Anastrozole withdrawal may reverse anastrozole-induced bone loss

 

“[Our study is] the first [to report] BMD changes after stopping anastrozole in a breast cancer prevention setting … Following completion of endocrine therapy, anastrozole withdrawal was associated with an increase in BMD, [which could be] due to an increase of oestrogen levels, hence a decrease in bone resorption,” said the researchers. [Lancet Oncol 2012;13:275-284] “[These imply] that the negative effects of anastrozole on BMD in the preventive setting are partially reversible.”

 

Despite the benefits of AIs in this setting, they speed up BMD loss during active treatment, the researchers stressed. “It is thus important to understand the effects of long-term AI therapy on [BMD] changes in the preventive setting in more detail.”

 

A total of 3,864 women were initially randomized to daily anastrozole 1 mg or placebo for 5 years. Following which, women on anastrozole withdrew from treatment for 2 years (off-treatment period). To evaluate BMD recovery during this phase, 1,410 of women from the initial cohort entered a substudy, wherein they were stratified according to baseline T-score***: stratum (S)1 (n=761), S2 (n=500; women with osteopenia), and S3 (n=149; women with osteoporosis). The S1 cohort did not receive additional treatment. Half of the S2 cohort received risedronate 35 mg/week (n=137 and 116 in the initial anastrozole and placebo arms, respectively), while the other half remained on placebo. Those in S3 were given risedronate. [Br J Cancer 2021;doi:10.1038/s41416-020-01228-2]

 

This group comprised all non-risedronate recipients with available DXA scans^# (n=404 and 105 for S1 and S2, respectively).

 

In S1, LS BMD improvement was more significantly pronounced in the anastrozole vs the placebo arm (mean increase, 1.25 percent vs 0.14 percent; p=0.0044). Total hip (TH) BMD change in the anastrozole arm was nonsignificant (p=0.99).

 

A similar trend was observed in S2 (mean increase in LS BMD, 2.58 percent vs 0.41 percent; p=0.0284). TH BMD slightly increased in the anastrozole arm (0.44 percent; p=0.99).

 

These findings suggest that, 2 years after stopping anastrozole, and in the absence of a bisphosphonate, LS BMD improved while TH BMD partially recovered and stabilized, the researchers explained. They attributed the stabilization to “the fact that age-related BMD loss has been prevented by an increase in oestrogen levels after stopping AI.”

 

This group involved risedronate recipients in S2 and S3 with available DXA scans (n=108 and 80, respectively).

 

In S2, mean LS BMD improved in the anastrozole but not in the placebo arm (1.09 percent vs −1.06 percent; p=0.0004). TH BMD loss in the anastrozole arm was nonsignificant (−0.60 percent; p=0.48).

 

Findings from the S3 cohort mirrored those observed in S2 (1.92 percent vs −0.54 percent; p=0.04). Both anastrozole and placebo arms saw TH BMD reductions (−0.30 percent and –0.57 percent).

 

These results imply that the use of a bisphosphonate in women with osteopenia and osteoporosis who stopped anastrozole was associated with LS, but not TH, BMD improvements, noted the researchers.

 

“[Moreover,] our results showed no further BMD loss … therefore, there should be no further increase in the risk of fracture in [this setting],” they said. However, they stressed that the improvements may only suggest partial recovery. “If we had measured BMD for all participants after a further 3 years … there may have been a full recovery, but that is unlikely.”

 

Despite the relatively large sample and long follow-up period, follow-up DXA datasets were incomplete, primarily due to withdrawal owing to anastrozole-related adverse effects. “[Nonetheless,] we only included women … who had full sets of DXA scans [at the evaluated follow-up timepoints]; hence, all women finished their allocated treatment. Therefore, anastrozole-induced BMD changes during this period are the true effect and no selection bias was introduced,” they said.

 

“[Our findings imply that] anastrozole-related bone loss seems manageable, and any risk to bone health should be weighed against overall efficacy and tolerability for the preventive treatment of high-risk women,” the researchers said. “This knowledge will help physicians and women who are eligible to take this drug to have a full picture of its effects, so that risks and benefits can be discussed in the decision-making process.”