The osteocyte is the ringmaster and is in control of bone health throughout life. These cells manage the activity or the other principal bone cell, the osteoclast. It is also controls the development, fate, and activity of its replacement cell, the osteoblast. The osteocytes are derived from the mesenchymal stem cell and the osteoclast hails from the hematologic stem cell line. The mesenchymal stem cells are multipotential adult stem cells with the ability to differentiate into bone, muscle, cartilage, fat, fibrocytes, blood vessels, joint tissues, and nerves. The hematologic stem cells are multipotential stem cells capable of changing into osteoclasts, lymphocytes, red blood cells, platelets, macrophages, and neutrophils.

While osteocytes and osteoclasts directly manage bone health, there are legions of other cell types all over the body that influence bone health. These influences are transmitted through endocrine or paracrine means but all must pass through these cells to have an affect on bone.

The bone modeling/remodeling unit is abbreviated BMU and by this is meant the osteocyte, its youthful form the osteoblast, and the osteoclast. When you add in the triple helix cartilage buddle formed by the BMU and the subsequent calcification of the bundle to form composite mineralized bone tissue then together with the cells they are referred to as a basic structural unit or BSU.

Each bone in the body is a separate and complete living organ composed of billions of BSUs lined up in a specified manner that is determined by genetics and the mechanical demands placed upon the bone during growth and development. Each bone is controlled by a different set of genes and the genes for one bone are often different that for another. An extreme example is the index finger and femur. They have only 1 in 10 genes in common.

The BSU is a living tissue. Once the absorption phase is complete, the osteoclasts leave the area to roam through the bone compartment looking for more bone to remove. The osteoblasts come to the site, form up in rows, and begin laying down new bone matrix called osteoid, which is the template that becomes mineralized. The osteoid is laid down in regular rows or lamella that imparts strength to the bone once it is mineralized. During the process, each osteoblast extends numerous small tubules from its cytoplasm into the osteoid forming tiny canals called cannaliculi. One by one the osteoblasts nest within the osteoid by forming a space within it just big enough for its cell body. When its cannaliculi comes into contact with an adjacent osteoblast cannaliculi they form a connection called a desmosome. It is through the desmosome that all the cells with the BMU can communicate with one another. As the cartilage bundles become mineralized, the osteoblast is able to manage the state of mineral saturation of the fluid that surrounds the crystal by moving water, calcium, magnesium, and/or phosphorus through the cannaliculi membrane. In this way the osteoblast can keep the crystals that compose the BSU and hence the bone organ as a specific state of mineralization. This is important to provide the organism with the opposing physical properties bone strength and at the same time resilience.

All cells in the mesenchymal line become senescent and die. Bone and skeletal muscle cells live for about 7 years before requiring replacement. This is a natural process and occurs everyday to everyone all over the body. It is a non-synchronized event so that even though there may be a million dead BSU in your femur right now, they are scattered randomly and at different stages of the remodeling process. This is natures way of replacing us a little bit at a time here and there so quietly and painless that we don’t even know it.

Bone modeling and remodeling follows a stereotypic script of bone absorption by osteoclasts followed by bone formation by osteoblasts. This is a tightly coupled process and bone formation does not occur under normal circumstances without bone absorption occurring first. Osteoclasts only remove dead bone, never living bone. Osteoclasts like all normal cells respect the boundaries of other living tissues.

Osteoclasts are derived from the hematologic stem cell and while they live exclusively in the bone space they are really most like macrophages in every way. They even have the same cell surface receptors and respond to inflammatory cytokines like IL1 the same. Bone formation is dependent and coupled to bone absorption for two simple reasons. The first is physiology. Once the osteoclast detects a dead BSU they set to work taking the whole thing down. They leave nothing behind. Everything must go! They take it all down to the cement line that demarcates the next door living BSU neighbor with the dead one but don’t cross that line. Absolutely not, that is the prime directive and it is always followed by every normal osteoclast. All the old BSU tissue is taken out, broken down into elemental calcium, magnesium, and phosphorus. Collagen fragments are released and the resorption bay is left clean as a whistle for the osteoblasts. During the mayhem of bone absorption, bone growth factors including bone morphogenic protein and transforming growth factor beta that were stored 7 years ago by the osteoblasts that laid down the osteoid during formation is released into the local environment. These growth factors cause the mesenchymal stem cells hanging around the bone compartment to become activated and differentiate into pre-osteoblasts. They are also chemotactic for these same cells meaning that the call them to the site of bone absorption. The pre-osteoblast can “smell” the growth factors and track the strength or gradient of the factor back to the source. Once there, the sit on the sidelines maturing all along, basking in the concentrated growth factor environment surrounding the bay until the osteoclasts complete the deed. Now ready for business, the mature osteoblasts move into the bay and get to work.

The second reason is anatomic. There is no space for new bone to be formed or need to form new bone except where the old bone was replaced. This reason while true in healthy young and middle-aged adults becomes less true or false in menopausal women most particularly those with osteoporosis. There is space within the bone compartment that could be filled in with new bone. Anabolic therapies including the parathyroid group and androgens take advantage of this.