N-BPs are widely used in the treatment of osteoporosis and fracture prevention. Although
alendronate is the first-line antiosteoporosis medication in many countries, it is associated
with esophageal and gastrointestinal irritation. In addition, the regimen for alendronate is
one tablet per week and careful use of alendronate is required to avoid gastrointestinal
irritation (e.g. take the tablet on an empty stomach, stay upright for at least 30 minutes
after taking the medication), leading to relative low drug compliance. On the other hand, the
regimen of zoledronate is 5mg infusion once a year. Since the route of administration is
intravenous infusion, it avoids the gastrointestinal irritation problem. In terms of fracture
prevention, zoledronate has a proven better efficacy than alendronate. Most importantly,
previous HORIZON recurrent fracture trial showed that zoledronate use reduced risk of
mortality in addition to fracture prevention. Thus, zoledronate is considered the most
efficacious N-BP in clinical use.
N-BPs could exert extra-skeletal beneficial effects. In 2018, our real-world propensity score
matched study (N=34,991) using the Clinical Data Analysis and Reporting System (CDARS), a
clinical database managed by the Hong Kong Hospital Authority, showed that use of N-BPs was
significantly associated with reduced risk of myocardial infarction and stroke in hip
fracture patients. Later in the same year, a randomized controlled trial (RCT) in 2,000
osteopenic women showed that zoledronate may reduce risk of myocardial infarction with an
odds ratio of 0.61 (95% CI: 0.36-1.02) after following up for 6 years. They subsequently
performed a detailed post-hoc analysis and showed that zoledronate use was significantly
associated with reduced risk of myocardial infarction, composite cardiovascular end-point,
and fatal stroke. This example demonstrated not only the extra-skeletal effect of N-BPs, but
also showed that high-quality real-world data with state-of-the-art statistical method could
potentially be useful in causal inference.
In addition to cardiovascular diseases, N-BPs may be useful in preventing pneumonia.
Preclinical study showed that N-BPs are anti-inflammatory and may modulate macrophages in
response to pneumonia. In addition, pharmacokinetic studies showed that the highest
concentration of N-BPs was detected in trachea other than bone after oral ingestion or
intravenous infusion of N-BPs. Among various N-BPs, alendronate was detected in the trachea
with a concentration of 607 ng/ml 72 hours after oral ingestion, which was almost half of the
concentration (1370 ng/ml) detected in vertebrae. Thus, we conducted a real-world
population-based propensity score matched study in a cohort of 54,047 hip fracture patients
to investigate the association of N-BP use with risk of pneumonia. Among hip fracture
patients, N-BP use was significantly associated with 24% risk reduction in pneumonia (hazard
ratio [HR]: 0.76; 95% confidence interval [CI]: 0.70-0.83), with an absolute risk difference
of 2%. Similar significant association was observed for pneumonia mortality. To further
reduce the potential bias of confounding by indication, we performed a sensitivity analysis
by including users of other anti-osteoporosis medications in the control group, instead of
patients without using any anti-osteoporosis medications. A similar significant association
was observed. In agreement with the preclinical studies, we provided evidence for N-BPs in
pneumonia prevention. This finding attracted wide media coverage, including Reuters and the
New York Times.
Although utilisation of real-world data is an emerging approach in evaluating drug
effectiveness, RCT is still considered the gold standard in evaluating drug efficacy.
However, traditional explanatory RCT may have poor generalizability due to highly selected
patients and controlled environments. Thus, pragmatic clinical trial is developed to evaluate
if the tested intervention is effective in real-life routine clinical practice, by reducing
bias using randomization and improving generalizability using real-world setting. We aim to
evaluate if zoledronate reduces risk of pneumonia in hip fracture patients using pragmatic
clinical trial approach.