Bone remodeling in adults involves two main processes: the destruction of fatigued or microdamaged bone, which releases calcium, phosphate, and fragmented bone matrix into the bloodstream, and the synthesis of osteoid (unmineralized bone matrix) at the site of resorption, followed by the controlled mineralization of the osteoid with calcium and phosphate to form new bone. Throughout the skeleton, bone remodeling occurs at approximately 2 million discrete sites by groups of bone cells known as the basic multicellular units (BMU).

The cells involved in bone remodeling can be classified into two major groups: osteoblasts, which form bone, and osteoclasts, which resorb or destroy bone. The process of bone remodeling is highly coordinated. Osteoblast-lineage cells produce factors that induce the differentiation of osteoclasts from progenitors of the monocyte/macrophage lineage and also enhance the function of mature osteoclasts. One factor released by osteoblasts is monocyte colony-stimulating factor (M-CSF), which promotes the expansion and differentiation of early hematopoietic progenitors (CFU-GM) into preosteoclasts expressing a cell surface receptor called RANK (receptor activator of nuclear factor [NF]-κB). Osteoblast-lineage cells display RANK ligand (RANKL) on their cell surface, which binds to RANK on preosteoclasts and triggers osteoclastogenesis. This process involves the fusion of multiple osteoclast precursors, resulting in the formation of a large multinucleated osteoclast. The periphery of the osteoclast membrane facing the mineralized bone tightly adheres to it, creating a seal at the site of osteoclast-bone contact. Within this sealed zone, a highly invaginated membrane called the ruffled border is formed, from which hydrochloric acid (HCl) and hydrolytic lysosomal enzymes are secreted. The acidic and enzyme-rich microenvironment beneath the osteoclast dissolves the bone mineral, releasing calcium and phosphate into the bloodstream and breaking down the bone matrix. The RANK/RANKL system also includes an inhibitory component. Osteoblast-lineage cells can produce osteoprotegerin (OPG), a soluble factor that acts as a decoy receptor for RANKL and inhibits osteoclast differentiation and function. Thus, the balance between RANKL and OPG expression by osteoblasts determines the extent of osteoclast differentiation and bone resorption.

After bone resorption in the BMU, a brief reversal phase occurs, followed by the migration of adjacent osteoblasts into the resorbed area, where they begin depositing osteoid. Various components within the osteoid, such as pyrophosphate, alkaline phosphatase, and specific glycoproteins, facilitate slow and controlled mineralization, which removes calcium and phosphate from the bloodstream. As the osteoblasts become surrounded by and trapped within the bone, they transform into osteocytes and occupy small spaces known as lacunae. Osteocytes remain connected through cellular processes that run within canaliculi and establish communication with neighboring cell processes. The newly formed concentric layers of bone, along with the interconnected osteocytes and the central canal, are collectively referred to as a Haversian system or osteon. Emerging evidence suggests that osteocytes can detect mechanical stress in bone and signal the need for additional local bone formation. They are also capable of detecting microdamage in bone, initiating remodeling at the affected site.
In adults, bone remodeling involves (1) destruction of fatigued or microdamaged bone with the release of Ca++, Pi, and hydrolyzed fragments of bone matrix into blood and (2) synthesis of osteoid (yet to be mineralized bone matrix) at the site of resorption, followed by controlled mineralization of the osteoid by Ca++ and Pi to form new bone. Bone remodeling occurs continually at about 2 million discrete sites throughout the skeleton by packets of bone cells referred to as the basic multicellular units (BMU).
The cells involved in bone remodeling fall into two major classes: cells that form bone (osteoblasts) and cells that destroy or resorb bone (osteoclasts). The process of bone remodeling is a highly integrated process (
Fig. 40.9 ). Osteoblast-lineage cells express factors that induce differentiation of osteoclasts from progenitors of the monocyte/ macrophage lineage and also promote mature osteoclast function. Osteoblasts release monocyte colony-stimulating factor (M-CSF), which expands and differentiates early hematopoietic progenitors (CFU-GM) into preosteoclasts that express a cell surface receptor called RANK (receptor •Fig. 40.9 Osteoblastregulationofosteoclastdifferentiationandfunction.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.) activator of nuclear factor [NF]-κB). Osteoblast-lineage cells display RANK ligand (RANKL) on their cell surface. RANKL then binds to RANK on preosteoclasts and induces osteoclastogenesis. This process involves fusion of several osteoclast precursors, giving rise to a large multinucleated osteoclast. The perimeter of the osteoclast membrane facing mineralized bone adheres tightly to the bone and seals off the area of osteoclast-bone contact (see
Fig. 40.9 ). The region within the sealed zone forms a highly invaginated membrane called the ruffled border, from which HCl and hydrolytic lysosomal enzymes are secreted. The acidic enzyme-rich microenvironment beneath the osteoclast dissolves the bone mineral, thereby releasing Ca++ and Pi into blood, and also degrades the bone matrix. There is an additional inhibitory component of the RANK/RANKL system. Osteoblast-lineage cells can also produce a soluble factor called osteoprotegerin (OPG), which acts as a decoy receptor for RANKL and inhibits osteoclast differentiation and function (see
Fig. 40.9 ). Therefore the balance between RANKL and OPG expression by osteoblasts determines how much osteoclast differentiation and bone resorption will occur.
Following bone resorption in the BMU, there is a brief reversal phase, then adjacent osteoblasts migrate into the resorbed area and begin to lay down osteoid. Several components within osteoid (pyrophosphate, alkaline phosphatase, specific glycoproteins) promote slow, controlled mineralization, a process that removes Ca++ and Pi from blood. As the osteoblasts become surrounded by and entrapped within bone, they become osteocytes that sit within small spaces called lacunae. Osteocytes remain interconnected through cell processes that run within canaliculi and form communicating junctions with adjacent cell processes. The new concentric layers of bone, along with the interconnected osteocytes and the central canal, are referred to collectively as a Haversian system or osteon. Emerging evidence indicates that osteocytes are able to sense mechanical stress in bone and signal that additional local bone formation is needed. They can also detect microdamage in bone that serves to initiate remodeling at that location.