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Originally published as JCO Early Release 10.1200/JCO.2008.18.0851 on August 25 2008 © 2008 American Society of Clinical Oncology.
Endocrine Therapy and Bone Loss in Breast Cancer: Time to Close in the RANK(L)?
Haukeland University Hospital, Department of Oncology, Bergen, Norway Osteoporosis is a major health problem for the aging female population worldwide. Defined as a T-score below –2.5, it has been estimated that 75 million females world-wide may fall into this category.1 The problem is illustrated by the fact that, of the female population, approximately 15% are expected to have vertebral fracture and 20% will suffer from hip joint fracture during their life time. In some places, like Scandinavia, the life-time risk for a hip-joint fracture may exceed 25%,2 probably due to a combination of factors, including low UV exposure. With osteoporotic fractures being most prominent in the very aged population, studies have suggested an elevated mortality ratio of more than 6 with respect to hip fractures and more than 8 for clinical osteoporotic vertebral fractures at least during the first year after the incident.3 In addition, many patients will experience reduced quality of life, with osteoporotic fractures inflicting significant demands on the health care system apart from suffering by the individual. Tamoxifen, the endocrine agent which up to recently was first choice of therapy for patients with pre- as well as postmenopausal early (and advanced) breast cancer, imposes little problems to bone health. While causing a moderate loss in bone mineral density (BMD) among premenopausal women, in postmenopausal women it expresses beneficial effects on bone tissue, improving the density of the lumbar spine (spongious) but also the hip (compact) bone.4 The issue is different for aromatase inhibitors, or for estrogen deprivation in general. Following a peak level around age of 30, females express a continuous reduced bone density for the rest of their life, but with an enhanced rate of loss during the years of menopause.5 Considering that estrogens prevent bone loss,6 a major concern for implementing potent third-generation aromatase inhibitors for early breast cancer has been the potential of a detrimental effect on bone metabolism. While the novel potent third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) each increase bone fracture rate moderately compared to tamoxifen, such a comparison is influenced by the bone-sparing effect of tamoxifen in postmenopausal women.4 Compared with placebo, exemestane and letrozole each enhanced bone loss in the hip area over a 24-month period by a mean of 2.5%7 and 2.9%,8 respectively (both significant); similar figures for the lumbar area were 0.7%7 (nonsignificant) and 4.7%8 (significant), respectively. For the total population in the National Cancer Institute of Canada MA.17 trial, a nonsignificant increase in total fracture rate of 137 events versus 119 events were recorded after a median follow-up time of 30 months.9 Notably, the effects of exemestane on BMD were partially reversed one year after terminating treatment.10 Similar, in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) adjuvant breast cancer trial11 the increased fracture risk on anastrozole therapy disappeared shortly after terminating treatment. While these data may be reassuring with respect to today's standard of therapy, this may change in the future. The first reason for that relates to the optimal duration of aromatase inhibitor therapy; clearly, to extend treatment beyond 5 into perhaps a 10-year time frame— or even life-long therapy—amplifies the problem. The second reason is the potential for aggravated estrogen suppression—using combinations of luteinizing hormone-releasing hormone (LHRH) analogs and aromatase inhibitors in premenopausal women. Although the Austrian Breast and Colorectal Cancer Study Group trial 12 has reported similar efficacy of anastrozole and tamoxifen in premenopausal women when combined with an LHRH analog,12 more follow-up is needed for definitive conclusions. The same trial has previously shown significantly more bone loss in the LHRH plus anastrozole arm when compared to the LHRH plus tamoxifen arm.13 The effects of calcium plus vitamin D supplementation on osteoporotic fracture rate is modest.14 The effect of bisphosphonates, in particular when administered by the parenteral route, is well documented by the finding of the Austrian Breast Group that zoledronic acid may fully prevent bone loss due to combined use of goserelin plus anastrozole in premenopausal women.13 While multiple adverse effects from bisphosphonates have been recorded, in general they are mild,15 except for the rare, but feared, complications of osteonecrosis of the jaw16 and tubular necrosis.17
We now face a new therapeutic option for osteoporosis; inhibition of the receptor activator of NF- Denosumab is a fully human antibody against RANKL. An advantage for this compound compared with osteoprotegerin is its long half-life (33 to 46 days) after subcutaneous administration,21 allowing 3 (or 6) monthly intervals for administration. Denosumab has been evaluated as a therapeutic agent for postmenopausal women with a low bone density in a phase II study.22 A total of 412 women were randomly assigned to one of seven different denosumab regimens (6, 14, or 30 mg every 3 months or 14, 60, 100, or 210 mg every 6 months), each dose administered subcutaneously, compared with alendronate administered orally as 70 mg weekly or placebo. Except for the lowest dose of denosumab (14 mg every 6 months), denosumab was at least as good as alendronate with respect to improving bone density in the lumbar spine, hip area, and radial bone. In a randomized study comparing denosumab at four different doses (0.1 to 3.0 mg/kg body weight subcutaneously), Body et al21 recorded more profound suppression of plasma N-telopeptide levels with denosumab (except from the lowest dose) compared with intravenous pamidronate. In this issue of Journal of Clinical Oncology, Ellis et al23 present the first mature results of a study evaluating the effect of denosumab 60 mg administered every 6 months compared with placebo on BMD among 252 patients receiving adjuvant therapy with an aromatase inhibitor. Over a 24-month period, denosumab increased BMD in the lumbar area by an average of 5.5% versus placebo at 12 months, increasing to 7.6% at 24 months. After 24 months on therapy the increase in BMD in the total hip, femoral neck, trochanter, and radius was 4.7%, 3.5%, 5.9% and 6.1%, respectively. While the findings mirror the results from a trial of denosumab in postmenopausal women not receiving any endocrine therapy,22 Ellis et al's data presented contributes significantly to our knowledge about this agent. First, in contrast with the dose-finding phase II study by McClung et al,22 the study by Ellis and colleagues used only one dose of denosumab, so the number of patients in the denosumab 60 mg— but, even more importantly, the placebo arm— exceeded the number in each arm of the previous study by a factor of 3. More importantly, it confirmed that the beneficial effect of denosumab was not antagonized by extensive estrogen suppression by potent aromatase inhibitors. Endocrine therapy may interact with the RANK receptor system, illustrated by the finding of an increased plasma levels of osteoprotegerin during raloxifene therapy.24 Thus, the effect of denosumab on BMD among women undergoing estrogen suppressive therapy resembles the effect observed with zoledronic acid.13 At this stage, some comments on the design of the Ellis study are warranted. A strength of the study is the fact that it is double blind and placebo controlled. The incidence of adverse effects was higher than in the study by McClung et al.22 Yet, for both studies, the frequency of adverse effects was similar in the actively treated and placebo arms, underlining the importance of a placebo-controlled study design when assessing adverse effects for novel compounds. Similar, while hot flashes have been ascribed to use of aromatase inhibitors, in a placebo-controlled study, 31% of patients on exemestane reported this adverse effect compared with 24% of patients on placebo.7 In contrast, the heterogeneous patient population enrolled in the study by Ellis et al may be a subject to criticism. While applying strict rules limiting previous exposure to bisphosphonates, patients eligible for the study could have been on treatment with any of the novel third generation aromatase inhibitors (anastrozole, letrozole, or exemestane), there was no fixed interval regarding duration of endocrine treatment at enrollment, and patients previously exposed to other hormone agents like tamoxifen and raloxifen were allowed provided there was a wash-out phase of at least 6 weeks, which may be too short. Yet, this reflects a real life situation; any postmenopausal patient undergoing treatment with an aromatase inhibitor (as well as other agents) may be diagnosed with osteoporosis at any time on therapy. In the Ellis et al study, parameters like frequency of previous endocrine therapy and duration of aromatase inhibitor therapy were well balanced between the two arms. In addition, the authors analyzed their data carefully with respect to all these parameters, revealing no significant impact on outcome results. This is of particular interest with respect to the subgroup of patients (nearly 50% in each arm) previously exposed to other endocrine agents; others25 have shown an enhanced bone loss over the first 6-month time period when switching patients from tamoxifen to an aromatase inhibitor. However, considering the number of patients receiving exemestane (14 v 18 in the two arms), the number is too small for any valid comparison against the two nonsteroidal compounds. Denosumab seems a promising agent which may well become standard therapy for patients with breast cancer in the future. However, to make a full assessment, we need mature results of multiple large trial evaluating potent bisphosphonates as well as more studies on denosumab, and in particular head to head comparisons of these agents. Considering the potential of preventing skeletal metastases (see below), denosumab should be compared not only with biphosphonates administered orally but also with compounds such as zoledronic acid administered parenterally. For the moment, low toxicity as well as convenient route of administration (subcutaneous injection v intravenous infusions) make denosumab an attractive option. Yet, the issue of cost-effectiveness applies also to treatments associated with moderate costs in many countries.26 In contrast, an increased hip fracture rate has a detrimental influence on the cost/utility ratio for patients treated with aromatase inhibitors, in particular among the older groups.27 Thus, any advantage for one compound preventing fracture rate may strongly influence our decision making. However, the key issue as we continue to evaluate and compare these different agents, may not be minor efficacy differences in preventing osteoporosis, or minor differences in adverse effects, convenience of administration or drug costs, but their ability to prevent skeletal (and probably nonskeletal) metastases. While there is prior conflicting evidence that bisphosphonates may prevent skeletal and nonskeletal metastases,28 the beneficial effect of intravenous zoledronic acid therapy in preventing bone and nonbone metastases, recently presented by the Austrian Breast Cancer Study Group12 should, if and when confirmed, have a deep impact on our clinical practice. Results from other studies, like the AZURE (Does Adjuvant Zoledronic Acid reduce recurrence in patients with high risk, localized breast cancer?) trial, are also expected in the near future. Nitrogen-containing bisphosphonates such as zoledronic acid have been shown to enhance drug-induced apoptosis and to influence multiple growth factors in experimental systems.28,29 In contrast, RANKL may interact with different processes, such as inflammation,18 and may stimulate cancer cell migration.30 Osteoprotegerin has been shown to prevent skeletal metastases in experimental systems.31 Finally, estradiol has been shown to inhibit osteoprotegerin in MCF-7 cells,32 indicating that an interaction between estrogen suppression and RANKL inhibition at the tumor level may occur. While we may not be ready to choose RANKL for clinical use outside of clinical trials, results are promising, and we may soon be there. The need for more research in this area cannot be overemphasized. It may very well turn out that denosumab as well as bisphosphonates may be effective not only in preventing bone mineral loss, but also in preventing the development bone (and nonbone metastases). Potentially, there may be lack of cross-resistance between these two classes of compounds with respect to their antitumor efficacy. The lesson from endocrine therapy, in which there is a lack of complete cross-resistance among different agents, including different classes of aromatase inhibitors33 may be applicable with the different classes of bone loss preventing agents. The options are there for exploring different strategies with respect to the sequential as well as the combined use of these agents. As such, the article by Ellis et al in this issue represents an important step forward, demonstrating efficacy of denosumab in preventing bone loss induced by endocrine therapy. With more results from ongoing denosumab trials evaluating bone health, on the way, the next generation of trials should be aiming at closing in the RANK(L) pathway, with the aim of preventing bone metastases (and possibly nonbone metastases) from breast cancer. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Per E. Lønning, Pfizer Inc, AstraZeneca, Novartis Research Funding: None Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on August 25, 2008 REFERENCES 1. International Osteoporosis Foundation. www.osteofound.org 2. Kanis JA, Johnell O, De Laet C, et al: International variation in hip fracture probabilities: Implications for risk assessment. J Bone Mineral Res 17:1237-1244, 2002[CrossRef][Medline] 3. Cauley JA, Thompson DE, Ensrud KC, et al: Risk of mortality following clinical fractures. Osteoporos Int 11:556-561, 2000[CrossRef][Medline] 4. Powles TJ, Hickish T, Kanis JA, et al: Effect of tamoxifen on bone mineral density measured by dual-energy X-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 14:78-84, 1996[Abstract] 5. Ahlborg HG, Johnell O, Nilsson BE, et al: Bone loss in relation to menopause: A prospective study during 16 years. Bone 28:327-331, 2001[CrossRef][Medline] 6. Eastell R: Drug therapy: Treatment of postmenopausal osteoporosis. N Engl J Med 338:736-746, 1998 7. Lønning PE, Geisler J, Krag LE, et al: Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol 23:5126-5137, 2005 8. Perez EA, Jesse RG, Pritchard KI, et al: Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: A companion study to NCICCTG MA. 17. J Clin Oncol 24:3629-3635, 2006 9. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCICCTG MA. 17. J Natl Cancer Inst 97:1262-1271, 2005 10. Geisler J, Lonning PE, Krag LE, et al: Changes in bone and lipid metabolism in postmenopausal women with early breast cancer after terminating 2-year treatment with exemestane: A randomised, placebo-controlled study. Eur J Cancer 42:2968-2975, 2006[CrossRef][Medline] 11. Forbes JF, Cuzick J, Buzdar A, et al: Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 9:45-53, 2008[CrossRef][Medline] 12. Gnant M, Mineritsch B, Schippinger W, et al: Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with hormone-responsive stage I and II breast cancer: First efficacy results from ABCSG-12. J Clin Oncol 26:1006s, 2008 (abstr LAB4)[CrossRef] 13. Gnant MFX, Mlineritsch B, Luschin-Ebengreuth G, et al: Zoledronic acid prevents cancer treatment–induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: A report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 25:820-828, 2007 14. Jackson RD, LaCroix AZ, Gass M, et al: Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 354:669-683, 2006 15. Rosen LS, Gordon D, Kaminski M, et al: Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: A phase III, double-blind, comparative trial. Cancer J 7:377-387, 2001[Medline] 16. Ruggiero SL, Drew SJ: Osteonecrosis of the jaws and bisphosphonate therapy. J Dental Res 86:1013-1021, 2007 17. Markowitz GS, Fine PL, Stack JI, et al: Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int 64:281-289, 2003[CrossRef][Medline] 18. Fouque-Aubert A, Chapurlat R: Influence of RANKL inhibition on immune system in the treatment of bone diseases. Joint Bone Spine 75:5-10, 2008[CrossRef][Medline] 19. Lacey DL, Timms E, Tan HL, et al: Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165-176, 1998[CrossRef][Medline] 20. Kostenuik PJ: Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol 5:618-625, 2005[CrossRef][Medline] 21. Body JJ, Facon T, Coleman RE, et al: A study of the biological receptor activator of nuclear factor-kappa B ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res 12:1221-1228, 2006 22. McClung MR, Lewiecki EM, Cohen SB, et al: Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 354:821-831, 2006 23. Ellis GK, Bone HG, Chlebowski R, et al: Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol doi: 10.1200/JCO.2008.16.3832 [epub ahead of print on August 25, 2008] 24. Messalli EM, Mainini G, Scaffa C, et al: Raloxifene therapy interacts with serum osteoprotegerin in postmenopausal women. Maturitas 56:38-44, 2007[CrossRef][Medline] 25. Coleman R, Banks L, Girgis S, et al: Skeletal effects of exemestane on bone-mineral density bone biomarkers and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study. Lancet Oncol 8:119-127, 2007[CrossRef][Medline] 26. Guest JF, Clegg JP, Davie AM, et al: Costs and consequences of using pamidronate compared with zoledronic acid in the management of breast cancer patients in the UK. Curr Med Res Opin 21:805-815, 2005[CrossRef][Medline] 27. Lønning PE: Comparing cost/utility of giving an aromatase inhibitor as monotherapy for 5 years versus sequential administration following 2-3 or 5 years of tamoxifen as adjuvant treatment for postmenopausal breast cancer. Ann Oncol 17:217-225, 2006 28. Kohno N: Treatment of breast cancer with bone metastasis: Bisphosphonate treatment - current and future. Int J Clin Oncol 13:18-23, 2008[CrossRef][Medline] 29. Yuasa T, Kimura S, Ashihara E, et al: Zoledronic acid - a multiplicity of anti-cancer action. Curr Med Chem 14:2126-2135, 2007[CrossRef][Medline] 30. Jones DH, Nakashima T, Sanchez OH, et al: Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440:692-696, 2006[CrossRef][Medline] 31. Canon JR, Roudier M, Bryant R, et al: Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clin Exp Metastasis 25:119-129, 2008[CrossRef][Medline] 32. Rachner TD, Schoppet M, Niebergall U, et al: 17 beta-Estradiol inhibits osteoprotegerin production by the estrogen receptor-alpha-positive human breast cancer cell line MCF-7. Biochem Biophys Res Comm 368:736-741, 2008[CrossRef][Medline] 33. Lønning PE, Geisler J: Indications and limitations of third-generation aromatase inhibitors. Expert Opin Investig Drugs 17:723-739, 2008[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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B ligand (RANKL) system. The RANK receptor (receptor activator of nuclear factor kappa B) is expressed on the surface of osteoclasts as well as several other cell types in the body.
