Osteoporosis in Breast and Prostate Cancer Survivors: Page 2 of 2
Osteoporosis in Breast and Prostate Cancer Survivors: Page 2 of 2
Prostate Cancer and Bone Loss Prostate cancer is one of the most common malignancies in men. It has been estimated that in 2005 there will be 232,000 new cases of prostate cancer causing approximately 30,000 deaths. Androgen-deprivation therapy (ADT) is the primary treatment for patients with metastatic disease; this therapy results in reduced morbidity and improved survival when combined with radiation therapy. Despite the fact that it can ameliorate survival, ADT is a palliative rather than curative treatment. More recently androgen-deprivation therapy has been used in patients presenting with locally advanced or locally recurrent disease. As these patients survive longer than patients with widespread metastatic disease, they are exposed longer to ADT and are at a higher risk to manifest the complications of chronic androgen deprivation. Androgen-deprivation therapy includes all treatments that will result in a reduction of testosterone level or blockade of testosterone action. These include bilateral orchiectomy, gonadotropin- releasing hormone (GnRH) agonists, antiandrogen therapy (androgen receptor blockers), and combined androgen blockade (GnRH agonist with antiandrogens). Androgen- deprivation therapy can result in loss of libido, erectile dysfunction, gynecomastia, loss of muscle, and loss of bone mass. In bone, testosterone deficiency results in increased bone turnover; osteoclast resorption exceeds bone formation resulting in a net loss of bone. Several prospective studies have investigated the effects of ADT on bone mass (Table 4). Despite the small number of patients enrolled in these studies, they clearly demonstrate sub- stantial bone loss.[7,8,32-34] Maillefert and colleagues evaluated BMD in six patients undergoing ADT; within 18 months they observed a 7.1% and 6.6% reduction in bone mass of the lumbar spine and femoral neck, respectively. Mittan and colleagues evaluated BMD at baseline and at 6 and 12 months after initiating ADT (15 patients), and compared the results to 13 sex-matched controls without prostate cancer. While no bone loss was observed in the control group, patients receiving ADT lost a significant amount of bone in the hips and distal radius. Another study by Daniell showed a 10% decrease in BMD 2 years following orchiectomy (10 patients) and a 6.5% reduction in bone mass in 16 men receiving GnRH agonist alone or in combination with antiandrogens. In summary, the observed rates of bone loss during ADT are higher than those associated with menopause. The rates observed vary by study population and by the type of ADT, but ranged from 2% to 8% in the lumbar spine and from 1.8% to 6.5% in the femoral neck after 12 months of continuous ADT.[32,35] The fracture risk in these patients has been retrospectively reviewed (Table 5). Fractures start to occur within 2 years of treatment and increase in frequency with longer durations of ADT. Melton and colleagues reported a fracture prevalence of 40% in a group of patients on ADT (bilateral orchiectomy) for a mean of 15 years. In a recent study, Shahinian and colleagues evaluated the records of 50,613 men with prostate cancer who were listed in the linked database of the Surveillance, Epidemiology, and End Results (SEER) program and Medicare from 1992 and 1997 and found that ADT was associated with an increase in risk of fracture; the risk was proportional to the number of doses of GnRH agonist administered in the first year after diagnosis. How to Prevent or Treat Bone Loss in Cancer Patients Early screening and identification of patients at increased risk for bone loss is a key element of management of bone health in breast and prostate cancer patients. The American Society of Clinical Oncology has published guidelines for the identification and management of bone loss in breast cancer patients. These guidelines recommend that any patient at risk for osteoporosis undergo a DXA scan to evaluate the bone mineral density followed by appropriate treatment. High-risk patients include women older than 65 years of age, postmenopausal women receiving aromatase inhibitors, women who develop premature menopause as a result of the breast cancer treatment, and patients with other known risk factors for osteoporosis (Table 6). All patients with breast cancer, including the ones not at risk for osteoporosis, should be counseled on lifestyle changes and appropriate calcium and vitamin D supplementation. All patients with natural or drug-induced estrogen deficiency should have periodic evaluation of their bone mass in addition to calcium/vitamin D supplementation and exercise; patients with osteoporosis or significant bone loss over time should be started on therapy. The American Society of Clinical Oncology has not yet provided guidelines for maintenance of bone health in prostate cancer patients. However, several authors have published recommendations for this group of patients. In a recent publication, Diamond and colleagues recommended that patients with risk factors for fractures (on ADT, previous fracture) undergo assessment of their bone mass by using DXA or QCT. Patients with osteoporosis should be started on treatment, patients with osteopenia should have a repeat BMD evaluation in 6 to 12 months, and patients with normal BMD should be reassessed in 2 years. Patients with osteoporotic fractures confirmed by imaging studies should also be started on therapy. While these guidelines are an important first step, there are compelling reasons for being more proactive. Current guidelines from several bone (www.nof.org/professionals/ clinical.htm), endocrine, and rheumatologic[ 39] societies recommend prevention of bone loss rather than the more passive approach of waiting until it happens suggested by oncologic guidelines. Current therapies for osteoporosis make it difficult to increase bone mass by more than 10%, arguing persuasively for a strategy focused on prevention. Oncologists should be mindful of these guidelines. There are several drugs approved or under investigation for treatment of osteoporosis.[40-44] The two classes of drugs available include bone resorption inhibitors and anabolic agents. The bone resorption inhibitors include estrogen, selective estrogen receptor modulators (SERMS), nasal calcitonin (Miacalcin), bisphosphonates, and the RANKL monoclonal antibody.[40,41,43,44] The only anabolic agent currently approved for use in osteoporosis is teriparatide (Forteo)-recombinant human parathyroid hormone (hPTH 1-34)-a potent enhancer of bone formation that results in significant improvement of bone mineral density in women with postmenopausal osteoporosis and in men with osteoporosis.[ 42] Teriparatide has not yet been investigated in breast or prostate cancer patients; therefore the risks and benefits of this agent should be carefully considered before using it in this group of patients. There is a fully humanized monoclonal antibody against RANKL (AMG 162) that has been under investigation and is a promising bone resorption inhibitor. AMG 162 has been investigated in postmenopausal osteoporosis in phase I and II studies. A single subcutaneous dose of AMG 162 (1 mg/kg or 60 mg) resulted in suppression of bone resorption for more than 6 months and increase in bone mineral density. Studies with AMG 162 in breast cancer patients for control of bone loss as well as for bone metastatic disease are currently under way. Bisphosphonates are potent inhibitors of osteoclast differentiation and activity. This class of drugs is widely used for treatment of postmenopausal, steroid-induced, and male osteoporosis. In breast cancer patients, several studies have addressed the role of bisphosphonates in preventing bone loss after chemotherapy-induced premature menopause. Clodronate and risedronate (Actonel), both oral bisphosphonates, have been investigated and were shown to be effective in reducing the rate of bone loss.[45,46] The use of intravenous bisphosphonates in these patients is still under investigation, but preliminary data from a study that has evaluated the effect of zoledronic acid (Zometa) in patients receiving tamoxifen or anastrozole have indicated that zoledronic acid is able to counteract the bone loss induced by anastrozole in these patients. In prostate cancer patients, intravenous bisphosphonates have proven to reduce bone loss in at least two studies. Smith and colleagues have investigated the effects of both intravenous pamidronate (Aredia) and zoledronic acid on bone mass in patients receiving androgen therapy and compared their bone mineral densities to individuals who received androgen-deprivation therapy alone.[48,49] In the pamidronate study, 47 patients who were being treated with androgen-deprivation therapy were randomized to receive pamidronate at 60 mg or placebo every 3 months. Pamidronate treatment protected patients from developing the bone loss associated with ADT. Another study investigated the use of zoledronic acid vs placebo in patients undergoing androgen deprivation therapy. Zoledronic acid was given at a dose of 4 mg every 3 months for 12 months. Patients who received zoledronic acid were not only protected against bone loss, but gained a significant amount of bone mass. Diamond and colleagues investigated the effect of an oral bisphosphonate (etidronate [Didronel]) in patients undergoing ADT. Despite the small number of patients included in the study, they were able to show a gain of bone mass at the lumbar spine in patients treated with etidronate. As estrogen plays an important role in male bone metabolism and can be used in patients with prostate cancer, it has been studied as a potential treatment for ADT-induced bone loss. Taxel and colleagues investigated the effects of micronized estradiol on bone turnover in prostate cancer patients on ADT; they observed a significant reduction in bone turnover markers.[ 51] Subsequently, two studies have addressed the question of whether estrogen or a SERM is a potential treatment for prevention or treatment of osteoporosis associated with ADT. Smith and colleagues have studied the effects of raloxifene (Evista), a SERM, in patients with nonmetastatic prostate cancer being treated with ADT. A total of 48 patients were randomized to receive raloxifene or placebo. At 12 months, patients on raloxifene maintained their bone mass at the spine and hips while patients receiving placebo suffered a reduction in BMD. Ockrim et al investigated transdermal estradiol in patients with prostate cancer and also noted a significant improvement in bone mass with this agent. Conclusion In conclusion, gonadal insufficiency caused by cancer treatment can cause rapid bone loss in women with breast cancer or men with prostate cancer. Therefore, high-risk patients should be assessed by bone mineral density testing. Patients with severe osteopenia or osteoporosis should undergo early treatment to prevent fractures, pain, and deformities associated with osteoporosis.
Dr. Hoff has received grants and research support from Novartis Pharmaceuticals.
1. Pfeilschifter J and Diel IJ: Osteoporosis due to cancer treatment: Pathogenesis and management. J Clin Oncol 18:1570-1593, 2000.
2. Headley JA, Theriault RL, LeBlanc A, et al: Pilot study of bone mineral density in breast cancer patients treated with adjuvant chemotherapy. Cancer Invest 16:6-11, 1998.
3. Vehmanen L, Saarto T, Elomaa I, et al: Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment. Eur J Cancer 37:2373-2378, 2001.
4. Shapiro CL, Manola J, Leboff M: Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 19:3306-3311, 2001.
5. Eastell R: Effect of anastrozole on bone mineral density: 2-year results of the Arimidex (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial (abstract M070). The 25th ASBMR Annual Meeting, S312, 2003.
6. Melton LJ, Alothman KI, Khosla S, et al: Fracture risk following bilateral orchiectomy. J Urol 169:1747-1750, 2003.
7. Ross RW and Small EJ: Osteoporosis in men treated with androgen deprivation therapy for prostate cancer. J Urol 167:1952-1956, 2002.
8. Daniell HW, Dunn SR, Ferguson DW, et al: Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 163:181-186, 2000.
9. Consensus Development Conference V, 1993. Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 90:646-650, 1994.
10. Center JR, Nguyen TV, Schneider D, et al: Mortality after all major types of osteoporotic fracture in men and women: An observational study. Lancet 353:878-882, 1999.
11. Kanis JA, Melton LJ III, Christiansen C, et al: The diagnosis of osteoporosis. J Bone Miner Res 9:1137-1141, 1994.
12. Greenspan SL, Maitland-Ramsey L, Myers E: Classification of osteoporosis in the elderly is dependent on site-specific analysis. Calcif Tissue Int 58:409-414, 1995.
13. Manolagas SC, Jilka RL: Mechanisms of disease: Bone marrow, cytokines, and bone remodeling: Emerging insights in the pathophysiology of osteoporosis. N Engl J Med 332: 305-311, 1995.
14. Riggs BL, Khosla S, Melton LJ III: A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res13:763-773, 1998.
15. Orwoll ES, Klein RF: Osteoporosis in men. Endocr Rev 16:87-116, 1995.
16. Frost HM: Bone Biodynamics, p 315. Boston, Little, Brown, 1964.
17. Boyle WJ, Simonet SW, Lacey DL: Os teoclast differentiation and activation. Nature 23:337-341, 2003.
18. Hofbauer LC, Schoppet M: Clinical implications of the osteoprotegerin/RANKL/ RANK system for bone and vascular diseases. JAMA 292:490-495, 2004.
19. Lacey DL, Timms E, Tan H-L, et al: Osteoprotegerin (OPG) ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165-176, 1998.
20. Eghbali-Fatourechi G, Khosla S, Sanyal A, et al: Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 111:1221-1230, 2003.
21. Hammett-Stabler CA: The use of biochemical markers in osteoporosis. Clin Lab Med 24:175-97, 2004.
22. American Cancer Society: Statistics. http://www.cancer.org/docroot/STT/stt_0.asp
23. Bland KI, Menck HR, Scott Conner CE et al: The National Cancer Data Base 10-year survey of breast carcinoma treatment at hospitals in the US. Cancer 83:1262-1273, 1998.
24. Kanis JA, McCloskey EV, Powles T, et al: A high incidence of vertebral fracture in women with breast cancer. Br J Cancer 79:1179-1181, 1999.
25. Winter EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: Status report 2004. J Clin Oncol 23:619-629, 2005.
26. Baum M, Buzdar A, Cuzick J, et al: Anastrozole alone versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: Results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 98:1802-1810, 2003.|
27. Goss P, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003.
28. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004.
29. Fornander T, Rutqvist LE, Sjoberg HE, et al: Long-term adjuvant tamoxifen in early breast cancer: Effect on bone mineral density in postmenopausal women. J Clin Oncol 8:1019-1024, 1990.
30. Love RR, Mazess RB, Tormey DC, et al: Bone mineral density in women with breast cancer treated with adjuvant tamoxifen for at least two years. Breast Cancer Res Treat 12:297-301, 1988.
31. Ward RL, Morgan G, Dalley D, et al: Tamoxifen reduces bone turnover and prevents lumbar spine and proximal femoral bone loss in early postmenopausal women. Bone Miner 22:87-94, 1993.
32. Krupski TL, Smith MR, Lee WC, et al: National history of bone complications in men with prostate carcinoma initiating androgen deprivation therapy. Cancer 101:541-549, 2004.
33. Maillefert JF, Sibilia J, Michel F, et al: Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. J Urol 161:1219- 1222, 1999.
34. Mittan D, Lee S, Miller E, el al: Bone loss following hypogonadism in men with prostate cancer treated with GnRH Analogs. J Clin Endocrinol Metab 87:3656-3661, 2002.
35. Diamond TH, Higano CS, Smith MR, et al: Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: Recommendations for diagnosis and therapies. Cancer 100:892-899, 2004.
36. Shahinian VB, Kuo Y-F, Freeman JL, et al: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352:154-164, 2005.
37. Hillner BE, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:1-16, 2003.
38. AACE Osteoporosis Task Force: American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis, 2001 edition, with selected updates for 2003. Endocr Pract 9:545- 564, 2003.
39. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocorticoid- Induced Osteoporosis. Arthritis Rheum 44:1496-1503, 2001.
40. Black DM, Cummings SR, Karpf DB, et al: Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348:1535-1541, 1996.
41. McLung MR, Geusens P, Miller PD, et al: Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 344:333- 340, 2001.
42. Neer RM, Arnaud CD, Zanchetta JR, et al: Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434-1441, 2001.
43. Reid IR, Brown JP, Burckhardt P, et al: Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 346:653-661, 2002.
44. Bekker PJ, Holloway DL, Rasmussen AS, et al: A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 19:1059-1066, 2004.
45. Saarto T, Blomqvist C, Valimaki M, et al: Clodronate improves bone mineral density in postmenopausal breast cancer patients treated with adjuvant antiestrogens. Br J Cancer 75:602-605, 1997.
46. Delmas PD, Balena R, Confraveux E, et al: Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: A doubleblind, placebo-controlled study. J Clin Oncol 15:955-962, 1997.
47. Gnant M, Hausmaninger H, Samonigg H, et al: Changes in bone mineral density caused by anastrozole or tamoxifen in combination with goserelin (± zoledronate) as adjuvant treatment for hormone receptor-positive premenopausal breast cancer: results of a randomized multicenter trial (abstract 12). 25th Annual San Antonio Breast Cancer Symposium, December 11-14, 2002.
48. Smith MR, McGovern FJ, Zietman AL, et al: Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 345:948-955, 2001.
49. Smith MR, Eastham J, Gleason DM, et al: Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 169:2008-2012, 2003.
50. Diamond T, Campbell J, Bryant C, et al: 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 83:1561- 1566, 1998.
51. Taxel P, Fall PM, Albertsen PC, et al: The effect of micronized estradiol on bone turnover and calcitropic hormones in older men receiving hormonal suppression therapy for prostate cancer. J Clin Endocrinol Metab 11:4907-4913, 2002.
52. Smith MR, Fallon MA, Lee H, et al: Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: A randomized controlled trial. J Clin Endocrinol Metabol 8:3841-3846, 2004.
53. Ockrim JL, Lalani EN, Banks LM, et al: Transdermal estradiol improves bone density when used as single agent therapy for prostate cancer. J Urol 172: 2203-2207, 2004.
54. Eriksson S, Eriksson A, Stege R, et al: Bone mineral density in patients with prostatic cancer treated with orchidectomy and with estrogens. Calcif Tissue Int 57:97-99, 1995.
55. Higano CS, Stephens C, Nelson P, et al: Prospective serial measurements of BMD in prostate cancer patients without bone metastases treated with intermittent androgen suppression. Proc Am Soc Clin Oncol 18: 314a, 1999.
56. Daniell HW, Dunn SR, Ferguson DW, et al: Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 163:181-186, 2000.
57. Berruti A, Dogliotti L, Terrone C, 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. J Urol 167:2361-2367, 2002.
58. Townsend SF, Sanders WH, Northway RO, et al: Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate adenocarcinoma. Cancer 79:545-550, 1997.
59. Hatano T, Oishi Y, Furuta A, et al: Incidence of bone fracture in patients receiving luteinizing hormone-releasing agonists for prostate cancer. BJU Int 86:449-452, 2000.
60. Oefelein MG, Richiutti V, Conrad W, et al: Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol 168:1005-1007, 2002.