**9. Osteoporosis and osteonecrosis**

### **9.1. Osteoporosis**

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].

GCs are the most common cause of drug-induced hyperglycemia and diabetes. Hyperglycemia and diabetes induced by GCs, is defined as an abnormal increase in blood glucose associated with the use of GCs in a patient with or without a prior history of hyperglycemia or diabetes. GCs cause an exaggerated postprandial hyperglycemia and insensitivity to exogenous insulin. Thus, GCs have a greater effect on postprandial compared to fasting glucose. Postprandial hyperglycemia (defined as blood glucose 200 mg/dL 2 hours after a meal) is a much more sensitive indicator for hyperglycemia and diabetes induced by GCs. The exact prevalence is not known. The incidence of hyperglycemia and diabetes in hospitalized patients treated with GCs without a known history of diabetes is >50%. GCs increases by two- to fourfold the risk of hyperglycemia and diabetes in non-diabetic subjects. Treatment with exogenous GCs

Development of glucocorticoid-induced diabetes depends on the dose and duration of exposure. A study found that the risk for hyperglycemia increased substantially with increasing daily steroid dose. The risk may change with the type of the GCs, related with biochemical properties (e.g. potency of the anti-inflammatory and metabolic effects and duration of the effects). But, there is little difference between the GCs most frequently used (i.e. prednisone, prednisolone, and methylprednisolone). The effects of GCs on glucose excursions are observed within hours (6–8 hours) of exposure. The predisposing factors for hyperglycemia and diabetes induced by GCs have been suggested to be overweight, old age, non-white ethnicity, previous glucose intolerance, reduced sensitivity to insulin or impaired insulin secretion stimulated by glucose, female sex, Down syndrome, puberty, the severity of the disease itself, a family history of diabetes, type A30, B27, and Bw42 human leukocyte antigens (HLA); and receiving a kidney transplant from a deceased donor. Solid organ transplant patients treated with GCs, 10–20% of them develop diabetes, especially within the first months of exposure. Other immunosuppressive agents can also disrupt glycemic control through other mechanisms. Usually, hyperglycemia and diabetes induced by GCs improves with dose reductions and usually reverses when therapy is discontinued, but patients with high risk may develop persistent diabetes [88–91]. The pathophysiology of glucocorticoid-induced diabetes involves (1) increase in insulin resistance and (2) reduced glucose uptake in muscle and adipose tissue (via insulin-sensitive glucose transporter type 4) as a consequence GCs cause decreasing glucose uptake and glycogen synthesis. On the other hand GCs have profound and reciprocal effects on glyceroneogenesis in liver and adipose tissue. GCs increase the amount of fatty acids released into the blood. Increased fatty acids interfere with glucose utilization and causes insulin resistance, particularly in skeletal muscle. (3) Increased glucose production, increased hepatic gluconeogenesis via peroxisome proliferator-activated receptor α. (4) Direct effects on pancreatic β cells including inhibition of the production and secretion of insulin, a proapoptotic effect on β cells, a reduction in insulin

**8. Hyperglycemia and diabetes**

disrupts the glycemic balance of known diabetics [84–87].

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

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


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


bioavailability are the most important factors for endothelial cell dysfunction. The risk of hypertension is 2.2 times higher in patients treated with GCs, whatever the duration of exposure. The risk seems to increase with duration of exposure and daily dosage. A family history of essential hypertension may also predispose hypertension induced by GCs. People with

Side Effects of Glucocorticoids

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

GCs have a very important role in energy homeostasis and on lipid metabolism. Chronic exposure to exogenous GCs is a secondary cause of dyslipidemia. But the degree of lipid abnormalities in different clinical conditions is quite variable. These variabilities are related with the heterogeneity of the populations treated in terms of age, sex, underlying condition, glucocorticoid dose, and concomitant medications. All possible changes in lipid profile (i.e. isolated increase of triglyceride levels, increase of both cholesterol and triglycerides levels, absence of changes in lipid parameters, and improvement in lipid profile with increased HDL cholesterol) have been reported, excluding organ transplant recipients. Because transplanted patients concomitantly treated with other immunosuppressive drugs with side effects on the lipid metabolism (e.g. cyclosporine), which is a confounding factor. People with glucocorticoid-induced lipodystrophy are more likely to develop an unfavorable lipid profile. But interestingly, findings from the Third National Health and Nutrition Examination Survey suggest that GCs may have a beneficial effect on lipid profile in adults ≥60 years of age. GCs stimulate lipolysis and modulate free fatty acid (FFA) mobilization through various mechanisms. These mechanisms are summarized in **Figure 2**. Stimulation of lipolysis depends on dose and duration. Therefore in patients treated with GCs at high doses or for prolonged periods, regular monitoring of

**Figure 3.** Effects of glucocorticoids on adipose tissue and hepatic fatty acid metabolism (adapted from [115]).

glucocorticoid-induced lipodystrophy are at higher risk [107–110].

lipid profile is recommended [111–114] (**Figure 3**).

**11. Dyslipidemia**

• Stimulation of osteoclast synthesis

1. Dose and duration of therapy

2. Intra-articular administration

3. Polymorphisms in VEGF, GR, 11β-HSD2, COL2A1, PAI1, P-glycoprotein

**Table 7.** Effects of glucocorticoids on bone metabolism (adapted from [103]).

4. Underlying disorders: renal insufficiency, transplantation, graft vs. host disease, inflammatory bowel disease, HIV, acute lymphoblastic leukemia, excessive alcohol intake, hypercoagulable states, sickle cell disease, radiation exposure

5. Dexamethasone causes greater skeletal complications than prednisone

VEGF: vascular endothelial growth factor; GR: glucocorticoid receptor; 11β-HSD2: 11β-hydroxysteroid dehydrogenase type2; COL2A1: collagen type II; PA1: plasminogen activator inhibitor 1; HIV: human immunodeficiency virus.

**Table 8.** Risk factors for glucocorticoid-induced osteonecrosis (adapted from [99]).

### **9.2. Osteonecrosis**

The most common joint involved is the hip and GCs are the second most common cause. The incidence of osteonecrosis induced by GCs increase with higher doses and prolonged treatment. But can be seen with short-term exposure to high doses, and without osteoporosis. Osteonecrosis develops in 9–40% of adult patients receiving long-term GCs. Risk factors are shown in **Table 8** [104–106].

### **10. Hypertension**

Glucocorticoid-induced elevation in blood pressure is classified as secondary hypertension and is a major risk factor for cardiovascular diseases. Blood pressure in humans is subjected to tight control by several physiologic systems that have pleiotropic effects and interact together in a complex fashion. GCs can cause hypertension by influencing these systems in different ways. One possible mechanism is the in vitro affinity of the non-selective mineralocorticoid receptor (MR) for the GCs. As a result, stimulation of the MR by exogenous GCs leads to renal Na<sup>+</sup> retention, volume expansion, and finally to an increase in blood pressure. Vascular tone (imbalance between vasoconstriction and vasodilation), centrally mediated mechanisms, renin-angiotensin system activation, cardiac hypercontractility, and endothelial cell dysfunction may also play a role. Enhanced reactive oxygen species and reduced nitric oxide (NO) bioavailability are the most important factors for endothelial cell dysfunction. The risk of hypertension is 2.2 times higher in patients treated with GCs, whatever the duration of exposure. The risk seems to increase with duration of exposure and daily dosage. A family history of essential hypertension may also predispose hypertension induced by GCs. People with glucocorticoid-induced lipodystrophy are at higher risk [107–110].
