Bones are not inert structures within the human body; they continue to change over the course of a lifespan. This process of skeletal change is known as bone remodeling, which both protects the structural integrity of the skeletal system and metabolically contributes to the body’s balance of calcium and phosphorus. Remodeling entails the resorption of old or damaged bone, followed by the deposition of new bone material.

The adult human skeleton is composed of 206 bones.  At birth, there are approximately 270 bones, with the final adult count decreasing as a portion of these bones fuses during phases of skeletal growth and maturation.  Bone is a metabolically active connective tissue that provides structural support, facilitates movement, and protects vital organs. It plays an important role in regulating mineral and acid-base balance homeostasis. It also provides the environment for hematopoiesis (blood cells production) within the bone marrow.  Bone is composed of an extracellular matrix and bone cells (osteocytes).

Types of Bone

Architecturally, bone categorizes into two subtypes: cortical and trabecular bones. Similarly, the primary mechanical determinants of the strength of bone are specific for the subtype as described: width and porosity for cortical bone, and shape, width, connectivity, and anisotropy for trabecular bone. Further differentiations regarding the two subtypes are as follows:

  • Cortical Bone – consists of about 80% of the total bone in the body and is much stronger than trabecular bone. It is very resistant to bending, torsion, and compression and is much denser with a minimal role in metabolism. It is seen mostly in the shaft of long bones like the femur and the tibia as well as in the outer shell of trabecular bone.
  • Trabecular Bone – consists of only 20% of the total bone but has ten times the surface/volume ratio of cortical bone. It responds eight times faster to changes in load making it far more dynamic. It occurs in areas that more subject to compression such as the vertebral body, pelvis, and the metaphyses.

Function of Bones

There are three main functions of the human skeletal system classified into the mechanical, formation of hematopoietic cells, and metabolism.

  • Mechanical – Bones provide a frame for other soft tissues of the musculoskeletal system to attach to such as muscles, tendons, and ligaments. These allow for support as well as the movement by contracting and relaxing of the muscles which then, in turn, result in flexion, extension, abduction, adduction, and other forms of movement. They also help form a mechanical barrier to different structures within the human body. For example, the rib cage and the skull help shield our vital organs, the heart/lungs, and the brain, respectively, from trauma.
  • Formation of hematopoietic cells – The marrow is found in the trabecular portions of bones and is responsible for hematopoiesis, or the production of red blood cells, white blood cells, and platelets.
  • Metabolism – The bone matrix can store several minerals, chiefly calcium and phosphorus as well as iron in the form of ferritin. Chondroitin sulfate, a carbohydrate moiety, is also a commonly found element in the matrices. Specific growth factors, including insulin-like growth factor or IGF-1, are housed in bone and then released periodically. pH balance is also regulated as bones may alter the composition of alkaline salts in the serum to maintain the optimal pH level. Moreover, osteocytes can engulf toxic molecules and heavy metals from the serum as a means of detoxification.

Bone Cells

Bone cells make up about 10% of total bone volume. There are four types of cells:

  • Osteoprogenitor (Stem) Cells – Osteoprogenitor cells retain the ability to re-differentiate into osteoblasts. They reside in the bone canals, endosteum, periosteum, and marrow. They may regulate the influx and efflux of mineral ions into and out of the bone extracellular matrix. They also are responsible for the formation of bone remodeling compartments (BRC) with a specialized microenvironment .
  • Osteoblasts – Bone Forming Cells – They are tightly packed on the surface of the bone. They synthesize and secrete bone matrix (osteoid). They also regulate bone mineralization by secreting alkaline phosphatase (a marker for bone formation) and a set of proteins known as dentin matrix protein (DMP-1) and bone sialoprotein, which act as nucleators for mineralization. Osteocalcin and osteonectin are calcium and phosphate binding proteins secreted by osteoblasts, which regulate the deposition of mineral by regulating the number of hydroxyapatite crystals. Osteoblasts ultimately have one of two fates: (1) remain quiescent osteoblasts lining cells or (2) become osteocytes. Osteoblasts regulate osteoclastogenesis (osteoclast formation) and osteocyte formation. Vitamin D and parathyroid hormone (PTH) stimulate osteoblasts to secrete macrophage CSF (M-CSF) and to express RANKL, which are important for osteoclastogenesis .
  • Osteocytes – Mechanosensing Cells – These account for 90% of all bone cells. They are derived from osteoblasts. They reside within the bone network known as the lacuna canalicular system. They do not normally express alkaline phosphatase but do express osteocalcin and other bone matrix proteins. They maintain a connection with each other and bone surfaces via their cytoplasmic processes. Osteocytes are linked metabolically and electrically through gap junctions. Their primary function is mechanosensation. Osteocytes detect mechanical loading through physical deformation of bone matrix and fluid flow shear stress resulting from the flow of canalicular fluid through the lacuna canalicular network. Osteocytes act as orchestrators of bone remodeling and as a result, are also considered endocrine cells. They secrete FGF23 to regulate serum phosphate levels. FGF23 decreases renal and intestinal sodium and phosphate co-transporter expression and subsequently increases renal phosphate excretion by both kidneys .
  • Osteoclasts – Bone Resorbing Cells – These are multinucleated cells that originated from mononuclear monocyte-macrophage cells. RANKL and macrophage CSF (M-CSF) are two cytokines that are critical for osteoclast formation. They are important for osteoclast precursors to proliferate and differentiate into mature osteoclasts. Osteoprotegerin (OPG) is a membrane-bound secreted protein that binds RANKL (see figure) to inhibit its action at the RANK receptor and subsequently inhibit osteoclastogenesis. Bone resorption depends on osteoclast secretion of hydrogen ions, tartrate-resistant acid phosphatase (TRAP), and cathepsin K enzymes. Hydrogen ions acidify the resorption compartment beneath osteoclasts to dissolve the mineral component of the bone matrix, whereas cathepsin K and tartrate-resistant acid phosphatase (TRAP) digest the proteinaceous matrix, which is mostly composed of type I collagen. PTH stimulates osteoclast activity while calcitonin inhibits it .   

Bone Extracellular Matrix

This makes up 90% of overall bone volume. It consists of inorganic (mineral) and organic matrices .

  • Inorganic Bone Matrix – accounts for 99% of the body storage of calcium, 85% of the phosphorus and 40-60% of the magnesium, and sodium. It is mainly in the form of hydroxyapatite [Ca10(PO4)6(OH)2] to provide the bone its strength, stiffness, and the resistance to compressive forces.
  • Organic Bone Matrix – is secreted by osteoblasts and is predominantly type I collagen. It also contains glycoproteins, growth factors, and proteoglycans. Growth factors (such as osteocalcin, osteonectin, and bone sialoprotein) play important roles in the osteoid formation, mineralization, and bone remodeling. The organic matrix gives bone its form and provides resistance to tensile forces.

Bone Remodeling

This is a physiological process in which old or damaged bone is removed by osteoclasts and then replaced by new bone formed by osteoblasts. There is a tight coupling of bone formation to bone resorption to ensure no net change in bone mass or quality after each remodeling. It requires the coordinated action of the four types of bone cells. The process involves four major distinct but overlapping phases:

  • Phase 1 – initiation/activation of bone remodeling at a specific site. The osteoclast precursors are recruited to bone remodeling compartments (BRC).
  • Phase 2 – bone resorption and concurrent recruitment of osteoprogenitors. Bone resorption represents the predominant event, but the recruitment of mesenchymal stem cells (MSCs) and/or osteoprogenitors into the BRC is also initiated.
  • Phase 3 – osteoblast differentiation and function (osteoid synthesis). Excavated bone is replaced with osteoid produced by osteoblasts.
  • Phase 4 – mineralization of osteoid and completion of bone remodeling. The osteoid is mineralized, and the bone remodeling cycle is concluded .

Hormonal Impact on Bone Remodeling

Parathyroid Hormone (PTH)

PTH is a polypeptide hormone secreted by the chief cells of the parathyroid glands. It acts to raise the level of calcium in the bloodstream with direct actions on bone and the kidneys, and indirectly on the intestines via the influence on vitamin D. The hormone has a physiological, negative feedback loop that is influenced by the amount of calcium present in the blood. When there is a decreased concentration of plasma calcium, there is less binding to calcium-sensing receptors (CaSR) on the parathyroid gland. This will lead to an increased release of PTH to raise the levels of calcium. PTH has an indirect action on the osteoclasts by increasing the activity of receptor activator of nuclear factor kappa ligand (RANKL), which regulates the osteoclastic activity of bone resorption and leads to more calcium released into the plasma. In contrast, high levels of plasma calcium bind to the CaSR on the parathyroid gland and inhibit the release of PTH. Stimulating the CaSRs causes a conformational change of the receptor and stimulates the phospholipase C pathway. This ultimately leads to higher intracellular calcium, thereby inhibiting exocytosis of PTH from the chief cells of the parathyroid gland. This is of course only one piece to the calcium homeostasis puzzle because PTH has actions at the kidneys and intestines to regulate the levels of calcium and phosphate. 

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Estrogen

A deficiency of estrogen leads to increased bone remodeling, where bone resorption outpaces bone formation and leads to a decrease in bone mass. It is believed, based on animal studies, that estrogen may influence local factors that regulate the precursors of osteoblasts and osteoclasts. Estrogen may block the production and action of interleukin-6 (IL-6), which would hinder bone resorption. Also, it is believed that the survival of osteoclasts thrives in the deficiency of estrogen, where the degree of bone turnover would be greater.

Calcitonin

Calcitonin, a polypeptide hormone, is released from thyroid C cells in response to elevated calcium levels. Regarding bones, calcitonin binds to calcitonin receptors on osteoclasts to inhibit bone resorption. It is believed that calcitonin does not play a prominent role in calcium homeostasis in adults, but it may be more important in skeletal development. However, calcitonin is clinically used as a treatment option to treat osteoporosis.

Growth Hormone

Growth Hormone (GH), a peptide hormone secreted by the pituitary gland, acts through insulin-like growth factors to stimulate bone formation and resorption. GH acts directly and indirectly via IGF to stimulate osteoblast proliferation and activity, but it also stimulates the bone resorption activity of osteoclasts; however, the cumulative net effect of this dual activity favors bone formation.

Glucocorticoids

Glucocorticoids decrease bone formation by favoring the survival of osteoclasts and causing the cell death of osteoblasts. There is an increase in RANKL action and a decrease in osteoprotegerin (OPG). OPG is a cytokine receptor and member of the tissue necrosis factor superfamily that acts a decoy receptor for RANKL, so it would normally hinder RANKL-RANK interaction and activity.

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Thyroid Hormone

Thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) cause bone elongation at the epiphyseal plate of long bones through chondrocyte proliferation and also stimulate osteoblast activity. In states of hypothyroidism or hyperthyroidism, the degree of bone turnover is low and high respectively. The rate of bone turnover is due to the effect of T3/T4 on the number and activity level of osteoblasts and osteoclasts. For example, the high metabolic state of thyrotoxicosis causes increased osteoblast function and increased osteoclastic number and activity and leads to a higher bone turnover.

Clinical Significance of Bone

Osteoporosis

This is a common disorder of bone remodeling which is characterized by low bone mass and structural deterioration of bone. It causes bone fragility and increased vulnerability to fractures. There are two types of osteoporosis: 

Primary Osteoporosis

Type I (Postmenopausal Osteoporosis)

  • Cause: a decline in estrogen levels associated with menopause.
  • Pathophysiology: estrogen deficiency causes an increase in osteoclast activity by increasing RANKL and M-CSF expression and inhibiting osteoclast apoptosis by reducing FasL expression by preosteoclasts.

Type II (Age-Related Osteoporosis or Senile Osteoporosis)

  • Cause – age-related and centered on osteoblasts (bone formation) [in addition to bone resorption in postmenopausal women].
  • Pathophysiology – decreased bone formation in men and women is caused by changes in reactive oxygen species (ROS), insulin-like growth factor 1 (IGF-1) and PTH levels associated with aging.

Glucocorticoid-induced Osteoporosis (Secondary Osteoporosis)

  • Cause – glucocorticoids are immunomodulatory drugs that are used to treat a variety of autoimmune disorders and inflammatory conditions such as rheumatoid arthritis and multiple sclerosis. Bone loss and increased risk of fractures are among the common side effects of glucocorticoid treatment.
  • Pathophysiology – glucocorticoids inhibit differentiation of osteoprogenitors into osteoblasts and promote their differentiation into adipocytes (fat cells). They also increase osteoblast apoptosis and impair their functions. Additionally, glucocorticoids target mature osteoclasts to prolong their life span which worsens the imbalance between bone formation and bone resorption in favor of bone resorption.

Treatment

Bisphosphonates (for example, alendronate) – These medications inhibit bone resorption by attaching to hydroxyapatite binding sites, so when the osteoclast begins to resorb bone that has bisphosphonates attached to it, this impedes the osteoclast from developing the ruffled border. This affects the ability of the osteoclast to adhere to the bone surface and produce the protons that are required for this task. In addition to decreased osteoclastic activity, there appears to be an osteoblastic survival benefit component as well.

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Calcitonin –  This medication inhibits bone resorption by inhibiting the activity of osteoclasts.

Raloxifene – Raloxifene is a selective estrogen receptor modulator (SERM), and it has agonist activity in bone and antagonist activity in other tissues, such as breast tissue. The agonist activity in bone allows estrogenic effects to occur. This means that it will decrease the survival of osteoclasts and hinder the effect of local bone resorption factors such as IL-6.

Denosumab –  This is a human monoclonal antibody that binds RANKL. By inhibiting the RANK-RANKL interaction, this decreases the activity and survival of osteoclasts, thereby limiting bone resorption.

References

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