Statin treatment and healthy adherer effects
Received: 6 April 2017 /Accepted: 26 April 2017 /Published online: 29 May 2017
International Osteoporosis Foundation and National Osteoporosis Foundation 2017
We sincerely thank Donzelli and colleagues  for their com-
ments on our work . Regarding the comments, we would
like to reply as follows.
Firstly, the healthy adherer was first proposed in 1980
when the healthy adherer effect which offered protection from
cardiovascular events and mortality . Subsequently, some
randomized clinical trials (RCTs) and observational trials were
carried out to see if there was an association between the
healthy adherer and the positive efficacy, but the conclusions
were not consistent.
There were two studies in which the healthy adherer effect
did not occur. The first was an RCT that the author Alberto
noted in the letter, the Fracture Intervention Trial (FIT) that
compared alendronate with placebo . Although women
with a high placebo compliance showed benefits compared
with low-adherers, there was a non-significant reduced risk
for hip fracture (adjusted HR = 0.65, 95 CI% 0.30–1.45).
Further, the reduction was not observed in other fractures.
Also, the second was a recent observational study, the
Swedish adherence register analysis (SARA) . In that study,
the healthy adherer effect was not a confounder, which could
not affect the association between the persistence and the frac-
Secondly, does the adherence to drug therapy mean a gen-
eral healthy behaviour? In a study of the healthy users and
healthy adherer bias , adherent statin users did not have a
healthier lifestyle compared with non-adherent statin users.
Statin users tended to be more overweight (OR = 1.15, 95%
CI 0.89–1.47), drink more alcohol (OR = 1.36, 95% CI 1.15–
1.62), do more exercise (OR = 1.31, 95% CI 0.79–2.16) and
have a healthier diet (OR = 1.32, 95% CI 1.05–1.67).
Moreover, the smoking habits showed no differences
(OR = 0.96, 95% CI 0.79–1.17). This study suggested that
good adherent users did not necessarily have healthier
Thirdly, many animal studies have demonstrated a consis-
tent trend that statins were effective for osteoporosis [7–9].
Also, the animals were given drugs by injecting or feeding
via the drinking water. Under such conditions, healthy adherer
effects did not exist. Thus, in the same adherence of the treat-
ment, statins still showed effectiveness on osteoporosis.
Fourthly, there were limited RCTs about statins for osteopo-
rosis, so we included many observational studies. The observa-
tional studies can combat the deficiency of clinical evidence.
Moreover, every included trial has been subjected to a quality
assessment. Also before the study, there many meta-analyses
were published including observational studies [10, 11].
Because the number of the patients in the RCTs was too small
for statistical analysis, the results of the RCTs could not be
proved signally. So we combined observational trials to prove
the efficacy of statins for osteoporosis.
Finally, we thank Donzelli and colleagues  for pointing
out the possibility of a potential confounder. Our results may
be influenced by the healthy adherer effect; nevertheless, they
still need to be verified by other trials in which the healthy
adherer effect was tested. Thus, statins are effective for oste-
oporosis from an integration of the existing findings.
Furthermore, we still need to critically assess the efficacy of
* M. Zou
Department of Life Sciences and Biopharmaceutics, Shenyang
Pharmaceutical University, Shenyang 110016, China
Department of Blood Purification, General Hospital of Shenyang
Military Command, Shenyang 110016, China
Department of Pharmacy, Shenyang Pharmaceutical University,
Shenyang 110016, China
Osteoporos Int (2017) 28:2737–2738