Bone remodeling is the process by which old bone is replaced by new bone in phases known as resting, resorption, reversal, and formation. 1-3 Resting bone surface is converted to a remodeling surface during activation of the bone remodeling process. 1-3 Recruitment of osteoclast precursors to the bone and their differentiation into mature, active osteoclasts occurs. 1-3 During the resorption phase, osteoclasts remove both mineral and organic components of bone matrix by generating an acidic microenvironment between the cell and bone surface. 1-3 The resorbing surface has scalloped, eroded pits known as Howship’s or resorption lacuna. 1 The reversal phase begins once the osteoclasts have resorbed most of the mineral and organic matrix. Apoptosis of osteoclasts occurs in this phase, and osteoblasts are recruited to the bone surface. 1-3 The removal of old bone by osteoclasts is followed by replacement with new, healthy osteoid (unmineralized collagen matrix) by osteoblasts. The collagen matrix provides the basic bone structure for mineral (predominantly hydroxyapatite) deposition. During the mineralization phase, these deposits gradually harden into the newly formed matrix, resulting in good quality bone. 1-3
An imbalance in bone resorption and formation can lead to decreased bone mineral density and microarchitectural deterioration. 4,5 This imbalance can be caused by estrogen deficiency, glucocorticoid exposure, inflammatory diseases with T-cell activation, osteotropic tumors (myeloma, osteolytic metastases), and other conditions that create situations favoring bone loss. 6 This systemic skeletal condition, known as osteoporosis, is due to excess osteoclastic activity, which results in an imbalance in bone remodeling that favors resorption. 4,5 Consequences associated with osteoporosis are an increase in bone fragility and a susceptibility to fractures. 4
Receptor activator of nuclear factor kappa B ligand (RANKL) plays a key role in bone destruction across a range of conditions including osteoporosis, treatment-induced bone loss, rheumatoid arthritis, and fuels a vicious cycle of bone destruction and tumor growth in metastatic disease and multiple myeloma.7-13 RANKL is the final common mediator that regulates bone remodeling. RANKL is the primary mediator of osteoclast formation, function, and survival. 14-17 Osteoclasts are the cells responsible for resorbing bone. Many different factors (eg, PTH, TNF, IL-1) can lead to bone loss, but they all stimulate the expression of RANKL by stromal and bone lining cells. RANKL binds to RANK on the preosteoclast and mature osteoclast. In addition to being expressed on osteoclasts and osteoclast progenitors, RANK has been observed on dendritic cells 5, mammary gland epithelial cells, and many other cells. 18,19 The RANKL polypeptide is a type II transmembrane protein found on the surface of expressing cells as well as in a proteolytically released (cleaved) soluble form. 16 Maturation of prefusion osteoclasts to multinucleated osteoclasts and finally to activated osteoclasts is initiated when RANKL binds to RANK. 5
RANKL is expressed and secreted by stromal and bone lining cells, and subsequently binds to RANK on immature and mature osteoclasts. 5 Maturation of prefusion osteoclasts to multinucleated osteoclasts and finally to activated osteoclasts is initiated when RANKL binds to the RANK receptor. RANKL is inhibited by naturally occurring osteoprotegerin (OPG). OPG, a member of the tumor necrosis factor (TNF) receptor family, binds to and neutralizes the effects of RANKL, thereby inhibiting bone resorption. OPG is an important inhibitor of the differentiation and function of osteoclasts. OPG binds with RANKL, thereby inhibiting osteoclastogenesis and decreasing the survival of pre-existing osteoclasts. 5,16,17,20,21
The relative balance between RANKL and OPG activity is regulated by cytokines and hormones and ultimately determines osteoclast activity. Excess RANKL activity is critical in the pathogenesis of bone diseases that result in increased bone resorption. Excess RANKL activity within the skeleton promotes bone loss, while inhibiting RANKL to restore a normal level of activity decreases osteoclast activation and bone resorption. In many diseases involving increased bone resorption, RANKL expression is upregulated by osteoclastogenic factors (growth factors, hormones, cytokines) while OPG expression is simultaneously down-regulated. 5,6,16
Excess RANKL activity has been implicated in bone destruction across the spectrum of bone loss pathology. The effects of RANKL are physiologically counterbalanced by the soluble receptor OPG. Estrogen deficiency, glucocorticoid exposure, T-cell activation (eg, rheumatoid arthritis), and skeletal malignancies (eg, myeloma, bone metastases) enhance RANKL activity and, thus, promote osteoclastogenesis, accelerate bone resorption, and induce bone loss. 5-6
For more information on the important role of RANKL inhibition in specific types of bone loss, see the section on Types of Bone Loss.
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