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  • Research article
  • Open Access
  • Open Peer Review

Tamoxifen use reduces the risk of osteoporotic fractures in women with breast cancer in Asia: a nationwide population-based cohort study

  • 1, 2, 3,
  • 4,
  • 5, 6,
  • 2,
  • 3, 5 and
  • 1, 3, 5Email author
BMC Musculoskeletal Disorders201516:123

https://doi.org/10.1186/s12891-015-0580-8

  • Received: 3 February 2015
  • Accepted: 12 May 2015
  • Published:
Open Peer Review reports

Abstract

Purpose

Bone mineral density changes with tamoxifen treatment have been reported in pre- and post-menopausal women with breast cancer. However, there remains controversy as to whether tamoxifen significantly reduces fracture rates in different age groups. Breast cancer occurs at 10-20 years younger in Asian women compared with Western women. Therefore we conducted this population-based case-control study to determine whether or not tamoxifen use is associated with osteoporotic fractures.

Patients and methods

We selected 75488 women with breast cancer with no prior history of fractures from the Longitudinal Health Insurance Database for Catastrophic Illness Patients in 2000-2011. They were followed from the date of the diagnosis of breast cancer to the date a hip, vertebral or wrist fracture occurred. Because the use of tamoxifen was a time-dependent variable, we used a Cox proportional hazard model with time-dependent exposure covariates to estimate the risk of a fracture.

Results

There were 50257 and 25231 women with breast cancer who did and did not receive tamoxifen treatment, respectively. The tamoxifen users had lower risks for overall fractures with hazard ratios (HRs) of 0.52 and 0.59 in the crude and adjusted models (95 % CI = 0.45-0.61 and 0.51-0.69), respectively. They also had lower risks for hip (HR = 0.55, 95 % CI = 0.45-0.67) and vertebral (HR = 0.64, 95 % CI = 0.50-0.82) fractures in the adjusted model. The risk of fractures decreased with an increasing dosage of tamoxifen. Regardless of the age group, the tamoxifen users had a lower risk of fractures than the non-users.

Conclusion

In this Asian population-based case-control study, tamoxifen use was associated with a reduction in osteoporotic fractures, especially in hip fractures.

Keywords

  • Breast cancer
  • Fracture
  • Risk
  • Tamoxifen
  • Population-based cohort study

Background

Breast cancer survivors have an increased risk of osteoporosis and fractures [1, 2]. This elevated risk of fracture could be due to the effects of chemotherapy, ovarian failure, early menopause, and the use of aromatize inhibitors (AI) [35]. Although the peak in the age of breast cancer among Asian women occurs much earlier than in Western women (40-50 years vs. 60-70 years) [6], we previously showed that Asian breast cancer survivors have a higher risk of fractures, particularly those below the age of 50 [7].

Tamoxifen has been used since the 1990s as an adjuvant treatment for breast cancer patients who are estrogen receptor (ER)-positive. Tamoxifen has estrogen-like effects on bone metabolism that may result in an increase and stabilization of BMD. However, the effectiveness of this bone protection between pre- and post-menopausal women remains debatable. A significant loss of BMD in pre-menopausal women receiving Tamoxifen treatment has been reported, whereas it has been shown to prevent bone loss in post-menopausal women [8]. In addition, the proactive effect in terms of fractures related to tamoxifen is also controversial in clinical practice. Kristensen et al. showed that tamoxifen offered no further protection against fractures in old age and may even increase the risk of fractures at particular sites [9]. On the other hand, a large population-based study in Canada revealed a protective effect of concurrent tamoxifen treatment against overall osteoporotic fractures, especially hip fractures [10].

Whether or not tamoxifen offers a protective effect with regards to the risk of fractures in Asian women with breast cancer should ideally be investigated among those whose major peak age is 10 years younger than in Western women with breast cancer. Therefore, we used National Health Insurance (NHI) claims data in Taiwan to assess this relationship.

Methods

We used the Longitudinal Health Insurance Database for Catastrophic Illness Patients (LHID-CIP), a part of the National Health Insurance Research Database (NHIRD), from the National Health Research Institutes (NHRI) for this retrospective cohort study. The Taiwan Bureau of National Health Insurance (TBNHI) established a universal NHI Program in 1995, which currently covers over 99 % of the population in Taiwan. The TBNHI entrusted the NHRI to construct and maintain the NHIRD for research purposes. The NHIRD includes all inpatient and outpatient claims for each beneficiary from 1997 to 2011. The LHID-CIP includes all patients conforming to the guidelines of the TBNHI for a catastrophic illness certificate. Patients with a catastrophic illness certificate are exempt from copayment for medical care, and this certificate is formally reviewed by a physician upon application. Diseases are, identified in the NHIRD based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Based on the Personal Information Protection Act, the identification of beneficiary is scrambled by the TBNHI, and all researchers are required to sign a written agreement regarding their intentions when attempting to obtain the private data of patients when the NHIRD is released. This study was also approved by the Institutional Review Board of China Medical University Hospital.

We collected data on women with a diagnosis of breast cancer (ICD-9-CM 174) from 2000 to 2011 from the LHID-CIP as the study population, and the date of diagnosis was used as the index date. However ,the data dose not record the stage of breast cancer. Those that received tamoxifen [Anatomical Therapeutic Chemical code (ATC code) L02BA01] before the index date or those with a prior history of fractures (ICD-9-CM 800-829) within 1 year before the index date were excluded. All of the included breast cancer patients were followed from the index date until the date a hip (ICD-9-CM 820), vertebral (ICD-9-CM 805) or wrist (ICD-9-CM 815) fracture occurred. Those without a fracture were followed to the date of withdrawal from the NHI program or to the end of 2011.

The exposure was defined the breast cancer women received Tamoxifen during the study period. According to the World Health Organization defined the assumed average maintenance dose per day for a drug used for its main indication in adults, defined daily doses (DDD) is a statistical measure of drug consumption. (WHO Collaborating Centre for Drug Statics Methodology. Available from: http://www.whocc.no/use_of_atc_ddd/#Pharmaceutical). The accumulated Tamoxifen DDDs during the study period was calculated for each user.

The comorbidities considered were hypertension (ICD-9-CM 401-405), hyperlipidemia (ICD-9-CM 272), diabetes (ICD-9-CM 250), peripheral artery disease (PAD, ICD-9-CM 440.0, 440.2, 440.3, 440.8, 440.9, 443, 444.0, 444.22, 444.8, 447.8 and 447.9), stroke (ICD-9-CM 430-438) and osteoporosis (ICD-9-CM 733.0 and 733.1). All comorbidities were defined before the index date. The medical treatments considered were hormone replacement therapy (HRT, ATC codes G03AA08, G03AC06, G03CA57, G03DA02, G03DA03, G03DA04, G03FA01, G03FA02, G03FA12, G03FB01, G03FB06 and L02AB02) and aromatase inhibitors (AIs, ATC code L02BG). HRT users were defined as those who received treatment before the index date. Because AIs are used to treat women with breast cancer, AI users were defined as those who received treatment before the fracture occurred.

The chi-square test was used to test differences between age groups (<50, 50-59, 60-69 and ≥70 years), and comorbidities between the women with breast cancer who did and did not receive tamoxifen treatment. Because the breast cancer patients may not always have received tamoxifen and AIs during the study period and this may have overestimated the effect of the drugs, we used a Cox proportional hazard model with time-dependent exposure covariates to estimate the risk of fractures in order to reduce this bias. The multivariate Cox proportional hazard model with time-dependent covariates was adjusted for age, monthly income, comorbidities and medicine used, and significant differences were found (Table 1). The effects of dose on fractures were estimated according to the dosage or duration of tamoxifen treatment. The association between different locations of fractures and tamoxifen use was then assessed. The age-specific risk and each comorbidity-specific risk for different locations of fractures among those who did and did not receive tamoxifen were also estimated. All statistical analyses were performed using SAS software version 9.3 (SAS Institute Inc., Carey, NC), and a two-tailed p value of less than 0.05 was considered to indicate statistical significance.
Table 1

Demographic characteristics of the study subjects

 

All N = 75488

With tamoxifen N = 50257

Without tamoxifen N = 25231

 

Variable

n

%

n

%

n

%

p-value

Age, years

      

<0.0001

<50

35715

47.3

25778

51.3

9937

39.4

 

50-59

21676

28.7

13124

26.1

8552

33.9

 

60-69

11353

15.0

7001

13.9

4352

17.6

 

70+

6744

8.93

4354

8.66

2390

9.47

 

Urbanization

      

0.34

Urban

50793

67.3

33874

67.4

16919

67.1

 

Rural

24695

32.7

16383

32.6

8312

32.9

 

Month income, NTD

      

<0.0001

<= 15000

12795

17.0

8231

16.4

4564

18.1

 

15001-20000

39463

52.3

26326

52.4

13137

52.1

 

>20000

33230

30.8

15700

31.2

7530

29.8

 

Comorbidity

       

Hypertension

21882

29.0

14142

28.1

7740

30.7

<0.0001

Hyperlipidemia

15458

20.5

9952

19.8

5506

21.8

<0.0001

Diabetes

8948

11.9

5698

11.3

3250

12.9

<0.0001

PAD

1477

1.96

905

1.80

572

2.27

<0.0001

Stroke

1715

2.27

1012

2.01

703

2.79

<0.0001

Osteoporosis

8024

10.6

5114

10.2

2910

11.5

<0.0001

Medicine, n (%)

       

HRT used before the index date

36690

48.6

24487

48.7

12203

48.4

0.35

Aromatase inhibitors used before the end point

20507

27.2

16273

32.4

4234

16.8

<0.0001

Chi-square test

PAD, peripheral artery disease

Results

We collected data on 75,488 women with breast cancer, of whom 50,257 and 25,231 did and did not receive tamoxifen treatment, respectively. Compared with the patients who did not receive tamoxifen treatment, the tamoxifen users were younger (mean age 51.7 vs. 53.5 years, data not shown) and had fewer comorbidities (Table 1). There was no significant difference in the urbanization of residential area between the tamoxifen users and non-users, however the tamoxifen users had a higher income than the non-users.

According to the Cox proportional hazard model with time-dependent covariates, the tamoxifen users had lower risks of fractures with hazard ratios (HRs) of 0.52 and 0.59 in the crude and adjusted models (95 % CI = 0.45-0.61 and 0.51-0.69), respectively (Table 2). The same trends for hip, vertebral and wrist fractures were also noted, however only wrist fractures were found to not be significantly different. The risk of fractures significantly decreased with the dosage and duration of tamoxifen use for both overall and hip fractures.
Table 2

Hazard ratios (HRs) and 95 % confidence intervals (CIs) for different locations of fractures in the time-dependent model

Location

Crude HR (95 % CI)

p-value

Adjusted HR (95 % CI)

p-value

Overall

      

Tamoxifen use (yes vs. no)

0.52

(0.45-0.61)

<0.0001

0.59

(0.51-0.69)

<0.00001

Increased dose of tamoxifen, per 100 DDD

0.98

(0.97-0.99)

0.0003

0.98

(0.97-0.99)

0.0002

Increased duration of tamoxifen use, per 100 days

0.98

(0.97-0.99)

0.0004

0.98

(0.97-0.99)

0.0002

Hip fracture

      

Tamoxifen use (yes vs. no)

0.48

(0.39-0.57)

<0.0001

0.55

(0.45-0.67)

<0.0001

Increased dose of tamoxifen, per 100 DDD

0.97

(0.96-0.99)

0.0003

0.97

(0.96-0.99)

0.0005

Increased duration of tamoxifen use, per 100 days

0.98

(0.96-0.99)

0.001

0.97

(0.96-0.99)

0.0004

Vertebral fracture

      

Tamoxifen use (yes vs. no)

0.59

(0.46-0.75)

<0.0001

0.64

(0.50-0.82)

0.0003

Increased dose of tamoxifen, per 100 DDD

0.98

(0.97-1.00)

0.15

0.98

(0.97-1.00)

0.06

Increased duration of tamoxifen use, per 100 days

0.98

(0.97-1.00)

0.09

0.98

(0.97-1.00)

0.06

Wrist fracture

      

Tamoxifen use (yes vs. no)

0.86

(0.43-1.71)

0.66

0.84

(0.42-1.68)

0.62

Increases dose of tamoxifen, per 100 DDD

1.01

(0.96-1.06)

0.83

1.01

(0.96-1.06)

0.76

Increased duration of tamoxifen use, per 100 days

1.01

(0.96-1.05)

0.83

1.01

(0.96-1.05)

0.86

Manually adjusted for tamoxifen use, age, monthly income, comorbidity and aromatase inhibitor use before the end point

DDD, defined daily dose

The associations between fractures and potential risk factors are presented in Table 3. In the multivariate Cox proportional hazard model with time-dependent covariates, the risk of fractures increased with age. Compared with the patients who had a higher monthly income (>20000 NTD), those with a lower monthly income had a higher risk of fractures. The patients with diabetes had the highest risk (HR = 1.59, 95 % CI = 1.37-1.85), followed by stroke, osteoporosis and hypertension. However, the patients with hyperlipidemia and AI treatment had a significantly lower risk of fractures (HR = 0.83 and 0.80, 95 % CI = 0.72-0.96 and 0.68-0.95, respectively).
Table 3

Hazard ratios (HRs) and 95 % confidence intervals (CIs) for fractures and potential risk factors in the time-dependent model

Variable

Crude HR (95 % CI)

p-value

Adjusted HR (95 % CI)

p-value

Age, years

1.10

(1.10-1.11)

<0.0001

1.09

(1.08-1.10)

<0.0001

Monthly income, NTD

      

<= 15000

4.85

(3.98-5.91)

<0.0001

1.34

(1.08-1.66)

0.009

15001-20000

2.25

(1.86-2.71)

<0.0001

1.51

(1.25-1.82)

<0.0001

>20000

1.00

Ref.

 

1.00

Ref.

 

Comorbidity (yes vs. no)

      

Hypertension

4.48

(3.94-5.09)

<0.0001

1.27

(1.09-1.48)

0.002

Hyperlipidemia

2.19

(1.92-2.50)

<0.0001

0.83

(0.72-0.96)

0.01

Diabetes

3.65

(3.18-4.19)

<0.0001

1.59

(1.37-1.85)

<0.0001

PAD

2.74

(2.00-3.74)

<0.0001

0.99

(0.72-1.36)

0.96

Stroke

5.40

(4.27-6.83)

<0.0001

1.38

(1.08-1.76)

0.01

Osteoporosis

3.11

(2.70-3.58)

<0.0001

1.38

(1.19-1.59)

<0.0001

Aromatase inhibitor use before the end point

1.18

(1.00-1.40)

0.049

0.80

(0.68-0.95)

0.01

Manually adjusted for tamoxifen use, age, monthly income, comorbidity and aromatase inhibitor use before the end point

PAD, peripheral artery disease

Table 4 shows the age-specific risk of fractures among those who did and did not receive tamoxifen treatment. In each age group, the risks of overall and hip fractures were lower in the tamoxifen users than in the non-users. For vertebral fractures, only the tamoxifen users who were 70 years and older had a significantly lower risk of fractures. Comorbidity-stratified analysis is shown in Table 5. Regardless of the comorbidities, the tamoxifen users tended to have a lower risk of fractures than the non-users.
Table 4

Adjusted hazard ratios (HRs) and 95 % confidence intervals (CIs) for different fracture locations in the time-dependent model among age group

Age group

Tamoxifen user vs. non-user HR (95 % CI)

p-value

Interaction p

Overall

   

0.29

  <50

0.54

(0.36-0.82)

0.004

 

  50-59

0.58

(0.40-0.83)

0.003

 

  60-69

0.66

(0.50-0.88)

0.005

 

  70+

0.59

(0.48-0.74)

<0.0001

 

Hip fracture

   

0.046

  <50

0.39

(0.19-0.81)

0.01

 

  50-59

0.38

(0.20-0.72)

0.003

 

  60-69

0.56

(0.38-0.81)

0.002

 

  70+

0.61

(0.47-0.78)

0.0001

 

Vertebral fracture

   

0.86

  <50

0.59

(0.34-1.03)

0.06

 

  50-59

0.74

(0.46-1.19)

0.21

 

  60-69

0.84

(0.54-1.32)

0.46

 

  70+

0.54

(0.34-0.85)

0.008

 

Wrist fracture

   

0.26

  <50

0.90

(0.31-2.57)

0.84

 

  50-59

0.76

(0.25-2.34)

0.63

 

  60-69

1.44

(0.20-10.6)

0.72

 

  70+

1.10

(0.07-17.9)

0.94

 

Manually adjusted for monthly income, comorbidity and aromatase inhibitor use before the end point

Table 5

Hazard ratio (HRs) and 95 % confidence intervals (CIs) for fractures in the tamoxifen users compared with non-users using the time-dependent model stratified by comorbidity

Comorbidity

Tamoxifen user vs. non-user HR (95 % CI)

p-value

Interaction p

Hypertension

  

0.18

No

0.67 (0.53-0.85)

0.001

 

Yes

0.55 (0.46-0.66)

<0.0001

 

Hyperlipidemia

  

0.97

No

0.60 (0.50-0.72)

<0.0001

 

Yes

0.58 (0.45-0.74)

<0.0001

 

Diabetes

  

0.56

No

0.62 (0.52-0.74)

<0.0001

 

Yes

0.54 (0.41-0.71)

<0.0001

 

PAD

  

0.58

No

0.59 (0.50-0.68)

<0.0001

 

Yes

0.73 (0.37-1.46)

0.38

 

Stroke

  

0.32

No

0.59 (0.50-0.69)

<0.0001

 

Yes

0.68 (0.41-1.13)

0.14

 

Osteoporosis

  

0.33

No

0.61 (0.51-0.73)

<0.0001

 

Yes

0.54 (0.40-0.72)

<0.0001

 

PAD, peripheral artery disease

Manually adjusted for monthly income, comorbidity and aromatase inhibitor use before the end point

Discussion

Tamoxifen, a non-genomic ER ß agonist but selective antagonist of ER α, has been shown to have a beneficial effect on bone metabolism [11]. Tamoxifen may increase BMD in the lumbar spine and especially in post-menopausal women with breast cancer. However, little is known regarding its effect on fractures, and the results of previously published studies remain controversial in clinical practice. Cooke et al reported that current use of tamoxifen led to a significantly lower overall risk of osteoporotic fractures in a population-based case-control study [10]. However, a number of reports in the literature have reported no statistically significant bone protection at an age of 65 years and older [12, 13].

In comparison with previous population-based fracture risk studies, of which most have included post-menopausal woman, approximately 50 % of the cases were under 50 years of age in our study. Our results parallel another study in terms of the protective site of tamoxifen use. Tamoxifen has been shown to preserve BMD in the lumbar spine and femoral neck, and to protect against bone loss in the hip and spine but not the wrist in post-menopausal woman [1417]. The preservation of BMD by tamoxifen in post-menopausal women is associated with a reduced risk of osteoporotic fractures.

Despite these findings, several studies have demonstrated that tamoxifen accelerates bone loss in pre-menopausal women. The results of the current study indicate that, after adjustment for potential confounding factors, patients receiving tamoxifen are at a lower risk of developing osteoporotic fractures overall, including spine and hip fractures, compared with those not receiving tamoxifen. The protective effect was also related to age, and especially those under 50 years of age. A lower risk of fractures was seen in both the older and younger patients. Another population-based study suggested that the protective effect of prior tamoxifen use was quickly lost after the treatment was changed to letrozole [10].

We did not compare the effect of other AIs with tamoxifen. Our results revealed that the protective effect was not related to the duration or dosage, so it may have been due to the steady usage of tamoxifen once a patient had been prescribed with this drug. There is a debate regarding the use of AIs and tamoxifen for the treatment of women with ER-positive breast cancer. The risk of relapse has been reported to persist after 5 years of treatment with adjuvant tamoxifen in post-menopausal women with hormone-sensitive early stage breast cancer [16]. Published cost-effectiveness analyses comparing AIs to tamoxifen have assumed an overall survival and indicated a higher risk of fractures with AIs, although this has not been shown in RCTs, leading to an overestimation of the cost-effectiveness of AIs [18]. If anastrozole use is associated with an increased risk of hip fractures, then the long-term benefits associated with this agent are reduced by approximately 25 % [19]. Less than half of hip fracture patients resume baseline levels of functioning, and nearly one in five requires long-term nursing home care after a hip fracture [20]. Concerns regarding the use of tamoxifen include menopausal symptoms, deep vein thrombosis, and endometrial cancer [21]. It has also been reported to increase the risk of abnormal endometrial thickness in post-menopausal women, although this has not been proven in pre-menopausal Asian women with breast cancer [22]. In addition, a recent study reported no increased risk of venous thromboembolism in Asian breast cancer patients receiving adjuvant tamoxifen treatment [23].

The strength of our study is the use of a population-based data set with the enrollment of a large number of patients. However, several limitations must be considered when interpreting these findings. The insurance claims files do not provide information on serum estrogen level, BMD, cancer stage or menopausal status. We were therefore unable to determine whether patients with advanced stages of the cancer or post-menopause were at a greater risk of fractures. Serum estrogen has been reported to be a risk factor for breast cancer, and a higher exposure to estrogen has been reported to preserve BMD and thereby decrease the risk of osteoporotic fractures [2427]. A correlation between a higher BMD and a higher risk of breast cancer has been reported [28]. Therefore, the reduced risk of osteoporotic fractures in tamoxifen users may be due to prior exposure to endogenous estrogen [10].

Physicians need to weigh the benefits and risks of tamoxifen treatment in various clinical situations. In our opinion, the protective effect of tamoxifen is advised for younger patients, especially in Asian patients who have a higher risk of fractures at a younger age.

Declarations

Acknowledgements

We thank the National Health Research Institute in Taiwan for providing the related insurance claims data. This study was supported by the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002) and the China Medical University Hospital (Grant #1MS1).

Authors’ Affiliations

(1)
Graduate Institute of Clinical Medicine, China Medical University, #91 Hsueh-Shih Road, Taichung, 404, Taiwan
(2)
Division of Hematology/Oncology, Taichung Veterans General Hospital, Taichung, Taiwan
(3)
School of Medicine, China Medical University, Taichung, Taiwan
(4)
Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
(5)
Department of Orthopedics, China Medical University Hospital, Taichung, Taiwan
(6)
School of Chinese Medicine, China Medical University, Taichung, Taiwan

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© Tzeng et al.; licensee BioMed Central. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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