**7. Cardiovascular disease**

**5.1. Steroid withdrawal or adrenal insufficiency?**

102 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

**6. Weight gain and lipodystrophy**

**Figure 2.** Mechanisms of glucocorticoid-induced weight gain and lipodystrophy.

When GCs are tapered and their effects decline, patients might experience lethargy, myalgias, nausea, vomiting, and postural hypotension. In this situation, increasing the dose of GCs to prevent AI may delay recovery of the adrenal function. The treatment plan should be made by evaluating the risk/benefit ratio. At this point, patients may just need reassurance, symptomatic treatment, or if necessary, a brief (1-week) increase of the previous lowest dose, followed by reevaluation. Maximal caution is advised with any taper. Fortunately, the adrenal cortex repairs the ability to secrete sufficient amounts of cortisol for some period of time. Repair of endogenous cortisol secretion is expected after stopping the exogenous GCs. But the recovery time may vary among patients. The inhibition of the HPA axis function induced by exogenous GCs may persist for 6–12 months after treatment is withdrawn. In conclusion, all patients using GCs are at risk for AI. Clinicians should inform patients about the risk, signs, and symptoms of AI; and consider testing patients after cessation of high dose or long-term treatment with GCs [68].

GCs have reciprocal effects on adipose tissue metabolism, promoting both lipolysis and lipogenesis/adipogenesis, inducing irregularity of adipose tissue distribution (i.e. lipodystrophy). These effects are shown in **Figure 2** (adapted from [69]). About 60–70% of patients treated with GCs for a long-term period report weight gain. This is different from classical weight gain. A central hypertrophy of adipose tissue develops. Characteristic findings are facial adipose tissue (moon face), truncal obesity and dorsocervical adipose tissue (buffalo hump). In contrast, peripheral and subcutaneous adipose tissues get thinner. This specific changes are called Cushingoid features and related with lipodystrophy induced by GCs. Weight gain is the most common self-reported side effect. About two-thirds of patients exhibit Cushingoid features within the GCs have complex, and often conflicting, influences on cardiovascular disease (CVD) and cardiovascular risk. Patients chronically using exogenous GCs are at higher risk of CVD, such as coronary artery disease, heart failure, and stroke. In patients with rheumatoid arthritis, chronic obstructive pulmonary disease, and other conditions who were exposed to chronic exogenous GCs, a case-control study found a dose-response relationship between daily glucocorticoid dose and the risk of heart failure. The risk of ischemic heart disease was also increased. Patients taking ≥7.5 mg of prednisone per day or the equivalent had a significantly higher mixed risk of myocardial infarction, angina, coronary revascularization, hospitalization for heart failure, transient ischemic attack, and stroke. Exposure to GCs within the preceding 6 months was related with increased cardiovascular risks. The risks were higher with continuous use than intermittent use. The relationship between cardiovascular risk and GCs is confounded by the underlying inflammatory disease (e.g. rheumatoid arthritis and systemic lupus erythematosus). Because of chronic inflammation and treatment with higher doses of GCs, chronic inflammatory conditions may further increase the incidence of CVD. This increased risk is cumulative and dose-dependent, is mainly observed during the first month of treatment and is reduced when treatment is interrupted. In patients with inflammatory arthritis, increased mortality from heart disease has been established. Moreover, an association between GCs and the risk for atrial fibrillation and flutter has been established by several studies. Pulse GCs are additionally related with CVD. Sudden death caused by pulse dose GCs has been reported. But this tends to occur in patients with underlying CVD. Therefore, patients with underlying severe cardiac and renal disease should be closely monitored during pulse therapy with GCs [75–78].

Cardiovascular side effects of GCs can be explained by two mechanisms: (1) direct influence on the function of the heart and vasculature and (2) increasing cardiovascular risk factors. Glucocorticoid receptor is known to be expressed in the heart. By this way GCs exert direct effects on cardiomyocytes. The interaction of GCs with the vascular wall is impaired in CVD. Some well-known cardiovascular risk factors, such as hypertension, insulin resistance, hyperglycemia, and dyslipidemia are more commonly observed in glucocorticoid exposed people. The main effects of GCs on cardiovascular risk are likely due to interaction with the kidney, liver, adipose tissue, and central nervous system. The effects of GCs on homeostasis are presumably due to renal sodium retention and intravascular volume overload. There is also evidence for additional, non-renal mechanisms. This confirms that GCs can interact directly with the cells of the heart and vascular wall. By this way, GCs may alter their function and structure. In patients with chronic inflammatory disease, carotid plaque and arterial distensibility (independent of cardiovascular risk factors and clinical manifestations) have been established. In patients with systemic lupus erythematosus administration of GCs decreased the effectiveness of pravastatin [79–83].

biosynthesis, and β cell failure. (5) GCs may modulate the expression and activity of adipokines, such as adiponectin, leptin, and resistin. By this way GCs may disrupt insulin sensitivity and

Side Effects of Glucocorticoids

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http://dx.doi.org/10.5772/intechopen.72019

GCs are the most common cause of secondary osteoporosis and nontraumatic osteonecrosis. GCs increase fracture risk in both adult men and women, regardless of bone mineral density (BMD) and prior fracture history. But fracture risk is related to the dose and duration of GCs, age, and body weight. Risk factors for osteoporosis induced by GCs are shown in **Table 6**. GCs cause significantly stronger losses of trabecular than of cortical bone. Fractures are most common in regions of the skeleton that are predominantly cancellous, such as the vertebral bodies and ribs. After discontinuation of GCs, fracture risk gradually declines to baseline over a year or two [98–100].

GCs induce osteoclastic activity initially (first 6–12 months), followed by a decrease in bone formation. GCs decrease bone formation by inhibiting osteoblastic activity in the bone marrow, suppressing osteoblast function, decreasing osteoblast life span, and promoting the apoptosis of osteoblasts and osteocytes. The effect of GCs on bone turnover is complex and

Advancing age Elderly patients receiving glucocorticoid therapy have a 26-fold higher risk

Underlying disease Rheumatoid arthritis, polymyalgia rheumatica, inflammatory bowel disease,

Glucocorticoid receptor genotype Individual glucocorticoid sensitivity may be regulated by polymorphisms in the glucocorticoid receptor gene 11β-HSD isoenzymes 11β-HSD1 expression increases with aging and glucocorticoid administration

Low BMD Glucocorticoid-induced fractures occur independently of a decline in bone

studied in patients receiving glucocorticoids

and thereby enhances glucocorticoid activation

Low body mass index Significant risk factor for GIO and probably fractures as well

skeleton

11β-HSD, 11β-hydroxysteroid dehydrogenase; BMD, bone mineral density.

**Table 6.** Risk factors for glucocorticoid-induced osteoporosis (adapted from [99]).

initiation of treatment and the occurrence of fracture

of vertebral fractures than younger patients and a shorter interval between

chronic pulmonary disease, and transplantation are independent risk factors

All are independent risk factors for osteoporosis but have not been well

There may be no safe dose, although this is somewhat controversial. However, the risk of fracture unarguably escalates with increased doses and duration of therapy. Alternate day or inhalation therapy does not spare the

mass but patients with very low bone density may be at higher risk

may also reduce the insulinotropic effects of glucagon-like peptide-1 [92–97].

**9. Osteoporosis and osteonecrosis**

can be divided into two groups (**Table 7**) [101–103].

**Risk factor Explanation**

Family history of hip fracture, prevalent fractures, smoking, excessive alcohol consumption, frequent falls

Glucocorticoid dose (peak, current, or cumulative, duration of therapy,

interval)

**9.1. Osteoporosis**
