162 / 236
Bone Metabolism
The role of steroids in bone loss is well described and may occur
through several different mechanisms. First, steroids reduce intestinal
calcium absorption; increase urinary calcium excretion, which stim-
ulates parathyroid hormone production; and increase osteoclast ac-
tivity and release calcium into the blood stream. In addition, steroids
inhibit osteoblast activity, which negatively impacts trabecular bone
formation.
21,22
Corticosteroids also suppress the production of adre-
nal androgens, which decreases their beneficial effect on bone forma-
tion.
22
Lastly, glucocorticoids have been found to cause apoptosis of
osteoblasts and osteocytes,
23
which has been shown to occur within
several weeks of use but slows after 6 months.
23
There are conflicting data as to whether a daily dose or a cumula-
tive dose has a more significant clinical effect on bone density. Frac-
ture risks have also been shown to increase based on dose, duration,
age, sex, and body weight.
4
Studies have demonstrated that supple-
mental calcium and vitamin D as well as bisphosphonates can help
reduce the corticosteroid-induced loss of bone mineral density.
4
Anal-
ysis of data indicates that these effects are reversible with cessation of
the steroids.
24
Avascular Necrosis
Corticosteroid use has also been associated with avascular necrosis
(AVN) or osteonecrosis. This complication has been correlated with
cumulative dose and has been seen primarily in the head of the
femur, although other bones can be affected.
21
The etiology is not
understood but is thought to be due to decreased blood flow or
impaired perfusion of the bone.
21,25,26
Two retrospective reviews of patients with AVN of the femoral
head outlined the steroid courses in those patients.
27,28
The first
review had a mean cumulative dose of 850 mg of prednisone (range,
290–3300 mg), and the mean duration of therapy was 20.5 days
(range, 6–39 days). The second review reported an AVN risk of 0.3%.
The mean cumulative dose was equivalent to 673 mg of prednisone
(range, 389–990 mg of prednisone equivalents), and the mean dura-
tion was 20 days (range, 15–27 days).
28
Ophthalmic
The most commonly encountered ophthalmologic adverse effects
include posterior-subcapsular cataract formation and increased intra-
ocular pressure or glaucoma.
29
The incidence seems to be dependent
on dose and duration of steroid use, with most doses of 10 mg daily
for at least 1 year before the onset of cataract formation.
29
How
steroids lead to cataracts is unclear. Theories include binding of lysine
residues that lead to opacities in the lens and coagulation of lens
proteins due to steroid impairment of the sodium-potassium pumps
of the lens.
29
Increased intraocular pressure can lead to visual field loss, optic
disc cupping, and optic nerve atrophy. Steroids can cause significant
increases in intraocular pressure in 5% of the patients within the
first few weeks of therapy, with up to 36% of patients developing at
least a moderate (5 mm Hg or higher) increase in pressure with
prolonged use.
22
The route of administration seems to play an impor-
tant role, with topical ophthalmic and systemic administration having
very high correlations with the incidence of glaucoma. The exact
mechanism by which corticosteroids cause glaucoma is unknown.
21,22
Gastrointestinal
Large meta-analyses of randomized, placebo-controlled trials failed
to show an association between steroid use and peptic ulcer dis-
ease.
9,30
Interestingly, these studies did find that patients who used
prednisone had peptic ulcer–type symptoms more frequently than
did the control patients. The researchers hypothesized that this may
be due to the lower sensitivity of barium studies that detect ulcers in
the preendoscopic era.
9
Adrenal Suppression
In the normal, nonstressed adult, the adrenal gland secretes the
equivalent of 5–7 mg of prednisone per day.
7,31
Exogenous steroids
increase the circulating corticosteroid levels, which can lead to a
negative feedback on the hypothalamic-pituitary-adrenal axis.
32
There is a lack of consistency in the dose of exogenous steroids
required for adrenal suppression due to individual variability as well
as the specific synthetic corticosteroid administered.
4,33
Postmortem
studies showed atrophy of adrenal glands after as few as 5 days of
corticosteroid therapy.
4
Retrospective studies identified no definitive
cases of adrenal suppression with prednisone doses 5 mg per day,
even if that dose is taken for many months; however, when the doses
were increased to 10 mg daily for only 4 days, there was a significant
decrease in plasma cortisol.
34,35
The incidence of clinically evident
adrenal insufficiency is unknown, yet it is believed to be much lower
than the incidence based on objective measures.
4
Psychiatric
The most common psychiatric manifestations of steroids include
agitation, anxiety, distractibility, fear, hypomania, indifference, in-
somnia, irritability, lethargy, mood lability, pressured speech, rest-
lessness, and tearfulness. Severe reactions include mania, depression,
or a mixed state.
36
There is a dramatic variability in the reported incidence of steroid-
induced psychiatric adverse effects, reflective of the unpredictability
of these reactions. A meta-analysis reported an incidence of 27.6%
(range, 13–62%) of individuals experienced mild-to-moderate psychi-
atric complications from corticosteroid use, whereas only 5.7% (range,
1.6–50%) reported severe complications.
37
Steroid dose has been found to be the most significant risk factor,
with a reported 1.3% incidence in patients who received a daily
prednisone dose of 40 mg. That risk increased to 18.4% in those who
received 80 mg daily.
38
The reduction of the dose resulted in reso-
lution of symptoms. Interestingly, a past reaction is not predictive of
a future reaction, nor is past tolerance predictive of future tolerance.
36
Additional studies have not been able to correlate a history of psy-
chiatric illness with a psychiatric reaction to prednisone.
39
LITIGATION
Several studies reviewed specific litigation that involved steroid
use. The National Association of Insurance Commissioners, the state
officials who oversee the insurance industry, reported their malprac-
tice claims in 1976. In their review, adrenal steroids accounted for
5.9% of claims.
40
In 1977, the California Medical Association and the
California Hospital Association reviewed 20,000 patient charts to
look for both claims filed and events that had the potential for
compensation but claims were not filed. They found that adrenocor-
ticoids were responsible for 7.6% of events.
40
A review performed by
the Physician Insurers Association of America studied lawsuit data
provided by the liability insurance companies within their associa-
tion.
41
The association reviewed 117,000 claims and found that med-
ication errors were the second most frequent reason for claims against
physicians and that steroids were the second most common drug
class implicated in the lawsuits, which involved 12% of the claims.
The Risk Management Foundation of the Harvard Medical Institution
analyzed the malpractice claims between 1990 and 1999.
42
Three
percent of the medication-related claims involved corticosteroids.
A review of the WESTLAW computerized legal database (Thomson
Reuters, New York, NY) searched for all jury verdict reports that
involved steroid use from 1996 to 2008.
43
Eighty-three cases that
involved steroid use were analyzed. The most common allegation
was AVN, which resulted from steroid use and accounted for 39% of
the cases. Changes in mood, including anxiety, depression, and psy-
chosis, were the second most common allegation, in 16%. Infection
and vision change each accounted for 12% of the allegations from
September–October 2015, Vol. 29, No. 5
140