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?

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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[1][2] 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.[3] 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.[4] 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.[5] 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.[6] In contrast oestrogen monotherapy may preserve BMD[7] 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.[1][2] 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[8][9] 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.[10]

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%)[11]and a significantly higher risk of an osteoporotic fracture than the age-specific general population, with a standardised incidence ratio of 3.50.[12]

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[13]. 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)[14][15] 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.

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Evidence summary and recommendations

Evidence summary Level References
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 [7], [8], [11], [14], [4], [5], [9], [10], [12], [6], [13], [16], [17], [18], [19], [20], [21], [22], [23], [24]
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 [7], [8], [11], [14], [4], [5], [9], [10], [12], [6], [13], [16], [17], [18], [19], [20], [21], [22], [23], [24]
Bicalutamide monotherapy is not associated with reductions in BMD. II [1], [2]
Evidence-based recommendationQuestion mark transparent.png Grade
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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References

  1. 1.0 1.1 1.2 Smith MR, Goode M, Zietman AL, McGovern FJ, Lee H, Finkelstein JS. Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition. J Clin Oncol 2004 Jul 1;22(13):2546-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15226323.
  2. 2.0 2.1 2.2 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.
  3. Diamond TH, Higano CS, Smith MR, Guise TA, Singer FR. Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: recommendations for diagnosis and therapies. Cancer 2004 Mar 1;100(5):892-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14983482.
  4. 4.0 4.1 4.2 Mittan D, Lee S, Miller E, Perez RC, Basler JW, Bruder JM. Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab 2002 Aug;87(8):3656-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12161491.
  5. 5.0 5.1 5.2 Lee H, McGovern K, Finkelstein JS, Smith MR. Changes in bone mineral density and body composition during initial and long-term gonadotropin-releasing hormone agonist treatment for prostate carcinoma. Cancer 2005 Oct 15;104(8):1633-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16116596.
  6. 6.0 6.1 6.2 Higano C, Shields A, Wood N, Brown J, Tangen C. Bone mineral density in patients with prostate cancer without bone metastases treated with intermittent androgen suppression. Urology 2004 Dec;64(6):1182-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15596194.
  7. 7.0 7.1 7.2 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.
  8. 8.0 8.1 8.2 Bergström I, Gustafsson H, Sjöberg K, Arver S. Changes in bone mineral density differ between gonadotrophin-releasing hormone analogue- and surgically castrated men with prostate cancer--a prospective, controlled, parallel-group study. Scand J Urol Nephrol 2004;38(2):148-52 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15204403.
  9. 9.0 9.1 9.2 Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z, Stratte PT. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000 Jan;163(1):181-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10604342.
  10. 10.0 10.1 10.2 Diamond T, Campbell J, Bryant C, Lynch W. The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma: longitudinal evaluation and response to intermittent cyclic etidronate therapy. Cancer 1998 Oct 15;83(8):1561-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9781950.
  11. 11.0 11.1 11.2 Daniell HW. Osteoporosis after orchiectomy for prostate cancer. J Urol 1997 Feb;157(2):439-44 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8996327.
  12. 12.0 12.1 12.2 Melton LJ 3rd, Alothman KI, Khosla S, Achenbach SJ, Oberg AL, Zincke H. Fracture risk following bilateral orchiectomy. J Urol 2003 May;169(5):1747-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12686824.
  13. 13.0 13.1 13.2 Janoff DM, Peterson C, Mongoue-Tchokote S, Peters L, Beer TM, Wersinger EM, et al. Clinical outcomes of androgen deprivation as the sole therapy for localized and locally advanced prostate cancer. BJU Int 2005 Sep;96(4):503-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16104900.
  14. 14.0 14.1 14.2 Smith MR, Boyce SP, Moyneur E, Duh MS, Raut MK, Brandman J. Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer. J Urol 2006 Jan;175(1):136-9; discussion 139 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16406890.
  15. Smith MR. Therapy Insight: osteoporosis during hormone therapy for prostate cancer. Nat Clin Pract Urol 2005 Dec;2(12):608-15; quiz 628 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16474548.
  16. 16.0 16.1 Dickman PW, Adolfsson J, Aström K, Steineck G. Hip fractures in men with prostate cancer treated with orchiectomy. J Urol 2004 Dec;172(6 Pt 1):2208-12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15538233.
  17. 17.0 17.1 Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005 Jan 13;352(2):154-64 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15647578.
  18. 18.0 18.1 Krupski TL, Smith MR, Lee WC, Pashos CL, Brandman J, Wang Q, et al. Natural history of bone complications in men with prostate carcinoma initiating androgen deprivation therapy. Cancer 2004 Aug 1;101(3):541-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15274067.
  19. 19.0 19.1 Berruti A, Dogliotti L, Terrone C, Cerutti S, Isaia G, et al. Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. Gruppo Onco Urologico Piemontese (G.O.U.P.), Rete Oncologica Piemontese,. J Urol 2002 Jun;167(6):2361-7; discussion 2367 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11992038.
  20. 20.0 20.1 Townsend MF, Sanders WH, Northway RO, Graham SD Jr. Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma. Cancer 1997 Feb 1;79(3):545-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9028366.
  21. 21.0 21.1 Smith MR, Fallon MA, Lee H, Finkelstein JS. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab 2004 Aug;89(8):3841-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15292315.
  22. 22.0 22.1 López AM, Pena MA, Hernández R, Val F, Martín B, Riancho JA. Fracture risk in patients with prostate cancer on androgen deprivation therapy. Osteoporos Int 2005 Jun;16(6):707-11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15714259.
  23. 23.0 23.1 Maillefert JF, Sibilia J, Michel F, Saussine C, Javier RM, Tavernier C. Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. J Urol 1999 Apr;161(4):1219-22 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10081873.
  24. 24.0 24.1 Agarwal MM, Khandelwal N, Mandal AK, Rana SV, Gupta V, Chandra Mohan V, et al. Factors affecting bone mineral density in patients with prostate carcinoma before and after orchidectomy. Cancer 2005 May 15;103(10):2042-52 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15830347.

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Appendices