Normal Bone Anatomy and Physiology Bart Clarke Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota This review describes normal bone anatomy and physiology as an introduction to the subsequent articles in this section that discuss clinical applications of iliac crest bone biopsy. The normal anatomy and functions of the skeleton are reviewed first, followed by a general description of the processes of bone modeling and remodeling. The bone remodeling process regulates the gain and loss of bone mineral density in the adult skeleton and directly influences bone strength. Thorough understanding of the bone remodeling process is critical to appreciation of the value of and interpretation of the results of iliac crest bone histomorphometry. Osteoclast recruitment, activation, and bone resorption is discussed in some detail, followed by a review of osteoblast recruitment and the process of new bone formation. Next, the collagenous and noncollagenous protein components and function of bone extracellular matrix are summarized, followed by a description of the process of mineral- ization of newly formed bone matrix. The actions of biomechanical forces on bone are sensed by the osteocyte syncytium within bone via the canalicular network and intercellular gap junctions. Finally, concepts regarding bone remodeling, osteoclast and osteoblast function, extracellular matrix, matrix mineralization, and osteocyte function are synthesized in a summary of the currently understood functional determinants of bone strength. This information lays the groundwork for understanding the utility and clinical applications of iliac crest bone biopsy. Clin J Am Soc Nephrol 3: S131–S139, 2008. doi: 10.2215/CJN.04151206 The Skeleton composed primarily of dense cortical bone, whereas the me- The adult human skeleton has a total of 213 bones, excluding taphysis and epiphysis are composed of trabecular meshwork the sesamoid bones (1). The appendicular skeleton has 126 bone surrounded by a relatively thin shell of dense cortical bones, axial skeleton 74 bones, and auditory ossicles six bones. bone. Each bone constantly undergoes modeling during life to help it The adult human skeleton is composed of 80% cortical bone adapt to changing biomechanical forces, as well as remodeling and 20% trabecular bone overall (3). Different bones and skel- to remove old, microdamaged bone and replace it with new, etal sites within bones have different ratios of cortical to tra- mechanically stronger bone to help preserve bone strength. becular bone. The vertebra is composed of cortical to trabecular The four general categories of bones are long bones, short bone in a ratio of 25:75. This ratio is 50:50 in the femoral head bones, flat bones, and irregular bones. Long bones include the and 95:5 in the radial diaphysis. clavicles, humeri, radii, ulnae, metacarpals, femurs, tibiae, fib- Cortical bone is dense and solid and surrounds the marrow ulae, metatarsals, and phalanges. Short bones include the car- space, whereas trabecular bone is composed of a honeycomb- pal and tarsal bones, patellae, and sesamoid bones. Flat bones like network of trabecular plates and rods interspersed in the include the skull, mandible, scapulae, sternum, and ribs. Irreg- bone marrow compartment. Both cortical and trabecular bone ular bones include the vertebrae, sacrum, coccyx, and hyoid are composed of osteons. bone. Flat bones form by membranous bone formation, Cortical osteons are called Haversian systems. Haversian whereas long bones are formed by a combination of endochon- systems are cylindrical in shape, are approximately 400 mm dral and membranous bone formation. long and 200 mm wide at their base, and form a branching The skeleton serves a variety of functions. The bones of the network within the cortical bone (3). The walls of Haversian skeleton provide structural support for the rest of the body, systems are formed of concentric lamellae. Cortical bone is permit movement and locomotion by providing levers for the typically less metabolically active than trabecular bone, but this muscles, protect vital internal organs and structures, provide depends on the species. There are an estimated 21 ϫ 106 cortical maintenance of mineral homeostasis and acid-base balance, osteons in healthy human adults, with a total Haversian remod- serve as a reservoir of growth factors and cytokines, and pro- eling area of approximately 3.5 m2. Cortical bone porosity is vide the environment for hematopoiesis within the marrow usually Ͻ5%, but this depends on the proportion of actively spaces (2). remodeling Haversian systems to inactive cortical osteons. In- The long bones are composed of a hollow shaft, or diaphysis; creased cortical remodeling causes an increase in cortical po- flared, cone-shaped metaphyses below the growth plates; and rosity and decrease in cortical bone mass. Healthy aging adults rounded epiphyses above the growth plates. The diaphysis is normally experience thinning of the cortex and increased cor- tical porosity. Cortical bone has an outer periosteal surface and inner en- Address correspondence to: Dr. Bart Clarke, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, W18-A, 200 1st Street SW, Rochester, dosteal surface. Periosteal surface activity is important for ap- MN 55905; Phone: 507-266-4322; Fax: 507-284-5745; E-mail [email protected] positional growth and fracture repair. Bone formation typically Copyright © 2008 by the American Society of Nephrology ISSN: 1555-9041/303–0131 S132 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: S131–S139, 2008 exceeds bone resorption on the periosteal surface, so bones independent action of osteoblasts and osteoclasts in response to normally increase in diameter with aging. The endosteal sur- biomechanical forces. Bones normally widen with aging in face has a total area of approximately 0.5 m2, with higher response to periosteal apposition of new bone and endosteal remodeling activity than the periosteal surface, likely as a result resorption of old bone. Wolff’s law describes the observation of greater biomechanical strain or greater cytokine exposure that long bones change shape to accommodate stresses placed from the adjacent bone marrow compartment. Bone resorption on them. During bone modeling, bone formation and resorp- typically exceeds bone formation on the endosteal surface, so tion are not tightly coupled. Bone modeling is less frequent the marrow space normally expands with aging. than remodeling in adults (4). Modeling may be increased in Trabecular osteons are called packets. Trabecular bone is hypoparathyroidism (5), renal osteodystrophy (6), or treatment composed of plates and rods averaging 50 to 400 mm in thick- with anabolic agents (7). ness (3). Trabecular osteons are semilunar in shape, normally Bone remodeling is the process by which bone is renewed to approximately 35 mm thick, and composed of concentric lamel- maintain bone strength and mineral homeostasis. Remodeling ϫ 6 lae. It is estimated that there are 14 10 trabecular osteons in involves continuous removal of discrete packets of old bone, healthy human adults, with a total trabecular area of approxi- replacement of these packets with newly synthesized protein- 2 mately 7 m . aceous matrix, and subsequent mineralization of the matrix to Cortical bone and trabecular bone are normally formed in a form new bone. The remodeling process resorbs old bone and lamellar pattern, in which collagen fibrils are laid down in forms new bone to prevent accumulation of bone microdam- alternating orientations (3). Lamellar bone is best seen during age. Remodeling begins before birth and continues until death. microscopic examination with polarized light, during which The bone remodeling unit is composed of a tightly coupled the lamellar pattern is evident as a result of birefringence. The group of osteoclasts and osteoblasts that sequentially carry out mechanism by which osteoblasts lay down collagen fibrils in a resorption of old bone and formation of new bone. Bone re- lamellar pattern is not known, but lamellar bone has significant modeling increases in perimenopausal and early postmeno- strength as a result of the alternating orientations of collagen pausal women and then slows with further aging, but contin- fibrils, similar to plywood. The normal lamellar pattern is ab- ues at a faster rate than in premenopausal women. Bone sent in woven bone, in which the collagen fibrils are laid down remodeling is thought to increase mildly in aging men. in a disorganized manner. Woven bone is weaker than lamellar The remodeling cycle is composed of four sequential phases. bone. Woven bone is normally produced during formation of Activation precedes resorption, which precedes reversal, which primary bone and may also be seen in high bone turnover states precedes formation. Remodeling sites may develop randomly such as osteitis fibrosa cystica, as a result of hyperparathyroid- but also are targeted to areas that require repair (8,9). Remod- ism, and Paget’s disease or during high bone formation during eling sites are thought to develop mostly in a random manner. early treatment with fluoride. Activation involves recruitment and activation of mononu- The periosteum is a fibrous connective tissue sheath that clear monocyte-macrophage osteoclast precursors from the cir- surrounds the outer cortical surface of bone, except at joints where bone is lined by articular cartilage, which contains blood