- 1 What is the incidence of osteoporosis and reduction in bone mineral density at 2, 5 and 10 years and what is the risk of osteoporotic bone fracture due to bilateral orchidectomy (or orchidectomy), LHRH agonist or long term androgen deficiency?
- 2 Evidence summary and recommendations
- 3 References
- 4 Appendices
What is the incidence of osteoporosis and reduction in bone mineral density at 2, 5 and 10 years and what is the risk of osteoporotic bone fracture due to bilateral orchidectomy (or orchidectomy), LHRH agonist or long term androgen deficiency?
Effects on bone health and the risk of fractures
There are numerous studies reporting the effects of medical or surgical castration on bone mineral density (BMD) and fracture rates in men with prostate cancer. Most were observational with results from both prospective and retrospective analyses of hospital and collated organisational data. There were two randomised studies comparing changes in BMD in patients randomised to bicalutamide or LHRH agonists. Many studies had industry support, including the two randomised studies that were supported by AstraZeneca.
Measurement methods: Two methods were used to measure BMD changes with Dual Energy X-ray Absorptiometry (DEXA) was the more commonly employed method. However DEXA is not ideal for measuring changes in lumbar spine BMD in older individuals as it does not distinguish aortic calcification and sclerosis of spinal discs and joints known to increase with age. There were fewer manuscripts reporting use of the more sensitive barometer of quantitative computerised tomography (QCT) which, however, exposes patients to more radiation and is subject to quality control issues.
This review focuses on changes in femoral BMD as measured by DEXA and lumbar BMD as measured by QCT. There were a number of other limitations arising out of study designs and the modes of reporting outcomes. The criteria used for reporting changes in BMD varied, reflecting a lack of accepted and standardised or validated yardsticks for men compared with those agreed and accepted for women. Most studies reported the change in mean BMD rather than the incidence of clinically significant decrease in bone mineral density or osteoporosis. Few studies attempted to distinguish osteoporotic fractures from metastatic and traumatic fractures, and the definition of osteoporotic fractures varied. Finally, in comparative studies there were usually baseline differences between the groups that have the potential to confound the results. This was so even when comparing prostate cancer patients with and without ADTs, as ADT may be associated with more aggressive disease or more advanced disease stage. In many studies, disease stage was unclear.
Despite these reservations and the variety of sites at which BMD was measured, the results were consistent in terms of BMD being reduced with LHRH agonists and bilateral orchidectomy, increasingly so over time, but maintained (or slightly increased) with bicalutamide monotherapy. Non-metastatic disease: For men with non-metastatic disease, most studies showed a decline in bone mineral density in the 12 months following initiation of castration therapies. Total hip BMD decreased on average by 3.3 % in a group of 15 men after 12 months of LHRH agonist treatment. This was significantly different from the rise in total hip BMD seen in aged-matched controls (n = 13). In this small study, at least 20% of men were osteopenic at baseline. Declines appeared to continue after 12 months with a 1.95 % decrease in proximal femoral bone mineral density reported for the 12 months after at least 18 months of LHRH agonist treatment. A small case series suggest that combined androgen blockade also results in bone mineral density decreases and that its temporary cessation may induce a temporary stabilisation of bone loss. In contrast oestrogen monotherapy may preserve BMD and there is evidence from two RCTs that the anti-androgen bicalutamide, unlike castration therapies, maintains or increases hip and lumbar spine bone mineral density. These data are consistent with the known biology of testosterone depletion and its consequent decrease in oestrogen, and bone mineral depletion.
Metastatic disease: Studies that included men with metastatic disease reported mean decreases in femoral neck bone density of 2.4 – 4.5% in the first 12 months of castration therapies and 10% at two years41, with declines continuing to occur after three or more years of treatment.41 In a case series of 50 men, the prevalence of osteoporosis in the lumbar spine rose from 24% at baseline to 48% within six months of starting castration therapies.42 After 12 men with metastatic disease started CAB, femoral neck BMD reportedly decreased on average by 6.5% and lumbar spine BMD by 6.6% at six months.
Osteopaenia, osteoporosis and fractures: The significant clinical impact of BMD changes is based on reports of a considerable background of osteopaenia in patients at baseline, and the reasonable presumption that continuing reductions in BMD predispose patients to clinically meaningful outcomes of osteoporosis and associated pathological fractures. Other risk factors for osteoporotic fractures include decreased muscle strength and frailty, which also may be influenced by androgen deficiency. It is also worth noting that the clinical significance of osteoporotic fracture is greater for hip than for vertebral bodies because of the high mortality rate related to the former. The data showed an increased likelihood of fractures over time with LHRH agonist therapy and bilateral orchidectomy although likelihood estimates varied, reflecting differences in study designs, type of fractures assessed and criteria used. In studies including men with both metastatic and non-metastatic disease, those who underwent orchidectomy had a significantly higher five-year cumulative incidence of osteoporotic fractures (12%) when compared with prostate patients who had not (1%)and a significantly higher risk of an osteoporotic fracture than the age-specific general population, with a standardised incidence ratio of 3.50.
Fractures in non-metastatic disease patients: For men with non-metastatic disease, in a small case series 21% of 81 men receiving castration therapies experienced a non-metastatic fracture over a median follow-up period of 52 months. In two large prospective studies, those who had received LHRH agonists had a significantly higher risk of hip or femur osteoporotic or traumatic fractures (risk ratios reported of 1.76 for a maximum of five years follow-up and 1.36 for a maximum of seven years follow-up) and a significantly higher risk (risk ratio = 1.50) of vertebral fractures for seven years maximal follow-up48 when compared with those who had not taken LHRH agonists. These findings are of particular clinical significance as these men without metastatic disease may be destined to live for many years.
The findings are directly applicable to the Australian population to the extent that LHRH agonists and, to a lesser extent, bilateral orchidectomy are the only primary forms of androgen therapy available on the PBS for locally advanced and metastatic disease either as monotherapy or part of CAB. The evidence provided in favour of bicalutamide monotherapy having a BMD-protective property is not relevant as this agent (and class of drug) is not approved for use as monotherapy in Australia.
Evidence summary and recommendations
| For men with prostate cancer, both LHRH agonists and bilateral orchidectomy significantly reduce bone mineral density, continuing to do so over time, resulting in an increased likelihood of pathological fracture of vertebral bodies and hips from osteoporosis.
There is insufficient evidence to make a definite comment on intermittent androgen deprivation.
|III-2, III-3, IV||, , , , , , , , , , , , , , , , , , , |
|There is insufficient evidence to comment on whether there is a worse or diminished effect on BMD with combined androgen blockade (CAB) versus castration monotherapy.||III-2, III-3, IV||, , , , , , , , , , , , , , , , , , , |
|Bicalutamide monotherapy is not associated with reductions in BMD.||II||, |
|Before commencing patients on androgen deprivation therapy, consider the likely duration of that treatment and the risk–benefit analysis for the indication for treatment, and take into account the effects on bone mineral density and risks of pathological fractures from osteoporosis.||C|
In addition, consider BMD measurements at baseline and subsequently during treatment with the possibility of instituting preventative measures (calcium, vitamin D and exercise) as appropriate for good musculoskeletal health, as well as the use of bisphosphonates as indicated by the Pharmaceutical Benefits Scheme for osteoporosis.
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- Sieber PR, Keiller DL, Kahnoski RJ, Gallo J, McFadden S. Bicalutamide 150 mg maintains bone mineral density during monotherapy for localized or locally advanced prostate cancer. J Urol 2004 Jun;171(6 Pt 1):2272-6, quiz 2435 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15126801.
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- Eriksson S, Eriksson A, Stege R, Carlström K. Bone mineral density in patients with prostatic cancer treated with orchidectomy and with estrogens. Calcif Tissue Int 1995 Aug;57(2):97-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7584882.
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