©TheCanadian Journal ofUrology™: International Supplement, April 2014
MonitoringandpreventionofCTIBL inADT
treatedpatients
DXAcanbeused tomonitor spine, hip, or total body
BMD. Thespine isthepreferredsiteofdensitometryfor
serialmeasurementofbonemasstomonitorchanges in
BMD.
18
TheEuropeanAssociationofUrology (EAU)
guidelines recommend performing a DXA every 2
years after initiationof castration, provided there are
no other risk factors, and every year if there are risk
factors.
19
Patients should be encouraged to make
specific lifestylechanges:quitsmoking, reducealcohol
and caffeine consumption, engage in regularweight-
bearing exercises, and favor a healthy diet of foods
andbeveragescontainingcalcium (dairy)andvitamin
D (fattyfish).
20
TheNational ComprehensiveCancer
Network (NCCN) guidelines recommend assessing
fracture risk using the FRAX algorithm (
.
ac.uk/FRAX/index.htm) by considering CTIBL as
“secondaryosteoporosis”.
21
Pharmacologicalpreventionand treatmentof
ADT inducedCTIBL
Oneof themost importantquestions for thephysicians
iswhen to initiatepreventive treatment inADT treated
patients.
Physicians should make the difference between
osteopenia and osteoporosis. This can be evaluated
using theT-scoreonDXAand theWHOclassification.
TheT-score is thenumberofstandarddeviationsabove
or below themean for a healthy 30-year-old adult of
the same sexandethnicityas thepatient. Osteopenia
is definedby aT score<-1 and>-2.5; osteoporosis by
a T score ≤ -2.5, and severe osteoporosis by a T score
≤ -2.5 with history of 1 or more fragility fracture.
Osteoporosis is a condition that must be corrected
notwithstanding initiation of ADT. The question is
moreabout thebenefit of treatingosteopenicpatients
before theyarereallyosteoporotic, asanalternative to
monitorBMDduringADT.
The EAU guidelines recommend treating
osteoporotic patients (DXA T-score ≤ -2.5) with
denosumab or bisphosphonates, but provide no
guidance forosteopenicpatients.
19
NCCNguidelines
recommend treatment with zoledronic acid (ZA) (5
mg IV annually), alendronate (70mgPOweekly), or
denosumab (60mg sc every 6months) formenwith
a 10year probabilityof hip fracture ≥ 3%or a 10year
probability of major osteoporosis-related fracture
≥ 20%on theFRAX algorithm.
21
Denosumab (denosumabis) a fully human
monoclonal antibody that specifically inhibits the
receptor activator of nuclear factor-KB (RANK)
ligand (RANKL), which is produced by osteoblasts
and progenitor cells and plays a central role in the
maturation of pre-osteoclasts into osteoclasts.
22
Denosumab, administered subcutaneously (sc) every
6months at the dose of 60mg, is currently the only
agent approved by Food and Drug Administration
(FDA) and European Medicines Agency (EMA)
for the prevention of osteoporotic facture in non-
metastaticADT treatedpatients. Inclusion criteriaof
the registration trial were: ≥ 70 years old, or a DXA
T-score <−1.0 at baseline, or a history of osteoporotic
fracture.
23
These criteria actually describe a mixed
population of osteopenic and osteoporotic patients.
In the registration trial, denosumab significantly
increased BMD and decreased the incidence of new
vertebral fracturesat36months(1.5%versus3.9%with
placebo; p= 0.006).
23
In that setting, the incidence of
side effectswas low.
Althoughnot registered for that specific indication,
bisphosphonateszoledronicacid (4mg IVevery3or12
months)andalendronate(90mgoralweekly)havebeen
studied in that indication, insmallershorterstudiesnot
poweredtodetectareductionoftheincidenceoffracture,
Figure 1.
24-26
Although recommended by guidelines,
prescriptionofbisphosphonates inosteopenicpatients
not supportedby specific registration shouldbe left to
thediscretionof thephysician.
19
Preventionofcomplicationsofbonemetastases
With thewidespreaduse of prostate-specific antigen
(PSA), most patients are diagnosedwith localized or
locally advanceddisease andADT is usually started
inabsenceof any radiological evidenceofmetastases.
Similarly, most patients will progress and become
resistant to castrationwithnodetectablemetastasis.
27
Butultimately, the skeletonwill be thefirstmetastatic
site in 80% of patients and, later on, 90% of patients
will havebonemetastases.
4,5
Prostate cancer cells disseminating in the bone
marrowdonotdestroy theboneon theirown. Instead,
they alter the functions of osteoclasts and osteoblasts,
and hijack signals coming from the bone matrix,
thereby disrupting physiological bone remodeling.
28
Specifically, there isa ‘viciouscycle’wherebymetastatic
cells residing in the bone marrow secrete factors that
stimulateosteoclast-mediatedbone resorptionwhereas
growth factors released from resorbed bone stimulate
tumorgrowth. Takentogether,thisleadstoanimbalance
betweenboneresorptionandboneformation,resultingin
enhancedskeletaldestructionandoccurrenceofSREs.
29
SREsarepresentatdiagnosisofbonemetastasisin10%of
86
Practical guide tobonehealth in the spectrumof advancedprostate cancer
