Glucocorticoid-induced osteoporosis

Introduction

Oral glucocorticoids are commonly prescribed in a variety of medical conditions, particularly in the field of rheumatology. Glucocorticoids are very useful in controlling inflammation in the short term and serve as an important immunosuppressive agent. In addition, some patients require long-term glucocorticoids at low doses for a number of conditions, including polymyalgia rheumatica, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), among others. However, despite their many clinical benefits, their use is associated with significant morbidity and mortality. One of the most significant adverse effects is glucocorticoid-induced osteoporosis (GIOP) and resultant fractures. The association between glucocorticoid excess and osteoporosis has been known for more than 80 years. Glucocorticoid therapy is the most common cause of secondary osteoporosis.

Pathophysiology of Glucocorticoid Bone Loss

Glucocorticoids affect bone metabolism through a variety of mechanisms ( Fig. 203.1 ). GIOP mainly affects areas rich in cancellous bone, particularly the lumbar spine and proximal femur. Both bone formation and bone resorption processes are affected, with an increase in bone resorption and a decrease in new bone formation. The combination of these processes leads to a significant decline in bone mineral density (BMD) and increases risk for fractures. Bone loss in GIOP occurs in a biphasic pattern. There is an early transient phase of increased bone resorption that occurs in the first year of glucocorticoid use. With chronic glucocorticoid therapy, there is a large rapid decline in BMD (6%–12%) within the first 12 months, but the rate of BMD decline slows significantly (3% per year) after the rapid resorption phase.

A reduction in bone formation is likely the most important process in GIOP, which contributes to the large reduction in BMD. Glucocorticoids have a direct effect on the osteoblast lineage, leading to decreased new bone formation. Glucocorticoids are lipophilic, so they are able to pass easily through the cell plasma membrane into the cytosol and bind to glucocorticoid receptors. This newly formed complex then enters the cell nucleus and interacts with glucocorticoid response elements, which subsequently regulates the transcription of certain genes ( Figs. 203.2 and 203.3 ). This interaction, through the activation of the caspase-3 pathway, leads to an increase in production of dickkopf-related protein 1 (Dkk1) and sclerostin, key regulators of osteoblast differentiation and survival. The Wnt signaling pathway is downregulated by dickkopf-1 (DKK-1) and sclerostin. Both inhibit the binding of Wnt to lipoprotein receptor–related proteins 5 and 6 (LPR 5/6), which in turn limits the ability for β-catenin to be stabilized. The loss of β-catenin from preosteoblasts causes a cell-fate shift of these cells from the osteoblast lineage to the adipocyte lineage, thus leading to a reduction in osteoblastogenesis. In addition, sclerostin leads to an increase in receptor activator of nuclear factor-κB ligand (RANKL) and decreases circulating levels of osteoprotegerin (PG). Overall, there is an increased rate of osteoblast apoptosis, a decreased rate of differentiation of premature osteoblast into mature osteoblasts, and a decrease in the rate of proliferation of osteoblast precursors. Even low doses of glucocorticoids are sufficient to significantly suppress markers of osteoblast activity, including propeptide of type 1 N-terminal procollagen (P1NP) and propeptide of type 1 C-terminal procollagen (P1CP). In addition, the activation of the caspase-3 pathway also results in increased apoptosis of osteocytes. The reduction in number of osteoblasts and osteocytes is confirmed in histomorphometric studies in patients with GIOP. Osteocyte apoptosis has been associated with a decrease in vascular endothelial growth factor (VEGF), which in turn reduces skeletal angiogenesis. This disruption of the osteocyte-canalicular circulation contributes to the reduction in the biomechanical strength of the affected cancellous bone. This process also plays an important role in the repair of damaged bone. Given the role of the osteocyte-canalicular circulation, a disruption in this network may also account for the loss of bone strength that occurs before a decline in BMD is seen in patients with glucocorticoid use ( Fig. 203.4 ).

Peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) is also upregulated with long-term glucocorticoid use, which also contributes to a decrease in osteoblastogenesis. When PPAR-γ2 is upregulated, undifferentiated bone marrow stromal cells are more likely to differentiate to the adipocyte lineage rather than the osteoblast lineage, which accounts for its effects on decreased osteoblastogenesis. Overall, a combination of an increase in osteoblast apoptosis and a decrease in osteoblastogenesis leads to a decline in new bone formation and an overall catabolic state.

In contrast to its effects on osteoblasts, osteoclastogenesis is promoted, and the rate of osteoclast apoptosis is suppressed with glucocorticoid use. This is most likely caused by an increased expression of RANKL and macrophage colony-stimulating factor by osteoblastic cells. There is also a downregulation of OPG, which increases osteoclastogenesis and reduces rates of osteoclast apoptosis. Aside from its effects on the osteoblast and osteoclast lineage, glucocorticoids also exert a number of indirect effects on bone metabolism ( Fig. 203.5 ).

The risk of fracture is higher in older adult patients with glucocorticoid use. The activity of the 11β-hydroxysteroid dehydrogenase (11β-HSD) system may play an important role in this observation. There are two isoenzymes, 11β-HSD1 and 11β-HSD2, that catalyze the conversion between hormonally active and inactive forms of glucocorticoids. Whereas the 11β-HSD1 enzyme serves as an activator, 11β-HSD2 enzyme serves as an inactivator. With aging, there is an increase in 11β-HSD1 activity and thus more conversion of glucocorticoids to a hormonally active form that leads to increased bone loss in older adults.

Epidemiology

Glucocorticoids are widely prescribed in medical practice, especially in the field of rheumatology. It is estimated that 2.5% of the older adult population (age 70–79 years) are prescribed oral glucocorticoid therapy at any given time. Of these patients, about 22% are prescribed a dose above 7.5 mg/day for the long term (>6 month duration). Epidemiologic data from Iceland revealed that an estimated 26% of patients treated with long-term oral glucocorticoids (>6 month duration) developed osteoporosis.

With increasing daily doses, fracture risk also increases. This was assessed using the U.K. General Practice Research Database, a large retrospective cohort study, which included 244,235 oral corticosteroid users and 244,235 control participants. Patients receiving high (≥7.5 mg per day) or even modest daily doses (2.5 to 7.5 mg per day) of prednisolone or equivalent had a significant increase in risk for developing clinical vertebral, hip, and nonvertebral fractures ( Fig. 203.6 ). With discontinuation of glucocorticoid therapy, the fracture risk declines. However, it is unclear if the risk returns to baseline values. A case-control study demonstrated that more than 1 year of discontinuation from oral glucocorticoids is required before the fracture risk returned to the levels of the background population. Ever being exposed to glucocorticoids increases the risk of developing an incident fracture at any site (relative risk [RR], 1.35; 95% confidence interval [CI], 1.02–1.78), incident nonvertebral fracture (RR, 1.47; 95% CI, 1.09–1.98), and incident hip fracture (RR, 2.11; 95% CI, 1.12–3.96) compared with no prior exposure. A metaanalysis of randomized controlled trials (RCTs) of glucocorticoid-treated patients found that the annual incidence of vertebral fractures was 5.1% (95% CI, 2.8–8.2), and the annual incidence of nonvertebral fractures was 2.5% (95% CI, 1.2–4.2) in patients newly initiated on glucocorticoids. The analysis was limited to include only the placebo or control arms to provide a natural history of fracture rates if left untreated with an osteoporotic agent.

Furthermore, patients receiving intermittent high-dose oral glucocorticoids (≥15 mg/day and cumulative exposure of ≤1 g) have a small increase in fracture rates but no effect on hip fractures. However, in patients receiving doses of 30 mg/day or more with a cumulative dose of 5 g or greater, the RR for an osteoporotic fracture was 3.63 (95% CI, 2.54–5.20), RR for a hip fracture was 3.13 (95% CI, 1.49–6.59), and RR for a vertebral fracture was 14.42 (95% CI, 8.29–25.08).

High doses of inhaled glucocorticoids have been associated with a decline in BMD. There are reports of increased fracture rates (hip and vertebral) in both adults and children treated with inhaled glucocorticoids. However, similar fracture rates were seen in those treated with inhaled nonsteroidal bronchodilators. This suggests the increase in fracture risk may be due to the underlying respiratory disease rather than the glucocorticoid treatment.

Investigations