Since the time of its discovery a century ago, there have been advances into what was erroneously called “vitamin” D. It is now acknowledged that it is not a vitamin, though we continue to use that term out of custom and tacit consensus. In fact, it is an endocrine system, the vitamin D endocrine system (VDES), similar to that of other steroid hormones. Cholecalciferol or “vitamin” D3, is the threshold (physiological) nutrient of the system, synthesized from 7-dehydrocholesterol, which is produced, and found, from single-celled organisms to the skin of higher animals, including human. This route represents around 90% of the physiological contribution to the body, the rest is obtained through diet. There is another isoform, of nutritional or pharmacological contribution, ergocalciferol, “vitamin” D2 or produced by ultraviolet irradiation of ergosterol contained in fungi, yeasts, etc…[1].

Osteoporosis poses a major health problem in modern societies, especially in women. Taking into account the aging of the Spanish population and the fact that osteoporosis an­­d fractures increase with age, with an estimate for 2029 of more than 11 million people over 65 years of age, this problem may become of the first order. Currently it is estimated that there are more than 200 million patients with osteoporosis worldwide, with increasing prevalence[1]. In Spain, the prevalence of osteoporosis in postmenopausal women over 50 years is 26.1% and in men 8.1%.
Therefore, in daily clinical practice, this condition should be diagnosed establishing the previous clinical suspicion and the patients labeled as such in order to avoid its progression and its consequences, which are fragility fractures.

In 1994, the WHO defined criteria for the diagnosis of osteoporosis using the measurement of bone mineral density (BMD). The DXA technique has established itself as the dominant technology for quantifying BMD due to:
a) strong correlation between BMD measured by DXA and bone strength in biomechanical studies,
b) Epidemiological studies that show a strong relationship between the risk of fracture and BMD,
c) For its use in clinical trials of treatments for the selection of subjects and monitoring based on its excellent precision and low radiation dose.
DXA is indicated to diagnose osteoporosis, assess fracture risk, and monitor changes in BMD over time. In recent years, there have been improvements to the initial DXA technology and it is used for other measurements beyond BMD (eg, femur geometry, vertebral fracture detection, body composition analysis).

The diagnosis of osteoporosis has evolved over the years along the disease’s conceptual development. The definition of osteoporosis comes from a description offered by Albright at the outset of the 1940s for postmenopausal and corticoid-induced osteoporosis. This is considered nowadays paradigm of primary and secondary osteoporosis. Its characteristics are reduced bone mass, micro-architectural disorders, unaltered mineralization and presence of fractures[1,2]. It is a histopathological definition with the secondary clinical event. Although osteoporosis is currently the most common metabolic bone disease, rickets and osteomalacia were the main metabolic bone disease from the time of Galen and well into the 20th century[3].

The nucleus contains most of the genetic information, distributed throughout the approximately 3 billion nucleotides of human haploid DNA. The approximately 21,000 genes that encode the proteins necessary for the various organic functions are represented there, as well as an indeterminate number of genes that are transcribed into RNAs that do not encode proteins, but have regulatory functions[1].
Mitochondrial DNA is smaller, having about 16,000 nucleotides, with genes to encode 13 proteins and 24 non-coding RNAs (transfer and ribosomal)[2].
DNA changes that lead to disease can be classified according to various criteria, including:

Osteoporosis is a bone disease characterized by a decrease in bone mineral density (BMD) and an increased risk of fragility fractures. Osteoporotic fractures, particularly hip fractures, cause significant mortality and morbidity in men and lead to considerable social costs in this population, including direct medical costs and indirect costs resulting from reduced quality of life, disability and death[1].
Of all osteoporotic fractures, it is hip fractures that contribute to the highest morbidity and mortality in men. Each year about 80,000 men will have a hip fracture. Of these, one in three will die during the first year after this hip fracture and another third will fracture again[2]. However, there is a lack of awareness among healthcare professionals about the need to screen men for osteoporosis so that male osteoporosis remains largely underdiagnosed and untreated.

Conventionally, calcium, phosphorus, calcitriol and PTH were considered the only regulators of bone and mineral metabolism. In recent years, this axis of regulation has been complicated due to emergence of other factors with a crucial role in bone and mineral metabolism, such as fibroblast growth factor 23 (FGF-23) and the so-called klotho anti-aging protein.

Biological actions of FGF-23 and PTH
Biological action of FGF-23
FGF-23 is a 251 amino acid protein synthesized and secreted by bone cells, mainly osteoblast[1]. FGF-23 has been identified as the main regulatory factor of phosphorus metabolism, a critical element for maintaining skeletal integrity and for the development of multiple enzymatic processes[2]. In addition, in the last decade it has been attributed a notable role in the pathophysiology of vascular calcifications[3] and cardiovascular disease (CV), both in the general population[4-6] and in patients with chronic kidney disease[7].

Antiresorptive (or antiresorptive) drugs are the cornerstone of osteoporosis treatment. For decades, they have been considered the first step in treating this disease, although more recently some have been discontinued as indication. Others do not always have to be used as the first therapy in the current sequential treatments supported by the main scientific societies. There are five classes of purely antiresorptive drugs: bisphosphonates (BF), estrogen, selective estrogen receptor modulators (SERMs), calcitonin, and monoclonal antibodies against the activating receptor for nuclear factor κB ligand (RANKL) such as denosumab. For its part, a dual-action antiresorptive and osteoforming drug (strontium ranelate) was widely used from 2004 until its marketing cessation in 2017 in Europe for the reasons that will be detailed later. The treatments to be developed here are based on studies in postmenopausal women, although they can be extrapolated to men and to glucocorticoid-induced osteoporosis, although with less evidence[3].

Osteoporotic fractures, especially those of the hip, are one of the main causes of disability in the elderly population, triggering a considerable decrease of life quality and lifespan. Besides, more than 30% of people die during the first year after suffering one of these fractures[1]. In 2010, the European Union recorded nearly 3.5 million fragility-induced fractures that led to 43,000 deaths. From an economical point of view, these fractures meant an expenditure of 37 billion euros, a sum that is expected to rise by 52% in 2025[2].
Vitamin D and calcium are essential compounds for bone metabolism and prevention of osteoporotic fractures. Two recent meta-analyses have reported that low levels of 25(OH)D are related to the increase of fragility-induced fractures due to bone mass loss and bone structure deterioration[3,4].

Sodium fluoride (FNa) was used in the past as a bone-forming drug. Administering fluoride causes the number of osteoblasts to increase as the proliferation of osteoblastic precursors is stimulated, which leads to increased activity. In addition, it has antiresorptive capacity. The combination of osteogenic effect and inhibition of bone resorption leads to an increase in bone mineral density (BMD)[1].
Although the number of randomized clinical trials conducted with FNa is relatively limited, the salt types and dosages used in them, as well as their combination with calcium and vitamin D, make every trial very different from each other and therefore the global assessment of the results turns very difficult.
There are some studies that have shown an increase in BMD and a reduction in the risk of vertebral fractures, but in general the published results have been disappointing. Despite almost uniformly observing a statistically significant increase of BMD, these studies do not record a reduction in the risk of fractures[2].

Hip fractures represent a general public health problem due to their high incidence and their impact on mortality and loss of quality of life [1]. In the coming years, with the progressive aging of the population, its incidence is expected to increase, incurring a significant drain on resources [2]. Crude mortality figures after a hip fracture are considered in most studies. An estimated 5% of patients die in-hospital and approximately 20% do so during the first year, depending on the series [3]. However, hip fractures occur in elderly patients who have an associated comorbidity that also influences their survival [4]. The highest mortality rates are reported mainly in the elderly, sick or disabled populations [5]. A recent meta-analysis exploring the magnitude and duration of the excess risk of mortality after hip fracture found the highest risk in the first 3 months after the fracture, and mortality remained high even after 10 years [6]. Excess risk increases with age and, at any age, is higher for men than for women [6].

Osteoporosis is defined as a skeletal disease in which there is a decrease in bone strength that leads to an increased risk of fracture, usually due to mild trauma [1]. Although any fracture can be observed in clinical practice, with the exception of the skull bones, the most prevalent is the vertebral one and the most serious that of the proximal extremity of the femur [2], given its significant morbidity and mortality [3]. Genetic, anthropometric, nutritional and lifestyle factors [4,11] influence the appearance of fragility fractures or osteoporotic fractures, but also gynecological and obstetric factors [12]. Among them, breastfeeding reportedly exerts an essential reproductive function in women and protects the mother from developing many diseases, such as cancer or diabetes [11-14].