How do glucocorticoids (GCs) lead to osteopenia?

How Glucocorticoids Lead to Osteopenia

Glucocorticoids cause osteopenia through multiple direct and indirect mechanisms that simultaneously increase bone resorption and decrease bone formation, with the most rapid bone loss occurring within the first 3-6 months of treatment. 1

Direct Effects on Bone Cells

Glucocorticoids exert predominantly inhibitory effects on osteoblasts and osteocytes, which are the bone-forming cells, while simultaneously stimulating osteoclast activity, the cells responsible for bone resorption. 1

Decreased Bone Formation

• Glucocorticoids suppress osteoblast function and inhibit osteoblastogenesis, directly reducing the capacity of bone to form new tissue. 1, 2
• They promote apoptosis (programmed cell death) of both osteoblasts and osteocytes, further diminishing bone formation capacity during long-term use. 2
• Bone formation markers (osteocalcin and bone-specific alkaline phosphatase) decrease by approximately 40-50% within 6-12 months of glucocorticoid treatment. 3
• Glucocorticoids decrease the repair of microdamaged bone, compromising skeletal integrity even without net bone loss. 1

Increased Bone Resorption

• Glucocorticoids stimulate osteoclast recruitment and differentiation, leading to increased bone resorption, particularly during the initial phase of treatment (first year). 1, 2
• The effects on osteoclasts are mediated indirectly through osteoblasts via increased RANKL and M-CSF production, which are key signaling molecules for osteoclast activation. 1
• Bone resorption markers (deoxypyridinoline and N-telopeptides) increase rapidly, with urinary excretion of these markers rising by approximately 50-70% early in treatment. 3

Indirect Effects on Calcium Homeostasis

Beyond direct bone effects, glucocorticoids disrupt calcium metabolism through multiple organ systems, creating a cascade that further promotes bone loss. 1

Intestinal Effects

• Glucocorticoids reduce intestinal calcium absorption by decreasing sensitivity to vitamin D and interfering with vitamin D metabolism. 1, 4
• This reduction in calcium absorption occurs through both direct and indirect mechanisms, including interference with the vitamin D receptor pathway. 1

Renal Effects

• Glucocorticoids decrease renal tubular calcium reabsorption, leading to increased urinary calcium excretion. 1, 4
• They increase 24-hydroxylase activity, which accelerates the breakdown of active vitamin D (1,25-dihydroxyvitamin D), further impairing calcium absorption. 1
• Urinary phosphate excretion also increases, contributing to mineral imbalance. 1

Secondary Hyperparathyroidism

• The combination of decreased intestinal calcium absorption and increased urinary calcium loss leads to compensatory secondary hyperparathyroidism. 5, 4
• Elevated parathyroid hormone (PTH) further stimulates bone resorption, creating a vicious cycle of bone loss. 5, 4
• Glucocorticoids may also increase bone cell sensitivity to PTH, amplifying the resorptive effects. 4

Effects on Other Organ Systems

Muscle and Mechanical Loading

• Glucocorticoids have catabolic effects on muscle tissue, reducing muscle mass and strength. 1
• Reduced muscle mass decreases mechanical loading on bone, which is a critical stimulus for bone formation and maintenance. 1
• Muscle weakness increases fracture risk independently through increased fall risk. 1

Gonadal Function

• Glucocorticoids suppress gonadotropin secretion, leading to reduced sex steroid production (estrogen and testosterone). 1
• Loss of sex steroids removes a critical protective factor for bone, as these hormones normally suppress bone resorption and support bone formation. 1

Growth Factors

• Glucocorticoids suppress production of insulin-like growth factor 1 (IGF-1) and growth hormone, both of which are important for bone formation. 2
• In children, this suppression affects bone strength, growth, and total adult skeletal mass, with similar risk factor profiles to adults. 1

Temporal Pattern and Dose-Response

Rapid Initial Phase

• The highest rate of bone loss occurs within the first 3-6 months of glucocorticoid treatment, with bone mineral density (BMD) decreasing by approximately 5-7% in the spine during this period. 1
• A slower but continued decline in BMD persists with ongoing glucocorticoid use. 1

Dose-Dependent Effects

• Both high daily doses and high cumulative doses increase fracture risk, with particular impact on trabecular bone (vertebrae) compared to cortical bone. 1
• Doses as low as prednisone 5 mg/day for ≥3 months can cause significant bone loss, though risk stratification typically uses 7.5 mg/day as a threshold. 1
• Very high doses (prednisone ≥30 mg/day with cumulative dose >5 gm) markedly increase vertebral and hip fracture risk. 1

Clinical Consequences

Fracture Risk

• More than 10% of patients receiving long-term glucocorticoid treatment are diagnosed with clinical fractures, and 30-40% have radiographic evidence of vertebral fractures. 1
• Fracture risk increases rapidly, within 3 months of commencing oral glucocorticoids, making early intervention critical. 6
• Vertebral fractures are particularly common due to greater glucocorticoid effects on trabecular bone. 1

Reversibility

• Glucocorticoid-induced osteoporosis is potentially reversible; if treatment is terminated, BMD increases and fracture risk declines. 1
• However, the damage accumulated during treatment may not be fully reversible, particularly in patients with prolonged high-dose exposure. 1

Common Pitfalls to Avoid

• Do not assume that low-dose glucocorticoids (<7.5 mg/day prednisone equivalent) are safe for bone; even doses ≥5 mg/day for ≥3 months warrant fracture risk assessment. 1
• Do not wait for BMD testing results before initiating calcium and vitamin D supplementation in patients starting glucocorticoids; these should be started immediately. 1
• Do not underestimate fracture risk in patients receiving very high-dose glucocorticoids (≥30 mg/day prednisone); standard risk calculators may underestimate their risk. 1
• Do not overlook the rapid onset of bone loss; the first 3-6 months are critical, and preventive measures must be implemented early. 1, 6