Physiology, Bone


Article Author:
Suzan El Sayed
Trevor Nezwek


Article Editor:
Matthew Varacallo


Editors In Chief:
Sisira Reddy
Joseph Nahas
CHOKKALINGAM SIVA


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
7/29/2019 6:46:44 PM

Introduction

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 fuse 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). [1][2]

Function

Bone Cells 

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

  1. 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 [3].
  2. 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 deposition of mineral by regulating the amount 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 [4]
  3. 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 [5]
  4. Osteoclasts - Bone Resorbing Cells: These are multinucleated cells 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 [6] 

Bone Extracellular Matrix

This makes up 90% of overall bone volume. It consists of inorganic (mineral) and organic matrices [7].

  1. 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.
  2. 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 osteoid formation, mineralization, and bone remodeling. 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 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 [8].

Clinical Significance

Osteoporosis [9][10][11][12][13][14]

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.

  • Image 489 Not availableImage 489 Not available
    Contributed by Kathleen E. Doyle M.Ed., Instructional Designer at the Oakland University William Beaumont School of Medicine.
Attributed To: Contributed by Kathleen E. Doyle M.Ed., Instructional Designer at the Oakland University William Beaumont School of Medicine.

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Physiology, Bone - Questions

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Activins are a group of molecular agents belonging to what type of cellular or molecular categorical family?



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A 57-year-old male presents to the emergency department with right arm pain after falling off a step ladder. Physical examination shows tenderness along the right distal humerus. An x-ray of the right arm and shoulder reveal a nondisplaced distal humerus fracture. Which of the following cytokines is most likely to be involved with normal bone healing in this patient?



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A medical student is participating in research on the study of bone metabolism. He compares the serum studies and bone biopsy findings of two different cohorts of women, one group is composed of healthy women aged 25-30 years, and the other is composed of women aged 55-60 years. Which of the following processes is most likely decreased in the group of younger women compared to older women?



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A 79-year-old male presents to his primary care provider for a routine physical examination. A review of systems is positive for hearing loss and increased hat size. Laboratory results show a calcium concentration of 9.0 mg/dL, a phosphorus concentration of 3.4 mg/dL, and an elevated bone-specific alkaline phosphatase concentration. Which of the following is the most likely explanation for this patient’s laboratory findings?



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A 65-year-old male presents to the office for follow up. He was recently diagnosed with prostate cancer after 3 months of reported weight loss and low back pain. A physical examination today is concerning for metastasis to the L3 and L4 vertebrae. A bone biopsy is performed, and the results show irregular bone trabeculae and star-shaped cells with cytoplasmic processes located within the lacunae. Molecular exchange of nutrients and waste products between these cells occurs through which of the following structures?



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A 46-year-old female with a longstanding history of well-controlled rheumatoid arthritis presents to the emergency department for left wrist pain after sustaining a trip and fall onto an outstretched hand. She currently only takes methotrexate and has had numerous treatments with glucocorticoids over the past 20 years. An x-ray of the left wrist demonstrates decreased bone density throughout the radius and ulna and a dorsally displaced fracture of the distal radius. What is most likely responsible for the pathologic fracture in this patient?



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Physiology, Bone - References

References

Varacallo M,Pizzutillo P, Osteopenia . 2018 Jan     [PubMed]
Varacallo M,Pizzutillo P, Osteoporosis, Spinal Cord Injury . 2018 Jan     [PubMed]
Varacallo MA,Fox EJ, Osteoporosis and its complications. The Medical clinics of North America. 2014 Jul     [PubMed]
Varacallo MA,Fox EJ,Paul EM,Hassenbein SE,Warlow PM, Patients' response toward an automated orthopedic osteoporosis intervention program. Geriatric orthopaedic surgery & rehabilitation. 2013 Sep     [PubMed]
Clarke B, Normal bone anatomy and physiology. Clinical journal of the American Society of Nephrology : CJASN. 2008 Nov     [PubMed]
Dallas SL,Prideaux M,Bonewald LF, The osteocyte: an endocrine cell ... and more. Endocrine reviews. 2013 Oct     [PubMed]
Feng X,McDonald JM, Disorders of bone remodeling. Annual review of pathology. 2011     [PubMed]
Henriksen K,Bollerslev J,Everts V,Karsdal MA, Osteoclast activity and subtypes as a function of physiology and pathology--implications for future treatments of osteoporosis. Endocrine reviews. 2011 Feb     [PubMed]
Corradetti B,Taraballi F,Powell S,Sung D,Minardi S,Ferrari M,Weiner BK,Tasciotti E, Osteoprogenitor cells from bone marrow and cortical bone: understanding how the environment affects their fate. Stem cells and development. 2015 May 1     [PubMed]
Caetano-Lopes J,Canhão H,Fonseca JE, Osteoblasts and bone formation. Acta reumatologica portuguesa. 2007 Apr-Jun     [PubMed]
Aarden EM,Burger EH,Nijweide PJ, Function of osteocytes in bone. Journal of cellular biochemistry. 1994 Jul     [PubMed]
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