What Are Glucocorticoids?Systemic glucocorticoids are used in dermatologic practice long term glucocorticoid use side effects various diseases including connective tissue disorders, bullous diseases, and many other dermatologic conditions. Patients with these diseases are at times treated with long-term courses of glucocorticoids, which place them at increased risk for glucocorticoid-induced side effects. Therefore, dermatologists must be knowledgeable of risks related to glucocorticoid use and be familiar with guidelines to manage them. To provide an update of recent advances in the prevention and treatment of major glucocorticoid-induced side effects. Data regarding the prevention and treatment of glucocorticoid-induced side effects are presented.
Prednisone and other corticosteroids: Balance the risks and benefits - Mayo Clinic
Systemic glucocorticoids are used in dermatologic practice for various diseases including connective tissue disorders, bullous diseases, and many other dermatologic conditions. Patients with these diseases are at times treated with long-term courses of glucocorticoids, which place them at increased risk for glucocorticoid-induced side effects. Therefore, dermatologists must be knowledgeable of risks related to glucocorticoid use and be familiar with guidelines to manage them. To provide an update of recent advances in the prevention and treatment of major glucocorticoid-induced side effects.
Data regarding the prevention and treatment of glucocorticoid-induced side effects are presented. This review should help dermatologists optimally manage and prevent glucocorticoid-induced side effects. Glucocorticoids are commonly used to treat severe skin diseases. They are effective because of their immunosuppressive and anti-inflammatory effects.
Prolonged high-dose glucocorticoid therapy has many potential side effects. Side effects resulting from glucocorticoid use are common and potentially serious. We summarize guidelines on the prevention and treatment of some of the major glucocorticoid-induced side effects, including those related to the musculoskeletal, endocrine, cardiovascular, and central nervous systems.
Bone loss is one of the most common and debilitating side effects associated with prolonged high-dose glucocorticoid therapy [ 1 ]. Glucocorticoids reduce bone formation and increase bone resorption [ 2 — 6 ]. Bone loss associated with glucocorticoid therapy is most pronounced in the first few months after initiating treatment.
The rate of bone loss slows considerably thereafter [ 4 , 8 — 9 ] and bone density can increases after discontinuation of glucocorticoids [ 10 ]. The glucocorticoid-induced bone loss is dose-dependent and patients taking higher doses have significantly increased risk of bone loss relative to patients using glucocorticoids at lower doses [ 7 , 10 — 12 ]. The prevention and treatment of glucocorticoid-induced bone loss include decreasing the dose of glucocorticoid, calcium and vitamin D supplementation, and pharmacologic therapy to prevent further bone loss or increase bone density [ 13 ].
The duration of glucocorticoid therapy and the glucocorticoid dose should be as low as possible, because even low-dose glucocorticoid replacement therapy can decrease bone mineral density [ 14 ]. Alternative therapy with other medications is recommended.
The published data on alternate-day glucocorticoid therapy suggests that this therapy can also produce osteoporosis [ 15 — 16 ]. Short-term high-dose pulse glucocorticoid therapy is preferred over continuous therapy with oral glucocorticoids [ 17 ]. In all individuals on glucocorticoid therapy, general principles include avoiding smoking and excess alcohol, weight-bearing exercises, and taking proper precautions to prevent falls.
Multiple treatments have been introduced to prevent or treat bone loss and will be reviewed here. Calcium supplementation is recommended in all individuals treated with glucocorticoids, because glucocorticoids decrease intestinal calcium absorption and increase renal calcium excretion.
A study assessed the effects of calcium and vitamin D on bone density of patients with rheumatoid arthritis and the relation between this effect and low-dose glucocorticoid use [ 12 ]. A total of 96 patients with rheumatoid arthritis, 65 of whom receiving prednisone at a mean dosage of 5. Patients receiving prednisone therapy who were given placebo lost bone in the lumbar spine and trochanter at a rate of 2. In patients receiving prednisone therapy, bone density of the femoral neck did not increase with calcium and vitamin D3.
Calcium and vitamin D3 did not improve bone density at any site in patients who were not receiving prednisone. Calcium and vitamin D is generally not sufficient to prevent bone loss in patients treated with high-dose glucocorticoids.
The data on the role of active vitamin D metabolites, such as calcitriol 1, dihydroxy vitamin D , in the prevention of glucocorticoid-induced bone loss and fracture is not sufficient. The combination of calcitriol and calcium protect against spine bone loss more than calcium alone in patients receiving glucocorticoids [ 4 , 19 ].
Active vitamin D metabolites are associated with an increased risks for hypercalcemia and hypercalciuria in patients with an already increased rate of urinary calcium excretion [ 20 ], and have been largely replaced by other safer and more effective available therapies [ 19 , 21 ]. Bisphosphonates are a class of drugs that are favorably used in the prevention and treatment of glucocorticoid-induced bone loss.
The mechanism for the majority of the effects of these drugs is thought to be via their ability to prevent osteoclastic bone resorption [ 22 ]. Alendronate and risedronate are the most commonly used bisphosphonates in osteoporosis. In a study of patients on glucocorticoids, 17 to 83 years of age, who were randomly assigned to receive one of two doses of alendronate or placebo, bone density in the lumbar spine increased by 2. The bone density of the femoral neck, trochanter, and total body also increased significantly in the alendronate group.
There were also proportionally fewer new vertebral fractures in the alendronate group than in the placebo group 2. In a two-year randomized trial comparing once-weekly 70mg and daily alendronate 10mg in postmenopausal women, once-weekly regimen is therapeutically as effective as daily dosing [ 24 ].
However, once-weekly administration of alendronate is more convenient for patients and can enhance their adherence to therapy. The efficacy of risedronate in patients receiving glucocorticoids was demonstrated in 2 one-year randomized, placebo-controlled studies.
In a study of patients receiving glucocorticoids, bone density of the lumbar spine did not change significantly in the risedronate treated groups 2. Ibandronate is a newer and highly potent bisphosphonate and every three month IV ibandronate 2mg has been shown to be efficacious and well-tolerated for prevention and treatment of glucocorticoid-induced osteoporosis [ 25 — 26 ].
Other bisphosphonates used in the prevention and treatment of glucocorticoid-induced osteoporosis include pamidronate, zoledronic acid, etidronate, and clodronate. The efficacy of oral and intravenous pamidronate in preventing glucocorticoid-induced osteoporosis has been demonstrated [ 27 — 28 ]. Oral pamidronate is not available in the United States and intravenous infusions are very expensive.
Intravenous bisphosphonates may be associated with flu-like symptoms and hypocalcemia. Flu-like symptoms can be prevented by acetaminophen. Hypocalcemia is more likely to occur in patients with vitamin D deficiency and can be prevented by calcium and vitamin D supplementation. Intravenous bisphosphonates are reasonable options in some patients who do not tolerate oral bisphosphonates.
Zoledronic acid is one of the other IV bisphosphonates currently marketed in the United States. Etidronate has been largely replaced by alendronate and risedronate which are more potent. Clodronate, a novel drug used for inhibiting osteoclastic activity, has been shown to increase bone density in asthmatic patients treated with continuous oral and inhaled glucocorticoids [ 29 ].
Clodronate is not available in the United States. For further information regarding dose and administration of bisphosphonates, please refer to Table 1.
Bisphosphonates are usually preferred over active vitamin D metabolites. In an month trial in patients with rheumatic diseases, who were randomly assigned to either alfacalcidol or alendronate, alendronate was more effective in the prevention of glucocorticoid-induced bone loss than was alfacalcidol.
At 18 month, the absolute group difference in bone density was 4. In another study, 38 patients with glomerular disease receiving high-dose glucocorticoids were randomized into three groups: The combination of risedronate and alfacalcidiol was similar to risedronate monotherapy for preventing or reversing bone loss [ 31 ].
In a randomized trial in patients with established glucocorticoid-induced osteoporosis, three-monthly IV ibandronate 2 mg was more effective than oral daily alfacalcidiol 1 mg in improving spine, femoral neck, and calcaneal bone density after two and three years[ 25 — 26 ]. Glucocorticoid therapy reduces serum sex hormone levels due to its effect on the hypothalamic-hypophysial axis [ 32 ].
However, considering its unfavorable risk-benefit profile, long-term hormone replacement therapy is no longer recommended as a first-line therapy for prevention of postmenopausal osteoporosis. American College of Rheumatology Ad Hoc Committee on Osteoporosis suggests that premenopausal women taking glucocorticoids who have menstrual irregularities receive an oral contraceptive when there is no contraindication [ 18 ].
However, there is no evidence to support estrogen therapy in premenopausal women with normal menstrual cycles. In a randomized, placebo-controlled trial of androgens in 51 men on glucocorticoids, lumbar spine bone density and muscle mass increased significantly in men treated with testosterone [ 34 ].
Testosterone can be considered for prevention of osteoporosis in men taking high-dose steroids who become hypogonadal. Parathyroid hormone promotes both bone formation and resorption; however, intermittent administration promotes bone formation more than resorption. Both treatments significantly increased lumbar spine bone density which was the primary outcome of the study. However, bone mineral density at the lumbar spine increased more in patients receiving teriparatide than in those receiving alendronate 7.
Calcitonin attenuates bone loss by directly reducing osteoclastic resorption. It also reduces the pain in patients who have pain-causing fractures. In a two-year prospective trial in 44 steroid-dependent asthmatic patients, patients were randomly treated with either salmon calcitonin nasal spray IU every other day or calcium alone [ 36 ]. Bone density in the calcitonin group increased by 2.
Calcitonin maintained bone mass in a steady state during the second year, while bone loss continued in the calcium alone group. However, the lack of efficacy of calcitonin on the rate of vertebral or nonvertebral fractures does not permit its recommendation as a first line therapy for the prevention or treatment of glucocorticoid-induced osteoporosis. Calcitonin can be considered in patients who cannot tolerate oral or intravenous bisphosphonates or when bisphosphonates are contraindicated.
Due to its ability to reduce bone pain, calcitonin can also be considered in patients who have sustained an acute fracture. Thiazides and dietary sodium restriction both reduce urinary calcium excretion, and may have a favorable effect on calcium homeostasis in patients receiving glucocorticoids. A study investigating the effect of thiazide diuretics and dietary sodium restriction on calcium metabolism in patients taking glucocorticoids suggested that this regimen may have a beneficial effect on calcium balance in patients receiving glucocorticoids by decreasing the fractional excretion of calcium and increasing intestinal calcium absorption [ 37 ].
However, their effect on bone density is uncertain. Thiazides and sodium restriction can be considered in patients with substantial hypercalciuria or hypertension. Glucocorticoids use can cause myopathy by direct catabolic effect on skeletal muscle via activation of the glucocorticoid receptor [ 39 — 40 ]. Blockade of the glucocorticoid receptor has been shown to prevent myopathy in the rat [ 39 ].
Subjects with glucocorticoid-induced myopathy typically present with proximal muscle weakness and atrophy in both the upper and lower extremities. The onset of symptoms is usually subacute and over several weeks or months. Higher doses of glucocorticoids are associated with earlier onset of symptoms [ 41 ]. The diagnosis of glucocorticoid-induced myopathy is one of exclusion. The symptoms improve within three to four weeks after reduction in glucocorticoid dose and resolves after discontinuation of glucocorticoids [ 42 ].
Moderate exercise has also been demonstrated to attenuate glucocorticoid-induced muscle atrophy [ 43 ]. Critical illness myopathy, the most common form of intensive care unit ICU -acquired myopathy, has been attributed in part to IV glucocorticoids.
An interaction between glucocorticoids and neuromuscular blocking agents, which are widely used in ICU, appears to be involved. The occurrence and severity of myopathy is correlated with glucocorticoid dose [ 44 — 47 ].
The most common presenting symptoms of critical illness myopathy include flaccid quadriparesis and difficult weaning from mechanical ventilation [ 45 — 46 ]. The onset of symptoms is typically acute and over several days. Critical illness myopathy is associated with increased mortality, prolonged ventilator dependence, and prolonged ICU stays. Treatment of critical illness myopathy includes discontinuation or reduction of glucocorticoids and aggressive management of medical comorbidities.
Symptoms usually improve over weeks to months; however, severe necrotizing myopathy may never recover [ 48 ].