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Originally published as JCO Early Release 10.1200/JCO.2007.12.3430 on June 18 2007 © 2007 American Society of Clinical Oncology.
Bone Density in Breast Cancer: When to Intervene?
University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA The increased fracture risk associated with treatment-related loss of bone mineral density is an increasingly important problem for women diagnosed with breast cancer. In premenopausal patients, chemotherapy-induced ovarian failure and adjuvant ovarian suppression/ablation can lead to rapid and profound loss of bone mineral density.1 In addition, in contrast to its bone mineral density–preserving effects seen in the postmenopausal setting, tamoxifen is associated with decreases in bone mineral density in premenopausal women.2,3 In postmenopausal patients, the progressive loss of bone density associated with natural ovarian failure and aging, and the increasingly common use of adjuvant aromatase inhibition, which exacerbates the estrogen deprivation state, contribute to increased osteoporosis and fracture rates. In recognition of the increasing impact of cancer treatment on our patients' bone health, the 2003 American Society of Clinical Oncology (ASCO) clinical practice guideline panel on bisphosphonates and bone health in women with breast cancer stated strongly that "oncology professionals, especially medical oncologists, need to take an expanded role in the routine and regular assessment of osteoporosis risk in women with breast cancer."4 The optimal use of bisphosphonates in preventing fractures and loss of bone mineral density in early-stage breast cancer patients receiving systemic cancer treatment is under evaluation. A recent issue of the Journal of Clinical Oncology (March 1, 2007) included results of two clinical trials evaluating zoledronic acid as prevention for cancer treatment–induced bone loss. Gnant et al5 presented 3-year bone density results from a premenopausal adjuvant endocrine therapy trial conducted by the Austrian Breast Cancer Study group 12 (ABCSG-12), whereas Brufsky et al6 reported 1-year bone density results for the Zometa-Femara Adjuvant Synergy Trial (Z-FAST) in postmenopausal women.
In the ongoing 1,800-patient primary ABCSG-12 trial, premenopausal breast cancer patients receive ovarian suppression with a gonadotropin-releasing hormone (GnRH) analog, goserelin, and are randomly assigned to also receive either anastrozole or tamoxifen. In a second randomization, patients receive or do not receive zoledronic acid every 6 months. The ABCSG-12 bone density subprotocol was designed to evaluate prospectively the effect of these endocrine regimens on the skeleton, as well as the impact of zoledronic acid on preserving bone density. Four hundred women at three of the study's clinical centers underwent (or will undergo) dual-energy x-ray absorptiometry (DEXA) scans at baseline, 6, 12, 36, and 60 months. The current report includes DEXA results on approximately 25% of patients at 36 months. As reported, the endocrine regimens led to substantial bone mineral density loss that increased with treatment duration, and was most severe in patients receiving anastrozole/goserelin. As expected in this premenopausal age group, the majority of bone density measurements were within normal range at baseline, with
In the Z-FAST study, 602 postmenopausal women with early-stage breast cancer and T scores Zoledronic acid clearly is effective in preventing cancer treatment–associated bone mineral density loss. In the premenopausal setting, the ABCSG-12 trial shows that zoledronic acid effectively prevents loss of bone density at 3 years in women undergoing ovarian suppression in combination with tamoxifen or anastrozole.5 In postmenopausal women, zoledronic acid has demonstrated effectiveness in preserving bone mineral density in patients receiving adjuvant letrozole at 12-month evaluation points in the North American Z-FAST study reported by Brufsky et al,6 and the similarly designed international ZOmeta-Femara Adjuvant Synergy Trial (ZO-FAST) trial.7 In nonmetastatic prostate cancer patients receiving androgen-deprivation therapy, intravenous zoledronic acid administered every 3 months has demonstrated preservation of bone mineral density.8 In addition, in osteoporotic postmenopausal women without breast cancer, several dosing schedules of intravenous zoledronic acid, including 4 mg annually, have demonstrated efficacy in increasing bone density.9 None of these trials, most of which have a short follow-up, have demonstrated a reduction in fractures. Whether early implementation of bisphosphonates will influence long-term fracture rates in newly diagnosed breast cancer patients remains a critical and clinically important question. Is zoledronic acid, a potent third-generation intravenous amino-bisphosphonate, the optimal agent for preventing cancer treatment–related bone loss? Evidence from several clinical trials indicates that other intravenous and oral bisphosphonates can be effective in maintaining bone density in breast cancer patients receiving endocrine or chemotherapy. Intravenous pamidronate and the oral agents clodronate and risedronate have been shown to diminish treatment-related bone density loss in breast cancer patients, and additional studies with these drugs are ongoing.10-13 Alendronate has been shown to protect against bone mineral density loss in a small trial of women receiving 6 months of GnRH analog therapy for noncancer indications.14 None of these agents have been compared head-to-head in the cancer treatment–induced bone loss setting, and several additional antiresorptive agents approved for the prevention and treatment of osteoporosis in the general population have not been tested specifically in cancer patients. The intravenous route of administration of zoledronic acid may be viewed as an advantage by some women and a disadvantage and inconvenience by others, compared to daily, weekly, or monthly dosing schedules of oral bisphosphonates. How much of the loss of bone mineral density observed in the ABCSG-12 and Z-FAST studies will be reversible on cessation of endocrine therapy? In the ABCSG-12 trial, patients will complete their endocrine therapy at 36 months, with a follow-up 60-month DEXA scan planned. Because adjuvant chemotherapy was excluded, it is expected that many of these women will regain ovarian function with cessation of goserelin. Although the primary end point of the Z-FAST trial was lumbar spine bone mineral density at 12 months, patients will continue receiving letrozole and their assigned zoledronic acid dosing regimen for a full 5 years, and annual DEXAs will continue until year 5. It will be of great interest to follow bone mineral density changes after cessation of endocrine and bisphosphonate therapy. Evidence for at least partial post-treatment recovery of endocrine therapy–induced bone mineral density loss has been reported recently in both premenopausal breast cancer patients treated with GnRH analog with or without tamoxifen and in postmenopausal women treated with exemestane.15,16 When considering the use of any drug, all potential risks, benefits, adverse effects, and costs must be weighed carefully. As a group, bisphosphonates are generally well tolerated when administered either orally or intravenously. With administration of intravenous bisphosphonates, mild to moderate infusion-related flu-like symptoms, including nausea, vomiting, fever, and myalgias, can be seen, but generally are limited to the first infusion. There is also a small risk of renal impairment that is related to the dose, infusion time, and infusion volume, which has led to renal-adjusted dose modifications on the zoledronic acid package label. In the ABCSG-12 study, no renal dysfunction was reported for the zoledronic acid arm. In the Z-FAST study, one patient in the up-front zoledronic acid group experienced a grade 1 increase in serum creatinine (serum creatinine > 1.5x the upper limit of normal). No occurrences of bisphosphonate-associated osteonecrosis of the jaw have been observed in either study. The short-term safety profiles of twice-yearly zoledronic acid observed in these studies seems favorable. One of the biggest barriers to the widespread use of up-front zoledronic acid (or other bisphosphonate) to prevent bone loss in early-stage breast cancer patients initiating systemic therapy would seem to be the not insubstantial drug- and infusion-related costs. How can we select early-stage breast cancer patients optimally and cost effectively who will benefit most from the addition of zoledronic acid to preserve bone mineral density? Who should receive up-front versus delayed treatment? Is bone loss irreversible, and is there harm incurred in delaying therapy until patients meet criteria for significant increased fracture risk? Are DEXA scans the optimal screening tool, and what is the optimal screening interval? Do markers of bone turnover provide additional information to help in our decision making? Ongoing trials will provide answers to some, but not all, of these questions. It is clear that a strong body of evidence supports the early detection and treatment of osteoporosis.17 In stratifying patients at greatest risk of future fracture, low bone mineral density and a prior history of fracture are two of the strongest risk factors. The ASCO Breast Cancer Bisphosphonate Guideline specifically identifies patients receiving ovarian suppression and/or aromatase inhibitors as being at particularly high risk for osteoporosis, and recommends a baseline DEXA scan in these patients with annual DEXA follow-up.4 This recommendation for annual DEXA scans has been somewhat controversial, but it should be noted that the commonly practiced biannual DEXA interval in postmenopausal women is based primarily on insurance/Medicare coverage and not on scientific data. Per the ASCO guideline, breast cancer patients who meet DEXA criteria for osteoporosis should have pharmacologic therapy initiated. The guideline recommends that patients with osteopenia should have therapy individualized, given that current evidence does not support routine intervention in this group. Initiating pharmacologic therapy for significant osteopenia (ie, T scores in the –2.0 range) in breast cancer patients with early ovarian failure or receiving aromatase inhibitors would certainly seem reasonable, giving data on expected annual rates of bone loss in this population. The authors of the ABCSG-12 study also reasonably suggest that women who lose more than 10% bone mineral density in the first year of treatment might be good candidates for initiation of pharmacologic intervention. Defining fracture risk and determining when to initiate pharmacologic intervention in breast cancer patients who do not meet criteria for osteoporosis must go beyond simple bone density numbers, and must take into account type of cancer therapy, patient age, and other risk factors. It is in this group of women that we currently struggle for answers when weighing risks, benefits, and costs of antiosteoporotic monitoring and treatment, and the population in which we need more data. Are there agents that should not be used in managing skeletal health in breast cancer patients? Both estrogen and the selective estrogen receptor modulator raloxifene have documented efficacy in preserving bone mineral density in healthy postmenopausal women.18,19 Neither are recommended for this indication in women with a diagnosis of breast cancer. In the case of raloxifene, a selective estrogen receptor modulator similar to tamoxifen, concurrent use of raloxifene and aromatase inhibitors is specifically not recommended based on the adverse effect of combining tamoxifen with anastrozole seen in the Anastrozole and Tamoxifen, Alone and in Combination trial.20 In addition, concurrent and/or sequential use of tamoxifen and raloxifene is not recommended, based on their similar mechanisms of action and laboratory studies showing raloxifene may stimulate tamoxifen-dependent cells.21 Teriparatide, a synthetic parathyroid hormone with anabolic effects on the skeleton, is also approved for osteoporosis therapy. Because of package label warnings against use in patients with a history of bone radiation or bone metastases, it is also not recommended for use in breast cancer patients.22 Are there other recommendations for bone mineral density preservation besides (or in addition to) bisphosphonates for breast cancer patients? Some basic healthy lifestyle recommendations for bone health include adequate calcium (1,200 to 1,500 mg/d) and vitamin D intake (400 to 800 U), weight-bearing exercise, and avoidance of smoking. In the recently reported Women's Health Initiative calcium plus vitamin D trial of postmenopausal women unselected for low bone mineral density, the primary intent-to-treat analysis showed that supplementation increased total hip bone mineral density by 1% compared with placebo, although it failed to show any beneficial effect of calcium with vitamin D on the rates of fractures.23 A subgroup analysis of women who were compliant with their calcium and vitamin D intake suggested that supplementation reduced hip fracture. A Cochrane review of the role of exercise in preventing and treating osteoporosis concluded that aerobic, weight-bearing, and resistance exercises are all effective in increasing bone mineral density in postmenopausal women.24 In addition, exercise also improves muscle mass, strength, balance, and coordination, and serves to reduce falls and fracture risk unrelated to changes in bone density. Are there any early take-home points regarding the tamoxifen versus anastrozole efficacy comparison in the premenopausal ABCSG-12 trial? Enrollment onto the primary study is complete, with efficacy analysis of the disease-free and overall survival end points expected within the next year. Until that time, strong caution is urged against assuming that combination ovarian suppression plus aromatase inhibition can be considered a proven standard in premenopausal women. Whether ovarian suppression adds to chemotherapy and/or tamoxifen in premenopausal women with hormone receptor–positive disease is an unresolved question, and will not be answered by this trial. Three ongoing international trials (Suppression of Ovarian Function Trial, Tamoxifen and Exemestane Trial, and Premenopausal Endocrine Responsive Chemotherapy Trial) will establish definitively the roles of chemotherapy, ovarian ablation, tamoxifen, and aromatase inhibitors in early-stage premenopausal women with hormone receptor–positive breast cancer. Participation in these important trials is strongly encouraged. Trends in adjuvant therapy suggest that osteoporosis and skeletal fractures are likely to become increasingly important clinical issues for our breast cancer patients. The common incorporation of anthracyclines and taxanes into adjuvant chemotherapy regimens have led to higher rates of chemotherapy-induced amenorrhea.25,26 The use of aromatase inhibitors in postmenopausal patients is also causing increased osteoporosis rates and fracture risk. In adjuvant endocrine therapy trials in which an aromatase inhibitor was substituted for some duration of tamoxifen, excess fractures have been reported in postmenopausal women receiving the aromatase inhibitor.20,27-30 The adjuvant aromatase inhibitor study with the longest follow-up is the Anastrozole and Tamoxifen, Alone and in Combination trial. At 68 months, anastrozole significantly increased fractures compared with tamoxifen, with a fracture incidence of 11% seen in patients receiving anastrozole versus 7.7% in patients receiving tamoxifen (P < .0001).27 What will be the impact of longer follow-up and longer duration of exposure to aromatase inhibitors, as is being tested in ongoing trials? A question currently under investigation, the answer to which could dramatically influence decision making regarding inclusion of bisphosphonates as part of the breast cancer treatment regimen, is whether these drugs can decrease the development of bone metastases and influence survival. Three randomized clinical trials of 2 to 3 years of clodronate as adjuvant therapy in nonmetastatic breast cancer patients have been reported, with survival benefits seen in two of the trials.31-33 We await results of several large, randomized adjuvant bisphosphonate trials with survival (not bone density) as end points. Bisphosphonate doses used in these trials are high, generally doses effective in decreasing skeletal-related events in patients with documented bone metastases. The NSABP B-34 trial is evaluating daily oral clodronate versus placebo for 3 years in patients with stage I or II breast cancer. The AZURE trial has randomly assigned early-stage breast cancer patients to receive or not receive zoledronic acid for a total of 5 years. The recently activated Southwest Oncology Group S0307 study compares the effects of three bisphosphonates (clodronate, ibandronate, and zoledronic acid) in stage I to III breast cancer patients. If these trials confirm earlier suggestions of a disease-free or overall survival benefit, this would solidify a clear role for the up-front and widespread adjuvant use of bisphosphonates in early-stage breast cancer, separate from the bone density effects. More women are surviving breast cancer than ever before. The Institute of Medicine's recent cancer survivorship report states that the long-term sequelae of a cancer diagnosis and its treatment have largely been ignored.34 Osteoporosis and its associated increased fracture risk, exacerbated by systemic cancer therapy, is a serious long-term health issue for breast cancer survivors that cannot be ignored. The ABCSG-12 and Z-FAST investigators are to be congratulated for their studies of the skeletal consequences of cancer treatment and one possible approach to preserving bone mineral density in breast cancer patients. This is an important first step, but many questions remain. Given the emerging data on rates of bone loss and fracture in women receiving breast cancer treatment, we are obligated to define optimal, cost-effective ways to determine who is at greatest risk, how to monitor bone loss, how best to treat, and when to intervene. The oncology community must be cognizant of the long-term physical and emotional impact of all of our therapies, as we strive to minimize breast cancer recurrence while maximizing our patients' overall health and well-being. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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: None Research Funding: Julie R. Gralow, Novartis, Roche Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on June 18, 2007. REFERENCES
1. 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 2. 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] 3. Vehmanen L, Elomaa I, Blomqvist C, et al: Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status. J Clin Oncol 24:675-680, 2006 4. Hillner BE, Ingle JN, Cheblowski 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 21:4042-4057, 2003 5. 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 6. Brufsky A, Harker W, Beck J, et al: Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol 25:829-836, 2007 7. Bundred N, Campbell I, Coleman R, et al: Zoledronic acid in the prevention of cancer treatment-induced bone loss in postmenopausal women receiving letrozole as adjuvant therapy for early breast cancer (ZO-FAST study). Eur J Cancer Suppl 4:48, 2006 (abstr 12) 8. Smith MR, Eastham J, Gleason DM, et al: Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy of nonmetastatic prostate cancer. J Urol 169:2008-2012, 2003[CrossRef][Medline] 9. 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 10. Vehmanen L, Saarto T, Elomaa I, et al: Long-term impact of chemotherapy-induced ovarian failure on bone mineral density in premenopausal breast cancer patients: The effect of adjuvant clodronate treatment. Eur J Cancer 37:2373-2378, 2001[CrossRef][Medline] 11. Fuleihan Gel-H, Salamoun M, Mourad YA, et al: Pamidronate in the prevention of chemotherapy-induced bone loss in premenopausal women with breast cancer: A randomized clinical trial. J Clin Endocrinol Metab 90:3209-3214, 2005 12. 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 13. McCloskey E, Paterson AH, Powles TJ: Oral clodronate maintains bone mass in women with primary breast cancer. J Clin Oncol 23:12s, 2005 (suppl; abstr 535) 14. Ripps BA, VanGilder K, Minhas B, et al: Alendronate for the prevention of bone mineral loss during gonadotropin-releasing hormone agonist therapy. J Reprod Med 48:761-766, 2003[Medline] 15. Lonning PE, Geisler J, Krag LE, et al: Changes in bone metabolism after two years of exemestane in postmenopausal women with early breast cancer at low risk: Follow-up results of a randomized, placebo-controlled study. J Clin Oncol 23:10s, 2005 (suppl; abstr 531) 16. Sverrisdóttir A, Fornander T, Jacobsson H, et al: Bone mineral density among premenopausal women with early breast cancer in a randomized trial of adjuvant endocrine therapy. J Clin Oncol 22:3694-3699, 2004 17. US Preventive Services Task Force: Screening for osteoporosis in postmenopausal women: Recommendations and rationale. Ann Intern Med 137:526-528, 2002 18. Ettinger B, Black DM, Mitlak BH, et al: Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial—Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 282:637-645, 1999 19. Cauley JA, Robbins J, Chen Z, et al: Effects of estrogen plus progestin on risk of fracture and bone mineral density: The Women's Health Initiative randomized trial. JAMA 290:1729-1738, 2003 20. Baum M, Buzdar AU, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomized trial. Lancet 359:2131-2139, 2002[CrossRef][Medline] 21. O'Regan RM, Gajdos C, Dardes RC, et al: Effects of raloxifene after tamoxifen on breast and endometrial tumor growth in athymic mice. J Natl Cancer Inst 94:274-283, 2002 22. Tashjian AH, Gagel RF: Teriparatide: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis. J Bone Min Res 21:354-365, 2006[Medline] 23. 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 24. Shea B, Bonaiuti D, Iovine R, et al: Cochrane review on exercise for preventing and treating osteoporosis in postmenopausal women. Eura Medicophys 40:199-209, 2004[Medline] 25. Martin M, Pienkowski T, Mackey J, et al: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352:2302-2313, 2005 26. Parulekar WR, Day AG, Ottaway JA, et al: Incidence and prognostic impact of amenorrhea during adjuvant therapy in high-risk premenopausal breast cancer: Analysis of a National Cancer Institute of Canada Clinical Trials Group Study—NCIC CTG MA.5. J Clin Oncol 23:6002-6008, 2005 27. Howell A, Cuzick J, Baum M, et al: Results of the ATAC trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365:60-62, 2005[CrossRef][Medline] 28. Thürlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005 29. 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 30. Jakesz R, Jonat W, Gnant M, et al: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455-462, 2005[CrossRef][Medline] 31. Saarto T, Vehmanen L, Virkkunen P, et al: Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. Acta Oncol 43:650-656, 2004[CrossRef][Medline] 32. Jaschke A, Bastert EF, Solomayer EF, et al: Adjuvant clodronate treatment improves the overall survival of primary breast cancer patients with micrometastases to bone marrow: A longtime follow-up. J Clin Oncol 22:9s, 2004 (suppl; abstr 529) 33. Powles T, Paterson A, McCloskey E, et al: Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer. Breast Cancer Res 8:R13, 2006[CrossRef][Medline] 34. Hewitt M, Greenfield S, Stovall E, eds: From Cancer Patient to Cancer Survivor: Lost in Transition. Washington DC, Institute of Medicine and National Research Council, National Academies Press, 2006 Related Articles
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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1% of patients classified as osteoporotic and approximately 20% osteopenic. After 36 months of combination goserelin/anastrozole therapy, 24% of women met the clinical definition for osteoporosis, and another 50% were osteopenic. In the goserelin/tamoxifen group, no patients were within the osteoporotic range at 36 months, but 46% were osteopenic. The addition of zoledronic acid to both of these endocrine regimens inhibited loss of bone mineral density and effectively stabilized bone density at baseline levels. No fractures have been reported to date in any arm of this study. 
–2.0 were started on 5 years of oral letrozole and randomly assigned to receive up-front intravenous zoledronic acid every 6 months versus delayed zoledronic acid (to start only if T scores decreased below –2.0 or if a nontraumatic clinical fracture occurred). Bone mineral density of the hip and spine were measured at 6 and 12 months, and will be repeated annually for 5 years. At the end of 1 year, bone mineral density was statistically higher in the up-front zoledronic acid group compared with the delayed group for both the lumbar spine (4.4% higher) and hip (3.3% higher). By month 12, only 8.3% of patients on the delayed treatment arm had been started on zoledronic acid per the study protocol. For the 72% of study patients who enrolled with normal baseline bone mineral density, 12.6% of the delayed group had T scores decrease below –1.0 at 12 months, compared with 3.4% in the up-front arm. None of these patients had T scores that decreased below –2.0 in the first year. For patients who enrolled with baseline osteopenia, 14.8% of patients in the delayed group and 1.4% of patients in the up-front group had T scores decrease below –2.0 at 1 year. Nontraumatic and traumatic fracture rates to date are low, with no difference between treatment arms. 
