Bones provide structural support for ambulatory activities and protection for vital organs, such as the brain and heart. They also respond to changing concentrations of circulating hormones and locally released cytokines and growth factors, and along with cells in other organs regulate the blood concentration of calcium, an element essential for many critical functions, such as cell division and heart contraction. This regulatory activity takes precedence over the support function because bones can be weakened to the point of fracture following excessive removal of bone by osteoclasts (large multinucleated cells, associated with bone resorption) in response to estrogen or vitamin D deficiency. During embryonic development, the size, shape, position, and number of bones are determined by the activities of genes that are expressed at specific times by distinct groups of cells. Some of these genes also regulate the formation and activity of cells that remodel bones after they are formed.