What factors influence bone healing?

Factors Influencing Bone Healing

Bone healing is influenced by both local and systemic factors, with local trauma severity, blood supply, mechanical stability, and inflammation being the most critical determinants of successful fracture repair. 1, 2

Local Factors

Mechanical Stability and Fixation

• Biomechanical stability at the fracture site is fundamental to successful healing, as inadequate fixation can prolong inflammation and impair bone regeneration 2, 3
• The degree of immobilization directly affects healing progression through all three phases (inflammatory, reparative, and remodeling) 1
• Insufficient mechanical conditions within the fracture zone can amplify local inflammation and delay healing 2

Blood Supply and Revascularization

• Adequate vascularization is essential, as the blood supply to the healing site determines nutrient and oxygen delivery to regenerating bone 2
• Local trauma severity affects the extent of vascular disruption and subsequent healing capacity 1

Degree of Bone Loss and Soft Tissue Injury

• The extent of initial bone loss and soft tissue damage significantly impacts healing time and complication rates 4, 1
• Open fractures with extensive soft tissue injury have higher infection rates (up to 30%) compared to closed fractures (1-2%) 4

Infection and Biofilm Formation

• Fracture-related infection (FRI) severely compromises healing, as biofilm formation on fixation devices allows bacteria to survive high antibiotic concentrations 4
• Successful management requires combined surgical and antimicrobial treatment, as antibiotics alone cannot eradicate biofilm-associated infections 4

Type of Bone Affected

• Trabecular versus cortical bone composition influences healing patterns and timelines 1
• Bones with higher proportions of trabecular bone (spine, proximal/distal long bones) are more susceptible to metabolic influences 4

Systemic Factors

Age

• Increasing age (>65 years) is associated with impaired bone healing capacity and increased fracture risk 4, 1
• Younger patients with open epiphyses have different healing dynamics but should avoid certain bone-active medications like teriparatide 5

Metabolic and Endocrine Factors

Vitamin D Deficiency:

• Vitamin D insufficiency (<20-30 ng/mL) impairs bone turnover, mineralization, and metabolism 4
• Deficiency is extremely common in chronic kidney disease (60-75% prevalence in HIV-infected cohorts) and contributes significantly to bone disease 4, 6
• Supplementation improves bone-titanium integration and various bone properties 4

Calcium Homeostasis:

• Adequate calcium intake (1000 mg/day) is essential for mineralization during healing 4
• Hypercalcemia can impair healing, while hypocalcemia (common in CKD) disrupts normal bone metabolism 4, 6

Parathyroid Hormone (PTH) Dysregulation:

• Secondary hyperparathyroidism in chronic kidney disease leads to increased bone resorption and impaired healing 4, 6
• Elevated PTH levels require monitoring and treatment with active vitamin D sterols or calcimimetics 6

Phosphate Balance:

• Hyperphosphatemia in CKD-mineral bone disorder disrupts normal bone formation 4, 6
• Elevated FGF23 levels are associated with poor bone quality and impaired osseointegration 4

Hormonal Status

• Estrogen deficiency accelerates bone loss, leading to 40-50% increased fracture incidence in breast cancer patients and men receiving androgen deprivation therapy 4
• Hypogonadism contributes to low bone mineral density and impaired healing 4

Inflammatory and Immune Conditions

Systemic Inflammation:

• Chronic systemic inflammation (rheumatoid arthritis, diabetes, multiple trauma, sepsis) increases healing time and complication rates including non-unions 2
• HIV infection increases osteoclastic activity and promotes osteoblast apoptosis, with elevated TNF-α increasing bone resorption 4
• Immune cells exhibit critical crosstalk with bone cells during the repair phase 2

Immunosuppression:

• Immunosuppressive therapy impairs the inflammatory phase necessary to initiate the repair cascade 3
• Risk factors for calciphylaxis (which impairs healing) include autoimmune disease, kidney failure, and corticosteroid use 5

Medications

Glucocorticoids:

• Prolonged corticosteroid use (>6 months) is a major risk factor for impaired bone healing 4
• Glucocorticoids inhibit osteoblasts and osteocytes (decreasing bone formation), stimulate osteoclasts (increasing resorption), reduce calcium absorption, and cause muscle catabolism 4
• Effects depend on dose, duration, cumulative exposure, and specific compound used 4

Fluoroquinolones:

• Fluoroquinolones inhibit osteoblast proliferation and mineralization in a dose-dependent manner, potentially impairing bone healing 4
• Caution should be exercised when using fluoroquinolones locally where bone healing is occurring 4
• Associated with increased delayed union and non-union rates in animal studies 4

Antiretroviral Therapy:

• ART induces 2-6% bone loss within first 2 years of treatment, with tenofovir showing strongest association with acute BMD decrease 4

Nutritional Factors

• Low body mass index (<20 kg/m²) impairs healing capacity 4
• Malnutrition and inadequate protein intake compromise the reparative phase 4
• Combined calcium and vitamin D supplementation (vitamin D 1000-2000 IU/day) is more effective than monotherapy 4

Lifestyle Factors

Smoking:

• Cigarette smoking negatively affects bone quality and significantly increases fracture risk and healing complications 4
• Smoking cessation should be strongly emphasized in all fracture patients 4

Physical Activity:

• Decreased physical activity or immobilization increases bone resorption and negatively affects bone mineral density 4
• Weight-bearing exercise is recommended despite mixed evidence on BMD preservation, due to benefits for overall health, fitness, and fall prevention 4

Alcohol:

• Chronic alcohol use is associated with low bone density and high fracture risk 4
• Even moderate consumption (one drink per day) can lead to poor balance, falls, and increased fracture risk 4

Comorbid Conditions

Diabetes Mellitus:

• Diabetes is an established risk factor for impaired fracture healing and increased infection rates 4, 2
• Biologics may be particularly beneficial in diabetic patients where poor healing is anticipated 4

Chronic Kidney Disease:

• CKD-mineral bone disorder causes bone demineralization, decreased trabeculation, abnormal healing after extraction, and jaw fractures 4
• Multiple metabolic derangements (hyperphosphatemia, hypocalcemia, hyperparathyroidism, vitamin D deficiency) disrupt bone structural integrity 4, 6

Osteoporosis:

• Pre-existing osteoporosis (T-score <-2.5) significantly impairs healing capacity 4
• Biologics may promote bone formation in osteoporotic patients where impaired healing is anticipated 4

Temporal Considerations

• Biofilm maturation occurs over weeks and determines antimicrobial therapy efficacy in infected fractures 4
• Fracture healing to bony consolidation takes weeks to months and is crucial for infection cure 4
• Within the first 2 weeks post-fixation, bone shows no osteomyelitis signs despite bacterial presence; histological changes appear over subsequent weeks 4

Clinical Pitfalls

• Do not assume antibiotics alone will treat fracture-related infections—surgical intervention is mandatory due to biofilm formation 4
• Avoid teriparatide in patients with metabolic bone diseases other than osteoporosis (including Paget's disease), bone metastases, prior skeletal radiation, or hereditary disorders predisposing to osteosarcoma 5
• Monitor for hypercalcemia when using bone-active agents, as it can impair healing and predispose to digitalis toxicity 5
• Recognize that polymicrobial infections are frequent (20-35%) in open fractures and require broad-spectrum coverage 4