How does hyperglycemia affect bone health?

How Hyperglycemia Damages Bone Health

Hyperglycemia significantly impairs bone health through multiple mechanisms, leading to increased fracture risk despite normal or higher bone mineral density, with an 8% increased fracture risk for each 1% rise in A1C levels. 1

Pathophysiological Mechanisms

Advanced Glycation End Products (AGEs)

• Hyperglycemia drives systemic formation of AGEs that accumulate in bone tissue 2
• AGEs cross-link collagen fibers in bone matrix, making bone more brittle and less able to absorb energy before fracturing
• AGEs diminish fracture resistance by altering bone's mechanical properties 2
• Higher skin intrinsic fluorescence (a measure of AGE accumulation) is independently associated with lower total hip BMD 3

Impaired Bone Formation and Remodeling

• Hyperglycemia suppresses osteoblast function and bone formation 4
• Poor glycemic control leads to suppressed periosteal bone apposition and reduced bone formation 4
• Bone turnover markers are typically suppressed in people with diabetes 1
• Hyperglycemia impairs the flow-induced intracellular calcium signaling in osteocytes 4

Altered Response to Mechanical Loading

• Diabetic bone shows attenuated response to anabolic mechanical loading 4
• Severe hyperglycemia significantly inhibits flow-induced downstream responses in osteocytes, including:
  • Reduced anti-apoptotic effects
  • Altered sRANKL secretion
  • Impaired PGE2 release 4

Clinical Impact on Fracture Risk

Type 1 Diabetes

• Fracture risk increased by 4.35 times for hip fractures 1
• 1.83 times increased risk for upper limb fractures 1
• 1.97 times increased risk for ankle fractures 1
• Fractures occur 10-15 years earlier than in people without diabetes 1
• Often associated with low bone mass 1

Type 2 Diabetes

• Hip fracture risk increased by 1.79 times 1
• Lifetime fracture risk 40-70% higher than individuals without diabetes 1
• Increased fracture risk despite normal or higher BMD, indicating poor bone quality 1, 5
• Bone loss is accelerated over time 1

Glycemic Control and Fracture Risk

• Meta-analysis shows 8% increased fracture risk per 1% rise in A1C level 1
• Poor glycemic control (A1C >9%) over 2 years correlates with 29% heightened fracture risk 1
• Higher mean HbA1c is independently associated with lower total hip BMD 3
• Risk is higher in White demographic than other racial groups 1

Duration of Disease

• Longer disease duration significantly elevates fracture risk 1
• Type 2 diabetes >10 years and type 1 diabetes >26 years face significantly higher fracture risks 1
• Attributed to microvascular and macrovascular damage affecting the skeleton 1

Assessment and Management Implications

Screening Recommendations

• DXA scan should be performed at least 5 years after diagnosis of type 2 diabetes 1
• Reassessment recommended every 2-3 years depending on risk factors 1
• BMD underestimates fracture risk in people with diabetes 1, 5
• Consider using trabecular bone score (TBS) and peripheral quantitative computed tomography (pQCT) for better assessment of bone quality 5

Preventive Strategies

• Maintain optimal glucose control to minimize AGE formation 1
• Avoid hypoglycemic episodes, which increase fracture risk (RR 1.52) 1, 6
• Recommend moderate physical activity to enhance muscle health, gait coordination, and balance 1
• Ensure adequate calcium and vitamin D intake 1

Medication Considerations

• Avoid thiazolidinediones when possible, especially in women (doubles fracture risk with 1-2 years of use) 1
• Consider antiresorptive medications and osteoanabolic agents for those with T-score ≤2.0 or fragility fractures 1

Special Considerations

• Hypoglycemia also increases fracture risk, creating a complex clinical challenge 1, 6
• Diabetes complications (nephropathy, retinopathy, neuropathy) further increase fracture risk 1
• Kidney disease is independently associated with lower BMD in diabetic patients 3
• Target individualized glycemic goals to balance fracture risk from both hyper- and hypoglycemia 1

Understanding these mechanisms is crucial for developing effective strategies to prevent fractures in patients with diabetes, as traditional fracture risk assessment tools may underestimate their actual risk.