The accumulated evidence over the past few years has established that the Wnt/β-catenin pathway is crucial for bone formation and the maintenance of skeletal homeostasis [1,2]. Wnt proteins exert their cellular functions by activating different signaling pathways, commonly called canonical pathway and non-canonical pathways [3]. The former acts by controlling the amount of β-catenin not associated with cadherin, while the other routes do not require the presence of β-catenin [4]. At present, the signaling pathway mediated by β-catenin is the best studied and understood. Activation of the Wnt/β-catenin pathway begins at the cell membrane with the binding of certain Wnt ligands, such as Wnt3a, to the transmembrane receptors of the Frizzled family. This binding recruits the LRP5/6 co-receptor (low-density-lipoprotein receptor-related protein 5/6), to form a ternary complex that destabilizes a cytoplasmic conglomerate of proteins that would otherwise phosphorylate the β-catenin of the cytoplasm for its destruction in the proteasome [5-7]. So, after ligand binding to the receptor, β-catenin is not phosphorylated or destroyed, and, therefore, can accumulate in the cytoplasm, from where it will be transferred to the nucleus. There it joins the transcription factor TCF/LEF (T-cell factor/lymphoid enhancer factor) and induces target gene expression [8].

Osteoarthritis (OA) is a chronic disease that is characterized by a progressive degradation of the articular cartilage that covers the surface of the synovial joints, which allow the movement of the skeleton without causing pain. Chondrocytes from patients with osteoarthritis undergo changes in the phenotype associated with an increase in catabolic and inflammatory activity [1,2], along with an increase in cellular senescence and senescence-associated secretory phenotype (SASP) [2,3]. Our research group has previously shown that chondrocytes in the articular cartilage have long cytoplasmic projections that cross the extracellular matrix (ECM) [4], which form connections and gap junctions (GJs) through connexin-43 channels (Cx43) [4,5]. In 2013, our research group published relevant results associated with alterations in the activity of Cx43 in osteoarthritis, indicating that from the disease’s early stages there is an increase and changes in the localization of the protein in the cartilage of patients with arthrosis [6]. Subsequently, using animal models, we observed that the C-terminal domain of Cx43 plays a fundamental role in the structure and composition of articular cartilage [7].

Osteonecrosis of the jaw (ONJ) is a disease described fairly recently. After the reported findings by Marx [1], bisphosphonates were considered the etiological agent responsible for the disease, even being called osteonecrosis due to bisphosphonates [2-5], which is wrong since many factors in addition to these drugs may be implicated in the etiopathogenesis of ONJ [1,6,7].
One of the hypothesis about ONJ’s development would be the existence of an excess suppression of bone remodeling, which can be produced by bisphosphonates or by other potent anti-resorptives, such as denosumab, a drug that is also involved in ONJ [8,9]. Since these drugs act on the entire skeleton, if there is such an excess of oversupression of bone remodelling, one could expect the existence of alterations in both the amount of BMD and bone quality in other locations. Although there are many descriptions of isolated cases or series of this disease in the literature, outlining its clinical characteristics and possible association with different diseases and risk factors [1,3-7,10], we have not found publications that analyze the possible quantitative alterations and/or qualitative bone in patients with ONJ.

The appearance of metastatic disease seriously threatens the survival rate of patients who develop a tumor. Certain types of tumors have been found to present a high tendency to colonize specific organs. From the hypothesis formulated by Paget (“seed-and-soil”) [1], few studies have deciphered the regulatory mechanisms of metastatic organotropism. Initial studies focused on the function of the intrinsic properties of the tumor cell, such as gene expression and colonization regulation pathways, in the direction of organotropism [2-4].
Bone is an organ frequently infiltrated by the metastatic spread of solid tumors [5,6]. The appearance of metastatic disease is a serious threat in the survival rate of patients who develop a tumor. From 65-80% of subjects with prostate cancer or metastatic breast present skeletal complications [5]. The study of bone metastases has mainly focused on the interaction of the tumor cell with the bone, once the metastasis has been established, ignoring the subclinical stages of the process that occurs previously. The establishment of tumor cells in the bone microenvironment alters the balance of the bone remodeling process between bone formation, induced by osteoblasts, and osteoclast-mediated resorption. Consequently, the survival and proliferation pathways of tumor cells are favored, inducing the formation of “a vicious cycle of bone metastases” [7].
Though not exclusive, tumors cause two different types of skeletal lesions. The most common form, represented by breast cancer is the osteolytic lesion associated with an alteration of bone remodeling with an increase in osteoclastic activity and subsequent osteolysis [8-11].

The aging process is associated with a loss of muscle mass and strength, as well as a decrease in bone mineral density (BMD), which can lead to reduced mobility, greater risk of falls and the appearance of fractures [1,2]. In recent years, special emphasis has been placed on maintaining an adequate vitamin D status to optimize muscle strength and BMD in order to reduce falls and fractures [3-5]. Although a recent meta-analysis questions the usefulness of vitamin D supplements to reduce the risk of falls, BMD decrease and fractures [6], there are sufficient arguments that demonstrate the importance of vitamin D on muscle and bone health. Vitamin D stimulates the absorption of calcium from the intestine and maintains the serum calcium levels that are required for normal bone mineralization and for the maintenance of muscle function [7]. Several in vivo studies suggest vitamin D’s role in regulating muscle mass and its function. Observational studies show that vitamin D deficiency in the elderly is associated with reduced muscle mass and strength [8-10], lower physical performance [8,11], and increased risk of falls [12].

Mechanical force is one of the most important stimuli that the bone receives to regulate bone mass, shape and microarchitecture. The endoskeleton reacts to an increase in load by forming more bone or decreasing its mass in the absence of mechanical stress [1]. This is because the stimulation triggers the mechanotransduction process in which osteocytes, considered bone’s key mechanosensory cells, when stimulated, send chemical signals that affect the paracrine regulation of osteoblast and osteoclast behavior [2,3]. It also has been found to have an anti-apoptotic effect on osteocytes [4].
With mechanical loading, the expression of sclerostin, which is an inhibitor of the protein signaling pathway Wnt/β-catenin constitutively secreted by osteocytes, decreases thus causing an increase in osteoblastogenesis [5,6]. On the other hand, apoptotic osteocytes induce the secretion of the receptor activator for nuclear factor κ B ligand (RANKL), indirectly stimulating osteoclastogenesis [7]. In addition, some chemokines, a family of chemotactic cytokines, could be involved in bone remodeling when expressed by bone cells and provide key signals to recruit different cellular subpopulations [8].

Osteoporosis is a metabolic disease characterized by low bone mass and microstructural deterioration of the bone tissue that leads to increased bone fragility. The main complication involves the appearance of fragility fractures [1]. Osteoporotic fractures are an important health problem [2] associated with high healthcare costs [3]. To prevent the appearance of fractures, different drugs are available that act on bone metabolism and are associated with reduced fracture risk [4]. The most commonly used in Spain are bisphosphonates [5]. However, in order to observe this protective effect, adequate therapeutic compliance is required [6]. In osteoporosis, as in all chronic diseases, compliance is low. In a recent study conducted in Spain, the overall persistence per year after commencing osteoporosis drug is 47%, and at two years, close to 27% [7].

Solid organ transplantation is an effective alternative in the final stage of multiple chronic diseases, increasing patients’ survival. However, this improvement is associated with certain complications, such as a higher incidence of osteoporosis and an increased risk of fractures [1]. Numerous studies have concluded that there is a loss of bone mass after transplantation, more marked between the first three and six months, which lasts up to a year after the same. Subsequently there is a stabilization and even recovery of bone mass in the two subsequent years [2-4].
Liver transplantation is considered an independent risk factor in the development of osteoporosis [1-3]. In the case of patients with a liver graft, the incidence of fracture is estimated at 10-43% [1], with the spine location being the most frequent [2-4]. Among the factors that contribute to the increased risk of osteoporosis and fractures in these patients are: prolonged treatment with immunosuppressants (mainly calcineurin inhibitors) [2,5-8] and glucocorticoids [9,10], vitamin D deficiency (very common due to malnutrition) and alterations in liver function found in most patients with cirrhosis [1-3].