Physiology, Bone Remodeling


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.[1] There are two primary cells 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.[2] 


The Cells of Bone Remodeling: The Major Players

The bone remodeling cycle, which begins in early fetal life, depends on the interaction between two cell lineages. Osteoblast cells contribute to bone growth and derive from the mesenchymal origin. Mesenchymal cells are stem cells that can differentiate into various cell types, such as osteoblasts, chondrocytes, myocytes, and adipocytes. Osteoclast cells cause bone resorption and originate from a hematopoietic lineage, which includes various 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.[2]


Once the fusion of osteoblast and osteoclastic precursors has occurred, the resulting multinucleated osteoclast attaches to the bone surface and commences resorption. These cells use a combination of lysosomal enzymes and hydrogen ions which work 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 the bone matrix (Howship lacunae). It is then believed that a "reversal" phase is conducted by mononuclear cells of macrophage lineage, which continue to degrade and deposit organic material while releasing growth factors to initiate the bone deposition phase.[3]


The differentiated mesenchymal precursors fill the Howship lacunae by depositing new collagen and minerals. Once the osteoblast has completed the task, it will encounter three fates: flatten and become a cell to line the bone surface, become an osteocyte, or undergo cell death (apoptosis).[4]


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 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 a process called mechanotransduction, where the mechanical forces are converted to biochemical signals. Osteocytes act as conductors for this signal (or lack thereof) and instruct surrounding cells on how to compensate for and adapt to the mechanical stress.[5]


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 influenced by the amount of calcium present in the blood. When there is a decreased plasma calcium concentration, there is less binding to calcium-sensing receptors (CaSR) on the parathyroid gland. This will lead to an increased release of PTH to raise calcium levels. PTH has an indirect action on the osteoclasts by increasing the receptor activator activity 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 PTH release. 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, details only one piece to the calcium homeostasis puzzle because PTH also acts at the kidneys and intestines to regulate the levels of calcium and phosphate.[6] 


An estrogen deficiency leads to increased bone remodeling, where bone resorption outpaces bone formation and decreases bone mass. Based on animal studies, it is believed 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 osteoclast survival thrives in the deficiency of estrogen, where the degree of bone turnover would be more significant.[7]


Calcitonin, a polypeptide hormone, is released from thyroid C cells in response to elevated calcium levels. 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 critical in skeletal development. However, calcitonin is clinically used as a treatment option to treat osteoporosis.[2]

Growth Hormone

Growth Hormone (GH), a peptide hormone secreted by the pituitary gland, acts through insulin-like growth factors (IGF) to stimulate bone formation and resorption. GH acts directly and indirectly via IGF to stimulate osteoblast proliferation and activity, but it also stimulates osteoclastic bone resorption activity; however, the cumulative net effect of this dual activity favors bone formation.[8]


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 as a decoy receptor for RANKL, so it would typically hinder RANKL-RANK interaction and activity.[9]

Thyroid Hormone

Thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) stimulate osteoblastic activity and cause bone elongation at the epiphyseal plate of long bones through chondrocyte proliferation. 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, leading 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)


 Serum Markers of Bone Resorption

Bone resorption markers include, but are not limited to, hydroxyproline (OHP), pyridinoline (PYD), deoxypyridinoline (DPD), bone sialoprotein (BSP), and tartrate-resistant acid phosphatase (TR-ACP). OHP is a significant 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)




TR-ACP = colorimetry, RIA, ELISA [11]

Imaging Techniques

Bone Scintigraphy: nuclear medicine is used as a means of diagnosing various conditions such as bone cancer (or metastasis), fractures, and infection/inflammation. This 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 (DEXA): two X-ray beams of different energy levels are used 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]


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


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 outpaces bone formation as the body ages.[13] 


This disease process is comprised of primary, secondary, and tertiary causes. Primary hyperparathyroidism may be due to the development of an adenoma or hyperplasia of a parathyroid gland, which causes the production and release of excess 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 overproduced PTH, leading to hypercalcemia. As it pertains to bone remodeling, the mechanism of hyperparathyroidism was discussed in the prior "Mechanism" section.[14] 

Paget Disease

Paget disease is a condition of disorganized bone resorption patterns due to abnormal activation of osteoclasts. Along with this distorted resorption comes a strong, irregular osteoblastic response in the form of woven bone. Though bone turnover is present, it is abnormal and leads to architecture with unfavorable integrity, leading to pathologic fractures.[15]


Osteopetrosis is a disease that involves the failure of osteoclasts to resorb the bone matrix appropriately, resulting in increased bone mass. Despite increased bone mass, bone integrity is weak due to the inability to resorb older portions of bone.[16]

Clinical Significance

The medications used to mitigate the effects of osteoporosis are particularly noteworthy for their clinical significance on bone remodeling. The commonly used medications are listed below and accompanied by their mechanism of action. These medications are not listed in any particular order and are presented here for the sake of discussion regarding 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 osteoclast's ability to adhere to the bone surface and produce the protons 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), with 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 local bone resorption factors such as IL-6. 

Denosumab: This is a human monoclonal antibody that binds RANKL. It decreases the activity and survival of osteoclasts by inhibiting the RANK-RANKL interaction, thereby limiting bone resorption.[17]

Article Details

Article Author

Paul Rowe

Article Author

Adam Koller

Article Editor:

Sandeep Sharma


1/27/2022 9:40:12 AM



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