This study showed that ZA administered every 12 weeks for four doses leads to a statistically significant improvement in BMD at the lumbar spine, total femur, trochanter and calcaneus. These results are consistent in trend and magnitude with previous studies, which have shown that bisphosphonates can slow or reverse bone loss in women with breast cancer.[9
]. Recently, Ellis et al published an article about the impact of denosumab on BMD in adjuvant breast cancer.[16
] At 12 months, they report an increase in lumbar spine BMD of 5.5% for denosumab. This contrasts with an improvement of 4.28% in our study. Such BMD changes could be expected to reduce fracture risk by approximately 35–50% in women with osteoporosis.[17
] Our regimen (ZA 4 mg IV every 3 months) was safe and well-tolerated.
] demonstrated a statistically significant improvement in BMD at the spine and hip whether ZA was administered immediately or in a delayed fashion. Our study supports this finding, showing a BMD benefit to initiating ZA even up to five years after breast cancer diagnosis in a population of women largely receiving tamoxifen. To our knowledge, this also represents the first time that the impact of ZA on calcaneal BMD has been assessed. Our results suggest that ZA also influences calcaneal BMD, making this site a possible surrogate for other BMD measurement sites when using bisphosphonate therapy. Calcaneal BMD measurement is simple and used in parts of the world where spine and hip BMD measurements are not practicable or cost-effective[19
However, limitations were imposed on this study because of its long accrual period. For instance, at the time of the initial protocol development, only tamoxifen was commonly used for hormone-receptor positive breast cancer. Thus, the definitions of menopausal status do not reflect current concerns regarding the impact of adjuvant chemotherapy on menses. In addition, use of calcium and vitamin D was not routinely assessed or controlled for. Furthermore, the study did not prospectively follow patients for subsequent fractures, the ultimate endpoint of any study in BMD. Additionally, later use of bisphosphonate was not tracked, thus potentially clouding recurrence and survival data. Lastly, the ZA schedule used (4 mg every 3 months) was more frequent than the schedules used in ABSCG-12 and Z-FAST but less frequent than that employed in AZURE. The overall duration of ZA was a shorter period than has been employed in other studies (see ). This makes it more difficult to compare and contrast our results.
Relapse does remain a significant concern in the node-positive breast cancer population. Analysis of annual hazard rates of recurrence for breast cancer patients entered onto seven ECOG adjuvant trials by Saphner et al demonstrated that patients 5 years post-surgery for breast cancer appeared to have a very slow decreasing hazard of recurrence with a mean 5–12 years post-surgery of 4.3% per year.[20
] Although small, our study did examine the impact of ZA on DFS and OS in the adjuvant setting. Despite our small numbers, we included these results given the ongoing debate over the impact of bisphosphonates on breast cancer DFS and OS. The large, randomized phase III trials assessing adjuvant bisphosphonate use in breast cancer are assigning patients to bisphosphonate therapy within a short time frame from diagnosis (see ). Only ZO-FAST includes patients starting bisphosphonate therapy in a delayed fashion,[9
] albeit in relatively small number, with 20% of women in the delayed group receiving ZA at the 36-month follow-up. Even if the findings of ABSCG-12 are confirmed, the question of benefit to a delayed start for adjuvant ZA will remain unanswered. In the wake of positive results from other clinical trials, the temptation may exist to initiate adjuvant bisphosphonates for any adjuvant breast cancer patient, even if such a patient is relatively distant from diagnosis. Our study was not adequately powered to detect significant differences in DFS or OS, and given the small numbers must be regarded as purely exploratory. However, there is no suggestion that the addition of ZA altered the rate of DFS or OS. There was also no suggestion that adjuvant ZA delayed or slowed the onset of recurrence.
In conclusion, our study showed ZA significantly improved the BMD at the lumbar spine, total femur, trochanter and calcaneus. This is the first time that ZA has been shown to improve BMD at the calcaneus. The improvement in BMD persisted even when the study population was limited to women who received tamoxifen during the study period.