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Aromatase inhibitors and bone health.

Introduction

Hormone-receptor positive breast cancer is increasingly targeted with chemotherapy, ovarian suppression or the use of AIs. AIs block oestrogen production in peripheral tissues and reduce circulating oestrogen levels, leading to accelerated bone loss and an increased risk of fracture.

Tamoxifen is reported to reduce fracture incidence [1] but in the Women's Health Initiative (WHI) study, breast cancer survivors had a 31% increased risk of fragility fracture compared to the general population [1]. Risk factors for premature bone loss and fracture include a low body mass index (BMI), family history or personal history of fragility fracture after the age of 50, oral corticosteroid use >6 months and cigarette smoking (Panel 1). Emerging evidence supports concomitant use of bisphosphonates in all women on AIs to prevent fracture and breast cancer recurrence. Adjuvant aromatase inhibitor (AI) therapy, administered either alone for 5 years or sequentially with adjuvant tamoxifen, improves disease-free survival in postmenopausal women with endocrine-responsive breast cancer when compared with tamoxifen alone [2-5]. Trials of third-generation AIs have shown increased bone loss and fracture rate on AIs compared to tamoxifen. AIs are associated with a favourable safety profile with fewer thrombo-embolic and gynaecological adverse events. However, the increasing use of AIs requires selection of patients for anti-resorptive therapy and careful bone health management to reduce bone loss and prevent fragility fractures.

Women who have a reduced bone mineral density (BMD) compared to peak bone mass have a 1.5-2.5-times increased risk of fragility fracture. Fragility fractures cause serious disability and excess mortality [6]. For every 1 standard deviation (SD) of bone mineral density from normal, fracture rate increases 1.5 to 2 fold. Individuals with a BMD T-score of -2.5 (i.e. 2.5 SD below normal), defined as osteoporosis by the World Health Organization (WHO), are recommended to undergo therapeutic intervention to prevent fragility fracture. Osteopaenia (low bone mass), defined as BMD T-score between -1 and -2.5 SD from normal would usually undergo DEXA scanning biannually to identify individuals with worsening bone density. Although fracture risk rises with declining BMD, assessment of risk cannot be guided solely by BMD. The management of bone complications associated with AI therapy is evolving. ASCO and the European National Osteoporosis Foundation (NOF) guidelines select patients for anti-resorptive therapy on the basis of bone mineral density scanning using dual x-ray absorptiometry of the lumbar spine and hip but several other risk factors for fragility fracture can be utilised to select for treatment [7].

Bisphosphonate therapy (oral or intravenous) which inhibits osteoclast activity has been shown to reduce fracture risk within months of starting therapy in osteoporotic women [6]. Recent studies indicate bisphosphonates prevent AI-induced bone loss (AIBL).

Aromatase inhibitors and bone complications

In the ATAC trial [2] comparing the non-steroidal drug, anastrozole with tamoxifen, an 11% fracture rate occurred in the anastrozole arm, compared to a 7.5% rate in the tamoxifen arm (P<0.001) equating to a fracture rate per 1000 women years of 22.6 for anastrozole compared to 15.6 for tamoxifen. Bone mineral density loss on anastrozole was -8.1% at the lumbar spine whereas tamoxifen was associated with small gains in BMD [8]. The increase in fractures commenced within 6 months of starting anastrozole but did not continue once treatment was stopped.

In the BIG1-98 Study, in the monotherapy arms after 5 years the 2463 women on letrozole had an 8.6% fracture rate compared to 5.8% in the 2459 tamoxifen-treated women (P<0.0001) [4].

The Intergroup Exemestane Study (IES) [5] reported, at 58 months, a 7% fracture rate on the steroidal AI exemestane, compared to a lower fracture rate (5%) on tamoxifen (P<0.003).

[FIGURE 1 OMITTED]

Recently postmenopausal women with chemotherapy or LHRH analogue-induced menopause have been found to have a higher rate of bone loss when combined with AI therapy. Premenopausal women undergoing treatment with an LHRH analogue were randomised to either tamoxifen or anastrozole, with or without zoledronic acid, to assess long-term bone safety in the ABCSG-12 trial [10,11] (Figure 2). Early combined hormonal therapy-induced menopause resulted in very substantial bone loss (LHRH and anastrozole -1.7 reduction in T-score at 36 months).

The magnitude of BMD loss on goserelin was more pronounced with anastrozole than with tamoxifen but was effectively prevented by immediate administration of intravenous zoledronic acid.

Risk factors for fragility fracture in postmenopausal women

Peak bone mass is achieved at 30 years of age and decreases at the menopause [6]. There is an initial fast bone loss of 3% per year for the first few years followed by a slower 1% loss per annum of BMD [6]. The speed of decrease of BMD is affected by a number of factors including AI therapy (which accelerates bone loss), cigarette smoking and corticosteroid use [6].

Hip fractures increase with age and are caused by a combination of falls and bone weakness. Vertebral fractures occur in a younger postmenopausal population and often result from routine activities such as bending and lifting light objects [6].

Cummings et al. [12] showed that in women over 65 years of age with undetectable oestrogen levels (<5 pg/ml) there is a 2.5-fold increased risk for subsequent hip or vertebral fracture, indicating that residual oestrogen levels provide protection against fracture. Compared to postmenopausal women, the reduction in serum oestradiol by aromatase inhibition increases fracture risk by around 2.5 fold.

The American Society of Clinical Oncology (ASCO) approach is to use BMD solely as an indicator for the need for early introduction of anti-resorptive therapy with bisphosphonates, whilst low BMD is used by some clinicians as a contra-indication to AI therapy.

Risk factors for fragility fracture

Bone mineral density is assessed using dual energy x-ray absorptiometry. In women with either osteopaenic BMD (T-score between -1.0 and -2.5) or osteoporosis (T-score <-2.5), an increased risk of fracture of 2 to 4 fold, according to the actual T-score, is observed. Around 82% of fractures will occur in women with T-scores >-2.5 (i.e. non-osteoporotic women) and 52% of fractures occur in women with osteopaenia in the National Osteoporosis Risk Assessment study (NORA) of over 200,000 healthy post-menopausal women [13].

Bone mineral density scores give an assessment of current bone density but the risk of fracture is dependent not only on the BMD, but also on how fast bone turnover is occurring [6]. Certain factors, such as premature menopause (induced by chemotherapy or ovarian suppression), cigarette smoking or AI use, markedly accelerate bone turnover [6].

A natural decline in ovarian oestrogen production occurs initially at the menopause and then subsequently with age leads to increased incidence of fractures in women older than 65 years when the 5-year fracture is 2.5-fold higher in women younger than 65 years [6]. A low BMI (<20 kg/[m.sup.2]) is associated with an increased risk of fracture in 12 prospective studies enrolling 44,757 women in total. Fracture risk associated with a low BMI is strongest for hip fracture and independent of age, sex and BMI [14].

A meta-analysis of more than 45,000 women with information on prior fractures from 11 multinational prospective trials demonstrated that a past history of an adult fragility fracture increased the risk of any fracture by 84% and subsequent hip fracture by 77% compared with no past history of fragility fractures [14].

In women with a prior fragility fracture, low BMD is not responsible for the majority of this increased risk of subsequent fracture. A personal history of fragility fracture after the age of 50 predicts a strong and independent risk factor for further osteoporotic fractures.

Combined results of 10 independent studies including 48,832 women found that (adjusting for BMD) current female smokers have a 55% increased risk of hip fracture and a 33% increased risk of any fracture. Previous smokers have an elevated risk of fracture compared to those who have never smoked [6].

Corticosteroid use is associated with increased bone loss and fracture risk. Bone loss occurs at a rapid rate during the first 6 months of oral corticosteroid use and slows after one year [14]. Fracture risk increases within 3-6 months of beginning corticosteroid therapy and patients on daily corticosteroids (>7.5mg/day) had a 54% increased risk of non-vertebral fracture in the first year of treatment, compared to their risk at baseline [6,15]. In a General Practice Research Database (GPRD) study, corticosteroid use resulted in a 2.6-fold increased risk of vertebral fracture and a 33% increased risk of any fracture. Any corticosteroid use for longer than 6 months appears significantly to increase fracture risk and should be factored into any decision to offer treatment to prevent fracture [7].

The World Health Organization (WHO) and, more recently the National Osteoporosis Foundation (NOF), indicate that factors other than BMD, including age >65 years, AI use, smoking and previous fragility fracture, should be taken into account when managing bone health in postmenopausal women.

Osteopaenic patients with two or more clinical risk factors, such as prior fragility fracture, cigarette smoking and low BMI, should be prescribed anti-resorptive agents.

Evidence for treatment intervention

A higher lifetime calcium intake risk in the NORA study reduced the risk of osteoporosis by 20%, and it is particularly important to have adequate dietary calcium intake if patients are commencing bisphosphonate therapy [13]. Calcium alone or in combination with vitamin D has only a modest effect on fracture risk (especially in patients who are not vitamin D deficient).

Physical exercise in several small studies has been shown to increase BMD compared to standard care. Although HRT prevents osteoporotic fractures, its use is contra-indicated with AIs.

Bisphosphonate therapy

Over the last 10-15 years randomised trials have demonstrated bisphosphonates increasing bone density of the spine by 3-5% at 5 years, with a 20-45% reduction in vertebral and hip fractures in individuals with osteoporosis. Reductions in fractures occur within months, well before BMD increases can be demonstrated [16].

Several small randomised trials indicate that the use of oral bisphosphonates increases BMD in patients on AIs, but there is no evidence currently that they prevent fractures. Two small studies, in which either postmenopausal women with breast cancer received oral clodronate or premenopausal women with chemotherapy induced menopause received oral risedronate, showed increases in BMD, after 2 years of bisphosphonate treatment, of between 2.5 and 2.9% compared to placebo.

In the SABRE study [17] (anastrozole with risedronate in postmenopausal women with hormone-receptor-positive early breast cancer), results have indicated that risedronate reduced bone marker levels and prevented bone loss in osteopaenic patients receiving anastrozole. In the bone sub-study of the IBIS II Prevention Trial [18], risedronate has been found to prevent bone loss in the osteopaenic and osteoporotic group.

A major concern is the poor bioavailability of oral bisphosphonates, and in studies of women with postmenopausal osteoporosis receiving oral bisphosphonates, 57% of patients were noncompliant with therapy after 2 years of study [6,19]. Non-compliance was associated with a 37% increased risk of hip and vertebral fractures compared with compliant patients. To increase compliance, weekly regimens (rather than daily) have been developed but, despite emerging evidence that oral bisphosphonates prevent AI-induced bone loss (AIBL) additional evidence that adequate compliance can be achieved, with appropriate reduction in fracture incidence, is required before their recommendation as standard of care.

Intravenous bisphosphonate therapy

Intravenous bisphosphonate studies encompassing 2600 pre- and postmenopausal women with early breast cancer and utilising zoledronic acid provide the main support for the use of bisphosphonates in AI-induced bone loss.

[FIGURE 3 OMITTED]

The bone substudy of the ABCSG-12 Trial [10] (n=401) indicated that zoledronic acid (4 mg intravenously every 6 months) prevents bone loss associated with ovarian suppression and endocrine therapy in premenopausal women with hormone receptor-positive breast cancer. During 3 years of ovarian suppression with goserelin (3.6 mg every 28 days) combined with either anastrozole or tamoxifen endocrine therapy, patients receiving zoledronic acid maintained baseline BMD, whereas significant overall bone loss was seen at the lumbar spine with both anastrozole (-13.6%; P<0.0001) and tamoxifen (-9.0%; P<0.0001). In addition, this trial has recently reported a 36% reduced risk of distant recurrence after 60 months in patients given zoledronic acid and endocrine treatment, compared to those given only endocrine therapy (P<0.015). Breast cancer recurrence was reduced at both distant (bone and other sites) and locoregional sites [11] (Figure 2).

In postmenopausal women with early breast cancer the Zometa-Femara adjuvant synergy trials Z-FAST in America (n=602), ZOFAST in Europe and the rest of the world (n=1066) and the E-ZOFAST study, compare the efficacy of zoledronic acid treatment (4 mg intravenously every 6 months) administered together with letrozole therapy (upfront group) or after a BMD decrease to <-2.0 or fragility fracture (delayed group) [20].

In both the Z-FAST and ZO-FAST study, delayed zoledronic acid treatment resulted in a 2.4% and 2.0% loss in BMD at lumbar spine and total hip respectively [20]. Patients receiving upfront zoledronic acid experienced significant gains in lumbar spine and total hip BMD (1.9% and 1.3% respectively; P<0.0001). Subsequent 36-month analysis of the Z/ZOFAST trials indicated that women receiving upfront zoledronic acid continue to gain BMD during the 3 years of therapy. These studies were not powered to detect differences in fracture rate or recurrence but there appears to be a trend towards fewer fractures and lower breast cancer recurrence in patients who received upfront zoledronic acid [20]. These provocative results await confirmation from the AZURE trial and other trials which are collecting breast cancer recurrence data.

The administration of zoledronic acid is well tolerated, with mild flu-like symptoms and occasional infusion site reactions but few other adverse events seen. Out of a total of 2195 patients in these studies, only six cases of osteonecrosis of the jaw have been reported (Figure 3).

Other anti-resorptives

Denosumab, an investigational monoclonal antibody that targets a protein essential for the maturation and activation of osteoclasts, thereby inhibiting osteoclast-mediated osteolysis, has recently demonstrated efficacy in preventing AIBL [24]. In a double-blind, randomised, Phase III study in women receiving aromatase inhibitor therapy (n=252), denosumab increased lumbar spine BMD at 12 and 24 months versus placebo (P<0.0001 for both) [24,25]. Results from these recent clinical trials indicate that upfront treatment with bone-targeted therapies preserves, and in some cases increases, BMD in postmenopausal women receiving AI therapy.

Selection of patients on AIs for prevention of aromatase-inhibited bone loss

In the ATAC trial [2], fractures increased within 6 months of starting treatment and continued until the end of the 5-year treatment period. However, BMD is a poor guide to which individual will suffer a fragility fracture, since 82% of fractures occur in women with normal or osteopaenic BMD scan results. Reid et al. [26] have recently issued guidelines suggesting that all patients on AIs should undergo baseline BMD scanning (Figure 4).

In the bone substudies of the three AI trials (ATAC [2], BIG1-98 [4], IES [5]), no patient who commenced AI therapy with a T-score >1.0 (i.e. normal BMD) subsequently became osteoporotic, and fracture rates appear low in this group--so further intervention would appear unnecessary, particularly in those patients switching to an AI after 2 years of tamoxifen.

In osteoporotic women (T-score >-2.0) it is clear that intervention with a bisphosphonate will be required, as well as advice regarding calcium and vitamin D supplementation (particularly if a patient is vitamin D deficient).

[FIGURE 4 OMITTED]

In patients with a T-score which is >-1.0 but lower than -2.0 (i.e. osteopaenic), a significant number of these women will become osteoporotic or will fracture on AI therapy if they are not given appropriate lifestyle advice and calcium and vitamin D supplementation. These patients as a minimum require repeat BMD scanning after 24 months of therapy--and those with an annual rate of bone loss >4% at lumbar spine or total hip, and/or those whose T-score becomes greater than -2.0, require initiation of adjuvant bisphosphonate therapy. An emerging consensus would be that all women on AIs with a bisphosphonate, who have a low BMD (T-score >-1.0) with one more risk factor for fragility fracture, should be treated with bisphosphonate therapy until they have stopped AI treatment or BMD T-score has increased to <-1.0 (Figure 4).

The World Health Organization has developed an online assessment model of fracture risk [27] which can be used to predict risk of fracture for an individual patient. The WHO Fracture Risk Assessment Tool (FRAX[R]) primarily uses BMD but can also calculate using body mass index (BMI) and considering AI use as a factor causing secondary osteoporosis. The index allows a physician to chose the race or country of origin of the patient and then utilises age, weight, height, previous fracture, parent fractured hip, current smoking, glucocorticoids use, rheumatoid arthritis, secondary osteoporosis, alcohol consumption >3 units per day and the femoral neck or lumbar spine BMD (or alternatively the patient's BMI) to provide a 10-year probability of fracture--which, if it is over 10%, should lead to consideration of bisphosphonate therapy. Thus, the WHO FRAX index is a useful tool for selection of which individual to treat.

Aromatase inhibitors have become the treatment of choice in the adjuvant setting and monitoring of AI-induced bone loss is critical, particularly in patients with low BMD or low BMI.

The bone substudies of the AI trials were small and provided little data on fractures and fracture risk because of the small number of patients in the studies. Osteopaenic patients (approximately 25-30% of all breast cancer survivors) represent the group who produce the largest clinical problem with the highest incidence of fractures, even if the actual risk of fracture is greater for an individual in the smaller osteoporotic group (around 5%).

For patients having upfront AI therapy, baseline BMD measurement and biannual assessment is required for all those who do not have a normal baseline BMD at the outset of AI therapy. Bisphosphonates given at commencement of AI therapy, in pre and postmenopausal women, prevent bone loss--and their benefit may extend beyond preserving BMD loss and preventing fractures. Emerging data suggest that concomitant AI and intravenous bisphosphonate therapy prevent metastatic disease--but the AZURE study is yet to confirm this.

Adjuvant bisphosphonate therapy provides bone-protective effects to early breast cancer patients receiving AIs and should be standard of care for all osteoporotic women.

Conclusion

Recent clinical studies have provided the rationale for the development of evidence-based, expert recommendations for bone health management in patients receiving AI therapy for early breast cancer [26,28]. A combination of risk factors may be used to determine the optimal treatment option to preserve bone integrity in this setting. Based on these assessments, it is recommended that patients who are at high risk for rapid bone loss receive early intervention with bisphosphonates.

References

[1.] Chen Z, Maricic ML, Bassford TL et al. Fracture risk among breast cancer survivors: results from the Women's Health Initiative Observational Study. Arch Intern Med, 2005, 165, 552-558.

[2.] Howell A, Cuzick J, Baum M et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer, Lancet, 2005, 365, 60-62.

[3.] Thurlimann B, Keshaviah A, Coates AS et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer, N Engl J Med, 2005, 353, 2747-2757.

[4.] Coates AS, Keshaviah A Thurlimann B et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG1-98. J Clin Oncol, 2007, 25, 486-492.

[5.] Coombes RC, Kilburn LS, Snowdon CF et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial, Lancet, 2007, 369, 559-570.

[6.] Sambrook P and Cooper C. Osteoporosis. Lancet, 2006, 367, 2010-2018.

[7.] Kanis JA, Johansson H, Oden A et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res, 2004, 19, 893-899.

[8.] 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.

[9.] Siris ES, Chen YT, Abbott TA et al. Bone mineral density threshold for pharmacological intervention to prevent fractures. Arch Intern Med, 2004, 164, 1108-1112.

[10.] Gnant M, 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.

[11.] Gnant M, Mlineritsch B, Luschin-Ebengreuth G et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with breast cancer: 5 year follow-up of the ABCSG-12 bone mineral density substudy. Lancet, 2008, 9, 840-849.

[12.] Cummings SR, Browner WS, Bauer D et al. Study of Osteoporotic Fractures Research Group. Endogenous hormones and the risk of hip and vertebral fractures among older women. N Engl J Med, 1998, 339, 733-738.

[13.] Siris ES, Brenneman SK, Miller PD et al. Predictive value of low BMD for 1-year fracture outcomes is similar for postmenopausal women ages 50-64 and 65 and older: results from the National Osteoporosis Risk Assessment (NORA). J Bone Miner Res, 2004, 19, 1215-1220.

[14.] de Laet C, Kanis JA, Oden A et al. Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos Int, 2005, 16, 1330-1338.

[15.] van Staa TP, Leufkens HG and Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int, 2002, 13, 777-787.

[16.] Cranney A, Wells G, Willan A et al. Meta-analyses of therapies for postmenopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev, 2002, 23, 508-516.

[17.] van Poznak C, Hannon, Mackey JR et al. Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE Trial J Clin. Oncol, 2010, 28, 967-975.

[18.] Cuzick J. IBIS II: a breast cancer prevention trial in postmenopausal women using the aromatase inhibitor anastrozole. Expert Rev Anticancer Ther, 2008, 8, 1377-1385.

[19.] Siris ES, Harris ST, Rosen CJ et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and non vertebral fractures from 2 US databases. Mayo Clin Proc, 2006, 81, 1013-1022.

[20.] Eidtmann H, de Boer R, Bundred N et al. Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST Study. Ann Oncol, 2010, May 5 [epub ahead of print].

[21.] Bundred NJ, Campbell ID, Davidson N et al. Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results. Cancer, 2008, 112, 1001-1010.

[22.] De Boer R, Eidtmann H, Lluch A et al. The ZO-FAST trial: zoledronic acid effectively inhibits aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: 24 month BMD results. San Antonio Breast Cancer Symposium, December 2007, Abstr. 501.

[23.] Eidtmann H, Bundred NJ, de Boer R et al. The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36 months follow-up of ZO-FAST. San Antonio Breast Cancer Symposium, December 2008, Abstr. 44.

[24.] Ellis GK, Bone HG, Chlebowski R et al. Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study. Breast Cancer Res Treat, 2009, 118, 81-87.

[25.] Ellis G, Bone HG, Chlebowski R et al. A phase 3 study of the effect of denosumab therapy on bone mineral density in women receiving aromatase inhibitors for non metastatic breast cancer. San Antonio Breast Cancer Symposium, December 2007, Abstr. 47.

[26.] Reid DM, Doughty J, Eastell R et al. Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group. Cancer Treat Rev, 2008, 34, S3-S18.

[27.] WHO Fracture Risk Assessment Tool. Available at: www.shef.ac.uk/FRAX (accessed 7 July 2010).

[28.] Hadji P, Body JJ, Aapro MS et al. Practical guidance for the management of aromatase inhibitor-associated bone loss. Ann Oncol, 2008, 19, 1407-1416.

Nigel J Bundred

University Hospital of South Manchester, Wythenshawe, UK

Correspondence to: Nigel J Bundred

University Hospital of South Manchester

2nd Floor, Education and Research Centre

Southmoor Road, Wythenshawe

Manchester M23 9LT, UK

(email. bundredn@manchester.ac.uk)
Panel 1: Risk factors for fragility: any two of the
following:

* AI therapy

* Low BMD (T-score < -1.5)

* Age >65 years

* Low BMI (<20 kg/[m.sup.2])

* Family history of hip fracture

* Personal history of fragility after age 50

* Oral corticosteroid use of >6 months

* Smoking (current or history of)

Figure 2. Continued improvement in
BMD 2 years after cessation of
zoledronic and treatment (adapted
from data published by Gnant et al.
[11]).

Change in BMD, g/[cm.sup.2]

No zoledronic acid 36 60

Tamoxifen -9.0% -4.5%
Anastrozole -13.6% -7.8%

Zoledronic acid 36 60

Tamoxifen +1.0% +5.2%
Anastrozle -0.1% +3.1%

Note: Table made from bar graph.
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Title Annotation:Feature Article
Author:Bundred, Nigel J.
Publication:Advances in Breast Cancer
Article Type:Clinical report
Date:Jul 1, 2010
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