This study is based on a retrospective record of postmenopausal women, survivors to a non-metastatic breast cancer, who initiated adjuvant treatment with AI and were referred to the Osteoporosis Unit of the Basurto University Hospital (Spain) between January 2006 and December 2010 for bone health assessment. Only patients with surgically removed hormone receptor-positive cancers treated with AI for at least 3 years were considered for the study. Patients diagnosed with osteomalacia or imperfect osteogenesis were excluded from the record. Patients signed an informed consent before their clinical data were transferred, and the study protocol was approved by the independent ethics committee of our center. At the first assessment visit (baseline), scheduled at the beginning of AI treatment, all patients were provided with written recommendations on dietary and lifestyle habits for fracture prevention (adapted from Ruiz et al., 2004, see Supplementary Material).22 At baseline, a preventive treatment was established following the T-score cutoffs recommended by the NOF in 200319,20: T-scores <−1.5 and <−2.0 for patients with and without other risk factors, respectively. The risk factors considered in the assessment included two different sources: when available, the algorithm proposed by Hadji et al.18 was used whereas, before its publication, the risk factor list proposed by the Spanish Society of Rheumatology21 was considered (Fig. 1). After the baseline assessment, patients were followed-up every 6 months for 5 years. Densitometric controls were performed every 2 years.

Fig. 1.

Criteria used for establishing preventive treatment at the baseline visit. (A) Algorithm proposed by Hadji et al.18 (B): risk factor list proposed by the Spanish Society of Rheumatology.21

(0.26MB).

Data collected at baseline included demographic characteristics (i.e. age, weight, and height), lifestyle habits potentially associated with bone loss (i.e. smoking history and alcohol consumption), risk factors for fractures, and the presence of comorbidities. Tumor characterization included the date of diagnosis, the stage, the presence of hormone and Her-2 receptors, and adjuvant treatment with chemotherapy and/or radiotherapy. The presence of osteopenia/osteoporosis was determined by a central bone densitometry (dual energy X-Ray absorptiometry [Electric Lunar DPX-NT, General Electric Healthcare, United Kingdom]) of the hip, femur, and column (from L1 to L4), performed after starting treatment with AI and every 2 years during the follow-up. The lowest T-score in any of the assessed areas was compared with the mean T-score of overall women aged between 20 and 40 years. Normality was considered when the patient's T-score was ≥−1 standard deviations (SDs) with respect the reference population mean. Accordingly, osteopenia was considered when the T-score decreased from −1.1 to −2.4 SDs, and osteoporosis when the T-score decreased −2.5 or more SDs with respect the reference population mean. The presence of an osteoporotic fracture on X-ray films was also considered for osteoporosis diagnosis. The screening of low-energy fractures was performed by dorsal and lumbar plain X-ray when a new risk factor for osteoporotic fractures was identified in a follow-up visit. Vertebral fractures were considered when the X-ray revealed a ≥20% deformity, according to the classification of Genant et al.23

The study endpoints included the presence of a fracture not present at the beginning of AI treatment, and a new diagnosis of osteopenia or osteoporosis during the follow-up. Only image-confirmed fractures (i.e. X-ray, computerized axial tomography, or magnetic resonance image) due to bone fragility were considered. Accident- or sport-related fractures were excluded from the analysis. In addition to the diagnosed fractures, we used column X-ray (thoracolumbar spine, lateral view) to investigate the presence of fractures in all patients with risk factors, and those who referred back pain and had not been previously explored by X-ray. Osteopenia or osteoporosis diagnosis was established by bone densitometry as described for the baseline visit.

Normally-distributed quantitative variables were described as the mean and SD, whereas variables showing a skewed distribution were described as the median and the interquartile range (IR), defined by 25 and 75 percentiles. Qualitative variables were described as frequency and percentage. The prevalence of high-risk and moderate-risk factors for fracture was calculated according to the consensus statement of the Spanish Society of Rheumatology.16 The incidence of fractures was described as cumulative survival (using the Kaplan–Meier estimate), and cumulative frequency and percentage for the overall population and for patients with moderate- or high-risk factors, according to the updated consensus of the Spanish Society of Rheumatology.16 The proportion of patients with fractures or newly diagnosed osteoporosis/osteopenia in each group was compared using the chi-square test with a significance α-level of 0.05. All analyses were performed using the IPSS statistical package (IBM SPSS Statistics for Windows, Version 20. Armonk, NY).

Between January 2006 and December 2010, 209 breast cancer survivors were referred to the osteoporosis unit for bone health assessment upon beginning AI treatment. Of them, 166 met all inclusion criteria and none of the exclusion criteria but 36 rejected entering the study, leading to a final sample of 130 women with a mean (SD) age of 62.3 (8.5) years. The tumor was at stage T1 in 72 (56%) patients, and 76 (60%) patients were node-negative. All tumors were hormone receptor positive (94% had estrogen receptors and 89% progesterone receptors), and 12 (9%) were Her-2 positive. Eighty-three (64%) patients received adjuvant treatment with chemotherapy after surgical excision of the tumor.

Table 1 summarizes the risk factors found in the baseline visit. Forty-nine percent of patients had one or more high-risk factors, and 47% had one or more moderate-risk factors. None of the patients had been treated with corticosteroids in the 12 months prior to starting treatment with IA. Of all fractures recorded before the beginning of AI treatment, 11 were low-energy fractures: 6 vertebral fractures, 5 wrist fractures (one patient experienced 2 wrist fractures) and 1 foot fracture.

The baseline examination of BMD was performed in a median (IR) of 3 (1–8) months after starting treatment with AI. Mean values of BMD at baseline for the overall study sample in the assessed regions were the following: 0.940 in the column (T-score −2.02), 0.875 in the hip (T-score −1.05), and 0.829 in the femoral neck (T-score −1.26). The exam revealed the presence of osteoporosis in 50 patients (39%) (the mean BMD was 0.820 in the column [T-score −3.01], 0.811 in the hip [T-score −1.59], and 0.776 in the femoral neck [T-score −1.72]). Osteopenia was identified in 71 patients (55%) (the mean BMD was 0.984 in the column [T-score −1.65], 0.894 in the hip [T-score −0.89], and 0.847 in the femoral neck [T-score −1.1]). Only 1 (1%) patient received treatment with bisphosphonates in the 12 months preceding the baseline visit.

Patients were treated with AI for a median (IR) of 60 (36–60) months. Table 2 summarizes the main characteristics of AI treatment, including the treatment regimen administered. Seven (5%) patients received hormonal treatment in the 12 months preceding the baseline visit.

At the time of starting the analysis, 15 (11%) patients had cancer relapse (local in 2 cases, and metastatic in 13 cases), and 13 (10%) had died, 9 of them because of cancer.

The proportion of patients experiencing fractures was greater among those with at least one high-risk factor than those without high-risk factors (15% vs. 3%). Furthermore, the time to first fracture was significantly shorter in patients with at least one high-risk factor: mean of 99 months (95% CI 88–111) vs. 102 months (95% CI 98–105) (P=0.023). On the other hand, the proportion of fractures among patients with moderate-risk factors was similar to that of patients without moderate-risk fractures (9.8% vs. 7.6%), and no significant differences were observed in the time to first fracture: mean of 106 months (95% CI 99–114) and 96 months (95% CI 90–101) for patients with and without moderate-risk factors, respectively (P=0.290). The baseline risk factors identified in patients experiencing a fracture were age over 65 years (8 patients), previous fracture (3 patients), early menopause (i.e. before 45 years of age) (3 patients), smoking history or currently smoking (2 patients), liver failure (1 patient), and hyperparathyroidism (1 patient). The comparative analysis of each risk factor did not reveal significant differences regarding fracture incidence.

The comprehensive assessment of bone health was performed in a median (IR) of 3 (1–8) months after initiating AI treatment. The baseline assessment was performed considering the risk factors proposed by the Spanish Society of Rheumatology in 101 patients (77.7%) and the risk factors proposed by Hadji et al. in 29 patients (22.3%). As a result of the assessment, 102 (79%) patients started treatment with bisphosphonates, administered orally in 94 (72%) patients (alendronate, risedronate or ibandronate) and intravenously in 8 (6%) patients (zoledronate). Reasons for using the intravenous route were low tolerability to an oral bisphosphonate (5 cases), osteoporosis with multiple fractures (1 case), and worsening in the BMD score during treatment with oral bisphosphonates (2 cases). Overall, 114 (88%) patients received calcium supplement and 102 (79%) vitamin D supplement.

Table 3 summarizes the mean BMD values and T-scores of patients with and without bisphosphonate treatment at baseline and at the end of the follow-up period (median follow-up of 65 months; IR 50–77). Overall, 97 patients (79%) maintained their baseline BMD diagnosis (i.e. normality, osteopenia or osteoporosis), 5 (4.1%) experienced a worsening of their BMD diagnosis, and 17 (14%) an improvement. Fig. 2 summarizes the BMD diagnosis at the end of the follow-up period, grouped according to the baseline BMD diagnosis.

Fig. 2.

Changes in the bone mineral density diagnosis during 5 years of treatment with aromatase inhibitors in patients with BMD assessment at the end of the follow-up (n=123). Patients were classified into three groups according to the baseline BMD assessment: normality, osteopenia, and osteoporosis. The percentages displayed in the bar diagram correspond to patients with normality, osteopenia, and osteoporosis at the end of the follow-up period.

(0.14MB).

Following the screening criteria for low-energy fractures detailed in the methods section, 77 patients (59.7%) underwent plain X-ray at baseline visit, and 117 (90.0%) during the follow-up period. During that time, 11 patients (8.5%) experienced a total of 15 fractures; Fig. 3 shows the survival curve of recorded fractures. In 5 patients (45%), the fracture occurred during the first 3 years of AI treatment. In most cases, patients experienced only one fracture, with the exception of two patients who experienced 2 and 4 fractures, respectively during the follow-up. Regarding the fracture location, 9 (60%) affected the vertebrae, 4 (26%) the limbs, 1 (7%) the pelvis-sacrum, and 1 (7%) the rib. No hip fractures were recorded. Eighty percent of vertebral fractures were asymptomatic and were therefore identified by X-ray in a follow-up visit. All patients who experienced a fracture were receiving preventive treatment for bone loss: 9 were being treated with calcium, vitamin D, and bisphosphonates (administered orally and intravenously in 7 and 2 patients, respectively), one was being treated with a bisphosphonate and vitamin D, and one was being treated with calcium and vitamin D.

Fig. 3.

Survival curve for fractures (Kaplan–Meier estimate).

(0.06MB).

Regarding the fractures in patients treated with the various AIs, of 71 patients receiving anastrozole, 6 (8%) experienced a fracture; all of them had a history of previous fracture (5 vertebral, 1 in the wrist, and 1 in the sacrum), 5 had osteoporosis at baseline and 1 osteopenia. Of 36 patients treated with letrozole, 1 (3%) experienced a fracture; the patient had previous vertebral fracture and osteoporosis at baseline. Finally, of 23 patients treated with exemestane, 4 (18%) experienced a fracture; all of them had a history of previous fracture (2 vertebral, one in the wrist, and one patient had fractures in the rib, wrist, and vertebrae), 3 had osteoporosis at baseline and 1 osteopenia.

The authors declare that no experiments were performed on humans or animals for this study.

The authors declare that they have followed the protocols of their work center on the publication of patient data.

The authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.