Download Algorithm for Osteoporosis Treatment

CLINICAL
THERAF’EUTICS’WOL.
21, NO. 6, 1999
Diagnosis and Management of Osteoporosis
in Postmenopausal Women: Clinical Guidelines
Pierre J. Meunier, MD,I Pierre D. Delmas, MD,’ Richard Eastell, MD,2
Michael R. McClung, MD,3 Socrates Papapoulos, MD,4
Rene Rizzoli, MD,5 Ego Seeman, MD,6 and Richard D. Was&h, MD,7
the International Committee for Osteoporosis Clinical Guidelines
‘H6pital Edouard Herriot, Lyon, France, 2Northem General Hospital, Shefield,
United Kingdom, 30regon Osteoporosis Centel; Portland, 4Vniversity Hospital, Leiden,
the Netherlands, 5University Hospital, Geneva, Switzerland, 6Austin Medical Centel;
University of Melbourne, Australia, and 7Hawaii Osteoporosis Centel; Honolulu
ABSTRACT
The authors, all physicians involved in
clinical research on bone and practicing
clinicians, propose practical guidelines for
identifying persons with osteoporosis or
those at high risk of developing the disease and for managing patients who may
benefit from therapy. These guidelines are
based on an analysis of peer-reviewed articles published before November 1998. A
flowchart of women who might benefit
from treatment is provided, including clinical presentation (recent fracture of the
spine, hip, or other bone or no fracture;
risk factors for osteoporosis); relevant investigations (bone mineral density measurement and laboratory tests required for
the differential diagnosis); and therapeutic
Accepted
for publication
Printed in the USA.
Reproduction
in whole
0149-2918/99/$19.00
May
3, 1999.
or part is not permitted
management (general measures such as
calcium and vitamin D supplementation
and specific pharmacologic interventions
such as estrogen, bisphosphonates, intranasal calcitonin, raloxifene, fluoride
salts, and other compounds that have been
assessedin randomized clinical trials). The
strongest evidence for antifracture efficacy
(reduction of vertebral and nonvertebral
fracture risk) was observed with alendronate. Key words: osteoporosis, bone mineral density, fracture, postmenopausal.
INTRODUCTION
As physicians involved in clinical research on bone and practicing clinicians
who routinely see patients with osteoporosis, we are often asked by colleagues
for practical guidance on how to identify
women with osteoporosis or at high risk
of developing the disease, as well as how
to manage patients who may benefit from
1025
CLINICAL
therapy. The present guidelines provide
an up-to-date summary based on an analysis of peer-reviewed articles as of November 1998. Research on osteoporosis is
ongoing, and future developments will no
doubt be incorporated into subsequent
versions of these guidelines.
The Clinical Challenge: Frequency
and Consequences of Osteoporotic
Fractures
Osteoporosis is a systemic skeletal diseasecharacterized by low bone mineral density (BMD) and microarchitectural deterioration of bone tissue, leading to bone
fragility and increased fracture risk.’ It is especially prevalent in older postmenopausal
women.*3 If untreated, more than half of
white women will experience al osteoporotic fracture during their lifetime.ti The
burden of pain, physical disability, and reduced quality of life among these women
represents a major public health problem.5-7
For white women, the cumulative lifetime risk for fractures includes a 16% risk
of nl painful vertebral fracture, 15% risk
of Colles’ (wrist) fracture, and 16% risk
of hip fracture.s9 When all fractures are
considered, the lifetime risk of experiencing ~1 fracture is >50%.& Many women
who have 1 osteoporotic fracture will experience further fractures, partly because
prior fracture is itself an important independent risk factor for future fracture.i@i4
Furthermore, women with very low BMD
have much higher risks than the average,
and many of them will experience fractures if untreated.
Although all fractures are debilitating
to some degree, hip fracture is the most
serious consequence of osteoporosis.
Women with hip fracture are 2 to 4 times
more likely to die within 12 months of the
1026
THERAPEUTICS”
event as are women of the same age without hip fracture in the general population,15 but the extent to which these deaths
are related to comorbid conditions rather
than hip fracture remains controversial.1c18 In women surviving 12 months
after suffering a hip fracture, severe functional declines are observed.19-22 In one
prospective study of women with hip fractures, a respective 50%, 70%, and 87%
did not recover the ability to walk independently, transfer from one place to another independently, and climb stairs independently. I9 Other studies based on
recall reported that depending on the activity, between 20% and 60% of women
with hip fracture failed to recover baseline function within 6 to 12 months after
the event.19-** A Scandinavian study23 reported that 31% of surviving hip-fracture
patients were bedridden 6 years later,
compared with 1.5% of the control group,
and that only 9% of the fracture cases
could walk outdoors by themselves, compared with 55% of the control group.
In one report, hip fractures were responsible for more hospital bed days
among women after age 45 than were myocardial infarction, breast cancer, chronic
obstructive pulmonary disease, or diabetes.24 Moreover, hip fractures represent
only a small part (~10%) of the fractures
and use of outpatient services related to osteoporosis, with as few as 16% of fracturerelated hospitalizations among the elderly
associated with hip fractures.25J6
Vertebral fracture is the most common
osteoporotic fracture and occurs earlier in
life than hip fracture. Like hip fracture,
vertebral fracture is associated with considerable morbidity.727 The acute pain can
range from mild to intolerable, and chronic
pain can persist for years. Among women
with symptomatic vertebral fracture and
P.J. MEUNIER
ET AL.
chronic pain, 60% to 87% reported problems with carrying, lifting, walking, doing
housework, and shoppingF8 Although less
common, difficulties traveling, dancing,
and athletic activities were rated as important. Approximately two thirds of all
vertebral fractures are not recognized clinically, but both diagnosed and undiagnosed
vertebral fractures are associated with pain
and impaired physical function.29,30 Declines in physical function and changes in
appearance (kyphosis and height loss) contribute to social isolation and loss of selfesteem, impairing quality of life.27J1J2
The incidence of wrist fracture increases rapidly around menopause.33 Thus
wrist fracture represents the earliest effect
of osteoporosis in some patients and, like
other low-trauma fractures, indicates an
increased risk of future fracture.9 Most
studies have estimated that 8% to 10% of
patients experiencing wrist fracture are
hospitalized, but one study found that the
percentage increased to 76% after age
85 .34J5Another sometimes severe consequence of wrist fracture is algodystrophy
(reflex sympathetic dystrophy); ~10% of
patients were affected in most surveys,
but the number has been reported to be as
high as 30%.s5
Thus both spinal and nonspinal osteoporotic fractures contribute to declines in
physical function and quality of life, and
the severity of these declines increases
with the number of fractures. Women who
have had spinal or nonspinal fractures
are 2 to 6 times more likely to report
difficulties performing activities of daily
living than are those without fractures.23J9,36*37Furthermore, decreases in
physical function often lead to an increased risk of falls and fractures and to
the fear of falling, which further restrict
activities and independence. The need for
chronic care in the home or nursing home,
medications, and rehabilitation and the
lost productivity of those caring for these
elderly patients at home further add to
the very substantial burden imposed by
osteoporosis. These burdens will increase
dramatically in the coming decades because of the growing population of elderly persons.38
BMD peaks during the third decade,
declines rapidly around menopause, and
continues to decrease thereafter.39-41 As a
result, in the absence of treatment, postmenopausal women commonly develop
osteoporosis and fractures in later life
(Figure 1). On average, women lose between one third and one half of their peak
BMD in the course of their lifetime.39A2
This severely compromises bone strength
at later ages, when fracture can result from
minimal trauma. A World Health Organization (WHO) study group has defined
osteoporosis as a BMD ~2.5 standard deviations below the young adult mean.43
Patients with a BMD between 1 and 2.5
standard deviations below the young adult
mean are classified as having low bone
mass, or osteopenia. The number of standard deviations above or below the mean
for young women is referred to as the Tscore (Figure 1). By WHO definition,
-95% of young women have BMD values
between -2.0 and 2.0; many untreated
older women have lower values.2J9*42
Extensive epidemiologic data demonstrate that fracture risk increases progressively as bone density decreases (Figures
2 and 3). Because of the continuous relationship between BMD and fracture risk,
there is a much greater range of fracture
risk than is implied by the use of 3 categories (ie, normal, low bone mass, and
osteoporosis) based on T-score.10,44,45
Within the category of osteoporosis, for
1027
CLINICAL THERAPEUTICS”
l
Mean value at each age
1 SD either side of mean
2 SDS either side of mean
n T-Score
0.8
0.6
0.5
0.4
30
40
50
60
Age
70
80
90
(v)
Figure 1. Pattern of decline in bone mineral density (BMD) with age in untreated women,
by World Health Organization category!3 Data from NHANES III.s9
example, a woman with a T-score of A.0
has a greater risk of fracture than one with
a T-score of -2.5. Other risk factors such
as age, preexisting fracture, thinness, and
high bone turnover may contribute to increased risk independent of low BMD and
should be considered when making decisions about treatment.*e13,46
The Aim of Therapy
Effective therapies for treatment and
prevention of osteoporosis with good
safety profiles are now available. The aim
of such therapy is to reduce osteoporosisrelated morbidity and mortality by safely
reducing the risk of fracture. Consequently, an important clinical goal is to
identify patients with osteoporosis or at
high risk of developing the disease. Al1028
though fractures tend to occur relatively
late in life, they result from the bone loss
and microarchitectural deterioration that
occur from menopause onward. The purpose of therapy is to maintain or increase
bone strength to prevent fractures
throughout the patient’s lifetime.
Figure 4 illustrates our approach to
identifying
candidates for treatment,
which is similar to that in osteoporosis
guidelines published by other authors.24v47
The National Osteoporosis Foundation
guidelines47 are somewhat more liberal
than ours, basing therapeutic decisions on
a T-score cutoff of -2.0. Our guidelines
also differ from others in making a distinction between prevention and treatment. Our rationale is that certain therapies are approved only for treatment in
some countries and for both prevention
P.J. MEUNIER
ET AL.
3025-
Low
Bone
Mass
Normal
20-
BMD T-Score
Figure 2. The relationship between bone mineral density (BMD) and fracture risk, based
on a doubling of risk with each SD decrease in BMD. A T-score of 0 represents
the mean BMD for young healthy women and is assigned a relative risk of 1.O
as the reference value. T-scores between -1.0 and -2.5 indicate low bone mass,
and values below -2.5 indicate osteoporosis.43
S-2.5 T-score
Osteoporosis
Fx=116
N = 3591
~-2.5 and
c-l T-score
Low Bone
Mass
Fx = 36
N = 3404
z-1 T-score
Normal
Fx = 2
N=603
Figure 3. Incidence of hip fracture per 1000 woman-years in 3 categories of femoral-neck
BMD, using World Health Organization definitions of osteoporosis and osteopenia.43 Incidence increases in proportion to that of the 3 corresponding categories in Figure 2. Fx = number of women with hip fracture; N = number of
women. (Reprinted with permission from the EPIDOS study, Schott et aLa)
and treatment in others. The aim of treatment is to provide a maximum benefit in
terms of increased BMD and decreased
fracture risk in women who are already at
high risk, whereas the goal of prevention
is to maintain BMD and thereby avoid an
increase in fracture risk.
CLINICAL
PRESENTATION
Postmenopausal women who require management of osteoporosis may present with
21 of the following: (1) evidence of a vertebral fracture; (2) after a hip fracture; (3) after
another type of fracture (eg, wrist fracture);
1029
-
No
A--
I-’
)
i
I ’
I
l
None of the above
Low-trauma fracture’ since age 45
Maternal history of hip fracture
Age 265 years
Early menopause
Prolonged amenorrhea
Thin body build
Chronic corticosteroid
use
(~6 months)
Diseases predisposing
to
osteoporosis
3isk factors for osteoporosis
about osteoporosis
Kyphosis
Acute back pain
l Loss
of ~3 cm in height
Confirm fracture on spine
roentgenogram
Vertebral fracture
Concern
l
Clinical Presentation
t
t
I
I
BMD
BMD T-score
Measure
Differential diagnosis
investigations
and
Investigation
I
I
c
-)
+
or HRT
If age ~65 and one or
more risk factor for
fracture,* use alendronate
or raloxifene
Use HRT if accepted
Cyclical etidronate or
intranasal calcitonin
General measures,
including fall prevention
and adequate nutrition
Alternatives
Alendronate
Treatment
First line+
Management
Figure 4. Clinical flowchart of the presentation, investigation, and management of postmenopausal osteoporosis. BMD = bone
mineral density; HRT = hormone replacement therapy. *Indicates a fracture resulting from a fall from standing height
or lesser trauma and excludes fractures of the skull, facial bones, and digits. tBenefits may be limited if life expectancy
is short (particularly if age is >80 years), unless additional risk factors are present or BMD is c-3.5. ‘For example, thin
body build, high markers for bone turnover, BMD between -2 and -2.5, and maternal hip fracture.
-
Recent
fracture?
Yes
I
E
$
8
3
EB
P.J. MEUNIER
ET AL.
(4) risk factors for osteoporosis; and (5) concern about the possibility of osteoporosis.
Most patients with osteoporosis are
asymptomatic. Many patients who have experienced sl fracture will have continuing
pain, impaired mobility, and fear of further
fractures that may reduce their quality of
life. Moreover, such patients have often lost
30% to 50% of their peak bone mass. Although effective therapy can substantially
reduce the risk of further fractures, the risk
remains appreciable. It is preferable to intervene early in the process of bone loss and
thus reduce the risk of the first fracture. This
is now achievable, because even in the absence of previous fracture, the diagnosis of
osteoporosis or high risk for developing osteoporosis can be made by measuring BMD.
Patient management varies somewhat
according to the mode of presentation.
Wrist fracture is common. It tends to
occur at a somewhat younger age than
vertebral or hip fracture and hence often
represents the first clinical expression of
osteoporosis.48 Wrist fracture justifies
BMD measurement to confirm the presence of osteoporotic disease.
Other types of fracture, as of the
humerus, rib, or pelvis, are also common
in patients with osteoporosis and require
further assessment.
Vertebral Fracture
Risk Factors for Osteoporosis
Physicians should be alert for features
suggesting vertebral fracture in women
aged 265 years, such as kyphosis, height
loss, and acute or chronic back pain. Many
vertebral fractures are not associated with
acute symptoms. Because some degree of
kyphosis and height loss may occur in the
absence of osteoporosis, it is important to
confirm the presence of a vertebral fracture on lateral spine roentgenograms.
Figure 4 delineates the major risk factors for osteoporosis. White and Asian
women are at greater risk for osteoporosis
and associated fractures than black women.
Other risk factors, such as smoking and
lack of exercise, also contribute to the development of osteoporosis, but they are not
strong risk factors.4920 In general, the more
risk factors a woman has, the higher the
likelihood that she has or will develop osteoporosis. However, some risk factors,
such as chronic use of high-dose corticosteroids, are sufficiently strong that even in
isolation they signal the need for further
evaluation, including BMD testing.5’
Hip Fracture
With the exception of hip fractures
caused by severe trauma, most hip fractures
occur after a fall and are due to osteoporosis. In addition to having often-severe osteoporosis, patients who have suffered a
hip fracture are generally frail and prone to
falling, which places them at risk for further fractures. Therefore, patients who have
experienced hip fracture should be managed actively, with the possible exception
of those with a short life expectancy. Contributing causes, such as vitamin D de&
ciency, protein malnutrition, and other illnesses, are common in this population.
Other Types of Fracture
Concern About Osteoporosis
Many women present without specific
risk factors for osteoporosis but are concerned that they may have osteoporosis or
1031
CLINICAL
be at risk for developing it. The absence of
risk factors does not mean that a woman’s
BMD is normal or that a fracture will not
occur. Therefore, if available, BMD testing should be offered to these patients.
DIFFERENTIAL
INVESTIGATION
Dl~erentiul
DIAGNOSIS
AND
Diagnosis
Malignancies with skeletal metastases
and multiple myeloma may cause vertebral fracture or, less commonly, fracture at
other sites. The diagnosis is usually suggested by the severity of the pain or the
general physical findings and is confirmed
by laboratory tests, roentgenograms, or
bone scintigraphy. In some cases, the diagnosis may be more difficult to confirm,
necessitating a computed tomography
scan, magnetic resonance imaging, or histologic examination of a bone specimen.
Osteomalacia can mimic osteoporosis
and induce biconcavity of several vertebrae. The defect of mineralization of bone
matrix is usually a result of impaired intake, production, or metabolism of vitamin D, although less commonly it may be
due to intestinal malabsorption or impaired phosphate transport. The diagnosis
is usually suggested by the clinical history and by abnormalities on biologic
tests, as by low serum and urinary calcium, high serum alkaline phosphatase,
and low serum 25hydroxyvitamin
D in
the case of vitamin D deficiency. If the diagnosis is uncertain, a transiliac bone
biopsy may be necessary.
Other spinal disorders can produce vertebral deformities that may mimic vertebral fracture on roentgenograms, including
osteoarthrosis, severe scoliosis, and longterm sequelae of Scheuermann’s disease.
1032
THERAPEUTICS”
Investigation
The clinical history, physical examination, and laboratory tests are directed at
excluding a disease that resembles osteoporosis, identifying contributory factors
that may require specific interventions,
and assessing the severity of confirmed
osteoporosis (ie, the magnitude of fracture risk). The following diagnostic procedures fulfill these requirements.
Routine Procedures
The physical examination should include
measurement of height (using a stadiometer, if possible) to detect height loss. In addition to the history and physical examination, the following laboratory measurements
are obtained routinely: a complete blood
cell count; erythrocyte sedimentation rate;
and levels of serum calcium, phosphate, alkaline phosphatase, creatinine, and albumin.
Lateral roentgenograms of the lumbar and
thoracic spine are obtained to document or
exclude the presence of vertebral fracture
(particularly in patients aged %5 years with
kyphosis or height loss) and to exclude other
skeletal pathology (eg, metastatic bone disease). BMD measurements include dualenergy x-ray absorptiometry (DXA) of the
spine and hip; single energy x-ray absorptiometry or DXA of the forearm or heel if
spine/hip DXA is not available; and heel ultrasound or another validated technique if
none of the above are available. Analysis of
serum or urine markers of bone turnover are
not required but are helpful in assessingthe
rate of bone turnover and in monitoring the
response to treatment with inhibitors of bone
tumover.4652
The availability of the technology for
measuring BMD is improving, although
access remains limited in some practice
settings. Where available, BMD measure-
P.J.MEUNIER ET AL.
ment should be performed in patients with
recent fracture, as well as in those with risk
factors for osteoporosis. Risk factors include prolonged amenorrhea during the reproductive years, early menopause (before
age 49, current age of 265 years, thin
build, maternal history of hip fracture, use
of corticosteroids (including inhaled forms,
particularly if equivalent to 27.5 mg/d
prednisone) for 26 months, any fracture after age 45 (particularly of the hip, vertebra,
wrist/forearm, humerus, rib, or pelvis), or
the presence of any disease or condition
known to predispose to osteoporosis (eg,
malabsorption, hyperparathyroidism, hyperthyroidism, chronic inflammatory diseases, alcoholism, and prolonged immobilization in bed or wheelchair).
DXA of the spine is useful in women
aged <65 years, but in older women osteoarthritis of the lumbar spine often results in
overestimation of lumbar spine BMD. The
hip is generally a preferred site for BMD
measurement, because the BMD of the hip
is the best predictor of hip fracture. However, for assessing the risk of fracture in
general, measurement of more peripheral
sites, such as the heel or distal radius, are
as useful as measurement of the spine or
hip. Average T-scores for specific age
groups may differ by measurement site and
technique used, but there is some evidence
suggesting that these differences may not
impair the ability to diagnose osteoporosis
and low bone mass.53 Thus BMD measurement at any site is of value in making
the diagnosis of osteoporosis.
Additional Laboratory Investigations
The clinical circumstances should guide
the use of the additional investigations
listed in Table I to exclude or confirm specific diagnoses of disorders having effects
on bone.
Zdentifcation of Contributory Factors
and Assessment of Prognosis
It is necessary to identify the presence
of various factors and disorders that are
associated with an increased risk for osteoporosis, since they may require specific interventions. These include inactivity, smoking, excessive alcohol intake,
medical disorders (eg, primary hyperparathyroidism, thyrotoxicosis, gastrointestinal malabsorption, rheumatoid arthritis, chronic obstructive lung disease), and
use of particular drugs (especially chronic
corticosteroid therapy, but also use of anticonvulsant agents, drugs that induce hypogonadism, and excessively high levels
of thyroid hormone replacement therapy).
Assessment of the prognosis of osteoporosis may be valuable for making treatment decisions. The severity of osteoporosis (ie, the magnitude of the risk for
subsequent vertebral and peripheral fractures) is established mainly by (1) the
BMD (ie, the lower the BMD, the higher
the risk of fracture-fracture
risk approximately doubles with each l-SD decrease
in BMD); (2) a history of previous fractures (number of vertebral fractures, history of appendicular fractures) or a maternal history of hip fracture’2g13; (3) an
increased rate of bone turnover, as assessed
by biochemical markers (increased bone
turnover is an independent risk factor for
vertebral and hip fracture52v54);and (4) the
presence of risk factors not captured by
BMD measurement, including frailty, advanced age, and increased risk of falling.13
For simplicity, the current definition of
osteoporosis focuses exclusively on current BMD. Thus a patient whose current
T-score falls below -2.5 is considered to
have osteoporosis. One whose T-score is
between -1 and -2.5 has “low bone mass.”
1033
CLINICAL
THERAPEUTICS”
Table I. Additional laboratory investigations for osteoporosis.
Clinical Indication
Test
Serum and urine markers of bone turnover
Assess bone turnover
Monitor antiresorptive therapy
Serum PIH
Hypercalcemia
25hydroxyvitamin
D, 24-hour urinary calcium
Possible vitamin D insufftciency
TSH, free T,
Possible hyperthyroidism
24-Hour
cortisol
Possible Cushing’s disease/syndrome
urinary free cortisol or fasting serum
Serum protein electrophoresis, serum and urine
immunoelectrophoresis,
cancer markers, bone
marrow examination
Possible malignancy, particularly
patients with vertebral fracture
Transiliac bone biopsy after tetracycline
labeling for histomorphometry
Possible osteomalacia
PTH
= pamthyroid
hormone;
TSH
double
= thyroid-stimulating
and patients with T-scores above this
range have normal bone mass.43
However, these diagnostic thresholds
should not be applied rigidly to determine
the appropriateness of treatment for an individual. Physicians should consider the probability that a particular patient will develop
fractures during her lifetime as a result of
other factors combined with BMD. For example, a woman who has had 21 vertebral
fracture has approximately 4 times the risk
of having another vertebral fracture and
twice the risk of hip fracture compared with
a woman of the same age and BMD who
has not had a fracture; therefore, she should
be treated even if her current T-score is
above -2.5.10~12*13J5~6A42-year-oldwoman
who has just undergone menopause and has
a T-score of -1.5 is at increased risk for osteoporosis and fractures in later life and
1034
hormone;
in
T, = thyroxine.
would be a good candidate for treatment to
prevent bone loss. However, a T-score of
-2.6 in a W-year-old woman with no history of fracture or other risk factors may not
require. specific intervention, since her relifetime risk of fracture is likely to
be low. There are tools for evaluating the remaining lifetime risk of fracture that may be
useful to both physicians and patients when
maining
considering
the need for treatment.57
MANAGEMENT
General Measures
The treatment of acute back pain due to
a recent vertebral fracture includes bed
rest (as short as possible), back support,
analgesic agents/nonsteroidal anti-inflammatory drugs (NSAIDs), heat, and gentle
P.J. MEUNIER
ET AL.
massage. The treatment of chronic back
pain due to vertebral fracture is difficult
but includes analgesic agents/NSAIDs,
physiotherapy, intermittent use of spinal
support for some activities, and a program
of physical activity to maintain muscle
strength and flexibility of the spine.58
In all patients, it is important to treat
diseases that can increase bone loss and
contribute to osteoporosis. An important
part of the management of patients with
osteoporosis-particularly
those who
have had a hip fracture and otherwise frail
patients-is
attending to their general
health status (eg, ensuring adequate protein intake) and suggesting measures to
decrease their risk of falls or the degree of
trauma resulting from falls (eg, installation of carpeting, better lighting, or
handrails; removal of obstacles; attention
to use of such drugs as sedative, narcotic
analgesic, anticholinergic, and antihypertensive agents that may predispose the patient to falls; and use of hip padding)?9
Regular exercise may be of value in
maintaining mobility and improving muscle mass, thus reducing patients’ risk of
falling. Patients with osteoporosis should
avoid heavy weight-bearing and vigorous
exercise programs, because such activity
may trigger a new fracture.
Calcium and Vitamin D
Low calcium intake and vitamin D deliciency should be remedied in all patients.
Because many hip fractures occur in patients aged 980 years and this population is
particularly prone to low calcium intake
and vitamin D deficiency, it is important to
ensure that these patients receive adequate
calcium and vitamin D as part of their management. In patients who habitually consume little calcium, the use of calcium
alone has been reported to induce small increases in spine BMD and a possible decrease in the incidence of fractures.-’
However, the use of low-dose vitamin D
(400 IU/d) alone did not reduce fracture
incidence in a free-living, ambulatory population of Dutch postmenopausal women.63
In contrast, in a French study of women in
nursing homes, many of whom had insufficient vitamin D intake, the use of calcium
and vitamin D (800 IU/d) together decreased the incidence of hip fractures.64,65
These data underscore the importance
of ensuring that all postmenopausal
women receive adequate calcium and vitamin D. Ambulatory patients exposed to
sunlight for >15 minutes a day generally
produce sufficient vitamin D through skin
photoconversion, but others should receive a supplement containing 400 to 800
IU/d of vitamin D. Total daily intake of
calcium, including supplements if necessary, should be at least 1000 mg. Despite
the necessity of adequate calcium and vitamin D for bone health, treatment with
calcium and vitamin D alone is insufficient to prevent postmenopausal bone loss
or to reduce fracture risk markedly in patients with osteoporosis.
Pharmacologic
Intervention
As with all therapeutic decisions, physicians should consider the benefits, risks,
and costs of each pharmacologic treatment as it applies to the individual patient
and should refer to current package inserts for complete details of a drug’s indications and use.@j
Whenever possible, our advice conceming the selection of pharmacologic therapy
has been based on the scientific evidence
from randomized clinical trials that include
a prospectively defined fracture end point.67
1035
CLINICAL
The prospective controlled data strongly
support the efficacy of alendronate in preventing vertebral and nonvertebral fractures
(including hip fracture)?7-71 Several observational studies have indicated that estrogen
use is also associated with a substantial reduction in fracture risk.72-75The strength of
the data from randomized, controlled trials
concerning vertebral and hip fracture are
summarized in Table II. In most of the clinical trials, all patients were given adequate
calcium and vitamin D; thus in these studies antifracture efficacy reflects a decrease
in fracture incidence beyond that achievable
with calcium and vitamin D alone.
Estrogen
Considerations associated with the decision to initiate estrogen therapy include its
THERAPEUTICS”
potential benefits (eg, relief from the symptoms of estrogen deficiency [hot flashes]
and cardioprotection) and its risks (eg, increased risk of breast and endometrial cancer). Concomitant use of estrogen with a
progestin (hormone replacement therapy
[HRT]) in women with an intact uterus minimizes the increased risk of endometrial
cancer. Estrogen use increases the risk of
venous thromboembolic events by 2 or 3
times. Some women cannot tolerate estrogen or HRT, although side effects can sometimes be alleviated by changing the treatment regimen. In older postmenopausal
women, it is important to begin therapy at
a low dose that is increased over several
months.
The long-term clinical data on estrogen
use are derived principally from observa-
Table II. Evidence of antifracture efficacy from randomized clinical trials.
Therapy
Alendronate
Estrogen+
Etidronate
Risedronatet
Raloxifenet
Intranasal
calcitonin
Fluoride
salts
Vitamin
D analogues
Anabolic
steroids
Tibolone
Ipriflavone
Reference*
68-7 1
76
77-79
None
None
80
81-83
84,85
None
None
None
Evidence
for
Reduction
of Vertebral
Fracture
Risk
++
+
+
0
0
+
f
+
0
0
0
Evidence
for Reduction
of Nonvertebral
Fracture
Risk
+
0
0
0
0
0
0
0
0
0
++ = strong evidence
for antifracture
efficacy;
+ = some evidence for antifracture
efficacy;
0 = insufftcient
evidence for antifracture
efficacy;
f = variable or equivocal effects reported; - = increased fracture risk reported.
*In the majority of these studies, the control group received calcium supplements
and adequate vitamin D. Thus
the effects noted are in excess of those produced by calcium and vitamin D alone.
%ubstantial
evidence for antifracture
efftcacy of estrogen is available from several observational
studies. There
are no published fracture dam (as of November
1998) on tisedronate
or raloxifene.
Studies are in progress, as
is a new study of calcitonin,
and data are likely to be published in the near future.
1036
P.J.MEUNIER ET AL.
tional studies, with relatively few data
available from randomized, controlled
studies. At adequate doses, estrogen maintains or increases bone mass, including
increases of 2% to 8% in spine and hip
BMD.86 Although women who take estrogen have fewer fractures than those who
do not, previous users of estrogen do not
appear to have any significant residual reduction in fracture risk compared with
women who never take estrogen after
menopause.72-75 Therefore, to reduce lifetime fracture risk significantly, a woman
must continue taking estrogen. However,
most postmenopausal use of estrogen is
directed at treating climacteric symptoms,
and once these subside the majority of
women discontinue estrogen use.
Alendronate
Data are available from several large,
randomized, controlled clinical trials of
up to 5 years’ duration in patients with osteoporosis or low BMD treated with alendronate.68-71,87-89 These studies demonstrate that alendronate increases bone
density by 5% to 10% at the spine and hip
and decreases the risk of fracture at these
sites by about 50%. Other studies of alendronate have shown prevention of bone
loss in early postmenopausal women.9091
In these studies, bone density increased
by 3% to 5% at the spine and hip compared with placebo. Some patients taking
alendronate developed esophagitis or
esophageal ulcer, which was often associated with improper administration.92 In
some patients, upper gastrointestinal (GI)
symptoms may lead to discontinuation of
treatment.93 However, in many cases the
relationship between alendronate use and
upper GI symptoms is unclear.” Bone loss
resumes once a patient stops taking alendronate, but this is not accelerated com-
pared with placebo. Thus previous gains
in BMD are maintained,*’ but continued
therapy is required to obtain progressive
increases in BMD.s5
Cyclic Etidronate
Data are available from 2 randomized,
controlled trials of up to 3 years’ duration
in patients with osteoporosis treated with
cyclic etidronate.77-79 In these studies,
cyclic etidronate increased bone density
by 1% to 5% at the spine and hip, and, in
post hoc analyses of a subset of patients,
the incidence of spine fractures decreased.
However, this decrease was not significant when all patients were included in
the analyses. Some patients from these
trials have been treated for up to 7 years.96
Etidronate has also been reported to prevent bone loss in early postmenopausal
women.9798 Some cases of impaired mineralization of bone have been reported
with cyclic etidronate.99q1””
Raloxifene
Published data are available from a 2year, randomized, controlled clinical trial
of raloxifene in early postmenopausal
women.101 Bone density increased by 2%
at the spine and hip compared with
placebo. Low-density lipoprotein cholesterol levels decreased by lo%, but no
effects were observed on levels of highdensity lipoprotein cholesterol. The effects on cardiovascular end points have
not been reported. Hot flashes and muscle
cramps occurred at a higher incidence in
patients taking raloxifene than in those
taking placebo. lo2 Like estrogen, raloxifene is associated with a twofold to threefold increase in the risk of venous thromboembolic events.‘O* However, unlike
estrogen, raloxifene does not stimulate the
endometrium .
1037
CLINICAL THERAPEUTICS”
Intranasal Calcitonin
In a small, controlled, 2-year dose-finding study of intranasal calcitonin in postmenopausal women with osteoporosis,
spine BMD increased by 2%.80 There was
no effect on other skeletal sites. A lower
incidence of vertebral fractures was noted
compared with placebo.
Other Treatments
Other treatments for osteoporosis include fluoride salts, various vitamin D analogues, anabolic steroids, tibolone, and ipriflavone. These agents are available in some
countries but not others, and evidence for
their antifracture efficacy varies markedly
and is less strong than the evidence for estrogen and alendronate (Table II).
Fluoride salts have been reported to increase spine BMD substantially.81 Despite
this, vertebral fracture rates have not been
shown to decrease in adequate controlled
trials.81~82In addition, fluoride induces a
dose-dependent increase in stress fracture
and possibly in hip fracture. For these reasons, fluoride salts should not be used in
routine clinical practice.
Calcitriol (1,25[0H],vitamin
Ds) and
other analogues of vitamin D have variable effects on BMD, showing no change,
increases of 1% to 2%, or decreases compared with placebo. 85Potential side effects
include hypercalcemia and hypercalciuria.
These agents have not demonstrated consistent antifracture efficacy in masked,
placebo-controlled studies.84,103,104
No fracture end point studies have been
conducted for anabolic steroids, tibolone,
or ipriflavone.
FOLLOW-UP
Once patients have been identified and
treatment initiated, it is important to
1038
arrange adequate follow-up to reinforce
the importance of compliance with treatment and to evaluate the response. At minimum, all treated patients should be seen
after 3 to 6 months of treatment and thereafter at least annually. The importance of
adherence to treatment should be stressed.
The regimen of estrogen (with or without
added progestin) may require adjustment
to patients’ needs.
The response to therapy can be monitored using tests of biochemical markers
or repeat BMD measurement and may be
of value in assessing compliance and providing patient feedback. Although optional, it is possible to assessthe response
to such antiresorptive treatments as estrogen or alendronate after 3 to 6 months by
assessing the change in biochemical markers of bone turnover, such as N-terminal
or C-terminal crosslinks of type I collagen, serum osteocalcin, or serum bonespecific alkaline phosphatase. In most patients, these markers decrease by >30%
compared with baseline (ie, pretreatment)
or are reduced to within the premenopausal reference range, evidence that
treatment is having the desired effect of
decreasing bone turnover. Changes in
BMD occur over a longer period, and it
is generally not useful to repeat BMD
measurement until completion of 1 or 2
years of therapy and every 2 years thereafter. The majority of patients receiving
efficacious therapy will have a measurable increase in BMD at the spine and
hip (especially at the trochanter subregion) after 2 years of treatment. The typically small increases in BMD at peripheral sites, such as the heel and forearm,
relative to the precision of the measurements make these sites unreliable for the
purposes of assessing the response to
treatment.
P.J. MEUNIER
ET AL.
ACKNOWLEDGMENT
Development
of these guidelines was supported by an educational grant from Merck
& Co., Inc., Whitehouse
Station, New Jersey. The opinions expressed represent the
consensus of the committee members and
are independent
of the sponsor.
Address correspondence
Meunier,
MD,
HapitaI Edouard
d’Arsonval,69437
to: Pierre J.
Professor
of Medicine,
Hertiot-Pavillon
F, Place
Lyon cedex 03, France.
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