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Risedronate
A Clinical Review
Carolyn Crandall, MD
Arch Intern Med. 2001;161:353-360.
ABSTRACT
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Background Risedronate sodium has recently been approved for the prevention and
treatment of postmenopausal and corticosteroid-induced osteoporosis.
Methods Studies of risedronate were obtained from the MEDLINE database (1966
to the present) of references using risedronate, risedronic
acid, osteoporosis, and human subject as keywords.
Additional references were sought from the reference lists of the articles
obtained.
Results Nine randomized controlled trials and 7 other clinical trials were obtained.
In postmenopausal women with normal bone density, risedronate increases lumbar
spine bone density and preserves femoral neck density. In postmenopausal women
with prior vertebral fracture, risedronate decreases new vertebral and nonvertebral
fracture incidence. In patients who experienced breast cancer and who have
chemotherapy-induced menopause, risedronate preserves bone. Risedronate prevents
vertebral bone loss in patients beginning long-term corticosteroid therapy.
Risedronate decreases pagetic bone pain and induces radiological improvement
in pagetic lesions. Risedronate induces normalization of biochemical abnormalities
and may be more effective than etidronate disodium for Paget disease. Only
one study, a trial in patients with postmenopausal osteoporosis using a low
dose (2.5 mg) of risedronate, did not have a positive result. Adverse effects
in patients with postmenopausal osteoporosis, breast cancer, and Paget disease
and in those taking corticosteroids are similar to those of patients taking
placebo, and do not include notable upper gastrointestinal tract adverse event
rates or serious adverse events.
Conclusions Risedronate prevents postmenopausal bone loss, decreases fracture in
those with established postmenopausal osteoporosis, effectively treats Paget
disease, and prevents corticosteroid-induced bone loss. Long-term toxic effects
and efficacy, particularly fracture end point data, are unknown. Also undefined
are optimal duration of therapy, potential for use in combination with other
agents, and direct comparison with other bisphosphonates used for osteoporosis.
INTRODUCTION
RISEDRONATE SODIUM, also known as NE-58095 or risedronic acid, is an
aminobisphosphonate. Its chemical name is 2-hydroxyethylidene-2-(3-pyridinyl)-1,1
bisphosphonate disodium.1 Risedronate was approved
in the United States for the treatment of Paget disease in 1998.1, 2
On April 24, 2000, it was approved in the 5-mg/d dose for the prevention and
treatment of corticosteroid-induced and postmenopausal osteoporosis.
The first bisphosphonate is said to have been synthesized in 1897 by
Von Baeyer and Hofmann.3 Since 1962, it has
been known that inorganic pyrophosphate, a by-product of human physiological
reactions, could bind to hydroxyapatite crystals.4
However, because of gastrointestinal tract hydrolysis, the pyrophosphates
were inactive when given orally to laboratory animals. Thus, the diphosphonates,
later called bisphosphonates, were developed as more stable analogues of pyrophosphate.
Etidronate disodium was the first bisphosphonate to be aggressively studied
for the treatment of osteoporosis.5 However,
it interfered with bone mineralization in doses that would be used clinically
for the treatment of osteoporosis.6 More recent
agents do not manifest this disadvantageous characteristic.
Bisphosphonates are pyrophosphate analogues in which the oxygen in the
P-O-P structure has been replaced with a carbon, yielding a P-C-P structure.7 The P-C-P structure confers resistance to hydrolysis
on exposure to acids or hydrolytic enzymes.4
One side chain provides affinity to bone mineral, while the other is responsible
for the potency of inhibition of osteoclastic activity.7
A hydroxyl group at the R1 position increases affinity for bone
mineral.4 The R2 position can be
manipulated to enhance potency while preserving the R1 affinity
for bone. (R1 and R2 are positions on the carbon atom
of the bisphosphonate structure. They represent side chains. R1
determines the affinity for bone mineral and R2 is responsible
for potency characteristics.)
There are 3 generations of bisphosphonates. Etidronate is a first-generation
agent. Alendronate sodium and pamidronate disodium, which are second-generation
agents containing a basic primary nitrogen atom in an alkyl chain, are 10-
to 100-fold more potent than are etidronate and clodronate. (Although tiludronate
does not contain an amino terminal group, it is considered second generation
because of the timing of development and potency.) Even more potent are agents
containing a tertiary nitrogen, such as the third-generation agent ibandronate.
The most potent agents contain a nitrogen atom within a heterocyclic ring,
eg, risedronate and zoledronate.4, 5, 8
Bisphosphonates have theoretical advantages over estrogen replacement
therapy in that they are bone specific, have minimal adverse effects, and
have no known carcinogenic potential.9 Cellular
mechanisms of the bisphosphonates are not yet understood in their entirety.
Russell and Rogers4 have recently reviewed
these mechanisms. The bisphosphonate most extensively studied for osteoporosis
treatment is alendronate.
In female rats that undergo ovariectomy, risedronate increases connectivity
density and total trabecular number, suggesting that it may help increase
bone connectivity in the estrogen-deficiency state.10
These and other similar findings have caused risedronate to be studied for
clinical use in the settings of osteoporosis and Paget disease.
MATERIALS AND METHODS
A MEDLINE search (1966 to the present) was performed for keywords risedronate, risedronic acid, osteoporosis, and human subject. All MEDLINE (1966 to the present) clinical trials with
the keyword risedronate or risedronic
acid were also retrieved. The reference lists from the retrieved articles
were reviewed for additional relevant studies.
RESULTS
In addition to several reviews and animal trials, 16 clinical trials11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26
of risedronate in humans were retrieved (additional data available from the
authors). Of these, 10 were randomized controlled trials.11, 12, 13, 14, 21, 22, 23, 24, 25, 26
Of the 16 clinical trials, 7 reports12, 15, 16, 17, 18, 19, 20
pertained to Paget disease, 311, 13, 14
focused on postmenopausal women with or without preexisting fractures, and
121 studied risedronate use in women with breast
cancer. Four additional studies23, 24, 25, 26
examined risedronate's properties in healthy volunteers. There was 1 trial22 of risedronate in the prevention of corticosteroid-induced
bone loss.
Dosing for postmenopausal osteoporosis prevention or treatment was 5
mg/d continuously. Dosing for Paget disease ranged from 28- to 84-day cycles.
Dosing in the breast cancer survivor study was 30 mg/d for 2 weeks and 10
weeks of no treatment. Dosing in the corticosteroid-induced osteoporosis prevention
study was 5 mg/d continuously. Dosing was cyclical for Paget disease, whereas
it was continuous for postmenopausal osteoporosis prevention, postmenopausal
osteoporosis treatment, and corticosteroid-induced osteoporosis prevention.
The 10 randomized controlled trials were performed on postmenopausal
women (n = 3),11, 13, 14
long-term corticosteroid users (n = 1),22 breast
cancer survivors with chemotherapy-induced menopause (n = 1),21
patients with Paget disease (n = 1),12 and
healthy volunteers (n = 4).23, 24, 25, 26
Study duration ranged from immediate follow-up of single-dose administration
to 3 years.11 There was one comparative trial.12
Five studies11, 13, 14, 21, 22
reported bone mineral density (BMD) effects of risedronate (data available
from the authors). Three studies11, 13, 22
included fracture outcome data (data available from the authors). Two11, 22 of the 3 reported some extent of
antifracture benefit of daily risedronate therapy. Data are more uniform in
showing fracture outcome benefit of the 5-mg dose, compared with the 2.5-mg
dose.
Data on safety evaluations in the clinical trials may be obtained from
the authors. Overall, risedronate was free of serious adverse effects.
COMMENT
POSTMENOPAUSAL OSTEOPOROSIS
Three clinical trials11, 13, 14
examined the bone effects of risedronate on postmenopausal women. All were
randomized, double-blind, placebo-controlled studies.
A phase 2 study13 administered 2.5 mg
of risedronate in continuous (daily) vs cyclic (risedronate daily for 2 weeks,
followed by 10 weeks of placebo) fashion vs placebo in double-blind randomized
fashion. The 132 subjects had at least 1, but no more than 4, preexisting
vertebral fracture at baseline, and were at least 1 year postmenopausal. Study
medication was taken orally 2 hours before bedtime, in the absence of food
consumption 2 hours before and afterward. All took a calcium supplement, 1
g/d. After the 2 years of treatment, the trial was extended for 1 year of
follow-up, during which calcium, 1 g/d, was taken. Seventy percent completed
3 years of risedronate therapy. The primary efficacy measure was spine BMD,
and secondary measures were hip BMD and bone turnover markers. Study findings
overall showed lack of effect of risedronate. There were no notable changes
in bone turnover markers, nor were there differences between groups in incidence
and rate of new vertebral fractures. Adverse events were similar across groups,
and none were believed to be causally related to risedronate.13
This is true even though patients with gastrointestinal tract diseases were
not excluded. (Gastrointestinal tract toxic effects have been a concern with
past bisphosphonates.) The researchers speculated that perhaps inadequate
dosing or absorption explained the lack of efficacy. Subsequent work, therefore,
made use of higher doses. Vertebral fracture incidence was a secondary outcome,
done as part of safety assessment in this study.
A double-blind placebo-controlled study14
randomized 111 early postmenopausal patients to oral placebo; risedronate,
5 mg/d; or risedronate, 5 mg, given cyclically for 2 years. At baseline, the
subjects all had lumbar BMD values within 2 SDs of age-matched mean bone mass
values. The cyclic regimen was risedronate, 5 mg/d, for the first 2 weeks
of every calendar month, followed by placebo daily for the rest of the month.
Patients were stratified according to calcium intake to address the possibility
that calcium intake affected response to therapy. The study medication was
taken with at least 236.56 mL (8 oz) of water 2 hours before bedtime and 2
hours after a meal. Subjects were told not to take dairy products; vitamins;
or calcium-, iron-, magnesium-, or aluminum-containing antacids within 2 hours
of taking the study medication. Patients were then followed up for 1 year
while not taking treatment. Primary efficacy was change in lumbar spine BMD
at 24 months, and other measures included change in proximal femur BMD and
bone turnover.
After 24 months, trochanteric bone mass increased by 5.4% in the daily
risedronate group, and by 3.3% in the cyclic group, compared with placebo.
Lumbar spine BMD increased by 5.7% in the risedronate cyclic group vs placebo.
Bone mass was maintained at the femoral neck in the 2 risedronate groups,
whereas 2.4% loss occurred with placebo. At the end of the third year, ie,
at the end of the 1-year observation period while subjects were not taking
treatment, lumbar BMD was lower than at baseline in all 3 groups. The 5-mg/d
dose thus increased BMD and the 5-mg cyclic dose prevented bone loss in these
early menopausal women with normal BMD.14 As
with the prior study,13 it is unfortunate that
vertebral fracture incidence was part of the safety assessment, as opposed
to primary fracture outcome. A strength of the study was its inclusion of
patients with a history of gastrointestinal tract disease.
The Vertebral Efficacy With Risedronate Therapy Study11
randomized 2458 ambulatory postmenopausal women younger than 85 years with
at least 1 baseline vertebral fracture to risedronate, 2.5 vs 5.0 mg, vs placebo
for 3 years. The protocol advised consumption of the medication once daily
on an empty stomach, 30 to 60 minutes before breakfast, with water, and while
remaining in the upright position for 1 hour afterward. All subjects received
calcium, 1000 mg/d, and those with low serum 25-hydroxyvitamin D levels also
received cholecalciferol (vitamin D) up to 500 IU/d. Patients were stratified
according to number of baseline vertebral fractures, and randomly assigned
within each stratum to each study group. Study outcomes included incidence
of new vertebral fractures (proportion of subjects with  1 incident fractures
in 3 years). The 2.5-mg arm of the study was stopped after 1 year because
of other trials13 showing relative lack of
effectiveness of the 2.5-mg dose. The study had at least 90% power to detect
40% reduction in vertebral fracture risk. Bone turnover markers and radiographically
confirmed nonvertebral fractures (of the clavicle, humerus, wrist, pelvis,
hip, or leg, either related or nonrelated to trauma) were other outcomes.
The 5-mg dose decreased cumulative new vertebral fracture incidence
by 41% compared with placebo. The cumulative incidence of nonvertebral fractures
in 3 years was decreased by 39% vs placebo. Lumbar spine, femoral neck, femoral
trochanter, and radius midshaft BMD measurements were all increased more in
the 5-mg group than in the placebo group. Bone biopsies performed at selected
study centers revealed bone to be histologically normal. The study included
patients with a history of gastrointestinal tract disease. Placebo and risedronate
safety levels were similar.11 The study was
well designed and included a much larger sample than did the other risedronate
studies.
In summary, based on randomized, double-blind, placebo-controlled trials
of 2 to 3 years' duration, risedronate is efficacious in preventing bone loss
in postmenopausal women with normal bone density, and in decreasing fractures
in patients with established (1 preexisting vertebral fractures) osteoporosis.
Risedronate was well tolerated in all studies. There are only a few studies
with fracture outcome, due at least in part to inadequate study size and duration,
with resultant inadequate statistical power.
PAGET DISEASE
Seven clinical trials12, 15, 16, 17, 18, 19, 20
of risedronate for Paget disease were retrieved.
Preliminary human testing of risedronate in Paget disease15
encouraged further investigation. An open-label study20
of patients with severe Paget disease of bone (alkaline phosphatase level
6 times the upper limit of normal) assigned 12 men and 8 women, aged 60 to
87 years, to receive risedronate, 30 mg/d, for 84 days, followed by observation
for 112 days without treatment.27 The cycle
was repeated in patients who did not have normalization of the alkaline phosphatase
level or who had an increase of 25% or more in the alkaline phosphatase level.
Primary efficacy end points were percentage change in baseline alkaline phosphatase
level and excess urinary hydroxyproline/creatinine levels. The secondary efficacy
measure was pain due to Paget disease. All patients responded during the initial
course of therapy. Most patients had a decrease in alkaline phosphatase level
with risedronate therapy. In 65% of the patients, the alkaline phosphatase
level normalized. There was progressive decline and elimination of pagetic
bone pain, to the extent that 0% of the patients had pain at re-treatment
day 56. Thereafter, all patients remained free of pain for the duration of
the study. Three-month courses of treatment with risedronate thus safely reduced
biochemical disease activity indexes, normalized the alkaline phosphatase
level in most of these patients with severe Paget disease, and significantly
reduced pagetic bone pain.20 The study was
well done but only had a few patients.
In another open-label study,19 8 male
and 5 female patients with severe Paget disease (alkaline phosphatase level
17 times the upper limit of normal) were given risedronate, 30 mg/d, for 8
weeks and then followed up for 16 weeks without treatment. Patients who did
not attain normal alkaline phosphatase levels after treatment received another
8-week course. The primary outcome measure was serum alkaline phosphatase
percentage change from baseline. All patients had a decrease of at least 77%
in alkaline phosphatase level vs baseline. Urinary hydroxyproline/creatinine
levels also decreased with treatment.19 Again,
the study appears to have been well performed but is small. In addition, pain
outcomes were not reported.
Siris et al18 performed an open-label
multicenter study in 102 men and 60 postmenopausal women with moderate to
severe Paget disease of bone, ie, a serum alkaline phosphatase level 3 times
the upper limit of normal. Patients received risedronate, 30 mg/d, orally
for 84 days, followed by 112 days without treatment. Patients whose alkaline
phosphatase level did not respond adequately, as defined as lack of normalization
or increase by 25% or more, received another 196-day cycle of treatment. Primary
efficacy end points were the percentage change from baseline in serum alkaline
phosphatase level and urinary hydroxyproline-creatinine ratio. The secondary
end point was pain due to Paget disease. Risedronate decreased pagetic bone
pain. On day 196, 42% of the subjects had no pagetic pain. Normalization of
the alkaline phosphatase level was observed in many (53.8%) of the patients
with the study protocol, and repeated administration was beneficial.18 The trial was larger than others. An additional benefit
of the trial was the inclusion of radiological assessment. In a subgroup (16
men and 10 women) of the study population, radiological improvement of pagetic
lesions occurred at all skeletal sites.16 Moreover,
it showed risedronate to be devoid of deleterious effect on osteolytic lesions
of weight-bearing bones. Risedronate treatment was thus highly effective for
improving bone lesions, without deleterious effects on osteolytic lesions
in weight-bearing bones.16 This report adds
another dimension to the pain and biochemical improvement previously reported
with risedronate.
An open-label, dose-escalation study17
of 62 patients, aged 18 to 75 years, with severe Paget disease of bone (alkaline
phosphatase level >3 times the upper limit of normal) compared 3 doses (10,
20, and 30 mg/d) of risedronate. Study medication was taken with 118.28 mL
(4 oz) of water 2 hours before or after any meal. Primary efficacy was percentage
change of serum alkaline phosphatase level. Patients were advised to use calcium
carbonate supplements as necessary to maintain daily calcium intake of at
least 700 mg. There was a dose-response relation, such that after 28 days
of treatment, the 30-mg dose benefited most patients. Time to response was
also shorter with the 30-mg dose. Histological analysis found that the bone
formed during therapy was normal, without characteristics of Paget disease
and without osteomalacia. Parathyroid levels declined during therapy. Although
all 3 doses were effective, safe, and tolerable, the researchers found the
30-mg/d single dose to be the most effective.17
The study had the advantage of comparing multiple doses, ie, establishing
a dose-response relation, and of including histologic bone assessment.
In the only comparative study,12 123
patients, aged 18 to 85 years, with Paget disease of bone (serum alkaline
phosphatase level 2 times the upper limit of normal) were randomized in
double-blind fashion to risedronate, 30 mg/d, for 2 months or etidronate,
400 mg/d, for 6 months. The main outcome of interest was response of alkaline
phosphatase level. A higher percentage of patients taking risedronate (73%)
than etidronate (15%) manifested normalization of the alkaline phosphatase
level. Risedronate caused a more rapid normalization of the alkaline phosphatase
level. Relapse rates, defined as an increase of 50%
or greater above the lowest serum alkaline phosphatase level, were lower in
the risedronate vs the etidronate group. At month 6, a higher percentage of
patients taking risedronate (77%) vs etidronate (11%) had normalization of
serum alkaline phosphatase. Pain reduction was significant in the risedronate,
but not the etidronate, group. Overall, although etidronate was effective,
risedronate had the advantages of shorter duration of therapy, higher rates
of (and longer-lasting) remission, and significant pain reduction, even in
patients who had not responded adequately to etidronate in the past.12 The adverse effect profiles of the 2 drugs were similar.
The study was unique in establishing the efficacy of risedronate in direct
comparison with a well-established treatment.
Therefore, all the available data suggest efficacy of cyclical risedronate,
30 mg/d, in relieving various signs and symptoms of Paget disease of bone,
and hint at a possible advantage over etidronate in this setting.
PATIENTS WITH BREAST CANCER
Fifty-three white women, aged 36 to 55 years, with breast cancer and
artificial (induced) menopause were randomized to receive risedronate or placebo.21 Patients taking tamoxifen citrate were stratified
into both groups. Risedronate and placebo were taken in cyclic fashion. Risedronate
dosing was 30 mg/d for 2 weeks, followed by 10 weeks without the drug, for
2 years. The study medication was taken with water 2 hours before lunch. Patients
were told to avoid dairy products, vitamins, or antacids containing calcium,
iron, magnesium, or aluminum within 2 hours of dosing. They were not to lie
down for at least 1 hour following ingestion. Further observation followed
for 1 year. Primary efficacy was lumbar and hip BMD measurements.
While the placebo group experienced a decrease in lumbar and hip BMD
values, BMD increased in the risedronate group. Moreover, accrued BMD was
lost on withdrawal of treatment. At 2 years, there was a 2.5% and 2.6% difference
between groups at the lumbar and femoral neck sites, respectively.21 Results were similar at the trochanter. Tamoxifen
itself partly reduced bone loss in the analysis by stratum. Risedronate was
well tolerated, without laboratory abnormalities. Thus, risedronate prevented
loss of trabecular and cortical bone in this study21
of patients with breast cancer who experience menopause due to chemotherapy.
PATIENTS TAKING CORTICOSTEROIDS
One study22 has examined risedronate
use in patients taking concurrent corticosteroids, and it is 1 of the 3 studies11, 13, 22 on risedronate that
have reported fracture outcome.
A 12-month randomized double-blind study22
noted the ability of risedronate to prevent corticosteroid-induced bone loss.
Men (n = 87) and women (n = 151 [premenopausal] and n = 105 [postmenopausal]),
aged 18 to 55 years, who were initiating long-term corticosteroid treatment
were randomized to risedronate, 2.5 or 5 mg, or placebo daily for 12 months.
Subjects had various rheumatologic, pulmonary, and dermatological indications
for corticosteroids. They were considered for the study if they were expected
to require prednisone, 7.5 mg/d or more, or equivalent for another 12 months.
Medication was to be taken on an empty stomach, 30 to 60 minutes before breakfast,
with 236.56 mL (8 oz) of water, and without lying down for 1 hour afterward.
All received elemental calcium, 500 mg/d. Cholecalciferol supplements were
recommended to subjects who had low serum 25-hydroxyvitamin D3
levels. Primary outcome was lumbar BMD, and secondary outcomes were proximal
femur BMD and vertebral fracture incidence. When the 2.5-mg dose was found
to be inadequate in other ongoing research,13
the 2.5-mg arm was discontinued.
After 12 months, lumbar BMD did not change from baseline in either risedronate
group, whereas it decreased in the placebo group.22
The BMD values of the 5-mg and placebo groups differed by 3.8% at the lumbar,
4.1% at the femoral neck, and 4.6% at the femoral trochanter sites. There
was a trend in reduction of vertebral fracture in the 5-mg risedronate group
vs the placebo group. The incidence of gastrointestinal tract adverse events
was similar between the groups, and risedronate was well tolerated.22 Risedronate therapy thus prevented bone loss in one
study of patients beginning long-term corticosteroid therapy. Unfortunately,
vertebral and nonvertebral fractures were not primary outcomes.
PHARMACOKINETIC CHARACTERISTICS
Intestinal absorption of all bisphosphonates is low, ie, 0.5% to 3%.
The bioavailability of risedronate in healthy volunteers is 0.63%.28 Dosing half an hour before breakfast or 2 hours after
dinner, as opposed to in the fasting state, decreases the extent of absorption
by 55%.28 In contrast, the extent of absorption
is only reduced by 30% if dosing is 1 hour before breakfast.28
Risedronate absorption was comparable in 127 healthy volunteers who
took the medication 2 hours after a standardized dinner and half an hour before
breakfast; however, absorption was significantly (1.4- to 2.3-fold) greater
when risedronate was given 1 or 4 hours before a meal.23
Also, the measured rate of absorption was greater with administration 0.5,
1, or 4 hours before a meal, compared with 2 hours after dinner. The researchers
believed that the comparable extent of absorption at 0.5 to 1 hour before
breakfast and 2 hours after dinner may give risedronate an advantage of dosing
flexibility.23 Consequently, risedronate is
recommended to be taken at least 30 minutes before the first food or drink
(other than water) of the day, without lying down for 30 minutes afterward,
and with a full glass of plain water in an effort to avoid upper gastrointestinal
tract adverse effects.28
Avoidance of concomitant ingestion of risedronate with calcium, antacids,
or other oral medication that contains divalent cations is prudent, due to
these agents' ability to interfere with absorption of risedronate.28 Studies regarding drug-drug interactions involving
risedronate are lacking.
In healthy men, the rate and extent of risedronate absorption are independent
of site of administration along the gastrointestinal tract (ie, stomach, second
part of the duodenum, or terminal ileum), and the extent of absorption is
not affected by the rate of administration.24
A study25 randomized 3 groups of healthy
male (n = 61) and female (n = 6) volunteers to a single oral dose of 2.5,
5, or 30 mg of risedronate in double-blind fashion. Urinary excretion was
found to be dose proportional, as were other pharmacokinetic variables (mean
maximum concentration of drug and area under the curve).
Risedronate is excreted unchanged by the kidneys.28
Dose adjustment in the setting of mild to moderate renal dysfunction is believed
to be unnecessary.8, 28 Safety
in the setting of hepatic impairment is unknown.
As with other bisphosphonates, after risedronate is administered, most
of the dose remains in the skeleton and is later released in the course of
skeletal remodeling. Thus, the bone turnover rate determines the amount of
drug released from the skeleton.7 Because of
the short circulating half-life, exposure of tissues other than bone to risedronate
is minimal. In clinical doses, the bisphosphonates concentrate to significant
degrees only at bone, especially inside osteoclasts during active bone resorption.
Bisphosphonates decrease osteoclast activity when they enter osteoclasts during
bone resorption.
SAFETY CONSIDERATIONS
In single-dose studies of healthy volunteers, some minor adverse effects
were reported. Adverse events were comparable between the 4 different dosage
groups (30 mg of risedronate given in different conditions of food intake)
in the study by Mitchell et al,23 with headache,
nausea, dizziness, diarrhea, and myalgia being the most common reported adverse
events. A small single-dose study24 of risedronate
in healthy men reported headaches and body aches possibly related to risedronate.
Single risedronate doses (2.5, 5, and 30 mg) in another study25
were not associated with serious adverse events. Adverse events were reported
by 64%, 82%, and 91% of the patients receiving 2.5, 5, and 30 mg, respectively.
The most frequent adverse events were headache and abdominal pain. There were
no serious adverse effects. All but one (diarrhea in one subject who took
the 30-mg dose) of the adverse events were of mild or moderate severity. One
study26 did not discuss adverse effects.
As previously mentioned, there is no suggestion of an adverse effect
of risedronate on bone quality in patients with Paget disease, postmenopausal
women, or corticosteroid users. Also, there is no evidence of a deleterious
effect on osteolytic lesions in weight-bearing bones, but rather improvement.16
The Paget disease studies had a low incidence of adverse effects. In
the study by Brown et al,17 2 patients taking
risedronate had gastrointestinal tract adverse effects that did not cause
them to drop out. No adverse events were related to the study drug, and there
were no withdrawals due to adverse events, in the trial of Hosking et al.20
The comparative study of etidronate (6 months) with risedronate (2 months)
in subjects with Paget disease of bone found the adverse effects of the 2
drugs to be similar.12 Adverse events possibly
related to the study drug occurred in 47% of each group. Twenty percent of
each group experienced upper gastrointestinal tract adverse events. There
were no cases of esophagitis. Eight percent of the etidronate and 6% of the
risedronate group withdrew because of adverse events.12
Small studies19 of patients with Paget disease
found risedronate to be well tolerated. Only one patient stopped treatment.
The patient's diarrhea was believed to be treatment related. Brown et al15 reported mild epigastric discomfort in 3 of 59 patients
with Paget disease, but there were no withdrawals for gastrointestinal tract
intolerance. Siris et al18 found no adverse
events related to risedronate.
Patients with breast cancer and corticosteroid users tolerate risedronate
well. The patients with breast cancer, studied by Delmas et al,21
who were assigned risedronate had a similar adverse event profile to those
taking placebo. Most adverse events were mild, and there were no severe gastrointestinal
tract adverse events. Of 27 patients assigned to risedronate, 4 had mild and
1 had moderate abdominal pain.21 The incidence
of upper gastrointestinal tract events was comparable with risedronate, 2.5
vs 5 mg, vs placebo in the report of Cohen et al22
of long-term corticosteroid users.
Postmenopausal women have similar overall safety profiles with risedronate
and placebo, even considering gastrointestinal tract safety.11
The study by Mortensen et al,14 which included
healthy early postmenopausal women and which is notable because it did not
exclude patients with a history of upper gastrointestinal tract disease, found
that risedronate was well tolerated. There was no difference in incidence
of adverse effects between risedronate and placebo. Reports of arthralgia
were low and similar in the placebo and risedronate groups. There was no increased
incidence of abdominal pain or dyspepsia in the risedronate vs placebo group.
Clemmesen et al13 found that the distribution
of adverse events was similar across treatment groups, and reported that none
of the serious adverse events appeared to be causally related to risedronate.
In summary, the safety data from all of the 6 randomized controlled
trials in settings of postmenopausal osteoporosis, breast cancer, corticosteroid
use, and Paget disease suggest that the adverse effect profile of risedronate
is similar to that of placebo, and does not include any particularly notable
upper gastrointestinal tract adverse event rate. In addition, the fact that
studies did not exclude patients with a history of such events is optimal
for assessment of potential advantages over alendronate and other bisphosphonates.
FUTURE QUESTIONS
The details of how risedronate and other bisphosphonates exert their
antiresorptive activities remain unclear, although relevant work is in progress.29 Additional research is needed along these lines.
Clinical studies are also needed comparing the bisphosphonates with
each other in patients with osteoporosis. Other clinical issues to be resolved
are optimal duration of therapy, schedule (cyclic vs continuous), optimal
timing of initiation, and use in combination regimens. Perhaps risedronate
could be used with other antiresorptive agents, such as estrogen, in an effort
to increase bone preservation. For example, recent work30
suggests that other bisphosphonates can be safely combined with estrogen replacement
for added BMD benefit in patients with postmenopausal osteoporosis. Mevastatin,
a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, is an even more
potent inhibitor of bone resorption in vivo than are bisphosphonates.4 The role of mevastatin in osteoporosis, including
whether it can or should be combined with bisphosphonates, remains to be elucidated.
Aside from attempting combination with other antiresorptive agents,
which solely stop the loss of bone and do not directly increase bone density,
it would be optimal to discover a bone formation inducer that could be used
in combination with risedronate.31 Such candidates
for further study include fluoride, bone growth factors, growth hormone, and
parathyroid hormone.31 For example, addition
of risedronate to another anabolic hormone, intermittent human parathyroid
hormone I34, in aged beagle dogs may help protect the cortical
and endocortical envelope.32 Similar research33 in rats found that addition of risedronate prevented
the fast and pronounced endosteal bone resorption and the decrease in mechanical
strength that was induced by withdrawal of human parathyroid hormone I34.
Prostaglandin E2 (PGE2) has marked anabolic bone
effects that are lost on cessation of administration. Female rats treated
with risedronate are able to maintain PGE2-induced new bone that
would have been otherwise lost with discontinuation of PGE2.34 Work35 in rats that
underwent ovariectomy has found that risedronate may prevent trabecular bone
loss that characterizes the off period of PGE2, thus precluding
the need for continuous PGE2 administration.
Risedronate's role in malignant neoplasms is also under investigation.
Pretreatment of breast and prostatic carcinoma cells with an analogue of risedronate,
NE-10244, has been found to inhibit tumor cell adhesion to mineralized and
unmineralized extracellular matrices in a dose-dependent manner.36
In mice, risedronate appears to have the ability to selectively decrease breast
cancer burden in bone, suppress progression of established osteolytic lesions,
and prevent development of new osteolytic lesions, thereby increasing survival.37 The question of how these data will influence breast
cancer in humans is an exciting line of inquiry.
Because of the poor absorption of bisphosphonates, the optimal method
of delivery is the subject of ongoing research. A comparison of the esophageal
transit of the film-coated tablet vs the original gelatin capsule of risedronate
in 25 elderly healthy volunteers (12 men and 13 women; mean age, 66 years)
suggested that esophageal transit of film-coated tablets is faster than that
of gelatin capsules.26
Although there is plenty of evidence of antifracture efficacy of alendronate,
fracture outcome data are needed for risedronate. Additional insights into
the safety of risedronate use in the setting of hepatic impairment or other
organ system disease are needed, as is information on long-term safety and
efficacy.
CONCLUSIONS
In postmenopausal women with normal bone density, risedronate, 5 mg/d,
increases lumbar spine bone density and preserves femoral neck density. In
postmenopausal women with prior vertebral fracture, it decreases new vertebral
and nonvertebral fracture incidence. In a study21
of patients who experienced breast cancer and who have chemotherapy-induced
menopause, risedronate, with or without tamoxifen, preserved trabecular and
cortical bone. Risedronate prevented corticosteroid-induced vertebral bone
loss in a study22 of men and women beginning
long-term corticosteroid therapy.
Clinical studies12, 15, 16, 17, 18, 19, 20
show that cyclical risedronate, 30 mg/d, for 28 to 84 days safely decreases
pagetic bone pain and induces normalization of the alkaline phosphatase level
in most subjects with Paget disease, in addition to inducing radiological
improvement in pagetic lesions, without causing deleterious bone effects.
It may turn out to be more effective than etidronate because of a shorter
required duration of therapy, higher rates of and longer-lasting remission,
and significant pain reduction in patients who have not adequately responded
to etidronate in the past.
The safety data from all of the randomized controlled trials in settings
of postmenopausal osteoporosis, breast cancer, corticosteroid use, and Paget
disease suggest that the adverse effect profile of risedronate is similar
to that of placebo. Risedronate, one of the most potent known bisphosphonates,
does not appear to interfere with bone mineralization in doses used clinically
for osteoporosis or Paget disease and is thus unlikely to increase long-term
fracture risk. However, long-term toxic effects and efficacy data, particularly
fracture end point data, are lacking at this time. Also unknown are the optimal
duration of therapy, the potential for use in combination with other agents,
and whether risedronate may hold any clinical advantage over alendronate.
Since the submission of the manuscript, 5 randomized controlled trials38, 39, 40, 41, 42
pertinent to risedronate in osteoporosis have been published. Two of the trials41, 42 show that regardless of the number
of years since menopause, risedronate, 5 mg/d given for 2 to 3 years, increased
spine and hip bone density and decreased the risk of new vertebral fractures
by 50%42 in postmenopausal women with low bone
density at baseline. Two other trials38, 40
reported that risedronate, 5 mg/d for 12 months, increased lumbar and hip
density in men and women chronically taking prednisone long-term (7.5
mg/d or the equivalent) and decreased vertebral fracture risk by 70%.38 Risedronate at a lower 2.5-mg/d dose or at 15 mg/d
for 2 of each 12 weeks preserved lumbar and hip bone mass in postmenopausal
women taking 2.5 mg or more of prednisolone daily for rheumatoid arthritis.39 All trials determined gastrointestinal adverse events
of risedronate to be similar to those of placebo.
AUTHOR INFORMATION
Accepted for publication September 14, 2000.
From the Department of Medicine, University of California, Los Angeles,
UCLA School of Medicine.
Corresponding author and reprints: Carolyn Crandall, MD, Department
of Medicine, University of California, Los Angeles, UCLA School of Medicine,
UCLA National Center of Excellence in Women's Health (US Department of Health
and Human Services), Iris Cantor–UCLA Women's Health Center, 100 UCLA
Medical Plaza, Suite 250, Los Angeles, CA 90095-7023 (e-mail: ccrandall{at}mednet.ucla.edu).
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