Why do glucocorticoids (GCs), such as prednisone (generic name), increase the risk of osteoporosis?

Mechanisms of Glucocorticoid-Induced Osteoporosis

Glucocorticoids cause osteoporosis primarily by decreasing bone formation through inhibition of osteoblast function and increasing bone resorption through enhancement of osteoclast activity, with the greatest bone loss occurring within the first 3-6 months of treatment. 1

Direct Effects on Bone Cells

• Glucocorticoids decrease bone formation by:

  • Inhibiting osteoblast proliferation and function 1, 2
  • Increasing osteoblast and osteocyte apoptosis 2, 3
  • Reducing protein matrix formation in bone due to increased protein catabolism 4
  • Suppressing osteoblast differentiation 3, 5

• Glucocorticoids increase bone resorption by:

  • Initially activating osteoclasts, leading to enhanced bone resorption 2, 3
  • Prolonging osteoclast lifespan 3
  • Disrupting the balance between bone formation and resorption 3

Effects on Calcium Metabolism

• Glucocorticoids interfere with calcium homeostasis through:
  • Decreasing intestinal calcium absorption 4, 5
  • Increasing urinary calcium excretion 1, 4
  • Interfering with vitamin D metabolism 1, 4

Structural Effects on Bone

• Glucocorticoids have greater effects on trabecular bone than cortical bone, explaining the higher risk of vertebral fractures 1
• Osteocyte apoptosis leads to rapid weakening of bone architecture, increasing fracture risk beyond what would be expected from bone mineral density measurements alone 5
• These changes affect bone quality independently of bone mineral density, which explains why fracture risk is higher than predicted by bone density alone 6, 5

Dose and Duration Relationship

• Bone loss is dose and duration-dependent 7, 5:
  • Even low doses (prednisone equivalent of ≥5 mg/day) can cause significant bone loss 7
  • The highest rate of bone loss occurs within the first 3-6 months of treatment 1, 5
  • Both high daily doses and high cumulative doses increase fracture risk 1
  • Very high doses (≥30 mg/day) with cumulative doses >5g significantly increase vertebral and hip fracture risk 1

Risk Factors and Reversibility

• Risk factors for glucocorticoid-induced fractures include:

  • Low bone strength at the beginning of treatment 1
  • Rate of bone mass decline during treatment 1
  • Age, postmenopausal status, and baseline bone density 8, 6
  • Absence of calcium/vitamin D supplementation 6

• Glucocorticoid-induced osteoporosis is potentially reversible:

  • If treatment is terminated, bone mineral density increases and fracture risk declines 1, 2
  • However, recovery may take up to 12 months after discontinuation 4

Prevention Strategies

• Preventive measures include:
  • Using the lowest possible effective dose for the shortest duration 4, 5
  • Calcium (800-1000 mg daily) and vitamin D (800 IU daily) supplementation 2, 5
  • Bisphosphonates (alendronate, risedronate) as first-line agents for prevention and treatment 8, 7
  • Lifestyle modifications (smoking cessation, limiting alcohol, weight-bearing exercise) 4
  • Considering preventive therapy for patients receiving prednisone equivalent of ≥5 mg/day for at least 3 months 4, 7

Understanding these mechanisms is crucial for implementing appropriate preventive and treatment strategies to reduce the significant morbidity associated with glucocorticoid-induced osteoporosis.