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.

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.

Osteoporosis is the most common bone metabolic disease. It is generally defined as “systemic skeletal disease characterized by decreased bone strength with consequent increase in bone fragility and susceptibility to fractures”1. The essential elements of this definition are low bone mass and microarchitectural alteration, which distinguish osteoporosis from other bone diseases. The alteration of the microarchitecture is characterized by the loss, thinning and lack of connection between the bony trabeculae, together with a series of factors, such as alterations in the bone remodeling and the bone geometry itself, among others that have been grouped under the concept of bone quality2. On the whole, osteoporosis involves a deterioration of the structural integrity of the bone which favors skeletal fragility and causes increased risk of fractures (fx).
The World Health Organization (WHO) established an operational definition based on bone mineral density (BMD) determination in any skeletal region for white women. Thus, normal BMD values were established to those higher than -1 standard deviation (SD) in relation to the mean of young adults.
Normal (T-score > of -1); osteopenia BMD values between -1 and -2.5 SD (T-score between -1 and -2.5); osteoporosis BMD values lower than -2.5 SD (T-score below -2.5) and established osteoporosis when, together with the previous conditions, one or more osteoporotic fx is associated3.
It is important to consider that the WHO criteria should be used preferably to ascertain the epidemiology of osteoporosis and not to apply them in isolation or to indicate preventive and therapeutic measures. Although not perfect, the definition of osteoporosis according to BMD is valid, since there is a strong association between BMD and fracture risk. Prospective studies show that the decrease of a SD in BMD increases the risk of fracture between 50 and 160% (relative risk: 1.5-2.6)4.

Osteoporosis is a metabolic bone disease characterized by a low bone mass and a deterioration of the microstructure of the bone tissue that leads to an increase in bone fragility and consequently to an increased risk of fracture1. Its real incidence is difficult to calculate since it is a silent process until the appearance of the fracture. It is one of the most prevalent osteo-articular diseases in primary care consultations. Since in 1994 the World Health Organization defined the densitometric values of osteoporosis which have been widely used to identify the population susceptible to suffering a fragility fracture2. Currently, population screening strategies3 are not recommended to identify patients with osteoporosis. Rather, a precautionary search is suggested in those subjects with a high risk of fracture4. In addition, in recent years the role of the exclusive assessment of bone mass to estimate the risk of fracture in patients has been questioned. Identifying these patients at risk to direct the necessary diagnostic and therapeutic options is one of our most difficult and controversial tasks.

Clinical practice guidelines (CPG) are a useful tool in medical practice, because they help guide the doctor in making decisions regarding a certain disease, based on a series of recommendations from the most up-to-date evidence available, combined with the consensus opinion of a group of experts on the subject1.
CPGs not only provide knowledge and recommendations to the clinician in managing a specific ailment, but are also useful for the sustainability of health services, as costs soar in an increasingly aging and more technologically advanced society.
With CPG, heterogeneity in clinical practice is reduced, maintaining the balance between scientific evidence, economic efficiency and competent variability of the medical professional.
This is especially important in the case of osteoporosis. Patients often require multidisciplinary care, participating in different levels of care, so that it is necessary to try to achieve maximum homogeneity in the management of patients.
Despite being governed by a series of statements or recommendations, the CPGs do not have to limit the doctor’s autonomy, as they are usually not binding. That is, they may not be followed in certain cases, if the patient’s specific characteristics or conditions advise another action guideline. In other words, the CPG will not replace the clinical judgment of the doctor who treats the patient.
In short, CPGs aim to maintain the quality of care through the adequate use of available resources, avoiding clinical decisions that are not scientifically based and reducing the variability of the practice.

Fracture fractures are the only clinical complication of osteoporosis1-3. Therefore, treatment should be aimed at preventing the appearance of fractures, since they are associated with an increase in morbidity and mortality4,5. In this sense, the presence of fragility fractures is a cause for alarm and treatment needs to be established as early as possible. It is wrong to think that when we treat a fractured patient we have arrived late and that it is not cost-beneficial to start treatment, because, on the one hand, having suffered a fragility fracture is a risk factor for a new fracture and on the other hand, the establishment of treatment for osteoporosis not only reduces the risk of new fractures, but also decreases the mortality of patients who have suffered them5,6.