Receptor activator of nuclear factor-κB ligand (RANKL) is a key factor in osteoclastogenesis and bone resorption and has been established as a therapeutic target in skeletal pathologies, including osteoporosis and bone metastases. However, RANKL expression has been demonstrated in extraskeletal tissues, and thus a potential role for RANKL beyond its function in bone biology has been emphasized by the discovery of a multitude of pleiotropic nonskeletal effects. In this chapter, we will summarize the role of RANKL in mammary gland development and tumorigenesis, cancer cell migration and metastasis, the development and function of the immune system, and thermoregulation.

Estrogen and androgen deficiency have been associated with the incidence of osteoporosis in postmenopausal women and elderly men over the last many decades. Estrogen and androgen function through signaling pathways that originate from binding to their cognate nuclear receptors, which collectively impact sexual function, growth and development, and skeletal health. These effects range from gain-of-function paradigms involving their cognate ligands that target these nuclear hormone receptor-mediated signaling pathways to loss-of-function paradigms that involve menopause/aging or rare allelic variants that abrogate ligand or receptor function. This review summarizes our current knowledge of the gain-of-function and loss-of-function attributes of these two steroid hormones with specific emphasis on androgens and male skeletal health.

Bone modeling and remodeling assemble bone's structure during growth. Abnormalities in this cellular machinery appear around midlife and cause microstructural deterioration and bone fragility. For over 60years, the gain and loss of bone strength have been inferred by measuring bone mineral density (BMD). This is an insensitive surrogate of bone fragility caused by microstructural deterioration, because microstructural deterioration compromises strength disproportionate to the bone loss producing it and the modest deficits in BMD found in most patients with fragility fractures. Quantification of microstructure is now available, but whether these measurements improve the detection of individuals at risk for fracture and improve treatment efficacy is unknown. Antiresorptive agents slow remodeling and microstructural deterioration. Anabolic agents may reconstruct bone, but available therapy produces mainly remodeling-based bone formation, which is limited for a range of reasons. Whether modeling-based bone formation or combined therapy offers better anti-fracture efficacy is unknown.

Fibroblast growth factors (FGFs) play essential roles during skeletal development and in the regulation of postnatal chondrogenesis and osteogenesis. This chapter updates our current knowledge of the expression of FGFs and FGF receptors (FGFRs) during development and postnatal skeletogenesis, describes the role of FGFs in the regulation of bone and other tissues, and reviews the functions of FGF/FGFR signaling in skeletal growth, bone formation and resorption, bone remodeling, and repair. We also update the mechanisms by which mutations in FGFRs induce abnormalities in chondrogenesis and osteogenesis in skeletal dysplasias and review how this knowledge may be exploited to treat genetic bone diseases associated with FGFR mutations.

This chapter reviews in vivo imaging techniques used in the field of osteoporosis for diagnosis of osteoporosis, fracture prediction, or monitoring of therapeutic interventions and age-related changes. Standard techniques include radiography to diagnose fractures, quantitative computed tomography (QCT) to determine bone mineral density (BMD) and cortical geometry, and finite element analysis to measure bone strength. New developments include advanced dual-energy X-ray absorptiometry (DXA) analysis to obtain the trabecular bone score for assessing vertebral bone texture and the possibility of generating CT-like volumetric data from DXA scans[VK1] . High-resolution peripheral QCT can be used to measure trabecular structure and cortical porosity at the distal forearm and tibia. Magnetic resonance imaging (MRI) offers the unique possibility of determining cortical water to characterize collagen content and cortical porosity. Another application of MRI is the measurement of bone marrow fat content and composition, marrow perfusion, and marrow molecular diffusion. Most recent applications of CT include opportunistic screening, the reuse of existing CT images obtained for routine clinical purposes such as tumor diagnosis, to identify patients at high risk for osteoporotic fracture. Another emerging field is the combination of muscle parameters determined either by MRI or by CT with standard BMD and geometry parameters to improve fracture risk prediction by potentially addressing the components of a fall, which are related to muscle characteristics

Bone differs from soft connective tissues in that it is composed of a mineralized hydroxyapatite phase and an organic phase. Although the organic matrix of bone consists primarily of collagen(s) (as reviewed early in this volume), the existence of other secreted noncollagenous components was first postulated by Herring and co-workers in the 1960s. Historically, using degradative techniques, a variety of carbohydrate-containing moieties were extracted and partially characterized. A major breakthrough in the isolation and characterization of noncollagenous proteins of bone came with the development of “dissociative” techniques whereby proteins could be extracted in an intact, nonaggregated form. Although they are not as abundant as so-called structural components such as collagen, their importance in bone physiology cannot be underestimated. This is emphasized by the identification of mutations in a number of these proteins that result in abnormal bone. This chapter discusses secreted noncollagenous proteins found in bone matrix. Since the publication of the previous edition of this work in 2008, substantial additions have been made to include recently reported functional studies, inclusion of noncollagenous proteins that were not previously considered, and new information regarding the developing area of bone–muscle/fat/pancreas/testis cross-talk signaling and the role that these proteins play in those interactions.

The extracellular calcium receptor (CaR) is a G-protein-coupled receptor that monitors and maintains the level of ionized calcium (Ca2+) in the circulation and extracellular fluids. It is expressed at its highest levels in the parathyroid glands and the kidney, where it regulates, respectively, the secretion of parathyroid hormone and the tubular reabsorption of Ca2+. Soon after the discovery of the CaR, diseases associated with its function became evident and therapeutic approaches to the hyperparathyroid states were appreciated. These advances were covered in the last edition of this chapter, including understanding the genetic basis of some disorders associated with hyper- or hypocalcemia, the development of calcimimetic drugs, and insights into the molecular mechanisms of action of calcimimetic and calcilytic molecules. In this chapter, we provide a comprehensive update on the use of calcimimetics in primary and secondary hyperparathyroidism as well as introducing you to newer calcimimetics that have been developed. In addition, we update the status of calcilytic agents with regard to disorders in which stimulation of endogenous parathyroid hormone is a desirable therapeutic goal.

Parathyroid hormone (PTH) stimulates bone remodeling by modulating the synthesis of critical proosteoclastogenic factors, mainly RANKL, and the level of proosteoblastogenic signals that couple bone formation to bone resorption. Coupling involves growth factors released from the bone matrix during resorption and/or from osteoclasts as well as other PTH-regulated proosteoblastogenic events such as Wnt signaling. In contrast, daily injections of PTH cause bone accretion by improving coupling, resulting in overfill of resorption cavities. This effect is due to inhibition of apoptosis of osteoblasts and their progenitors and to stimulation of differentiation. In addition, intermittent PTH reactivates the quiescent lining cell descendants of osteoblasts. Overfill of resorption cavities and lining cell activation does not occur under physiologic conditions or in hyperparathyroidism. Thus, the anabolic effect of PTH results from the intensification of ongoing mechanisms as well as induction of novel mechanisms that require pulsatile exposure to high levels of PTH.

It has been over 150years since the term “collagen” was first adopted in the English language. This ropelike structure that yields gelatin upon boiling made its early appearance in evolution in primitive animals such as jellyfish, coral, and sea anemones. Today, the collagen family of proteins has grown to 28 different types and is used as a versatile biomaterial for delivery of drugs as well as for cosmetic purposes.

It has been long established that a functional vascular system is crucial for skeletal development and homeostasis. Skeletal blood vessels not only supply oxygen and nutrients to ensure proper functioning of bone-forming and bone-resorbing cells, but also deliver calcium and phosphate to sites of active bone mineralization, together with hormones and growth factors that regulate the function of skeletal cells. Moreover, the bone marrow vasculature provides a niche for skeletal stem and progenitor cells next to blood-forming hematopoietic stem cells. Particular to the skeleton is that in contrast to the highly vascularized bone tissue, the cartilaginous part is avascular. The intimate connection of the vascular system with bone cells occurs not only during development, but also during bone repair, indicating that a better understanding of the mechanisms that couple bone and blood vessels may provide new therapeutic options for skeletal pathologies.