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Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis.

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ARTHRITIS & RHEUMATISM
Vol. 39, No. 11, November 1996, pp 1791-1801
0 1996, American College of Rheumatology
1791
RECOMMENDATIONS FOR THE PREVENTION AND TREATMENT OF
GLUCOCORTICOID-INDUCED OSTEOPOROSIS
AMERICAN COLLEGE OF RHEUMATOLOGY TASK FORCE ON OSTEOPOROSIS GUIDELINES
Glucocorticoids are widely used in the treatment
of patients with chronic noninfectious inflammatory
diseases, especially asthma, chronic lung disease, rheumatoid arthritis and other connective tissue diseases,
inflammatory bowel disease, and in organ transplantation. Although the beneficial antiinflammatory and
immunosuppressive effects of glucocorticoids necessitate their use, adverse side effects are frequent. Osteoporosis and related fractures are one of the most serious
adverse effects; indeed, glucocorticoids are the most
common cause of drug-related osteoporosis. While our
knowledge of this condition is not complete, many
comprehensive reviews of this topic have appeared
during this decade, some of which include recommendations for prevention and treatment (1-16). In this
article, we briefly review the clinical significance and
pathophysiology of glucocorticoid-induced osteoporosis
and provide recommendations for the prevention and
treatment of this disorder.
Clinical significance
It is generally accepted that moderate-to-highdose glucocorticoid therapy is associated with loss of
bone and increased risk of fracture. Skeletal wasting is
most rapid during the first 6 months of therapy; trabecular bone is affected to a greater degree than cortical
Members of the Task Force on Osteoporosis Guidelines are
as follows. Marc C. Hochberg, MD, MPH (co-chair): University of
Maryland, Baltimore; Mark J. Prashker, MD, MPH (co-chair): Edith
Nourse Rogers Memorial Veterans Hospital, Bedford, MA; Maria
Greenwald, MD: Rancho Mirage, CA; Marian T. Hannan, DSc, MPH:
Boston University School of Medicine, Boston, h.4A,Nancy E. Lane,
MD: University of California at San Francisco; Stephen M. Lindsey,
MD: Ochsner Clinic, Baton Rouge, LA; Daniel J. Lovell; MD, MPH:
Children’s Hospital Medical Center, Cincinnati, OH; Elizabeth A.
Tindall, MD: Portland, OR.
The American College of Rheumatology is an independent
professional, medical, and scientific society which does not guarantee,
warrant, or endorse any commercial product or serlice.
Address reprint requests to The American College of Rheumatology, 60 Executive Park South, Suite 150, Atlanta, GA 30329.
Submitted for publication July 16, 1996; accepted in revised
form September 3, 1996.
bone. The skeletal effects of glucocorticoids appear to
be both dose and duration dependent, with daily prednisone doses of 27.5 mg often resulting in significant
bone loss and increased fracture risk (17-24). The
cumulative dose also affects the severity of bone loss. It
is not known whether there is a threshold dose of
glucoconicoid below which osteopenia does not occur;
alternate-day glucocorticoid regimens, however, have
not been shown to produce less bone loss than daily
regimens (25,26). Even inhaled steroids have been
shown to increase bone loss (27-29).
The magnitude of this problem has been demonstrated by cross-sectional studies, which suggest that the
majority of patients receiving long-term glucocorticoid
therapy have low bone mineral density, and that over
one-fourth sustain osteoporotic fractures. The prevalence of vertebral fractures in asthma patients receiving
steroid therapy for at least 1 year is 11% (17), and
steroid-treated patients with rheumatoid arthritis have
an increased incidence of fractures of the hip, rib, spine,
leg, ankle, and foot (20-22). Thus, glucocorticoidinduced osteoporosis is an important clinical problem
which commands the physician’s attention to both prevention and treatment.
Pathogenesis
Glucocorticoid-induced osteoporosis occurs as a
result of increased osteoclast-mediated bone resorption
and decreased osteoblast-mediated bone formation.
Specific mechanisms include 1) effects on calcium homeostasis, 2) effects on sex hormones, and 3) inhibition
of bone formation, as well as other effects. These
mechanisms are briefly summarized below.
Effects on calcium homeostasis. Glucocorticoids
cause a decrease in intestinal absorption of both calcium
and phosphate. The mechanisms of this action are
poorly understood, but are thought to be mediated by
factors independent of vitamin D (30,31). Urinary calcium excretion is increased in glucocorticoid-treated
1792
ACR TASK FORCE ON OSTEOPOROSIS GUIDELINES
patients, possibly due to a direct effect on tubular
reabsorption of calcium (32,33). Decreased gastrointestinal absorption and increased renal excretion of calcium
can lead to secondary hyperparathyroidism with elevated serum levels of parathyroid hormone (PTH)
(31,32). Persistently elevated PTH levels can increase
bone resorption. Of note, no consistent abnormalities in
vitamin D, PTH, or calcitonin levels have been found in
glucocorticoid-treated patients (31,34).
Effects on sex hormones. Glucocorticoids cause a
reduction in sex hormone production both indirectly, by
reducing endogenous pituitary hormone levels and adrenal androgen production, and directly, through effects
on gonadal hormone release (35-37). Secretion of luteinizing hormone from the pituitary is decreased, with a
resultant decrease in estrogen and testosterone production by the ovaries and testes, respectively. Circulating
levels of estradiol, estrone, dehydroepiandrosterone sulfate, androstenedione, and progesterone are lowered in
both men and women. Deficiencies of these anabolic
hormones likely play a significant role in the pathogenesis of glucocorticoid-induced osteoporosis.
Inhibition of bone formation. Long-term exposure to glucocorticoids inhibits osteoblast proliferation,
attachment of osteoblasts to matrix, and synthesis of
both type I collagen and noncollagenous proteins by
osteoblasts (38,39). This is reflected in a dose-related
reduction in the circulating levels of osteocalcin, and is
likely mediated by effects on the expression of oncogenes (40), prostaglandin E production (41), and synthesis of insulin-like growth factors (42) and transforming
growth factor /3 (43).
Other effects. Glucocorticoid-induced myopathy
and muscle weakness may also contribute to bone loss by
removing the normal forces on bone that are produced
by muscle contraction. Finally, the underlying inflammatory disease (e.g., rheumatoid arthritis), or concomitant
drug therapy (e.g., cyclosporine), may also contribute to
osteoporosis in the patient being treated with glucocor t icoi ds.
sex) or a Z score (the difference in SD compared with
healthy age-matched controls of the same race and sex);
persons with a BMD >1 SD below the mean in young
adults (i.e., T score >-1) are considered to have low
BMD, while those with a BMD >2.5 SD below the mean
in young adults (i.e., T score >-2.5) are considered to
have osteoporosis (45). Current indications for bone
densitometry delineated by the Scientific Advisory
Board of the National Osteoporosis Foundation include
glucocorticoid treatment (46).
Because trabecular or cancellous bone and the
cortical rim of the vertebrae are lost more rapidly than
cortical bone from the long bones, the earliest changes
of glucocorticoid-induced bone loss can be detected in
the lumbar spine using the techniques of quantitative
computed tomography (QCT) or DXA. QCT provides
information only on trabecular bone, while DXA measures a combination of both cortical and trabecular
bone. Because most medical practices do not have access
to QCT and because QCT requires a larger radiation
exposure, the Task Force recommends that physicians
obtain an anteroposterior (AP)DXA measurement of
both the lumbar spine and femoral neck. If only one site
can be obtained, we recommend the lumbar spine in
men and women below age 60 and the femoral neck in
men and women age 60 and above, since measurements
of the lumbar spine in the elderly may be unreliable
because of osteophyte formation at the vertebral bodies
and facet joints (47). DXA of the lumbar spine in the
lateral position may be a more sensitive indicator of
glucocorticoid-induced bone loss than in the AP position; however, preliminary data from the Study of Osteoporotic Fractures failed to demonstrate that lateral spine
DXA measurements were better predictors of vertebral
fracture than AP spine DXA measurements (Black D:
personal communication). Ideally, baseline bone mineral densitometry should be performed before long-term
(i.e., 2 6 months) corticosteroid therapy is initiated, or
very soon thereafter.
Prevention and treatment
Evaluation of the patient
Advances in the measurement of bone mineral
density, especially the development of dual-energy x-ray
absorptiometry (DXA), make it possible to precisely and
rapidly quantify the amount of bone in the lumbar spine,
proximal femur, forearm, and entire body with minimum
radiation exposure (44). The bone mineral density
(BMD) in a patient is expressed as a T score (the
difference in standard deviation [SD] compared with
peak bone mass in a young adult of the same race and
Glucocorticoid-induced bone loss can be both
prevented and treated. Evidence from studies of patients
cured of Cushing’s syndrome indicates that bone density
increases following the restoration of normal glucocorticoid levels (48). Optimal management strategies to
prevent bone loss should include the use of the lowest
effective dose of glucocorticoid that is possible. As noted
above, use of alternate-day dosing does not offer protection against glucocorticoid-induced bone loss. Topical and inhaled preparations should be used whenever
TREATMENT OF STEROID-INDUCED OSTEOPOROSIS
possible. In addition, all patients should be encouraged
to modify their lifestyles to include smoking cessation,
limitation of alcohol consumption, and participation in a
weight-bearing exercise program for 30-60 minutedday.
The Task Force’s recommendations will be divided into the following groups: 1) approach to the
patient receiving long-term glucocorticoid treatment
who has an osteoporotic fracture; 2) approach to the
patient receiving long-term glucocorticoid treatment
who does not have an osteoporotic fracture; and 3)
approach to the patient who is beginning long-term
glucocorticoid treatment. We have also included specific
comments for 3 treatment groups: postmenopausal
women, premenopausal women, and men aged 18 years
and older. Finally, we have included a separate section
on recommendations for the prevention and treatment
of glucocorticoid-induced bone loss in children.
Evidence of the effectiveness of therapy for
glucocorticoid-induced bone loss
Numerous therapeutic approaches have been
used for glucocorticoid-induced bone loss. The evidence
supporting the use of these pharmacologic therapies is
summarized below.
Calcium. Since glucocorticoid-induced bone loss
results in part from decreased calcium absorption from
the gastrointestinal tract and increased calcium loss in
the urine, an attempt to normalize calcium balance may
limit the extent of bone loss. Indeed, in one study of
patients taking steroids, calcium supplementation alone
inhibited bone resorption and decreased bone loss (49).
The Task Force recommends that all patients maintain
an adequate calcium intake of 1,500 mglday, through
either diet or supplements, unless contraindicated.
Vitamin D. Vitamin D is of benefit in both the
treatment and prevention of glucocorticoid-induced
bone loss. Hahn and colleagues showed that, in rheumatic disease patients taking corticosteroids, the addition of vitamin D (50,000 units 3 times per week) or
25-hydroxyvitamin D (40 pglday) with 500 mg of elemental calcium had beneficial effects on bone density
measured in the radius (31,50). Neither of these studies,
however, was randomized or measured BMD in the
lumbar spine or hip. In a recent primary prevention
study, patients beginning prednisone therapy were randomized to received either vitamin D (50,000 units per
week) and calcium (1,000 mglday) or double p1acebo
(51). Although there was a slightly smaller decline in
lumbar spine BMD at 12 months in the treated group
(2.6% versus 4.1%), the changes in lumbar spine BMD
measured at 36 months were not significantly different
-
1793
between the groups. Thus, this regimen did not appear
to be of benefit in primary prevention.
In another primary prevention study, patients
were randomized to 1 of 3 groups: 1) a combination of
1,25-dihydroxyvitamin D (calcitriol; 0.5-1.0 pg/day),
salmon calcitonin nasal spray (400 IU/day), and calcium
(1,000 mglday); 2) calcitriol (0.5-1.0 pglday) and calcium (1,000 mglday) with placebo nasal spray; or 3)
calcium (1,000 mglday) alone with placebo calcitriol and
placebo nasal spray (52). The patients who took calcitriol, with or without intranasal calcitonin, were shown to
lose significantly less bone from the lumbar spine than
those who took calcium alone during the first year of
corticosteroid therapy. Bone loss at the radius and
femoral neck did not significantly differ between the 3
groups. Unfortunately, about one-fourth of patients
taking calcitriol developed hypercalcemia, and most
showed worsening of their hypercalciuria. This illustrates the narrow margin of safety of calcitriol and
emphasizes the need to closely monitor serum calcium
levels in patients receiving this therapy. Concern about
these side effects led us to recommend that vitamin D
(either 800 IU/day or 50,000 I U 3 times per week) or
calcitriol (0.5 pglday) be used in the management of
glucocorticoid-induced osteoporosis. If either high-dose
vitamin D or calcitriol ,is used, then careful followup of
both serum and urine calcium levels is essential.
Thiazide diuretics. Sodium restriction and thiazide diuretics have been shown to improve gastrointestinal absorption and decrease urinary excretion of
calcium (53). These effects can ameliorate the hypercalciuria that is associated with glucocorticoid therapy and
would be expected t o improve calcium balance.
Glucocorticoid-treated patients who, while consuming a
normal diet, excrete >300 mg of calcium in their urine
over a 24-hour period may benefit from the addition of
a low-dose thiazide diuretic (e.g., hydrochlorothiazide 25
mglday), with potassium supplements as needed. Although the effects of thiazide diuretics on bone density
have not been adequately assessed in glucocorticoidtreated patients, in the absence of glucocorticoid treatment, thiazide use is associated with higher bone density
and a modest reduction in fracture risk (54-56). Serum
calcium levels must be monitored carefully in patients
receiving both vitamin D, especially calcitriol, and thiazides because these patients are more prone to hypercalcemia than those receiving either vitamin D or thiazides alone.
Hormone replacement therapy (HRT).
Glucocorticoid-induced hypogonadism should be corrected if possible. One small study of 15 women with
asthma who were receiving glucocorticoid therapy
1794
ACR TASK FORCE ON OSTEOPOROSIS GUIDELINES
showed that a combination of estrogen and progesterone therapy was associated with increased lumbar spine
BMD after 1 year (57). In a trial of women with
rheumatoid arthritis who were taking prednisone and
were randomized to receive HRT or placebo, those who
received HRT had a significant increase in their lumbar
spine BMD compared with controls (58). There was no
significant change in femoral neck BMD in either group.
Based on the results of these 2 studies, postmenopausal
women taking glucocorticoids should receive HRT if
there are no contraindications. Premenopausal women
who experience menstrual irregularities (i.e., oligo- or
amenorrhea) while taking steroids should be offered
therapy with oral contraceptives if contraindications are
not present. Although no studies have been performed
in glucocorticoid-treated premenopausal women, observational epidemiologic studies and studies in premenopausal athletic women with menstrual irregularities suggest that women who received oral contraceptives had
higher adjusted BMD than did women who did not take
oral contraceptives (59).
A recent randomized crossover trial demonstrated the effectiveness of testosterone therapy in 15
men with glucocorticoid-treated asthma (60). All men
had low serum testosterone levels prior to therapy.
Lumbar spine BMD, but not hip BMD, was significantly
increased after 12 months of monthly testosterone injections. Associated with this change in BMD, there was a
significant decrease in the percentage of body fat and a
significant increase in lean body mass. Thus, if serum
testosterone levels are low in men who are taking
glucocorticoids, they may benefit from testosterone replacement, since testosterone deficiency is a recognized
cause of osteoporosis in men. Guidelines for the use of
androgens in men have been published recently (61).
Bisphosphonates. Bisphosphonates are pyrophosphate analogs that bind to hydroxyapatite at sites of
active bone remodeling. There, they inhibit bone resorption by directly inhibiting the action of osteoclasts, and
have a sustained effect because of their long half-life in
bone (62). There are currently 3 bisphosphonates available in the United States: etidronate, pamidronate, and
alendronate. Etidronate has been shown to be effective
in the primary prevention, and both etidronate and
pamidronate have been shown to be effective in the
secondary prevention of glucocorticoid-induced osteoporosis. Trials of alendronate in secondary prevention
are currently in progress.
Mulder and Struys studied 20 postmenopausal
women with temporal arteritis who were beginning
glucocorticoid therapy (63). The women were alternately assigned to receive either etidronate 400 mglday
for 2 weeks every 13 weeks or no therapy in addition to
their prednisone. The change in lumbar spine BMD
from baseline was significantly different between treated
and control patients (+ 1.4% versus -5.0%, respectively). Diamond and colleagues studied 15 postmenopausal
women with rheumatoid arthritis, polymyalgia rheumatica, or asthma who were beginning prednisone therapy and who received cyclical etidronate 400 mglday for
4 weeks of the first 3-month cycle followed by 400
mglday for 2 weeks of every other 3-month cycle for 2
years (64). Data from these patients were compared with
data from 11 female historical control subjects who
received only calcium supplements. At 12 months, the
etidronate-treated patients had significant increases in
lumbar spine and femoral neck BMD compared with
controls. At 24 months, the change in lumbar spine
BMD was sustained while that at the femoral neck
increased.
Two additional studies have demonstrated the
effectiveness of etidronate in secondary prevention of
glucocorticoid-induced osteoporosis (65,66). Adachi and
colleagues compared 35 glucocorticoid-treated patients
who received cyclical etidronate to 33 control patients
who received calcium supplements alone (65). There
was a significant increase in lumbar spine BMD in the
etidronate-treated patients compared with a reduction
in those who received calcium alone; no changes were
noted in femoral neck BMD. Struys and colleagues
studied 39 patients receiving glucocorticoids for a variety
of conditions; 19 received open-label cyclical etidronate
and 20 received calcium supplements alone (66). Both
lumbar spine and femoral neck BMD were significantly
increased in the etidronate-treated patients at 6 and 12
months. In a randomized controlled trial of 40 patients
with chronic lung disease, oral pamidronate (150 mg/
day) and calcium (1,000 mglday) produced a significant
increase in lumbar spine BMD after 12 months in
patients taking long-term steroids (67). Two-year followup data in 13 of these patients showed that lumbar
spine BMD was maintained in the pamidronate-treated
group but further declined in the controls (68). Because
of the long skeletal retention of bisphosphonates, caution should be exercised in treating young patients with
long-term bisphosphonates.
Calcitonin. Calcitonin, which is approved by the
Food and Drug Administration for the treatment of
osteoporosis, inhibits bone resorption through a direct
effect on osteoclasts. Given subcutaneously (100 IU/day
or every other day) or intranasally (200 IU/day), it is
effective in the prevention of bone loss and fractures in
established osteoporosis, and it also prevents bone loss
caused by glucocorticoids (52,69-71). Ringe and Welzel
TREATMENT OF STEROID-INDUCED OSTEOPOROSIS
found that salmon calcitonin injections led to an increase in forearm BMD in glucocorticoid-treated patients with chronic lung diseases (69). Montemurro and
colleagues studied 68 patients with sarcoidosis at the
beginning of prednisone therapy and found that treatment with salmon calcitonin, either by injection or
intranasally, prevented bone loss at the lumbar spine
(70). In a recent randomized, 2-year, placebo-controlled
study of patients with temporal arteritis and polymyalgia
rheumatica, Healey and colleagues found that the lumbar spine BMD of patients who received injections of
salmon calcitonin remained stable but did not increase
(71). Thus, calcitonin appears to be effective for both the
primary and secondary prevention of glucocorticoidinduced bone loss. A multicenter trial of intranasal
salmon calcitonin in the treatment of glucocorticoidinduced osteoporosis has recently been completed; results are pending.
Anabolic steroids. Adami and Rossini performed
an 18-month controlled trial in 35 postmenopausal
women receiving long-term glucocorticoid therapy (72).
Patients who received nandrolone decanoate (50 mg
intramuscularly every 3 weeks) had a rapid increase in
forearm BMD at 6 months, which was sustained, while
controls had a decline in BMD. The authors suggested
that anabolic steroids could be used for the treatment of
glucocorticoid-induced osteoporosis. The Task Force
believes that further controlled trials of the efficacy of
anabolic steroids in patients with glucocorticoid-induced
osteoporosis need to be conducted before these agents
can be recommended for therapy.
Fluoride. Greenwald and colleagues administered a slow-release enteric-coated preparation of sodium fluoride, 20-30 mg/day, to 10 patients who had
glucocorticoid-induced osteoporosis (73). Patients had a
mean annual increase of 18.7% in lumbar spine BMD
despite the continued use of corticosteroids; there was
no significant change in BMD at the femoral neck. None
of the patients reported adverse effects from the sodium
fluoride treatment; one patient sustained a vertebral
compression fracture after 14 months of therapy. The
authors suggested that controlled trials of the efficacy of
sodium fluoride should be conducted in patients with
glucocorticoid-induced osteoporosis. The Task Force
agrees and further recommends that such trials utilize
low-dose slow-release preparations of sodium fluoride.
Approach to the patient receiving long-term
glucocorticoid treatment who has an osteoporotic
fracture
The initial visit for a patient who has been treated
long term with glucocorticoids and has sustained an
1795
Table 1. Initial evaluation of a patient taking glucocorticoids who
has a nontraumatic fracture
History and physical
Documentation of height, weight, muscle strength, balance, vision
Documentation of medication history
Documentation of menstrual history in menstruating women/
infertility in men
Family history (mother and father) of fractures
Lifestyle modification
Documentation of modifiable influences
Calcium and vitamin D intake
Smoking
Medications
Prevention of falling
Alcohol intake
Patient education
Prevention of falling
Physical therapy
Back extension exercises
Posture training
Balance
Gait evaluation
Assistive devices
Kypho-orthosis (as needed)
Pain control
Nonpharmacologic strategies
Calcitonin (intranasal or injectable)
Muscle relaxants
Analgesics; narcotics when necessary
Laboratory
Complete blood cell count
Erythrocyte sedimentation rate
Serum creatinine
24-hour urinary calcium
Serum calcium
Serum phosphorus
Serum alkaline phosphatase
Serum electrolytes
Serum 25-hydroxyvitamin D
Serum testosterone (male)
Serum luteinizing hormone (female)
Serum albumin
Serum levels of liver enzyme
Dual-energy x-ray absorptiometry
Hip (all patients)
Spine (patients below age 60)
osteoporotic fracture should include a history and physical examination that documents potentially modifiable
risk factors for osteoporosis, including dietary calcium
and vitamin D intake, smoking history, alcohol consumption, medication use, and menstrual history in
women and, in men, any history of infertility or impotence (Table 1).In addition, the history should include a
survey of potentially modifiable risk factors for falls and
fractures. Physical examination should include a measure of height and weight, tests of lower extremity
muscle strength and balance (e.g., arising from a seated
position to a standing position [chair stands], and attempts to stand with the feet next to one another
[tandem stands]), and tests of visual acuity and depth
perception (74,75). Laboratory tests should focus on
.
1796
ACR TASK FORCE ON OSTEOPOROSIS GUIDELINES
1
I
Initial Visit (see Table 1)
1
Physical Therapy
Patient Education
1
Communicate results of initial visit within 2 weeks
DXA: T score 1 -1
Normal lab results
DXA: T score 2 -1
Abnormal lab results
Calcium and Vitamin D
supplementation
Reinforce physical
therapy
Calcium and Vitamin D
supplementation
Reinforce physical
therapy
HRT (see Table 2)
Treat underlying causes
(see Table 3)
Reinforce physical
therapy
Treat underlying
conditions
Reinforce physical
therapy
Calcium and Vitamin D
supplementation
HRT
Calcium and Vitamin D
supplementation
Normal lab results
DXA: T score c -1
Abnormal lab results
HRT
Figure 1. Approach to the patient receiving long-term treatment with glucocorticoids who has an osteoporotic fracture. DXA
dual-energy x-ray absorptiometry; HRT = hormone replacement therapy.
identifying secondary causes of osteoporosis and assessing urinary calcium excretion. The tests should include a
complete blood cell count, erythrocyte sedimentation
rate, serum electrolytes, calcium, phosphorus, alkaline
phosphatase, creatinine, and 25-hydroxyvitamin D,
among others, and a 24-hour urine collection to quantify
urinary calcium excretion; men should also have a serum
testosterone level determined. As part of the initial
evaluation, DXA of the hip and/or spine should be done
to measure BMD.
After the history, physical examination, and laboratory tests have been obtained, treatment should be
initiated. First, the patient may require analgesia for the
recent fracture. Simple analgesics including acetaminophen or nonsteroidal antiinflammatory drugs may be
tried; if found to be insufficient, short-acting narcotic
analgesics or intranasal or subcutaneous calcitonin can
be prescribed. The analgesic effects of calcitonin have
been documented with both the subcutaneous and
intranasal preparations (69,76). Treatment with calcitonin is recommended until the pain is controlled,
=
then the medication can be tapered over the next 4-6
weeks.
At the initial visit, the patient should also be
given educational materials about glucocorticoidinduced bone loss and instructed in lifestyle modifications. Since glucocorticoids reduce muscle mass, patients
should be educated by the physician or a physical
therapist regarding exercises they can perform to maintain or increase muscle strength. Also, patients who have
sustained an osteoporotic fracture should receive a
balance and gait evaluation. All patients who have
osteoporosis should receive posture training, back extension exercises, assistive devices, and kypho-orthoses as
needed, as well as nonpharmacologic strategies to control acute and chronic pain (77). Patients with a vertebral compression fracture need to avoid bending and
lifting, because these movements may increase the biomechanical forces in the vertebrae and lead to additional
fractures. Furthermore, exercises which involve back
flexion, including sit-ups and toe-touches, should be
avoided as well.
TREATMENT OF STEROID-INDUCED OSTEOPOROSIS
Recommendations for pharmacologic therapy
will depend on the results of laboratory tests and the
DXA measurement (Figure 1).These should be given to
the patient at a followup visit within 2 weeks of the initial
visit. Depending on the BMD measurement, a number
of different treatment options are available to the physician and patient. In general, wlcium and vitamin D
supplementation and patient education and physical
therapy are recommended for all patients.
If the BMD measurement is abnormal (i.e., T
score >-1 [see above]), gonadotropin H R T is recommended for all patients (Table 2). HRT should be
recommended for postmenopausal women, an oral contraceptive containing the equivalent of 50 pg of estradiol
recommended for premenopausal women with menstrual irregularities, and testosterone replacement for
men if serum testosterone levels are found to be low.
Patients in whom H R T is contraindicated or refused
should receive other antiresorptive agents such as
bisphosphonates or calcitonin. The Task Force thought
that, at this time, it could not recommend the use of
bisphosphonates in premenopausal women and men
under age 50 because of a lack of data about long-term
safety. In patients with osteoporotic fractures who have
failed to improve with the above therapeutic interventions, consideration may be given to the use of combinations of antiresorptive agents or the use of investigational anabolic agents (e.g., anabolic steroids or
fluoride). Such therapies should only be administered by
specialists in the treatment of patients with osteoporosis
and metabolic bone disease.
Patients who are receiving long-term steroid therapy who sustain an osteoporotic fracture and have a
normal BMD and normal laboratory values should have
Table 2.
Hormone replacement therapy*
~~
~~~
May elect to initiate immediately or after results of DXA reveal a
BMD T score 2-1. (Adjustment of testosterone levels in men
should be considered only after results of DXA reveal a BMD
T score 2 - 1.)
Postmenopausal women
Estrogen replacement therapy: A progestin must be added for any
woman with an intact uterus. If refused or contraindicated,
prescribe calcitonin or bisphosphonates.
Premenopausal women with intact ovarian function (ages 13-50)
Estrogen-containing oral contraceptives (minimum of 50 pg of
estradiol or equivalent). If refused or contraindicated, prescribe
calcitonin.
Men
Testosterone (if serum testosterone abnormally low). If refused or
contraindicated, prescribe calcitonin or bisphosphonates.
* DXA
density.
=
dual-energy x-ray absorptiometry; BMD
=
bone mineral
1797
Followup for abnormal laboratory findings in patients
taking glucocorticoids who have a nontraumatic fracture
Table 3.
Abnormal finding
Followup evaluation
High serum calcium, low serum
phosphorus, low urinary calcium
Low serum calcium, low serum
phosphorus, low urinary calcium
Taking thyroid replacement
Measure intact parathyroid
hormone
Measure 25-hydroxyvitamin D
High serum creatinine
Elevated 24-hour urinary calcium
Elevated total protein or serum
globulin
Measure thyroid-stimulating
hormone
Evaluate for renal
osteodystrophy
Add thiazide diuretic with
potassium supplement
Obtain serum protein
electrophoresis and
serum and urine
i mm u noelect rophoresis
a further evaluation as to the cause of their fracture.
Patients taking long-term steroids who have abnormal
laboratory values, irrespective of the BMD results,
should undergo further evaluation (Table 3). The most
common causes of osteoporosis in the setting of abnormal laboratory findings unrelated to steroids include
hyperparathyroidism, osteomalacia, thyroid disease or
over-supplementation with thyroid medication, renal
osteodystrophy syndromes, and multiple myeloma. Appropriate laboratory tests should be ordered for further
evaluation of these diseases.
A followup visit should be scheduled in 6-12
months. At that time, a repeat BMD measurement
should be obtained to determine the efficacy of the
therapeutic interventions. In general, if the BMD is
increased, has remained stable, or declined less than 5%,
it is reasonable to continue the present therapy. If the
BMD loss over the 12-month period is more than 5%,
either alternative or additional therapy may be required.
If the patient had been receiving HRT, consideration
should be given to either the addition or substitution of
either a bisphosphonate or calcitonin to the regimen.
Approach to the patient receiving long-term
glucocorticoid treatment who does not have a fracture
The evaluation is similar to that outlined above.
At the initial evaluation a detailed history and physical
examination is performed, laboratory tests obtained and
a DXA measurement for BMD is recommended. All
patients should be given patient education, a referral for
a physical therapy appointment, calcium and vitamin D
supplementation, as well as H R T in postmenopausal
women. If the BMD measurement is normal, no further
therapy is indicated other than a return visit at 1 month
ACR TASK FORCE ON OSTEOPOROSIS GUIDELINES
1798
Initial Visit (see Table 1)
Calcium and Vitamin D Supplementation
Patient Education
Communicate results of initial visit within 2 weeks
LL
DXA: T score 2 -1
HRT (see Table 2)
m
DXA: T score c -1
HRT only in
postmenopausalwomen
Figure 2. Approach to the patient starting long-term glucocorticoid
treatment. DXA = dual-energy x-ray absorptiometry; HRT = hormone replacement therapy.
to adjust the calcium supplementation or for the addition of a thiazide diuretic if hypercalciuria is detected.
Although no studies have been performed of the role of
exercise in patients with glucocorticoid-induced osteoporosis, several studies have documented the effectiveness of weight-bearing and resistive exercise in postmenopausal women with low BMD (78,79). For patients
on long-term steroids with an abnormal BMD and/or
abnormal laboratory tests, all recommendations remain
the same as those for patients with an osteoporotic
fracture.
Approach to the patient who is beginning long-term
glucocorticoid treatment
Given that bone is lost most rapidly during the
first 6 months of steroid use, primary prevention measures should begin as soon as steroids are prescribed.
Importantly, attempts to preserve bone should not be
delayed until the underlying disease process is quiescent.
On the initial visit when the patient is about to initiate
long-term steroid therapy, a complete history should be
obtained with a special emphasis on modifiable risk
factors for osteoporosis (Figure 2). The history should
include a review of medications that increase the risk of
osteoporosis, including thyroid hormone replacement,
diphenylhydantoin, long-term coumadin or heparin,
cyclosporin A, and antigonadotropins, including
gonadotropin-releasing hormone agonists. The physical
examination should include a measurement of height (in
bare feet) and weight, and evaluation of balance and
muscle strength.
As part of this evaluation, a BMD measurement
of the spine and hip should be obtained; this measurement can determine the patient’s risk of osteoporosis
independent of glucocorticoid therapy, and provides a
baseline measurement for monitoring changes in bone
mass. The results of this measurement may help patient
compliance with the therapy (SO). After the BMD
measurement, the patient should be educated about
glucocorticoid-induced bone loss and lifestyle modifications they can make to prevent bone loss. Since steroids
alter muscle mass, patients should be educated by the
physician or a physical therapist about exercises they can
perform to maintain muscle strength while taking steroids. Also, for elderly patients or patients who have
problems with their balance, education on fall prevention should be provided. For all patients starting steroids, calcium and vitamin D supplementation should be
initiated. Further therapy depends on the results of the
DXA measurement. Patients who have an abnormal
BMD value (i.e., T score >- 1) for their lumbar spine or
hip should initiate HRT. If there are contraindications
to HRT, a bisphosphonate or calcitonin should be
started. If the BMD of the lumbar spine and hip is
normal, calcium and vitamin D supplementation should
be started, and postmenopausal women should be encouraged to initiate H R T for general health reasons,
unless contraindicated, while taking steroids.
Approximately 1 month after starting therapy,
the patient should return and a 24-hour urine should be
obtained to measure calcium excretion. If the urinary
calcium is >300 mg/day and the patient is not taking
calcitriol, a thiazide diuretic with or without potassium
supplementation should be added. If the urine calcium is
>300 mg/day and the patient is taking calcitriol, the
dosage of either the calcium supplement or calcitriol
should be adjusted. Six or 12 months after the initiation
of steroids, a repeat BMD measurement should be done
to determine the efficacy of the therapeutic interventions. If the BMD has decreased more than 5% from
baseline, the medication can be changed or another one
added. If the BMD measurement has increased, remained stable, or declined less than 5% from baseline,
no change in therapy is required.
Prevention and treatment of glucocorticoid-induced
bone loss in children
Glucocorticoid-induced osteoporosis and associated fractures are a common complication in children
TREATMENT OF STEROID-INDUCED OSTEOPOROSIS
and adolescents, for scvcral reasons. First, childhood
and adolescence arc a time of high bone turnover, with
very high rates of bone formation being required to
maintain adequate mineralization of the rapidly growing
skeleton. Second, the use of glucocorticoids during
adolescence may prevent the patient from reaching
hidher peak bone mass (81), since glucocorticoids are
potent inhibitors of bone formation. Finally, a numbcr of
pediatric disorders for which glucocorticoids are prcscribed
are indepcndently associated with osteoporosis (82).
Methods of monitoring bone mincralization in
childrcn and adolescents arc similar to those in adults.
DXA has been shown to be rcliable and safc, and
normal valucs for BMD havc bcen established for
healthy children and adolescents (83). Treatment issues,
however, differ between children and adults. Only a fcw,
small. open, short-tcrm studies of pharmacologic approaches to increasing BMD in children havc been
publishcd. Although these results are promising, larger
controlled studics of longcr duration will be required
before these agents can be broadly recommended for
use in children. Fortunately. significant improvement in
BMD can often be achieved with oral administration of
calcium and vitamin D (84).
In a crossover study of childrcn with rheumatic
diseases receiving glucocorticoid therapy, significant improvement in BMD was demonstrated after 6 months of
treatment with a combination of 1.000 mg/day of calcium
and 400 IU/day of vitamin D. At this time, thc most
prudent approach to minimizing the negative effcct of
glucocorticoids on BMD is by ensuring that patients
consistently ingest, through either dict or supplements,
the following daily calcium intake: 800 mg/day at ages
1-5 years, 1,200 mg/day at ages 6-10 years, and 1,500
mg/day at ages 11-24 years (85). I n addition, all children
should reccivc at lcast 400 IU/day of vitamin D. Currently, a number of studies are being performed that will
hopefully address the role of other forms of interventions for glucocorticoid-induced osteoporosis in children
and adolescents.
Future therapeutic possibilities
Much work remains to be donc to improve o u r
management of glucocorticoid-induccd osteoporosis.
Future possibilities for treatmcnt include attempts to
stimulate growth factors in bone that arc altered by
glucocorticoids, such as insulin-like growth factor 1 and
transforming growth factor p. Therapics that stimulatc
the osteoblast include intermittent PTH, and recombinant human growth hormone (hGH). In glucocorticoid-
1799
treated children, hGH has been shown to improve
protein balance and to stimulate collagen synthcsis and
linear growth (86). Another area under invcstigation is
the use of biochemical markers of bone tumovcr to
assess the cffccts of treatment on glucocorticoid-induced
changes in bone formation and resorption. Markers of
bone formation includc serum levels of osteocalcin and
bone-specific alkaline phosphatase; markers of bone
resorption include urinary excretion of deoxypyridinoline and n-telopeptidc crosslinks of collagen (87). These
markers have been used extensively in studies of antiresorptivc agents in postmenopausal women and are just
beginning to be used to evaluate bone metabolism in
glucocorticoid-treatcd patients. In the future, thcy may
prove useful in monitoring response to therapy in
glucocorticoid-treatcd patients.
Conclusions
Glucocorticoid therapy at doses of 7.5 mg/day of
prednisone or abovc for 6 months or more often rcsults
in a rapid loss of trabecular bone in the spine, hip, and
forcarm. Corticosteroids act through multiple mechanisms to promote skcletal loss, and preventive measures
include selecting the lowest possible steroid dose. It is
reasonable to measure BMD in all individuals who
appear likcly to be taking corticosteroids long term, and
to begin preventive therapies as soon as the clinical
situation permits. Calcium and vitamin D supplements,
sex hormone replacement, and a weight-bearing exercise
program that maintains muscle mass arc suitable firstline thcrapies. lhiazide diuretics and sodium restriction
are useful in reducing the hypercalciuria associated with
glucocorticoid use. In paticnts who 1) are unablc to take
sex hormone replacement, 2) havc cstablished osteoporosis, or 3) are showing deterioration in Bh4D dcspite
these interventions, other agents, including bisphosphonates or calcitonin, are indicated. In the future, the
availability of agents that stimulatle bone formation in
the presence of glucocorticoids may make the prevcntion and trcatment of this condition much more straightforward. Thcsc recommendations will be updated as new
therapies for preventing and treating this condition
become available.
REFERENCES
1. iMitchcll DR. Lyles KW: Glucocorticoid-induccd osteoporosis:
mechanisms for bone loss; evaluation of strategies for prevention.
J Gcrontol 45:M153-M155. 1990
2. Lukert BP, R a w LG: (jlucocorticoid-induced osteoporosis:
1800
ACR TASK FORCE ON OSTEOPOROSIS GUIDELINES
pathogenesis and management. Ann Intern Med 112352-364,
1990
3. Smith R: Corticosteroids and osteoporosis. Thorax 45573-578,
1990
4. Libanati CR, Baylink DJ: Prevention and treatment of
glucocorticoid-induced osteoporosis: a pathogenetic perspective.
Chest 102:1426-1435, 1992
5. Adachi JD, Bensen WG, Hodsman AB: Corticosteroid-induced
osteoporosis. Semin Arthritis Rheum 22375-384. 1993
6. Hahn TJ: Steroid and drug induced osteoporosis. In, Primer on the
Metabolic Bone Diseases and Disorders of Mineral Metabolism.
Second edition. Edited by MJ Favus. New York, Raven Press, 1993
7. Olbricht T, Benker G: Glucocorticoid-induced osteoporosis:
pathogenesis, prevention and treatment, with special regard to the
rheumatic diseases. J Intern Med 234:237-244, 1993
8. Reid IR. Grey AB: Corticosteroid osteoporosis. Baillieres Clin
Rheumatol 7573-587, 1993
9. Lukert BP, Raisz LG: Glucocorticoid-induced osteoporosis.
Rheum Dis Clin North Am 20:630-651, 1994
10. Joseph JC: Corticosteroid-induced osteoporosis. Am J Hosp
Pharm 51:188-197, 1994
11. Sambrook PN, Jones G: Corticosteroid osteoporosis. Br J Rheumatol 348-12, 1995
12. Eastell R on behalf of a UK Consensus Group Meeting on
Osteoporosis: Management of corticosteroid-induced osteoporosis. J Intern Med 237:439-447, 1995
13. Lane NE,Mroczkowski PJ, Hochberg MC: Prevention and management of glucocorticoid-induced osteoporosis. Bull Rheum Dis
44:l-4, 1995
14. Dequeker J, Westhovens R: Low d,ose corticosteroid associated
osteoporosis in rheumatoid arthritis and its prophylaxis and treatment: bones of contention. J Rheumatol 22:1013-1019, 1995
15. Hahn BH: Glucocorticoid-induced osteoporosis. Hosp Pract 4556, 1395
16. Gulko PS, Mulloy AL: Glucocorticoid-induced osteoporosis:
pathogenesis, prevention and treatment. Clin Exp Rheumatol
141199-206, 1996
17. Adinoff AD, Hollister JR: Steroid-induced fractures and bone loss
in patients with asthma. N Engl J Med 309265-268, 1983
18. Verstraeten A, Dequeker J: Vertebral and peripheral bone mineral content and fracture evidence in postmenopausal patients
with rheumatoid arthritis: effect of low dose corticosteroids. Ann
Rheum Dis 45:852-857, 1986.
19. Dykman TR, Gluck OS, Murphy WA, Hahn TJ, Hahn BH:
Evaluation of factors associated with glucocorticoid-induced osteopenia in patients with rheumatic diseases. Arthritis Rheum 28:
361-368, 1985
20. Michel BA, Bloch DA, Fries JF: Predictors of fractures in early
rheumatoid arthritis. J Rheumatol 18304-808, 1991
21. Michel BA, Bloch P.4, Wolfe F, Fries J F Fractures in rheumatoid
arthritis: an evaluation of associated risk factors. J Rheumatol
20:1666-1669, 1993
22. Cooper C, Coupland C, Mitchell M: Rheumatoid arthritis, corticosteroid therapy and hip fracture. Ann Rheum Dis 54:49-52, 1994
23 Saag KG, Koehnke R, Caldwell JR, Brasington R, Burmeister LF,
Zimmerman B, Kohler JA, Furst DE: Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious
adverse events. Am J Med 96:115-123, 1994
24 Marystone JF, Barrett-Connor EL, Morton DJ: Inhaled and oral
corticosteroids: their effect on bone mineral density in older
adults. Am J Public Health 85:1693-1695, 1995
25 Gluck OS,Murphy WA, Hahn TJ, Hahn BH: Bone loss in adults
receiving alternate day glucocorticoid therapy: a comparison with
daily therapy. Arthritis Rheum 242392-898, 1981
26. Ruegsegger F, Medici TC, Anliker M: Corticosteroid-induced
bone loss: a longitudinal study of alternate day therapy in patients
with bronchial asthma using quantitative computed tomography.
Eur J Clin Pharmacol 25:615-620, 1994
27. Ward MJ: Inhaled corticosteroids-effect on bone? Respir Med
87 (SUPP~
A):33-36, 1993
28. Boyd G: Effect of inhaled corticosteroids on bone. Respir Med 88
(suppl A):45-54, 1994
29. Hanania NA, Chapman KR, Sturtridge WC, Szalai JP, Kesten S:
Dose-related decrease in bone density among asthmatic patients
treated with inhaled corticosteroids. J Allergy Clin Immunol
96~571-579, 1995
30. Klein RG, Arnaud SB, Gallagher JC, Deluca HF, Riggs BL:
Intestinal calcium absorption in exogenous hypercortisolism: role
of 25-hydroxyvitamin D and corticosteraid dose. J Clin Invest
64:655-665, 1977
31. Hahn TJ, Halstead LR, Teitelbaum SL, Hahn BH: Altered
mineral metabolism in glucocorticoid-induced osteopenia: effect
of 25-hydroxy vitamin D. administration. J Clin Invest 64:655-665,
1979
32. Suzuki Y, Ichikawa Y, Saito E, Homma M: Importance of
increased urinary calcium excretion in the development of secondary hyperparathyroidism of patients under glucocorticoid therapy.
Metabolism 321.51-156, 1983
33. Brandli DW, Golde G , Cireenwald M, Silverman SL:
Glucocorticoid-induced osteoporosis: a cross-sectional study. Steroids 56518-523, 1991
34. Seeman E, Kumar R, Huder GG, Scott M, Heath H, R i g s B L
Production, degradation and circulating levels of 1,25-dihydroxy
vitamin D in health and in chronic glucocorticoid excess. J Clin
Invest 66:664-669, 1980
35. Hsueh AJ, Erickson G F Glucocorticoid inhibition of FSHinduced estrogen production in cultured rat granulosa cells. Steroids 32639-648;1978
36. MacAdams MR, White RH, Chipps BE: Reduction in serum
testosterone levels during chronic glucocorticoid therapy. Ann
Intern Med 104:648-651, 1986
37. Reid IR, France JT, Pybus J, Ibbertson H K Low plasma testosterone levels in glucocorticoid-treated male asthmatics. BMJ
291574-578, 1985
38. Dempster DW, Arlot MA, Meunier PI: Mean wall thickness and
formation periods of trabecular bone packets in corticosteroidinduced osteoporosis. Calcif Tissue Int 35410-417, 1983
39. Gronowicz G, McCarthy MB: Glucocorticoids inhibit the attachment of osteoblasts to bone extracellular matrix proteins and
decreases p-1 integrin levels. Endocrinology 136598-608, 1995
40. Hughes-Fulford M, Blaug S: Down regulation of c-fos and cell
growth with upregulation of p53 oncogene in glucocorticoid
treated osteoblasts (abstract). J Bone Miner Res 8:S365, 1993
41. Canalis EM: Effect of glucocorticoids on type I collagen synthesis,
alkaline phosphatase activity, and deoxyribonucleic acid content in
cultured rat calvariae. Endocrinology 112:931-939, 1983
42. Jonsson KB,Ljunghall S, Karlstrom 0, Johansson AG, Mallmain
H, Ljunggren 0: Insulin-like growth factor I enhances the formation of type I collagen in hydrocortisone-treated human osteoblasts. Biosci Rep 13297-302. 1993
43. Centrella M, McCarthy TL, Canalis E: Glucocorticoid control of
transforming growth factor p activity and binding and effects in
osteoblast-enriched cultures from fetal rat bone. Mol Cell Biol
11:4490-4496, 1991
44. Genant HK,Engelke K, Fuerst T, Gluer CC, Grampp S, Harris
ST, Jergas M, Lang T, Lu Y, Majumdar S, Mathur A, Takada M:
Noninvasive assessment of bone mineral and structure: state of the
art. J Bone Miner Res 11:707-730, 1996
45. Miller PD, Bonnick SL, Rosen GI,for the Society for Clinical
Densitometry: Clinical utility of bone mass measurement in adults:
consensus of an international panel. Semin Arthritis Rheum
25:361-372, 1996
46. Johnston CC Jr, Melton LJ 111, Lindsay R, Eddy DM: Clinical
TREATMENT OF STEROID-INDUCED OSTEOPOROSIS
indications for bone mass measurements: a report from the
Scientific Advisory Board of the National Osteoporosis Foundation. J Bone Miner Res 4 (suppl 2):l-28, 1989
47. Yu W, Gluer CC, Fuerst T, Grampp S, Li J, Lu Y , Genant HK:
Influence of degenerative joint disease on spinal bone mineral
measurements in postmenopausal women. Calcif Tissue Int 57:
169-174, 1995
48. Lufkin EG, Wahner HW, Bergstralh EJ: Reversibility of steroidindu.ced osteoporosis. A m J Med 85:887-885, 1988
49. Reid IR, Ibbertson HK: Calcium supplements in the prevention of
steroid-induced osteoporosis. Am J Clin Nutr 44:287-290, 1986
50. Hahn TJ, Hahn BH: Osteopenia in patients with rheumatic
diseases: principles of diagnosis and therapy. Semin Arthritis
Rheum 6:165-188, 1976
51. Adachi JD, Bensen WG, Bianchi F, Cividino A, Pillersdorf S,
Sebaldt RJ, Tugwell P, Gordon M, Steele M, Webber C, Goldsmith CH: Vitamin D and calcium in the prevention of corticosteroid induced osteoporosis: a 3 year followup. J Rheumatol
23:995-1000, 1996
52. Sambrook P, Birmingham J, Kelly P, Kempler S, Nguyen T,
Pocock N, Eisman J: Prevention of corticosteroid osteoporosis: a
comparison of calcium, ci$citriol, and calcitonin. N Engl J Med
328:1747-1752, 1993
53. A d a m JS, Wahl TO, Lukert BP: Effects of hydrochlorothiazide
and dietary sodium restriction on calcium metabolism in corticosteroid treated patients. Metabolism 30:217-221, 1981
54. Cauley JA, Cummings SR, Seeley DG, Black D, Browner W,
Kuller LH, Nevitt MC: Effects of thiazide diuretic therapy on bone
mass. fractures and falls: The Study of 'Osteoporotic Fractures
Research Group. Ann Intern Med 118:666-673, 1993
55. Morton DJ, Barrett-Connor EL, Edelstein S L Thiazides and bone
mineral density in elderly men and women. Am J Epidemiol
139:1107-1115, 1994
56. Jones G, Nguyen T. Sambrook PH, Eisman JA: Thiazide diuretics
and fractures: can meta-analysis help? J Bone Miner Res 10:106111, 1995
57. Lukert BP, Johnson BE, Robinson RG: Estrogen and progesterone replacement therapy reduces glucocorticoid-induced bone
loss. J Bone Miner Res 7:1063-1069, 1992
58. Hall GM, Daniels M, Doyle DV, Spector TD: Effect of hormone
replacement therapy on bone mass in rheumatoid arthritis patients
treated with and without steroids. Arthritis Rheum 37:1499-1505,
1994
59. Sowers MFR, Galuska DA: Epidemiology of bone mass in premenopausal women. Epidemiol Rev 15:374-398, 1993
60. Reid IR, Wattie DJ, Evans MC, Stapleton JP: Testosterone
therapy in glucocorticoid-treated men. Arch Intern Med 156:11731177, 1996
61. Bagatell CJ, Bremner WJ: Androgens in men-uses and abqses.
N Engl J Med 334707714, 1996
62. Rodan GA, Fleisch HA: Bisphosphonates: mechanisms of action.
J Clin Invest 97:2692-2696, 1996
63. Mulder H, Struys A: Intermittent cyclical etidronate in the prevention of corticosteroid-induced bone loss. Br J Rheumatol
33:348-350, 1994
64. Diamond T, McGuigan L, BarbagaUo S, Bryant C: Cyclical
etidronate plus ergocalciferol prevents glucocorticoid-induced
bone loss in postmenopausal women. Am J Med 98:459-463,1995
65. Adachi JD, Cranney A, Goldsmith CH. Bensen WG, Bianchi F,
Cividino A, Craig GL, Kaminska E, Sebaldt RJ, Papaioannou A,
Boratto M, Gordon M, Steele M: Intermittent cyclic therapy with
etidronate in the prevention of corticosteroid induced bone loss.
J Rheumatol 21:1922-1926, 1994
66. Struys A, Snelder AA, Mulder H: Cyclical etidronate reverses
bone loss of the spine and proximal femur in patients with
1801
established corticosteroid-induced osteoporosis. Am J Med 99:
235-242, 1995
67. Reid IR. King AR, Alexander CJ, Ibbertson H K Prevention of
steroid-induced osteoporosis with (3-amino-1-hydroxypropy1idene)1,l-bisphosphonate (APD). Lancet 1:143-146, 1988
68. Reid IR, Heap SW, King AR, Ibbertson HK: Two-year followup of
biphosphonate (APD) treatment in steroid osteoporosis. Lancet
21144-1145, 1988
69. Ringe JD, Welzel D: Salmon calcitonin in the therapy of corticosteroid-induced osteoporosis. Eur J Clin Pharmacol 33:35-39,
1987
70. Montemorro L, Schiraldi G, Fraioli P, Tosi G , Ribddi A, Rizzato
G: Prevention of corticosteroid-induced osteoporosis with salmon
calcitonin in sarcoid patients. Calcif Tissue Int 49:71-76, 1991
71. Healey J. Paget S, Williams-Russo P, Szatrowski T, Schneider R,
Spiera H, Mitnick H, Ales K, Schwartzberg P: Randomized trial of
salmon calcitonin to prevent bone loss in corticosteroid-treated
temporal arteritis and polymyalgia rheumatica. Calcif Tissue Int
58173-80, 1996
72. Adami S, Rossini M: Anabolic steroids in corticosteroid-induced
osteoporosis. Wien Med Wochenschr 44:395-397, 1993
73. Greenwald 'M, Brandli D, Spector S, Silverman S, Golde G:
Corticosteroid-induced osteoporosis: effects of a treatment with
slow-release sodium fluoride. Osteoporosis Int 2203-204, 1992
74. Tinetti ME: Performance-oriented assessment of mobility problems in elderly patients. J Am Geriatr SOC34:119-126, 1986
75. Rubenstein LZ, Robbins AS, Josephson KR, Schulman BL,
Osterweil D The value of assessing falls in an elderly population.
Ann Intern Med 113308-316, 1990
76. Pun KK,Chan LWL Analgesic effect of intranasal salmon calcitonin in the treatment of osteoporotic vertebral fractures. Clin
Ther 11205-209, 1989
77. Sinaki M: Musculoskeletal rehabilitation. In, Osteoporosis: Etiology, Diagnosis, and Management. Second edition. Edited by BL
Riggs, LJ Melton 111. Philadelphia, Lippincott-Raven, 1995
78. Simkin A, Ayalon J, Leichter.1 Increased trabecular bone density
due to bone-loading exercises in postmenopausal osteoporotic
women. Calcif Tissue Int 40:59-63, 1987
79. Dalsky GP, Stocke KS, Ehsani AA, Slatopolsky E, Lee WC, Birge
SJ: Weight-bearing exercise training and lumbar bone mineral
content in postmenopausal women. Ann Intern Med 108:824-828,
1988
80. Rubin S, Cummings S: Results of bone densitometry affect
women's decisions. Ann Intern Med 116:990-995, 1992
81. Slemenda CW, Reister TK, Hui SL, Miller JZX, Christian JC,
Johnston CC: Influences on skeletal mineralization in children and
adolescents: evidence for varying effects of sexual maturation and
physical activity. J Pediatr 125:201-207, 1994
82. Kreipe RE: Bones of today, bones of tomorrow. Am J Dis Child
14622-25, 1992'
83. Thomas KA, Cook SD, Bennett JT: Femoral neck and lumbar
spine bone mineral densities in a normal population 3-20 years of
age. J Pediatr Orthop 11:48-58, 1991
84. Warady BD, Lindsley CB, Robinson RG, Lukert BP: Effects of
nutritional supplementation on bone mineral status of children
with rheumatic diseases receiving coflicosteroid therapy. J Rheulnatol 21530-535, 1994
85. NIH Consensus Development Panel on Optimal Calcium Intake:
Optimal calcium intake. JAMA 2721942-1947, 1994
86. Allen DB, Goldberg BD: Stimulation of collagen synthesis and
linear growth by growth hormone in glucocorticoid-treated children. Pediatrics 89:416-421, 1984
87. Taylor AK, Leuken SA, Libanati C, Baylink DJ: Biochemical
markers of. bone turnover for the clinical assessment of bone
metabolism. Rheum Dis Clin North Am 20:589-607, 1994
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