Physiology of Bone Formation, Remodeling, and Metabolism 2 Usha Kini and B. N. Nandeesh Contents 2.1 Introduction 2.1 Introduction ................................................ 29 Bone is a highly specialized supporting frame- 2.2 Physiology of Bone Formation .................. 30 2.2.1 Bone Formation ............................................ 30 work of the body, characterized by its rigidity, 2.2.2 Osteoblasts ................................................... 31 hardness, and power of regeneration and repair. It 2.2.3 Bone Matrix ................................................. 31 protects the vital organs, provides an environ- 2.2.4 Bone Minerals .............................................. 32 ment for marrow (both blood forming and fat 2.2.5 Osteocytes .................................................... 32 2.2.6 Intramembranous (Mesenchymal) storage), acts as a mineral reservoir for calcium Ossification ................................................ 32 homeostasis and a reservoir of growth factors and 2.2.7 Intracartilaginous (Endochondral) cytokines, and also takes part in acid–base bal- Ossification ................................................ 33 ance (Taichman 2005 ) . Bone constantly under- 2.2.8 Biological Factors Involved in Normal Bone Formation and Its Regulation ........... 37 goes modeling (reshaping) during life to help it 2.2.9 Bone Modeling ............................................. 37 adapt to changing biomechanical forces, as well 2.2.10 Determinants of Bone Strength .................... 37 as remodeling to remove old, microdamaged 2.3 Physiology of Bone Metabolism ................ 38 bone and replace it with new, mechanically stron- 2.3.1 Cellular and Intracellular Calcium ger bone to help preserve bone strength. and Phosphorus Metabolism ...................... 38 The bones have two components – the cortical 2.3.2 Regulation of Skeletal Metabolism .............. 38 bone which is dense, solid, and surrounds the 2.4 Bone Remodeling ........................................ 42 marrow space and the trabecular bone which is 2.4.1 Mediators of Remodeling ............................. 43 composed of a honeycomb-like network of trabe- 2.4.2 Remodeling Phases ...................................... 44 2.4.3 Regulatory Factors in Bone Remodeling ..... 46 cular plates and rods interspersed in the bone 2.4.4 Markers of Bone Metabolism ....................... 51 marrow compartment. Cortical bone has an outer 2.4.5 Pathophysiology of Bone Remodeling ......... 53 periosteal surface and inner endosteal surface. References ............................................................... 55 The periosteum is a fi brous connective tissue sheath that surrounds the outer cortical surface of bone, except at joints where bone is lined by articular cartilage. It contains blood vessels, nerve fi bers, osteoblasts, and osteoclasts. It pro- tects, nourishes, and aides in bone formation. It U. Kini , M.D., DCP, DNB, FICP () plays an important role in appositional growth B. N. Nandeesh , M.D., DNB and fracture repair. The endosteum is a membra- Department of Pathology , nous structure covering the inner surface of corti- St. John’s Medical College and Hospital , Koramangala , Bangalore , Karnataka 560034 , India cal and cancellous bone and the blood vessel e-mail: [email protected] ; [email protected] canals (Volkmann’s canals) present in bone. I. Fogelman et al. (eds.), Radionuclide and Hybrid Bone Imaging, 29 DOI 10.1007/978-3-642-02400-9_2, © Springer-Verlag Berlin Heidelberg 2012 30 U. Kini and B.N. Nandeesh Fig. 2.1 Woven bone/ immature bone ( W ) rimmed by osteoblasts ( B ) with peripheral lamellar bone (L ) showing a Haversian canal ( H ) Further, based on the pattern of collagen form- within the matrix. During life, the bones undergo ing the osteoid, two types of bone are identi fi ed: processes of longitudinal and radial growth, mod- woven bone , which is characterized by a haphaz- eling (reshaping), and remodeling (Clarke 2008 ) . ard organization of collagen fi bers (Eriksen et al. Longitudinal growth occurs at the growth plates, 1994 ) , and lamellar bone , which is characterized where cartilage proliferates in the epiphyseal and by a regular parallel alignment of collagen into metaphyseal areas of long bones, before subse- sheets (lamellae) (Fig. 2.1 ). Lamellar bone, as a quently undergoing mineralization to form pri- result of the alternating orientations of collagen mary new bone. fi brils, has a signi fi cant mechanical strength sim- ilar to plywood. This normal lamellar pattern is absent in woven bone, in which the collagen 2.2.1 Bone Formation fi brils are laid down in a disorganized manner. Hence, the woven bone is weaker than lamellar Ossi fi cation (or osteogenesis) is the process of for- bone. Woven bone is produced when osteoblasts mation of new bone by cells called osteoblasts. produce osteoid rapidly. This occurs initially in These cells and the bone matrix are the two all fetal bones and in fracture healing, but the most crucial elements involved in the formation resulting woven bone is replaced by a process of bone. This process of formation of normal called remodeling by the deposition of more healthy bone is carried out by two important pro- resilient lamellar bone. Virtually all the bone in cesses, namely: the healthy mature adult is lamellar bone. 1. Intramembranous ossi fi cation characterized by laying down of bone into the primitive connective tissue (mesenchyme) resulting in 2.2 Physiology of Bone Formation the formation of bones (skull, clavicle, man- dible). It is also seen in the healing process of Bone is composed of support cells, namely, fractures (compound fractures) treated by osteoblasts and osteocytes ; remodeling cells, open reduction and stabilization by metal namely, osteoclasts ; and non-mineral matrix of plate and screws. collagen and noncollagenous proteins called 2. Endochondral ossi fi cation where a cartilage osteoid , with inorganic mineral salts deposited model acts as a precursor (e.g., femur, tibia, 2 Physiology of Bone Formation, Remodeling, and Metabolism 31 humerus, radius). This is the most important Mesenchymal stem cell process occurring during fracture healing when treated by cast immobilization. Hemopoietic If the process of formation of bone tissue stem cell occurs at an extraskeletal location, it is termed as Osteoblast heterotopic ossi fi cation . precursor Three basic steps involved in osteogenesis Osteoclast precursors are: Osteoblasts Osteoclast (a) Synthesis of extracellular organic matrix (osteoid) (b) Matrix mineralization leading to the forma- Bone tion of bone (c) Remodeling of bone by the process of resorp- tion and reformation Fig. 2.2 Diagram to show evolution of osteoblasts and osteoclasts in the formation of bone 2.2.2 Osteoblasts tors, physical activity, and other stimuli act mainly through osteoblasts to bring about their Osteoblasts originate from mesenchymal stem effects on bone (Harada and Rodan 2003 ) . cells (osteoprogenitor cells) (Fig. 2.2) of the bone marrow stroma and are responsible for bone 2.2.2.1 Wnt Pathway on matrix synthesis and its subsequent mineraliza- Osteoblastogenesis tion. Commitment of mesenchymal stem cells to Wnts are secreted glycoproteins that regulate a the osteoblast lineage requires the canonical Wnt/ variety of cellular activities, such as cell fate, deter- j3-catenin pathway and associated proteins mination, proliferation, migration, survival, polar- (Logan and Nusse 2004 ) . ity and gene expression (Cadigan and Liu 2006 ; Osteoblasts are mononucleated, and their shape Caetano-Lopes et al. 2007 ) . This pathway is essen- varies from fl at to plump, re fl ecting their level of tial for the differentiation of mature osteoblasts cellular activity, and, in later stages of maturity, and consequently for bone formation. Reduced lines up along bone-forming surfaces (Fig. 2.1 ). Wnt signaling has been associated with osteoporo- Osteoblasts are responsible for regulation of sis (Krishnan et al. 2006 ) . The Wnt system is also osteoclasts and deposition of bone matrix (Mackie important in chondrogenesis and hematopoiesis 2003 ) . As they differentiate, they acquire the and may be stimulatory or inhibitory at different ability to secrete bone matrix. Ultimately, some stages of osteoblast differentiation. osteoblasts become trapped in their own bone matrix, giving rise to osteocytes which, gradu- ally, stop secreting osteoid. Osteocytes are the 2.2.3 Bone Matrix most abundant cells in bone; these cells commu- nicate with each other and with the surrounding The structure of bone is constituted by: medium through extensions of their plasma mem- (a) Inorganic (69 %) component, consisting of brane. Therefore, osteocytes are thought to act as hydroxyapatite (99 %) mechanosensors, instructing osteoclasts where (b) Organic (22 %), constituted by collagen (90 %) and when to resorb bone and osteoblasts where and noncollagen structural proteins which and when to form it (Boulpaep and Boron 2005 ; include proteoglycans, sialoproteins, gla- Manolagas 2000 ) . The osteoblasts, rich in alka- containing proteins, and 2HS-glycoprotein line phosphatase, an organic phosphate-splitting The functional component of the bone includes enzyme, possess receptors for parathyroid hor- growth factors and cytokines. The hardness and mone and estrogen. Also, hormones, growth fac- rigidity of bone is due to the presence of mineral 32 U. Kini and B.N. Nandeesh salt in the osteoid matrix, which is a crystalline important mediators of calcium regulation,