(  PDF )   Rev Osteoporos Metab Miner. 2019; 11 (4): 87-91 DOI: 10.4321/S1889-836X2019000400002 Ormeño Illanes JC1, Quevedo Langenegger EI2 1 Faculty of Medicine. University of Concepción. Concepción (Chile) 2 Endocrinology...

Without a doubt, vertebral fracture (VF) is the most prevalent type of bone rupture in patients with low bone mass [1]. The most recent epidemiological data in the Spanish population indicate about 35% VF prevalence in women over 45 years of age [2]. In men, the prevalence at 50 years is estimated 5 times lower than that of the female population, although this increases beyond 70 years of age [3].
Osteoporotic VFs (OVF) are conservatively treated, usually including rest, analgesia (in combination with muscle relaxants), orthotics and rehabilitation. This treatment is crucial in the first weeks post-fracture, so that proper follow-up usually resolves OVFs effectively. However, in 10-35% of patients, complications may arise from the fracture itself, such as delayed bone union, increased kyphosis, appearance of neurological disorders or the appearance of pseudo-arthrosis (Kümmell’s disease). In these cases, patients frequently do not respond well to conservative treatment, complicating the management of their symptoms. This tends to worsen over time [4].

Genome-wide association studies (GWAS) and candidate gene studies have found some single nucleotide polymorphisms (SNPs) in the SOST gene, which encodes sclerostin, associated with bone mineral density (BMD) and predisposition to fractures [1-4]. However, the mechanism responsible for this association is unknown. Among the general mechanisms by which genetic variants predispose to complex diseases are epigenetic mechanisms, such as DNA methylation, that modulate gene transcription directly (locally) or indirectly (remotely) [5]. In this sense, it should be noted that the DNA methylation of the SOST promoter is inversely related to the gene expression levels of the gene [6].
DNA methylation is an epigenetic mark that consists in the addition of a methyl group at the 5 ’position of the cytosine ring, usually in cytosines that precede guanine, forming the so-called CpG sites. They are distributed throughout the genome and abundant in some specific regions, such as promoters, called CpG islands. Methylation levels of CpG sites and/or islands have specific profiles according to the tissue of origin and modulate gene expression in many tissues, including bone [7-10].

Fragility fractures are the relevant hallmark of osteoporosis [1]. The risk of fracture is closely related to bone strength, which, in turn, depends on bone mass, geometry and material quality [2-6]. Bone mass and geometry can be evaluated clinically using bone densitometry and high resolution imaging techniques. However, the mechanical properties of bone tissue are more difficult to explore. These properties determine bone quality, a concept that represents the intrinsic capacity of tissue to resist tension states, regardless of the amount of material (bone density) or its spatial distribution (bone architecture). Bone quality depends on the chemical composition and organization of the bone matrix [7].
In an indentation or hardness test, a sample is subjected to quasi-static loading by means of a small indenter, recording the size of the resulting footprint; Sometimes the curve that relates the applied load and the displacement experienced by the indenter during the test is also determined. Hardness is defined as the maximum force applied divided by the area of the footprint that remains in the material after the test. Hardness is the property of the material that characterizes its resistance to permanent/plastic deformation [8].

In recent years there has been an impressive increase in the number of scientific articles related to the metabolism of calcium and vitamin D. We have gained a much deeper knowledge of many patho-physiological aspects. However, and in spite of this, a series of fraudulence, myths and legends have been developed in parallel on both calcium and vitamin D, many of them absolutely unjustified, and others derived from a misunderstanding of some scientific articles. Since this can lead to the abandonment of treatments or taking them in the wrong way, we have developed this article in order to clarify, with scientific evidence, some of these aspects.

Review of the physiology of calcium and vitamin D.
Calcium absorption depends on vitamin D and is a saturable mechanism. From a certain amount and reach the optimum level of absorption, all calcium that is ingested is not absorbed and is eliminated by feces.
Between 100 and 200 mg of calcium are removed by the kidney on a daily basis under normal conditions. Also, between 800 to 900 mg of calcium is lost by stool, as a result of the secretion of bile salts and pancreatic juices. These are known as “mandatory calcium losses” and together they constitute about 1,000 mg (Figure 1). Calcium cannot be synthesized by any metabolic route and, therefore, must be taken by diet [1].

Calcium and vitamin D requirements for health in general and bone in particular are well established. While the medical community recommends maintaining serum levels of 25 hydroxy-vitamin D (25(OH)D) above at least 20 ng/ml, the calcemia should remain between 8.5 and 10.5 mg/dl. However, these amounts, which should be obtained naturally from diet (calcium) and sun exposure (vitamin D), are not attained by a high percentage of the population.
Calcium levels, so essential for the operation of multiple systems, are maintained thanks to the store that constitutes the bone. From this, the body obtains calcium to maintain its homeostasis if necessary, to the detriment, obviously, of the bone itself, which undergoes an increased resorption that, in turn, produces osteoporosis.
Vitamin D, for its part, lacking a storage system, sees its serum levels fall as sun exposure decreases. We know that the foods richest in calcium are dairy. The intake of these foods is very low in the general population, for different reasons. Furthermore, the risk of skin cancer causes sun exposure to be avoided “drastically”, which prevents vitamin D production. Calcium and vitamin D supplements help people reach the appropriate levels in these situations and shore up deficiencies.
In this paper, we will discuss the recommendations made in various clinical guidelines. These are selective, given the limited space, but we believe they are representative and shed light on the usefulness of giving calcium and vitamin D supplements for the treatment of osteoporosis or to ensure bone health . The approach that different societies and institutions have made varies from the one carried out in the framework of the general treatment of osteoporosis to the specific one of such supplements, either only of vitamin D, of calcium alone, or of both.

The role of calcium and vitamin D in bone metabolism has been known for many years. Calcium is one of the main components of bone and, together with the collagen matrix, it is responsible for facilitating the strength and resistance of the skeleton [1].
The maximum bone mass is acquired by 30 years of age and depends on genetic and environmental factors, including calcium intake. Once the bone mass peak is achieved, it is necessary to maintain a minimum calcium intake to avoid bone loss.
Vitamin D is responsible for maintaining calcium and phosphorus homeostasis, favoring its reabsorption at the renal and intestinal levels. Its deficit is associated with an alteration of bone mineralization, causing rickets in children and osteomalacia in adults.
Osteoporosis is a prevalent chronic process. It poses a public health problem associated with significant morbidity and mortality [2]. With the aging of the population its prevalence is expected to increase [3]. Physical activity and proper nutrition are two measures associated with a reducted risk of osteoporosis [4]. Adequate calcium intake, together with sufficient levels of vitamin D, have proven to be a good option to maintain a healthy bone state [5].

The proximal femur fracture, or hip fracture, is the most serious complication of osteoporosis, due to its high mortality and morbidity, as well as the significant social, economic and welfare cost it entails. In fact, the hip fracture is capable, on its own, of decreasing life expectancy in almost two years and one in five patients who suffer from it will require permanent health care [1]. Risk factors that favor this type of fracture include a greater tendency to fall and a decrease in bone resistance.
Since the discovery of vitamin D in 1922, it has been associated not only with bone health but also with muscle health [2]. Therefore, and although there is no evidence that determines its effectiveness, calcium and vitamin D administration is recommended for every patient with osteoporosis, to avoid their deficiency, which may be harmful. Thus, in most clinical practice guidelines, treatment with antiresorptive or anabolic drugs must be accompanied by an adequate intake of vitamin D, in addition to an appropriate amount of calcium, which usually ranges between 1,000 and 1,200 mg daily [3-5].

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].