tions induce apoptosis of osteoclasts and inhibit
certain osteoclast cellular pathways. In turn, they
stop bone resorption and can increase BMD. The
FDA approved the use of zoledronic acid in 2002
for the prevention of SREs in patients on ADT
with metastatic prostate cancer to the bones after
3 large phase III trials showed its efficacy for such
patients.62–64 Zoledronic acid is an intravenous
medication that is given monthly and is shown to
prevent SREs and improve bone pain in this setting. The other FDA-approved medication for the
prevention of SREs in metastatic prostate cancer
is denosumab. Denosumab is a RANK (receptor
activator of nuclear factor kappa-B) ligand mono-clonal antibody that inhibits osteoclast activity
through its competitive binding of RANK ligand.
It is given as a subcutaneous injection every
month. Denosumab was FDA-approved in November 2010 for the prevention of SREs in patients
with metastatic prostate cancer, and in September 2011 for patients with nonmetastatic/high-risk
prostate cancer on ADT to increase bone mass.
In a study comparing denosumab with zoledronic
acid, denosumab showed superiority in delaying
time to SRE (20.7 months versus 17. 1 months,
P = 0.008).65 An important adverse effect of these
medications is osteonecrosis of the jaw in patients
who have chronic dental issues, seen in 1% to 2%
of patients. Hypocalcemia was noted more often
with denosumab, but most adverse events were
minor and similar between the 2 therapies. While
there remains no standard protocol, performing a baseline dual-energy X-ray absorptiometry
(DEXA) scan before starting long-term ADT and
then every 1 to 2 years is recommended. Use
of plain film X-rays for suspected fractures and
nuclear bone scans (99m-technetium bone scintigraphy) to evaluate for new bone metastases are
also recommended.66
CASE;PRESENTATION;CONTINUED
One year after starting ADT, the patient
starts to complain of pain in his right hip
and has persistent weight loss. A repeat bone scan
shows uptake in the right sacrum and iliac crest
consistent with bony metastatic disease. Restaging CT scans show retroperitoneal lymphadenopa-thy and his PSA level continues to climb despite
being on ADT. His PSA level is now 14. 3 ng/mL.
•;How;would;this;patient’s;disease;stage;be
defined?
•;What;are;the;options;for;therapy;now;that
he;continues;to;progress?;Should;ADT;be
continued?
CASTRATION-RESISTANT;PROSTATE;CANCER
This patient is now at the metastatic castration-resistant stage. CRPC, previously termed
hormone-refractory or androgen-independent prostate cancer, is defined as cancer progression despite castrate levels of testosterone. It has always
been clear that progression despite castration
is ultimately inevitable. Previously it was thought
that alternate stimulation of prostate cancer cells
unrelated to the androgen axis brought about this
resistance. Recent research has shown that there
are multiple pathways along the androgen axis,
such as increased androgen receptor activity and
autocrine production of testosterone, which remain active in the presence of very low (castrate)
androgen levels.67,68 It is thus important to verify
castrate levels of testosterone in men who are progressing, despite apparently adequate treatment
with ADT. Due to the overactivity of the androgen
receptor, ADT (LH-RH agonists, antiandrogens)
is continued throughout progression to CRPC, to
avoid overstimulation of the receptors. Treatment
modalities for CRPC patients now include chemo-
