Mechanism of Glucocorticoid-Induced Pathologic Fractures
Glucocorticoids cause pathologic fractures primarily by suppressing bone formation through direct toxic effects on osteoblasts and osteocytes, while simultaneously increasing bone resorption, with the most rapid bone loss occurring within the first 3-6 months of therapy. 1
Primary Pathophysiologic Mechanisms
Direct Effects on Bone Cells
Glucocorticoids impair osteoblast replication, differentiation, and function, while inducing apoptosis (programmed cell death) of mature osteoblasts and osteocytes, which are the cells responsible for building and maintaining bone. 2
This suppression of bone formation is the central feature in the pathogenesis of glucocorticoid-induced osteoporosis, distinguishing it from other forms of osteoporosis where resorption predominates. 2
Glucocorticoids simultaneously favor osteoclastogenesis (formation of bone-resorbing cells) and consequently increase bone resorption, creating a dual mechanism of bone loss. 2
Preferential Trabecular Bone Loss
Both high daily and high cumulative glucocorticoid doses increase fracture risk, particularly vertebral fractures, due to greater effects on trabecular bone than cortical bone. 1
This preferential trabecular bone loss explains why vertebral fractures occur early and at higher bone mineral density levels than in postmenopausal osteoporosis. 2
Temporal Pattern of Bone Loss
Rapid Early Phase
The highest rate of bone loss occurs within the first 3-6 months of glucocorticoid treatment, with fracture risk increasing rapidly within 3 months of commencing oral glucocorticoids. 1, 3
This early rapid decline in bone mineral density is followed by a slower progressive decline with persistent glucocorticoid use. 1, 2
Dose-Dependent Risk
Doses ≥2.5 mg/day of prednisone equivalent increase fracture risk at the spine and hip, with even lower doses (<2.5 mg/day) already increasing the risk of vertebral fractures. 4
Very high doses (≥30 mg/day) with cumulative doses >5 grams result in markedly increased relative risk of vertebral and hip fractures, which may be underestimated by standard risk calculators. 1, 4
Indirect Mechanisms Contributing to Fracture Risk
Calcium Metabolism Disruption
Glucocorticoids impair intestinal calcium absorption, leading to secondary hyperparathyroidism that further increases bone resorption. 5
This calcium malabsorption necessitates adequate calcium supplementation (1,000-1,200 mg daily) and vitamin D (800-1,000 IU daily) in all patients on long-term glucocorticoid therapy. 4, 5
Muscle and Balance Effects
- Glucocorticoids cause myopathy and affect muscle strength, indirectly increasing fall risk and fracture susceptibility beyond the direct skeletal effects. 6
Clinical Fracture Patterns
High Fracture Burden
More than 10% of patients receiving long-term glucocorticoid treatment are diagnosed with clinical fractures, and 30-40% have radiographic evidence of vertebral fractures, many of which are asymptomatic. 1, 2
Fractures occur at higher bone mineral density levels than in postmenopausal osteoporosis, meaning traditional BMD thresholds underestimate fracture risk in glucocorticoid users. 2
Reversibility Considerations
- Glucocorticoid treatment is a potentially reversible risk factor; if therapy is terminated, bone mineral density increases and fracture risk declines, though complete recovery may not occur. 1
Critical Clinical Pitfalls
Do not wait for significant BMD decline before intervening, as fractures occur early and at higher BMD values than other forms of osteoporosis. 2
Do not underestimate fracture risk at low doses, as even prednisone <2.5 mg/day increases vertebral fracture risk. 4
Standard fracture risk calculators may significantly underestimate risk in patients on very high doses (≥30 mg/day) or with cumulative doses >5 grams, requiring clinical judgment beyond calculator results. 1, 4