Glucocorticoid

Infections and Relative Glucocorticosteroid Insensitivity

Up to 80% of asthma exacerbations in adults and children are associated with viral infections, particularly rhinovirus (RV).¹⁹⁹ These infections are relatively refractory to high doses of ICS or OCS clinically, which correlates with the lack of effect of ICS on the expression of nasal inflammatory mediators.¹⁹⁹ Experimental viral challenge is associated with enhanced oxidative and nitrosative stress and the reduction in HDAC2 expression in COPD patients, and it is likely that this is also the case in severe asthma.²⁰⁰

Corticosteroids also have little clinical benefit in bronchiolitis driven by respiratory syncytial virus (RSV). One action of RSV is to prevent GR nuclear translocation in nasopharyngeal aspirates from RSV-infected infants,²⁰¹ confirming in vivo evidence previously reported in primary human bronchiolar epithelial cells by RV16.²⁰² With RSV infection the mechanism involves competition of the viral nonstructural protein 1 with GR for importin 13 (IPO13) binding,²⁰¹ whereas NF-κB and AP-1 pathways are associated with prevention of GR nuclear import, presumably because of changes in GR phosphorylation status, with RV16 infection.²⁰²

IFN-γ is induced by viral infection, and this is a dominant variable for chronic persistent obstruction in severe asthma.²⁰³ Previous studies have demonstrated that Th1 cytokines, such as TNF-α and IFN-γ, promote corticosteroid resistance in adult human ASM.⁷⁴ This effect is related, in part, to the induction of interferon regulatory factor (IRF), which competes with GR for limit levels of the transcriptional co-regulator glutamate receptor–interacting protein (GRIP)-1.²⁰⁴ This relative steroid responsiveness is also seen in cells from children with steroid-refractory severe asthma and is selective because corticosteroid-induced gene expression is similar to that in cells from steroid responsive asthmatics.²⁰⁵ GR uses multiple mechanisms to suppress inflammatory gene expression, and activation of TLR9 drives inflammatory responses that are suppressed by activated GR. This effect is via a transcription-independent, rapid, and nongenomic GC suppression of TLR9 ligand-mediated IL-1R-associated kinase 1 (IRAK1) ubiquitination.²⁰⁶

It is evident that different genes within each cell type have a variable GR responsiveness and this also varies with cell type, which highlights the concept of pleiotropic gene- and cell-specific effects of dexamethasone.¹¹⁶ In A549 epithelial cells, this variable response to dexamethasone may reflect the relative requirement for the transcription factor IRF1 for inflammatory gene induction.²⁰⁷

Glucocorticoid-Induced and Male Osteoporosis

As detailed previously, glucocorticoids are a major cause of and the most common etiology of medication-related secondary osteoporosis. Glucocorticoids are prescribed for a number of common inflammatory conditions, often in a chronic, long-term manner. They are potent suppressors of bone formation and at higher doses likely increase bone resorption, principally through central suppression of sex steroid production. This resultant “uncoupling” of bone turnover can result in dramatic declines in BMD within the first 6 months of starting therapy. In addition to bone loss, there is good evidence to support that individuals on glucocorticoids may fracture at a higher level on BMD compared with non-glucocorticoid-treated patients. Fracture rates are increased as well with doses of prednisone as low as 2.5 mg per day, although the increase in risk appears to attenuate with glucocorticoid discontinuation. The treatment approach to glucocorticoid-induced osteoporosis is similar to osteoporosis in general, with the exception that attempts should be made to reduce the steroid dose to as low as the underlying treated disease will permit.²¹ Calcium and vitamin D are important adjuncts but are insufficient to prevent bone loss or fractures. Although not clearly evidence-based, replacement of deficient sex steroids is a reasonable strategy in younger individuals who are at lower risk for fracture. The bisphosphonates alendronate, risedronate, and zoledronic acid are FDA approved for glucocorticoid-induced osteoporosis in women and men.^A21 However, data suggest that either denosumab or teriparatide is superior to bisphosphanates for this purpose.^A21b For example, 60 mg of subcutaneous denosumab every 6 months is superior to 5 mg oral risedronate daily at 12 months for its effect on BMD in patients with glucocorticoid-induced osteoporosis.^A22 Teriparatide, which more directly addresses the osteoblast inhibition that is the primary mechanism of bone loss in glucocorticoid-induced osteoporosis, is superior to alendronate in improving BMD and reducing the risk of vertebral fractures in this situation.^A23 Teriparitide should not be used for more than 24 months because of safety considerations.

Male osteoporosis historically has been underrecognized and underappreciated by primary care clinicians and patients alike, although the current data support a significantly more prevalent and clinically significant disorder. More than 2 million men in the United States have osteoporosis, and one in four men older than 50 years will suffer a fragility fracture in their remaining lifetime. Roughly 30% of vertebral and hip fractures combined occur in men, and these are the more common fractures in older men. In addition, men have a substantially higher mortality after hip fracture compared with women. As in women, aging, low body weight, and prior fragility fractures are independent predictors of fracture. In some contradistinction to women, however, osteoporosis in men is more commonly multifactorial in etiology, with the most common secondary causes being excess glucocorticoids, hypogonadism, and alcohol overuse. Despite these associations and others (current smoking, history of falls), there is not at present sufficient evidence to warrant use of a specific testing or screening strategy to identify men at higher risk for fracture. The laboratory work-up of male osteoporosis is similar to that for women, with the exception of a morning fasting testosterone level. Idiopathic osteoporosis may also occur, particularly in younger men with no discernable cause. Genetic factors may well be important in these men, with studies suggesting an association with lower production and circulating levels of estrogen. As in women, primary treatment of male osteoporosis is targeted at lifestyle changes, adequate nutrition (calcium and vitamin D), and exercise. Bisphosphonates (oral and intravenous), denosumab, and teriparatide are all effective at improving BMD in men, although a recent meta-analysis confirmed antifracture efficacy for vertebral and possibly for nonvertebral fractures with bisphosphonates alone, whereas the antifracture efficacy of nonbisphosphonates in men remains unconfirmed.^A24 Although more limited in scope, antifracture efficacy appears evident for denosumab in men with prostate cancer on androgen deprivation therapy. True antifracture efficacy for the other agents and clinical scenarios is either less convincing or absent, based on the paucity of randomized controlled trial data, although this should not be construed as a reason not to treat. Testosterone replacement in men with significant biochemical hypogonadism (total T score <200 ng/dL) does improve bone density, although data on fracture risk reduction are lacking. In older men (>50 years) at a substantial risk for fracture based on history and risk factors, androgen replacement should be considered second line behind the aforementioned other therapies, based on overall risk-benefit and lack-of-fracture data.

Osteoporosis

Osteoporosis is one of the most prevalent side effects in patients receiving long-term systemic glucocorticoid therapy. Without preventative measures, osteoporosis develops in 30–50% of all patients treated chronically with glucocorticoids¹⁵. A rapid decline in bone mineral density occurs within the first 3 months of usage, and the rate of loss peaks at 6 months¹⁶. Postmenopausal Caucasian women are at highest risk for complications such as fractures, because they have the lowest bone mass before beginning therapy. The greatest amount of bone loss is usually observed in young men, because they have the highest pretreatment bone mass. The development of osteopenia and osteoporosis is not avoided by alternate-morning treatment schedules.

Trabecular bone, which is present in the axial skeleton (vertebrae, ribs), has a metabolic turnover rate eight times that of cortical bone (long bones), making trabecular bone much more prone to demineralization¹⁷. Although many patients with osteoporosis have no symptoms, more advanced disease can produce bone pain, fractures, and vertebral collapse. The mechanism of glucocorticoid-induced bone loss includes both direct and indirect effects¹⁸. Glucocorticoidsdirectly reduce the proliferation and function of osteoblasts, increase apoptosis of osteoblasts, and promote proliferation of osteoclasts. They actindirectly by increasing urinary calcium excretion and reducing intestinal absorption of calcium. This decreases serum calcium and stimulates parathyroid hormone release, which drives osteoclasts to resorb bone.

Although routine radiographs can detect vertebral compression fractures, these plain X-ray studies are not sensitive enough to detect osteoporosis until 20–60% of bone mass is lost (Fig. 125.3). Currently, the best measurement of osteoporosis is quantification of bone mineral density with dual-energy X-ray absorptiometry (DEXA), which is preferred because of its sensitivity, reproducibility, and low radiation exposure. Ideally, patients on long-term glucocorticoids should have a baseline DEXA examination of the hip and lumbar spine, with a repeat study performed every 1–3 years at the same sites. In densitometry reports, T scores are used to connote a standard deviation from the mean of a healthy control population. Osteopenia is defined as a T score between −1 and −2.5 standard deviations below the mean, with a T score less than −2.5 defining osteoporosis¹⁵. For patients beginning long-term glucocorticoid therapy, risk factors for decreased bone density should be assessed and guidelines for the prevention and treatment of osteoporosis followed (Fig. 125.4)^16,19. Endocrinologic consultation should be obtained in patients who develop significant osteopenia or osteoporosis. Further information on recommended regimens for osteoporosis prevention and treatment in patients receiving long-term glucocorticoid therapy is provided inFig. 125.4^19a.