents compared withbisphosphonates will be of great interest. Whetherthese agents will be optimally used as an alternativefor or in combination or sequence with bisphosphonatesremains to be studied.RANK-L: RANK-L mediates the formation, function,and survival of osteoclasts. Denosumab, themonoclonal antibody that binds and neutralizesRANK-L, has been evaluated in phase II studies inpatients with bone metastases naïve to intravenousbisphosphonate therapy and those with elevatedlevels of the bone resorption marker urinary-N-telopeptidedespite ongoing intravenous bisphosphonatetreatment. 179,180 Denosumab was well tolerated, withstrong suppression of bone-resorption markers. PhaseIII clinical trials are ongoing comparing denosumabto zoledronic acid in the treatment of bone metastasesin patients who have not previously receivedintravenous bisphosphonates.Src: Src is involved in signaling cascades importantfor receptor-mediated osteoclast formation and function,including RANK. Preclinical data show thatSrc plays a role promoting bone metastases. Therefore,inhibition of Src could have negative effects notonly on osteoclast activity, but also on tumor cellsthat invade bone and promote osteoclast activity.Src inhibitors represent potential novel therapeuticsfor bone metastases and are currently under investigationin patients with metastatic bone disease.Dasatinib is approved by the FDA for treatment ofimatinib-resistant or intolerant chronic myeloid leukemiaand Philadelphia chromosome–positive acutelymphoblastic leukemia. It is currently being evaluatedin clinical trials for patients with metastaticbone disease from solid tumors. 181–183Cathepsin K: Cathepsin K is a cysteine proteaseproduced by osteoclasts. It mediates bone resorptionand degradation. 184 Cathepsin K is also produced bycancer cells and helps promote cancer cell invasion.Preclinical studies have shown that inhibitors of cathepsinK can reduce osteolysis and skeletal tumorburden by breast cancer cells. 185 Odonacatib, a cathepsinK inhibitor, is currently in clinical trial. 186Imaging of Bone MetastasesNumerous imaging techniques are available to evaluatebone metastases, including plain film radiography,CT, MRI, 99m Tc bone scanning (radionuclidebone scan), and PET, both with fluorodeoxyglucose(FDG) and 18 F sodium fluoride. Imaging has an importantrole in detection, diagnosis, treatment planning,and follow-up of bone metastases. The resultsof imaging studies must be interpreted within clinicalcontext. If bone metastases are present or suspected,imaging or biopsy may be required to confirm the diagnosisand establish the extent of disease. Responseto therapy can be evaluated using radiographs (plainfilms) and by correlating the radiographic changes© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


SupplementS-21Bone Health in Cancer Carewith bone scan, clinical, and laboratory findings.Plain film radiography, the oldest imaging techniquefor evaluating bone metastases, recognizesalterations in bone density, such as osteolytic andosteoblastic changes. In case of indeterminate bonescan findings, plain film may be helpful in furthercharacterizing a suspicious lesion. Plain films mayalso be helpful in detecting the cause of bone pain.Plain films can assess cortical destruction by the cancer,providing valuable information regarding fracturerisk. Unfortunately, plain films are relatively insensitivein the detection of early or small metastaticlesions. A 30% to 50% loss in bone density must occurto recognize an osteolytic lesion on plain film.CT, like plain films, is a map of bone density,with tomographic capability. Compared with plainfilms, CT has an improved target-to-backgroundratio and improved sensitivity. Muindi et al. 187 andDurning et al. 188 found that CT is more sensitivethan plain film radiography in detecting metastaticlesions. CT is used to assess lesion size and corticalreaction and can also identify alterations in adjacentsoft tissue. As with plain films, CT is useful forcharacterizing suspicious lesions on bone scans. Theusefulness of CT in detecting early involvement ofthe bone marrow, however, is limited. In addition,skeletal coverage is limited with CT because of itsrelatively high radiation dose, making it unsuitableas a screening tool.MRI is associated with a high sensitivity (82%–100%) and specificity (73%–100%) for bone marrowmetastases. Unlike CT and plain film, MRI does notassess bone density, but is helpful in assessing tissuealterations. Therefore, MRI can detect metastasesthat have infiltrated bone marrow 189 before they provokean osseous bone response. MRI is more sensitivefor detecting early lesions and marrow-basedmetastases than plain films, CT, or radionuclidebone scans. Although MRI is a good choice for detectingmarrow infiltration, its role in bone metastasesis generally limited because it is more expensiveand not as readily available as CT.Skeletal scintigraphy (bone scan) is an effectivemethod for screening the whole body for bone metastases.190 99m Tc-methylene diphosphonate (MDP),is the most frequently used radiotracer. Becausetechnetium-labeled MDP is taken up by active osteoblasts,99m Tc-planar bone scans detect metastatictumor deposits in bone by the increased osteoblasticactivity they induce. Radionuclide bone scansare relatively insensitive for purely osteolytic lesionsfound commonly in cancers of the kidney and thyroidand multiple myeloma, but they are highly sensitiveto osteoblastic and mixed osteolytic-osteoblasticlesions such as from prostate and breast cancer. Bonescans have the disadvantages of poor spatial and contrastresolution.Sensitivity of 99m Tc bone scan is estimated atbetween 62% and 100%, with the lowest sensitivityseen in patients with predominantly lytic disease.Many benign processes and other entities (i.e.,trauma fractures, Paget disease) can produce an areaof increased radiotracer uptake that mimics a metastaticdeposit. Bone scans are not optimal for monitoringresponse to treatment, because the osteoblastchanges induced by cancer metastases can be longlived.Osteoblastic activity resulting from healingafter therapy (i.e., flare phenomenon) may misleadinglysuggest advancing disease on bone scans. Inmany patients, further imaging, such as plain filmsor CT, is required.PET can help in identifying bone metastasesat an early stage of growth, before host response ofthe osteoblasts occur. It has higher spatial resolutionthan bone scan and a quantitative capability.Therefore, PET can better assess response to therapy.Two currently available PET tracers are 18 F sodiumfluoride and 18 F FDG. 18 F sodium fluoride is taken upby osteoblasts and therefore is reflective of a reparativeresponse, making fluoride PET scans similar to99mTc bone scan. 18 F fluoride gets incorporated intonewly formed bone in increased amounts, reflectingincreased turnover. 18 F sodium fluoride PET hasimproved lesion detection over technecium bonescans. However, finding additional lesions may notnecessarily alter therapy.18F FDG-PET can detect early malignant bonemarrowinfiltration because of the early increasedglucose metabolism in neoplastic cells. 191 Unlike99mTc-MDP bone scans and 18 F sodium fluoride PETbone scans, 18 F FDG-PET directly assesses the metabolicactivity of the metastatic tissue rather thanthe bony response to the presence of the metastasis.Therefore, FDG-PET can be helpful in detectingpurely osteolytic lesions and marrow infiltration, butit may not be helpful for osteoblastic lesions with relativelylow metabolic activity. Consequently, lesionspresent on MRI or PET may not be visible on bone© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


SupplementS-23Bone Health in Cancer Carefully treated patients may appear to be progressivedisease on MRI or PET. For evaluation of impendingfracture and the need for surgical intervention, plainfilms and CT scans provide the best information. Resultsof imaging studies must be interpreted withinthe clinical context of the individual patient.Surgical and Radiation Treatment ofBone MetastasesComplications caused by bone metastases, includingpain, fractures, and decreased mobility, can affectquality of life and reduce a patient’s performance status.Localized therapies, including radiation and surgery,can be used for preventing impending events, aswell as for palliation.Radiation TreatmentRadiation therapy is commonly used in the managementof bone metastases, both for pain relief andprevention of morbidity and disease progression. Radiationtherapy has shown responses rates of 60% to70%. Complete pain relief may occur in 20% to 30%of patients receiving radiotherapy. 196,197 However, inmany patients, the effects may not be felt for severalweeks after treatment starts and relief may last only3 to 4 months.External Beam Radiation Therapy: External beamradiation therapy is widely used for cancer patientswho present with localized bone pain. The optimaltreatment schedule—single versus multiple fraction—is under debate. A systematic review of published trialsshow no difference between single and multiplefraction in terms of efficacy and toxicity, although aslightly higher re-treatment rate has been seen withsingle fraction. The Radiation Therapy and OncologyGroup (RTOG) conducted one of the largest trials inthe United States to study effects of single versus multiplefractions of external beam radiation therapy intreating bone metastases in breast and prostate cancerpatients. 198 Patients (n = 898) were randomized to asingle 8-Gy fraction or 30 Gy given in 10 fractions.No significant difference in response rates were seenbetween the 2 arms, although a significantly higher retreatmentrate was seen in the single-fraction arm. Inthe RTOG trial, more acute toxicity (grades 2-4) wasseen in the multiple fraction arm compared with thesingle-fraction arm. 198 The higher re-treatment ratewith single fraction treatment may be attributed tothe bias that giving additional doses of radiation mayhelp patients who not have experienced relief from asingle dose. A cost-utility analysis performed in theNetherlands compared 2-year quality-adjusted life expectanciesand 12-week societal costs. 199 Total societalcosts for radiation therapy (including re-treatments,non-medical costs, and non-radiation treatment costs)were estimated at $4700 and $6453 for single fractionsand multiple fractions, respectively. Despite multiplestudies indicating no difference in response rate, durationof response, use of pain medication, side-effects,or quality of life, radiation oncologists in the UnitedStates appear to be reluctant to deliver single-fractionradiation for uncomplicated bone metastases. 200Stereotactic Body Radiation Therapy: Stereotacticbody radiation therapy was initially developed fortargeting lung lesions and is now being used to treatspine metastases. Although conventional radiationtherapy of spinal metastatic tumors is useful for palliation,its effectiveness is limited by spinal cord tolerance.In patients with spinal metastases not causingcord compression, stereotactic radiation can be usedto overcome some of the dose limitation associatedwith conventional radiotherapy. It can also be usedfor patients who have a good prognosis and for whommore aggressive treatment may be warranted. Thistechnique is characterized by high-dose radiationdelivered precisely to an extracranial target in 1 to 5fractions. Researchers have found response rates arearound 90% and duration of 13 months, with little tono long-term toxicity. Re-treatment rates range from0% to 15%. 201 This technique is relatively technicallysophisticated and costly but allows better sparingof adjacent critical normal structures.Radioisotopes: When symptomatic bone metastasesare widespread and present on both sides of the diaphragm,radionuclides can be useful. Radionuclidetherapy using strontium-89 chloride, samarium-153,rhenium-186, and rhenium-188 treatments have resultedin palliation of bone pain and improvementin quality of life in patients with advanced hormonerefractoryprostate cancer. 202–208 These radionuclideslocalize to regions of enhanced bone turnover anddeliver high local doses of radiation through theemission of beta particles. Patients with diffuse multifocaldisease are good candidates for systemic radioisotopetherapy.Surgical TreatmentSurgical management of bone metastasis is performedto relieve pain, provide stabilization, and prevent© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


S-24SupplementNCCN Task Force Reportimpending fracture or spinal cord compression. Insome situations, surgery provides a greater likelihoodof return to ambulatory status than radiation alone.Although surgical treatment of pathologic fracturesis often straightforward, treatment of patientswith impending pathologic fractures is preferable.Compared with treatment of fractures of the femur,treatment of impending fractures is associated with ashorter hospital stay, a greater likelihood of dischargeto home versus extended care, and a greater likelihoodof support-free ambulation. 209 The widespreaduse of bisphosphonate therapy has resulted in a decreasein the incidence of fracture due to bone metastases.Identification of bones at risk remains a “movingtarget” in the face of better anti-cancer therapies.Surgeons identify lesions at high-risk for fracturebased on general criteria. These include lytic lesionsgreater than 2.5 cm in diameter, encompassing morethan 50% of the bone diameter, or the presence oflesser trochanter avulsion. Other indications forsurgery for impending fractures include a lesion in aweight-bearing area and a readily identifiable painfullesion that is refractory to external beam radiationtherapy. Verifying that the lesion is the sourceof pain is important.These general guidelines must also be interpretedin the specific clinical context. Fracture stabilizationmust be preceded by an assessment of metastaticdisease in other bones, which could compromiserehabilitation. When considering stabilization of afemoral fracture, a long bone survey or a bone scanwithin 2 to 3 months is recommended to detect othersites of disease that may relate to weight bearing.Differentiating pathologic fractures from traumaticfractures clinically is also important. Preoperativeassessment should include estimation of life expectancy,mental status, mobility status, pain level, metabolicstatus, skin condition, and nutritional status.From a technical standpoint, one of the easiestbones to stabilize is the proximal femoral shaft; stabilizationis more challenging in the pelvis-acetabulum,spine, and periarticular areas. For a periarticular fracture,prosthetic replacement confers fairly predictablepain relief and a return to ambulatory status.Procedures that are applicable to nonmetastatic traumaticfractures often do not apply in the setting ofpathologic fractures. For example, a sliding hip screwis commonly used in patients with intertrochantericosteoporotic fractures. However, these devices arenot effective in patients with pathologic fractures,because of the lack of bone healing, particularly withplanned subsequent bone radiation.Fractures within the femoral diaphysis can bestabilized using intramedullary nailing. Some of theinterlocking capabilities of plates and nails have increasedover the past 3 years with new locking platetechnology. Insertion of intramedullary nails is arelatively straightforward procedure that requiresgeneral or regional anesthesia and a hospital stayof about 2 days. Humeral shaft metastases are oftentreated with locked intramedullary nailing or, morerecently, an inflatable nail, with excellent pain reliefand regained use of the extremity in several days. 210,211Case series of patients treated with intramedullarynailing have reported good outcomes, with completepain relief and resumption of ambulation in a largeproportion of patients. However, these outcomes aremay be related to patient selection criteria. 212,213Stabilization of acetabular disease is technicallychallenging but can generally be done with a variationof hip replacement. Marco et al. 214 reported ona case series of 55 patients who were treated withcurettage of the tumor, protrusio cup, cement, andpin or screw fixation. Although 76% of patients hada decrease in narcotic usage and half of the nonambulatorypatients regained the ability to walk, thisprocedure has been associated with a 22% complicationrate. Saddle prosthesis is another option; a caseseries of 20 patients showed a similar improvementin analgesia, independence, and ambulation. Again,however, the complication rate was high at 20%. 215This high morbidity underscores the importance ofpatient selection for extensive surgery.Additional Minimally Invasive Techniques: A varietyof minimally invasive techniques are available,including radiofrequency ablation, percutaneous osteoplasty,also referred to as cementoplasty, percutaneousvertebroplasty, and kyphoplasty.Radiofrequency ablation uses thermal energy todestroy tumor cells and has been used to treat painfulbony metastases. Goetz et al. 216 reported on a multicenterprospective study of radiofrequency ablationin which 43 patients with painful bone metastases,the majority of whom had undergone prior radiationtherapy, had significant pain relief and reduction inopioid use with minimal side effects.Percutaneous vertebroplasty and kyphoplastyare the injection of surgical cement, usually poly-© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


SupplementS-25Bone Health in Cancer Caremethylmethacrylate, into fractured vertebral bodies.Kyphoplasty uses a bone tamp that is inflated beforethe procedure to create a space for injection of polymethylmethacrylate.Kyphoplasty may result in anincrease in vertebral height, which may provide abiomechanical advantage over vertebroplasty. Thatthis technique is effective for pain reduction in bothmetastatic disease and osteoporosis seems clear, althoughthe mechanism of the effect remains unclear.This technique is growing in popularity; however,published outcomes for the treatment of metastaticdisease are still minimal. Fourney et al. 217 describeda case series of 97 procedures in 56 patients.A total of 84% of patients had marked or completepain relief. These results appear comparable to thelarger volume of literature on kyphoplasty as a treatmentof osteoporosis-related vertebral fractures. 218Cementoplasty is the percutaneous injection ofpolymethylmethacrylate into a metastatic lesion topalliate pain. 219 This technique is similar to vertebroplasty.The difference is that it is performed inareas other than the spine and uses 3-dimensionalimaging, most commonly CT. This technique is mostsuited to the pelvis.Image-guided cryoablation is a relatively newminimally invasive technique. Similar to radiofrquencyablation, the metastatic lesions are accessedpercutaneously. Cryoprobes are introduced underanesthesia. As the argon gas released from the probesrapidly expands, it produces rapid cooling with temperaturesclose to −100°C, leading to intracellularice ball formation, dehydration, and cell death.Callstrom et al. 220 reported on 14 patients with bonemetastases treated with image-guided cryoablation.Improvement in pain, decrease in pain interferencewith activities of daily living, and noted reductionsin narcotic use were seen using this therapy.In conclusion, advances in surgery provide anumber of techniques for treating bone pain frommetastases. The key to surgical management remainsidentifying patients with impending fractures and referringthem for stabilization before fracture occurs.ConclusionsBone health is an increasingly critical issue for allcancer patients and their health care providers.Evaluation and treatment of cancer treatmentrelatedbone loss should be incorporated into comprehensivecancer care. Strategies to reduce morbidityinclude educating patients about fracture risk,encouraging healthy lifestyle modifications, providingsupplementation with calcium and vitamin D,screening for osteoporosis, and starting drug therapyas clinically indicated. BMD combined with clinicalrisk factors for fracture determined using the FRAXcalculator, provides a better estimation of fracturerisk than BMD or clinical risk factors alone.In patients with documented bone metastases,treatment and monitoring should involve a multidisciplinaryapproach that includes systemic anticancertherapy, osteoclast-targeted therapy, pain control,imaging studies, and surgery and radiation therapyif indicated. In breast cancer, emerging data suggeststhat bisphosphonates may impact recurrencein early stage breast cancer in addition to impactingbone density.References1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CACancer J Clin 2008;58:71–96.2. Coleman RE. 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Smith MR, McGovern FJ, Zeitman AL, et al. Pamidronateto prevent bone loss during androgen-deprivation therapy forprostate cancer. N Engl J Med 2001;345:948–955.48. Tauchmanova L, Colao A, Lombardi G, et al. Bone loss and itsmanagement in long-term survivors from allogeneic stem celltransplantation. J Clin Endocrinol Metab 2007;92:4536–4545.49. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefitsof estrogen plus progestin in healthy postmenopausal women:© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


SupplementS-27Bone Health in Cancer Careprincipal results from the Women’s Health Initiative randomizedcontrolled trial. JAMA 2002;288:321–333.50. Khan MN, Khan AA. Cancer treatment-related bone loss: areview and synthesis of the literature. Curr Oncol 2008;15:S30–40.51. Chang JT, Green L, Beitz J. Renal failure with the use of zoledronicacid. N Engl J Med 2003;349:1676–1679.52. Van Poznak C, Estilo C. Osteonecrosis of the jaw in cancerpatients receiving IV bisphosphonates. Oncology (WillistonPark) 2006;20:1053–1062.53. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associatedosteonecrosis of the jaw: report of a task force of the AmericanSociety for Bone and Mineral Research. J Bone Miner Res2007;22:1479–1491.54. Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review:bisphosphonates and osteonecrosis of the jaws. Ann Intern Med2006;144:753–761.55. Brufsky A, Bundred N, Coleman R, et al. 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S-28SupplementNCCN Task Force ReportBone and Mineral Research 30th Annual Meeting; September12–16, 2008; Montreal, Quebec, Canada. Abstract 138.81. Chesnut CH III, Bell NH, Clark GS, et al. Hormone replacementtherapy in postmenopausal women: urinary N-telopeptide of typeI collagen monitors therapeutic effect and predicts response ofbone mineral density. Am J Med 1997;102:29–37.82. Ravn P, Clemmesen B, Christiansen C. Biochemical markers canpredict the response in bone mass during alendronate treatmentin early postmenopausal women. Alendronate OsteoporosisPrevention Study Group. Bone 1999;24:237–244.83. Tonino RP, Meunier PJ, Emkey R, et al. Skeletal benefits ofalendronate: 7-year treatment of postmenopausal osteoporoticwomen. Phase III Osteoporosis Treatment Study Group. J ClinEndocrinol Metab 2000;85:3109–3115.84. Black DM, Schwartz AV, Ensrud KE, et al. 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SupplementS-29Bone Health in Cancer Care115. Coleman RE. Effect of anastrozole on bone mineral density: 5-yearresults from the ‘Arimidex’, Tamoxifen, Alone or in Combination(ATAC) trial [abstract]. J Clin Oncol 2006;24(Suppl 1):5s.Abstract 511.116. Van Poznak C, Hannon RA, Clack G, et al. The SABREstudy: effects of risedronate on bone mineral density and bonemetabolism in postmenopausal women using anastrozole asadjuvant therapy for hormone receptor-positive early stagebreast cancer—first results [abstract]. Breast Cancer Res Treat2006;100(Suppl 1):Abstract 4061.117. Van Poznak C, Hannon R, Clack G, et al. Managing cancertreatment-induced bone loss: 24-month results from the Study ofAnastrozole with the Bisphosphonate RisedronatE (SABRE). SanAntonio Breast Cancer symposium, Abstract 1137.118. Lester JE, Gutcher SA, Ellis S, et al. 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SupplementS-31Bone Health in Cancer Careclinicaltrial.gov/ct2/show/NCT00237146?term=hormone+naive+prostate+cancer&rank=4. Accessed May 2009.178. ClinicalTrials.gov. Double-blind study of denosumab comparedwith zoledronic acid in the treatment of bone metastases in menwith hormone-refractory prostate cancer. Available at: http://www.clinicaltrial.gov/ct2/show/NCT00321620?term=denosumab+and+prostate+cancer&rank=2. Accessed May 2009.179. Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trialof denosumab in patients with bone metastases from prostatecancer, breast cancer, or other neoplasms after intravenousbisphosphonates. J Clin Oncol 2009;27:1564–1571.180. Lipton A, Steger GG, Figueroa J, et al. Randomized activecontrolledphase II study of denosumab efficacy and safety inpatients with breast cancer-related bone metastases. J Clin Oncol2007;25:4431–4437.181. ClinicalTrials.gov. Dasatinib in treating patients with stage IVbreast cancer that has spread to the bone. 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Whole-body MRimaging for detection of bone metastases in children and youngadults: comparison with skeletal scintigraphy and FDG PET. AmJ Roentgenol 2001;177:229–236.193. Ohta M, Tokuda Y, Suzuki Y, et al. Whole body PET for theevaluation of bony metastases in patients with breast cancer:comparison with 99Tcm-MDP bone scintigraphy. Nucl MedCommun 2001;22:875–879.194. Kao CH, Hsieh JF, Tsai SC, et al. Comparison and discrepancyof 18F-2-deoxyglucose positron emission tomography and Tc-99m MDP bone scan to detect bone metastases. Anticancer Res2000;20:2189–2192.195. Hamaoka T, Madewell JE, Podoloff DA, et al. Bone imaging inmetastatic breast cancer. J Clin Oncol 2004;22:2942–2953.196. Chow E, Harris K, Fan G, et al. Palliative radiotherapy trials forbone metastases: a systematic review. J Clin Oncol 2007;25:1423–1436.197. Wu JS, Wong R, Johnston M, et al. Meta-analysis of dosefractionationradiotherapy trials for the palliation of painful bonemetastases. Int J Radiat Oncol Biol Phys 2003;55:594–605.198. Hartsell WF, Scott CB, Bruner DW, et al. Randomized trial ofshort- versus long-course radiotherapy for palliation of painfulbone metastases. J Natl Cancer Inst 2005;97:798–804.199. van den Hout WB, van der Linden YM, Steenland E, et al. Singleversusmultiple-fraction radiotherapy in patients with painfulbone metastases: cost-utility analysis based on a randomized trial.J Natl Cancer Inst 2003;95:222–229.200. Bradley NM, Husted J, Sey MS, et al. Review of patterns of practiceand patients’ preferences in the treatment of bone metastases withpalliative radiotherapy. Support Care Cancer 2007;15:373–385.201. Gerszten PC, Burton SA, Welch WC, et al. Single-fractionradiosurgery for the treatment of spinal breast metastases. Cancer2005;104:2244–2254.202. Quilty PM, Kirk D, Bolger JJ, et al. A comparison of the palliativeeffects of strontium-89 and external beam radiotherapy inmetastatic prostate cancer. Radiother Oncol 1994;31:33–40.203. Porter AT, McEwan AJB, Powe JE, et al. Results of a randomizedphase III trial to evaluate the efficacy of strontium-89 adjuvantto local field external beam irradiation in the management ofendocrine resistant metastatic prostate cancer. Int J Radiat OncolBiol Phys 1993;25:805–813.204. Robinson RG. Strontium-89-precursor targeted therapy for painrelief of blastic metastatic disease. Cancer 1993;72:3433–3435.205. Sartor O, Reid RH, Hoskin PJ, et al. Samarium-153-Lexidronamcomplex for treatment of painful bone metastases in hormonerefractoryprostate cancer. Urology 2004;63:940–945.206. Maxon HR, Schroder LE, Hertzberg VS, et al. Rhenium-186(Sn)-HEDP for treatment of painful osseous metastases: results of adouble blind crossover comparison with placebo. J Nucl Med1991;32:1877–1881.207. Palmedo H, Manka-Waluch A, Albers P, et al. Repeated bonetargetedtherapy for hormone-refractory prostate carcinoma: randomizedphase II trial with the new, high-energy radiopharmaceuticalrhenium-188 hydroxyethylidenediphosphonate. J ClinOncol 2003;21:2869–2875.208. Tu S, Millikan RE, Mengistu B, et al. Bone targeted therapy foradvanced androgen-independent carcinoma of the prostate: arandomised phase II trial. Lancet 2001;357:336–341.209. Ward WG, Holsenbeck S, Dorey FJ, et al. Metastatic disease ofthe femur: surgical treatment. Clin Orthop Relat Res 2003:S230–244.210. Redmond BJ, Biermann JS, Blasier RB. Interlockingintramedullary nailing of pathological fractures of the shaft of thehumerus. J Bone Joint Surg Am 1996;78A:891–896.211. Franck WM, Olivieri M, Jannasch O, Hennig FF. An expandablenailing system for the management of pathological humerusfractures. Arch Orthop Trauma Surg 2002;122:400–405.© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


S-32SupplementNCCN Task Force Report212. Samsani SR, Panikkar V, Venu KM, et al. Breast cancer bonemetastasis in femur: surgical considerations and reconstructionwith Long Gamma Nail. Eur J Surg Oncol 2004;30:993–997.213. Moholkar K, Mohan R, Grigoris P. The Long Gamma Nail forstabilisation of existing and impending pathological fractures ofthe femur: an analysis of 48 cases. Acta Orthop Belg 2004;70:429–434.214. Marco RA, Sheth DS, Boland PJ, et al. Functional and oncologicaloutcome of acetabular reconstruction for the treatment ofmetastatic disease. J Bone Joint Surg Am 2000;82:642–651.215. Benevenia J, Cyran FP, Biermann JS, et al. Treatment of advancedmetastatic lesions of the acetabulum using the saddle prosthesis.Clin Orthop Relat Res 2004:23–31.216. Goetz MP, Callstrom MR, Charboneau JW, et al. Percutaneousimage-guided radiofrequency ablation of painful metastasesinvolving bone: a multicenter study. J Clin Oncol 2004;22:300–306.217. Fourney DR, Schomer DF, Nader R, et al. Percutaneousvertebroplasty and kyphoplasty for painful vertebral body fracturesin cancer patients. J Neurosurg 2003;98:21–30.218. Lane JM, Hong R, Koob J, et al. Kyphoplasty enhances functionand structural alignment in multiple myeloma. Clin Orthop RelatRes 2004;426:49–53.219. Kelekis A, Lovblad KO, Mehdizade A, et al. Pelvic osteoplastyin osteolytic metastases: technical approach under fluoroscopicguidance and early clinical results. J Vasc Interv Radiol2005;16:81–88.220. Callstrom MR, Charboneau JW, Goetz MP, et al. Image-guidedablation of painful metastatic bone tumors: a new and effectiveapproach to a difficult problem. Skeletal Radiol 2006;35:1–15.221. Kalantaridou SN, Davis SR, Nelson LM. Premature ovarianfailure. Endocrinol Metab Clin North Am 1998;27:989–1006.222. Berenson JR, Lichtenstein A, Porter L, et al. Long-termpamidronate treatment of advanced multiple myeloma patientsreduces skeletal events. Myeloma Aredia Study Group. J ClinOncol 1998;16:593–602.223. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacyand safety of zoledronic acid in the treatment of skeletal metastasesin patients with nonsmall cell lung carcinoma and other solidtumors: a randomized, phase III, double-blind, placebo-controlledtrial. Cancer 2004;100:2613–2621.© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


S-33Post-testPlease circle the correct answer on the enclosed answer sheet.1. Which of the following statement regarding theFRAX algorithm is FALSE?a. FRAX is a risk assessment tool that combinesboth bone density measurements and clinicalfactors in assessing fracture risk.b. FRAX provides an individualized 10-yearfracture risk estimate that can be used to guideintervention and therapy.c. FRAX analysis is optimized for all women andmen regardless of age and is intended to predictrisk for patients previously untreated for boneloss.d. FRAX has separate calculation tools for U.S.white, black, Asian, and Hispanic populations.2. Pharmacologic intervention with bisphosphonatesshould be strongly considered for which of thefollowing patients?a. Cancer patients at increased risk for bone lossdue to therapy or age with T-score less than -2.0OR FRAX 10-year fracture risk of greater than20% for major fracture or greater than 3% forhip fractureb. Cancer patients at increased risk for bone lossdue to therapy or age with T-score less than -2.0AND FRAX 10-year fracture risk greater than20% for major fracture or greater than 3% forhip fracturec. All cancer patients regardless of T-score orfracture risk3. Which of the following statements is FALSEregarding dual x-ray absorptiometry (DXA)measurement?a. Osteoarthritis or calcification of the aorta mayindicate a falsely high bone mineral density(BMD).b. A DXA scan exposes patients to low levels ofradiation, equal to 1/10 of a chest x-ray.c. DXA machines are standarized so that resultsare consistent between machines.4. Which bisphosphonate of those below is NOTapproved by the FDA for osteoporosis prevention andtreatment?a. Ibandronateb. Pamidronatec. Zoledronic acidd. Alendronate5. Recombinant parathyroid hormone (PTH (1-34)or teriparatide) is an anabolic agent approved fortreating osteoporosis in postmenopausal women. Itcan be used in management of osteoporosis of allcancer patients at increased risk of bone loss as well.a. Trueb. False6. Raloxifene is currently FDA approved for theprevention and treatment of osteoporosis inpostmenopausal women. However, based on theresults of the ATAC trial, raloxifene should notbe used in postmenopausal breast cancer patientsreceiving aromatase inhibitors to improve BMD.a. Trueb. False7. The Austrian Breast and Colorectal CancerStudy Group Trial 12 (ABCSG-12) examined, inpremenopausal women with endocrine-responsivebreast cancer, the efficacy of ovarian suppressionusing the GnRH analogue goserelin in combinationwith anastrozole or tamoxifen with or without:a. pamidronate.b. denosumab.c. zoledronic acid.d. toremifene.8. Denosumab, a fully human immunoglobulin G2monoclonal antibody, specifically targets which ofthe following?a. Osteoblast/osteoclast matrix receptorsb. Receptor activator of nuclear factor kappa Bligandc. Osteoprotegerin9. Which of the following statements is FALSEregarding imaging of bone metastases?a. If bone marrow infiltration is suspected, 18 Ffluorodeoxyglucose (FDG)-PET or MRI is the bestway to follow and evaluate disease in the bone.b. Lesions present on MRI or FDG-PET, such asthe osteolytic lesion, are visible on technetium-99m bone scans also.c.18F FDG-PET assesses the metabolic activityof the metastatic tissue directly rather thanassessing the bony response to the metastasis.d. Interpreting imaging modalities for bonemetastases requires simultaneous review ofall relevant imaging studies with full clinicalcontext.© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009SU70603 Post test and Eval 060909 OK.indd 336/23/09 11:10 AM


S-3410. According to a pooled analysis of approximately1600patients from the Zometa-Femara Adjuvant SynergyTrials (Z-Fast and ZO-Fast), which of the followingstatements is TRUE?a. Upfront use of zoledronic acid was associatedwith relative preservation of BMD.b. Delaying treatment of zoledronic acid is betterfor preservation of BMD.c. There is no difference seen with either upfrontor delayed treatment with zoledronic acid.12. The NCCN Clinical Practice Guidelines inOncology for Prostate Cancer recommend calciumand vitamin D supplementation for all patients. Astherapeutic options in men receiving androgendeprivationtherapy who are at substantial risk forfracture, the Guidelines also include consideration ofbisphosphonate therapy with:a. zoledronic acid or pamidronate.b. zoledronic acid or alendronate.c. ibandronate and alendronate.11. Oral and intravenous bisphosphonates can mitigatethe bone loss effects of aromatase inhibitors but havenot shown reduced fracture rates.a. Trueb. False© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009SU70603 Post test and Eval 060909 OK.indd 346/23/09 11:10 AM


S-35Post-Test Answer SheetPlease circle one answer per question. A score of at least 70% on the post-test is required.1. a b c d 7. a b c d2. a b c 8. a b c3. a b c 9. a b c d4. a b c d 10. a b c5. a b 11. a b6. a b 12. a b cThe activity content helped me to achieve the following objectives:(1 = Strongly disagree; 3 = Not sure; 5 = Strongly agree)Implement recommended techniques for screening and detection of osteoporosis1 2 3 4 5Define biomarkers in bone health1 2 3 4 5Describe the pathophysiology, imaging techniques, and surgical management of bone metastases1 2 3 4 5Summarize the skeletal complications that arise from direct effects of cytotoxic chemotherapy, includingtreatment-induced ovarian failure1 2 3 4 5Choose the appropriate management strategy for treatment-induced bone loss and skeletal complications associatedwith breast and prostate cancer1 2 3 4 5Please indicate the extent to which you agree or disagree with the following statements:You were satisfied with the overall quality of this activity.Strongly agree Agree Undecided Disagree Strongly disagreeParticipation in this activity changed your knowledge/attitudesStrongly agree Agree Undecided Disagree Strongly disagreeYou will make a change in your practice as a result of participation in this activity.Strongly agree Agree Undecided Disagree Strongly disagreeThe activity presented scientifically rigorous, unbiased, and balanced information.Strongly agree Agree Undecided Disagree Strongly disagreeIndividual presentations were free of commercial bias.Strongly agree Agree Undecided Disagree Strongly disagree© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009


S-36Registration for CreditNCCN Task Force Report:Bone Health in Cancer CareRelease Date: June 26, 2009Expiration Date: Jun 26, 2010To receive credit, please complete this page, the post-test,and the evaluation, and mail to the following address:Continuing Education DepartmentNCCN275 Commerce Drive, Suite 300Fort Washington, PA 19034There is no fee for participating in this activity.Comments and suggestions:Please print clearly.NameDegreeTitle/PositionAffiliation (University or Hospital)Business AddressCity State ZipBusiness TelephoneBusiness FaxEmail AddressI am claiming credits (maximum 1.25)I certify that I have participated in this activity as designed.SignatureDateTo re ceive cre dit, y ou mu st su bmi t this form by J U NE 26, 2010.© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 3 | June 2009SU70603 Post test and Eval 060909 OK.indd 366/23/09 11:10 AM

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