The New England Journal of Medicine
Review Article
Drug Therapy
A L A S T A I R J . J . W O O D , M. D. , Editor
T REATMENT OF P OSTMENOPAUSAL
O STEOPOROSIS
RICHARD EASTELL, M.D.
O
STEOPOROSIS affects an estimated 75 mil-
lion people in Europe, the United States,
and Japan.1 It is a preventable and treatable
condition, yet many people with osteoporosis re-
main unrecognized and untreated. The purpose of
this review is to consider the evidence that treat-
ments for postmenopausal osteoporosis are effective
and safe.
DEFINITION OF OSTEOPOROSIS
Definitions of osteoporosis have usually been con-
ceptual and therefore difficult to apply to individual
patients. For example, a Consensus Development
Conference defined osteoporosis as “a systemic skel-
etal disease characterised by low bone mass and
microarchitectural deterioration with a consequent
increase in bone fragility and susceptibility to frac-
ture.”1 A Working Group of the World Health Or-
ganization has operationally defined osteoporosis as
a bone mineral density (T score) that is 2.5 SD
below the mean peak value in young adults.2 This
definition is useful as an entry criterion for a clinical
trial or as a tool to study the epidemiology of os-
teoporosis, but it has limitations in clinical practice.
It raises a risk factor for fracture to the status of a
diagnostic criterion, ignores the importance of other
determinants of bone strength,3 ignores the higher
risk of fracture associated with a certain level of bone
mineral density in older women, and does not spec-
ify the technique by which or the site at which bone
mineral density should be measured.
Bone mineral density can also be compared with
the mean value in normal subjects of the same age
From the Division of Clinical Sciences, University of Sheffield, Sheffield,
United Kingdom. Address reprint requests to Dr. Eastell at the Section of
Medicine, Division of Clinical Sciences, Clinical Sciences Centre, Northern
General Hospital, Herries Rd., Sheffield S5 7AU, United Kingdom.
©1998, Massachusetts Medical Society.
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and sex (z score). A z score below 1 at either the
lumbar spine or the proximal femur would indicate
a value in the lowest 25 percent of the reference
range, a value at which the risk of fracture is approx-
imately doubled. A z score below 2 would indicate
a value in the lowest 2.5 percent of the reference
range, a level associated with a considerably larger
increase in the risk of fracture.
RISK FACTORS
A number of risk factors for osteoporosis have
been identified (Table 1). Bone loss can be slowed
or even reversed if risk factors such as physical inac-
tivity, low dietary calcium intake, and primary hy-
perparathyroidism are identified and reversed. A re-
port from the National Osteoporosis Foundation
concluded that the following factors were useful in
identifying women at risk for fracture: low body
weight (58 kg), current smoking, first-degree rel-
ative with low-trauma fracture, and personal history
of low-trauma fracture.4 These risk factors are com-
mon and easy to ascertain.
DIAGNOSTIC EVALUATION
Bone mineral density should be measured in
women with strong risk factors for osteoporosis (Ta-
ble 1). It should also be measured in those with os-
teoporosis-related fractures (fracture of the wrist,
spine, proximal femur, or humerus after mild or
moderate trauma) and those with osteopenia or spi-
nal deformities noted on spinal radiographs. Several
techniques are available for the measurement of
bone mineral density (Table 2). Among them the
most useful in clinical practice is dual-energy x-ray
absorptiometry. With this technique, measurement
of the density of the proximal femur is the most use-
ful for predicting fractures, and measurement of
lumbar-spine density is the most useful for monitor-
ing therapy (Fig. 1).
Bone density can be useful in making the diagno-
sis of osteoporosis and in decisions about starting
therapy. A T score lower than 2.5, especially in the
presence of the risk factors listed above, indicates the
need for treatment to prevent fractures.4 A T score
lower than 1 within five years after menopause or
a z score lower than 1 at the lumbar spine or prox-
imal femur at any age indicates the need to prevent
further bone loss.6 A bone-mineral–density value at
any site below the reference range (a z score lower
than 2) indicates accelerated bone loss, and fur-
ther studies to identify a major risk factor (Table 1)
are indicated.
Biochemical markers of bone turnover reflect
 D R UG TH ER A PY

TABLE 1. RISK FACTORS FOR OSTEOPOROSIS TABLE 2. TECHNIQUES FOR THE NONINVASIVE MEASUREMENT
IN POSTMENOPAUSAL WOMEN. OF BONE MASS.

Genetic factor
First-degree relative with low-trauma fracture TECHNIQUE SITE COMMENTS
Environmental factors
Cigarette smoking Single-energy x-ray Forearm and heel Inexpensive
Alcohol abuse absorptiometry Precise
Physical inactivity Uses low doses of radiation
Thin habitus Measures sites unresponsive to
Diet low in calcium therapy
Little exposure to sunlight Does not need skilled operator
Menstrual status Dual-energy x-ray Lumbar spine Fairly expensive
Early menopause (before the age of 45 years) absorptiometry Precise
Previous amenorrhea (e.g., due to anorexia nervosa, Uses low doses of radiation
hyperprolactinemia) Measures site responsive to
Drug therapy therapy
Glucocorticoids (7.5 mg/day or more of prednisone for Needs skilled operator
more than 6 mo) Subject to artifacts (spondylo-
Antiepileptic drugs (e.g., phenytoin) sis)
Excessive substitution therapy (e.g., thyroxine, hydrocor- Proximal femur Fairly expensive
tisone) Less precise
Anticoagulant drugs (e.g., heparin, warfarin) Uses low doses of radiation
Endocrine diseases Measures best site for fracture
Primary hyperparathyroidism prediction
Thyrotoxicosis Needs skilled operator
Cushing’s syndrome Total body Expensive
Addison’s disease Precise
Hematologic diseases Uses low doses of radiation
Multiple myeloma Measures sites unresponsive to
Systemic mastocytosis therapy
Lymphoma, leukemia Needs skilled operator
Pernicious anemia Allows assessment of body
Rheumatologic diseases composition
Rheumatoid arthritis Quantitative Spine Expensive
Ankylosing spondylitis computed Less precise
Gastrointestinal diseases tomography Uses high doses of radiation
Malabsorption syndromes (e.g., celiac disease, Crohn’s Measures sites responsive to
disease, surgery for peptic ulcer) therapy
Chronic liver disease (e.g., primary biliary cirrhosis) Needs skilled operator
Allows assessment of trabecu-
lar bone alone
Forearm Inexpensive
Precise
Uses low doses of radiation
bone formation or bone resorption (Table 3). These Measures sites unresponsive to
therapy
markers show large changes early in the course of Does not need skilled operator
treatment.5 Because the markers vary from day to Ultrasonography Heel, fingers, tibia, Inexpensive
patella Less precise
day, several measurements should be made before Uses no radiation
and during treatment for these to be useful in mon- Measures sites unresponsive to
itoring treatment response. therapy
Does not need skilled operator
Several drugs will cause an increase in bone min- Fairly portable
eral density, which is best monitored at the lumbar
spine (Fig. 1). However, the bone mineral density of
the lumbar spine cannot be measured in all women,
because of lack of access to densitometry services,
fractures, or degenerative changes in the lumbar sites within the skeleton and proceeds in an orderly
spine. Among these women, measurements of bio- fashion, with bone resorption always being followed
chemical markers may be useful in determining the by bone formation, a phenomenon referred to as
response to treatment. coupling. The sequence is similar in cortical and
cancellous bone.9 The process of resorption of bone,
PATHOPHYSIOLOGY OF OSTEOPOROSIS followed by synthesis of bone matrix and its subse-
Bone mineral density in a patient is related to quent mineralization, takes up to eight months. If
bone mass at maturity (peak bone mass) and subse- the processes of bone resorption and bone forma-
quent bone loss. Bone is remodeled throughout life, tion are not matched, there is remodeling imbal-
and the rate of remodeling is increased in older ance. Such an imbalance would be magnified if the
adults. The rate of resorption exceeds the rate of for- rate of initiation of new cycles of bone remodeling
mation in older adults,7,8 resulting in too little bone, were to increase.
or osteoporosis. Bone remodeling occurs at discrete Most of the drugs used to treat osteoporosis act

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 The New England Journal of Medicine

Lumbar Spine
TABLE 3. BIOCHEMICAL MARKERS OF BONE TURNOVER.
14 Placebo
Alendronate Bone formation
12
Serum alkaline phosphatase (bone isoenzyme)
10 Serum osteocalcin
Serum C - and N-propeptides of type I collagen
8 Bone resorption
Urinary excretion of pyridinium cross-links of collagen (e.g., deoxypyri-
6 dinoline)
Urinary excretion of C - and N-telopeptides of collagen
4
Urinary excretion of galactosyl hydroxylysine
2 Urinary excretion of hydroxyproline
Serum tartrate-resistant acid phosphatase
0
Change in Bone Mineral Density (%)

2
4
6
0 12 24 36
Month by decreasing bone resorption9 and are referred to as
antiresorptive drugs. They include estrogens, bis-
phosphonates, and calcitonin. The name is mislead-
Femoral Neck
ing: because the processes of bone resorption and
12 bone formation are coupled, these drugs decrease
10 the rates of both processes. When an antiresorptive
8
drug is given, the rate of bone resorption decreases
within weeks and the rate of bone formation de-
6 creases within months. This difference in timing re-
4 sults from the time sequence of the bone-remodel-
2
ing cycle.
At any time, some bone will have been resorbed
0 and not yet replaced, which is referred to as the re-
2 modeling space. It is increased in postmenopausal
4 osteoporosis. Antiresorptive therapy decreases the
rate of initiation of new remodeling cycles, resulting
6
in fewer remodeling sites and a decrease in the re-
8 modeling space. The filling in of the remodeling
0 12 24 36
space accounts for the increase in bone mineral den-
Month sity of 5 to 10 percent that occurs in postmenopaus-
Figure 1. Bone Mineral Density at the Lumbar Spine and Fem-
al women given antiresorptive therapy. This process
oral Neck in Postmenopausal Women with Osteoporosis Treat- usually takes two to three years, after which bone
ed with Alendronate for Three Years. density changes very little (Fig. 2).
Alendronate (10 mg per day) resulted in a greater increase in Some drugs used to treat osteoporosis act by in-
bone mineral density in the lumbar spine than in the femoral creasing bone formation. They include fluoride and
neck. The values shown are means SD. The shaded area rep- intermittent parathyroid hormone. The newly formed
resents the changes that can occur as a result of measurement
error (the smallest change that is significant is 5 percent for the bone either overfills resorption cavities or is laid
lumbar spine and 8 percent for the femoral neck). After one down on surfaces not previously resorbed. Drugs
year, more than half the women taking alendronate had re- that stimulate bone formation result in annual rates
sponded to therapy, as defined by a change above the shaded of increase in bone mineral density similar to those
area, according to measurements at the lumbar spine. In con-
trast, after three years, fewer than half of these patients had re-
resulting from antiresorptive therapies, but the in-
sponded to therapy according to measurements at the femoral crease continues beyond two years (Fig. 2).
neck. Reprinted from Eastell,5 with the permission of the pub- Hormones and drugs affect different regions of
lisher. the skeleton by differing amounts. For example, es-
trogen deficiency and glucocorticoid therapy 14 result
primarily in cancellous-bone loss, whereas parathy-
roid hormone excess15 results primarily in cortical-
bone loss. These differences may be due to different
effects on cortical and cancellous bone, on bones
subjected to weight-bearing and those subjected to
non–weight-bearing stresses, or on bones containing
red marrow and those containing yellow marrow.

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 D R UG TH ER A PY

Filling in of remodeling space

1.2
Therapy stimulating

Mineral Density (g/cm2)

Lumbar-Spine Bone
bone formation

1.1
Antiresorptive therapy

1.0
Placebo

0.9
1 0 1 2 3 4
Year
Figure 2. Effect of Therapy on Lumbar-Spine Bone Mineral Density in Postmenopausal Women with
Osteoporosis.
Therapy that stimulates bone formation results in continued increases in bone mineral density beyond
two years (broken line). This increase does not always translate to an increase in bone strength. Anti-
resorptive therapy results in an increase in bone mineral density, followed by a plateau (dotted line).
The increase may persist beyond two years with the use of estrogen10,11 or bisphosphonates,12 perhaps
as a result of a prolonged period of secondary mineralization or of positive remodeling imbalance.
Administration of placebo may be associated with bone loss (solid line). However, in many trials there
was no statistically significant bone loss. The absence of bone loss may be a result of the supplemen-
tal calcium therapy and recommended lifestyle measures, or it may be due to artifacts or to drift in
bone-mineral–density measurements. Adapted from Parfitt,13 with the permission of the publisher.

EVALUATION OF DRUG EFFICACY
The response to a drug is usually evaluated by se-
rial measurements of bone mineral density. As noted
above, antiresorptive drugs result in a 5 to 10 per-
cent increase in the bone mineral density of the lum-
bar spine in two years in women with postmeno-
pausal osteoporosis. This change is associated with a
decrease in the fracture rate of approximately 50
percent. In prospective studies of the relation be-
tween bone mineral density and risk of fracture, the
risk of fracture approximately doubled for each de-
crease of 1 SD in bone mineral density (Fig. 3).16,19
The benefit of antiresorptive therapy in reducing the
risk of fracture is greater than expected from the
change in bone mineral density.12,18
Bone turnover is another determinant of the risk
of fracture.20 High bone turnover is associated with
a greater rate of bone loss.21 It may be a risk factor
for fracture that is independent of bone mineral
density,22 possibly because of the increased number
of bone-remodeling sites that can buckle.23
Bone strength may be determined by factors other
than bone mineral density and bone turnover.3 So-
dium fluoride therapy results in large increases in
bone mineral density, but the effect on fracture rates
is small (Fig. 3).17 Fluoride is incorporated into the
hydroxyapatite crystals of bone, thus weakening the
bone.24
Because the aim of treatment is to prevent frac-
tures, fractures are the key end point of any clinical
trial of therapy for osteoporosis.25 The diagnosis of
nonvertebral fractures is straightforward. The diag-
nosis of vertebral fractures is difficult, because they
may be painless,26 and other vertebral deformities
may mimic fractures.
There is now strong evidence that a number of
drugs prevent further fractures in postmenopausal
women with osteoporosis. This evidence, based on
randomized, controlled trials, cohort studies, and
cross-sectional studies, is reviewed below.
CURRENT THERAPIES
Estrogen-Replacement Therapy
Information about the effect of estrogen-replace-
ment therapy on rates of vertebral fracture in post-
menopausal women is limited (Table 4). In a one-
year study of transdermal estrogen therapy in 75
postmenopausal women with osteoporosis, the rela-
tive risk of vertebral fractures was 0.39 in the treat-
ment group as compared with the placebo group.18
There was also an increase in the bone mineral den-
sity of the lumbar spine of 5.1 percent and a de-
crease in bone turnover, as assessed by biochemical
markers and bone histomorphometry. In a primary-
prevention study of 100 women who underwent bi-
lateral oophorectomy and who were treated with
mestranol or placebo for 6 to 12 years, there was no
bone loss from the radius and the metacarpal bones

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14
Relative Risk of Vertebral Fracture
12
10
8
6 Bisphosphonates
4
2 Alendronate
Estradiol
0 mode of action is uncertain, but their net effect is
4 3 2
Lumbar Spine Bone Mineral Density
(SD units)
0.52 0.76
Bone Mineral Density (g/cm )
Figure 3. Relation between Lumbar-Spine Bone Mineral Densi-
ty and Rate of Vertebral Fracture.
For every decrease of 1 SD in lumbar-spine bone mineral den-
sity, the rate of vertebral fracture approximately doubled.16 The
effect of sodium fluoride on lumbar-spine bone mineral densi-
ty according to the same densitometer was an increase of 31
percent, with a 17 percent decrease in vertebral fractures (P not
significant).17 The effect of transdermal estradiol on lumbar-
spine bone mineral density according to a different densitom-
eter (but with a correction factor) was an increase of 5 percent,
with a decrease in vertebral fractures of 61 percent.18 Alendro-
nate therapy resulted in an increase in bone mineral density of
9 percent and a decrease in vertebral fractures of 48 percent.12
Sodium fluoride had a smaller effect on fractures than was ex-
pected from the change in bone mineral density, and estrogen
and alendronate had a greater effect than expected.
in the group receiving estrogen during the first
8 years, with slow bone loss thereafter. Spinal radio-
graphs at the end of the study also revealed fewer
wedge deformities of the vertebrae in this group.27
Additional evidence that estrogen-replacement
therapy prevents fractures comes from prospective
cohort studies.48-50 For example, in the Study of Os-
teoporotic Fractures,51 the relative risk of nonspinal
fracture was 0.66 in postmenopausal women cur-
rently taking estrogen as compared with those not
taking estrogen. The beneficial effect of estrogen-
replacement therapy was more marked in women
who began therapy within five years after meno-
pause, and it was unaffected by age18,51-53 or concom-
itant progestin therapy.10,51 Concurrent smoking
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The New England Journal of Medicine
may48 or may not 51 attenuate the benefits of estro-
gen-replacement therapy. Whether bone loss is ac-
celerated after estrogen-replacement therapy is dis-
continued is controversial.54-57
Other beneficial effects and side effects of estrogen
are listed in Table 5. These will not be discussed here,
except to say that they all contribute importantly to
the decision whether to choose estrogen as therapy
for osteoporosis in a postmenopausal woman.
Bisphosphonates are stable analogues of pyro-
phosphate. They are poorly absorbed from the intes-
tine (absorption, less than 10 percent)64 and must
Sodium fluoride
not be taken with food. They are deposited in bone
at sites of mineralization and in the resorption lacu-
nae or are eliminated by the kidneys. The exact
1 0 1 2 on osteoclasts or their precursors, with a resultant
increase in cell death and therefore a decrease in
bone resorption.65 Bisphosphonate therapy results in
increased bone mineral density and a decreased frac-
ture rate. Several compounds of this family have
1.00 1.24 been evaluated for the prevention of bone loss (clo-
2 dronate, pamidronate, tiludronate, risedronate, and
ibandronate). Data on fractures are available for eti-
dronate and alendronate (Table 4).
Etidronate given continuously at high doses can
result in impaired mineralization, which can be
avoided by low-dose intermittent therapy.66 There-
fore the drug is usually given at a dose of 400 mg
per day for 2 weeks, followed by 500 mg of supple-
mental calcium per day for 11 weeks. This regimen
resulted in an increase in bone mineral density of
4 to 8 percent in the lumbar spine and of 2 percent
in the femoral neck in three years, as well as a de-
crease in the vertebral-fracture rate (Table 4).28,29,67
Alendronate is given at a dose of 10 mg per day
for the treatment of osteoporosis in postmenopausal
women. Alendronate resulted in an increase in bone
mineral density of 8.8 percent in the lumbar spine
and of 5.9 percent in the femoral neck in three
years.12 This increase in bone mineral density was
matched by a decrease in biochemical markers of
bone turnover, with the markers of bone resorption
decreasing maximally at two months and the mark-
ers of bone formation decreasing maximally at six
months. The change in markers of bone resorption
at three months appears to predict the response in
terms of bone mineral density at two years.68 Alen-
dronate therapy also resulted in a 48 percent de-
crease in the proportion of women with new frac-
tures and prevented height loss.12 In a report from a
two-year prevention study, 5 mg of alendronate per
day had less effect on bone mineral density than es-
trogen-replacement therapy but resulted in fewer ad-
verse events.69
Among the 2027 women with vertebral fractures
 D R UG TH ER A PY

TABLE 4. CLINICAL TRIALS OF TREATMENT OF POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS THAT USED FRACTURE AS AN END POINT.

STUDY TREATMENT DOSE NO. OF WOMEN DURATION (YR) COMMENTS

Lindsay et al.27 Mestranol 25 mg/day 100 Up to 12 Vertebral deformity less common

in mestranol group*†
Lufkin et al.18 Estradiol (transdermal) 100 mg/day, 21 of every 28 75 1 Decrease in number of new verte-
days bral fractures†
Storm et al.28 Cyclic etidronate 400 mg/day, 2 of every 15 wk 66 3 Decrease in number of new verte-
bral fractures in period from 60
to 150 wk†
Watts et al.29 Cyclic etidronate 400 mg/day, 2 of every 13 wk 429 2 Decrease in number of new verte-
bral fractures†‡
Liberman et al.12 Alendronate 5–20 mg/day 994 3 Decrease in number of patients
with new vertebral fractures
Black et al.30 Alendronate 5–10 mg/day 2027 3 Decrease in number of patients
with new vertebral, hip, or
wrist fractures
Orimo et al.31 Alfacalcidol 1 mg/day 61 2 Decrease in number of new verte-
bral fractures§¶
Orimo et al.32 Alfacalcidol 1 mg/day 80 1 Decrease in number of new verte-
bral fractures
Gallagher and Goldgar33 Calcitriol 0.5–1 mg/day 50 2 No effect on vertebral fractures
Heikinheimo et al.34 Vitamin D injection 150,000–300,000 IU/yr 341 Up to 5 Decrease in nonvertebral (espe-
cially upper-limb) fractures‡
Tilyard et al.35 Calcitriol 0.5 mg/day 622 3 Decrease in new vertebral and
nonvertebral fractures§¶
Chapuy et al.36 Vitamin D (oral) and 800 IU/day and 3270 1.5 Decrease in number of patients
calcium 1200 mg/day with hip fractures
Dawson-Hughes et al.37 Vitamin D (oral) and 700 IU/day and 389 3 Decrease in number of patients
calcium 500 mg/day (men and women) with nonvertebral fractures
Lips et al.38 Vitamin D (oral) 400 IU/day 2578 Up to 3.5 No decrease in number of pa-
tients with hip fractures
Reid et al.39 Calcium 1000 mg/day 86 4 Decrease in number of patients
with new nonvertebral frac-
tures
Recker et al.40 Calcium 1200 mg/day 197 4.3 Decrease in number of patients
with new vertebral fractures
among those with vertebral
fractures at base line
Overgaard et al.41 Calcitonin (intranasal) 50–200 IU/day 208 2 Decrease in number of new verte-
bral fractures
Rico et al.42 Cyclic calcitonin (intra- 100 IU/day, 10 of every 30 72 2 Decrease in number of new verte-
muscular) days bral fractures§
Mamelle et al.43 Sodium fluoride 50 mg/day 257 2 Decrease in number of new verte-
bral fractures§¶
Riggs et al.17 Sodium fluoride 75 mg/day 202 4 No effect on vertebral-fracture
rate, but increase in nonverte-
bral-fracture rate
Meunier et al.44 Sodium fluoride or 50 mg/day or 354 2 No effect on rate of vertebral or
monofluorophosphate 150–200 mg/day nonvertebral fracture
Kleerekoper et al.45 Sodium fluoride 75 mg/day 84 4 No effect on rate of vertebral or
nonvertebral fracture
Pak et al.46 Cyclic sodium fluoride 50 mg/day, 12 of every 14 mo 110 Up to 5 Decrease in number of patients
(slow-release) with new vertebral fractures§
Lindsay et al.47 Parathyroid hormone 400 U/day 34 3 Decrease in vertebral deformities

*There were no spine radiographs at base line, so vertebral morphometry was cross-sectional.
†The extension study was uncontrolled.
‡The treatment groups were pooled.
§The study was not blinded.
¶The study had no placebo group.
The number of women with fractures was small (10).

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 The New England Journal of Medicine
TABLE 5. BENEFITS AND RISKS OF ESTROGEN THERAPY
IN POSTMENOPAUSAL WOMEN.
BENEFITS RISKS
Relief of menopausal symptoms Return of menstrual bleeding
Prevention of bone loss and Risk of endometrial carcinoma58
fractures10,49,51 Breast tenderness
Prevention of ischemic heart Risk of breast carcinoma61,62
disease59
Migraine
Prevention of dementia60
Risk of deep venous thrombosis and
pulmonary embolism63
in the Fracture Intervention Trial30 who were treated
with 5 mg of alendronate daily for two years, with a
subsequent increase to 10 mg per day for the final
nine months of the study, the rate of new vertebral
fractures (including those that were apparent clini-
cally) decreased by 47 percent as compared with the
rate in the placebo group. There were similar de-
creases in the frequency of hip and wrist fractures
but not of other fractures.
Alendronate has been associated with esophagitis,
including erosive esophagitis.70 The symptoms of
esophagitis usually begin within one month after
therapy is started. To minimize the risk of esophagi-
tis and increase drug absorption, the patient should
take alendronate with a glass of water while upright
at least 30 minutes before breakfast. Upper gastro-
intestinal problems, such as achalasia and esophageal
stricture, are absolute contraindications to alendro-
nate therapy, and gastroesophageal reflux disease is
a relative contraindication.
Bone turnover increases to the previous level in six
to nine months in women who take alendronate for
six months and then stop.71 In contrast, among
women treated with pamidronate for six years,72
bone mineral density did not decrease during the
first two years after therapy was discontinued. The
optimal duration of bisphosphonate therapy is not
known.
Calcium and Vitamin D
Elderly women adapt poorly to a low-calcium di-
et, and those who live at far northern or southern
latitudes or who avoid sunlight may become defi-
cient in vitamin D. In a study of 3270 institutional-
ized women in France who were treated with calci-
um (1200 mg per day) and vitamin D (800 IU per
day) for three years, the risk of hip fractures was 30
percent lower than the risk in the placebo group.36
This therapy also resulted in a reversal of secondary
hyperparathyroidism and an increase in the bone
mineral density of the femoral neck.
Care must be taken in generalizing the results of
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these studies. In another study of 2578 women of a
similar age in the Netherlands who were treated with
vitamin D (400 IU per day) or placebo for three and
a half years (but no supplemental calcium), the rate
of hip fracture in the two groups was similar.38 The
likely explanations for the differences between these
two studies36,38 include differences in the women
(the French women had lower dietary calcium in-
takes, were more frail, and had lower serum 25-
hydroxyvitamin D concentrations), in the dose of vi-
tamin D, and in the coadministration of calcium. It
may be that calcium and vitamin D are effective only
in housebound elderly women.
In a more recent study of 389 men and women
over the age of 63 years who were treated with cal-
cium (500 mg per day) and vitamin D (700 IU per
day) in the United States, the rate of nonvertebral
fractures was decreased.37 This decrease was surpris-
ing, because the increases in the bone mineral den-
sity of the lumbar spine (0.9 percent), femoral neck
(1.2 percent), and total body (1.2 percent) were
small. The major differences between this study and
the Dutch study were the lower base-line dietary in-
take of calcium and the higher serum 25-hydroxy-
vitamin D concentrations in the U.S. patients. In
another study vitamin D given annually by intramus-
cular injection resulted in a decrease in nonvertebral
fractures (Table 4).34
Calcium alone may be partially effective in pre-
venting bone loss, especially in older women and
those with a low calcium intake (Table 4).73 In a
study of 86 women treated with 1000 mg of calcium
per day or placebo for four years, there was a sus-
tained reduction in the loss of total-body bone min-
eral density in the calcium group; there was also a
reduction in the loss of lumbar-spine and proximal-
femur bone mineral density, with most of the differ-
ence occurring during the first year of calcium sup-
plementation.39 There was a borderline reduction in
the rate of symptomatic fractures in the calcium
group as compared with the placebo group. In an-
other study of women who were over 60 years old
and consumed less than 1000 mg of calcium per
day, a calcium supplement of 1200 mg per day pre-
vented bone loss from the forearm over a period of
four years.40 There was a 59 percent reduction in the
rate of vertebral fracture in the women who had ver-
tebral fractures at base line.
The active metabolite of vitamin D, calcitriol, and
the related alfacalcidol (1a-hydroxyvitamin D) in-
crease calcium absorption and may have direct ef-
fects on bone cells. They may reduce the rate of frac-
ture.31-33,74 In a study of 622 postmenopausal women
with vertebral fractures treated with calcitriol or cal-
cium for three years, calcitriol resulted in no change
in the rate of vertebral fractures, whereas calcium in-
creased the rate of vertebral fractures.35 Bone miner-
al density was not measured.
 D R UG TH ER A PY
Calcitonin
Calcitonin is a 32-amino-acid peptide that is nor-
mally produced by the thyroid C cells and results in
decreased bone resorption. Osteoclasts have calcito-
nin receptors, and calcitonin rapidly inhibits the ac-
tion of osteoclasts.
Salmon or human calcitonin is given by subcuta-
neous or intramuscular injection at doses of up to
100 IU daily (Table 4). Calcitonin therapy results in
an increase in bone mineral density, and in one un-
blinded study it resulted in a decrease in the rate of
vertebral fracture.42 Calcitonin is less effective at pre-
venting cortical-bone loss than cancellous-bone loss
in postmenopausal women.75 It is expensive, must be
given by injection, and can cause nausea, flushing,
and diarrhea. Some patients become resistant to its
action with long-term use, perhaps as a result of the
development of neutralizing antibodies.76
The development of intranasal salmon calcitonin
may make calcitonin therapy more acceptable. At
least 200 IU per day must be given to have an effect
on bone mineral density. Intranasal calcitonin is not
effective in preventing bone loss in early postmeno-
pausal women.77-79 In older women it decreased the
vertebral-fracture rate,41 but the number of fractures
was small. The spray has few side effects (nasal dis-
comfort, nausea, and facial flushing) and, like sub-
cutaneous calcitonin, it has an analgesic effect.80
Suppositories of calcitonin are only weakly effective
and are poorly tolerated.81,82
Fluoride
Sodium fluoride stimulates bone formation by
unknown mechanisms. In one study of 202 women
with osteoporosis who were treated with sodium flu-
oride, lumbar-spine bone mineral density increased
by 8 percent per year during all four years of the trial
(Table 4).17 There was substantial bone loss from the
forearm, indicating redistribution of bone mineral
from cortical to cancellous bone. Biochemical mark-
ers of bone formation increase in fluoride-treated
women, but markers of bone resorption do not. The
large increase in bone mineral density would be ex-
pected to be associated with a large decrease in the
fracture rate (Fig. 3). In most studies the effect on
fracture was small,17,43,45 but in one study there was
a significant reduction in the rate of vertebral frac-
ture (relative risk, 0.3).46 The dose of fluoride was
smaller than in the earlier studies, and it was given
intermittently as slow-release sodium fluoride. The
Fluoride and Vertebral Osteoporosis Study was a
randomized, placebo-controlled, two-year trial of
sodium fluoride (50 mg per day) and monofluoro-
phosphate (two doses) in 354 women with os-
teoporosis.44 Fluoride therapy, as compared with
placebo, had a large effect on bone mineral density
in the lumbar spine (increase, 10.8 percent vs. 2.4
Downloaded from www.nejm.org on August 9, 2009 . Copyright © 1998 Massachusetts Medical Society. All rights reserved.
percent), but no effect on the rate of vertebral frac-
ture. Thus, even at relatively low doses, fluoride had
little beneficial effect on fracture rates.
Sodium fluoride causes gastric irritation, which
can be reduced if the drug is given along with a cal-
cium supplement. It also causes stress fractures, the
so-called lower-extremity pain syndrome.17,44
FUTURE TREATMENTS
Raloxifene
Raloxifene has mixed estrogen-agonist and estro-
gen-antagonist activity and is referred to as a selec-
tive estrogen-receptor modulator.83 In a two-year
study in postmenopausal women, raloxifene therapy
resulted in a decrease in bone resorption84 and an in-
crease in bone mineral density in the lumbar spine
(2.4 percent), total hip (2.4 percent), and total body
(2.0 percent).85 It decreases serum low-density lipo-
protein cholesterol concentrations but does not
stimulate endometrial growth. (Tamoxifen has a sim-
ilar beneficial effect on bone mineral density,86 but
it can cause endometrial carcinoma.87) The results of
studies of bone mineral density need to be support-
ed by fracture studies, but raloxifene and other se-
lective estrogen-receptor modulators under develop-
ment (droloxifene, idoxifene, and levormeloxifene)
may provide an alternative to estrogen-replacement
therapy.
Parathyroid Hormone
Daily injections of parathyroid hormone stimulate
bone formation. It may be given as the intact hor-
mone or as a synthetic fragment. Treatment for up
to two years results in increased bone mineral den-
sity of the spine, but no change in bone mineral
density of the femoral neck, and an increase in bio-
chemical markers of bone formation and resorp-
tion.88 Its effects on the fracture rate are not yet
known. In 34 women with osteoporosis who were
already receiving estrogen-replacement therapy, ad-
ministration of parathyroid hormone for three years
increased the bone mineral density of the lumbar
spine (13 percent), femoral neck (3 percent), and
total body (8 percent), with a borderline decrease in
vertebral deformities.47 Drugs that stimulate the se-
cretion of endogenous parathyroid hormone or
mimic its action might also be effective.
Other Therapies
A number of cytokines and growth factors have
potent effects on bone cells. These factors also affect
other organs; for example, cytokines modulate the
immune system. The challenge will be to target such
factors to bone. Other drugs that have been devel-
oped for the treatment of osteoporosis include vita-
min D analogues, strontium salts (S12911),89 and
ipriflavone.90
Vol ume 338 Numbe r 11  743
 The New England Journal of Medicine
THERAPEUTIC CHOICES
The women who are most at risk for fractures
should be treated. Among them are women who
have already sustained a fracture with minimal or no
trauma and those who have low bone mineral den-
sity, especially if they also have other risk factors for
fracture.
Women with osteoporosis often present with
acute vertebral fracture. During the acute phase, the
pain can usually be managed with analgesic drugs
and a lumbar-support corset. If this is ineffective, a
short period of bed rest and calcitonin therapy (for
its analgesic properties) should be tried.
Lifestyle changes should be recommended, in-
cluding the avoidance of heavy lifting and the en-
couragement of exercise, such as walking. Falls can
be prevented by exercise and the avoidance of sedat-
ing drugs.91 In frail elderly women, hip protectors
can protect against hip fracture, but compliance with
use of the protectors now available is poor.92 Calci-
um intake should be increased to 1500 mg per day,93
either with diet or with supplements. Soluble salts of
calcium, such as calcium citrate, are better absorbed
than insoluble salts, such as calcium carbonate,
which need to be taken with meals. The effect on
bone resorption is greater if the calcium is taken at
bedtime.94 Excess consumption of alcohol should be
avoided, and tobacco use eliminated.
It is important to select the appropriate treatment
for each woman. Estrogen-replacement therapy is
the treatment of first choice, because of long-term
experience and its other benefits besides the treat-
ment of osteoporosis. The treatment should be giv-
en for at least five years, and preferably longer, be-
cause the benefits may not persist after treatment
is stopped. Compliance is enhanced by a detailed
discussion of the risks and benefits of estrogen-
replacement therapy (Table 5), by using preparations
that do not cause uterine bleeding (continuous
combined estrogen and progestin), and by monitor-
ing the response to treatment. A bisphosphonate is
an effective alternative to estrogen-replacement ther-
apy. It is particularly useful for women who are con-
cerned about the adverse effects of estrogen therapy.
The importance of the timing of administration
should be stressed, and the response to treatment
should be monitored (Fig. 1). There is no evidence
that combining estrogen-replacement therapy and
bisphosphonates is more effective than either treat-
ment alone. Vitamin D therapy is necessary for
housebound patients and is given orally (800 IU per
day) or intramuscularly (250,000 IU per year).95
The goals of therapy should be realistic. The ef-
fect of these therapies on osteoporosis is to halve the
risk of fracture. A new fracture should not be con-
sidered a setback, and the woman should be encour-
aged to continue therapy.
744  Mar ch 1 2 , 1 9 9 8
Downloaded from www.nejm.org on August 9, 2009 . Copyright © 1998 Massachusetts Medical Society. All rights reserved.
I am indebted to Mrs. Penny Bainbridge, Dr. Claudia Pereda,
and Professor Graham Russell for their comments during the prep-
aration of the manuscript.
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 The New England Journal of Medicine

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