©TheCanadian Journal ofUrology™: International Supplement, April 2014
ZA).
31,42
Grade 3 hypocalcemia (corrected serum
calcium (CSC) < 7.0 mg/dL-6.0 mg/dL; ionized
calcium< 0.9mmol/L-0.8mmol/L; hospitalization
indicated) or 4 (CSC < 6.0mg/dL; ionized calcium
< 0.8 mmol/L; life-threatening consequences) has
been reported in 5.1% of patients with denosumab
and 1.4% with ZA. The risk of developing
hypocalcemia is mainly increased among patients
with impaired renal function (creatinine clearance
< 30mL/min).
43
This is likelydue to reduced renal
calcium reabsorption, insufficient conversion of
vitamin D to its active metabolite and impaired
phosphorus excretion. Pre-existing hypocalcemia
mustbecorrectedbefore startingdenosumaborZA.
Initialmonitoringof calcium levels is recommended.
All patients but thosewith hypercalcaemia should
be given calcium (≥ 500 mg/d) and vitamin D
oral supplements (≥ 400 IU/d) and should have
their serum calcium concentration checked on a
monthly basis for instance. Should hypocalcemia
occur, denosumab should be held until correction
of hypocalcemia has been achieved.
44
Osteonecrosis of the jaw (ONJ) was observed in
1%-2%of the study cohort (12 caseswith zoledronic
acid, 22 caseswithdenosumab; p= 0.09). Although
ONJ may also occur spontaneously, local invasive
dental procedures and concomitant oral disease
havebeen identifiedas themost important local risk
factors.
45
The cornerstone ofONJ prevention is thus
traditionally to improve dental care and avoidance
of invasive dental procedures once therapy has
been started.
46,47
Wemust agree however that such
recommendations are based on position papers
and case reports, while evidence-based treatment
recommendations are lacking.
The “HolyGrail”ofmetastasesprevention
Non-metastatic (M0)CRPCpatientsareusuallystrictly
asymptomatic and it has become a major challenge
to cherish this asymptomatic health state as long as
possible by extending bone metastasis free survival
(BMFS).
27
This has consequently been the subject of
several clinical trials, most of them being negative
or inconclusive, Table 5. The tested agents include
bisphosphonates clodronate and ZA, endothelin
receptor typeA inhibitors atrasentan and zibotentan,
and denosumab. One of the reasons for failure is
clearly the heterogeneity of that patient group and
the usual very prolonged BMFS. In the first trial
evaluating the benefit of ZA in M0 CRPC, median
BMFSwas 30months and at 2 years, only 33%of the
patientshaddevelopedbonemetastases.
48
Smith et al have recently reported the results on
denosumab in aplacebo-controlled trial inM0CRPC
patientswithPSA≥8ng/mLand/or aPSAdoubling
time (DT) ≤ 10 months.
49
Denosumab significantly
prolongedBMFSbyamedianof4.2monthscompared
with placebo, but the benefit/side effects ratio was
deemed insufficient tograntregistration in thatsetting.
Therewas indeedasignificant riskofosteonecrosisof
the jaw (5% in the denosumab arm versus 0% in the
placeboarm)andhypocalcemia (2% in thedenosumab
armversus< 1% in theplacebo arm).
Prevention of bone metastasis is therefore still a
major issue tobe tackled.
TABLE4.
Safety resultsof interest inapooledanalysisof thedenosumab registrationprogram. Adapted from
Liptonet al
52
Patient incidence, n (%)
Zoledronic acidn (%)
Denosumabn (%)
Total patients
2386
2841
InfectiousAEs
1218 (42.9)
1233 (43.4)
Infectious seriousAEs
309 (10.9)
329 (11.6)
Acutephase reactions (first 3days)
572 (20.2)
246 (8.7)
Cumulative rateofONJ
37 (1.3)
52 (1.8)
Year 1
15 (0.5)
22 (0.8)
Year 2
28 (1.0)
51 (1.8)
Hypocalcemia
141 (5.0)
273 (9.6)
Newprimarymalignancy
18 (0.6)
28 (1.0)
AEs leading to studydiscontinuation
280 (9.9)
270 (9.5)
AEs= adverse effects;ONJ =osteonecrosis of the jaw
89
ButoescuANDTombal
