Long term androgen deprivation therapy in prostate cancerBMJ 2008; 337 doi: https://doi.org/10.1136/bmj.a1361 (Published 22 September 2008) Cite this as: BMJ 2008;337:a1361
All rapid responses
With the increasing indications for and duration of androgen
deprivation therapy (ADT) in men with prostate cancer using gonadotrophin-
releasing hormone (GnRH) agonists, the many side-effects of reduced levels
of serum sex-steroids are becoming apparent. Presumably the new GnRH
antagonists will have similar toxicity.
The rapid response from Sherriff et al that osteoporosis is another
potentially serious adverse event in men on ADT is therefore an important
reminder that the toxicity of this treatment is not limited to the
cardiovascular system, the topic specifically discussed in our editorial
and prompting their rapid response.
Testosterone deficiency is associated with muscle weakness, diabetes,
changes in body composition and erectile dysfunction. Oestrogen deficieny
is a consequence of testosterone deficiency because oestrogen is produced
through aromatisation of testosterone. Adverse effects of oestrogen
deficiency include increased fracture risk, lipid changes, memory loss,
gynaecomastia and hot flushes (1). It may well be that in future, a
battery of screening tests will precede the initiation of ADT with GnRH,
including for example, dual-energy X-ray absorptiometry scans as well as
serum lipids, cholesterol and glucose.
Some of these issues have been covered in a recent review of the
topic in which a rationale for the re-emergence of oestrogen as a
treatment for prostate cancer is offered (2). In addition to its role in
reducing testosterone to castrate levels, oestrogen should also diminish
the toxicity of GnRH ADT. This hypothesis has developed into the subject
of a multicenter randomised trial comparing the efficacy and toxicity of
transdermal oestrogen with GnRH in this group of men (3).
In the meantime, perhaps it is timely for guidelines for the use of
GnRH in prostate cancer to be produced as suggested by Sherriff et al?
Could this be a role for NICE?
1. Freedland SJ, Eastham J, Shore N. Androgen deprivation therapy
and oestrogen deficiency induced adverse effects in the treatment of
prostate cancer. Prostate Cancer and Prostatic Diseases 2009;12:333-338.
2. Ockrim JL, Lalani EN, Abel PD. Parenteral oestrogen treatment for
prostate cancer: a new dawn for an old therapy. Nature Clin Pract Oncol
3. Langley RE, Godsland IF, Clarke N, Dearnaley D, Knockelbergh R,
Kynaston H, et al. Early hormone data from a multi-centre randomized trial
using transdermal oestrogen patches as first-line hormone therapy in
patients with locally advanced or metastatic prostate cancer. Brit J Urol
1. Principal Investigator for Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) randomised controlled trial of LHRH vs transdermal estrogens in prostate cancer.
2. Consultant for Ascend Pharmacueticals
Competing interests: No competing interests
We read with interest this editorial regarding the potential
cardiovascular effects of long term androgen deprivation therapy. Also
important and at present under-recognised is the risk of osteoporosis
amongst this patient group. At present few guidelines exist to assist with
detection and management of bone loss in males receiving long term
androgen deprivation therapy.
The use of a gonadotrophin-releasing hormone (GnRH) agonist with
radical radiotherapy for two to three years in high risk prostate cancer
offers significant improvement in disease free and overall survival (1,2).
As treatments for prostate cancer advance, even in poor risk disease,
osteoporosis and its complications are likely to become increasingly
common. A large retrospective study has considered the fracture rate in
over 50,000 males with prostate cancer and revealed a significant
relationship between number of doses of GnRH agonist and fracture risk
(3). This is important as there is clear evidence that the development of
a fracture in a male with prostate cancer is an independent, adverse
predictor of survival (4).
There is a need for more consistent, effective and evidence-based
management of potential bone loss in such patients. Patients commenced
upon ADT and their general practitioners should be given clear information
and lifestyle advice to reduce their risk of osteoporosis as much as
possible. This should emphasise the need for exercise, reducing smoking,
limiting alcohol consumption along with a diet including calcium and
vitamin D. Exercise and diet are particularly important in this context
given that the other effects of long term ADT include loss of muscle bulk
and increased body fat.
In the absence of guidelines, teams managing prostate cancer need to
formulate and implement coherent strategies to minimise potential
morbidity from ADT. Dual-energy X-ray
absorptiometry (DXA) scans are cheap, relatively easy to perform and
currently underutilised in this patient group in the UK. We recommend that
a DXA scan be considered for all men commencing long term ADT.
1. Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G,
et al. Improved survival in patients with locally advanced prostate cancer
treated with radiotherapy and goserelin [see comments]. N Engl J Med
2. Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P,
et al. Endocrine treatment, with or without radiotherapy, in locally
advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III
trial. Lancet 2009;373(9660):301-8
3. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture
after androgen deprivation for prostate cancer. N Engl J Med
4. Oefelein MG, Ricchiuti V, Conrad W, Resnick MI. Skeletal fractures
negatively correlate with overall survival in men with prostate cancer. J
Janet Brown has received speakers bureau honoraria from Novartis and Amgen and has served as a consultant
and/or on advisory boards for Novartis, Amgen, Roche, and Bristol- Myers Squibb.
Jennifer Sherriff has no competing interests.
Nicholas D. James has received research funding from and has carried out consultancy work for Novartis, Sanofi
Avantis and Pfizer.
Competing interests: No competing interests