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Maintaining Bone Health in ProstateCancer Throughout the Disease Continuum

Fred Saada and James Easthamb

Prostate cancer (PC) is the most prevalent malignancy in men, with 604,506 new cases diagnosedyearly worldwide. Maintaining bone health is important during all stages of PC, including patientswho experience bone loss from androgen-deprivation therapy and patients who develop bonemetastases. Patients with bone metastases often experience severe bone pain and are at increasedrisk for potentially debilitating skeletal-related events. Bisphosphonates are a well-establishedtreatment option for patients with bone metastases from solid tumors and bone lesions frommultiple myeloma. Zoledronic acid (ZOL) is the only bisphosphonate (BP) that has been extensivelystudied in patients with castration-recurrent PC and is indicated for treating patients with bonemetastases from PC in conjunction with standard antineoplastic therapy. This review will examinethe breadth of evidence supporting a role for ZOL and emerging therapies in managing patientswith PC throughout the disease continuum.Semin Oncol 37 (Suppl 1):S30-S37. © 2010 Published by Elsevier Inc.

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rostate cancer (PC) is the most prevalent malig-nancy in men, with 604,506 new cases diag-nosed worldwide in a single year,1 and an esti-

ated 192,280 new cases and 27,360 related deaths inhe United States in 2009.2 In all stages of PC, maintain-ng bone health is important. Men diagnosed with high-isk disease receive surgery or radiation therapy asrimary treatment and are subsequently monitored. Ifrostate-specific antigen (PSA) levels remain elevatedr increase after primary treatment, surgical or hor-onal castration (androgen-deprivation therapy [ADT])

o lower testosterone levels may be considered.3 How-ver, ADT may lead to adverse effects on bone health,ncluding osteoporosis and greater incidence of frac-ures.4–7

Bone is the most common site of metastasis, andpproximately 65% to 75% of patients with metastaticrostate cancer will develop bone metastases.8 Boneetastases disrupt the normal homeostasis between

steoclasts (resorption) and osteoblasts (formation),

Centre Hospitalier de l’Université de Montréal, Montréal, Quebec,Canada.

Memorial Sloan-Kettering Cancer Center, New York, NY.ovartis provided financial support for medical editorial assistance.ublication of this article was supported by Novartis.ddress correspondence to Fred Saad, MD, FRCS, Centre Hospitalier del’Université de Montréal, Hôpital Notre-Dame, 1560 Rue SherbrookeEast, Montréal, PQ H2L 4M1 Quebec, Canada. E-mail: fred.saad@umontreal.ca

270-9295/ - see front matter2010 Published by Elsevier Inc.

poi:10.1053/j.seminoncol.2010.06.007

Seminars in30

nd weaken the skeleton.8 Bone lesions from PC typi-ally appear osteoblastic; however, excess bone forma-ion is not necessarily at the site of bone resorption andoes not contribute to overall bone stability. In addi-ion, osteolysis remains an important component ofone disease in this setting.8 As a result, patients withone metastases often experience severe bone painnd are at increased risk of skeletal-related eventsSREs) including pathologic fracture, spinal cord com-ression, need for surgery, and bone pain requiringalliative radiotherapy or changes in antineoplasticherapy, which can result in severe skeletal morbidity.pproximately 50% of patients with bone metastases

rom PC will experience an SRE during their diseaseourse in the absence of bone-targeted therapy.9

The median overall survival for men with metastaticrostate cancer is 2 to 3 years.10 During this timeatients are at risk of developing several potentiallyebilitating SREs (1.47 SREs per year),9 and patientuality of life is often notably reduced.11 In a 5-yearatabase analysis (N � 342), SREs experienced mostrequently by patients were radiation therapy (89%),ollowed by pathologic fracture (23%) and bone sur-ery (12%).12 Of the patient population analyzed, 78%f patients experienced one SRE and 22% experiencedwo or more SREs.12 Mean annualized SRE cost for thisatient population was $12,469, and the cost for oneRE was $8,484 compared with $26,384 (P �.001) forwo or more SREs.12 Moreover, an analysis from a sep-rate study found that pathologic fractures can be es-

ecially detrimental to men with castration-recurrent

Oncology, Vol 37, No 3, Suppl 1, June 2010, pp S30-S37

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Bone health in PC S31

C (CRPC), increasing the risk of death by 29% (P �04).13,14

Bisphosphonates (BPs), inhibitors of osteoclast-me-iated bone resorption,15 are a well tolerated treatmentption for patients with bone metastases from solidumors and bone lesions from multiple myeloma.oledronic acid (ZOL) is the only BP that has beenxtensively studied in patients with CRPC and is indi-ated for disease treatment in patients with multipleyeloma and patients with bone metastases from solid

umors in conjunction with standard antineoplasticherapy.14,16 ZOL is a well-established treatment optionor reducing or delaying SREs associated with boneetastases from CRPC.17–21 This review will examine

he breadth of evidence supporting a role for ZOL inanaging patients with PC across the disease contin-

um and will describe some emerging therapies cur-ently under investigation.

ONE-TARGETED THERAPY

ancer Treatment-Induced Bone Loss

ADT is used after initial treatment when curativentent fails to reduce PSA levels in patients with high-isk localized PC, locally advanced PC, hormone-sensi-ive PC, and in PSA-recurrent PC.3 However, ADT de-reases bone mineral density (BMD), and this decreases cumulative during treatment. Therefore, risk of aracture increases with treatment duration.4,6 Therapyor cancer treatment-induced bone loss thus becomesn important aspect of treating men undergoing ADTor PC.

A number of BPs, including oral alendronate andisedronate and intravenous ZOL, are approved for thereatment of osteoporosis in men and women,22–24 andultiple agents have demonstrated efficacy in prevent-

ng bone loss in men. However, lumbar-spine bone lossuring ADT (�4.8% v baseline; P � .001)25 is approx-

mately sixfold higher than that observed in healthyging men (�0.82% v baseline; P � .429).25 Alendro-ate, pamidronate, and ZOL all maintain BMD in pa-ients with PC during ADT; however, several studieshow that alendronate and ZOL also improve BMD inatients with PC receiving ADT (Table 1).26–34

Another bone-directed agent that is being evaluatedn patients with PC is denosumab, a monoclonal anti-ody against receptor activator of nuclear factor-kappaligand (RANKL; a mediator of osteoclast development

nd function). In a large, multicenter trial (N � 1,468)atients with hormone-sensitive PC who were at highisk of fracture received denosumab 60 mg subcutane-usly every 6 months or placebo.35 Lumbar-spine BMD

n the denosumab group increased 5.6% comparedith a 1% loss in the placebo group (P �.001).35 How-

ver, the rate of serious adverse events in the deno-

umab group was 34.6% compared with 30.6% in the r

lacebo group, and the number of serious infections inhe denosumab group (5.9%) was higher comparedith the placebo group (4.6%).35 Cataracts were re-orted in 3.7% of patients receiving denosumab com-ared with 1.2% of patients receiving placebo; how-ver, this event was not considered to be drugelated.35 Additionally, a modest increased rate of met-static events (8.2%) was observed in the denosumabroup compared with placebo (5.5%).36

etastatic Bone Disease

Bone metastases may lead to considerable morbidityrom SREs.8 Zoledronic acid is the only BP that hasemonstrated objective long-term (2-year) efficacy inatients with bone metastases from CRPC and haschieved widespread regulatory approval in this set-ing, and several organizations recommend the use ofPs for patients with bone metastases from prostateancer, including the National Comprehensive Canceretwork (NCCN, USA),5 the European Association ofrology (EAU),37 and the British Association of Urolog-

cal Surgeons (BAUS).38 The NCCN specifically recom-ends ZOL and alendronate, BAUS recommends ZOL,

nd EAU generally recommends BPs.In a 2-year, randomized, double-blind trial in patients

ith bone metastases from CRPC (N � 122), ZOL (4g via 15-minute infusion every 3 weeks) significantly

educed the proportion of patients with an on-studyRE compared with placebo (38% v 49%; P � .028).OL significantly delayed the median time to first SREy almost 6 months and reduced the ongoing risk ofREs by 36% (P �.01).9 Additionally, ZOL reduced theurvival-adjusted cumulative mean incidence of radia-ion to bone and SREs overall39 (Figure 1).40 Althoughot statistically significant, patients receiving zoledroniccid trended toward improved survival compared withlacebo (2.6-month increase; P � .103).39 Analyses ofhe first 15 months of this trial (N � 422) showed thatOL decreased the proportion of patients with an SREs early as 3 months compared with placebo.41

Patients receiving ZOL experienced reduced boneain levels, although several other BPs have shownalliative effects (Table 2).9,42–48 ZOL also had a greater

ikelihood of producing clinically meaningful reduc-ions in pain levels compared with placebo (P � .024 at4 months).39 ZOL reduced the risk of skeletal compli-ations by 56% when administered early in men withone metastases from PC compared with no bone-argeted therapy.49

A non-inferiority study in patients with bone metas-ases from PC (N � 1,901) compared the efficacy andafety of denosumab versus ZOL.19,50 Results demon-trated that denosumab significantly prolonged time torst SRE (HR � 0.82; 95% CI: 0.71, 0.95; P � .004)50

hese findings indicated that denosumab reduces the

isk of SREs in this setting.50

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EYOND BONE HEALTH

Bone turnover markers may have utility for assessinghe extent of bone disease in patients with PC. Bio-hemical markers of bone turnover include peptidesnd enzymes released during bone remodeling and cane measured in blood or urine. Bone marker levels mayrovide insight and be potentially useful in identifyingatients with an increased risk of SREs. Exploratorytudies demonstrated that patients with CRPC had ele-ated levels of N-telopeptide of type I collagen (NTX) ataseline.51 ADT leads to elevations in bone-formationarkers (eg, bone-specific alkaline phosphatase

BALP]) and bone-resorption markers (eg, urinaryTX), whereas serum BALP levels are further increased

n men who develop bone metastases during ADT.52 Inetastatic PC, elevated baseline levels of the bone

ormation marker BALP were associated with increasedisks of SREs53 and death.54

Table 1. Changes in BMD During BisphosphonateADT

Bisphosphonate Patients, N

Alendronate (70 mg POweekly)

22 Alendron(� betwboth)26

112 Alendron(� betwboth)27

skeletalPamidronate (60 mg IV

q 3 mo)47 Pamidron

hip (�for bot

Zoledronic acid (4 mgIV q 3 mo)

200 Zoledronspine, fand 2.9

106 Zoledronspine, fgroupsfor all)3

120 Zoledronneck, t3.8%,

215 ZoledronBMD (�for bot

93 Zoledronthe lumgroups

�, change; ADT, androgen-deprivation therapy; BP, bisphosphon3 months; ZOL, zoledronic acid.

Elevated on-treatment bone marker levels also corre- s

ate with increased risk of SREs and reduced survival inatients with bone metastases from solid tumors. In atudy in patients with bone metastases receiving hor-onal therapy for PC,55 bone marker levels increased inatients with PSA failure and progression of bone metas-ases. Studies evaluating the efficacy of BPs for preventingone loss during ADT have revealed strong correlationsetween changes in bone marker levels during treatmentnd improvements in BMD.33,56,57 Generally, BMD de-reases within the first 6 months of ADT treatment inatients with bone metastases from PC. However, ZOLdministration 1 week before ADT initiation resulted inncreased BMD at 6 months compared with baseline.58

dditionally, a recent study assessed the role of biomark-rs for predicting the probability of new SREs and dura-ion of continued benefit from ZOL treatment. Overallurvival was prolonged in patients whose bone markerevels decreased by the 3-month assessment.59 These re-

ment in Patients With Prostate Cancer Receiving

BMD Changes

BP � ADT v ADT Alone

us ADT) prevented bone loss at the spine and hiproups: 2.7% and 1.9%, respectively; P �.05 for

reased BMD at the spine and femoral neckroups: 5.1% and 2.3%, respectively; P �.01 forond year of alendronate provided additionalts28

lus ADT) prevented bone loss at the spine andn groups: 3.8% and 2.0%, respectively; P �.01

(plus ADT) increased mean BMD at the lumbarl neck, and hip (� between groups: 4.8%, 3.5%,pectively; P �.0012 for all)30

(plus ADT) increased mean BMD at the lumbarl neck, trochanter, and total hip (� between, 3.3%, 4.9%, and 3.9%, respectively; P �.001

(plus ADT) increased mean BMD in the femoral, and lumbar spine (� between groups: 3.6%,%, respectively; P �.0004 for all)32

(plus ADT) increased lumbar-spine and total-hipeen groups: 6.7% and 3.7%, respectively; P �.04

(plus ADT for � 1 yr) increased mean BMD atine, left total hip, and right total hip (� between, 1.6%, and 1.9%, respectively; P �.031 for all)34

D, bone mineral density; IV, intravenous; PO, oral; q 3 mo, every

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fter starting treatment in the early phase of the diseaseay predict longer overall survival.In exploratory analyses of data from the phase III

rial of ZOL versus placebo in patients with bone me-astases from CRPC (N � 643), 70% of patients treatedith ZOL who had elevated baseline NTX (n � 193)ad normalized NTX levels within 3 months, comparedith only 8% in the placebo group. Compared withersistently elevated levels, normalization of NTX lev-ls was associated with 59% decrease in the risk ofeath (P �.0001; Figure 2),51 and was associated withcontinuum of survival benefits.51

Phase II trials of denosumab in patients with boneetastases from PC and elevated NTX levels despite BP

igure 1. Time course of cumulative expected skeletal-elated events (SREs) per patient with prostate cancer. Theurvival-adjusted cumulative mean number of administra-ions of (A) radiotherapy (RT) to bone and (B) incidence ofREs were significantly reduced by treatment with 4 mgoledronic acid compared with placebo. Reprinted withermission from Major PP, et al.40

reatment demonstrated reductions in bone marker lev- r

ls.20,21 These studies revealed a correlation betweenecreased bone marker levels and decreased SRE

ncidence in patients with BP-naive and BP-resistantone disease. However, no conclusions were madeetween decreased bone marker levels and clinicalutcomes.20,21 The study results suggest that deno-umab may be an effective secondary treatment optionor patients with bone metastases from PC in whomntravenous BP treatment failed to lower urinary NTXevels. Further investigations are needed to determinehether bone marker reductions from denosumab corre-

ate with clinical outcomes in this setting. Moreover, bonearker reductions and potential corresponding benefits

f denosumab therapy may require continuous treatment,s denosumab is rapidly cleared after treatment discontin-ation, resulting in osteolytic activity markers returning toaseline, pretreatment levels.60

Other areas of investigation involving ZOL includereventing metastasis to bone and inducing potentialnticancer effects. Several preclinical studies demon-trated this anticancer activity. For example, ZOL re-uced the survival and proliferation of androgen-inde-endent and androgen-dependent PC cell lines initro.61 Another preclinical study found that the com-ined treatment with clinically relevant doses of doxo-ubicin and ZOL synergistically induced apoptosis inC cell lines in vitro.62 Several other preclinical studiesemonstrated that ZOL promotes PC cell-line apoptosis

n vitro, alone and in combination with chemotherapygents.62–66

These preclinical data provided the rationale tonvestigate the potential anticancer activity of BPs inhe clinical setting. Accumulating evidence to dateuggests that the observed preclinical activity mayranslate into clinical benefits. Two clodronate stud-es evaluated overall survival in men with stage M0local) or M1 (metastatic) PC.67 Long-term data fromhese clinical trials show that clodronate improvesverall survival in men with M1 disease beginning

ong-term hormone therapy, but not in men with M0isease. The authors concluded that further investi-ation with newer BPs is needed. The STAMPEDErial (ISRCTN78818544) is assessing ZOL in this set-ing,67 and the RADAR study is evaluating whetherOL can prevent bone loss and bone metastases fromccurring in patients with PC initiating ADT.68 TheEUS study is evaluating whether ZOL can preventone metastases from occurring in patients withsymptomatic recurrent PC.69

Several investigational agents and combination ther-pies are being evaluated in patients with PC. Thesegents have various targets, including signaling path-ays (eg, cell surface receptors, Src pathway, phospha-

ase and tensin homologue/mammalian target of rapa-ycin pathway), soluble growth factors (eg, epidermal

rowth factor receptor, platelet-derived growth factor

eceptor-b [PDGFR-b], vascular endothelial growth fac-

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or, cytokines), and the bone stroma (endothelium re-eptor, bone interface, RANKL).70 Some examples ofhese investigational agents are sasatinib, which targetshe Src pathway; lapatinib, which affects phosphatidyl-nositol 3-kinase activation by human epidermal growthactor receptor-2; trastuzumab, which targets PDGFR-b;nd thalidomide, which targets insulin-like growth fac-or-1. Atrasentan and zibotentan target bone epitheliumeceptor, whereas samarium 153 and strontium 89 tar-et the bone interface.70 Finally, denosumab is a mono-lonal antibody against RANKL (a mediator of oste-clast development and function). A bone metastasesrevention study evaluating whether denosumab canrevent bone metastases from occurring in patients

Table 2. Summary of Trials With Bisphosphonat

Trial TreatmentDoRe

Zoledronic acidRandomized, double-blind

study in metastaticprostate cancer(N � 422)9

Zoledronicacid,placebo

4 mg Iweekyears

ClodronateRandomized, double-blind

study in metastaticprostate cancer(N � 209)42

Clodronate 1,500 m3 wee

Open-label, single-armstudy in prostate cancer(N � 58)43

Clodronate IV ever

Open-label, single-armstudy in prostate cancer(N � 32)44

Clodronate IV ever

Open-label, single-armstudy in prostate cancer(N � 78)45

Clodronate Oral 80

PamidronatePooled analysis of 2

randomized, double-blind studies in prostatecancer (N � 378)46

Pamidronatev placebo

90 mg3 wee

IbandronatePhase II study in prostate

cancer (n � 45)47Ibandronate 6 mg I

consedays,IV eve

BPI, Brief Pain Inventory; IV, intravenous; NR, not reported; NS, nQuestionnaire; VAS, visual analogue scale.

Adapted with permission from Table 2 of Saad F.48

ith PC is ongoing (NCT00286091).19 c

ONCLUSIONS

Bone health in patients with PC is important regardlessf disease stage. In early PC, ADT is associated withecreased BMD and increased fracture risk. Although noone-targeted therapy is approved in the adjuvant setting,everal BPs have shown efficacy for maintaining or im-roving bone loss during ADT. Denosumab has alsohown improved BMD, although patients had lower base-ine lumbar-spine BMD and may have had higher fractureisk. In the metastatic PC setting, patients may experienceultiple SREs. Failure to prevent or delay SREs may re-

uce survival because fractures are associated with in-reased risk of death.14 ZOL is the only BP approved foratients with bone metastases from CRPC to be used in

Reducing Bone Pain in Prostate Cancer

PainMeasurement Results

PValue

3 BPI Significantly reducedmean compositeBPI compared withplacebo at 24months

.024

very PPI (0–5 scale) Reduced pain scores NS

ys Visual painscale (0–10)

Average improvedfrom 7.4 to 2.4over 3 years

NR

ys Visual painscale (0–10)

Average improvedfrom 7.7 to 2.1over 2 years

NR

d Visual painscale (0–10)

Reduced pain scores NR

ry BPI Reduced pain score NS

mgeeks

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Reduced pain score NR

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In addition to potentially preserving BMD in early PCnd treating metastatic bone disease, BPs may haventicancer effects. Bone marker levels are altered inatients receiving ADT for hormone-sensitive PC oriagnosed with metastatic disease. Changes in bonearker levels may reflect the magnitude of response to

ntiresorptive therapies. The ongoing ZEUS trial is sec-ndarily evaluating the relationship between bonearker levels and antiresorptive therapy in patientsith PC. Therapies that improve bone metabolism may

lso have efficacy in preventing bone metastases. Stud-es investigating ZOL or denosumab for preventingone metastases in patients with PC are ongoing.aken together, the clinical evidence suggests thatone health needs to be considered in patients diag-osed with PC.

TATEMENT OF CONFLICT OF INTEREST

F.S. has received research funding, attended advi-ory board meetings, and received honoraria for speak-ng on behalf of Novartis Oncology. J.E. has no conflictf interest to declare.

cknowledgmentsinancial support for medical editorial assistance wasrovided by Novartis Pharmaceuticals Corporation. Theuthors thank Duprane Pedaci Young, PhD, ProEdommunications, Inc, for her medical editorial assis-

ance with the manuscript.

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