Climacteric

ISSN: 1369-7137 (Print) 1473-0804 (Online) Journal homepage: https://www.tandfonline.com/loi/icmt20

Bone health in women with breast cancer

S. K. Ramchand, Y. M. Cheung & M. Grossmann

To cite this article: S. K. Ramchand, Y. M. Cheung & M. Grossmann (2019): Bone health in
women with breast cancer, Climacteric, DOI: 10.1080/13697137.2019.1580257

To link to this article: https://doi.org/10.1080/13697137.2019.1580257

Published online: 21 Mar 2019.

Submit your article to this journal

Article views: 8

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=icmt20
CLIMACTERIC
https://doi.org/10.1080/13697137.2019.1580257

REVIEW

Bone health in women with breast cancer

S. K. Ramchanda,b, Y. M. Cheunga,b and M. Grossmanna,b
a
Department of Endocrinology, Austin Health, Heidelberg, VIC, Australia; bDepartment of Medicine, Austin Health, The University of
Melbourne, Heidelberg, VIC, Australia

ABSTRACT ARTICLE HISTORY

Women with early, estrogen receptor-positive breast cancer are treated with adjuvant endocrine ther- Received 27 November 2018
apy, using aromatase inhibitors or selective estradiol receptor modulators such as tamoxifen, to Revised 12 January 2019
deprive breast tissue from the deleterious effects of estradiol action, hence improving long-term prog- Accepted 3 February 2019
nosis. Aromatase inhibitors and, in premenopausal women, tamoxifen accelerate bone loss and Published online 22 March
2019
increase fracture risk. Therefore, all women commencing endocrine therapy need a targeted work-up
to assess the baseline fracture risk, and monitoring of bone health during endocrine therapy should KEYWORDS
be individualized based on this baseline risk. While high-level evidence specific to early breast cancer Bone density; breast cancer;
is lacking, non-pharmacologic measures to maintain optimal bone health such as weight-bearing exer- estradiol deprivation;
cise and calcium and vitamin D sufficiency should be implemented in all women. Antiresorptive treat- fracture
ment should be initiated in all women with preexisting fragility fractures (including vertebral
morphometric fractures) and should be considered in women with areal bone mineral density (BMD)
T-scores <
2.0 (or Z-scores in women aged <50 years) or those experiencing rapid bone loss (5%
per year), taking into consideration the baseline BMD and other risk factors for fracture. Further clinical
trial evidence is required to provide definitive guidance regarding criteria to initiate antiresorptive
treatment, choice of agents, and duration of treatment, taking into account potential oncologic bene-
fits of antiresorptive therapy on breast cancer-related outcomes.

Introduction treatment, is not fully understood. Limited studies in postme-

nopausal women suggest that chemotherapy may be an
Breast cancer is the most common cancer diagnosed in
independent contributor to bone loss5, but definitive evi-
Australian women, estimated to account for 28.4% of all new
dence is lacking.
cancers in Australian women in 20181. While the average age
In this review, we will focus on bone health in women
of breast cancer diagnosis is 61 years, 20% of breast cancers
with early (non-metastatic) ER-positive breast cancer who
are diagnosed in premenopausal women.
receive adjuvant endocrine therapy. The material discussed is
About 80% of breast cancers express estrogen receptors
based on peer-reviewed journals indexed on the PubMed
(ERs) and are responsive to endocrine therapies designed to
database from 1970 to November 2018, using, in various
counter estrogen-mediated effects on breast cancer progres-
combinations, the search terms ‘breast cancer’, ‘bone health’,
sion. Due to earlier diagnosis and improved treatments, the
10-year relative survival after diagnosis is now 83%, and in ‘osteoporosis’, ‘aromatase inhibitor’, ‘tamoxifen’, and
2012 an estimated 190,000 women were living with breast ‘selective oestrogen modulator’. Original research articles,
cancer in Australia1. These epidemiological Australian data authoritative reviews, and societal guidelines were consid-
are representative globally especially for the developed ered. The recommendations provided here are based on a
world such as Europe and the United States. Given the over- recent position statement on the assessment and manage-
all good prognosis, optimizing the long-term health of the ment of bone health in women with ER-positive breast can-
many breast cancer survivors is of prime importance. cer receiving endocrine therapy made by an expert group on
Breast cancer treatment-induced bone loss can occur con- behalf of several Australian stakeholder societies, including
sequent to a variety of treatment modalities, including endo- the Endocrine Society of Australia, the Australian and New
crine therapy-induced estradiol deprivation, the topic of this Zealand Bone & Mineral Society, the Australasian Menopause
review, chemotherapy and associated medications such as Society, and the Clinical Oncology Society of Australia6.
glucocorticoids, and radiotherapy2,3. The extent to which
chemotherapy-induced accelerated bone loss in premeno-
Principles of endocrine therapy
pausal women is due to premature ovarian insufficiency
occurring in 40–90% of women, depending on age and treat- The effect of estradiol on the development and growth of
ment regimen4, rather than due to direct toxicity of the breast tumors can be inhibited in two ways: first, by blocking

CONTACT S. K. Ramchand [email protected] Department of Medicine, Austin Health, The University of Melbourne, 145 Studley Road,
Heidelberg, VIC 3084, Australia
ß 2019 International Menopause Society
2 S. K. RAMCHAND ET AL.

aromatase, the rate-limiting enzyme in the synthesis of estro- positive breast cancer14. However, this is at the expense of
gens from androgenic substrates; and, second, by blocking increased bone toxicity, with an almost doubling of osteo-
estradiol binding to the ER in breast tissue, using a breast ER porosis (11% vs. 6%) and a 3.5% absolute increase in fracture
antagonistic selective estrogen receptor modulator (SERM), rates, despite the fact that almost half of the women in this
usually tamoxifen. study13 received bisphosphonates. A recent systematic
It is important to note that, in premenopausal women, review including 16,349 women confirmed that extending
90% of circulating estradiol is produced by the ovary, and aromatase inhibitor treatment beyond 5 years was associated
only 10% from extragonadal aromatization of adrenal andro- with increased odds of bone fractures (odds ratio 1.34, 95%
gens7. In postmenopausal women, when ovarian estradiol confidence interval [CI] 1.16–1.55)15. Therefore, the length of
production essentially ceases, estrone, formed by aromatiza- endocrine treatment has to be carefully individualized. The
tion of androstenedione in peripheral tissues, is the predom- oncologic benefits of endocrine treatments, as well as their
inant circulating estrogen8. In postmenopausal women, adverse effects, validate the concept that low residual post-
aromatase inhibitors are sufficiently potent to block the low menopausal estradiol concentrations are physiologic-
level of extragonadal aromatase activity and to prevent the ally important.
synthesis of estrone from androstenedione and estradiol
from testosterone. Therefore, in postmenopausal women,
they can be used as monotherapy to achieve >95% systemic Premenopausal women
deprivation of circulating estrogens9. The situation is differ- In two pivotal phase III trials that randomized 4690 women
ent in premenopausal women, where the estradiol-mediated to OFS with either tamoxifen or aromatase inhibitor, the
negative hypothalamic–pituitary feedback is intact. Here, aro- combination of OFS and aromatase inhibition improved dis-
matase inhibitors, by initially causing a relative decrease in ease-free survival by 3.8% (number needed to treat of 26)
estradiol, remove this negative feedback, leading to gonadal and marginally reduced distant recurrence (absolute risk
axis activation7. This aromatase inhibitor-mediated gonadal reduction 1.8%, p ¼ 0.02) at 5 years, but this was again at the
axis activation leads to increased ovarian androgen produc- expense of a doubling of osteoporosis rates (13.6% vs. 6.4%)
tion and increased aromatase activity, thus failing to sup- compared to OFS and tamoxifen16. A recently published
press estradiol production. Therefore, in premenopausal extended 8-year follow-up of this premenopausal cohort17
women with breast cancer, aromatase inhibitors cannot be reported benefits with more aggressive compared to less
used as monotherapy but must be combined with ovarian intense estradiol deprivation on more definitive oncologic
function suppression (OFS), either by gonadotropin releasing outcomes, such as overall survival and distant recurrence17,
hormone analogs or bilateral ovariectomy. so that OFS combined with aromatase inhibition will likely
Tamoxifen, the most commonly used SERM, acts as an ER be used more frequently, especially in high-risk premeno-
antagonist in breast tissue and is effective irrespective of cir-
pausal women18.
culating estradiol concentrations. Therefore, tamoxifen can
be used as monotherapy in both premenopausal and post-
menopausal women10. Principles of endocrine therapy-related effects
on bone
Oncologic benefits of endocrine therapy SERMs such as tamoxifen, while acting as pure ER antago-
nists in breast tissue, have partial ER agonistic effects at the
Postmenopausal women
level of the skeleton, but are less potent than native estra-
Aromatase inhibitors are considered first-line adjuvant ther- diol10. Therefore, in premenopausal women, where endogen-
apy in postmenopausal women because, as reported in a ous estradiol is high, tamoxifen competes with estradiol for
meta-analysis of 9855 women with early ER-positive breast ER binding sites and acts as a partial antagonist, leading to
cancer, they reduce breast cancer recurrence and mortality net bone loss19.
compared to tamoxifen, with absolute 10-year benefits of In young women receiving therapeutic OFS who are iatro-
3.6% and 2.1%, respectively, corresponding to numbers genically estradiol deprived, combining OFS with tamoxifen
needed to treat of around 25–5011. The clinical meaningful- causes less bone mineral density (BMD) loss compared to the
ness of these benefits, however, is dependent on underlying combination of OFS and aromatase inhibitor. This may be
breast cancer characteristics, and it is important to note that, because tamoxifen acts as a partial agonist and slows the
in absolute terms, the added benefits of aromatase inhibitors accelerated bone loss consequent to premature menopause,
versus tamoxifen are four-fold less than those of tamoxifen although this hypothesis has not been directly proven20. In
versus placebo11,12. Tamoxifen can therefore be a reasonable postmenopausal women who naturally have low estradiol
alternative especially in low-risk women who, for example, concentration, the partial agonistic activity of tamoxifen in
cannot tolerate aromatase inhibitors due to adverse effects bone tissue leads to a net gain of bone mass21. Aromatase
such as arthralgia. inhibitors, given they are clinically used for adjuvant breast
Extending aromatase inhibitor treatment duration from 5 cancer therapy only in the context of absent ovarian estra-
to 10 years increases disease-free survival by 3.8%, largely diol production (either due to natural or iatrogenic meno-
due to reduced risk of local recurrence13, and can be worth- pause), cause profound systemic (including skeletal) estradiol
while for high-risk women, especially in those with node- depletion and therefore accelerated bone loss.
 CLIMACTERIC 3

Evidence for accelerated bone loss and fractures releasing hormone monotherapy28, and 9.3% with combined
OFS and aromatase inhibitor treatment20.
In the majority of women, irrespective of menopausal status,
However, there is evidence that DXA may underestimate
bone loss is most marked in the first year of endocrine ther-
the adverse effect of endocrine therapy on the skeleton. In a
apy and is particularly evident at the lumbar spine (using
longitudinal breast cancer prevention study in healthy post-
dual-energy X-ray absorptiometry [DXA]).
menopausal women assessing bone microarchitecture by
high-resolution peripheral quantitative computed tomog-
Postmenopausal women raphy, aromatase inhibitor therapy for 2 years compared to
placebo was associated with volumetric BMD and cortical
In a meta-analysis of trials designed for oncologic endpoints
thickness loss at the radius of 4.3% and 6.8%, respectively,
including 30,032 postmenopausal women with early ER-posi-
whereas bone loss by DXA was <2% at all sites29. Moreover,
tive breast cancer, primary therapy with aromatase inhibitors,
in a cross-sectional study of premenopausal women (mean
compared to tamoxifen, accelerated bone loss, measured by
age 43 years) with early breast cancer, estradiol depletion for
DXA, by about three-fold and almost doubled the fracture
a median duration of 17 months (range 6–120 months) was
risk (odds ratio 1.47, 95% CI 1.34–1.61), with a number
associated with markedly reduced volumetric BMD compared
needed to harm to cause one fracture of 4622. However, the
to healthy age-matched premenopausal controls, and bone
aromatase inhibitor-associated fracture risk in these oncology
microstructure in these women was similar to that of much
trials is almost certainly underestimated, given that fractures
older women (mean age 62 years) who were at least 10 years
were not uniformly collected or prospectively adjudicated as
post onset of natural menopause30.
is customary in dedicated fracture endpoint trials. The wide
variation in reported fracture rates in the individual trials
included in this meta-analysis22, ranging from 0.9 to 11%, is
consistent with underdetection. Indeed, in a dedicated frac-
Efficacy for non-pharmacological and
ture endpoint trial among postmenopausal women with
pharmacological measures
early breast cancer (discussed later), a staggering 10% of pla-
cebo-treated women sustained a clinical fracture within Effects of exercise on bone health are not well studied in
3 years23, a fracture rate similar to that reported in placebo- women with breast cancer. In premenopausal and postmeno-
treated women enrolled in the HORIZON Recurrent Fracture pausal women without breast cancer, randomized controlled
Trial24 and in the FREEDOM trial25, despite the fact that trials (RCTs) and meta-analyses have demonstrated improved
women enrolled in these trials24,25 had established osteopor- bone health outcomes with certain forms of weight-bearing
osis and were 5–10 years older. exercise and/or progressive resistance training, either alone
While, in the trials so far discussed, bone-catabolic effects or in combination (multimodal programs)31,32. In the majority
of aromatase inhibitors might be exaggerated because of the of these studies, the skeletal benefits have been modest
comparison to tamoxifen, breast cancer prevention26 and (BMD gains of 1–3%)33. One 12-month study in women with
extended duration endocrine therapy13 trials comparing aro- early breast cancer (n ¼ 498) using combined step aerobic
matase inhibitors to placebo, rather than to tamoxifen, and circuit training reported a modest benefit on femoral
clearly confirm that aromatase inhibitors accelerate bone loss neck BMD (þ1.2%, 95% CI 0.2–2.2) in premenopausal
by about three-fold and increase fracture risk by 30% even women, but not in postmenopausal women34. However, a
compared to placebo, despite the fact that in these studies13 larger meta-analysis of seven RCTs (n ¼ 1199 women with
up to 50% of women received bisphosphonate treatment. early breast cancer) incorporating a variety of exercise pro-
For reasons already discussed, the effects of tamoxifen on grams for at least 12 months’ duration did not demonstrate
the skeleton depend on the menopausal status. In postme- a benefit of exercise on BMD35.
nopausal women, compared to placebo, tamoxifen increases A recent Exercise and Sports Science Australia position
areal bone mineral density and reduces fracture risk by statement on exercise prescription for the prevention and
about a third (relative risk 0.68, 95% CI 0.51–0.92)21. management of osteoporosis in the general population pro-
vides a tailored prescription of weight-bearing exercise, pro-
gressive resistance training, and balance training, taking into
Premenopausal women
account the individual’s BMD and functional and clinical risk
In premenopausal women, relative rates of bone loss during factors for falls and fracture36.
endocrine therapy are more marked than in postmenopausal Extrapolating from general population evidence, and in
women. In general, the degree of bone loss, measured by light of multiple potential benefits of exercise in women
DXA, parallels the degree to which the endocrine therapy with early breast cancer beyond bone health, including qual-
decreases estradiol action at the skeleton: in controlled stud- ity of life, aromatase inhibitor-associated arthralgia, and
ies, annual bone loss rates have been reported to be 1.4% oncologic outcomes37, exercise should be recommended
with tamoxifen monotherapy19, 5.6% with combined OFS routinely. Given that evidence specific to breast cancer is
and tamoxifen treatment20, 7.7% with chemotherapy-associ- lacking, the rationale to ensure calcium and vitamin D suffi-
ated premature ovarian failure27, 8.2% with gonadotropin ciency (see later) is based on evidence outside breast cancer.
4 S. K. RAMCHAND ET AL.

Pharmacological measures in postmenopausal women endocrine treatment (13.6% with OFS combined with aroma-
tase inhibition over 3 years). However, none of the studies
With respect to antiresorptive therapy in postmenopausal
conducted in premenopausal women have been powered
women, immediate zoledronic acid at the time of aromatase
for fracture outcomes, and information regarding denosumab
inhibitor commencement dosed at 4 mg given 6-monthly
is currently not available. In premenopausal women, there
increased BMD during aromatase inhibitor treatment com-
appears to be a recovery of bone density after cessation of
pared to a strategy of delayed initiation, at the time of clin-
endocrine treatment20. It is unclear whether this increase in
ical fracture or if BMD T-scores decreased to <
2.0. There
bone mineral density is due to an increase in bone mass
was a cumulative BMD difference of 10% at 5 years (4.3%
related to the resumption of menses or whether this increase
lumbar spine BMD gain in upfront zoledronic acid group vs.
is due to a reduction in the remodeling rate, allowing more
5.4% loss in delayed group)38. Overall, the RCT evidence for
time for secondary mineralization of existing bone matrix.
bisphosphonate-associated prevention of postmenopausal
bone loss in women treated with aromatase inhibitors is
most robust for zoledronic acid, currently encompassing Assessment and management of bone health
about 3000 women enrolled for up to 5 years (for a review
see reference 6). By contrast, RCT evidence for oral Several guidelines and position statements have been devel-
bisphosphonates, while similar, is limited to about 650 oped by international societies with regards to the assess-
women enrolled for up to 3 years6, and treatment adherence ment and management of bone health in women with
can be more variable. ER-positive breast cancer receiving endocrine therapy39–46.
While bisphosphonates consistently prevent aromatase The recommendations provided here are based on a position
inhibitor-induced bone loss, the only study designed and statement developed by an expert working group on behalf
powered for fracture outcomes used denosumab (dosed at of several Australian stakeholder societies6 and are summar-
60 mg given 6-monthly) in postmenopausal women23. In this ized in Tables 1 and 2.
study, denosumab halved the clinical fracture risk at It is essential that all women commencing an aromatase
36 months, with an absolute risk reduction of 5% (estimated inhibitor and premenopausal women commencing tamoxifen
fracture rate 9.6% in the denosumab group vs. 5.0% in the have an individualized clinical and biochemical bone health
placebo group)23. This benefit increased over time, and esti- evaluation. This includes a skeletal health-focused history
mated fracture rates at 84 months were 11.1% in the denosu- and examination as well as baseline DXA, although in
mab group vs. 26.2% in the placebo group. Interestingly, the Australia DXA is currently not reimbursed for this indication.
benefit appeared similar irrespective of whether baseline DXA should be repeated at 1 year after commencement of
bone density was normal or reduced (T-scores <
1.5), endocrine therapy and at individualized frequency thereafter
although the study may have been underpowered for (Table 1).
this analysis23. All postmenopausal and osteopenic premenopausal
women should be considered for spine imaging to assess for
morphometric vertebral fractures, which may be clinically
Pharmacological measures in premenopausal women
silent (Table 1). Indeed, cross-sectional studies (n ¼ 156,497)
In the largest RCT of premenopausal women (n ¼ 404) receiv- in postmenopausal women have reported a relatively high
ing endocrine treatment, upfront zoledronic acid (4 mg given prevalence of morphometric fractures: 20% before endocrine
6-monthly) prevented bone loss, as assessed by DXA20, while therapy is commenced47, and 31% if assessed during aroma-
placebo-treated women experienced marked bone loss with tase inhibitor therapy48, with odds ratios in aromatase

Table 1. Initial bone health evaluation in all women.

History Blood/urine tests Imaging
Prior fragility fracture/s >50 years UEC, LFT, 25OHD, TSH, Ca, Mg, PO4 1. Baseline BMD by DXA
Parental history of hip fracture If reduced bone massa is present, consider: Repeat 1 year after commencement of AI and then
Preexisting metabolic bone conditions Serum PTH, celiac serology every 2 years or every 1 year if:
Age at menopause Serum and urine electrophoresis if aged >60 years Annual bone loss > 5% at any site T-scoreb <
1.5
Smoking status or presence of risk factors for myeloma at any site Commencing/changing anti-resorptive
Alcohol consumption >3 SD/day Urinary fractional calcium excretion rate (to assess therapy
Assessment of falls risk for hypercalciuria) 2. Thoracolumbar X-ray or VFA by DXA
Chronic glucocorticoid use 5 mg for Baseline: postmenopausal women only or premeno-
3 months pausal women if Z-score <
1.5. Subsequent analysis
Diabetes (type 1 or 2) if T-score <
1.5, back pain or loss of height 4 cm
Malabsorptive conditions Note: VFA may miss vertebral fractures associated
Rheumatoid arthritis with mild height loss; thus, lateral radiographs would
Low BMI <20 kg/m2 be preferential in individuals with a history of back
pain or height loss
Adapted from Grossmann et al6. 25OHD, 25-hydroxy vitamin D; AI, aromatase inhibitor; BMD, bone mineral density; BMI, body mass index; Ca, calcium; DXA,
dual-energy X-ray absorptiometry; LFT, liver function test; Mg, magnesium; PO4, phosphate; PTH, parathyroid hormone; SD, standard drinks; TSH, thyroid stimu-
lating hormone; UEC, urea, electrolytes, creatinine; VFA, vertebral fracture assessment.
a
T-scores or Z-scores <
1.0.
b
Use Z-score for women aged <50 years.
 CLIMACTERIC 5

Table 2. Bone health management.

Lifestyle modifications Antiresorptive therapy
Weight-bearing exercise: at least 30 min per day most days of the week If any of the following criteria are met:
Calcium  Prevalent or incident fragility or morphometric fracture/s
1000–1200 mg daily.  T-scorea <
2.0 at any site
Dietary sources optimal.  Annual bone loss 5% and/or 0.05 g/cm2 considering baseline BMD and
Consider supplemental elemental calcium if unable to meet target through other fracture risk factors
diet alone FRAXc 10-year riskb for major fracture >20% or hip fracture >3%
25(OH)-vitamin D
Target level 75 nmol/l (do not exceed 150 nmol/l)
Adapted from Grossmann et al.6. BMD, bone mineral density.
a
Use Z-score for women <50 years.
b
For postmenopausal women only. FRAX not validated for women <40 years old, and may underestimate fracture risk as aromatase inhibitor treatment is not
included in the algorithm.
c
The FRAX tool is a fracture risk calculator based on a number of clinical risk factors and bone mineral density at the femoral neck.

inhibitor-treated women to aromatase inhibitor-naïve women receiving aromatase inhibitors compared to tamoxifen during
ranging from 1.9 to 4.748,49. the active treatment phase (between-group fracture incidence
The use of conventional fracture risk assessment tools rate ratio 1.55, 95% CI 1.31–1.83), but not during follow-up
such as FRAX and the GARVAN Fracture Risk Calculator do (median 100 months) after completion of endocrine therapy
not include chemotherapy or aromatase inhibitor treatment (incidence rate ratio 1.03, 95% CI 0.81–1.31)51. These findings
as part of their fracture risk assessment algorithms and may suggest endocrine therapy-associated fracture effects (either
underestimate the fracture risk in women receiving these increased aromatase inhibitor-induced fracture risk and/or tam-
treatments. Additionally, these tools have not been validated oxifen treatment-associated protection) may not persist after
for use in women younger than 40 years old. cessation of endocrine therapy. Overall, these data suggest
Weight-bearing exercise, including impact and resistance that cessation of antiresorptive (at least bisphosphonate ther-
training, as well as achieving calcium and vitamin D suffi- apy, see considerations regarding denosumab later) should be
ciency is routinely recommended. All women should be considered at completion of endocrine therapy, with ongoing
advised to stop smoking, to minimize alcohol consumption, individualized BMD monitoring, unless a high fracture risk (e.g.
and to avoid, where possible, medications with adverse persistent osteoporotic T-scores, recent fragility frac-
effects on bone density. Antiresorptive treatment should be tures52) persists.
commenced for secondary prevention in women with preex- While a detailed discussion regarding risks of antiresorp-
isting fragility fractures (including morphometric vertebral tive treatment is beyond the scope of this article, in general,
fractures). Antiresorptive treatment should also be consid- benefits far outweigh the very low risk of serious adverse
ered in women with T-scores (or Z-scores if aged 50 years or effects (such as osteonecrosis of the jaw or atypical femoral
younger) <
2.0 at any site, if annual BMD loss is 5% and/ fractures), especially if doses approved for osteoporosis treat-
or 0.05 g/cm2, considering baseline BMD and other risk fac- ment are used and prolonged duration of treatment
tors for fracture, or in those with increased absolute fracture (>5–10 years) is carefully considered6.
risk (Table 2). Notably, governmental subsidy for the use of With respect to denosumab, the potential for accelerated
antiresorptive therapy varies among countries and is cur- bone remodeling following delayed administration or cessa-
rently not subsidized for these circumstances in Australia. tion of treatment could be of particular concern in women
In premenopausal women, relatively limited evidence is with breast cancer. First, although the absolute risk is low,
available to guide treatment, and discussions should be care- there is potential risk of increased multiple vertebral fractures
fully individualized, taking into account the potential for soon after denosumab cessation. In a recent case series of 24
future maternity. Potential thresholds for commencing antire- women with denosumab cessation-associated ‘rebound frac-
sorptive treatment, based on limited evidence, may include tures’, five of these women were receiving aromatase inhibi-
Z-scores 
2.0, or Z-scores 
1.0 if there has been an tors53. Second, preclinical data suggest that increased bone
annual decrease of BMD of 5%50. More research is needed. remodeling promotes release of factors that stimulate tumor
There is no high-level evidence specific to women with growth from osteoclasts and that, in turn, tumor-derived fac-
early breast cancer receiving endocrine therapy to guide the tors stimulate bone remodeling, potentially setting up a self-
duration of antiresorptive treatment. Most guidelines, reviewed perpetuating cycle stimulating development of metastases54.
in a recent Australian position statement6, while noting limited Therefore, according to current evidence, a course of deno-
evidence, recommend continuation of antiresorptive treatment sumab should be followed by a bisphosphonate, although
at least until the endocrine therapy is completed. In postmeno- firm data regarding mode and duration of bisphosphonate
pausal women, modest increases in BMD after aromatase therapy after denosumab cessation are lacking55.
inhibitor cessation and modest decreases in BMD after tamoxi- The preclinical findings linking accelerated bone remodeling
fen have been reported6, consistent with their differential to breast cancer progression54 are supported by clinical trials
effect on BMD as already discussed. Moreover, a study in post- reporting that, in women with early breast cancer, bisphospho-
menopausal women with early breast cancer randomized to nate treatment improved oncologic outcomes including bone
either adjuvant aromatase inhibitor therapy or tamoxifen for recurrence (relative risk 0.72, 95% CI 0.60–0.86) and breast can-
5 years demonstrated an increased fracture risk in women cer mortality (relative risk 0.82, 95% CI 0.73–0.93) only in
6 S. K. RAMCHAND ET AL.

estradiol-deprived women (due to either natural or breast can- References

cer treatment-related menopause) but not in premenopausal
1. Australia BCN. Current breast cancer statistics in Australia. https://
women54,56. However, contradictory results were reported in wwwbcnaorgau/media/6101/bcna-2018-current-breast-cancer-sta-
the recently completed, but not yet peer-reviewed, phase III D- tistics-in-australia-31jan2018pdf
CARE trial, with no reductions observed in breast cancer recur- 2. Ramchand SK, Lim E, Grossmann M. Adjuvant endocrine therapy
rence or death in women with early breast cancer receiving in women with oestrogen-receptor-positive breast cancer: how
should the skeletal and vascular side effects be assessed and man-
adjuvant denosumab, a potent inhibitor of bone remodeling,
aged? Clin Endocrinol 2016;85:689–93
compared to those receiving placebo57. The improvement in 3. Milat F, Vincent AJ. Management of bone disease in women after
oncological outcomes with the use of bisphosphonates, in par- breast cancer. Climacteric 2015;18:47–55
ticular clodronate and zoledronic acid 4 mg every 6 months, 4. Torino F, Barnabei A, De Vecchis L, et al. Chemotherapy-induced
ovarian toxicity in patients affected by endocrine-responsive early
has led expert societies, such as the American Society of
breast cancer. Crit Rev Oncol Hematol 2014;89:27–42
Clinical Oncology, to propose the use of these agents as adju- 5. Rodriguez-Rodriguez LM, Rodriguez-Rodriguez EM, Oramas-
vant treatment in postmenopausal women with early breast Rodriguez JM, et al. Changes on bone mineral density after adju-
cancer, irrespective of their use in optimizing bone health in vant treatment in women with non-metastatic breast cancer.
these women58. Breast Cancer Res Treat 2005;93:75–83
6. Grossmann M, Ramchand SK, Milat F, et al. Assessment and man-
agement of bone health in women with oestrogen receptor-posi-
tive breast cancer receiving endocrine therapy: Position statement
Unresolved issues and future research of the Endocrine Society of Australia, the Australian and New
As is evident from the preceding discussion of the limited evi- Zealand Bone & Mineral Society, the Australasian Menopause
Society and the Clinical Oncology Society of Australia. Clin
dence, many important questions remain, such as which antire- Endocrinol (Oxf) 2018;89:280–96
sorptive to use and how long for, especially in young 7. Simpson E, Santen RJ. Celebrating 75 years of oestradiol. J Mol
premenopausal women. While RCTs assessing zoledronic acid Endocrinol 2015;55:T1–20
in women with early breast cancer have used 4 mg every 8. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl
J Med 2003;348:2431–42
6 months, whether alternative dosing schedules such as using
9. Geisler J, King N, Dowsett M, et al. Influence of anastrozole
5 mg every 12 months, a schedule with proven antifracture effi- (Arimidex), a selective, non-steroidal aromatase inhibitor, on in
cacy in postmenopausal osteoporosis59, is similarly effective in vivo aromatisation and plasma oestrogen levels in postmeno-
women with early breast cancer is not known. Moreover, the pausal women with breast cancer. Br J Cancer 1996;74:1286–91
clinical utility of bone remodeling markers and alternative 10. Maximov PY, Lee TM, Jordan VC. The discovery and development
of selective estrogen receptor modulators (SERMs) for clinical
bone imaging to DXA, such as high-resolution peripheral quan- practice. Curr Clin Pharmacol 2013;8:135–55
titative computed tomography, in fracture risk assessment and 11. Early Breast Cancer Trialists’ Collaborative G, Dowsett M, Forbes
in monitoring treatment response requires further study. The JF, et al. Aromatase inhibitors versus tamoxifen in early breast
optimal choice of antiresorptive therapy in postmenopausal cancer: patient-level meta-analysis of the randomised trials. Lancet
2015;386:1341–52
women is also not settled. For example, while bisphosphonates
12. Regan MM, Neven P, Giobbie-Hurder A, et al. Assessment of letro-
have proven oncologic benefits56, but currently no proven anti- zole and tamoxifen alone and in sequence for postmenopausal
fracture efficacy, denosumab has proven antifracture efficacy women with steroid hormone receptor-positive breast cancer: the
but no proven oncologic benefits23. While in postmenopausal BIG 1-98 randomised clinical trial at 8.1 years median follow-up.
women tamoxifen treatment may have modest benefits on Lancet Oncol 2011;12:1101–8
13. Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor
skeletal health21, when to add antiresorptive treatment is not adjuvant therapy to 10 years. N Engl J Med 2016;375:209–19
clear, but may need to be considered in women at high frac- 14. Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine
ture risk. therapy for women with hormone receptor-positive breast cancer:
Overall, therapeutic hypogonadism in hormone-sensitive ASCO Clinical Practice Guideline Focused Update. J Clin Oncol
2018;37:423–38.
breast cancer is not only a unique model to understand the
15. Goldvaser H, Barnes TA, Seruga B, et al. Toxicity of extended adju-
effects of severe estradiol depletion on the skeleton but vant therapy with aromatase inhibitors in early breast cancer: a
remains a clinical challenge in balancing benefits and harms systematic review and meta-analysis. J Natl Cancer Inst 2018;110:
of both endocrine as well as antiresorptive therapy. The 31–9.
intensity and duration of adjuvant endocrine therapy require 16. Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with
ovarian suppression in premenopausal breast cancer. N Engl J Med
a risk-adapted individualized approach, best guided by a
2014;371:107–18
multidisciplinary model of care. 17. Francis PA, Pagani O, Fleming GF, et al. Tailoring adjuvant endo-
crine therapy for premenopausal breast cancer. N Engl J Med
Potential conflict of interest M. Grossmann has received speaker 2018;379:122–37
18. Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine
honoraria and conference support from Besins and Amgen Australia, has
therapy for women with hormone receptor-positive breast cancer:
been an advisory board member for Otsuka, and has received research
american society of clinical oncology clinical practice guideline
support from Bayer, Novartis, Weight Watchers, and Eli Lilly. S. K.
update on ovarian suppression. JCO 2016;34:1689–701
Ramchand has received speaker honorarium from Counterpart (breast
19. Powles TJ, Hickish T, Kanis JA, et al. Effect of tamoxifen on bone
cancer support organization). Y.-M. Cheung has nothing to disclose.
mineral density measured by dual-energy x-ray absorptiometry in
healthy premenopausal and postmenopausal women. JCO 1996;
Source of funding Nil. 14:78–84
 CLIMACTERIC 7

20. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al. Adjuvant 41. Paterson AH, Shea-Budgell MA. Bone health in patients with
endocrine therapy plus zoledronic acid in premenopausal women breast cancer: recommendations from an evidence-based
with early-stage breast cancer: 5-year follow-up of the ABCSG-12 Canadian Guideline. JCM 2013;2:283–301
bone-mineral density substudy. Lancet Oncol 2008;9:840–9 42. Tremollieres FA, Ceausu I, Depypere H, et al. Osteoporosis man-
21. Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on agement in patients with breast cancer: EMAS position statement.
bone mineral density in postmenopausal women with breast can- Maturitas 2017;95:65–71
cer. N Engl J Med 1992;326:852–6 43. Coleman R, Body JJ, Aapro M, et al. Bone health in cancer
22. Amir E, Seruga B, Niraula S, et al. Toxicity of adjuvant endocrine patients: ESMO Clinical Practice Guidelines. Ann Oncol 2014;25:
therapy in postmenopausal breast cancer patients: a systematic iii124–37
review and meta-analysis. J Natl Cancer Inst 2011;103:1299–309 44. Hadji P, Aapro MS, Body JJ, et al. Management of aromatase
23. Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in inhibitor-associated bone loss (AIBL) in postmenopausal women
breast cancer (ABCSG-18): a multicentre, randomised, double- with hormone sensitive breast cancer: joint position statement of
blind, placebo-controlled trial. Lancet 2015;386:433–43 the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol
24. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid
2017;7:1–12
and clinical fractures and mortality after hip fracture. N Engl J Med
45. Juozaityte E, Aleknavicius E, Janciauskiene R, et al. Guidelines for
2007;357:1799–809
diagnostics and treatment of aromatase inhibitor-induced bone
25. Cummings SR, San Martin J, McClung MR, et al. Denosumab for
loss in women with breast cancer: a consensus of Lithuanian med-
prevention of fractures in postmenopausal women with osteopor-
ical oncologists, radiation oncologists, endocrinologists, and family
osis. N Engl J Med 2009;361:756–65
medicine physicians. Medicina 2014;50:197–203
26. Sestak I, Singh S, Cuzick J, et al. Changes in bone mineral density at
46. Singapore Cancer Network Breast Cancer Workgroup. Singapore
3 years in postmenopausal women receiving anastrozole and risedr-
onate in the IBIS-II bone substudy: an international, double-blind, Cancer Network (SCAN) guidelines for bisphosphonate use in the
randomised, placebo-controlled trial. Lancet Oncol 2014;15:1460–8 adjuvant breast cancer setting. Ann Acad Med Singapore 2015;44:
27. Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant 368–78
chemotherapy is associated with rapid bone loss in women with 47. Bouvard B, Hoppe E, Soulie P, et al. High prevalence of vertebral
early-stage breast cancer. JCO 2001;19:3306–11 fractures in women with breast cancer starting aromatase inhibi-
28. Fogelman I, Blake GM, Blamey R, et al. Bone mineral density in pre- tor therapy. Ann Oncol 2012;23:1151–6
menopausal women treated for node-positive early breast cancer 48. Pedersini R, Monteverdi S, Mazziotti G, et al. Morphometric verte-
with 2 years of goserelin or 6 months of cyclophosphamide, metho- bral fractures in breast cancer patients treated with adjuvant aro-
trexate and 5-fluorouracil (CMF). Osteoporos Int 2003;14:1001–6 matase inhibitor therapy: a cross-sectional study. Bone 2017;97:
29. Cheung AM, Tile L, Cardew S, et al. Bone density and structure in 147–52
healthy postmenopausal women treated with exemestane for the 49. Villa P, Lassandro AP, Amar ID, et al. Impact of aromatase inhibitor
primary prevention of breast cancer: a nested substudy of the treatment on vertebral morphology and bone mineral density in
MAP.3 randomised controlled trial. Lancet Oncol 2012;13:275–84 postmenopausal women with breast cancer. Menopause 2016;23:
30. Ramchand SK, Seeman E, Wang XF, et al. Premenopausal women 33–9
with early breast cancer treated with estradiol suppression have 50. Hadji P, Gnant M, Body JJ, et al. Cancer treatment-induced bone
severely deteriorated bone microstructure. Bone 2017;103:131–5 loss in premenopausal women: a need for therapeutic interven-
31. Kelley GA, Kelley KS, Kohrt WM. Exercise and bone mineral density tion? Cancer Treat Rev 2012;38:798–806
in premenopausal women: a meta-analysis of randomized con- 51. Arimidex TAoiCTG, Forbes JF, Cuzick J, et al. Effect of anastrozole
trolled trials. Int J Endocrinol 2013;2013:741639 and tamoxifen as adjuvant treatment for early-stage breast cancer:
32. Zhao R, Zhao M, Xu Z. The effects of differing resistance training 100-month analysis of the ATAC trial. Lancet Oncol 2008;9:45–53
modes on the preservation of bone mineral density in postmeno- 52. Adler RA, El-Hajj Fuleihan G, Bauer DC, et al. Managing osteopor-
pausal women: a meta-analysis. Osteoporos Int 2015;26:1605–18 osis in patients on long-term bisphosphonate treatment: report of
33. Kelley GA, Kelley KS, Kohrt WM. Effects of ground and joint reac- a task force of the American Society for Bone and Mineral
tion force exercise on lumbar spine and femoral neck bone min- Research. J Bone Miner Res 2016;31:1910
eral density in postmenopausal women: a meta-analysis of 53. Anastasilakis AD, Polyzos SA, Makras P, et al. Clinical features of
randomized controlled trials. BMC Musculoskelet Dis 2012;13:177 24 patients with rebound-associated vertebral fractures after
34. Saarto T, Sievanen H, Kellokumpu-Lehtinen P, et al. Effect of
denosumab discontinuation: systematic review and additional
supervised and home exercise training on bone mineral density
cases. J Bone Miner Res 2017;32:1291–6
among breast cancer patients. A 12-month randomised controlled
54. Croucher PI, McDonald MM, Martin TJ. Bone metastasis: the
trial. Osteoporos Int 2012;23:1601–12
importance of the neighbourhood. Nat Rev Cancer 2016;16:373–86
35. Fornusek CP, Kilbreath SL. Exercise for improving bone health in
55. Reid IR, Horne AM, Mihov B, et al. Bone loss after denosumab: only
women treated for stages I-III breast cancer: a systematic review
partial protection with zoledronate. Calcif Tissue Int 2017;101:371–4
and meta-analyses. J Cancer Surviv 2017;11:525–41
56. Early Breast Cancer Trialists’ Collaborative Group, Coleman R,
36. Beck BR, Daly RM, Singh MA, et al. Exercise and Sports Science
Powles T, et al. Adjuvant bisphosphonate treatment in early breast
Australia (ESSA) position statement on exercise prescription for
the prevention and management of osteoporosis. J Sci Med Sport cancer: meta-analyses of individual patient data from randomised
2017;20:438–45 trials. Lancet 2015;386:1353–61
37. Peterson LL, Ligibel JA. Physical activity and breast cancer: an 57. Coleman RE, Finkelstein D, Barrios CH, et al. Adjuvant denosumab
opportunity to improve outcomes. Curr Oncol Rep 2018;20:50 in early breast cancer: First results from the international multicen-
38. Coleman R, de Boer R, Eidtmann H, et al. Zoledronic acid (zoledro- ter randomized phase III placebo controlled D-CARE study. JCO
nate) for postmenopausal women with early breast cancer receiv- 2018;36:501
ing adjuvant letrozole (ZO-FAST study): final 60-month results. 58. Dhesy-Thind S, Fletcher GG, Blanchette PS, et al. Use of adjuvant
Ann Oncol 2013;24:398–405 bisphosphonates and other bone-modifying agents in breast can-
39. Hadji P, Coleman RE, Wilson C, et al. Adjuvant bisphosphonates in cer: a cancer care ontario and american society of clinical oncol-
early breast cancer: consensus guidance for clinical practice from ogy clinical practice guideline. JCO 2017;35:2062–81
a European Panel. Ann Oncol 2016;27:379–90 59. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid
40. Gralow JR, Biermann JS, Farooki A, et al. NCCN task force report: for treatment of postmenopausal osteoporosis. N Engl J Med 2007;
bone health in cancer care. J Natl Compr Canc Netw 2013;11:S1–S50 356:1809–22