Vertebral fractures among breast cancer survivors in China: a cross-sectional study of prevalence and health services gaps

Breast cancer incidence worldwide has risen by 20% and mortality rates by 14% since 2008, with the bulk of this increase sustained by women in low- and middle-income countries (LMICs) due to increasing life expectancy, urbanization, and adoption of Western lifestyles [1]. Although incidence rates have traditionally been low in Asia compared with the U.S. or Europe, due to the sheer population of many Asian countries, the absolute numbers of women with breast cancer in this region has risen dramatically [2].

Several studies have shown that women with breast cancer are at increased risk for osteoporosis and fracture [3‐5]. This is largely attributable to the negative impact of breast cancer treatments on skeletal health, which occurs through decreased estrogen exposure [6, 7]. The majority of such studies have been carried out in the U.S. and Europe, where most women are postmenopausal at the time of diagnosis and approximately 75% of patients have hormone-receptor positive disease [8]. By contrast, a nation-wide epidemiologic study found that the average age at breast cancer diagnosis in China is approximately 10 years earlier than in the West, and only 57.4% of women with breast cancer had hormone-receptor positive disease [9].

Because of these differences in epidemiology, risk factors for fracture may be significantly different among Chinese breast cancer survivors, and cannot simply be extrapolated from studies in U.S. and European populations. Furthermore, in China, as in many other LMICs, the infrastructure to monitor and manage osteoporosis and fracture is severely limited, with scarce access to dual-energy x-ray absorptiometry (DXA)—the gold-standard for bone mineral density assessment—outside of large tertiary care centers in major cities [10].

In order to quantify the scope of this problem and identify potential health services gaps, we designed a cross-sectional study to measure the prevalence of vertebral fractures among a cohort of breast cancer survivors in Beijing, and compared our data with fracture prevalence among community-dwelling healthy women in Beijing selected from a pre-existing cohort called the Peking Vertebral Fracture (PK-VF) Study, and hypothesized that vertebral fracture prevalence would be significantly higher among our cohort of breast cancer survivors.

Our study is the first to directly measure rates of fracture among breast cancer survivors in China compared to age- and BMI-matched healthy women. We found that history of breast cancer was associated with a four-fold increased odds of prevalent vertebral fractures. Furthermore, breast cancer survivors with fractures were more likely to have multiple fractures and higher grade fractures compared to their healthy counterparts. Finally, rates of DXA screening for bone disease were low among women with breast cancer, even among those who were postmenopausal at the time of diagnosis or treated with AIs, factors known to increase risk for fracture.

Rates of fractures have traditionally been higher in Europe and the U.S. compared to China [14]. Therefore, it is consistent that absolute prevalence of fractures in both of our cohorts were lower compared with previous studies among women from Caucasian populations. However, recent studies have also shown that rates of fracture are rapidly increasing in China due to urbanization and adoption of Western lifestyles [15]. In our study, the magnitude of the increased odds for fracture seen among breast cancer survivors is roughly on par with prior findings. Kanis et al., found that prevalence of vertebral fractures among women with soft-tissue breast cancer recurrence (without skeletal metastases) was six-fold higher compared with healthy controls or women newly diagnosed with breast cancer [4]. However, their study population was acutely ill and mean age was 2 years older than our cohort, whereas our cohort included predominantly recurrence-free breast cancer survivors.

To our knowledge only one prior study has been published from mainland China examining this issue [16]. This study retrospectively compared 70 postmenopausal women with breast cancer receiving AI therapy, with 52 women receiving tamoxifen, and 89 women who were not treated with endocrine therapy at a single institution. The authors found that women on AIs had an increased incidence of fractures (12.9%) compared with those not treated with endocrine therapy (1.1%, p = 0.001). By contrast, incidence of fractures among those treated with tamoxifen did not differ (1.9%, p = 0.372) compared with those not treated with endocrine therapy. Unfortunately, this study is significantly limited by the lack of description regarding how osteoporotic fractures were defined and measured, and sparse risk factor data.

Three studies from Taiwan using retrospective data from their National Insurance Research Database have also examined this issue among ethnically Chinese women with breast cancer. Tzeng et al. reported tamoxifen use was associated with reduced risk of osteoporotic fractures, however did not specify whether women in their cohort were pre- or postmenopausal [17]. Chang et al. studied fracture risk in young breast cancer patients and found that those receiving AIs, radiotherapy, or Herceptin were at increased risk for future fracture [18]. Tsa et al. showed that age-specific hazard ratio for fracture was higher for breast cancer patients < 50 years of age, both for traumatic and non-traumatic fractures [19]. However, these studies are all based upon insurance claims data and rely on International Conference for the Ninth Revision of the International Classification of Diseases (ICD-9) codes for diagnosis. Validation of the diagnostic codes was not described therefore further studies are needed to confirm these findings in prospective cohorts. Our data provide a meaningful comparison to these studies given the differences in lifestyle, nutrition, medical care and environmental exposures among women in mainland China compared with Taiwan, and provides direct assessment of fracture associated risk factors not available from insurance claims data.

Previous epidemiologic studies from Asian countries have demonstrated that the peak age of breast cancer diagnosis occurs approximately a decade earlier among Asian women compared with their Western counterparts [20, 21]. The age and menopausal status at diagnosis of our cohort are consistent with data from a nationally representative sample of 4211 Chinese women diagnosed with breast cancer (mean age at diagnosis = 48.7 ± 10.5 years, 62.9% premenopausal). Because the vast majority of studies on this subject have been conducted in Western populations, the long-term impact of breast cancer treatment on bone health among Asian women remains unknown. Furthermore, less is known about the long-term risk for fracture among premenopausal women and guidelines cannot simply be extrapolated from studies for postmenopausal women with breast cancer.

As a population, Chinese women undergoing treatment for breast cancer will become vulnerable to fracture at a younger age relative to their Western counterparts, during a period when comparatively little attention is typically given to fracture risk reduction. Furthermore, even when increased fracture risk is identified, management algorithms are less straightforward for premenopausal women compared with postmenopausal women. In 2012, Hadji et al. published a review of the complexities of cancer treatment-induced bone loss (CTIBL) among premenopausal women, and proposed a framework with which to approach this problem including indications for DXA screening and calcium and vitamin D supplementation [22]. However, in China, as in other rapidly modernizing Asian countries, lack of access to DXA and osteoporosis specialists is common, and presents a barrier to comprehensive fracture risk assessment. In 2013, there were only an estimated 0.0046 DXA machines per 10,000 individuals in China, which is far below the density (0.11 per 10,000 population) recommended by the International Osteoporosis Foundation [10]. The lack of DXA access at even the highest-tier cancer centers, including CHCAMS, also suggests a fundamental lack of recognition and prioritization at the health systems level regarding the long-term impact of CTIBL on health outcomes.

From a practice perspective, our study underscores the importance of awareness of fracture risk associated with breast cancer therapies both on the part of the provider and patient. Although fracture rates were relatively high, due to the asymptomatic nature of most vertebral fractures, the vast majority of women and their providers were not aware of these fractures. While guidelines exist in China for screening and management of CTIBL, it is apparent that gaps remain in terms of uptake of these recommendations in practice. Indeed, among breast cancer survivors with a prevalent vertebral fracture, less than 50% had obtained a DXA scan. While 49% of breast cancer survivors were on calcium supplements, only 9% were taking vitamin D supplements. Given age and postmenopausal status are known risk factors for fractures, it is not surprising that overall, more fractures occurred among women who were postmenopausal at the time of diagnosis. However, it is important to note that 8/108 (7.4%) of breast cancer survivors who were premenopausal at the time of diagnosis were also found to have vertebral fractures, which underscores the excess risk for fractures in this population. While studies have demonstrated bisphosphonates may be effective for mitigating CTIBL, such studies have not been powered to measure impact on fracture rates [23‐25].

Our study has several limitations that warrant mention. First, the PK-VF cohort has a few key differences compared with the breast cancer survivors cohort. It was enrolled 5 years earlier than the breast cancer survivors cohort, and carried out by a separate group of investigators and radiologists. However, the principal investigator of the PK-VF was a collaborator on this study and extensive care was taken to parallel the methodologies of the two studies to ensure comparability of findings. Second, although all breast cancer survivors were > 50 years of age, at baseline 6.5% of women in the breast cancer survivors cohort were not yet in menopause. This group also had higher education levels, earlier menarche, lower parity rates, lower personal fracture history, higher rates of calcium supplement use, and higher baseline 25OHD levels. During the design of our study, to avoid potential bias due to overmatching, we did not choose to match our controls based upon each of these factors and instead, took them into account in our regression analyses. As these characteristics would have been expected to be associated with lower risk of fracture, if anything, our findings would underestimate the risk of fracture among Chinese breast cancer survivors. Third, given the cross-sectional design of our study, our data do not allow for calculation of incidence rates of vertebral fracture over time, nor change in laboratory parameters. Our study was also not powered to look for subgroup analyses based upon treatment regimen, therefore we are unable to provide formal comparisons of fracture rates by type of treatment or duration of those treatments. Finally, our study population was limited to breast cancer survivors presenting for routine follow up at a major cancer hospital in Beijing, and therefore may not generalizable to all Chinese women with breast cancer, nor to other regions of China.

In summary, our study found breast cancer survivors in China have a four-fold increased odds of prevalent vertebral fracture compared with age- and BMI-matched healthy women. However, rates of screening for osteoporosis and fracture risk by DXA were low reflecting a lack of standardization of care regarding screening, prevention and treatment of this problem. Future longitudinal studies are needed to elucidate the fracture risk specific to women who are premenopausal at the time of diagnosis and how risk relates to treatment regimens. Finally, infrastructure limitations such as lack of access to DXA imaging at cancer hospitals remain important barriers to timely intervention.