This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brufsky, A. M. Search for Related Content PubMed PubMed Citation Articles by Brufsky, A. M.

Symptom Management and Supportive Care

Cancer Treatment-Induced Bone Loss: Pathophysiology and Clinical Perspectives

University of Pittsburgh School of Medicine, Magee-Women's Hospital, Pittsburgh, Pennsylvania, USA

Key Words. Androgen deprivation therapy • Aromatase inhibitor • Bisphosphonate • Bone loss • Osteoporosis Zoledronic acid

Correspondence: Adam M. Brufsky, M.D., Ph.D., University of Pittsburgh School of Medicine, Magee-Women's Hospital, Suite 4628, Pittsburgh, Pennsylvania 15213, USA. Telephone: 412-641-6500; Fax: 412-641-2296; e-mail: brufskyam{at}upmc.edu

Received August 21, 2007; accepted for publication November 10, 2007.

Disclosure: A.M.B. has participated in the speakers bureau for Novartis Pharmaceuticals. Funding for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. No other potential conflicts of interest were reported by the author, planners, reviewers, or staff managers of this article.

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Cancer Treatment-Induced Bone... AI-Associated Bone Loss CTIBL in Patients with... Maintaining Bone Health in... Safety Conclusions Acknowledgments References

 
After completing this course, the reader will be able to:

1. Discuss the incidence of CTIBL in patients undergoing therapy for breast cancer and prostate cancer.
   
2. Describe the pathogenesis of CTIBL in patients undergoing therapy for breast cancer and prostate cancer.
   
3. Describe the current role of and indications for bisphosphonate therapy in the treatment of CTIBL.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Cancer Treatment-Induced Bone... AI-Associated Bone Loss CTIBL in Patients with... Maintaining Bone Health in... Safety Conclusions Acknowledgments References

 
Hormone-ablative therapies for breast or prostate cancer can cause marked and rapid reductions in circulating estrogen or testosterone levels, resulting in significant effects on bone metabolism and cancer treatment–induced bone loss (CTIBL). Most patients with cancer are over the age of 65 and are already at risk for osteoporosis. Thus, accelerated bone loss from CTIBL is especially concerning in this population. Although there are currently no approved therapies for the treatment or prevention of CTIBL, oral bisphosphonates have been used in settings other than oncology to treat bone loss. New-generation i.v. bisphosphonates have demonstrated promising activity in preventing CTIBL in patients receiving hormonal therapy for breast or prostate cancer. In particular, zoledronic acid not only prevents CTIBL in both breast and prostate cancer patients but also increases bone mineral density above baseline. Such agents have the potential to delay or prevent CTIBL in patients receiving hormonal therapies.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Cancer Treatment-Induced Bone... AI-Associated Bone Loss CTIBL in Patients with... Maintaining Bone Health in... Safety Conclusions Acknowledgments References

 
Patients with early-stage breast cancer or high-risk prostate cancer are often treated with antihormonal therapy to inhibit disease progression or prevent disease recurrence. Such therapies include gonadotropin-releasing hormone (GnRH), luteinizing hormone-releasing hormone (LHRH) agonists, antiandrogens (e.g., bicalutamide, flutamide), and aromatase inhibitors (AIs) [1, 2]. These therapies can lead to bone metabolism changes, resulting in loss of bone mass [3]. AIs and androgen deprivation therapy (ADT) deplete the circulating levels of estrogen and testosterone that maintain bone mass through suppression of bone resorption and promotion of bone formation [3, 4]. Early treatment with bisphosphonates may preserve skeletal integrity throughout disease progression by preventing bone loss and decreasing fracture risk [1, 5, 6].

Cancer treatment-induced bone loss (CTIBL) increases the risk for skeletal morbidity [7]. An understanding of CTIBL is critical for determining how to assess the risk and identifying which patients may benefit from preventive therapy. This information can guide screening and early intervention with therapies such as bisphosphonates, which have become the standard of care for reducing the risk for skeletal complications in patients with metastatic bone disease. Current American Society of Clinical Oncology (ASCO) guidelines and expert panels suggest that patients with bone metastases from breast or prostate cancer should receive bisphosphonates from the time of diagnosis [5, 6]. Preclinical and clinical data show that bisphosphonates can also prevent and treat CTIBL in patients with breast and prostate cancer, and bisphosphonates may inhibit malignant bone disease development in patients with early-stage cancer. Consistent with these findings, bisphosphonates are recommended for bone loss prevention in patients with prostate cancer receiving ADT [1]. Guidelines for the prevention of CTIBL in patients with breast cancer have not yet been established. This review focuses on CTIBL in patients with breast and prostate cancer and data from clinical trials that evaluate the effectiveness and safety of bisphosphonates for the prevention and treatment of CTIBL.

	CANCER TREATMENT-INDUCED BONE LOSS IN PATIENTS WITH BREAST CANCER

Top Learning Objectives Abstract Introduction Cancer Treatment-Induced Bone... AI-Associated Bone Loss CTIBL in Patients with... Maintaining Bone Health in... Safety Conclusions Acknowledgments References

 
Women with breast cancer have an increased risk for osteoporosis because of treatment-induced premature ovarian failure and the direct effects of cytotoxic chemotherapy [8]. Estrogens limit bone resorption, and decreases in available estradiol levels can accelerate bone resorption, resulting in overall bone loss [3].

Greater than 60% of women with breast cancer experience ovarian failure within 1 year of beginning postoperative adjuvant chemotherapy regimens [3]. Studies have shown that chemotherapy-induced menopause, either temporary or permanent, is associated with significant bone loss. Reductions in bone mineral density (BMD) of the spine (6%–7.5%) and femoral neck (2%–4.5%) have been reported within 1 year of initiation of adjuvant chemotherapy for breast cancer [9, 10]. In women treated with cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy who experienced permanent ovarian failure, clinically significant bone loss continued during the 2–5 years following chemotherapy [11].

	AI-ASSOCIATED BONE LOSS

Top Learning Objectives Abstract Introduction Cancer Treatment-Induced Bone... AI-Associated Bone Loss CTIBL in Patients with... Maintaining Bone Health in... Safety Conclusions Acknowledgments References

 
Ovarian suppression in premenopausal women receiving AIs is a major concern because of the near complete elimination of circulating estradiol levels. Long-term use of AIs (e.g., letrozole, anastrozole) is increasing because of their superior efficacy and safety profiles compared with those of tamoxifen [12, 13]. Another important clinical concern in patients with breast cancer is AI-associated bone loss (AIBL), because it is more rapid than bone loss associated with menopause (1.7% and 2.6% loss of total hip and lumbar spine BMD, respectively, during the first year) [14] and the severity increases with treatment duration.

The Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial in postmenopausal women with early-stage breast cancer demonstrated the superiority of AIs over tamoxifen for disease-free survival (hazard ratio [HR], 0.86; p = .03) and time to disease recurrence (HR, 0.83; p = .015) [12]. Although the anastrozole safety profile was better than that of tamoxifen overall, anastrozole was associated with a greater fracture incidence (11% versus 7.7%, respectively) [12]. Assuming a baseline annual fracture rate of 17 fractures per 1,000 healthy postmenopausal women, survivors of breast cancer not treated with adjuvant hormonal therapy have a relative fracture risk of 1.15 (20 fractures per 1,000 women) [15]. Based on the ATAC trial, patients with breast cancer treated with anastrozole have a relative fracture risk of 1.36 (23 fractures per 1,000 women). This translates into two additional fractures per year in 300 postmenopausal women with early breast cancer. In contrast, patients treated with tamoxifen have a relative fracture risk of only 0.91, suggesting that tamoxifen may have bone-protective effects.

Bone loss and fracture risk were also analyzed retrospectively in a patient-claims database of women with early-stage breast cancer and no osteoporosis who received an AI (n = 1,354) or did not (n = 11,014) [16]. The prevalence of osteoporosis was 8.7% in the AI group versus 7.1% in the control group (p = .01), and the risks for both bone loss and fracture were significantly higher in the AI group than in the control group (27% and 21%, respectively; p = .02) (Fig. 1) [16].

View larger version (20K): [in this window] [in a new window]   Figure 1. Cox regression models of the effect of aromatase inhibitors on bone loss and fracture risk. *p = .02. Data from Mincey BA, Duh MS, Thomas SK et al. Risk of cancer treatment-associated bone loss and fractures among women with breast cancer receiving aromatase inhibitors. Clin Breast Cancer 2006;7:127–132.

The nonsteroidal AI exemestane has also been shown to decrease BMD and increase the incidence of fractures. The Intergroup Exemestane Study assessed bone loss and fracture risk among patients with breast cancer who were randomized to tamoxifen or exemestane after 2–3 years of tamoxifen therapy (n = 4,274) [19]. In a subset of patients in whom BMD was assessed (n = 206), BMD significantly decreased from baseline by 2.7% (lumbar spine) and 1.4% (hip) (p < .0001 for both) within 6 months of exemestane treatment. A similar study by Gonnelli et al. [20] showed that patients receiving exemestane for 2 years had significant reductions in lumbar spine (–2.99; p < .01), femoral neck (–1.92; p < .01), and total hip (–2.01; p < .05) BMD. Finally, in a 2-year study in lower-risk women with early breast cancer (n = 147) who received either exemestane or placebo, the exemestane group had a significantly higher mean annual loss of femoral neck BMD than the placebo group (2.72% versus 1.48%, respectively; p = .024) [21]. However, the mean annual loss in lumber spine BMD did not reach significance (exemestane, 2.17%; placebo, 1.84%; p = .568).

Earlier studies have been reviewed previously [22], and their results provide ample evidence that AI treatment in women with breast cancer may lead to deleterious effects on bone health.

	CTIBL IN PATIENTS WITH PROSTATE CANCER

Top Learning Objectives Abstract Introduction Cancer Treatment-Induced Bone... AI-Associated Bone Loss CTIBL in Patients with... Maintaining Bone Health in... Safety Conclusions Acknowledgments References

 
Androgen deprivation–induced bone loss is a significant clinical concern in patients with hormone-sensitive prostate cancer receiving long-term ADT. ADT decreases circulating levels of estrogen and testosterone, both of which maintain bone mass through suppression of bone resorption and promotion of bone formation [3, 23]. Thus, similar to AIs in breast cancer, ADT ultimately accelerates bone loss beyond the levels seen with aging (1%–2% per year) [2, 4]. This is especially concerning because patients with prostate cancer typically have low BMD even before receiving ADT either because of age, underlying disease, or other comorbidities [1]. In a study of men with advanced prostate cancer for >2 years before initiation of ADT (n = 174), 42% were osteoporotic compared with 27% of age-matched controls (n = 106; p = .022) [24].

Long-term ADT is associated with significant and progressive decreases in BMD that correlate with duration of therapy [25, 26], and the risk for fragility fractures increases as BMD decreases [27]. In a retrospective analysis of patient-claims data (Medicare) from 1992–2001 (n = 4,494), ADT increased the risk for osteopenia/osteoporosis (30%) and pathologic and nonpathologic fractures (16% and 42%, respectively) [28]. In another retrospective analysis of patient databases (Surveillance, Epidemiology, and End Results program and Medicare) from 1992–1997 (n = 50,613), 19.4% of patients with prostate cancer receiving ADT for 5 years had a fracture compared with 12.6% of men who did not (p < .001) [29]. A population-based cohort study noted a correlation between ADT and clinical fractures in men with nonmetastatic prostate cancer (n = 7,774) [30]. When adjusted for survival, the fracture incidence was 83% in patients receiving a GnRH agonist compared with 56% in men who did not receive ADT, and longer treatment (>3 years) was associated with a greater fracture risk than with shorter (<1 year) treatment (HR, 1.5; p < .001) [30]. A smaller retrospective cohort study found a fourfold higher incidence of peripheral and vertebral fractures in patients with prostate cancer who received an LHRH agonist (n = 288) than in patients who did not (n = 300) [31]. The risk ratio was 3.6 (p = .001) after adjustment for age and prior fracture. In a retrospective chart review of patients with prostate cancer receiving ADT (n = 89), approximately 27% of the patients had osteoporosis and 51% had osteopenia of the hip or lumbar spine [32]. Among a subset of patients with radial BMD assessments (n = 53), 53% were osteoporotic at this site. Studies reported earlier than 2002 have been reviewed elsewhere and showed similar results [1].

Reducing bone loss is critical because fractures significantly correlate with shorter survival in men with prostate cancer [33]. When fracture history was evaluated in men with prostate cancer undergoing ADT (n = 195), the median overall survival time was 39 months longer in men without a history of skeletal fracture than in men with no prior fracture (p = .004) [33].

	MAINTAINING BONE HEALTH IN PATIENTS WITH CANCER

Top Learning Objectives Abstract Introduction Cancer Treatment-Induced Bone... AI-Associated Bone Loss CTIBL in Patients with... Maintaining Bone Health in... Safety Conclusions Acknowledgments References

 
Breast Cancer
The ASCO guidelines recommend strategies for the management of bone health in patients with breast cancer [5]. Osteoporosis screening should begin at age 65 or at age 60 for women with an increased osteoporosis risk [5]. Supplementation with calcium (1,200 mg/day) and vitamin D (800 IU) is also recommended for patients at risk for osteoporosis because these levels prevent decreases in femoral neck BMD and reduce the risk for hip fractures in elderly women [34–36]. Bisphosphonates (alendronate or risedronate) are also recommended for high-risk patients with breast cancer and T-scores of –2.5 or less [5]. A T-score represents the difference between a patient's BMD measurement and the mean BMD of young healthy adults and is expressed as a multiple of the standard deviation (SD) from the mean [3]. This classifies patients as normal (greater than –1 SD), osteopenic (–1 to –2.5 SD), or osteoporotic (less than –2.5 SD) and can provide an estimate of fracture risk [3, 37].

There are currently no approved treatment or prevention therapies for CTIBL or AIBL in patients with breast cancer [38]. However, both clodronate and risedronate have been shown to decrease the bone loss associated with chemotherapy-induced ovarian failure [9, 39]. In separate randomized, placebo-controlled trials, 2 years of oral clodronate (1,600 mg/day) or oral risedronate (30 mg/day during the first 2 weeks of a 12-week cycle) treatment resulted in less lumbar spine and femoral neck bone loss than in controls [9, 39]. At 2 years, in patients who experienced ovarian failure, oral clodronate resulted in a 38% lower mean lumbar spine bone loss and a 91% lower mean femoral neck bone loss than in the control group [9]. No specific adverse events (AEs) were listed, and no significant differences in AEs between treatment groups were reported. No renal impairment was observed during the study. However, one patient interrupted clodronate treatment because of diarrhea. In a similar study with oral risedronate, the mean lumber spine and femoral neck bone loss was significantly lower, by 2.5% (p = .041) and 2.6% (p = .029), respectively, than with placebo [39]. Risedronate also produced a significantly lower trochanter bone loss, by 3.1%, compared with placebo (p = .002). At 3 years (1 year after treatment ended), differences in BMD remained significant at the lumbar spine (p = .024), femoral neck (p = .011), and trochanter (p = .008). The majority of AEs were reported to be mild and similar between the treatment groups. The most common AEs were flu-like symptoms, which occurred predominantly during the first cycle of therapy. No severe upper gastrointestinal AEs were observed. These studies demonstrate that oral bisphosphonates may reduce the bone loss resulting from cancer therapies, but bone integrity was not fully protected.

The i.v. bisphosphonate zoledronic acid (Zometa®; Novartis Pharmaceuticals Corporation, East Hanover, NJ), has shown clinical benefits in the treatment of bone metastases among patients with solid tumors. Phase III studies demonstrated that zoledronic acid (4 mg) resulted in a significantly lower risk for developing skeletal-related events (SREs) such as pathologic fractures, by 31%–41% compared with placebo (p < .02 for all studies) [40–42]. Zoledronic acid has also been directly compared with pamidronate in patients with breast cancer, wherein zoledronic acid reduced the risk for an SRE by an additional 16% compared with pamidronate (p = .03) [43]. In a Cochrane review that assessed all approved oral and i.v. bisphosphonates for breast cancer treatment, zoledronic acid produced the largest reduction in the risk for SREs versus placebo (41% versus 14%–23% for ibandronate, clodronate, and pamidronate) [44].

Three clinical trials demonstrated that zoledronic acid may be effective in counteracting AIBL in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer. A randomized, open-label, phase III, four-arm trial (the Austrian Breast and Colorectal Cancer Study Group [ABCSG] trial ABCSG 12) in premenopausal women receiving goserelin (3.6 mg/month) compared tamoxifen (20 mg/day) with anastrozole (1 mg/day) with or without zoledronic acid (4 mg i.v. every 6 months) for 3 years after primary surgery for stage I or II estrogen- and/or progesterone-receptor–positive breast cancer [17]. In a subprotocol (n = 401), serial BMD measurements were taken at 0, 6, 12, 24, and 36 months. Women receiving anastrozole for 3 years had greater bone loss than patients receiving tamoxifen (17.3% versus 11.6% decrease in BMD, respectively) [17]. In contrast, the addition of zoledronic acid (4 mg i.v. every 6 months over 3 years) to either treatment regimen effectively inhibited bone loss in the lumbar spine and trochanter. Zoledronic acid also led to significantly better lumbar spine T-scores versus those of patients treated with goserelin plus anastrozole alone (p < .0001) (Fig. 2) [17]. Zoledronic acid combined with endocrine therapy was well tolerated, and there was no observed additive toxicity between zoledronic acid and either goserelin plus anastrozole or goserelin plus tamoxifen. The majority of AEs associated with zoledronic acid were mild to moderate flu-like symptoms (nausea, vomiting, fever, and myalgia), primarily limited to the first dose. There were no clinically relevant changes in serum creatinine, including no increases 1.5x the upper limit of normal, and no reported cases of osteonecrosis of the jaw (ONJ).

View larger version (21K): [in this window] [in a new window]   Figure 2. Patients with normal bone mineral density, osteopenia, or osteoporosis in the lumbar spine treated with goserelin and anastrozole without (A) or with (B) zoledronic acid, which resulted in significantly better T-scores than with hormone therapy alone (p < .0001). From Gnant MF, 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 2007;25:820–828, with permission from the American Society of Clinical Oncology.

View larger version (16K): [in this window] [in a new window]   Figure 3. Zometa®/Femara® Adjuvant Synergy Trial preliminary data. Difference in percent change in lumbar spine and total hip bone mineral density (BMD) after 1 year in postmenopausal women with breast cancer treated with letrozole and randomized to upfront or delayed zoledronic acid treatment. From Brufsky A, Harker WG, Beck JT et al. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol 2007;25:829–836, with permission from the American Society of Clinical Oncology.

Oral alendronate and risedronate are used to prevent or treat bone loss in men with osteoporosis [2]. However, recent trials of oral bisphosphonates for the prevention of CTIBL have yielded mixed results. In a retrospective review of men receiving oral alendronate or risedronate, the majority of patients had a decrease in BMD [48]. In contrast, in a study in men with nonmetastatic prostate cancer receiving ADT (n = 112), once-weekly alendronate significantly increased BMD in the spine and femoral neck (3.7% and 1.6% versus baseline, respectively; p .008 for both), whereas BMD in the placebo group decreased by 1.4% and 0.7% versus baseline, respectively, at 1 year [49]. No specific AEs were listed, but the authors noted that there were no differences in AEs between treatment groups. However, adherence with oral bisphosphonates is poor because of complicated administration requirements such as postdose fasting and posture restrictions to reduce upper gastrointestinal toxicity and because patients who are asymptomatic do not perceive treatment benefit [2, 50, 51].

Because bone loss during ADT is more severe than that associated with aging, more frequent administration of an i.v. bisphosphonate may provide greater benefit. Both zoledronic acid and pamidronate (i.v. once every 3 months) prevented androgen deprivation–induced bone loss in the hip and lumbar spine in men with nonmetastatic prostate cancer receiving a GnRH agonist [52, 53]. In contrast with pamidronate, zoledronic acid increased BMD. Versus baseline, the mean BMD in the lumbar spine increased by 5.6% in men receiving zoledronic acid and decreased by 2.2% in placebo-treated men (p < .001 versus placebo) (Fig. 4) [52]. Results were similar in the trochanter and total hip (p < .001 versus placebo). The majority of AEs were similar between the treatment and placebo groups. The most frequently reported AEs were hot flushes, fatigue, and arthralgia. Even a single dose of zoledronic acid has been shown to significantly increase BMD of the total hip and spine at 1 year (p < .001 for both) [54]. In a placebo-controlled trial in men with nonmetastatic prostate cancer treated with a GnRH, one infusion of zoledronic acid (4 mg i.v.) increased the mean BMD of the lumbar spine by 4.0% compared with a decrease of 3.1% in men receiving placebo (p < .001) [55]. Zoledronic acid also prevented bone loss in hormone-naive patients with nonmetastatic prostate cancer treated with goserelin acetate, a synthetic LHRH analogue (n = 200) [56]. At 1 year (n = 140), the mean BMD in the lumbar spine, femoral neck, and hip decreased from baseline (up to 2%) in patients treated with goserelin alone, whereas BMD significantly increased (up to 3.3%) in patients treated with zoledronic acid (4 mg i.v.) every 3 months (p .0012 for all). These studies have shown that infrequent dosing with an i.v. bisphosphonate such as zoledronic acid can reverse the bone loss associated with ADT. Unfortunately, neither of these studies followed patients long enough to detect changes in fracture risk. However, earlier bone loss literature has made a clear correlation between BMD and fracture risk [27]. Based on these data, clinical guidelines recommended bisphosphonate therapy for the prevention of osteoporosis for high-risk men with prostate cancer undergoing ADT or at any point that the patient has bone loss during ADT [1, 57]. Routine bone scans are required during treatment. Although there are no clear consensus recommendations regarding the optimal frequency of bone scans, current guidelines recommend that all patients initiating ADT should have a baseline scan and that follow-up scans should be done periodically in patients at high risk for skeletal morbidity. More routine imaging may also help to improve early detection of bone metastases.

View larger version (18K): [in this window] [in a new window]   Figure 4. Mean percent change from baseline in bone mineral density. Men with nonmetastatic prostate cancer undergoing androgen deprivation therapy received either zoledronic acid (4 mg) or placebo every 3 months for 1 year. p < .001 for all comparisons. From 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 2003;169:2008–2012, copyright ©2003, with permission from the American Urological Association.

	SAFETY

Top Learning Objectives Abstract Introduction Cancer Treatment-Induced Bone... AI-Associated Bone Loss CTIBL in Patients with... Maintaining Bone Health in... Safety Conclusions Acknowledgments References

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Cancer Treatment-Induced Bone... AI-Associated Bone Loss CTIBL in Patients with... Maintaining Bone Health in... Safety Conclusions Acknowledgments References

 
CTIBL is prevalent in patients with breast cancer receiving combination endocrine treatment and in patients with prostate cancer receiving ADT and is typically more severe than bone loss associated with the aging process or menopause [2, 4, 14]. This decrease in BMD increases the risk for fractures, which are associated with chronic pain, loss of mobility, and shorter survival [3, 33].

Bisphosphonates have been demonstrated to be promising in preventing CTIBL in patients with breast or prostate cancer [63, 64]. Early intervention with zoledronic acid prevents bone loss in patients with breast and prostate cancer [17, 45, 52]. Serum creatinine increases and uncommon events such as ONJ have been reported in patients with advanced cancer metastatic to bone; these patients have a greater number of potential risk factors for such AEs than patients in the AIBL setting. The studies presented here have shown that renal AEs are rare, and there have been no cases of ONJ reported to date during zoledronic acid treatment for AIBL. This improved safety profile is likely related to the relatively infrequent administration of zoledronic acid (every 3–6 months versus every 3–4 weeks) and the earlier stage of the cancers in these settings. Ongoing trials are investigating the optimum zoledronic acid regimen in this setting.

Current guidelines recommend that patients with bone metastases from breast or prostate cancer receive bisphosphonates from the time of diagnosis. Although proactive use of bisphosphonates in the AIBL and CTIBL settings in breast cancer is not currently included in society guidelines, regulatory approval of zoledronic acid in the AIBL setting is under consideration in both the U.S. and Europe. Furthermore, bisphosphonates are recommended for the prevention of bone loss in patients with prostate cancer receiving ADT [47].

	ACKNOWLEDGMENTS

Top Learning Objectives Abstract Introduction Cancer Treatment-Induced Bone... AI-Associated Bone Loss CTIBL in Patients with... Maintaining Bone Health in... Safety Conclusions Acknowledgments References

 
We thank Tamalette Loh, Ph.D., ProEd Communications, Inc.®, for her medical editorial assistance with this manuscript.

	REFERENCES

Top Learning Objectives Abstract Introduction Cancer Treatment-Induced Bone... AI-Associated Bone Loss CTIBL in Patients with... Maintaining Bone Health in... Safety Conclusions Acknowledgments References

 

1. Diamond TH, Higano CS, Smith MR et al. Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: Recommendations for diagnosis and therapies. Cancer 2004;100:892–899.[CrossRef][Medline]
2. Maxwell C, Viale PH. Cancer treatment-induced bone loss in patients with breast or prostate cancer. Oncol Nurs Forum 2005;32:589–603.[CrossRef][Medline]
3. Pfeilschifter J, Diel IJ. Osteoporosis due to cancer treatment: Pathogenesis and management. J Clin Oncol 2000;18:1570–1593.[Abstract/Free Full Text]
4. Hofbauer LC, Khosla S. Androgen effects on bone metabolism: Recent progress and controversies. Eur J Endocrinol 1999;140:271–286.[Abstract]
5. 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 2003;21:4042–4057.[Abstract/Free Full Text]
6. Saad F, Higano CS, Sartor O et al. The role of bisphosphonates in the treatment of prostate cancer: Recommendations from an expert panel. Clin Genitourin Cancer 2006;4:257–262.[Medline]
7. Kanis JA, Oden A, Johnell O et al. The components of excess mortality after hip fracture. Bone 2003;32:468–473.[Medline]
8. Mincey BA. Osteoporosis in women with breast cancer. Curr Oncol Rep 2003;5:53–57.[Medline]
9. Saarto T, Blomqvist C, Valimaki M et al. Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: A randomized study in premenopausal breast cancer patients. J Clin Oncol 1997;15:1341–1347.[Abstract/Free Full Text]
10. 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 2001;19:3306–3311.[Abstract/Free Full Text]
11. 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 2001;37:2373–2378.[CrossRef][Medline]
12. Baum M, Buzdar A, Cuzick J et al. Anastrozole alone or in combination with tamoxifen 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 2003;98:1802–1810.[CrossRef][Medline]
13. Eastell R, Hannon RA, Cuzick J et al. Effect of an aromatase inhibitor on BMD and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). J Bone Miner Res 2006;21:1215–1223.[CrossRef][Medline]
14. Eastell R, Adams J. Results of the ‘Arimidex’ (anastrozole, A), Tamoxifen (T), Alone or in Combination (C) (ATAC) trial: Effects on bone mineral density (BMD) and bone turnover (ATAC Trialists' Group). Presented at the 27th Congress of the European Society for Medical Oncology; October 18–22, 2002; Nice, France.
15. Bell R. Relative risk of fractures in postmenopausal women, postmenopausal breast cancer survivors and postmenopausal women managed with adjuvant hormonal therapy. Presented at the 5th European Breast Cancer Conference; March 21–25, 2006; Nice, France.
16. Mincey BA, Duh MS, Thomas SK et al. Risk of cancer treatment-associated bone loss and fractures among women with breast cancer receiving aromatase inhibitors. Clin Breast Cancer 2006;7:127–132.[Medline]
17. Gnant MF, 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 2007;25:820–828.[Abstract/Free Full Text]
18. Perez EA, Josse 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 NCIC CTG MA. 17. J Clin Oncol 2006;24:3629–3635.[Abstract/Free Full Text]
19. Coleman RE, Banks LM, Girgis SI 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 2007;8:119–127.[CrossRef][Medline]
20. Gonnelli S, Cadirni A, Caffarelli C et al. Changes in bone turnover and in bone mass in women with breast cancer switched from tamoxifen to exemestane. Bone 2007;40:205–210.[Medline]
21. Lonning 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 2005;23:5126–5137.[Abstract/Free Full Text]
22. McCloskey E. Effects of third-generation aromatase inhibitors on bone. Eur J Cancer 2006;42:1044–1051.[CrossRef][Medline]
23. Leder BZ, LeBlanc KM, Schoenfeld DA et al. Differential effects of androgens and estrogens on bone turnover in normal men. J Clin Endocrinol Metab 2003;88:204–210.[Abstract/Free Full Text]
24. Hussain SA, Weston R, Stephenson RN et al. Immediate dual energy X-ray absorptiometry reveals a high incidence of osteoporosis in patients with advanced prostate cancer before hormonal manipulation. BJU Int 2003;92:690–694.[CrossRef][Medline]
25. 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 1999;161:1219–1222.[CrossRef][Medline]
26. Mittan D, Lee S, Miller E et al. Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab 2002;87:3656–3661.[Abstract/Free Full Text]
27. Kanis JA, Melton LJ 3rd, Christiansen C et al. The diagnosis of osteoporosis. J Bone Miner Res 1994;9:1137–1141.[Medline]
28. Krupski TL, Smith MR, Lee WC et al. Profile of men with prostate cancer on androgen deprivation therapy at greatest risk of bone complications. Proc Am Soc Clin Oncol 2004;22(July 15 suppl):726.
29. Shahinian VB, Kuo YF, Freeman JL et al. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352:154–164.[Abstract/Free Full Text]
30. Smith MR, Lee WC, Krupsi T et al. Association between androgen deprivation therapy and fracture risk: A population-based cohort study in men with non-metastatic prostate cancer. Proc Am Soc Clin Oncol 2004;22(July 15 suppl):382.
31. Lopez AM, Pena MA, Hernandez R et al. Fracture risk in patients with prostate cancer on androgen deprivation therapy. Osteoporos Int 2005;16:707–711.[CrossRef][Medline]
32. Bruder JM, Ma JZ, Basler JW et al. Prevalence of osteopenia and osteoporosis by central and peripheral bone mineral density in men with prostate cancer during androgen-deprivation therapy. Urology 2006;67:152–155.[CrossRef][Medline]
33. Oefelein MG, Ricchiuti V, Conrad W et al. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol 2002;168:1005–1007.[CrossRef][Medline]
34. Chapuy MC, Arlot ME, Duboeuf F et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 1992;327:1637–1642.[Abstract]
35. Chapuy MC, Pamphile R, Paris E et al. Combined calcium and vitamin D3 supplementation in elderly women: Confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: The Decalyos II study. Osteoporos Int 2002;13:257–264.[CrossRef][Medline]
36. Mincey BA, Moraghan TJ, Perez EA. Prevention and treatment of osteoporosis in women with breast cancer. Mayo Clin Proc 2000;75:821–829.[Abstract]
37. Hortobagyi GN. Moving into the future: Treatment of bone metastases and beyond. Cancer Treat Rev 2005;31(suppl 3):S9–S18.[CrossRef]
38. Lipton A. Toward new horizons: The future of bisphosphonate therapy. The Oncologist 2004;9(suppl 4):38–47.[Abstract/Free Full Text]
39. 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 1997;15:955–962.[Abstract/Free Full Text]
40. Kohno N, Aogi K, Minami H et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: A randomized, placebo-controlled trial. J Clin Oncol 2005;23:3314–3321.[Abstract/Free Full Text]
41. Rosen LS, Gordon D, Tchekmedyian NS et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: A randomized, phase III, double-blind, placebo-controlled trial. Cancer 2004;100:2613–2621.[CrossRef][Medline]
42. Saad F, Gleason DM, Murray R et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879–882.[Abstract/Free Full Text]
43. Rosen LS, Gordon D, Kaminski M et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: A randomized, double-blind, multicenter, comparative trial. Cancer 2003;98:1735–1744.[CrossRef][Medline]
44. Pavlakis N, Schmidt RL, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2005;(3):CD003474.
45. Brufsky A, Harker WG, Beck JT et al. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol 2007;25:829–836.[Abstract/Free Full Text]
46. Aapro M. Improving bone health in patients with early breast cancer by adding bisphosphonates to letrozole: The Z-ZO-E-ZO-FAST program. Breast 2006;15(suppl 1):S30–S40.[CrossRef][Medline]
47. National Comprehensive Cancer Network. Prostate Cancer V. 2.2007. Clinical Practice Guidelines in Oncology. Jenkintown, PA: NCCN, 2007:1-48.
48. Lam RY, Scholz M, Guess B et al. Oral bisphosphonates fail to prevent bone loss from androgen deprivation therapy in men with prostate cancer. Presented at the 2006 ASCO Prostate Cancer Symposium; February 24–26, 2006; San Francisco, CA.
49. Greenspan SL, Nelson JB, Trump DL et al. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: A randomized trial. Ann Intern Med 2007;146:416–424.[Abstract/Free Full Text]
50. Boniva® (ibandronate sodium) tablets [package insert]. Nutley, NJ: Roche, 2006.
51. Mangiapane S, Hoer A, Gothe H et al. Higher persistency with i.v. bisphosphonates in patients with bone metastasis. J Clin Oncol 2006;24(June 20 suppl):698s.
52. 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 2003;169:2008–2012.[CrossRef][Medline]
53. Smith MR, McGovern FJ, Zietman AL et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001;345:948–955.[Abstract/Free Full Text]
54. Black DM, Delmas PD, Eastell R et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809–1822.[Abstract/Free Full Text]
55. Michaelson MD, Lee H, Kaufman DS et al. Annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: A randomized placebo-controlled trial. J Clin Oncol 2006;24(June 20 suppl):220s.
56. Casey R. Zoledronic acid reduces bone loss in men with prostate cancer receiving goserelin: 12-month results. Presented at The Prostate Cancer Symposium; February 22–24, 2007; Orlando, FL.
57. Carroll PR. In: Denis L, Bartsch G, Khoury S, eds. Prostate Cancer: 3rd International Consultation on Prostate Cancer. Management of disseminated prostate cancer. Paris: Health Publications, 2003:249-284.
58. Conte P, Guarneri V. Safety of intravenous and oral bisphosphonates and compliance with dosing regimens. The Oncologist 2004;9(suppl 4):28–37.[Abstract/Free Full Text]
59. Sehbai AS, Mirza MA, Ericson SG et al. Osteonecrosis of the jaw associated with bisphosphonate therapy: Tips for the practicing oncologist. Commun Oncol 2007;4:w1–w11.
60. Weitzman R, Sauter N, Eriksen EF et al. Critical review: Updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients—May 2006. Crit Rev Oncol Hematol 2007;62:148–152.[CrossRef][Medline]
61. Mavrokokki T, Cheng A, Stein B et al. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 2007;65:415–423.[CrossRef][Medline]
62. Marx RE, Sawatari Y, Fortin M et al. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63:1567–1575.[CrossRef][Medline]
63. Nelson JB, Greenspan SL, Resnick NM et al. Once weekly oral alendronate prevents bone loss in men on androgen deprivation therapy for prostate cancer. Presented at the 2006 ASCO Prostate Cancer Symposium; February 24–26, 2006; San Francisco, CA.
64. 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 1996;14:78–84.[Abstract]

This article has been cited by other articles:

				J. F. S. Logman, B. M. S. Heeg, M. F. Botteman, S. Kaura, and B. A. van Hout Economic evaluation of zoledronic acid for the prevention of osteoporotic fractures in postmenopausal women with early-stage breast cancer receiving aromatase inhibitors in the UK Ann. Onc., December 2, 2009; (2009) mdp560v1. [Abstract] [Full Text] [PDF]

				T. Van den Wyngaert, M. T. Huizing, E. Fossion, and J. B. Vermorken Bisphosphonates in Oncology: Rising Stars or Fallen Heroes Oncologist, February 1, 2009; 14(2): 181 - 191. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brufsky, A. M. Search for Related Content PubMed PubMed Citation Articles by Brufsky, A. M.