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Bone mineral density in postmenopausal women with and without breast cancer

Densidade mineral óssea em mulheres na pós-menopausa com e sem câncer de mama

Abstracts

OBJECTIVE: The values of bone mineral density (BMD) were compared in postmenopausal women with and without breast cancer. METHODS: A cross-sectional study was conducted, including 51 breast cancer survivors (BCS) and 71 women without breast cancer, who were non-users of hormone therapy, tamoxifen, or aromatase inhibitors. BMD T-scores and measurements in grams per centimeter squared (g/cm²) were obtained at the femoral neck, trochanter, Ward's triangle, and lumbar spine. Osteopenia and osteoporosis were grouped and categorized as abnormal BMD. Unconditional logistic regression analysis was used to estimate the odds ratios (OR) of abnormal BMD values as measures of association, with 95% confidence intervals (CIs), adjusting for age, years since menopause, parity, and body mass index (BMI). RESULTS: The mean age of the women with and without breast cancer was 54.7 ± 5.8 years and 58.2 ± 4.8 years (p < 0.01), respectively. After adjusting for age, parity and BMI, abnormal BMD at the femoral neck (adjusted OR: 4.8; 95% CI: 1.5-15.4), trochanter (adjusted OR: 4.6; 95% CI: 1.4-15.5), and Ward's triangle (adjusted OR: 4.5; 95% CI: 1.5-12.9) were significantly more frequent in postmenopausal BCS than in women without breast cancer. Postmenopausal BCS had a significantly lower mean BMD at the trochanter (0.719 vs. 0.809 g/cm², p < 0.01) and at the Ward's triangle (0.751 vs. 0.805 g/cm², p = 0.03). CONCLUSION: The prevalence of abnormal BMD was higher in postmenopausal BCS than in postmenopausal women without breast cancer. Bone health requires special vigilance and the adoption of interventions should be instituted early to minimize bone loss in BCS.

Breast cancer; menopause; bone loss; abnormal bone mineral density


OBJETIVO: Comparar a densidade mineral óssea (DMO) de mulheres na pós-menopausa com e sem câncer de mama. MÉTODOS: Conduziu-se estudo de corte transversal, incluindo 51 mulheres com câncer de mama e 71 mulheres sem câncer de mama, não usuárias de terapia hormonal, tamoxifeno ou de inibidores da aromatase. Avaliou-se a DMO, em T-score e em gramas por centímetro quadrado (g/cm²), no colo do fêmur, trocânter, triângulo de Wards e na coluna lombar. Osteopenia e osteoporose foram agrupadas e categorizadas como DMO alterada. Utilizou-se a análise de regressão logística não condicional para estimar o odds ratios (OR) de DMO alterada como medida de associação, com intervalo de confiança de 95% (IC 95%), ajustando-se por idade, anos de menopausa, paridade e índice de massa corpórea (IMC). RESULTADOS: A média de idade de mulheres com e sem câncer de mama foi 54,7 ± 5,8 anos e 58,2 ± 4,8 anos (p < 0,01), respectivamente. Após ajustar por idade, paridade e IMC, DMO alterada no colo do fêmur (OR ajustado: 4,8; IC 95%: 1,5-15,4), trocânter (OR ajustado: 4,6; IC 95%: 1,4-15,5) e no triângulo de Wards (OR ajustado: 4,5; IC 95%: 1,5-12,9) foi mais frequente em mulheres com câncer de mama. Mulheres com câncer de mama apresentaram significativamente menor média de DMO no trocânter (0,719 vs. 0,809 g/cm², p < 0,01) e no triângulo de Wards (0,751 vs. 0,805 g/cm², p = 0,03). CONCLUSÃO: A prevalência de DMO alterada foi maior em mulheres na pós-menopausa com câncer de mama. A saúde óssea requer vigilância especial e a adoção precoce de intervenções para minimizar a perda óssea de mulheres com câncer de mama.

Câncer de mama; menopausa; perda óssea; densidade mineral óssea alterada


ORIGINAL ARTICLE

Bone mineral density in postmenopausal women with and without breast cancer

Densidade mineral óssea em mulheres na pós-menopausa com e sem câncer de mama

Délio Marques CondeI; Lúcia Costa-PaivaII; Edson Zangiacomi MartinezIII; Aarão Mendes Pinto-NetoIV

IMD, PhD; Mentor, Medical Residency Training Program in Breast Disorders, Breast Service, Hospital Materno Infantil (HMI), Goiânia, GO, Brazil

IIMD, PhD; Associate Professor, Department of Gynecology and Obstetrics, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil

IIIPhD; Associate Professor, Department of Social Medicine, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil

IVMD, PhD; Full Professor, Department of Gynecology and Obstetrics, UNICAMP, Campinas, SP, Brazil

Correspondence to Correspondence to: Délio Marques Conde Rua R-7 com Av. Perimetral, S/N St. Oeste Goiânia, GO, Brazil CEP: 74125-120 Phone: +55 62 3209-6151 delioconde@bol.com.br

SUMMARY

OBJECTIVE: The values of bone mineral density (BMD) were compared in postmenopausal women with and without breast cancer.

METHODS: A cross-sectional study was conducted, including 51 breast cancer survivors (BCS) and 71 women without breast cancer, who were non-users of hormone therapy, tamoxifen, or aromatase inhibitors. BMD T-scores and measurements in grams per centimeter squared (g/cm2) were obtained at the femoral neck, trochanter, Ward's triangle, and lumbar spine. Osteopenia and osteoporosis were grouped and categorized as abnormal BMD. Unconditional logistic regression analysis was used to estimate the odds ratios (OR) of abnormal BMD values as measures of association, with 95% confidence intervals (CIs), adjusting for age, years since menopause, parity, and body mass index (BMI).

RESULTS: The mean age of the women with and without breast cancer was 54.7 ± 5.8 years and 58.2 ± 4.8 years (p < 0.01), respectively. After adjusting for age, parity and BMI, abnormal BMD at the femoral neck (adjusted OR: 4.8; 95% CI: 1.5-15.4), trochanter (adjusted OR: 4.6; 95% CI: 1.4-15.5), and Ward's triangle (adjusted OR: 4.5; 95% CI: 1.5-12.9) were significantly more frequent in postmenopausal BCS than in women without breast cancer. Postmenopausal BCS had a significantly lower mean BMD at the trochanter (0.719 vs. 0.809 g/cm2, p < 0.01) and at the Ward's triangle (0.751 vs. 0.805 g/cm2, p = 0.03).

CONCLUSION: The prevalence of abnormal BMD was higher in postmenopausal BCS than in postmenopausal women without breast cancer. Bone health requires special vigilance and the adoption of interventions should be instituted early to minimize bone loss in BCS.

Keywords: Breast cancer; menopause; bone loss; abnormal bone mineral density.

RESUMO

OBJETIVO: Comparar a densidade mineral óssea (DMO) de mulheres na pós-menopausa com e sem câncer de mama.

MÉTODOS: Conduziu-se estudo de corte transversal, incluindo 51 mulheres com câncer de mama e 71 mulheres sem câncer de mama, não usuárias de terapia hormonal, tamoxifeno ou de inibidores da aromatase. Avaliou-se a DMO, em T-score e em gramas por centímetro quadrado (g/cm2), no colo do fêmur, trocânter, triângulo de Wards e na coluna lombar. Osteopenia e osteoporose foram agrupadas e categorizadas como DMO alterada. Utilizou-se a análise de regressão logística não condicional para estimar o odds ratios (OR) de DMO alterada como medida de associação, com intervalo de confiança de 95% (IC 95%), ajustando-se por idade, anos de menopausa, paridade e índice de massa corpórea (IMC).

RESULTADOS: A média de idade de mulheres com e sem câncer de mama foi 54,7 ± 5,8 anos e 58,2 ± 4,8 anos (p < 0,01), respectivamente. Após ajustar por idade, paridade e IMC, DMO alterada no colo do fêmur (OR ajustado: 4,8; IC 95%: 1,5-15,4), trocânter (OR ajustado: 4,6; IC 95%: 1,4-15,5) e no triângulo de Wards (OR ajustado: 4,5; IC 95%: 1,5-12,9) foi mais frequente em mulheres com câncer de mama. Mulheres com câncer de mama apresentaram significativamente menor média de DMO no trocânter (0,719 vs. 0,809 g/cm2, p < 0,01) e no triângulo de Wards (0,751 vs. 0,805 g/cm2, p = 0,03).

CONCLUSÃO: A prevalência de DMO alterada foi maior em mulheres na pós-menopausa com câncer de mama. A saúde óssea requer vigilância especial e a adoção precoce de intervenções para minimizar a perda óssea de mulheres com câncer de mama.

Unitermos: Câncer de mama; menopausa; perda óssea; densidade mineral óssea alterada.

INTRODUCTION

Breast cancer is the most frequently diagnosed cancer in women worldwide, representing 23% (1.38 million) of the total new cancer cases in 20081. Breast cancer is primarily a disease of postmenopausal women2. In the postmenopause, there is a reduction in serum estrogen levels leading to bone loss. Estrogen plays an important role in skeletal maintenance due to its osteoprotective action3. In this context, postmenopausal status is a major risk factor for low bone mineral density (BMD)4.

Previous studies have demonstrated a relationship between a higher BMD and a higher risk for postmenopausal breast cancer5,6. Although the mechanism of this relationship is not fully understood, cumulative exposure to estrogen may play a role5. BMD may be a predictor for breast cancer risk, but breast cancer survivors (BCS) can also develop bone loss related to cancer treatment7,8. Chemotherapy-induced ovarian failure7,8, aromatase inhibitor use9,10, and a potential direct toxic chemotherapy effect on bone tissue11 may induce and intensify bone loss in BCS. Tamoxifen use is associated with significant bone loss in premenopausal BCS. However, tamoxifen exerts a bone-protective action in women with early menopause induced by chemotherapy12.

Premenopausal women with breast cancer undergoing chemotherapy with preserved ovarian function do not have a significant reduction in bone mass7,8. However, those who develop amenorrhea have a rapid and significant bone loss7,8. Menopausal hormone therapy may be indicated for the prevention of bone loss13, and many women on hormone therapy at the time of breast cancer diagnosis are instructed to discontinue its use2. Discontinuation of hormone therapy is based on an increased risk of breast cancer recurrence14. This group of factors contributes to increased bone loss in postmenopausal BCS.

Previous studies have investigated BMD in post menopausal survivors of breast cancer15-22. However, few studies have evaluated a group of women without breast cancer for comparison18,19,22. In one study, mean BMD values in postmenopausal BCS were similar to those in population-based non-BCS18. In contrast, the prevalence of osteoporosis in another study was 27.2% in BCS and 19.4% in women without breast cancer19. Furthermore, it was demonstrated that postmenopausal BCS had a higher fracture risk than cancer-free women20.

Despite these findings, a notable proportion of postmenopausal BCS have undiagnosed abnormal 15,16,19. Considering these aspects, the present study was conducted aiming to compare BMD in Brazilian postmenopausal women with and without breast cancer

METHODS

PATIENTS

Participant selection has been previously described in detail23. The current sample was derived from a study that investigated menopause symptoms, sexual activity, quality of life, some cardiovascular risk factors, and BMD in BCS23. The present study focused on the findings of BMD in postmenopausal women with and without breast cancer.

A cross-sectional study of women undergoing routine follow-up care was conducted in the Women's Hospital of the School of Medicine of the Universidade Estadual de Campinas, Brazil. Patients who met the inclusion criteria were invited to participate in the study during outpatient consultation. Women aged 45-65 years, who were non-users of hormone therapy or tamoxifen in the last six months, and who had no history of other malignancies were invited. Only postmenopausal women who completed oncology treatment were included in this study. None of the BCS were using aromatase inhibitors. A total of 187 women were invited to participate in the study, 100 BCS and 87 without breast cancer. Among the BCS, three refused to participate in the study due to lack of time, 22 were undergoing oncology treatment, 12 were premenopausal, seven had no knowledge of time since menopause, and five did not have bone density measurements. Among women without breast cancer, two refused to participate in the study due to lack of time, four were premenopausal, and ten had no knowledge of time since menopause. Therefore, 122 postmenopausal women, 51 with breast cancer and 71 without breast cancer, constituted the present study sample.

Participants responded to an interview that assessed sociodemographic characteristics, including age, race/ethnicity, age at menarche, parity, smoking, age at menopause, and years since menopause. Clinical characteristics included body mass index (BMI) in kilograms per square meter (kg/m2), time since breast cancer diagnosis, type of surgery, tumor stage, chemotherapy, and radiotherapy. This study was approved by the institutional review board; all participants signed an informed consent.

BONE MINERAL DENSITY MEASUREMENT

BMD tests were ordered in the initial interview with the patient. BMD in grams per centimeter squared (g/cm2) was measured at the femoral neck, trochanter, Ward's triangle, and the lumbar spine (L2-L4; anteroposterior plane) using a Lunar DPX device (DXA; Lunar DPX, Madison, WI, USA). BMD values were also expressed as T-scores, using the World Health Organization criteria24: normal: T-score > -1 standard deviation (SD); osteopenia: T-score between -1 and -2.5 SDs; osteoporosis: T-score < -2.5 SDs. In this study, a BMD T-score < -1 SD was considered abnormal (osteopenia and osteoporosis grouped together).

STATISTICAL ANALYSIS

The means of descriptive continuous variables were compared between women with and without cancer using Student's t-test for independent samples. The frequencies of binary variables were compared by Fisher's exact test. Unconditional logistic regression analysis25 was used to estimate the odds ratios (OR) of abnormal BMD as measures of association, with 95% confidence intervals (CIs). In these models, the independent binary variable was breast cancer (with cancer/without cancer), and the dependent binary variable was BMD, classified as normal or abnormal. The ORs were estimated as measures of the association between cancer and abnormal BMD in the femoral neck, trochanter, Ward's triangle and lumbar spine with and without adjustment for age, parity, years since menopause, and BMI in quartiles. When age and years since menopause were considered, regression models could not be fitted because of the strong collinearity between these variables. The ORs adjusted for age, parity, and BMI, and adjusted for years since menopause, parity, and BMI were estimated. When bone density (g/cm2) was regarded as a continuous variable, linear regression models26 were used to compare the population means between women with and without cancer adjusting for covariates. All analyses were performed using the SAS version 9.2 software. The significance level was set at 5%.

RESULTS

The mean age of women with breast cancer was 54.7 ± 5.8 years and 58.2 ± 4.8 years for those without breast cancer (p < 0.01). The mean BMI was 27.5 ± 5.2 kg/m2 and 30.2 ± 5.7 kg/m2 for women with and without breast cancer (p < 0.01), respectively. The mean age at menopause was 47.1 ± 5.0 years for women with breast cancer and 47.4 ± 4.9 years for women without breast cancer (p = 0.98). Bone density measurement was performed from one to two months after the first interview. Other characteristics are shown in Table 1. In the breast cancer group, the mean time since breast cancer diagnosis was 67.9 ± 53.1 months. A little over half of the postmenopausal BCS (52.9%) underwent mastectomy, and 47.1% underwent breastconserving therapy. Approximately 72% of women underwent chemotherapy, 76.5% underwent radiation therapy, and 60.8% underwent chemotherapy and radiation therapy. Distribution according to tumor stage was (n, %): 0 (4, 7.8%), I (7, 13.7%), II (31, 60.8%), and III (9, 17.7%).

In the unadjusted analysis, the results in Table 2 show that postmenopausal BCS had a significantly higher prevalence of abnormal BMD at the femoral neck, trochanter, and Ward's triangle than women without breast cancer. After adjusting for age, parity, and BMI, abnormal BMD at the femoral neck (adjusted OR: 4.8; 95% CI: 1.5-15.4), trochanter (adjusted OR: 4.6; 95% CI: 1.4-15.5), and Ward's triangle (adjusted OR: 4.5; 95% CI: 1.5-12.9) was significantly more frequent in postmenopausal BCS than in women without breast cancer. After adjusting for years since menopause, parity, and BMI, the prevalence of abnormal BMD at the femoral neck, trochanter, and Ward's triangle remained significantly higher in postmenopausal BCS. In unadjusted and adjusted analysis, there was no significant difference in the prevalence of abnormal lumbar spine (L2-L4) BMD between BCS and women without breast cancer.

Figure 1 displays the mean BMD (g/cm2) of postmenopausal BCS and women without breast cancer. On analysis adjusted for age, parity, and BMI, BCS showed a significantly lower mean BMD at the trochanter (0.719 vs. 0.809 g/cm2, p < 0.01) and Ward's triangle (0.751 vs. 0.805 g/cm2, p = 0.03). After adjusting for years since menopause, parity, and BMI, BCS had a significantly lower mean BMD at the trochanter (p < 0.01), and Ward's triangle (p = 0.03).


DISCUSSION

This study aimed to compare BMD in women with and without breast cancer. Few studies have investigated BMD in postmenopausal BCS, in comparison to a group of postmenopausal women without breast cancer. Based on BMD T-scores, it was observed that abnormal BMD at the femoral neck, trochanter, and Ward's triangle was significantly more frequent in BCS than in women without breast cancer. Furthermore, BCS had a significantly lower mean BMD (g/cm2) at the trochanter and Ward's triangle.

In this case study, it was observed that the prevalence of abnormal BMD in postmenopausal BCS was higher at the Ward's triangle (59.5%), and lumbar spine (56.9%). In another study, including only postmenopausal BCS with a mean age of 54 years and 36.6% of tamoxifen users, it was observed that 56.3% of the participants had abnormal BMD at the lumbar spine15. The findings of these authors15 were similar to the present results regarding the high prevalence rate of abnormal BMD at the lumbar spine (56.9%), although the participants of the present cohort were nonusers of tamoxifen. Other studies have also reported a high frequency of abnormal BMD at the lumbar spine19,21,22. The lumbar spine and Ward's triangle have a high content of trabecular bone. A higher frequency of abnormal BMD at these bone sites may be related to a greater sensitivity of trabecular bone to estrogen deficiency27. This is a characteristic of postmenopausal women who do not use hormone therapy.

Few studies comparing BMD between postmenopausal BCS and women without breast cancer have been iden18,19,22. Based on cross-sectional data18, BMD Z-scores of BCS were investigated. This study found that postmenopausal patients who had not received adjuvant therapy had higher whole body BMD compared to age-matched women. Furthermore, the authors reported that hip and spine BMD measurements in postmenopausal BCS were similar to those in a population-based sample without breast cancer, suggesting that the treatment had caused no major deleterious effect on the BMD of BCS18. However, a retrospective study found that women who were postmenopausal at the time of breast cancer diagnosis and receiving adjuvant chemotherapy had lower BMD Z-scores at the total hip, femoral neck, trochanter, and lumbar spine than those who had not received chemotherapy17, indicating a potential detrimental effect of adjuvant therapy on the BMD of postmenopausal women.

In another study22, BMD was compared between a BCS group with chemotherapy-induced amenorrhea and a premenopausal control group without breast cancer. The authors of this study observed that significantly more BCS had low spine BMD based on T-scores22. In the Women's Health Initiative Observational Study (WHI-OS), data on the prevalence of low bone mass was reported in a large cohort of postmenopausal BCS, compared to cancer-free women19. In the WHI-OS, the frequency of osteoporosis was 27.2% in postmenopausal BCS and 19.4% in cancerfree women. A comparison of BMD T-scores in postmenopausal BCS and in women with no history of breast cancer, adjusting for covariables, except menopausal hormone therapy, showed BCS with a significantly higher prevalence of osteoporosis in the total hip, total body, and at any site19. In the present study, the prevalence of abnormal BMD T-scores at the femoral neck, trochanter, and Ward's triangle was higher in BCS in adjusted and unadjusted analyses. The mean BMD (g/cm2) at the trochanter and Ward's triangle was higher among postmenopausal non-BCS, adjusting for potential confounding variables (age, years since menopause, parity, BMI). In the WHI-OS, when menopausal hormone therapy was added as a covariate, the difference in the prevalence of osteoporosis between women with and without breast cancer was no longer significant19. Participants in the present study were not using hormone therapy, thus it was not possible to adjust for this variable.

Differences observed between the present findings and results of other studies may be related to the age difference between the participants, bone sites investigated, and variables evaluated. In the WHI-OS, a low BMD and high prevalence of osteoporosis in BCS occurred, especially because of lower hormone therapy use by these women19. The present study included women who did not take tamoxifen or aromatase inhibitors, since the aim at the time of study design was to gain knowledge about BMD in BCS who were not receiving any hormone therapy.

From the present findings and previous studies, it can be inferred that abnormal BMD is a concern for postmenopausal BCS15-19,21,22. Despite these findings, 77.8% of the WHI-OS postmenopausal BCS had undiagnosed osteoporosis at baseline. Thus, a considerable proportion of BCS women had no diagnosis of abnormal BMD and consequently did not receive therapy, as previously reported16.

The findings should be interpreted considering some limitations, such as the cross-sectional study design and a lack of information about chemotherapy regimen. The immunohistochemical profile of tumors in BCS, which could have allowed the investigation of a relationship between hormone receptor status and BMD, was not included. Physical activity, and calcium, caffeine, and alcohol consumption were not investigated. However, there was inconsistent evidence of an association between current physical activity or calcium intake and BMD in a systematic review4. In this review, there was fair evidence that current caffeine intake was not associated with BMD, and that moderate alcohol consumption was not associated with lower BMD4.

To the authors' knowledge, this was the first study conducted in Latin America investigating BMD in postmenopausal BCS. The existence of a control group of women with similar menopausal status, i.e., postmenopausal women with no history of breast cancer, is highlighted. Despite some differences between both groups, the comparisons between BMD were adjusted for potential confounding variables.

The current guidelines of the American Society of Clinical Oncology recommend the use of aromatase inhibitors in postmenopausal BCS with hormone receptorpositive tumors during adjuvant therapy as an initial treatment, or sequential or extended treatment after tamoxifen use28. Although further studies are still required, a recent randomized, placebo-controlled, double-blinded trial in healthy postmenopausal women has demonstrated that exemestane reduced the relative incidence of invasive breast cancers by 65%29. This group of data suggests that the use of aromatase inhibitors will become increasingly more frequent. In this context, the prevalence of abnormal BMD in BCS may be higher in the future than in the present study. In BCS, there is a need for increased vigilance of bone health, especially in postmenopausal women.

CONCLUSION

In conclusion, the authors believe that these results are of interest to healthcare professionals involved in the management of women with breast cancer. The prevalence of abnormal BMD was higher in postmenopausal BCS than in postmenopausal women without breast cancer. Bone health requires special vigilance and the adoption of interventions should be instituted early to minimize bone loss in BCS.

Submitted on: 02/02/2012

Approved on: 07/01/2012

Conflict of interest: None.

Study conducted at the Department of Gynecology and Obstetrics, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil

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  • Correspondence to:

    Délio Marques Conde
    Rua R-7 com Av. Perimetral, S/N St. Oeste
    Goiânia, GO, Brazil CEP: 74125-120
    Phone: +55 62 3209-6151
  • Publication Dates

    • Publication in this collection
      13 Dec 2012
    • Date of issue
      Dec 2012

    History

    • Received
      02 Feb 2012
    • Accepted
      01 July 2012
    Associação Médica Brasileira R. São Carlos do Pinhal, 324, 01333-903 São Paulo SP - Brazil, Tel: +55 11 3178-6800, Fax: +55 11 3178-6816 - São Paulo - SP - Brazil
    E-mail: ramb@amb.org.br