Volume 10 · Number 4 · December 2018
- Atypical femoral fractures: a rare complication possibly due to the accumulation of rare genetic variantsiabetes and bone: an unexpected but intense relationship [105-107]
- Genetic study of atypical femoral fractures using exome sequencing in three affected sisters and three unrelated patients [108-118]
- Functional studies of DKK1 variants present in the general population [119-124]
- Bone tissue mechanical strength is independent of age in healthy individuals [125-130]
- 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 [131-138]
- Isoflavones and bone health [139-145]
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.
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).
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.
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.
A proposal for reorganizing the world of scientific publications which would save Spain millions of euros
At the beginning of the twentieth century few scientific journals existed and their range of diffusion was limited. In the field of medicine, two publications stood out: in the United States, The New England Journal of Medicine, which was established in 1812, and The Lancet in Europe, which dates back to 1823. The main objective of the authors, most of whom were researchers, was to report important findings to their scientific community. These findings were often expected, as, for example, with Watson and Crick’s publication of the breakthrough in the structure of DNA in Nature 1 or Fleming’s discovery of penicillin 2, milestones in medicine that became known through their publication as scientific articles or simply as a letter, as in the case of the discovery of DNA 1.
More than 30 years ago, everything changed. Eugene Garfield’s impact factor for scientific journals 3 was initially conceived as an index to assess the quality of journals and to provide orientation for librarians (the essence of the impact factor is to list the frequency with which a given article is cited in other quality journals as well as the number of articles that the magazine publishes)4. The impact factor suffered a malevolent distortion in its use and, by extension, began to be used as an index of quality of the scientific articles published in the journals with an impact factor. From that point on, it conditioned the professional attitude of publishers, scientific journals, researchers and even of research institutes, universities and ministries, a phenomenon that has been recognized and lately called into question5.
Review of the scientific evidence regarding clinical use of the Trabecular Bone Score (TBS) SEIOMM official position (2018)
The incorporation of new technological applications in the medical field entails a prolonged period of evaluation of the scientific evidence generated in the clinical validation process.
Over the past 5 years, numerous publications, communications in congresses and meetings of scientific societies have been generated. The application of the Trabecular Bone Score (TBS) has also received the attention of the International Society for Clinical Densitometry (ISCD), which has integrated it into its official positions.
The concept of Evidence-Based Medicine (EBM) was developed by a group of internists and clinical epidemiologists led by Gordon Guyatt of McMaster University School of Medicine in Canada. The concept of EBM was defined by its creators as the conscious, explicit and judicious use of the best available clinical evidence to make decisions about the care of individual patients. In essence, EBM aims to have the best available scientific information, the evidence, to apply it to clinical practice.
In 2014, the Spanish Society of Bone Research and Mineral Metabolism (SEIOMM) began a project that facilitated its partners TBS software assessment, through a competitive call. The project ended in 2017. This application requires densitometry images with DXA (Dual X-ray Absorptiometry) of the lumbar spine, and by analyzing the image texture, offers information related to the microstructural quality of the trabecular bone. The project had the logistical support of Medimaps, a French developer, which distributed 20 TBS licenses among the partners that proposed their use in certain clinical and therapeutic settings.