Vascular endothelial growth factor (VEGF), a chemoattractant for endothelial cells, is one of the most important growth factors for endothelial cells.78 VEGF is a key player in the actions that occur during the end stage of endochondral bone formation; these actions include terminal differentiation of chondrocytes, vascular invasion, chondrocyte apoptosis, and replacement of chondrocytes with bone.27,79,80 When Gerber and colleagues27 inactivated VEGF in 24-day-old mice, they noticed suppressed blood vessel invasion and trabecular bone formation concomitant with an increased width of the hypertrophic zone.
Mechanical Regulation. Mechanical forces influence bone formation and adaptation.81 Growth rates from early infancy through late adolescence were found to be strongly correlated between an appropriate measure of mechanical loading (body size, or body weight–bone length) and bone strength (assessed by section modulus).82 The observation that compression inhibits bone growth was well known to the ancient Romans.83 In the 19th century, the Hueter-Volkmann law was proclaimed. This law is well known to pediatric orthopedic surgeons and is the basis of growth modulation for correcting angular deformities of the lower extremities and spinal deformities.4,84
If compression always inhibited bone growth, as it was believed, growth plates would be extremely unstable, as any slight deviation from the straight alignment of the long bones of the lower extremities would induce a vicious circle of positive feedback and result in catastrophic deformities.4 Mild compression leads to increased, not decreased, growth. Nevertheless, when compression on one side of the growth plate exceeds a certain level, growth is indeed suppressed, and the lesion begins to worsen.4
In 1997, Frost85 proposed using a single graph that combines the clinical observation of mechanical forces affecting longitudinal bone growth. Both mild tension and mild compression induce bone growth, whereas heavy compression inhibits growth (Figure 3).
Three rules describe bone adaptation in mathematical terms. First, bone adaptation is driven by dynamic, not static, loading. Second, only a short period of mechanical loading is needed to initiate an adaptive response (extending the loading period has a diminishing effect on further bone adaptation). Third, bone cells accommodate to a customary mechanical loading environment, making them less responsive to routine loading signals.81
Also playing a significant role in bone physiology is the nervous system, with leptin-dependent central control of bone formation via the sympathetic system.86 Several investigators have tried to determine the effect of muscle activity on bone growth in length.87 Pottorf88 in 1916 and Allison and Brooks89 in 1921 were among the first to study this correlation; they concluded that long bones grow less after denervation. On the other hand, Ring90 in 1961 reported that, despite innervation, longitudinal bone growth was increased. Investigators in more recent studies have advanced the idea that the nervous system plays a negative role in bone physiology. Dysart and colleagues87 showed that muscle pull affects periosteal tension and, consequently, bone form and growth in length. In a clinical study involving 32 children with neonatal brachial plexus injury,91 the ratio of skewness between the affected humeral head and the contralateral normal head was calculated. Skewness was determined by dividing the anterior area of the humeral head by the posterior area. There was a significant preoperative difference between the 2 sides, but the skewness ratio was significantly improved after surgery.
Bone Growth in Width
Bone growth in width has not received as much attention as longitudinal bone growth. Several studies have indicated that body mass and muscle strength have important influences on long bone strength in children and adolescents.92-97 As bone width changes only slowly after the growth period, bone growth in width is one of the most important determinants of bone strength throughout life.4 It is clear that, if bones grew in length without increasing in width, they would become unstable and break.4
Histologically, osteoblasts add mineralized tissue to the outer (periosteal) bone surface. This process is periosteal apposition.98 The periosteum has an outer layer, composed mainly of fibrous tissue, and an inner layer, the cambium, which harbors osteogenic cells.4 In children, bone formation is continuous, which is the hallmark of modeling99,100; in adults, periosteal bone may undergo cyclical resorption and formation, which are characteristic of remodeling.101,102
Macroscopically, bone grows rapidly during early life; then, growth continuously slows down until reaching a nadir during early school age.4 It is clear that wider bones must have higher midshaft periosteal apposition rates, as this is how they become wider.4,103
Regulation of Bone Growth in Width (Table)
Systemic Regulation. Periosteal apposition at diaphyseal bone sites is stimulated by androgen and GH and inhibited by estrogens.104-106 In an experimental study, Turner and colleagues104 found that androgen treatment stimulated bone formation in orchiectomized rats and suppressed bone formation in ovariectomized rats. A large dose of diethylstilbestrol also suppressed bone formation in ovariectomized rats. Parathyroid hormone is associated with faster periosteal expansion in adults, according to Parfitt.107 In addition, nutrition with high calcium intake has the same effects on children, especially those with high levels of physical activity.108
