Factors Affecting Bone Growth

Differences in bone size are established early in life, before puberty and perhaps even in utero.¹ Bone begins to form when mesenchymal cells form condensations—clusters of cells that adhere through expression of adhesion molecules² (Figure 1). Bone must be stiff, flexible enough to change shape to absorb energy, and light enough to allow mobility.^1,3 Longitudinal bone growth is detrimental to bone stability, but this effect is counteracted by concomitant bone growth in width.⁴ Bone growth in width has not been studied as extensively, despite its paramount role in skeletal development.⁵

Bone growth and development are products of the complex interactions of genetic and environmental factors, including diet, hormones, and mechanical stimuli.^6-9 Longitudinal bone growth is controlled by systemic and local hormones and local mechanical factors. Two models for control of bone growth in width have been suggested—the mechanostat theory (mechanical requirements regulate periosteal apposition) and the sizostat hypothesis (a master gene or set of genes regulates bone growth in width so bone reaches a preprogrammed size, independent of mechanical requirements).⁵

In this article, we review the most recent data regarding bone growth from the embryonic age and analyze the factors that control bone growth. An understanding of this complex system is important in identifying metabolic and developmental bone diseases¹⁰ and fracture risk.^11,12

Growth Plate

The growth plate consists mainly of collagen fibrils, proteoglycans, and water, arranged to form a sort of sponge with very small pores.¹³ The growth plate is located between epiphyseal and metaphyseal bone at the distal end of long bones¹⁴ and is strain-rate–dependent,^15,16 which means it is hard when squeezed rapidly but soft when deformed slowly. The growth plate becomes ossified after puberty and epiphyseal fusion.¹⁷

Histologically, the growth plate consists of horizontal zones of chondrocytes at different stages of differentiation.⁴ The germinal zone, at the epiphyseal end of the growth plate, contains resting chondrocytes, which seem crucial in orienting the underlying columns of chondrocytes and, therefore, in unidirectional bone growth, probably by secretion of a growth plate–orienting factor.^14,18 Next is the proliferative zone, a matrix-rich zone in which flattened chondrocytes undergo longitudinal cell division and orient themselves in typical column-wise fashion. At some point, proliferating chondrocytes lose their capacity to divide; they start to differentiate and become prehypertrophic, coinciding with a size increase.⁴ Proliferating chondrocytes are located in the transition (maturation or prehypertrophic) zone. In the hypertrophic zone, round chondrocytes secrete matrix proteins in large amounts.¹⁴ This stage is characterized by an increase in intracellular calcium concentration, which is essential in the production of matrix vesicles. These vesicles, small membrane-enclosed particles, are released from chondrocytes^19,20 and secrete calcium phosphates, hydroxyapatite, and matrix metalloproteinases, resulting in mineralization of the vesicles and their surrounding matrix.⁴ The chondrocytes in this mineralized zone eventually undergo programmed cell death (apoptosis), leaving a scaffold for new bone formation.

Longitudinal Bone Growth

Generally, bones increase in length as long as new material is being squeezed between the reserve zone of the growth plate and the zone of provisional calcification.⁴

Postnatal linear growth occurs in 3 phases. Phase 1 is characterized by a high rate of growth at the beginning of fetal life, and then rapid deceleration up to about 3 years; phase 2, by a lower, slowly decelerating growth rate up to puberty; and phase 3, by an increased rate of longitudinal growth until a peak is reached.^14,21,22

In 1964, Park²³ proposed that the structure of the epiphyseal cartilage may determine the pattern of the growing bone shaft. The changes within the hypertrophic zone are directly related to matrix mineralization, vascular invasion, and subsequent development.²⁴ Intracellular calcium concentration increases in the hypertrophic chondrocytes in the hypertrophic zone of growth plate cartilage; at some point, these chondrocytes begin to mineralize the longitudinal septa in the surrounding matrix²⁵ (Figure 2). At the growth cartilage junction, mononuclear cells of undetermined origin resorb the unmineralized horizontal septa of the growth cartilage. These cells are called septoclasts or chondroclasts.^25,26 Blood vessels invade the area and pave the way for bone cell precursors.²⁷ Eighty percent of the longitudinal septa of the growth cartilage is rapidly resorbed in the metaphyseal zone immediately behind the invading blood vessels, paving the way for bone cell precursors.²⁸ Fazzalari and colleagues²⁸ reported that about 40% of mineralized septa serves as scaffold for the formation of primary bone trabeculae; the other 60% is absorbed by chondroclasts (osteoclasts) near the vascular invasion front.

Regulation of Longitudinal Bone Growth

Longitudinal bone growth is regulated by genetic, hormonal, growth, and environment factors^17,29-31 (Table). It must be controlled on at least 3 different levels.⁴ Level 1 is systemic control by factors such as growth hormone (GH), sex hormones, and glucocorticoids. The major systemic hormones that control longitudinal bone growth during childhood are GH, insulin-like growth factor 1 (IGF-1), the thyroid hormones triiodothyronine (T₃) and thyroxine (T₄), and glucocorticoids; during puberty, the sex steroids play the most significant role.¹⁴ Level 2 is local control by factors such as Indian hedgehog (Inh), parathyroid hormone–related peptide (PTHrP), and fibroblast growth factors (FGFs).^14,31 Level 3 is mechanical control.⁴