Abstract
The aim of the study was to evaluate the progression of bone mineral density (BMD) during 3 years of aromatase inhibitors (AI) therapy in actual practice conditions. This prospective, clinical cohort study of Barcelona–Aromatase induced Bone Loss in Early breast cancer (B-ABLE) assessed BMD changes during 3 years of AI treatment in women with breast cancer. Patients with osteoporosis (T score < −2.5 or T score ≤ −2.0) and a major risk factor and/or prevalent fragility fractures were treated with oral bisphosphonates (BPs). Of 685 women recruited, 179 (26.1%) received BP treatment. By the third year of AI therapy, this group exhibited increased BMD in the lumbar spine (LS; 2.59%) and femoral neck (FN; 2.50%), although the increase was significant only within the first year (LS: 1.99% and FN: 2.04%). Despite BP therapy, however, approximately 15% of these patients lost more than 3% of their baseline bone mass. At 3 years, patients without BP experienced BMD decreases in the LS (−3.10%) and FN (−2.79%). In this group, BMD changes occurred during the first (LS: −1.33% and FN: −1.25%), second (LS: −1.19% and FN: −0.82%), and third (LS: −0.57% and FN: −0.65%) years of AI treatment. Increased BMD (>3%) was observed in just 7.6% and 10.8% of these patients at the LS and FN, respectively. Our data confirm a clinically relevant bone loss associated with AI therapy amongst nonusers of preventative BPs. We further report on the importance of BMD monitoring as well as calcium and 25-hydroxy vitamin D supplementation in these patients.
Introduction
Breast cancer is the most common invasive cancer in women, with approximately 80% of cases diagnosed after the age of 50. Despite the high incidence, the overall 5-year survival rate in women now exceeds 89%, according to the Surveillance, Epidemiology and End Results (SEER) data (http://seer.cancer.gov/statfacts/html/breast.html). This achievement is attributed to earlier detection and improved therapies.
Aromatase inhibitors (AIs) have become the standard adjuvant endocrine therapy for postmenopausal, estrogen receptor-positive, breast cancer patients. This treatment has improved disease-free survival, efficacy, and safety profile, compared with tamoxifen (Howell et al. 2005). Ovarian failure during menopause relegates estrogen synthesis to peripheral tissues via aromatization (Simpson et al. 1994); AIs effectively suppress estrogen levels, resulting in >90% inhibition (Geisler et al. 2008) of aromatase enzymatic activity within the first 3 weeks of therapy. Unfortunately, this marked reduction in estrogen levels further exacerbates the increased bone resorption and excess fracture risk induced by menopause (Howell et al. 2005). Clinical guidelines for the management of AI-associated bone loss (AIBL) strongly recommend a close monitoring of bone mineral density (BMD) and other risk factors to continuously assess antiresorptive therapy requirements (Hadji et al. 2008). Oral bisphosphonates (BPs) are widely used to prevent or reduce postmenopausal osteoporosis and have also demonstrated the efficacy in preventing or reducing AIBL in several trials (Reginster et al. 2000, Brufsky et al. 2009, Eidtmann et al. 2010, Van Poznak et al. 2010). Despite all these data, there is a scarcity of information on the effect of AI therapy on BMD in actual practice conditions, in which patient characteristics, as well as therapy adherence, might differ from those observed in the controlled and restrictive experimental conditions of randomized controlled trials (RCTs).
Our study is based on the Barcelona–Aromatase induced Bone Loss in Early breast cancer (B-ABLE) cohort, a prospective, observational, clinical cohort study of postmenopausal women diagnosed with early breast cancer and undergoing AI treatment. Previous reports from this cohort have established a relationship between 25-hydroxy vitamin D (25(OH)vitD) status and the attenuation of AIBL after 1 year of AI therapy (Nogues et al. 2010, Prieto-Alhambra et al. 2012), and have identified genetic determinants associated with AI-related arthralgia (Garcia-Giralt et al. 2013). The aim of this study is to characterize BMD changes during 3 years of AI therapy in actual practice conditions.
Patients and methods
Study design
B-ABLE is a prospective, nonselected, observational, clinical cohort study, conducted at the Breast Cancer Unit and Bone Metabolism Unit, Hospital del Mar, Barcelona, Spain.
Participants
From December 2005 to February 2014, Caucasian postmenopausal women diagnosed with hormone receptor-positive early breast cancer, and candidates for AI treatment were consecutively recruited in the B-ABLE cohort. A total of 685 women were finally included in the study.
Postmenopausal status was defined as patients (>55 years old) with amenorrhea for more than 12 months, or those (≤55 years old) with levels of luteinizing hormone >30 mIU/mL or follicle-stimulating hormone values >40 mIU/mL. Eligible participants were excluded for a history of any bone disease, rheumatoid arthritis, metabolic, or endocrine diseases; prior diagnosis of Paget’s bone disease or osteomalacia; and concurrent or prior treatment with BP, oral corticosteroids, or any other bone-active drug except tamoxifen.
Participants were treated with AIs (letrozole, exemestane, or anastrozole), according to the American Society of Clinical Oncology recommendations (Winer et al. 2005), starting within 6 weeks postsurgery or 1 month after the last cycle of chemotherapy, or alternatively, after 2, 3, or 5 years of tamoxifen therapy.
Patients were stratified by the BMD at the lumbar spine (LS), femoral neck (FN), and total hip (TH) at the outset of the study, and assigned to the corresponding therapeutic regimen: 1) those with osteoporosis (T score < −2.5) or with a T score ≤ −2.0 at any site as well as one major risk factor or prevalent fragility fractures were allocated to BP therapy of weekly oral risedronate or alendronate (BP-treated group) and 2) all others were allocated to calcium and 25(OH)vitD supplements (see later) but no active antiresorptive therapy (BP-untreated group). All patients had a BMD assessment every 12 months until the end of AI therapy. Those who developed osteoporosis during the treatment were immediately offered oral BP treatment, and they were censored from the study from that moment onward.
All participants were supplemented with calcium and 25(OH)vitD3 tablets (1000 mg and 800 IU daily, respectively), and those with baseline 25(OH)vitD deficiency (<30 ng/mL) received an additional dose of 16,000 IU of oral cholecalciferol (HIDROFEROL, FAES FARMA, Madrid, Spain) every 2 weeks.
Variables and measurements
BMD variation
The primary endpoints were annual and cumulative percentage changes in the LS and FN BMD at each assessment during a maximum 3 years of AI treatment in BP-treated and BP-untreated groups. At baseline and annually thereafter until treatment finalization, BMD was measured at the LS (L1–L4), FN, and TH using a dual-energy X-ray (DXA) densitometer QDR 4500 SL (Hologic, Waltham, MA, USA), following the usual protocol in our unit. In our department, the in vivo coefficient of variation of this technique ranges from 1.0% at the LS to 1.65% at the FN.
Other assessments
Information on a large number of clinical variables was recorded at the time of enrolment, including age at recruitment, age at menarche and menopause, parity, lactation, previous chemotherapy and radiotherapy, adjuvant treatments, weight, height, smoking status, plasma levels of 25(OH)vitD, and daily intake of calcium and supplements.
Ethics approval
The study protocol was approved by the Hospital del Mar Human Research Ethics Committee, and a written informed consent was obtained from all participants after they had read the study information sheet and any questions had been answered.
Statistical analyses
Unless otherwise specified, all results are expressed as mean ± 1 s.d. BMD changes from baseline were evaluated using 1-factor repeated measures ANOVA (means ± 95% CI are reported). If significance was achieved, Bonferroni post hoc comparison of means was performed.
Patient distribution throughout BMD-shift categories was studied after 2 years of AI therapy, because it was during this period that the most significant changes occurred. Potential differences in baseline characteristics between women experiencing >3% loss in the LS and/or FN BMD after 2 years of AI therapy and the rest of patients were assessed by t-test or χ2-test as required.
A subanalysis considering exclusively patients previously treated with tamoxifen, receiving only 3 years of AI, and therefore finishing the treatment within the timeframe of the study, was carried out in order to evaluate the final BMD outcome after completion of AI therapy. All statistical tests defined P<0.05 as significant. These analyses were performed with R version 2.15.2 for Windows using the foreign, ggplot2, car, plyr, scales, grid, and boot packages and SPSS 12.0.
Results
Participants
Baseline patient characteristics stratified by BP use are presented in Table 1. From a total of 685 recruited women, 179 (26.1%) were allocated to BP therapy (Fig. 1). Both groups revealed (as expected given the observational nature of our study) different baseline characteristics: on average, the BP-treated patients were older (P < 0.01) and had a lower body mass index (P < 0.001) than the BP-untreated group.
Flowchart showing the number of patients at baseline and at each follow-up visit until 3 years of AI treatment. BP (bisphosphonates); LS (lumbar spine); FN (femoral neck).
Citation: Endocrine-Related Cancer 23, 4; 10.1530/ERC-16-0025
Baseline characteristics of patients.
| Patient characteristic | Without BP (n = 506) | With BP (n = 179) |
|---|---|---|
| Mean age (years) (s.d.) | 61.3 ± 8.2 | 63.3 ± 8.4** |
| Mean BMI (s.d.) | 29.4 ± 5.4 | 26.9 ± 4.3*** |
| Mean age of menopause onset (years) (s.d.) | 49.5 ± 4.5 | 49.5 ± 4.1 |
| Median age of menarche (IQ) | 12 (3) | 13 (3) |
| Median breastfeeding (months) (IQ) | 3 (9) | 3 (9) |
| Median number of children (IQ) | 2 (2) | 2 (1) |
| Prior tamoxifen therapy n(%) | 175 (34.6%) | 71 (39.7%) |
| Prior chemotherapy n (%) | 298 (58.9%) | 106 (59.2%) |
| AI n (%) | † | |
| Letrozole | 362 (71.5%) | 120 (67.0%) |
| Exemestane | 140 (27.7%) | 52 (29.1%) |
| Anastrozole | 4 (0.8%) | 7 (3.9%) |
In t-test: **P < 0.01, and ***P < 0.001. In χ2-test: ‡
P < 0.05.BMI, body mass index; BP, bisphosphonate treatment; s.d., standard deviation; IQ, interquartile range.
Seven patients in the BP-untreated group developed osteoporosis during the first year and eight patients during the second year of AI treatment. These patients were immediately offered oral BP treatment, and they were censored from the study at that point. The mean follow-up time for non-withdrawn patients was 31.7 months, with a minimum of 3 months.
The mean 25(OH)vitD levels significantly increased over 3 years of follow-up and vitamin D supplementation, from 17.9 to 61.2ng/mL (+44.2 (95% CI: 38.4–50.2); P<0.001) in the BP-untreated group and from 16.7 to 55.3ng/mL (+38.3 (95% CI: 31.7–44.9); P<0.001) in BP-treated patients over the 3 years.
During the first 3 years of AI therapy, 14.0% (25/179) of BP-treated patients and 11.8% (60/506) of BP-untreated patients discontinued study participation. The causes of discontinuation were AI intolerance (n=29; 34.1%), personal reasons (n=27; 31.8%), recurrence (n=12; 14.1%), second neoplasms (n=8; 9.4%), concomitant disease (n=5; 5.9%), BP intolerance (n=2; 2.3%), and exitus (n=2; 2.3%) (Fig. 1).
AIBL assessment
Effects of AI on absolute BMD values and cumulative percentage changes are fully detailed in Table 2. After 3 years of AI therapy, BP-untreated group experienced significant BMD decreases of −3.10% (−0.030 g/cm2 (95% CI: −0.038 to −0.023); P<0.001) in the LS and −2.79% (−0.022 g/cm2 (95% CI: −0.028 to −0.016); P<0.001) in the FN. By contrast, the BP-treated group experienced significant increases in both the LS and the FN: 2.59% (0.019 g/cm2 (95% CI: 0.006–0.033); P<0.01) and 2.50% (0.015 g/cm2 (95% CI: 0.005–0.024); P<0.001), respectively.
Absolute BMD and cumulative percentage changes in BMD up to 3 years of AI treatment
| Time of follow-up | Site | Without BP | With BP | ||||
|---|---|---|---|---|---|---|---|
| N | BMD (g/cm2)mean ± s.d. | Cumulative percentage changes in BMD at baseline mean (95% CI) | N | BMD (g/cm2)mean ± s.d. | Cumulative percentage changes in BMD at baselinemean (95% CI) | ||
| Baseline | LS | 493 | 0.961 ± 0.111 | 168 | 0.793 ± 0.094 | ||
| FN | 493 | 0.748 ± 0.086 | 174 | 0.633 ± 0.084 | |||
| Year 1 | LS | 406 | 0.943 ± 0.111 | –1.33 [–1.77 to –0.89) | 141 | 0.808 ± 0.087 | 1.99 (1.17–2.82) |
| FN | 406 | 0.737 ± 0.083 | –1.25 (–1.76 to –0.74) | 146 | 0.645 ± 0.089 | 2.09 (1.27–2.92) | |
| Year 2 | LS | 327 | 0.933 ± 0.111 | –2.53 (–3.02 to –2.03) | 118 | 0.811 ± 0.093 | 1.88 (0.79–2.97) |
| FN | 326 | 0.733 ± 0.085 | –2.11 (–2.67 to –1.56) | 125 | 0.638 ± 0.078 | 2.10 (0.95–3.24) | |
| Year 3 | LS | 241 | 0.926 ± 0.106 | –3.10 (–3.66 to –2.54) | 78 | 0.818 ± 0.089 | 2.59 (1.37–3.82) |
| FN | 237 | 0.728 ± 0.085 | –2.79 (–3.36 to –2.24) | 85 | 0.646 ± 0.086 | 2.50 (1.39–3.62) | |
BP, bisphosphonate treatment; BMD, bone mineral density; s.d., standard deviation; CI, confidence interval.
In the case of BP-untreated patients, detailed analysis of annual percentage changes in the BMD (Fig. 2) revealed significant changes during the first year (−1.33% (95% CI: −1.77 to −0.89) at the LS and −1.25% (95% CI: −1.76 to −0.74) at the FN; P<0.001), the second year (−1.19% (95% CI: −1.55 to −0.83; P<0.001) at the LS and −0.82% (95% CI: −1.28 to −0.37; P<0.01) at the FN), and the third year of AI therapy (−0.57% (95% CI: −0.92 to −0.22) at the LS and −0.65% (95% CI: −1.07 to −0.23) at the FN; P<0.01). Over the 3 years, 4.3% of patients in the BP-untreated group experienced new osteoporotic fractures (n=22; five clinical vertebral fractures, one femoral, six wrist/forearm, and ten others).
Annual individual percentage change (mean (95% CI)) in bone mineral density of the lumbar spine and femoral neck up to 3 years of AI therapy. In Bonferroni post hoc comparison of 1-factor repeated measures ANOVA: **(P < 0.01), ***(P < 0.001). BP, oral bisphosphonates.
Citation: Endocrine-Related Cancer 23, 4; 10.1530/ERC-16-0025
Among BP-treated patients, the average BMD increased only within the first year of AI therapy (1.99% (95% CI: 1.17–2.82) at the LS and 2.09% (95% CI: 1.27–2.92) at the FN; P < 0.001). No significant variations took place at the LS or the FN in the second year (−0.11% (95% CI: −0.82–0.59) and 0.03% (95% CI: −0.89–0.96), respectively) or the third year (0.72% (95% CI: 0.007–1.44) and 0.47% (95% CI: −0.34–1.29), respectively). Over the 3 years, 8.4% of patients in the BP-treated group presented new osteoporotic fractures (n=15; six clinical vertebral fractures, two femoral, three wrist/forearm, and four others).
Results of patient distribution throughout BMD-shift categories revealed that in the BP-untreated group, 217/327 (66.4%) and 198/325 (60.5%) of patients experienced bone loss at both the LS and the FN, respectively, after 2 years of AI therapy; more than half of these patients had >3% BMD losses at the LS and/or the FN. Assessment of the baseline characteristics specific of this latter group revealed that patients with LS BMD decreases >3% by 2 years of AI therapy were significantly younger (57.7 vs 63.3 years (−5.5 (95% CI: −7.24 to −3.84); P < 0.001)) and more likely to be using tamoxifen treatment previously (53.1% vs 26.4%; P < 0.001) compared with those who experienced a lower LS BMD loss (i.e., <3% compared with baseline). Regarding patients with FN BMD decreases >3%, they had greater BMD values at baseline (0.760 vs 0.740 g/cm2 (+0.020 (95% CI: 0.001–0.038); P < 0.05)) and also had a higher proportion of patients who had been on prior tamoxifen treatment (53.1% vs 26.4%; P < 0.001).
By contrast, 25/327 (7.6%) and 35/325 (10.8%) of the BP-untreated group showed BMD increases >3% at the LS and FN, respectively. In the BP-treated group, 28/118 (23.7%) and 38/125 (30.4%) of patients lost BMD at the LS and FN, respectively, after 2 years of AI therapy. More than 13% of BP-treated patients lost >3% of their baseline bone mass despite BP therapy (Fig. 3).
Percentages of patient distribution in BMD-shift category for the LS and FN after 2 years of AI treatment. Three patients assigned to BP-untreated group at baseline reached T-scores <−2.0 and were immediately started on active treatment. BMD (bone mineral density); BP (bisphosphonates); LS (lumbar spine); FN (femoral neck).
Citation: Endocrine-Related Cancer 23, 4; 10.1530/ERC-16-0025
A subanalysis was performed, including only those patients who had received tamoxifen prior to AI therapy, and therefore had finished the AI treatment at 3 years (Fig. 4). BP-untreated participants accumulated a significant BMD reduction of −4.60% (−0.045 g/cm2 (95% CI: −0.053 to −0.036); P < 0.001) at the LS and −3.71% (0.029 g/cm2 (95% CI: −0.036 to −0.021); P < 0.001) at the FN. BP-treated patients did not lose BMD, but the observed gains were not significant either at the LS (1.90% (0.012 g/cm2 (95% CI: −0.006–0.034); P = 0.17)) or at the FN (1.50% (0.007 g/cm2 (95% CI: −0.007–0.022); P = 0.29)).
Cumulative individual percent change (mean (95% CI)) in bone mineral density of the lumbar spine and femoral neck up to end of AI-therapy for tamoxifen pre-treated patients. In Paired t-test: ***(P < 0.001). BMD, bone mineral density; BP, bisphosphonates.
Citation: Endocrine-Related Cancer 23, 4; 10.1530/ERC-16-0025
Discussion
This prospective study provides additional data about changes in BMD during 3 years of AI therapy in postmenopausal women with breast cancer. The analysis showed that patients without BP experienced significant BMD decreases by the third year of AI therapy. Patients at risk of fracture and therefore treated with weekly oral BP experienced a significant increase in BMD during follow-up. The bone loss recorded in our cohort was lower than that of previous studies, suggesting the importance of improved 25(OH)vitD and calcium status using supplementation to attenuate AI-associated bone loss.
Women without BP had significant BMD loss, achieving BMD decrease by −3.10% at the LS and −2.79% at the FN after three years of AI therapy. Rates of BMD loss at the LS were higher than at the FN. In this sense, the trabecular bone is thought to be more labile than the cortical bone in response to AI therapies (Eastell et al. 2008).
A great number of studies have evaluated the effects of different AIs on bone, but only one previous cohort study has analyzed the impact of AI therapy on BMD outside of RCT settings. In this study, Bouvard and coworkers described BMD changes as well as observed incidence of fracture after 3 years of AI therapy reporting BMD decreases by 3.5% at the LS and 2.0% at the FN in BP-untreated patients (Bouvard et al. 2014).
Regarding RCTs, the ATAC trial described higher bone loss rates, reaching a mean of approximately 5% by the third year (Eastell et al. 2008). Even at 2 years of follow-up, some randomized studies detected higher bone loss rates than our study. The MA-17 trial (Perez et al. 2006) examined letrozole after completing five or more years of tamoxifen therapy, reporting BMD reductions of −5.35% and −3.60%, respectively, at the LS and the TH. In the ARIBON trial (Lester et al. 2008), patients receiving anastrozole and placebo showed BMD reduction of −3.22% at the LS and −3.90% at the TH. Taken together, it seems that the average bone loss in our population was lower than that previously reported, especially the LS values. Differences in some characteristics, such as initial BMD values, could have contributed to this outcome. In this sense, most of the trials mentioned earlier report higher BMD values at baseline than those observed in our cohort, giving rise to a regression-to-the-mean bias.
Secondly, the B-ABLE cohort is subject to strict monitoring of not only BMD but also 25(OH)vitD and calcium levels. 25(OH)vitD status has been related to the BMD (Bischoff-Ferrari et al. 2009 a), and most of the trials and available meta-analyses have shown that 25(OH)vitD supplementation is protective against fractures (Bischoff-Ferrari et al. 2009 b) and falls (Sanders et al. 2010). Extensive data strongly recommend that individuals who are at low risk for fractures and not candidates for BP treatment should receive calcium and 25(OH)vitD supplements (Markopoulos et al. 2010). Patients in the current study receive much higher 25(OH)vitD supplementation than the amount recommended in the Institute of Medicine report: 25(OH) vitD levels improved significantly in our cohort with the proposed regimen, reaching an average >55 ng/mL, and persisting up to 3 years beyond (Prieto-Alhambra et al. 2012). In addition to the supplementation issue, intensive patient follow-up can lead to a Hawthorne effect that should be taken into account when interpreting study results.
Analyses of the percentage shift in BMD after 2 years of treatment revealed that 217/327 (66.4%) and 198/325 (60.9%) of BP-untreated patients experienced decreases at the LS and the FN, respectively; more than half of these patients had BMD losses greater than 3%. Nevertheless, only 15 patients with osteopenia at baseline became osteoporotic throughout the first 2 years of treatment. As soon as the change was detected during routine follow-up, BP treatment was promptly prescribed. Previous studies also demonstrate that very few patients with normal T-scores at baseline develop osteoporosis during AI treatment (Eastell et al. 2008, Lester et al. 2008, Van Poznak et al. 2010). The ATAC trial even suggests that when preexisting osteopenia can be excluded, no special monitoring would be necessary (Eastell et al. 2008).
The small increases in BMD observed in some patients of BP-untreated group could be attributed to the coefficient of variation of the DXA, but unexpectedly, 25/327 (7.6%) and 35/325 (10.8%) of these patients had increases greater than 3% at LS and FN, respectively. Lester and coworkers reported similar results in placebo-treated patients by the second year of AI treatment (Lester et al. 2008). As mentioned above, strict BMD monitoring and 25(OH)vitD and calcium supplements, as well as AI adherence, might contribute to this phenomenon in our cohort. Furthermore, the presence of osteophytes, a common feature of osteoarthritis, can overestimate BMD values at the LS due to the direct effect of being included in the DXA measurement (Liu et al. 1997).
Patients with osteoporosis or with osteopenia at high risk of fracture at baseline were allocated to BP therapy in our study. In this group, BMD increased significantly at both the LS (2.59%) and the FN (2.50%) after 3 years of AI therapy. Preexisting differences between BP-treated and BP-untreated patients did not allow us to stablish comparisons between both the groups. Hence, all the obtained data were analyzed and discussed separately for both groups.
A number of trials have reported BP effects on AIBL after 3 years of follow-up. ZO-FAST (Eidtmann et al. 2010) and Z-FAST (Brufsky et al. 2009) found BMD increases of 4.4% and 3.7% at the LS and 1.9% and 1.7% at the TH, respectively, in the immediate zoledronic acid patients at 3 years of follow-up. Similarly, in the ARIBON trial, BMD increases were reported at both the LS (5.5%) and the FN (3.0%) for patients treated with ibandronate (Lester et al. 2008). By contrast, the recent prospective study of Bouvard and coworkers described no significant increases in BMD after 3 years (Bouvard et al. 2014).
It should be noted that, despite receiving antiresorptive therapy, a nonnegligible 28/118 (23.7%) and 38/125 (30.4%) of BP-treated patients experienced BMD decreases at the LS and the FN, respectively; of these, 17 (60.7%) and 19 (50.0%) had BMD decreases >3%. Other studies have also reported clinically significant BMD reductions in some patients, whether in percentage rates or in T-score categories, within the BP group (Lester et al. 2008, Brufsky et al. 2009, Eidtmann et al. 2010). Large variation in patients’ adherence to oral BP has been previously described (Cramer et al. 2006). Daily dosing at start of therapy increased the number of co-medications, and new use of intestinal agents in the year after starting BP (Cramer et al. 2006) as well as their associated side effects (Anastasilakis et al. 2007) are among the determinants for nonadherence and/or discontinuation. Although BPs are established as an effective antiresorptive agent, the use of BP may not be enough to counteract the full effect of AI (Gnant 2014).
Fracture rates in our patients were similar to those previously reported in a recent observational study (Bouvard et al. 2014).
The subanalysis conducted in our study revealed that BMD losses were more pronounced in patients treated with AI after 2 or 3 years of tamoxifen than in the whole cohort (33% and 25% higher at the LS and the FN, respectively). Correspondingly, B-ABLE patients treated with BP who received previous tamoxifen did not achieve significant BMD increases. Moreover, a higher proportion of tamoxifen-treated patients in the BP-untreated subgroup experiencing BMD decreases >3% by the second year of AI was found. Tamoxifen not only acts as a competitive antagonist of the estrogen receptor in breast tissue, but also has partial estrogen–agonist effects in other tissues, such as bone. There is compelling evidence for its beneficial effects, from reducing bone resorption and stimulating bone formation in postmenopausal breast cancer patients (Resch et al. 1998). However, the current analysis is in accordance with some studies, indicating that prior tamoxifen treatment profoundly increases the effects of AIs on bone turnover, resulting in a greater decrease in BMD (McCaig et al. 2010). A possible explanation for this phenomenon is the rebound effect; unfortunately, the positive influence of tamoxifen not only ceases when tamoxifen therapy is finished (McCaig et al. 2010) but also causes a marked bone loss when switching to AI. Moreover, tamoxifen is a standard treatment for perimenopausal women, but not for postmenopausal women. This can contribute to accelerated BMD loss in these patients, taking into account the key role of age in BMD. All these evidences suggest that patients who take AI after tamoxifen therapy may need even closer monitoring than tamoxifen-naïve patients.
Our study has several limitations. First, this is not an RCT but a prospective cohort based on real-life clinical practice. Thus, our study lacks a control group of women with low baseline BMD and without BP treatment. Therefore, we could not logically conclude, on the basis of our own data, that the BP therapy was the cause of the observed improvements in BMD. However, the effect of BP on the bone has been previously reported in many RCTs and systematic reviews/meta-analyses, both as antiosteoporotic drug and as BMD loss preventive during AI treatment (Reginster et al. 2000, Brufsky et al. 2009, Eidtmann et al. 2010, Van Poznak et al. 2010). Secondly, the evaluation of AI and BP treatment adherence was only assessed by physician questionnaire. The patient number decrease in the follow-up due to either the AI treatment completion or patients still in the first 3 years of treatment, and therefore yet to finish their full treatment cycle, is another potential limitation of our study. In any case, this problem is inherent in the study design, but the expected impact of that on the conclusions is negligible because these patients are not different from the general cohort. Moreover, patient loss to follow-up does not allow the analysis of BMD changes beyond 3 years of AI treatment. Nonetheless, the study design enables close observation of actual practice conditions. Furthermore, the implementation of a specific protocol of bone health management in these patients showed better results in routine oncology practice. Finally, our findings were obtained from a southern Mediterranean region, and generalizability in other populations needs further investigation.
In conclusion, 3 years of AI treatment was associated with bone loss in more than half of postmenopausal, nonosteoporotic patients. In patients receiving oral BP therapy (those with osteoporosis or T < −2.0 and two risk factors at baseline), BMD significantly increased only in the first year and was thereafter maintained during the following 2 years of AI treatment. Monitoring of bone health and calcium and 25(OH)vitD supplementation is essential for the clinical management of the detrimental effects of AI on bone tissue.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work was supported by the Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF; RD12/0043/0022), and the Grant FIS PI10/01464 and PI13/00444 (Carlos III Health Institute, Science and Innovation Ministry); the Grants from the Generalitat de Catalunya (DIUE 2014 SGR 775) and FEDER funds have supported this study.
Author contribution
X N, N G G, M R S, S S, D P A, and I T conceived and designed the study. J A, X N, L G, S S, I T, M M G, J R M and I G performed patient and data collection.: X N and M R S managed database. M R S and D P A performed statistical analyses. M R S, X N, A D P, N G G, and D P A interpreted data and helped in drafting the manuscript. M R S, N G G, X N, D P A, A D P, S S, and I T contributed to the writing of the manuscript. All authors read and approved the final manuscript.
Acknowledgment
The authors thank Elaine M. Lilly, PhD, for helpful advice and critical reading of the manuscript.
References
Anastasilakis AD, Goulis DG, Kita M & Avramidis A 2007 Oral bisphosphonate adverse effects in 849 patients with metabolic bone diseases. Hormones 6 233–241.
Bischoff-Ferrari HA, Kiel DP, Dawson-Hughes B, Orav JE, Li R, Spiegelman D, Dietrich T & Willett WC 2009 a Dietary calcium and serum 25-hydroxyvitamin D status in relation to BMD among U.S. adults. Journal of Bone and Mineral Research 24 935–942. (doi:10.1359/jbmr.081242)
Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, Orav EJ, Thoma A, Kiel DP & Henschkowski J 2009 b Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Archieves of Internal Medicine 169 551–561. (doi:10.1001/archinternmed.2008.600)
Bouvard B, Soulie P, Hoppe E, Georgin-Mege M, Royer M, Mesgouez-Nebout N, Lassalle C, Cellier P, Jadaud E, Abadie-Lacourtoisie S, et al.2014 Fracture incidence after 3 years of aromatase inhibitor therapy. Annals of Oncology 25 843–847.
Brufsky AM, Bosserman LD, Caradonna RR, Haley BB, Jones CM, Moore HC, Jin L, Warsi GM, Ericson SG & Perez EA 2009 Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-month follow-up results. Clinical Breast Cancer 9 77–85. (doi:10.3816/CBC.2009.n.015)
Cramer JA, Lynch NO, Gaudin AF, Walker M & Cowell W 2006 The effect of dosing frequency on compliance and persistence with bisphosphonate therapy in postmenopausal women: a comparison of studies in the United States, the United Kingdom, and France. Clinical Therapeutics 28 1686–1694. (doi:10.1016/j.clinthera.2006.10.013)
Eastell R, Adams JE, Coleman RE, Howell A, Hannon RA, Cuzick J, Mackey JR, Beckmann MW & Clack G 2008 Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. Journal of Clinical Oncology 26 1051–1057. (doi:10.1200/JCO.2007.11.0726)
Eidtmann H, de Boer R, Bundred N, Llombart-Cussac A, Davidson N, Neven P, von Minckwitz G, Miller J, Schenk N & Coleman R 2010 Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST Study. Annals of Oncology 21 2188–2194. (doi:10.1093/annonc/mdq217)
Garcia-Giralt N, Rodriguez-Sanz M, Prieto-Alhambra D, Servitja S, Torres-Del Pliego E, Balcells S, Albanell J, Grinberg D, Diez-Perez A, Tusquets I, et al.2013 Genetic determinants of aromatase inhibitor-related arthralgia: the B-ABLE cohort study. Breast Cancer Research and Treatment 140 385–395. (doi:10.1007/s10549-013-2638-3)
Geisler J, Helle H, Ekse D, Duong NK, Evans DB, Nordbo Y, Aas T & Lonning PE 2008 Letrozole is superior to anastrozole in suppressing breast cancer tissue and plasma estrogen levels. Clinical Cancer Research 14 6330–6335. (doi:10.1158/1078-0432.CCR-07-5221)
Gnant M 2014 Role of bisphosphonates in postmenopausal women with breast cancer. Cancer Treatment Reviews 40 476–484. (doi:10.1016/j.ctrv.2013.07.003)
Hadji P, Body JJ, Aapro MS, Brufsky A, Coleman RE, Guise T, Lipton A & Tubiana-Hulin M 2008 Practical guidance for the management of aromatase inhibitor-associated bone loss. Annals of Oncology 19 1407–1416. (doi:10.1093/annonc/mdn164)
Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY & Tobias JS 2005 Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365 60–62.
Lester JE, Dodwell D, Purohit OP, Gutcher SA, Ellis SP, Thorpe R, Horsman JM, Brown JE, Hannon RA & Coleman RE 2008 Prevention of anastrozole-induced bone loss with monthly oral ibandronate during adjuvant aromatase inhibitor therapy for breast cancer. Clinical Cancer Research 14 6336–6342. (doi:10.1158/1078-0432.CCR-07-5101)
Liu G, Peacock M, Eilam O, Dorulla G, Braunstein E & Johnston CC 1997 Effect of osteoarthritis in the lumbar spine and hip on bone mineral density and diagnosis of osteoporosis in elderly men and women. Osteoporosis International 7 564–569. (doi:10.1007/BF02652563)
Markopoulos C, Tzoracoleftherakis E, Polychronis A, Venizelos B, Dafni U, Xepapadakis G, Papadiamantis J, Zobolas V, Misitzis J, Kalogerakos K, et al.2010 Management of anastrozole-induced bone loss in breast cancer patients with oral risedronate: results from the ARBI prospective clinical trial. Breast Cancer Research 12 R24.
McCaig FM, Renshaw L, Williams L, Young O, Murray J, Macaskill EJ, McHugh M, Hannon R & Dixon JM 2010 A study of the effects of the aromatase inhibitors anastrozole and letrozole on bone metabolism in postmenopausal women with estrogen receptor-positive breast cancer. Breast Cancer Research and Treatment 119 643–651. (doi:10.1007/s10549-009-0646-0)
Nogues X, Servitja S, Pena MJ, Prieto-Alhambra D, Nadal R, Mellibovsky L, Albanell J, Diez-Perez A & Tusquets I 2010 Vitamin D deficiency and bone mineral density in postmenopausal women receiving aromatase inhibitors for early breast cancer. Maturitas 66 291–297. (doi:10.1016/j.maturitas.2010.03.012)
Perez EA, Josse RG, Pritchard KI, Ingle JN, Martino S, Findlay BP, Shenkier TN, Tozer RG, Palmer MJ, Shepherd LE, et al.2006 Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. Journal of Clinical Oncology 24 3629–3635. (doi:10.1200/JCO.2005.05.4882)
Prieto-Alhambra D, Servitja S, Javaid MK, Garrigos L, Arden NK, Cooper C, Albanell J, Tusquets I, Diez-Perez A & Nogues X 2012 Vitamin D threshold to prevent aromatase inhibitor-related bone loss: the B-ABLE prospective cohort study. Breast Cancer Research and Treatment 133 1159–1167. (doi:10.1007/s10549-012-2013-9)
Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, Lund B, Ethgen D, Pack S, Roumagnac I, et al.2000 Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporosis International 11 83–91. (doi:10.1007/s001980050010)
Resch A, Biber E, Seifert M & Resch H 1998 Evidence that tamoxifen preserves bone density in late postmenopausal women with breast cancer. Acta Oncologica 37 661–664. (doi:10.1080/028418698430007)
Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D & Nicholson GC 2010 Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 303 1815–1822. (doi:10.1001/jama.2010.594)
Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S, Amarneh B, Ito Y, Fisher CR, Michael MD, et al.1994 Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocrine Reviews 15 342–355.
Van Poznak C, Hannon RA, Mackey JR, Campone M, Apffelstaedt JP, Clack G, Barlow D, Makris A & Eastell R 2010 Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE trial. Journal of Clinical Oncology 28 967–975. (doi:10.1200/JCO.2009.24.5902)
Winer EP, Hudis C, Burstein HJ, Wolff AC, Pritchard KI, Ingle JN, Chlebowski RT, Gelber R, Edge SB, Gralow J, et al.2005 American society of clinical oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer: status report 2004. Journal of Clinical Oncology 23 619–629.
