ORIGINAL ARTICLE

Preventive effect of risedronate on bone loss and frailty fracturesin elderly women treated with anastrozole for early breast cancer

Giuseppe Sergi • Giulia Pintore • Cristina Falci • Nicola Veronese •

Linda Berton • Egle Perissinotto • Umberto Basso • Antonella Brunello •

Silvio Monfardini • Enzo Manzato • Alessandra Coin

Received: 15 July 2011 / Accepted: 23 November 2011 / Published online: 13 December 2011

� The Japanese Society for Bone and Mineral Research and Springer 2011

Abstract The aim of this study was to assess the effect of

adjuvant anastrozole, alone or associated with risedronate,

on BMD and bone fracture risk in women more than 70

years old with hormone receptor-positive early breast can-

cer (EBC). In a group of 51 elderly women (aged

76.4 ± 5.0 years) considered for adjuvant aromatase

inhibitors for EBC, 24 patients with T-scores C -2 and no

prevalent fractures received anastrozole 1 mg/day (group

A), and 27 patients with T-scores\-2, or with T-scores C

-2 and prevalent fractures (group B), received anastrozole

(1 mg/day) plus risedronate (35 mg/week). Both groups

received supplementation with 1 g calcium carbonate and

800 IU vitamin D per day. Differences in BMD and frailty

fractures were evaluated after 1 and 2 years. In group A,

significant decreases in BMD were observed in the lumbar

spine (D BMD, -0.030 ± 0.04 g/cm2, P \ 0.05), femoral

neck (D BMD, -0.029 ± 0.05 g/cm2, P \ 0.05), and tro-

chanter (D BMD, -0.026 ± 0.03 g/cm2, P \ 0.01) after

2 years. The greatest percent reduction in height (Hpr)

emerged in the thoracic spine (3.6 ± 2.4%, P \ 0.01),

although only one incident vertebral fracture was observed.

In group B, BMD increased in the lumbar spine (D BMD,

0.038 ± 0.04, P \ 0.001), although no significant changes

were seen in the hip regions. The decline in Hpr was neg-

ligible (about 1%). No incident fractures were observed at

follow-up. In conclusion, anastrozole treatment for EBC in

elderly women seems to have only mild negative effects on

the femoral bone. Risedronate makes the use of anastrozole

safer, even for osteopenic or osteoporotic elderly patients.

Keywords Early breast cancer � Anastrozole �Osteoporosis � Vertebral fractures � Elderly

Introduction

In the past few decades, third-generation aromatase

inhibitors (AIs)—anastrozole, letrozole, and exemestane—

have emerged as an alternative to tamoxifen for the adju-

vant treatment of estrogen hormone receptor (HR)-positive

early breast cancer (EBC) in postmenopausal women. AIs

have proved superior to tamoxifen in efficacy, safety, and

tolerability, and they improve disease-free survival rates.

They are recommended either up front or as part of a

switch schedule (2–3 years of tamoxifen followed by AIs

until the fifth year, or vice versa) [1–3]. The estrogen

depletion induced by AIs improves their antitumor effi-

cacy, but it also raises concern regarding healthy organs

such as bone. Low levels of endogenous estrogens accel-

erate bone mass loss and increase the risk of fragility

fractures [2, 4–6]. This loss is particularly important in

women after menopause, who are already at risk of age-

related osteoporosis and bone fractures, and although the

negative effect of AIs on bone has been amply investigated

in postmenopausal women [4, 7, 8], for elderly women the

G. Sergi � G. Pintore � N. Veronese � L. Berton � E. Manzato �A. Coin

Department of Medical and Surgical Sciences,

University of Padova, Padua, Italy

G. Sergi (&)

Division of Geriatrics, Ospedale Giustinianeo (2� Piano),

via Giustiniani 2, 35128 Padua, Italy

e-mail: giuseppe.sergi@unipd.it

C. Falci � U. Basso � A. Brunello � S. Monfardini

Istituto Oncologico Veneto (IOV), IRCCS, Padua, Italy

E. Perissinotto

Department of Environmental Medicine and Public Health,

University of Padova, Padua, Italy

123

J Bone Miner Metab (2012) 30:461–467

DOI 10.1007/s00774-011-0341-1

evidence is scanty and inconclusive. With age, the

increasing incidence of HR-positive EBC [9–11] imposes

the need to also consider the use of AIs for treating geri-

atric patients. Aging is also per se an important factor that

increases bone loss and raises the risk of fractures [12],

which is why oncologists are generally unwilling to pre-

scribe AIs for HR-positive EBC in elderly women for fear

of accentuating their already high age-related risk of

osteoporosis and fractures. On the other hand, estrogen

receptor expression in bone declines with age [13], so AI-

related estrogen inhibition would presumably have less

negative effect on the bone of older women than on that of

younger postmenopausal women. A prior evaluation of the

fracture risk in elderly patients with breast cancer would be

the best approach to identify and treat any osteoporosis and

thereby limit the possible additional risk of AI therapy.

This approach is still not routinely adopted in oncological

and geriatric practice, however. The aims of our study were

to assess the effect of adjuvant anastrozole on bone mineral

density (BMD) and the risk of bone fractures in women

more than 70 years of age with HR-positive EBC and to

investigate whether antiresorptive therapy with risedronate

is useful in preventing the presumed influence of AIs on

bone density and fractures.

Materials and methods

Patients

This observational cohort study was conducted at the Geri-

atrics Department of Padua University. Elderly women more

than 70 years of age seen at the Medical Oncology Division,

Istituto Oncologico Veneto, Padua, and scheduled to receive

anastrozole (1 mg/day) for EBC in stages I–III, and attend-

ing our outpatient clinic for the diagnosis and treatment of

osteoporosis, were eligible for inclusion in the study.

Exclusion criteria were previous medication for osteo-

porosis and endocrine or chronic diseases interfering with

bone metabolism.

The study was designed in accordance with the Helsinki

Declaration and was approved by the Ethics Committee of

the Istituto Oncologico Veneto. All participants were fully

informed about the nature, purpose, procedures, and risks

of the study and gave their written informed consent.

Study design

All patients underwent the following instrumental tests at

the baseline:

• BMD and T-scores for the lumbar spine (L2–L4) and

main hip sites (neck, trochanter, and total hip) were

measured using dual-energy X-ray absorptiometry

(Hologic QDR 4500W). The NHANES (III) data were

used to edit the T-score reference population curve. In

accordance with the World Health Organization

(WHO) criteria [14], women with T-scores B2.5 were

considered osteoporotic.

• Anteroposterior and lateral radiography of the thoracic

and lumbar spine was used to identify morphometri-

cally detectable vertebral fractures. Six points defining

the anterior, middle, and posterior heights were marked

on each vertebra using a computed quantitative mor-

phometer (MorphoXpress) [15]. The greatest percent

reduction in height (Hpr) of the vertebral bodies was

recorded, and the mean Hpr of the thoracic (T5–T12)

and lumbar (L1–L4) spine were calculated.

A prevalent vertebral fracture was defined as a reduction

of at least 20% in its height (anterior, middle, or posterior)

according to the Genant criteria [16]. An incident vertebral

fracture was a reduction of at least 20% in height associ-

ated with a height reduction of more than 15% on follow-

up radiography.

Fasting blood samples were taken to analyze the fol-

lowing parameters: serum calcium and phosphorus, para-

thyroid hormone, 25(OH)D3, the bone isoform of alkaline

phosphatase, 24-h urinary calcium and phosphorus, and the

urinary dipyridoline/creatinine ratio.

After their baseline assessment for osteoporosis, patients

were treated according to their risk of fracture:

• Group A patients with T-scores C -2 at the lumbar or

total hip sites and with no prevalent vertebral fractures

received 1 mg/day oral anastrozole;

• Group B patients with T-scores \ -2 at the lumbar or

total hip sites or with T-scores C -2 and prevalent

vertebral fractures received 1 mg/day oral anastrozole

plus 35 mg/week risedronate sodium.

Both groups were given supplementation with 1,000 mg

elemental calcium (as calcium carbonate) and 800 IU

vitamin D per day.

Patients repeated the same tests 12 and 24 months later.

The study design is shown in Fig. 1.

Statistical analysis

All statistical analyses were conducted using the SAS rel.

9.1 (SAS Institute, Cary, NC, USA). The baseline findings

were expressed as mean ± standard deviations. Changes

in BMD and biochemical parameters after 12 and

24 months vis-a-vis the baseline were expressed as dif-

ferences (D) and evaluated using Student’s paired two-

sided t test. The level of statistical significance for each

test was set at 0.05.

462 J Bone Miner Metab (2012) 30:461–467

123

Results

Among 84 elderly women examined for EBC, 58 met the

inclusion/exclusion criteria and entered the study, and 51

completed the follow-up at 24 months. The general char-

acteristics and biochemical parameters for the patients

completing the study are shown in Table 1. No differences

were found in age, body mass index (BMI), or biochemical

parameters between the two treatment groups. The BMD

and T-scores in the lumbar spine and hip at the baseline,

and the differences (D) identified after 12 and 24 months,

of the two groups are shown in Table 2.

Based on the inclusion criteria, none of the patients in group

A were osteoporotic or had vertebral fractures at the baseline.

Significant declines in BMD and T-scores were observed after

12 months of treatment at the trochanter site (D BMD,

-0.01 ± 0.02 g/cm2, P \ 0.05) and after 24 months in the

lumbar spine (D BMD, -0.030 ± 0.04 g/cm2, P \ 0.05),

femoral neck (D BMD, -0.029 ± 0.05 g/cm2, P \ 0.05) and

trochanter (D BMD, -0.026 ± 0.03 g/cm2, P \ 0.01). No

patient was osteoporotic after 12 months, whereas 25%

became osteoporotic after 24 months. An incident vertebral

fracture was identified in one patient at 24 months.

In group B, 71% of the patients were osteoporotic at the

baseline and 76% had prevalent vertebral fractures. BMD

and T-scores increased in the lumbar spine after 12 months

(D BMD, 0.026 ± 0.04 g/cm2, P \ 0.01) and 24 months of

treatment (D BMD, 0.038 ± 0.04 g/cm2, P \ 0.001),

whereas no significant changes were seen in the hip regions.

The percentage of patients with osteoporosis dropped to 62%

after 12 months and to 57% after 24 months. No incident

fractures were observed at follow-up.

The greatest Hpr of the vertebral bodies at the baseline

was 10.9 ± 1.5% in group A and 13.5 ± 2.2% in group B

for the thoracic (T5–T12); for the lumbar spine (L1–L4), it

was 7.4 ± 1.8% in group A and 9.2 ± 2.6% in group B.

Figure 2 shows the variations in Hpr in the thoracic and

lumbar spine after 12 and 24 months. The Hpr was slightly

reduced (about 1%) at different sites in the two groups at

12 months. After 24 months, the greatest Hpr emerged for

the thoracic spine (3.6 ± 2.4%, P \ 0.01) in group A.

As for the biochemical parameters, no differences were

found between the baseline and follow-up values, apart

from the 25(OH)D3 levels, which increased in both groups

after 12 months (group A: 36.3 ± 26.0 mmol/l, P \ 0.001;

group B: 35.8 ± 32.4 mmol/l, P \ 0.001) and 24 months

(group A: 36.7 ± 31.8 mmol/l, P \ 0.001; group B:

39.4 ± 45.5 mmol/l, P \ 0.001).

Discussion

The present study confirms the negative effect of AIs on the

bone of elderly women, which can be controlled by antire-

sorptive therapy with risedronate. Our patients in group A,

treated with anastrozole alone, served as a model for

Fig. 1 Study design

J Bone Miner Metab (2012) 30:461–467 463

123

ascertaining the effect of AIs on the bone of elderly women,

whose BMD declined after 24 months by 3.0, 4.1, and 4.1% in

the lumbar spine, trochanter, and femoral neck, respectively.

The effect of aging alone would seem unable to explain

such reductions in BMD, as Valimaki et al. [17] found no

significant BMD reduction after 12 and 24 months in the

lumbar spine and total hip of elderly women (mean,

65.4 ± 7 years) with osteopenia receiving no AIs or

risedronate treatment. Moreover, the elderly women

(71 ± 7 years old) with osteoporosis in the control arm of

the VERT study [18, 19] had a positive but not significant

variation in BMD in the lumbar spine and femoral sites

after 1 and 2 years. The BMD losses that we recorded,

therefore, can presumably be attributed to the anastrozole

treatment administered to our patients.

Table 1 Age, anthropometric

characteristics, and biochemical

parameters for patients in group

A (anastrozole 1 mg/day,

calcium 1,000 mg/day, vitamin

D 800 IU/day) and group B

(anastrozole 1 mg/day,

risedronate sodium 35 mg/

week, calcium 1,000 mg/day,

vitamin D 800 IU/day)

Group A (n = 24) Group B (n = 27) P

Age 77.1 ± 4.2 76.0 ± 5.0

Weight (kg) 74.2 ± 10.3 65.6 ± 10.0 \0.01

Height (cm) 158.0 ± 5.33 154.6 ± 4.1 \0.05

Body mass index (BMI) (kg/m2) 29.79 ± 4.36 27.48 ± 4.26

S-calcium (mmol/l) 2.40 ± 0.11 2.41 ± 0.12

S-phosphorus (mmol/l) 1.10 ± 0.18 1.06 ± 0.17

Parathyroid hormone (ng/l) 88.17 ± 57.54 75.09 ± 38.92

Vitamin D3 (mmol/l) 28.23 ± 21.08 35.32 ± 19.32

Bone alkaline phosphatase (ALP) (lg/l) 18.89 ± 7.32 18.22 ± 11.84

DPD/creatinine ratio 8.85 ± 3.34 9.50 ± 4.69

U-calcium (mmol/24 h) 2.91 ± 2.12 3.07 ± 2.21

U-phosphorus (mmol/24 h) 19.13 ± 5.61 17.55 ± 6.92

Table 2 Bone mineral density (BMD) and T-scores at the baseline and differences (D) after 12 and 24 months in group A (anastrozole 1 mg/

day, calcium 1,000 mg/day, vitamin D 800 IU/day) and group B (anastrozole 1 mg/day, risedronate sodium 35 mg/week, calcium 1,000 mg/day,

vitamin D 800 IU/day)

Group A (n = 24) Group B (n = 27)

Baseline D 12 months D 24 months Baseline D 12 months D 24 months

Lumbar spine (L2–L4)

BMD (g/cm2) 0.998 ± 0.15 -0.015 ± 0.04 -0.030 ± 0.04* 0.854 ± 0.16 0.026 ± 0.04** 0.038 ± 0.04***

T-score -0.73 ± 1.41 -0.16 ± 0.33 -0.29 ± 0.41* -2.02 ± 1.52 0.20 ± 0.38* 0.31 ± 0.41**

Total hip

BMD (g/cm2) 0.824 ± 0.10 -0.000 ± 0.02 -0.015 ± 0.03 0.767 ± 0.11 -0.130 ± 0.58 0.001 ± 0.03

T-score -0.98 ± 0.80 0.00 ± 0.18 -0.12 ± 0.28 -1.44 ± 0.94 -0.04 ± 0.16 0.01 ± 0.25

Femoral neck

BMD (g/cm2) 0.707 ± 0.11 -0.018 ± 0.04 -0.029 ± 0.05* 0.642 ± 0.10 -0.119 ± 0.54 -0.014 ± 0.04

T-score -1.27 ± 0.99 -0.18 ± 0.38 -0.28 ± 0.43* -1.86 ± 0.85 -0.03 ± 0.26 -0.14 ± 0.38

Trochanter

BMD (g/cm2) 0.640 ± 0.08 -0.010 ± 0.02 -0.026 ± 0.03** 0.588 ± 0.11 -0.119 ± 0.56 0.118 ± 0.29

T-score -0.62 ± 0.77 -0.11 ± 0.18* -0.27 ± 0.30** -1.14 ± 1.03 -0.00 ± 0.26 0.08 ± 0.27

* P \ 0.05, ** P \ 0.01, *** P \ 0.001

Fig. 2 Mean percent reduction in height (Hpr) in the thoracic (T5–

T12) and lumbar (L1–L4) spine in the two treatment groups (groups

A and B) after 12 and 24 months

464 J Bone Miner Metab (2012) 30:461–467

123

Comparisons regarding the effect of anastrozole on

lumbar and femoral bone can be drawn with the ATAC [4]

and SABRE [20] studies, which involved postmenopausal

women who were a mean 65 years of age. In the ATAC

study, patients treated with anastrozole alone had a greater

BMD loss in the lumbar spine than at the femoral site, after

12 months (2.6 vs. 1.7%) and 24 months (4.0 vs. 3.2%) of

treatment. In the SABRE study, also [20], patients at low

and moderate risk of frailty fractures treated with anas-

trozole alone showed a greater BMD loss in the lumbar

region than at femoral sites after 24 months (-2.1 vs.

-0.4% for low-risk cases; -1.8 vs. -1.1% for moderate-

risk cases). These and other studies [21, 22] indicate that

AIs affect BMD in postmenopausal women, particularly at

the lumbar spine level.

In our study on elderly women, on the other hand, BMD

decreased more at femoral sites. Our results are consistent

with those of the ATAC [4] study, where BMD loss was

more severe at femoral sites than in the lumbar spine (-3.7

vs. -3.5%) in the subgroup of older women treated with

anastrozole. Sensitivity to AI-induced estrogen deprivation

probably decreases in the lumbar spine with advancing age,

enhancing femoral bone loss.

Our patients in group B, treated with anastrozole and

risedronate, could be seen as a model for investigating the

protective effect of risedronate in elderly women treated

with AIs. The BMD of these patients increased by 3.0% in

the lumbar spine after 1 year and by 4.5% after 2 years,

whereas their femoral BMD remained unchanged. These

results confirm the positive effect of risedronate in pro-

tecting lumbar bone, confirming the findings of previous

studies on postmenopausal women treated with AIs [20,

22]. In patients in the SABRE study with T-scores \ -2

[20] treated with anastrozole and risedronate, lumbar BMD

increased by 3% (P \ 0.0001) after 24 months: this

increase is lower than the 6% observed after 2 years in

elderly women with osteoporosis in the VERT trial [18]

who were treated with risedronate alone.

Considering that lumbar BMD decreased only slightly in

our patients treated with anastrozole alone (group A),

although it improved in our patients treated with anas-

trozole ? risedronate (group B) to a lesser degree than in

the patients treated with risedronate alone in the VERT

trial, we surmise that AIs have an acceptable negative

effect on BMD in the lumbar spine of elderly woman,

whereas risedronate confirms its protective effect.

We recorded no improvement in BMD at femoral sites

among patients treated with anastrozole plus risedronate,

although other reports in the literature have produced

conflicting results. In the SABRE study, femoral BMD

increased (?2%) after 2 years of anastrozole and risedro-

nate therapy, whereas it decreased (although not signifi-

cantly) in similar patients in the ARBI trial [22]. Given that

femoral BMD decreased in our patients on anastrozole

alone (group A) and did not change in those taking anas-

trozole and risedronate, anastrozole presumably has a

negative effect on femoral BMD as well, whereas risedr-

onate can prevent this BMD loss [23].

Evaluating the effects of different drugs on bone

involves investigating not only any related changes in

BMD and bone turnover markers but also their ability to

modify the risk of frailty fractures.

Only one vertebral fracture (4%) occurred in our group

A after 2 years, and no incident vertebral fractures occur-

red in group B. Previous studies investigating the action of

anastrozole and risedronate in EBC patients did not

investigate incident morphometric vertebral fractures. The

SABRE [20] and ATAC [4] studies only considered the

effect of anastrozole treatment on BMD, whereas the ARBI

study [22] only assessed prevalent nonvertebral fractures.

Among the untreated elderly women in the control group

for the VERT study [18], about 13% had new morpho-

metric vertebral fractures at the 2-year follow-up.

The use of intravenous bisphosphonates, such as

zolendronic acid, could be an alternative in the treatment of

bone loss by anastrozole, even if the use of oral bisphos-

phonates is associated with a lower incidence of adverse

effects such as renal toxicity, hypocalcemia, osteonecrosis

of the jaw (ONJ), and acute-phase response than intrave-

nous bisphosphonates [24]. However, ONJ was a rare

event, occurring in 0.24% patients with breast cancer

receiving bisphosphonates [25]. To minimize the adverse

effects of bisphosphonates, the patients were invited to

make correct use of these oral drugs and to maintain good

dental health.

A possible alternative to bisphosphonates in the treat-

ment of osteoporosis in EBC is the use of the selective

estrogen receptor modulator (SERM) as raloxifene. Nev-

ertheless, raloxifene has yet not been demonstrated to

provide protection from nonvertebral fractures, particularly

at the hip in elderly women [26], and bisphosphonates

appeared more protective than raloxifene to prevent frac-

tures at vertebral and nonvertebral sites [27].

Assessing the percent reduction in height (Hpr) of the

thoracic and lumbar vertebral bodies provides early infor-

mation on their frailty before morphometric fractures are

detectable. After a year, the Hpr variation seems irrelevant

(\1%) in both our groups, while after 2 years there was a

higher Hpr in group B, particularly in the thoracic region.

The small Hpr associated with a limited prevalence of

vertebral fractures in our group A indicates that anastrozole

would have only a mild negative effect in elderly patients

at low risk of fractures. The absence of fractures in group

B, associated with a preserved vertebral body height,

confirms the positive effect of risedronate in elderly

women at high risk of fractures.

J Bone Miner Metab (2012) 30:461–467 465

123

Throughout the study, bone metastasis were evaluated

applying the ASCO (American Society of Clinical Oncol-

ogy) guidelines. In fact, bone metastasis in early breast

cancer is about 4% after 8 years of follow-up [28]. Our

data are in agreement with this prevalence: no patient

evidenced bone metastasis after 2 years follow-up, even

though after 38 months of anastrozole therapy one patient

presented with a vertebral metastasis.

This study has some limits, particularly concerning the

small sample size resulting from our strict selection crite-

ria, which excluded patients under 70 years old, or with

associated diseases or concomitant treatments interfering

with bone metabolism; the period of observation was also

limited to 2 years although the treatment with anastrozole

is usually prolonged up to 5 years. Moreover, group A and

group B have no corresponding control groups for reasons

of ethical limits, particularly in the group at high risk; this

does not allow complete explanation of the independent

effect on bone of anastrozole in group A and of risedronate

in group B.

This study has some advantages over previous reports,

however; namely, the inclusion of very elderly patients, in

whom information on the effect of AIs on bone is still

incomplete, and morphometric measurements in the tho-

racic and lumbar spine, which enabled us to estimate not

only prevalent and incident vertebral fractures but also

mild and early vertebral body deformations.

In conclusion, we found that medium-term treatment

with AIs in women more than 70 years old with EBC had

only moderately negative effects on BMD (mainly

involving the femoral bone), which would not justify

limiting their use in geriatric patients. Antiresorptive drugs,

such as risedronate, enable the use of AIs to be safely

extended to osteopenic and osteoporotic elderly patients

with EBC.

Conflict of interest The authors have no conflict of interest to

declare.

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