Among the adverse effects of greatest concern are those related to increased cardiovascular risk. Glucocorticoid use has been demonstrated to accelerate the development of atherosclerosis and consequently is associated with increased risk of ischemic heart disease and congestive heart failure. A large population-based study showed that glucocorticoid users had a significantly higher risk of cardiovascular disease, defined as a composite outcome of myocardial infarction, coronary revascularization, angina, heart failure, stroke, or transient ischemic attack [11]. Additionally, glucocorticoid use has been found to be arrhythmogenic, and is associated with higher rates of atrial fibrillation and atrial flutter, even independent of the presence of preexisting cardiovascular or pulmonary disease [12]. Hypertension is also common with glucocorticoid administration. Interestingly, although hypertension is seen in 70–80 % of patients who develop Cushing’s syndrome [13], rates among patients taking exogenous glucocorticoids tend to be lower—roughly 20 % [14]. This difference is postulated to be a result of improvement in the underlying inflammatory state for which steroids were initiated.

Glucocorticoids have long been associated with disorders of glucose metabolism and are the most common causative agents of drug-induced diabetes. The effect is predominately through increased insulin resistance, which occurs via alterations in glucose utilization as well as upregulation of hepatic gluconeogenesis. Glucocorticoid-induced hyperglycemia tends to manifest as postprandial elevations in blood glucose more so than elevated fasting levels. One study of patients with rheumatoid arthritis found that 9 % of patients started on glucocorticoids developed diabetes within 2 years [15]. Another analysis of a large group of Medicaid enrollees found that glucocorticoid use portended a RR of 2.23 (95 % CI 1.92–2.59) among patients newly initiated on hypoglycemic therapy. The RR rose to 10.3 among patients taking an equivalent of 30 mg/day of prednisone [16]. In addition to diabetes, weight gain is among the most common adverse events, occurring in 70 % of long-term glucocorticoid users [17]. The pattern of weight gain tends to involve a redistribution of body fat and the development of truncal and central adiposity, with the so-called moon facies and buffalo hump.

The impact of glucocorticoid use on bone health is significant. The increased predilection toward the development of osteoporosis, and in turn fragility fractures, imposes a significant morbidity and mortality burden. Glucocorticoid use is the leading cause of secondary osteoporosis [18]. This is achieved through a variety of mechanisms which serve to increase bone resorption while decreasing bone formation. Glucocorticoids inhibit the differentiation and maturation of osteoblasts through interference with several cell signaling pathways and are also detrimental to the function of mature osteoblasts and osteocytes by inhibiting the expression of IGF-1 resulting in decreased production of type I collagen and higher rates of apoptosis [19]. Osteoclast formation is conversely promoted by glucocorticoids, as a result of decreased apoptosis and alterations of signaling cascades which upregulate differentiation of this cell line, leading to higher levels of osteoclasts and an increase in bone resorption [20]. Another mechanism by which resorption is increased is via glucocorticoid-mediated reduction in levels of gonadotropins, leading to lower levels of serum androgens and estrogens [21].

Glucocorticoids impact bone health through significant interactions with the Ca²⁺-Vitamin D-PTH axis as well. This is felt to occur via two main mechanisms. First, glucocorticoids decrease gut absorption of calcium via antagonism of vitamin D and downregulation of duodenal calcium channels [22]. Second, renal tubular reabsorption of calcium is inhibited thus promoting urinary calcium loss. Whether this leads to a form of secondary hyperparathyroidism remains uncertain as studies have failed to demonstrate elevations in parathyroid hormone levels among patients taking glucocorticoids [23]. Moreover, IBD may not actually be an independent risk factor for hypovitaminosis D, and the overall incidence of osteomalacia is actually not increased [24].

Fracture risk, especially of the vertebral body, is increased among glucocorticoid users, with risk rising steadily early after the initiation of steroid therapy, as this tends to correlate with the period of most rapid bone loss [23]. Despite clear evidence of steroid impact on bone density, other factors likely contribute to an increased fracture risk. A 2005 study showed that fracture risk remained elevated in glucocorticoid users even with normal BMD values [25]. A comprehensive systematic review of bone disease in IBD patients found that fracture risk in general is only modestly elevated (RR 1.4), though glucocorticoid use was consistently the largest independent risk factor [24].

An additional musculoskeletal concern among glucocorticoid users is steroid myopathy, a well-described phenomenon characterized typically by proximal muscle weakness and wasting, as a result of direct catabolic effect of steroids on skeletal myocytes [26]. Lower extremities tend to be involved more severely than upper extremities, and typically pain and myalgia are not seen. Serum muscle enzyme levels may be normal, and EMG or muscle biopsy may either be normal or show mild nonspecific findings. Diagnosis can thus be difficult to establish, but improvement in muscle strength upon dose reduction or discontinuation of the offending glucocorticoid is expected. Avascular necrosis or osteonecrosis is also seen more commonly among patients on glucocorticoids and potentially at a higher rate in IBD patients as compared to patients taking glucocorticoids for other indications [27].