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Post-menopausal Osteoporosis
a report by
S o l omon Ep s t e i n , MD , FRCP , FACP
Professor of Medicine and Geriatrics, Mount Sinai University
School of Medicine
I n t r o du c t i o n a n d B a c k g r ou nd
Fractures related to untreated osteoporosis greatly
contribute to increased morbidity and mortality in the
older population. In the US, an estimated 10 million
people over the age of 50 suffer from osteoporosis and
an additional 34 million people are at risk for
developing this condition. As a result, osteoporosis has
become widely recognized as a startlingly prevalent
bone disease and a foremost healthcare concern.
Osteoporosis is a chronic and progressive skeletal
disorder characterized by decreased bone mass and
deterioration of bone microarchitecture. Consequent
bone fragility predisposes the individual to an increased
risk of fracture. Due to the progressive nature of the
bone mass reduction, this condition can be initially
silent, without presenting symptoms even where
fractures are present.
While age-related osteoporosis can occur in both
women and men, women are at the highest risk for
developing osteoporosis due to the decrease in estrogen
that results from the menopause and the consequent
accelerated reduction in bone mass. Until recently, a
clinical diagnosis of osteoporosis, as defined by the
World Health Organization in 1994, has primarily
included a bone mineral density (BMD) reading,
measured by dual-energy X-ray absorptiometer, that is
2.5 standard deviations below the young adult mean.
This value is reported as a T-score of
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50% of the absorbed dose is excreted unmetabolized in
the urine and the remainder is retained on actively
resorbing bone surfaces. For ibandronate, the mean
terminal serum half-life was estimated to be between 10
and 60 hours.The estimated mean terminal elimination
half-life of alendronate (30mg given intravenously over
four days) was found to be greater than 10 years,
indicating prolonged retention in the skeleton.
B i s ph o s phon a t e s a n d I n t e rm i t t en t
D o s i n g
Osteoporosis is a chronic condition that requires
long-term therapy.While BPs have been shown to be
an effective option for reversing this bone disease, the
inconvenient dosing regimen and potential for upper
GI irritation have been obstacles to achieving
consistent patient adherence to daily therapy. In
addition, bone mineralization was found to be
defective with continuous treatment of some of the
older BPs such as etidronate.
In response to these challenges, weekly formulations for
alendronate and risedronate were investigated and found
to be therapeutically equivalent to daily therapy on the
basis of BMD increases while also providing a more
convenient dosing schedule. Adherence to weekly BP
therapy was found to be better than adherence to daily
BP therapy; however, overall adherence remains sub-
optimal.Considering these behaviors, the development of
a BP formulation that allows dosing intervals greater than
one week may offer a more convenient schedule for
patients. Certain molecular characteristics are necessary
for intermittent administration; the BP should
demonstrate potent bone resorption properties, high
binding affinity for bone mineral, and a favorable clinical
safety and tolerability profile.
Intermittent dosing was initially explored in two
studies, which administered 400mg of etidronate to
women with PMO in various dosing regimens.
Vertebral bone mineral content was significantly
increased in each trial. In a meta-analysis of trials
administering intermittent etidronate therapy, it was
determined that treatment with etidronate was effective
in reducing the relative risk of vertebral fractures, butthere
was no impact on non-vertebral fractures.
Cyclical treatment with etidronate has been associated
with rare cases of osteomalacia.
P r e - C l i n i c a l A n ima l Mode l s
The emergence of newer and more efficacious BPs has
driven the development of dosing intervals that are
greater than one week. Pre-clinical trials with rats, dogs,
and monkeys have suggested that intermittent dosing
with ibandronate is as effective as daily dosing in reducing
bone loss and increasing bone strength.An in vivo study
reported that ibandronate is 2-, 10-, 50-, and 500-fold
more potent than risedronate, alendronate, pamidronate,
and clodronate, respectively, as found by inhibition of
arotinoid-stimulated bone resorption in a rat model.
Studies conducted in rats with ovariectomy-induced
bone loss examined the effects of ibandronate on bonemass, bone
strength, and bone architecture.These studies
found that the prevention of bone loss was related to the
total dose of ibandronate, independent of treatment
schedule.The safety and efficacy of IV ibandronate (bolus
injection) given at 30-day intervals was examined in
cynomolgus monkeys; this study confirmed that
ibandronate IV injection had potential use in humans.
Histomorphology studies of bone conducted during
these pre-clinical trials verified that bone quality was
maintained with the use of intermittent ibandronate.
I n t e rm i t t en t O r a l D o s i n g
The optimal dose of oral daily ibandronate was found
to be 2.5mg when examined in a phase II dose-finding
trial.Another phase II trial compared 2.5mg daily with
intermittent oral dosing (20mg of ibandronate every
other day for the first 24 days, followed by nine weeks
without active drug).This study found that increases in
BMD and decreases in bone turnover in the
intermittent dosing group were equivalent to those
from the oral daily dosing group, thus confirming the
results of pre-clinical trials. Both phase II trials
described above found ibandronate to be well-tolerated
at the dosages studied.
The first trial to examine the safety, pharmacodynamics,
and pharmacokinetics of ibandronate used in a monthly
dosing paradigm was the phase I Monthly Oral Pilot
Study (MOPS). Post-menopausal women were given
once-monthly placebo or oral ibandronate at three
dosing strengths (50mg, 100mg, or 150mg).All of the
once-monthly ibandronate dosages were associated
with a safety profile that was similar to placebo and
were effective in suppressing bone resorption, as
indicated by reductions in bone turnover markers
(BTMs).While this preliminary study had limitations,
i.e. a small number of patients (n=144) and lack ofcalcium and
vitamin D supplementation, findings
clearly indicated that once-monthly dosing was a
feasible option.
The pivotal phase III oral iBandronate Osteoporosis
vertebral fracture trial in North America and Europe
(BONE) investigated daily as well as intermittent oral
dosing (20mg every other day for 12 doses every three
months) among women with PMO and examined the
rate of new morphometric vertebral fractures over three
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years. In the BONE trial, the rate of new vertebral
fractures was lower in the daily and intermittent groups
compared with placebo (4.7%, 4.9%, and 9.6%,
respectively).The risk of vertebral fractures was reduced
significantly in the daily and intermittent groups (52%
and 50%, respectively). This study also demonstrated
significant increases in lumbar spine and hip BMD and
normalization of bone turnover denoted by significantreductions
in biochemical BTMs.
The phase III Monthly Oral iBandronate In LadiEs
(MOBILE) clinical trial was a two-year, randomized,
double-blind, non-inferiority study in which four oral
ibandronate regimens were administered to 1,609 post-
menopausal women. The doses were 2.5mg daily,
50+50mg (50mg given for two consecutive days),
100mg monthly, and 150mg monthly. After one year,
treatment with the 150mg dose provided superior
increases in lumbar spine BMD when compared with
the daily dose (4.9% versus 3.9%).In this study,monthly
dosing was shown to be at least as effective as daily
dosing.After two years, results confirmed the one-year
findings and the 150mg monthly regimen consistently
produced greater increases in lumbar spine BMD and
suppression of bone turnover than the daily regimen.
Additionally, BMD at the proximal femur (total hip,
femoral neck, trochanter) substantially increased after
two years with the greatest gains seen in the 150mg
monthly dose cohort (p
