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Originally published as JCO Early Release 10.1200/JCO.2008.20.4057 on January 26 2009 © 2009 American Society of Clinical Oncology.
Bisphosphonates and Bone Turnover in Premenopausal Women Receiving Adjuvant ChemotherapyCancer Centre, University of Calgary, Calgary, Alberta, Canada Awareness of cancer-induced bone loss (CIBL) and treatment-induced bone loss has increased among clinicians. Premenopausal women who undertake chemotherapy for breast cancer may lose up to 7% or more of their bone mass in the first year postchemotherapy.(1) Chemotherapy induces ovarian atrophy and estrogen decline at a rate depending on the regimen used, but is much faster than occurs with natural menopause. The bone loss after chemotherapy (and the luteinizing hormone-releasing hormone agonists) in the first year implies a rapid and profound switching to a net resorption pattern of bone turnover. That all this results in real morbidity was shown by Kanis et al,(2) who reported a four- to five-fold increase in the first-year incidence of vertebral fractures in women with newly diagnosed breast cancer compared with an age-matched cohort of healthy women in the metropolitan London area. Attempts to ameliorate the unwanted side effect of CIBL have concentrated on the use of bisphosphonates, and it has sometimes been assumed that standard postmenopausal doses of bisphosphonates will be useful in this patient group. This may not be the case. Hines et al(3) report in this issue of Journal of Clinical Oncology a phase III, placebo-controlled, randomized trial of the bisphosphonate risedronate for the prevention of bone loss in premenopausal women receiving adjuvant chemotherapy for primary breast cancer. This article has unexpected, but explainable, results. Two hundred and sixteen premenopausal women receiving chemotherapy were allocated to weekly oral risedronate or a placebo, and their bone mineral density (BMD) was measured at baseline and 1 year. The change in average BMD at 1 year in the lumbar spine was similar in both active and placebo groups; there was also little difference in the total hip and femoral neck bone mineral densities at 1 year. There was a nonsignificant numerical trend for patients receiving risedronate to have less bone loss at the lumbar spine, femoral neck, and total hip, as well as a numerical but nonsignificant trend for less osteopenia and osteoporosis in the risedronate group. Compliance was good, running at more than 86% in the risedronate arm, and tamoxifen and taxane usage was evenly spread in the two arms. All except two patients had systemic adjuvant chemotherapy, and most would be expected to undergo premature menopause. The results support the clinical impression that it is harder to suppress bone turnover and subsequent bone loss with standard postmenopausal osteoporosis dosing of bisphosphonates in premenopausal women undergoing chemotherapy-induced premature menopause than in older, postmenopausal women. Is this merely a question of inadequate drug dosing in the presence of a powerful wave of estrogen deprivation–induced bone resorption? Or does a pre- or perimenopausal state confer some kind of protection from the effects of bisphosphonates? Successful inhibition of bone turnover has been achieved in premenopausal women in several studies. Delmas et al(4) have previously reported in JCO that risedronate was effective in the treatment of chemotherapy-induced bone loss in premenopausal women. In this smaller study, the patients (all of whom were premenopausal before adjuvant chemotherapy) were postmenopausal on entry to the trial with endocrine levels in the postmenopause range. Furthermore, patients were administered 30 mg risedronate orally daily for 2 weeks with a 10-week rest period for a total of eight cycles. This regime differs from the 35 mg weekly dose in this study (a standard dose for osteoporosis), and although the total amount of drug during 1 year is similar (1,680 mg in the Delmas et al4 study v 1,820 mg in the Hines et al3 study), the initial loading of 420 mg risedronate over 2 weeks may have been sufficient to inhibit bone turnover. However, using a 35 mg weekly dosing of residronate, van Londen et al(5) have demonstrated improvement in hip structural geometry and BMD compared with a placebo group at 1 year. Powles et al(6) reported BMD measurements at 1 and 2 years in women with breast cancer receiving oral clodronate versus placebo demonstrating inhibition of bone turnover in premenopausal women at 1 year (–1.57% compared with –4.4%), although the effect was lost at 2 years (–3.99% compared with –3.94%), possibly related to compliance. Postmenopausal women experienced a significant gain in BMD during the first and second years compared with the placebo group. Gnant et al(7) showed the effectiveness of parenteral bisphosphonates in patients who were premenopausal on study entry. All received continuous goserelin for 3 years, thereby converting them to a biologic state similar to postmenopause. In that setting, intravenous zoledronic acid was effective in preventing the reduction in BMD seen in the untreated postmenopausal woman. Likewise, Hershman et al(8) have shown a reduction of BMD loss with zoledronic acid in premenopausal women with CIBL. Estrogens have a beneficial effect on bone health by suppressing bone resorption and enhancing formation. Mechanisms for this effect include acceleration of osteoclast apoptosis;(9) suppression of pro-inflammatory cytokines and interleukins from marrow cells; inhibition of receptor activator of nuclear factor kappa B ligand (RANK-L); and an increase of osteoblast/stromal cell secretion of transforming growth factor–beta, all of which reduce the activity or number of functional osteoclasts. Estrogens also stimulate bone formation by reducing apoptosis of osteoblast cell lines and increasing the secretion of transforming growth factor–beta, bone morphogenetic proteins, and insulin-like growth factor–1.(10,11) Conversely, estrogen deprivation after chemotherapy-induced ovarian atrophy leads to a wave of new remodeling sites by upregulation of T cells, osteoblasts, and stromal cells to produce a surge of cytokines such as interleukin-1, interleukin-6, tumor necrosis factor–alpha, and RANK-L, all of which leads to enhanced osteoclast activity, the net effect of which is to tip the balance of bone turnover towards resorption. Declining estrogen stimulation in the osteoblast seems to induce estrogen receptor–alpha binding to transcriptional enhancers of Fas-ligand which upregulate the Fas-ligand gene, apparently increasing osteoclast apoptosis through a paracrine mechanism.(12) Risedronate is an oral amino-bisphosphonate with potency (in rats) intermediate between alendronate and ibandronate. Its adverse effect profile is good, and it can be taken in a convenient weekly dose. Compliance in the Hines et al3 study was good at 86% (much the same as the placebo). If the authors could identify those women who became postmenopausal subsequent to chemotherapy and those who did not, it is possible that there might have been less of a decrease in BMD in the postmenopausal group with residronate therapy. An attempt at this analysis would have added value. It is also possible that the measurement of BMD itself does not give a full picture of what is happening in premenopausal women. Bisphosphonates to a varying degree inhibit new bone formation as well as bone resorption. Given that the increase in bone density seen with bisphosphonates is partially an effect of increased mineralization of old bone and partially an effect of inhibition of new, soft bone,(13) circumstances in which circulating estrogens encourage new, soft bone formation may explain some of the differential effect in bone density between premenopausal and postmenopausal women receiving bisphosphonate therapy. Although it could be hypothesized that high levels of circulating estrogens (as occurs in the pre- or perimenopausal state) confer some antagonistic action on the mechanism of action of bisphosphonates, the balance of evidence suggests otherwise. In trials of hormone replacement therapy and bisphosphonates in the osteoporosis literature, the effect on BMD tends to be additive.(14,15) The likeliest explanation for the results of the study by Hines et al3 is that in the setting of CIBL where estrogen deprivation occurs quickly, a higher dose of an oral bisphosphonate is required, or alternatively, parenteral therapy can be used. It will be important to further explore bisphosphonates as well as nonbisphosphonate bone-active therapies (such as the anti–RANK-L antibodies) for prevention of CIBL as well as prevention of bone metastases in this group of patients. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Hirbe A, Morgan EA, Uluçkan Ö, et al: Skeletal complications of breast cancer therapies. Clin Cancer Res 12:6309s–6314s, 2006. 2. Kanis JA, McCloskey EV, Powles T, et al: A high incidence of vertebral fractures in women with breast cancer. Br J Cancer 79:1179–1181, 1999.[CrossRef][Medline] 3. Hines SL, Mincey BA, Sloan JA, et al: Phase III randomized, placebo-controlled, double-blind trial of risedronate for the prevention of bone loss in premenopausal women undergoing chemotherapy for primary breast cancer. J Clin Oncol 27:1047–1053, 2009. 4. Delmas PD, Balena R, Confravreux E, et al: Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: A double-blind, placebo-controlled study. J Clin Oncol 15:955–962, 1997. 5. van Londen GJ, Perera S, Vujevich KT, et al: Effect of risedronate on hip structural geometry: A 1-year, double-blind trial in chemotherapy-induced post-menopausal women. Bone 43:274–278, 2008.[CrossRef][Medline] 6. Powles TJ, McCloskey E, Paterson AHG, et al: Oral clodronate and reduction in loss of bone mineral density in women with operable primary breast cancer. J Natl Cancer Inst 90:704–708, 1998. 7. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al: Adjuvant endocrine therapy plus zoledronic acid in pre-menopausal women with early stage breast cancer: 5-year follow-up of the ABCSG-12 bone mineral density sub-study. Lancet Oncol 9:840–849, 2008.[CrossRef][Medline] 8. Hershman DL, McMahon DJ, Crew KD, et al: Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early stage breast cancer. J Clin Oncol 26:4739–4745, 2008. 9. Kameda T, Mano H, Yuasa T, et al: Estrogen inhibits bone resorption by directly inducing apoptosis of the bone-resorbing osteoclasts. J Exp Med 186:489–495, 1997. 10. Ott SM: Reproductive hormones and skeletal health in young women. J Clin Endocrinol Metab 93:1175–1177, 2008. 11. Riggs BL, Khosla S, Melton IJ III: Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:279–302, 2002. 12. Krum SA, Brown M: Unraveling estrogen action in osteoporosis. Cell Cycle 7:1348–1352, 2008.[Medline] 13. Ott SA: Long-term safety of bisphosphonates. J Clin Endocrinol Metab 90:1897–1899, 2005. 14. Harris ST, Eriksen EF, Davidson M, et al: Effect of combined risedronate and hormone replacement therapies on bone mineral density in postmenopausal women. J Clin Endocrinol Metab 86:1890–1897, 2001. 15. Tseng LN, Sheu WH, Ho ES, et al: Effects of alendronate combined with hormone replacement therapy on osteoporotic postmenopausal Chinese women. Metabolism 55:741–747, 2006.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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