An annual jab could take the pain
out of treating osteoporosis in your postmenopausal
patients. New research shows that zoledronic acid (Aclasta),
a drug used to treat Paget's disease, reduced bone fractures
in older women by 70% over three years. The HORIZON
(Health Outcomes and Reduced Incidence with Zoledronic
Acid Once Yearly) study, which appears in the May 3
issue of NEJM, suggests that zoledronic acid
is as effective as other osteoporosis meds, but the
once-yearly dose gives both compliance and bone mineral
density a big boost. Worryingly, though, an increased
risk of atrial fibrillation was observed in some women.
Zoledronic acid, a bisphosphonate,
works by hindering osteoclasts, cells that eat away
at bone, and thus reducing bone resorption. "If you
give this kind of drugs orally, such as alendronate
and residronate, once daily or once weekly, their activity
may last up to three weeks," says Dr Jacques Brown,
a rheumatologist at Laval University in Quebec City
who's studied zoledronic acid and osteoporosis in the
past. "By giving one IV infusion once a year, you can
interfere with osteoclastic activity for the whole year."
It's not clear why the infusion's effect lasts so long,
he adds, but it's thought that it's linked to the fact
that the drug firmly attaches to calcium and stays around
the bone cavity for many months, thus extending the
osteoclast activity interference.
COMPLIANCE
HOLY GRAIL
The study looked at women between the ages of 65 and
89, a population with well-known medication compliance
problems that range from trouble swallowing pills to
forgetting dosages. To make things worse, oral bisphosphonates
come with complex instructions, including fasting before
taking the pills, drinking a full glass of water and
remaining upright for half an hour after ingestion.
Many patients simply don't bother after a year.
"Most people using oral bisphosphonates
are only 30 to 35% adherent to treatment," says Dr Brown.
"This is a real trap if you want to reduce fracture.
The beauty of IV formulation is you make sure people
are getting the treatment and there's a nice, consistent
reduction in fracture."
The research team, led by Dennis
Black, PhD, an epidemiologist at the University of California,
San Francisco, was familiar with zoledronic acid's benefits
in decreasing bone turnover and improving bone density
after one year. However, the longer term effect on fracture
risk was a pleasant surprise. More than 7,600 osteoporosis
sufferers were monitored for a period of three years
and the results were astounding.
"The fact that zoledronic acid
is still reducing fracture after three years is specific
to this product," notes Dr Brown. "With others, you
start at 65% reduction, then end up at 35% reduction,
because of lack of adherence. The other very interesting
finding is that we see a further reduction of fracture
in stratum two patients, those already treated with
other medications such as calcitonin." According to
Dr Brown, this implies that zolidronic acid added to
other medication would result in a greater reduction
of fracture rate. The numbers add up quite nicely in
fact: 70% fewer vertebral fractures, 41% fewer hip fractures
and 25% fewer nonvertebral fractures.
IRREGULAR
SIDE-EFFECT
Most of the side-effects observed in the study group
were minor and common to all bisphosphonates. But there
was one side effect which hadn't been observed in other
trials. "Atrial fibrillation," says Dr Brown. "The number
of incidents is quite low, but nonetheless statistically
significant." In a NEJM editorial accompanying the study,
Dr Juliet Compston expresses some concern. "The significant
increase in atrial fibrillation... was unexpected, particularly
since the majority of these events occurred more than
30 days after infusion and therefore could not be attributed
to early, transient hypocalcemia," she writes.
Dr Brown is equally baffled. "Bisphosphonates
are very specific to cal-ci-um," he explains. "They
do not attach to any other cell or body component. There's
no firm explanation on how this kind of drug can cause
atrial fibrillation." But while both doctors are cautious,
they agree that the risks are not life-threatening.
BACKBONE
SLIDE
An estimated 1.4 million Canadians suffer from osteoporosis,
according to Osteoporosis Canada, the majority of them
women. While the disease can strike at any age, most
sufferers are over the age of 50, which adds particular
significance to the findings of Dr Black and his team.
Dr Compston was impressed. "The
inclusion of women until the age of 89 years ensured
that the number of hip fractures was sufficient to allow
for a demonstration of efficacy," she comments. In Canada,
70% of hip fractures are osteoporosis-related, and up
to 20% result in death.
The financial burden is equally
significant, considering that those who survive are
frequently disabled. Treating osteoporosis and related
fractures costs $1.9 billion each year in Canada. Long
term and hospital care are important contributors to
those figures. Dr Compston sees zoledronic acid as especially
appropriate for in-hospital use, at least for the first
infusion, where patients can be monitored and treated
for acute-phase reaction.
That's where the annual zoledronic
acid shot comes in. "For sure it's cost effective,"
says Dr Brown. "You're giving it and you're sure it
will be well-absorbed. You're sure you're inducing this
fracture reduction for the same amount of money you'd
have spent on other medication." He expects it will
be marketed at a similar price to the oral formulations
available. Health Canada is currently reviewing the
drug for osteoporosis.
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