Hip fracture patients have the highest risk for recurrent hip or other osteoporotic
fractures. We have efficient fracture preventing medication easily available, but few
patients receive them. We therefore need to create simple systems to ensure that these frail
patients with the highest risk for a new fracture are offered proper treatment early and any
delay in treatment should be avoided. Zoledronate is the most efficient bisphosphonate and
the drug of choice for hip fracture patients due to the results from the Horizon recurrent
fracture trial. It is given as an intravenous infusion once yearly. However, the appropriate
time to initiate zoledronate treatment after a hip fracture has not yet been established. The
summary of product characteristics (SmPC) for Aclasta (zoledronate) in Norway says that
Aclasta should not be administered within the first 2 weeks after the hip fracture, however
there have been a practice over years in Norway to give zoledronate to the hip fracture
patients during their stay in hospital for fracture treatment. There are logistical and
practical advantages of giving zoledronate while the patient is still in hospital for her
fracture. It has, however, been questioned whether the effect of zoledronate given within the
first 2 weeks postoperatively really is fracture preventing. The results from the post hoc
analysis from the Horizon recurrent fracture trial by Eriksen and co-workers in 2009,
suggested that given zoledronate within 2-weeks after hip fracture surgery may be a little
less fracture preventing. The results from this analysis can be due to the low number of
study subjects as well as frailty in the study population causing the large variations. On
the other hand, the lack of effect in the within 2-week group may be due to the affinity for
zoledronate to bone mineral and the accumulation of zoledronate in the fracture callus during
bone repair with less being incorporated in the rest of the skeleton.
To clarify the optimal timing of zoledronate to hip fracture patients we wanted to compare if
zoledronate administered early (within 5 days) after hip fracture surgery, while the patients
is still in hospital, is as good as zoledronate given late (3 months) after hip fracture
surgery.
To test our hypothesis we designed a non-inferiority randomized trial using the bone turnover
marker N-terminal propeptide of type I procollagen (P1NP) as the primary endpoint. PINP has
in recent years been widely used as a marker to follow the effect of anti-resorptive therapy
as it is more robust than the other well studied bone marker; cross-linked C-telopeptide of
type I collagen (CTX). P1NP and CTX are recommended as reference markers for bone turnover by
the International Osteoporosis Foundation (IOF). Anti-resorptive agents as bisphosphonates
influence bone remodeling by decreasing bone resorption (amino-bisphosphonates kills
osteoclasts) and thereby also reducing bone formation. This affects the bone turnover
markers: Both P1NP and CTX drops in value in a consistent manner reflecting the level of bone
suppression and has shown to correlate with the level of bone mineral density and the
subsequent fracture risk. P1NP and CTX are therefore well suited to monitor the effect of
anti-resorptive therapy as they reflect the bone turnover status in the entire skeleton. It
is likely to believe that if zoledronate given early after fracture is accumulated in the
fracture callus and too little is incorporated in the entire skeleton, the result will be
just a local decrease in bone resorption (only in the fracture callus). This will not to the
same extent as a decrease in bone resorption from the entire skeleton, be reflected by the
bone turnover markers P1NP and CTX and the fall in these markers will be less than if we give
zoledronate after the fracture has healed (after 6-12 weeks).
Eligible patients that meets the study requirements and with an informed consent will be
stratified on type of operation (arthroplasty versus internal fixation) and on hospital
before randomization 1:1 to either zoledronate early (ZOLearly: zoledronate given within 5
days after hip fracture surgery) or zoledronate late (ZOLlate: zoledronate given 3 months
after hip fracture surgery). The patients will be followed for 15 months with study visits at
3 months post fracture and at 6 and 12 months post treatment with zoledronate. The study is
double-blinded the first 3 months to be able to test for the "soft" secondary endpoints;
delirium and rehabilitation. Approximately 300 patients will be recruited. Estimated
recruitment time is 2 years.