Volume 13 · Number 3 · October 2021
Las innovaciones en la conducta terapéutica frente a una determinada enfermedad tienen, en general, la finalidad de mejorar su eficacia. Pero en algunas ocasiones pueden tener otros motivos; por ejemplo, evitar efectos secundarios, abaratar el coste o conseguir que la forma de administración de un fármaco sea más cómoda. La terapia secuencial supone una innovación terapéutica en el campo de la osteoporosis.
La primera forma de terapia secuencial utilizada en la osteoporosis fue probablemente la denominada ADFR (A = activate remodelling, D = depress resorption, F = free formation, and R = repeat) o “terapia de coherencia”, inicialmente propuesta por Frost alrededor de 1980 . El planteamiento teórico en que se basaba esta estrategia era sincronizar las unidades de remodelación, situándolas en fase resortiva, mediante la administración de un fármaco estimulador de los osteoclastos, para a continuación inhibirlos. Después se dejaba un tiempo libre de 2-3 meses, durante el cual se suponía que los osteoblastos, activados por el acoplamiento puesto en marcha con el estímulo inicial de los osteoclastos, desarrollaban el efecto osteoformador. La pauta ADFR fue una innovación terapéutica que pretendía mejorar la eficacia del tratamiento de la osteoporosis, pero que resultó un intento fallido.
Osteoporosis is a chronic systemic disease characterized by a deterioration in bone density and/or quality, which predisposes to a greater risk of fracture .
All treatments for osteoporosis have shown greater or lesser efficacy in reducing the risk of fracture, especially in postmenopausal women . This beneficial effect occurs from the modification of the bone remodeling process with the consequent increase in bone mineral density (BMD) and/or a modification of the bone’s microarchitecture, although this requires a prolonged treatment over years in most cases.
Although treatment with antiresorptives, menopausal hormone therapy [THM], selective estrogen receptor modulators [SERM], bisphosphonates [BP] and denosumab [DMAB]) can be maintained for at least 5-10 years, the balance between risk and benefit should always be taken into account, since in prolonged treatments with the highest antiresorptive potency drugs (BP and DMAB) an increased risk of some very infrequent complications such as osteonecrosis of the maxilla or atypical femur fracture has been described [3,4].
WNT16 is a ligand of the Wnt pathway that has been extensively studied for its importance in regulating bone homeostasis. This has been confirmed with the phenotype of knock-out (KO) mice and conditional KO mice in osteoblasts (cKO), which show spontaneous fractures due to low cortical bone mineral density (BMD), low bone strength and high cortical porosity, keeping the volume of trabecular bone unchanged [1-4]. On the contrary, Wnt16 overexpression in osteoblasts and osteocytes produces an increase in BMD and bone strength in both trabecular and cortical bone [5-7]. Despite this, the precise mechanism by which WNT16 acts is not known and different studies indicate that the effect on canonical and non-canonical Wnt pathways could be tissue specific [1,8-11]. In bone, WNT16 is expressed mainly by osteoblasts and carries out its function both by stimulating bone formation and by inhibiting its resorption indirectly through osteoprotegerin (OPG) or directly affecting the osteoclasts differentiation [1,12].
Several genome-wide association studies (GWAS) have shown an association between the locus containing WNT16 and various skeletal phenotypes, including BMD and risk of fractures [2,3,13-26]. WNT16 is found in a very complex locus, where several genes in the region show an important role in bone metabolism. The genes ING3 and CPED1 at 5 ‘and FAM3C at 3’ of WNT16 belong to this locus (figure 1).
Vitamin D is an essential micronutrient in bone and non-bone metabolism . The high prevalence of its deficit has been documented in multiple studies [2-5]. However, the definition of its reference values continues to be controversial and consequently doubts are raised about its diagnosis and treatment . Although rickets was eradicated in the mid 20th century with sun exposure and the enrichment of milk with vitamin D, in recent years there have been reports of rickets in different parts of the planet, the mainly affected black-skinned and exclusively breastfed babies [7-9]. While rickets is the most serious consequence of vitamin D deficiency, mere deficiency also has important health consequences .
Studies that measure the level of vitamin D show great geographic variability due to the great regional differences in climate, sun exposure and diet. For this reason, there is a need to specifically investigate the role of the different determinants of hypovitaminosis D  in each country. The diet meets only 10% of the human body’s vitamin D requirements, the remaining 90% being obtained through the photosynthesis process that occurs in the skin by the direct action of the sun’s rays . Risk factors repeatedly identified in the literature as causes of hypovitaminosis (dark skin phototype, low sun exposure, lack of physical exercise, latitude >40º north, and winter and spring seasons) act by interfering in the second mechanism [2,12]. Other factors associated with hypovitaminosis such as maternal deficit, obesity or advanced age could be related to both mechanisms of obtaining vitamin D [12-14].
Genetic relationship between pulmonary diseases of environmental or occupational origin and osteoporosis: a bioinformatic approach
Osteoporosis is currently defined as “a systemic skeletal disease characterized by decreased bone mass and a structural alteration of the bone tissue that determines a decrease in bone resistance resulting in a significant increase in fragility and susceptibility to fractures” . The classic risk factors associated with the development of osteoporosis are age, a history of previous fracture or family history of osteoporosis, and prolonged estrogen deficiency .
On the other hand, one of the most important risk factors for mortality at the population level is air pollution. The consequences derived from air pollution have a high economic and social impact. In 2015, the costs derived from pollution-related morbidity and mortality reached 21 billion dollars worldwide and an estimated number of premature deaths between 6 and 9 million people in 2060 due to outdoor air pollution . Air pollution has been shown to have a direct impact on health, causing various adverse effects . The relationship between air pollution and environmental lung diseases has been reported in numerous studies [4-6]. Likewise, there is strong scientific evidence that relates poor air quality in different work environments with the development of different respiratory diseases [7,8].
Type 2 diabetes mellitus (DM2) and osteoporosis are highly prevalent diseases due to the aging of the population that are associated with an increased risk of fragility fractures that substantially increase the morbidity and mortality of the population . Recently, sarcopenia, defined as muscle weakness related to aging, has been recognized as a complication of DM2 that often increases these patients’ frailty [2,3].
The musculoskeletal system is closely related, both by its physical connection and by its regulation through multiple common elements. Although muscle has been found to exert an influence on bone through the neuroendocrine system and mechanical forces, their relationship is complex and not entirely well known . Many studies have shown a link between sarcopenia and osteoporosis, but the results are inconsistent due to variable diagnostic criteria and divergent assessment methods for sarcopenia and osteoporosis.
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….
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. 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.
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.
Mitochondrial DNA is smaller, having about 16,000 nucleotides, with genes to encode 13 proteins and 24 non-coding RNAs (transfer and ribosomal).
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.
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. 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.