Chapter 224

Systemic
Glucocorticoids
Victoria P. Werth

PHARMACOKINETICS
When hydrocortisone is given in moderate-to-high
doses, its mineralocorticoid effects can be deleterious, and thus synthetic analogues of cortisol have
been developed that have greater anti-inflammatory properties and cause less sodium retention.
Small substitutions on the basic steroid structure
of three hexanes and a pentane ring (eFig. 224-0.1,
eTable 224-0.1) account for the differences in plasma half-life and the relative anti-inflammatory and
sodium-retaining potencies (Table 224-1). In general, most synthetic analogues bind less efficiently
to CBG (about 70 percent binding). This property
may explain, in part, their tendency to cause side
effects at lower dosages. The 11--hydroxyl group
in cortisol is essential for activity. Because cortisone
and prednisone are 11-keto compounds, they are
active only after being converted in the liver to the
corresponding 11--hydroxyl compounds (cortisol
and prednisolone) (Table 224-0.1). Patients with
severe liver disease generally maintain their ability
to convert the 11-keto compounds; nevertheless,
some authorities suggest that only the converted
active compounds should be administered to these
patients.26

COMPLICATIONS
Indications for Estrogen and
Testosterone Replacement.
Premenopausal women who become amenorrheic because of glucocorticoids benefit from
hormone replacement therapy (HRT). Such therapy
helps to prevent the effects of glucocorticoids on
bone.78,79 For postmenopausal women, hormone
replacement therapy (HRT) is effective for preventing osteoporosis. The Womens Health Initiative, a
large randomized controlled primary prevention
trial, demonstrated that combined estrogen plus
progestin significantly reduced fractures at the hip,
vertebrae, and other sites compared to placebo.80
Total fracture reduction was 24%, with 34% fracture

reduction at the hip and 34% fracture reduction

at the vertebrae. However, the trial also revealed
that estrogen plus progestin is associated with an
increased risk of breast cancer and cardiovascular
disease. Therefore, the risks and benefits of HRT
should be thoroughly discussed with the patient
before initiation of such therapy.
Postmenopausal women can be treated with oral
conjugated estrogen, 0.625 mg/day. Women with
a uterus should also receive medroxyprogesterone,
2.5 mg/day, which prevents the increased endometrial carcinoma that occurs in women receiving
estrogen alone.81 Transdermal estradiol is also a
common route of drug delivery. Newer selective
estrogen receptor modulators, such as raloxifene,
offer the option of HRT to women previously unable to tolerate estrogens, and mimic the effects
of estrogen on bone and blood lipid levels without
the stimulatory effects on the breast and uterus.
Raloxifene has more modest effects than conjugated estrogens on bone resorption and formation
parameters, and is less effective in increasing bone
mineral density; its role in glucocorticoid-induced
osteoporosis has not been specifically studied.82
Women who are to receive hormonal therapy
should not have a history of benign or malignant
breast disease or other hormone-sensitive tumors,
thrombophlebitis, smoking, gallstones, or a family
history of breast cancer. Breast and pelvic examinations should be performed initially and at regular
6- to 12-month intervals during hormone therapy.
Glucocorticoids suppress serum testosterone
in men.83 Low serum testosterone is associated
with low bone density in hypogonadal men; bone
density increases in these men when they receive
supplemental testosterone.84 Testosterone partially
reverses the effects of glucocorticoids on bone.85,86
Men with low serum testosterone levels who are
receiving glucocorticoids should have testosterone
supplementation.87 Testosterone replacement therapy can be considered if a patient has a normal PSA,
and benign findings on prostate exam. Replacement is administered either by the intramuscular
route (testosterone enanthate or cypionate, 200 mg
IM every 2 weeks or 100 mg every week to avoid
cycling) or by testosterone patches (Androderm, 4
or 6 mg applied daily) or gel. Serum testosterone
should be checked after replacement to assure
adequate treatment.

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320 Chapter 224: Systemic Glucocorticoids

The increased osteolysis caused by steroids has

led to the use of a number of agents that inhibit
bone resorption, such as the bisphosphonates and
calcitonin. Inhibition of bone resorption leads to
recoupling of the remodeling unit, thereby preventing further bone loss. In addition, because bone
formation proceeds at a much slower pace than
resorption, antiresorptive drugs produce a period
of time up to 2 years where formation is greater
than resorption. Several intravenous and oral
bisphosphonates are now available. Bisphosphonates have revolutionized the approach to prevention and treatment of steroid-induced osteoporosis,
and have largely replaced hormonal approaches.
Oral bisphosphonates include alendronate, 70 mg/
week or 5 mg/day (10 mg/day for postmenopausal
women not on HRT); risedronate, 30 mg/week or 5
mg/day; etidronate, 400 mg/day for 2 weeks every
13 weeks; ibandronate, 150 mg/month. Intravenous preparations include pamidronate, 3060 mg
intravenously every 612 months or zoledronic acid
4 mg every 12 months. All agents increase vertebral bone mineral density and decrease vertebral
fractures in patients receiving glucocorticoids,
and alendronate and risedronate are currently
recommended for prevention and treatment of
glucocorticoid-induced osteoporosis.8896 There is
evidence for increased efficacy of zoledronic acid
over risedronate, but the more potent bisphosphonates also have increased risks.97 Patients starting
bisphosphonates should receive adequate calcium
and vitamin D intake before and after initiation of
bisphosphonate therapy.98
Nitrogen-containing bisphosphonates, including the more potent agents such as pamidronate
and zoledronic acid, have been associated with
avascular necrosis of the jaw, predominantly in
patients with underlying malignancies like multiple
myeloma.99102 Alendronate has rarely been associated with AVN of the jaw.103,104 The incidence of AVN
associated with oral bisphosphonate therapy for osteoporosis seems to be low, estimated at between
1 in 10,000 and <1 in 100,000 patient-treatment
years.104 Guidelines are evolving for potential ways
to avoid this complication, and include thorough
dental evaluation before prescribing bisphosphonates, identifying and treating any potential
sources of infection, emphasizing oral hygiene and
routine dental prophylaxis, delaying bisphospho-

nate therapy when dental health is suboptimal,

and if possible, and starting therapy 4 to 6 weeks
after invasive dental procedures are completed and
nonrestorable teeth are extracted.105
Intranasal calcitonin may increase bone mineral
density, but less effectively than the bisphosphonates, and it does not reduce the risk of vertebral
fractures.106,107 Calcitonin offers a treatment for
patients unable to tolerate the bisphosphonates
or unwilling to add another pill to their regimen. It
is considered a second-line agent for treatment of
osteoporosis and is not recommended for prevention of bone loss in early glucocorticoid therapy.73
It is used as one spray to one nostril daily, alternating nostrils each day to minimize local irritation.
Calcitonin is often helpful in relieving the pain of
compression fractures.108110
Human parathyroid hormone (PTH, Teriparatide),
an 84 amino acid peptide, is an anabolic agent
that helps maintain calcium homeostasis.111 It was
approved in 2002 by the Food and Drug Administration (FDA) for the treatment of osteoporosis
in men with primary or hypogonadal osteoporosis at high risk for fracture and postmenopausal
women at high risk for fracture. PTH appears to
be a promising agent for the management of
glucocorticoid-induced osteoporosis (GIOP).112115 It
is given subcutaneously (20 g/day) and is contraindicated in patients at risk for osteosarcoma (Paget
disease, prior skeletal irradiation, adolescents in
whom epiphyses have not closed, and unexplained
increases in serum bone-specific alkaline phosphatase), women of reproductive age, and patients
who may have a metabolic bone disease such as
primary hyperparathyroidism.111 Its use is limited to
2 years and is used for patients with severe osteoporosis. Sequential treatment with PTH, followed by
bisphosphonates, is potentially quite beneficial and
currently under investigation.115,116 An algorithm for
treatment prevention and management of steroidinduced osteoporosis is presented (eFig. 224-0.2).
Current recommendations include baseline
measurements of bone density and a sequential
study to identify early those who are rapidly losing
bone density.46,73 Bone density is best measured in
the lumbar spine in patients younger than 60 years
of age and in the femoral neck in patients older
than 60 years of age. All men and postmenopausal
women in whom long-term glucocorticoid treat-

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Chapter 224:

Systemic Glucocorticoids 321

ment at 5 mg/day is being initiated or who have

below normal bone mineral density T-scores should
receive bisphosphonates at the time glucocorticoids are prescribed. Bisphosphonates were found
to be the most effective agents for managing
GC-induced osteoporosis, and their efficacy was
significantly enhanced when used in conjunction
with vitamin D.96,117 Premenopausal women treated
with bisphosphonates should prevent pregnancy.118
A decrease in bone mineral density of 5% or greater
warrants changing or starting additional treatment
strategies. Patients on chronic glucocorticoids benefit from bone prophylaxis, and physicians need to
ensure that patients receive appropriate treatment
to prevent osteoporosis119 (eFig. 224-0.3).

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