CLINICAL ORTHOPAEDICS AND RELATED RESEARCH
Number 443, pp. 61–65
Long-term Outcome of Weekly Bisphosphonates
René Rizzoli, MD
Bisphosphonates currently are the preferred therapy for
treating osteoporosis. Treatment with potent bisphospho-
nates such as alendronate or risedronate decreases biochemi-
cal markers of bone turnover and increases bone mineral
density. These changes are associated with significant reduc-
tions in vertebral and nonvertebral fracture risk. Clinical
trial data with up to 10 years of followup shows these agents
are effective and well tolerated for long-term periods. Daily
administration is effective and generally well tolerated. How-
ever, once weekly doses are more convenient, which may
enhance long-term compliance and lead to more successful
outcomes. The pharmacokinetics and mechanism of action
predict the short-term and long-term skeletal effects and
safety profile of once-weekly doses of bisphosphonates are
similar to daily doses. These predictions are supported by
authors of trials of up to 2 years who report once-weekly
doses are therapeutically equivalent to daily doses in terms of
BMD and biochemical markers of bone remodeling. Once-
weekly bisphosphonate doses have safety and tolerability
profiles as good as daily doses and are comparable with the
placebo.
Level of Evidence: Therapeutic study, Level V (expert opin-
ion). See the Guidelines for Authors for a complete descrip-
tion of the levels of evidence.
Osteoporosis is a systemic skeletal disorder characterized
by low bone mass and deterioration of skeletal microar-
chitecture that leads to reduced bone strength and in-
creased fracture risk.28 It is a progressive, chronic condi-
tion that has no symptoms until a fracture has occurred.
Fractures affect at least 1/2 of all women after menopause
and also affect many men.19 The fractures lead to signifi-
From the Division of Bone Diseases [WHO Collaborating Center for Osteo-
porosis Prevention], Department of Rehabilitation and Geriatrics, University
Hospital, Geneva, Switzerland.
The author certifies that he has no commercial associations (eg, consultan-
cies, stock ownership, equity interest, patent/licensing arrangements, etc.)
that might pose a conflict of interest in connection with the submitted article.
Correspondence to: René Rizzoli, MD, Service of Bone Diseases, Depart-
ment of Rehabilitation and Geriatrics, University Hospital, CH-1211 Geneva
14, Switzerland. Phone: 4122 372 99 50; Fax: 4122 382 99 73; E-mail:
Rene.Rizzoli@medecine.unige.ch.
DOI: 10.1097/01.blo.0000200249.12006.6e
61
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
© 2006 Lippincott Williams & Wilkins
cant pain, disability, decreased quality of life, and in-
creased mortality.13 Patients who sustain a fracture have
an increased risk of future fractures.21,27 Approximately
one in five women with a vertebral fracture will sustain
another vertebral fracture the next year.23 Hip fractures are
the most serious consequence, causing profound physical
disability and loss of independence for elderly patients.40
Twenty-five percent of patients 50 years and older die
within 1 year after a hip fracture.39
The most important goal of osteoporosis therapy is to
reduce fracture risk. Effective therapies for osteoporosis
do this by slowing the rate of bone turnover, increasing
bone mineral density (BMD), and preventing further bone
loss. The bisphosphonates alendronate and risedronate are
the preferred choice for the prevention and treatment of
osteoporosis.24 Both effectively increase bone density,
prevent bone loss, and reduce the risk of vertebral and
nonvertebral fractures. The safety and tolerability of daily
bisphosphonates have been well documented in large clini-
cal trials with durations up to 10 years for alendronate,3,6
and 7 years for risedronate.26
Noncompliance is of particular concern with chronic
asymptomatic conditions such as osteoporosis because it
leads to treatment failure.25,41 Long-term compliance with
medications with complex dosing regimens is also chal-
lenging.8 Bisphosphonates must be taken with a glass of
water 30 minutes before the first meal or beverage other
than water, while remaining in an upright position. Al-
though the standard regimen for daily bisphosphonates is
effective and generally is well tolerated, the availability of
once-weekly administration provides greater patient con-
venience and may improve compliance.4 Only alendronate
and risedronate currently are available as daily and once-
weekly doses.1,14
I will review selected literature addressing the long-
term efficacy and safety of weekly doses of bisphospho-
nates as they compare to daily doses.
Experience with Daily Bisphosphonates
Within 3 to 6 months of initiating treatment with alendro-
nate 10 mg daily, bone turnover markers are reduced to
normal premenopausal levels.5 Authors of large clinical

62 Rizzoli
trials of alendronate report increases in bone density of
approximately 8% at the spine and 7% at the hip within 3
years for the 10 mg daily dose22,30,38 and somewhat
smaller increases with risedronate.16,32 Alendronate re-
duces the risk of new vertebral fractures by approximately
50% compared with placebo in studies that included
women with or without osteoporosis.2,11 Vertebral fracture
risk reductions of 41% to 49% with risedronate have been
reported among women with osteoporosis as calculated by
Cox regression,16,32 with reductions of 31% to 38% when
the fracture risk of treatment and placebo groups were
compared as in trials of other agents.18 Alendronate re-
duced the risk of new hip fractures by approximately 50%;
this effect was consistent across different populations.29
The overall reduction of hip fracture risk with risedronate
was approximately 30%.25 In meta-analyses of data from
randomized trials (the highest level of evidence in evi-
dence based medicine) of antiresorptive agents the relative
risk reduction for vertebral fractures was 48% for alendro-
nate and 36% for risedronate, and for nonvertebral frac-
tures 49% for alendronate and 27% for risedronate.9,42
Long-term followup of the Phase III studies of alendro-
nate have shown spine BMD increases progressively for at
least 10 years (Fig 1), and the initial increases in BMD
with alendronate treatment at other skeletal sites are main-
tained.6 In addition, biochemical markers of bone turnover
are reduced to the normal premenopausal range, where
they remain stable for at least 10 years with no evidence of
progressive declines.6 The Phase III studies also suggest
the significant reductions in vertebral and nonvertebral
Fig 1. A chart shows how alendronate affected lumbar spine
BMD. Treatments of 5 mg and 10 mg doses lasted for 10
years. The discontinuation group was treated with 20 mg of
alendronate per day for 2 years, 5 mg daily for 3 years, and
placebo for 5 years. The mean percent change from baseline
to 10 years appears in parentheses after each treatment
group. Reprinted from Bone HG, Hosking D, Devogelaer JP, et
al. Ten years’ experience with alendronate for osteoporosis in
postmenopausal women. N Engl J Med. 2004;350:1189–1199
with permission of the Massachusetts Medical Society.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Clinical Orthopaedics
and Related Research
fracture risk with alendronate treatment were maintained
during long-term treatment, and stopping treatment re-
sulted in partial loss of the effects on the skeleton.6
Rationale for Once-weekly Dosing
with Bisphosphonates
The pharmacokinetics and mechanism of action of bis-
phosphonates suggest less frequent administration would
produce effects on bone mass and bone strength similar to
those achieved with daily dosing if the cumulative dose is
the same.4 Once bound to active bone remodeling sites,
bisphosphonates remain there for a prolonged period and
effectively inhibit bone resorption, provided sufficient
concentrations are present.31,34 The proportion of alendro-
nate that is absorbed from an oral dose is linear up to at
least 80 mg.31 Therefore, a single 70 mg dose would result
in the same amount of alendronate being absorbed and the
same concentration at bone remodeling sites as giving
seven 10 mg doses. Also, bone resorption by osteoclasts
requires 2 to 3 weeks for completion.4 If the resorption
process were to be interrupted at weekly intervals, most
active sites would be only several days old and relatively
little resorption would have occurred. Weekly doses of
bisphosphonates would be expected to produce similar
short-term skeletal effects as daily doses.
The pharmacokinetics and mechanism of action also
predict the long-term efficacy and safety (gastrointestinal
[GI] and skeletal) of weekly bisphosphonates would be the
same as with daily doses. Large scale clinical trials with
thousands of participants have demonstrated no significant
differences in the incidence of upper GI or other adverse
events with daily bisphosphonates and placebo.2,11,16,30,32
Some cases of esophageal irritation have been reported.10
The known mechanism of action, coupled with the expe-
rience of treating a large number of patients for up to 10
years in controlled trials, have identified the beneficial
effects of bisphosphonates on skeletal health and safety.34
Experience with Weekly Dosing of Bisphosphonates
Weekly does have been shown to be therapeutically
equivalent to daily doses for alendronate and risedronate.
In a 1-year double blind placebo controlled trial patients
with osteoporosis were randomized to receive alendronate
70 mg once weekly, 35 mg twice weekly, or 10 mg daily.36
At 12 months, reductions in bone turnover markers and
BMD increases were similar for all three dosing regimens.
For example, the once weekly, twice weekly, and daily
treatment groups had BMD increases at the lumbar spine
of 5.1%, 5.2%, and 5.4%, respectively.36 The effects of all
three regimens on urinary N-telopeptides of Type I colla-
gen (NTx), a biochemical marker of bone resorption, were
observed as early as 1 month.36 The effects were main-
Number 443
February 2006
tained over the 12 months of treatment with a mean re-
duction of 56%.36 Adverse event profiles, including upper
GI adverse events, were similar across all treatment groups
at the end of 12 months.36 The 2-year results of this
equivalence study showed similar mean increases in BMD
for the 10 mg daily, 35 mg twice weekly, and 70 mg once
weekly treatment groups (7.4%, 7%, 6.8%, respectively)
(Fig 2A).33
A similarly designed equivalence study compar-
ing daily and weekly risedronate treatments demonstrated
35 mg or 50 mg risedronate weekly regimes were equiva-
lent to the 5 mg daily regimen in increasing lumbar spine
bone density and reducing bone turnover.7 The mean
Fig 2A–B. (A) A chart shows the percent change in lumbar
spine BMD over 24 months. Results are means ± SEM.
Adapted from J Bone Miner Res 2002;17:1998–1996 with per-
mission of the American Society for Bone and Mineral Re-
search. (B) A chart shows the percent change in lumbar spine
BMD over 24 months. Results are means ± SEM. OAW rep-
resents once a week. Reprinted with permission from Harris
ST, Watts NB, Li Z, et al. Two-year efficacy and tolerability of
risedronate once a week for the treatment of women with
postmenopausal osteoporosis. Curr Med Res Opin. 2004;20:
757–764.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Long-term Outcome of Weekly Bisphosphonates 63
percent changes in lumbar spine BMD after 12 months of
treatment with risedronate were 4% in the 5 mg daily
group and 3.9% in the 35 mg once weekly group. Out-
comes of the secondary efficacy endpoints and safety as-
sessments were also similar with daily and weekly doses.7
After 24 months of treatment with risedronate, the mean
percent changes in lumbar spine BMD were 5.2% in the
5 mg daily group and 4.7% in the 35 mg once weekly
group (Fig 2B).17
Treatment with once weekly alendronate was similar to
placebo with regard to the incidence of upper GI adverse
events (9.8% versus 9.4%, respectively), the primary end-
point in a 12-week randomized double blind placebo con-
trolled trial in patients with osteoporosis.12 Additionally,
the proportion of patients who discontinued therapy be-
cause of drug related upper GI adverse events was similar
between the alendronate and placebo groups, and both
groups had similar overall tolerability profiles. The find-
ings of this multicenter international study confirm those
reported in an earlier trial.15
Data comparing the once weekly regimens of alendro-
nate and risedronate are also available. A 12-month double
blind head to head trial of once weekly alendronate 70 mg
and once weekly risedronate 35 mg was conducted in 1053
postmenopausal women with low bone density from
78 sites in the United States.35 At 12 months, there was a
considerably greater increase in BMD among patients
treated with alendronate compared to risedronate at the hip
trochanter (3.4% versus 2.1%), total hip (2.2% versus
1.2%), femoral neck (1.6% versus 0.9%), and lumbar
spine (3.7% versus 2.6%) (Fig 3).35 Significant differences
between treatment groups were seen at the first treatment
measurement (6 months) at all sites.35 Alendronate also
produced significantly greater reductions in biochemical
markers of bone turnover compared with risedronate at
3 months (the first measurement).35 There were no signifi-
cant differences between treatment groups in the incidence
of upper GI adverse events, or adverse events causing
discontinuation.35
In addition to the efficacy and safety of a once weekly
bisphosphonate, it is important to consider the impact of
the dosing regimen on a patient’s daily routine. Patient
satisfaction is associated with treatment compliance and
desired health outcomes. An open label, randomized,
crossover, international multicenter study comparing pa-
tient preference for once weekly versus once daily doses
reported most (84%) patients preferred once-weekly over
daily doses, and most (87%) believed once-weekly doses
were more convenient than daily doses, and would allow
them to achieve better long-term compliance (84%).20 All
results consistent across subgroups based on country, age,
number of concomitant medications, and medical condi-

64 Rizzoli
Fig 3A–C. Charts show the percent change in BMD of (A) hip trochanter, (B) spine and (C) urine N-telopeptide in patients treated
with once weekly 70 mg alendronate or once weekly 35 mg risedronate. OW = once weekly. Adapted from J Bone Miner Res
2005;20:141–151 with permission of the Journal of the American Society for Bone and Mineral Research.
tions.20 Similar findings were reported in a trial conducted
at 38 sites in the United States.37
DISCUSSION
Bisphosphonates currently are the preferred therapy for the
treatment of osteoporosis.24 Treatment with potent bis-
phosphonates such as alendronate and risedronate de-
creases biochemical markers of bone turnover and in-
creases BMD, with somewhat greater effects for alendro-
nate than risedronate.9,35 These changes are associated
with significant, clinically important reductions in the risk
of vertebral and nonvertebral fractures. Authors of clinical
trial data whose patients have up to 10 years followup
indicate these agents continue to be effective and are gen-
erally well tolerated in the long term.6 Once-weekly doses
are a convenient alternative to daily doses, and may en-
hance long-term compliance. In addition to being thera-
peutically equivalent, once-weekly doses of bisphospho-
nates have a safety and tolerability profile at least as good
as daily doses, and are comparable with placebos.
Acknowledgment
The author thanks Christine Sisk of Merck Research Laborato-
ries, who provided assistance with manuscript preparation.
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