Physiology, Bone Remodeling


Article Author:
Paul Rowe


Article Editor:
Sandeep Sharma


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


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:
3/9/2019 10:02:13 PM

Introduction

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 German anatomist and surgeon, Julius Wolff, developed a law that describes the nature of bone remodeling regarding stresses. Wolff's Law states that bones will adapt to the degree of mechanical loading, such that an increase in loading will cause the architecture of the internal, spongy bone to strengthen, followed by the strengthening of the cortical layer. Furthermore, a decrease in stress on the bone will cause these bone layers to weaken. The duration, magnitude, and rate of forces applied to the bone (in other words, tendons pulling at their attachments), dictate the way in which the integrity of the bone is altered. There are primarily 2 cells that are responsible for both the resorption and deposition phases of bone remodeling: osteoclasts and osteoblasts; however, osteocytes have a role in this process as well. The activity of these cells, particularly the osteoclasts, are influenced directly or indirectly by hormonal signals. This interaction between bone remodeling cells and hormones creates the opportunity for a multitude of pathophysiological consequences.[1][2]

Cellular

The Cells of Bone Remodeling: The Major Players

The bone remodeling cycle, which begins in early fetal life, depends on the interaction between 2 cell lineages. Osteoblast cells contribute to bone growth and derive from the mesenchymal origin. Mesenchymal cells are stems cells that can differentiate into a variety of cell types, such as osteoblasts, chondrocytes, myocytes, and adipocytes. Osteoclast cells cause bone resorption and originate from a hematopoietic lineage, which includes a variety of blood cell types from within the bone marrow. The cellular process of remodeling begins when osteoblast and osteoclast precursor cells fuse to form a multinucleated, osteoclastic cell.

Osteoclasts

Once the fusion of osteoblast and osteoclastic precursors has occurred, the resulting multinucleated osteoclast attaches to the bone surface and commence resorption. These cells use a combination of lysosomal enzymes and hydrogen ions to break down the bone matrix. This bone matrix is comprised of an inorganic portion of calcium phosphate crystals (hydroxyapatite) and an organic portion comprised of collagen, proteoglycans, and glycoproteins. The resorption process leaves "scooped out" regions of bone matrix (Howship Lacunae), and then it is believed that a "reversal" phase is conducted by mononuclear cells of macrophage lineage continue to degrade and deposit organic material while releasing growth factors to initiate the bone deposition phase.

Osteoblasts

The differentiated mesenchymal precursors fill the Howship Lacunae by depositing new collagen and minerals. Once the osteoblast has completed the task, it can enter 3 fates: flatten and become a cell to line the bone surface, become an osteocyte, or undergo cell death (apoptosis).

Osteocytes

Osteocytes are the most abundant cell type in mature bone. These cell types are situated within the bone matrix and occupy microscopic spaces called lacuna. They play a role in bone remodeling by transmitting signals to other nearby osteocytes regarding bone stress (tendons pulling on the bone). Osteocytes are also involved in regulating fluid flow within the bone, so this cellular signal may be due to changes in fluid flow in response to mechanical stresses on the bone. These cells are involved in the process called mechanotransduction, where the mechanical forces are converted to biochemical signals. Osteocytes act as conductors for this signal (or lack thereof), and they instruct surrounding cells on how to compensate for and adapt to the mechanical stress.[3][4][5]

Mechanism

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. [6][7]

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.[8]

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.[9]

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. 

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.[10]

Related Testing

Serum Markers of Bone Formation

Evidence of bone formation is indicated by the presence of alkaline phosphatase (ALP), bone alkaline phosphatase (B-ALP), osteocalcin (OC), and C- and N-terminal propeptide of type 1 procollagen (PICP and PINP). ALP is specific for bone formation, but only if the patient has no bile duct or liver disease. B-ALP is a specific product from osteoblast cells. OC is another specific osteoblast product, and there can be several active types. PICP and PINP are products of proliferating fibroblasts and osteoblasts.

Analytical Method

ALP = colorimetry, B-ALP = colorimetry, electrophoresis, immunoradiometric assay (IRMA), enzyme immunoassay (EIA), OC = radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), IRMA, electrochemiluminescence immunoassay (ECLIA), PICP and PINP = RIA, ELISA

Serum Markers of Bone Resorption

Bone resorption markers include, and are not limited to, hydroxyproline (OHP), pyridinoline (PYD), deoxypyridinoline (DPD), bone sialoprotein (BSP), and tartrate-resistant acid phosphatase (TR-ACP). OHP is a major part of protein collagen and plays a role in collagen stability. PYD has high concentrations of bone collagen and cartilage but is not present in the skin. Unlike PYD, DPD is highly concentrated in bone collagen but is absent in cartilage and skin. BSP is made by osteoblasts and is present in the extracellular bone matrix. Osteoclasts, thrombocytes, and erythrocytes make TR-ACP. 

Analytical Method

OHP = colorimetry, high performance liquid chromatography (HPLC); PYD = HPLC, ELISA; DPD = HPLC, ELISA; BSP = RIA, ELISA; TR-ACP = colorimetry, RIA, ELISA[11]

Imaging Techniques

Bone Scintigraphy: This scan uses nuclear medicine as a means of diagnosing various conditions such as bone cancer (or metastasis), fractures, and infection/inflammation. The imaging technique uses a gamma camera and requires an injection of technetium-99m-MDP to identify metabolically active regions of bone. This imaging technique highlights portions of bones that have changes in bone turnover and perfusion.

Dual-energy X-ray Absorptiometry: Uses 2 x-ray beams of differing energy levels to determine the amount of energy absorbed by bones (once soft tissue absorption is subtracted). This technique is used to follow osteoporosis, where bone resorption activity has out-paced bone mineralization.[12]

Pathophysiology

The following are conditions in which there is an imbalance between bone modeling and remodeling. The information presented here about these diseases is not extensive, but is meant to point out the cellular imbalance that exists:

Osteoporosis

The most common metabolic disorder of the skeleton is osteoporosis, which is a decrease in bone mass that increases the risk of bone fracture. The porous network of the trabecular bone beneath the cortical bone is particularly weakened in osteoporosis, so bones of the wrist, hip, and spine possessing more trabecular bone are more susceptible to fractures when exposed to sufficient forces. A major culprit of this disease is a decrease in estrogen. Postmenopausal women and estrogen deficient men have an accelerated bone turnover, where even though there is bone formation occurring, it is outpaced by the bone resorption that is taking place. It is believed that this may be due to osteoblast dysfunction or loss of template bone from excessive resorption. It is speculated that the decrease in osteoblast function may be due to decreased synthesis or inhibition of local growth factors. Aging is also a risk factor for osteoporosis, where there is a decrease in the number of osteoblasts relative to the demand for bone formation. Bone resorption out-paces bone formation as the body ages.

Hyperparathyroidism

This disease process is comprised of primary, secondary, and tertiary causes. Primary hyperparathyroidism can be due to the development of an adenoma or hyperplasia of a parathyroid gland, which causes the production and release of more PTH. The normal homeostatic system does not regulate the production and release of PTH from a parathyroid adenoma. Therefore, it does not abide by feedback inhibition. Secondary hyperparathyroidism due to vitamin-D deficiency or chronic kidney disease is a state of hypocalcemia that leads to a secondary increase in PTH. Tertiary hyperparathyroidism results from longstanding secondary hyperparathyroidism, where the parathyroid glands have hypertrophied over time and overproduce PTH, which leads to hypercalcemia. The mechanism of hyperparathyroidism, as it pertains to bone remodeling, was discussed in the prior "Mechanism" section.

Paget Disease

Paget disease is a condition where osteoclasts have become abnormally activated and lead to a disorganized pattern of bone resorption. Along with this distorted resorption comes a strong, irregular osteoblastic response in the form of woven bone. Even though bone turnover is present, it leads to an architecture with unfavorable integrity and can lead to pathologic fractures.

Osteopetrosis

This is a disease that involves the failure of osteoclasts to resorb the bone matrix appropriately. Even though this results in increased bone mass, the bone integrity is still weak because of the inability to resorb older portions of bone.[13]

Clinical Significance

Of particular note for the clinical significance of bone remodeling are the medications that are used to mitigate the effects of osteoporosis. The commonly used medications are listed below and accompanied by their mechanism of action. They are not listed in any particular order of any kind. They are presented here for the sake of discussion about the impact they have on bone remodeling. This is not an exhaustive list.

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.

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.[14][15][16][17]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Physiology, Bone Remodeling - Questions

Take a quiz of the questions on this article.

Take Quiz
Nonunion is least likely in which bone?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
In what manner, direct or indirect, does parathyroid hormone have an effect on osteoclast cells, what is the cellular response, and what is the physiologic response?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following hormones tend to favor bone resorption as the cumulative response?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What bone cell type is primarily responsible for bone resorption?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What serum bone turnover marker is present in bone collagen, but is absent from cartilage and skin?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Wolff's Law of bone remodeling states that bone will adapt to the stresses under which it is placed. This law embraces the concept of "mechanotransduction," where mechanical forces are translated into biochemical signals. Based on this concept, which cells involved in bone remodeling are primarily responsible for conducting signals for cellular change to other bone cells?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Physiology, Bone Remodeling - References

References

Relationship between bone remodeling and metabolism in the elderly, Basurto-Acevedo L,Saucedo-García R,Vázquez-Martínez A,Cruz-García M,Valle-Hernández MM,Rosales-Cruz E,Sánchez-Arenas R,, Revista medica del Instituto Mexicano del Seguro Social, 2018     [PubMed]
Long-term treatment strategies for postmenopausal osteoporosis., Cosman F,, Current opinion in rheumatology, 2018 Apr 4     [PubMed]
Mesenchymal Stem Cells-Derived Exosomes: A Possible Therapeutic Strategy for Osteoporosis., Li Y,Jin D,Xie W,Wen L,Chen W,Xu J,Ding J,Ren D,Xiao Z,, Current stem cell research & therapy, 2018 Apr 3     [PubMed]
Pro-inflammatory cytokines: cellular and molecular drug targets for glucocorticoid-induced-osteoporosis via osteocyte., Wang T,Yu X,He C,, Current drug targets, 2018 Apr 4     [PubMed]
Cross-talk between primary osteocytes and bone marrow macrophages for osteoclastogenesis upon collagen treatment., Elango J,Sanchez C,de Val JEMS,Henrotin Y,Wang S,Motaung KSCM,Guo R,Wang C,Robinson J,Regenstein JM,Bao B,Wu W,, Scientific reports, 2018 Mar 28     [PubMed]
Paget disease of bone among hospitalized patients in Poland., Kanecki K,Nitsch-Osuch A,Goryński P,Bogdan M,Tarka P,Tyszko PZ,, Annals of agricultural and environmental medicine : AAEM, 2018 Mar 14     [PubMed]
Bisphosphonates prevent age-related weight loss in Japanese postmenopausal women., Urano T,Shiraki M,Kuroda T,Tanaka S,Urano F,Uenishi K,Inoue S,, Journal of bone and mineral metabolism, 2017 Dec 13     [PubMed]
Computational Investigation on the Biomechanical Responses of the Osteocytes to the Compressive Stimulus: A Poroelastic Model., Wang L,Dong J,Xian CJ,, BioMed research international, 2018     [PubMed]
The Utility of Biomarkers in Osteoporosis Management., Garnero P,, Molecular diagnosis & therapy, 2017 Aug     [PubMed]
Value of bone scintigraphy for detection and ageing of vertebral fractures in patients with severe osteoporosis and correlation between bone scintigraphy and mineral bone density., Kucukalic-Selimovic E,Begic A,, Medicinski arhiv, 2004     [PubMed]
Lee JWY,Bance ML, Physiology of Osseointegration. Otolaryngologic clinics of North America. 2019 Apr;     [PubMed]
Anagnostis P,Gkekas NK,Potoupnis M,Kenanidis E,Tsiridis E,Goulis DG, New therapeutic targets for osteoporosis. Maturitas. 2019 Feb;     [PubMed]
Lee BS, Myosins in Osteoclast Formation and Function. Biomolecules. 2018 Nov 22;     [PubMed]
Bakr MM,Kelly WL,Brunt AR,Paterson BC,Massa HM,Morrison NA,Forwood MR, A single injection of PTH improves osteoclastic parameters of remodeling at a stress fracture site in rats. Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 2019 Feb 28;     [PubMed]
Rubin MR, Skeletal Manifestations of Hypoparathyroidism. Endocrinology and metabolism clinics of North America. 2018 Dec;     [PubMed]
Gallagher JC, Advances in osteoporosis from 1970 to 2018. Menopause (New York, N.Y.). 2018 Dec;     [PubMed]
Kenkre JS,Bassett J, The bone remodelling cycle. Annals of clinical biochemistry. 2018 May;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of PA-Hospital Medicine. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for PA-Hospital Medicine, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in PA-Hospital Medicine, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of PA-Hospital Medicine. When it is time for the PA-Hospital Medicine board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study PA-Hospital Medicine.