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Mineralization of osteoid involves an interaction of processes that either promote or inhibit deposition. Initial nucleation of mineral may be enhanced by the formation or exposure of nucleators and by the removal or modification of inhibitors. However, details of the mechanisms involved and the location in, on or around the fibrils remain subjects of controversy. Many believe that specific atomic groups located in the gap zones of collagen fibrils are arranged in such a way as to induce heterogeneous nucleation of hydroxyapatite [24]. These nuclei subsequently expand by addition of further inorganic ions, so giving rise to crystals. Certain factors, principally non‐collagenous proteins, have been shown to promote or inhibit mineralization. For example, phosphoproteins, such as bone sialoprotein, bind calcium and thereby act as mineral nucleators. Conversely, proteoglycans may inhibit the process by masking critical zones or occupying essential spaces within fibrils, thereby reducing diffusion, chemical interaction and sequestration of calcium ions.

The role of matrix vesicles as initiators is also contentious. These small (20–200 nm) spherical bodies are derived from osteoblasts. They are found in osteoid and are often associated with small crystals of calcium phosphate. They are bound by a lipid membrane, which has a composition that is different to that of the parent cell. They are enriched in tissue non‐specific alkaline phosphatase (TNAP), nucleotide pyrophosphatase phosphodiesterase annexins among other factors that are known to promote mineral deposition. Calcium ions are also concentrated within the vesicles. While it is generally accepted that matrix vesicles play a role in initiating bone mineralization, its exact nature and extent is controversial.

In most healthy adult bones, the mineral fraction (proportion of dry weight accounted for by mineral) is between 60 and 70%. Fractions in this range engender material properties that provide an optimal compromise between strength, stiffness and toughness. Osteoblasts and osteocytes limit the ultimate extent of matrix mineralization through the adjustment of extracellular ion concentrations [25, 26]. Loss of these cells, for instance in osteonecrosis, is associated with hypermineralization, which can have profound effects on material properties causing bone to become brittle.