In 1922, at Johns Hopkins University in Baltimore, Professor McCollum discovered a factor, which has since been referred to as vitamin D, following the alphabetical order of the other vitamins identified up to that time. It is capable of curing rickets in children and osteomalacia in adults. Diseases in which, as we know from the first scientific descriptions published in London in the mid-seventeenth century, muscle involvement consisting of weakness and generalized hypotonia is associated with bone involvement, its main characteristic. Therefore, since the discovery of vitamin D, it has been associated not only with bone health but also with muscle health . Paradoxically, at present, there is no consensus on the potential beneficial effects of vitamin D supplementation on muscle function, balance and risk of falls, a situation highlighted in the last meta-analysis published by Bolland et al. , who review in 81 randomized clinical trials (RCTs) that include 53,537 participants the effect of vitamin D on fractures and falls as a primary outcome. The pooled analyses showed that vitamin D supplementation had no effect on falls (37 RCTs, n=34,144, RR=0.97, 95% confidence interval -0.93 to 1.02), what the authors concluded that “vitamin D supplementation does not exert significant effects in falls”, affirming that “potential future trials will probably not alter those conclusions, and that, therefore, there is little justification for the use of vitamin D supplements.Read More
Calcidiol levels and muscle function maintenance, functional capacity and bone mineral bone density in non-selected Spanish population
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 , 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 . 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 .Read More
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 . 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 .
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 . 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 .
The determining role of a resorption marker, carboxyterminal telopeptide of collagen I, in assessing therapeutic compliance in patients treated with oral bisphosphonates
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 . Osteoporotic fractures are an important health problem  associated with high healthcare costs . To prevent the appearance of fractures, different drugs are available that act on bone metabolism and are associated with reduced fracture risk . The most commonly used in Spain are bisphosphonates . However, in order to observe this protective effect, adequate therapeutic compliance is required . 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% .Read More
Different development of serum sclerostin compared to other bone remodeling markers in the first year after a liver transplant
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 . 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% , 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].
In recent decades, vitamin D has attracted growing interest, not only in the medical field, but also among the general population. Initially, the evaluation of vitamin D was part of bone metabolism assessment when, for example, rickets or osteomalacia were suspected, or in populations at risk of osteoporosis . 25-hydroxyvitamin D (25-OHD) is the circulating metabolite of higher concentration and longer half-life, used to monitor the body status of vitamin D. Patients with chronic kidney disease and undergoing dialysis treatment are also controlled by measurements of the evaluation of this state . In this case, in addition to 25-OHD, the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25- (OH) 2D), produced mainly in the cells of the proximal tubule of the nephron.Read More
Atypical femoral fractures: a rare complication possibly due to the accumulation of rare genetic variants
Antiresorptive drugs, such as bisphosphonates and denosumab, are very effective in reducing the risk of vertebral and non-vertebral fractures in patients with osteoporosis. They can be administered conveniently, are generally well tolerated and the side effects are mild and infrequent. Occasionally, however, some patients may present complications peculiar to the treatment, such as atypical femoral fractures (FFA) and maxillary osteonecrosis. These complications occur very rarely, but are potentially serious and difficult to manage, so they are a source of concern for some doctors and many patients. This fear seems to have a negative influence, although not justified, on therapeutic compliance. Therefore, it would be extremely useful to identify the rare patients who are at risk of developing these complications.Read More
Genetic study of atypical femoral fractures using exome sequencing in three affected sisters and three unrelated patients
Osteoporosis and its associated fractures are the most common postmenopausal bone problems, affecting women and men of all ethnic groups. Nitrogen-containing bisphosphonates (N-BPs), including alendronate, risendronate, ibandronate and zolendronate figure as the most widely used osteoporosis treatments in millions of patients worldwide. Despite the significant anti-fracture efficacy of BPs, which has been widely demonstrated in several clinical trials and systematic reviews, some infrequent adverse effects associated with prolonged use have been described, including atypical femur fractures (AFFs). These fractures are non-traumatic and characterized by their subtrochanteric location or in the diaphysis of the femur, and are frequently bilateral.
AFFs’ pathogenic mechanisms are not completely known and much has been speculated about their causes. An excessive suppression of bone resorption by N-BPs could trigger an AFF but its pathophysiology is complex and other important factors are reportedly involved. Some proposed risk factors are cortical thickness and pelvic geometry. In addition, cases of AFF have been described in patients affected by other monogenic bone diseases, such as hypophosphatasia, osteogenesis imperfecta or the syndrome of osteoporosis pseudoglioma.
The Wnt pathway’s role in regulating bone remodeling has been demonstrated in multiple studies. On the one hand, polymorphisms have been described in several genes of the Wnt pathway that show an association with bone mineral density (BMD) and the risk of fracture. Rare or infrequent mutations have also been described in various genes of the Wnt pathway, which cause more rare bone phenotypes, such as osteoporosis-pseudoglioma (OPPG, OMIM 259770), autosomal recessive osteogenesis imperfecta of type XV (OMIM 615220)8, and osteosclerosis (OMIM 144750). The Wnt pathway begins with the formation of a heterotrimeric complex between the Frizzled receptor, the LRP5 co-receptor and the Wnt ligand. Once this complex is formed, β-catenin accumulates in the cytoplasm and translocates to the nucleus where it can activate the transcription of numerous target genes. In osteoblasts, the Wnt pathway has been shown to activate the transcription of genes that clearly contribute to bone formation. In addition, this pathway is finely regulated by a series of extracellular inhibitors, including the protein sclerostin, encoded by the SOST gene, and the DKK1 protein, encoded by a gene with the same name. These two proteins perform their function, preventing the formation of the heterotrimeric complex. The proteins sclerostin and DKK1 thus form other heterotrimeric complexes, together with LRP5 and LRP4 (in the case of sclerostin) and together with LRP5 and Kremen (in the case of DKK1).Read More
Osteoporotic fractures pose a serious public health problem given their high prevalence and enormous impact in terms of morbidity, mortality and economic cost. Hence there is considerable interest in understanding the underlying pathophysiology of bone fragility, which, from a mechanical standpoint, is determined by bone strength. Bone resistance, in turn, comes from the integration of bone mineral quantity, bone architecture, and the material properties of bone.
The mineral quantity of the bone is usually measured by bone densitometry (DXA), the most commonly used, standardized method for assessing bone mass and fracture risk. Bone architecture, both at the micro- and macroscopic level, is examined using different imaging techniques, including high-resolution peripheral quantitative tomography, bone magnetic resonance and the more accessible Trabecular Bone Score. However, the material properties of bone are difficult to assess due to its high complexity, reflected in its multiple constituents including non-collagenous proteins, crystallinity, hydration of bone tissue, and the characteristics of mineralization and collagen, among others. Furthermore, as researchers need bone tissue samples for analysis, the study of these properties has traditionally been restricted to a few centers specialized in bio-mechanics.
Factors secreted by bone cells induce intracellular calcium accumulation and cyclic AMP and activation of ERK 1/2 in prostate cancer cells; evaluation by fluorescence techniques in living cells
Bone metastasis is a frequent complication in advanced stages of patients with prostate cancer, one of the cancers with greater mortality and morbidity in developed countries. Avoiding the different stages necessary for the tumor cell to abandon the primary tumor, migrate and establish itself in the bone microenvironment is one of the main strategies to prevent bone metastases. The invasion of primary tumor cells into skeletal niches is associated with the activation of bone cells that release growth factors and cytokines, which in turn promote tumor growth in metastases. As a result, the so-called “vicious cycle” of bone metastases is generated, which varies the physiology of bone and alters bone remodeling. In the case of bone metastases caused by prostate cancer, osteolytic and osteoblastic lesions are produced as a result of the activation of osteoclasts and osteoblasts respectively. In bone metastasis processes, it has been observed that tumor cells are able to secrete factors such as tumor necrosis factor alpha (TNF-α), interleukin 11 (IL-11), matrix metalloprotease 1 (MMP1), Jagged1 and protein related to parathormone (PTHrP), which directly or indirectly activate osteoclasts, giving rise to osteoclast metastases. Matrix degradation by osteoclasts releases transforming growth factor β (TGF-β) and insulin-like growth factor (IGF-1) that promote the survival of tumor cells. In contrast, the secretion by tumor cells of other factors such as fibroblast growth factor (FGF) and bone morphogenetic proteins (BMPs) can stimulate osteoblast differentiation resulting in osteoblastic lesions.Read More
Phytoestrogens are a family of plant-derived components that present a steroid structure and can act in the estrogen receptor. They contain both estrogenic and antiestrogenic properties, depending on the tissue in which they act.
The potential mechanisms by which phytoestrogens can affect cell activities have been divided into genomic and non-genomic effects. The former act through estrogen receptors, and the latter are mediated by cellular proteins. The active mechanism of soy isoflavones in bone may be beneficial, as they act by stimulating the activity of the osteoblasts. On the other hand, through the RANK-L/OPG system they bring about a decrease in osteoclast survival and activity. This article reviews in vitro studies, in animals and humans, that involve isoflavones and bone health to ascertain how these substances affect those postmenopausal women who use them in treatment or prevention of the climacteric syndrome.
In general, the global assessment of human studies shows variability in the design, in the variety of isoflavone sources, in the time of the analysis and in the dose. In addition, the variability in the bioavailability and metabolism of isoflavones between the subjects must be considered. All this makes it difficult to obtain consistent conclusions.
To sum up, some positive results justify the need for further research. From a clinical point of view, isoflavones are used in women with climacteric symptoms who cannot or do not wish to undergo hormone therapy. They would not be indicated for treating osteoporosis, but those women who use them at the right doses and time can expect a benefit in maintaining bone mass.
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