Revista de Osteoporosis y Metabolismo Mineral

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Volume 7 · Number 4 · December 2015


Gastric protection or bone protection? The dilemma of proton-pump inhibitor

The arrival of H2 inhibitors and later the proton-pump inhibitor (PPI) changed the clinical course of gastroesophageal disease, greatly reducing the rate of peptic ulcers and their complications. At present they are used in a high proportion of patients with diverse clinical situations 1. They are recommended to treat gastro-esophageal reflux, Helicobacter pylori, Zollinger-Ellison syndrome, duodenal ulcer, gastric ulcer and NSAID-induced peptic ulcer. Their proven benefits in preventing ulcers and encouraging good tolerance have led them to be considered as a popular, safe “gastric protector“, with little adverse effects and used in many situations without indication.
But do not forget that the blockade of acid secretion by PPIs is the cause of some undesirable effects 2. Increased intestinal and systemic infections have been attributed to decreased gastric acid secretion and their bactericidal capacity. Other infections, such as pneumonia, are also more common among patients treated with PPIs. B12 production capacity and intestinal absorption may be reduced by malabsorption. A reduced of antiplatelet effect of clopidogrel therapy has also been described. Some cancers, especially colon cancer, could be more frequent. Finally, it is worth noting the increased risk of fracture in patients treated with long-term PPI. In this issue, a study by Vera Rodríguez et al. 3 on its possible association with increased fractures in the population of the Canary Islands is presented, confirming the increase in non-traumatic fractures in patients over 50 years undergoing long-term PPI treatment compared to those who have never taken these medications.

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Factors related to bone forming inadequate response to treatment (teriparatide/PTH 1-84) in patients with severe osteoporosis. Preliminary results

The aim of this study was to evaluate the long-term bone mineral density (BMD) response rate to osteoanabolic treatment in patients with severe osteoporosis and the factors related to “inadequate“ response (IR).
Methods: 49 patients (46F:3M) with a mean age of 69.5±11.1 years treated with teriparatide (41) or PTH1-84 (8) during 18/24months were included (84% had vertebral fractures and 84% had previously received bisphosphonates). Previous skeletal fractures and antiosteoporotic treatment, risk factors and cause of osteoporosis were recorded in all patients. Bone turnover markers (BTM) and 25-OH vitamin D (25OHD) levels were assessed before and at 3, 6, 12 and 18/24 months. Lumbar and femoral BMD and spinal X-ray were assessed at baseline and at 12 and 18/24 months. IR was defined by a lumbar BMD change <3% at 18/24 months. Results: 29% of patients showed IR to therapy. No significant differences were observed in age, baseline BMD and BTM and 25OHD levels between patients with or without IR. 92% of IR patients had been previously treated with bisphosphonates (vs 79%, p=0.34) during 7±4.8 years (vs 4.9±4.2 years, p=0.19). No significant differences were observed between groups in the magnitude of changes in BTM throughout the study. Conclusions: 29% of patients with severe osteoporosis presented IR to osteoanabolic therapy. Although no predictive factors related to this finding were identified, previous prolonged therapy with bisphosphonates may play a role.

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The VEGF (VEGFR2) 2 receptor and PTH (PTH1R) 1 receptor act as mediators in the anti-apoptotic response to mechanical stimulus in MLO-Y4 osteocyte-like cell

Mechanical stimulation plays a crucial role in bone mineral maintenance. This stimulation prevents osteocyte apoptosis by a mechanism that involves ß-catenin accumulation and nuclear translocation of extracellular-signal-regulated kinases (ERKs). The vascular endothelial growth factor (VEGF) and parathyroid hormone-related protein (PTHrP) modulate bone formation, although their interaction with osteocytes is unknown. In this paper we have considered the possible role of VEGF (VEGFR2) 2 receptor and PTH (PTH1R) type 1 receptor in the anti-apoptotic response to mechanical stimulation of MLO-Y4 osteocyte-like cells. The cells were subjected to mechanical stress by laminar fluid flow (10 min, 10 dinas/cm2) or hypotonic shock (240 mOsm, 1h), or stimulated with VEGF165 or PTHrP (1-36). We also compared the effects of overexpressed VEGFR2 and mechanical stimulation of these cells. Mechanical stimulation, VEGF165 or PTHrP (1-36) stimulated cellular viability and β-catenin stabilization in a similar manner, associated with its localization in the membrane. Mechanical stimulation increased PTH1R presence in the membrane. VEGFR2 inhibition as well as the PTHrP (7-34) antagonist reduced these effects. On the other hand, VEGFR2 overexpression in MLO-Y4 cells mimicked the mechanical stimulation effect on β-catenin and cellular viability. Our findings support a functional role for both systems, VEGF/VEGFR2 and PTHrP/PTH1R, in the early response to mechanical stimulation in promoting osteocyte-like viability.

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BMD evolution during treatment with aromatase inhibitors and its relation to the CYP11A1 gene: prospective study in the B-ABLE cohort

Objectives: The aim of this study was to analyze bone mineral density (BMD) changes throughout aromatase inhibitor (AI) treatment in clinical cases and also consider its association with the CYP11A1 gene and the BMD variation after treatment.
Material and methods: The B-ABLE cohort is a prospective study of postmenopausal women with breast cancer, in AI treatment. BMD variation was analyzed during AI treatment, as well as the differences those patients who were treated and not treated previously with tamoxifen (TMX). Three polymorphisms (rs4077581, rs11632698 and rs900798) of the CYP11A1 gene were genotyped for their association with BMD variation.
Results: TMX-treated patients presented more rapid BMD loss than those who did not undergo prior TMX treatment (60% less in spine and 46% in femur at 2 years and 70% less in the spine and 63% in the femur at 3 years). However, no significant BMD loss was detected after treatment in either group. The 3 CYP11A1 gene polymorphisms were significantly associated with BMD variation in the femur at the end of the treatment.
Conclusions: BMD was reduced more rapidly in patients with prior TMX treatment than in those who only received AI, although no significant differences were detected after treatment. The 3 CYP11A1 gene polymorphisms were associated with BMD variation in response to AI treatment.

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Inappropriate use of proton-pump inhibitors and fragility fracture risk. A preliminary study

Introduction: Proton-pump inhibitors (PPIs) are widely used drugs, though it should be noted that excessive use is not in line with the accepted indications in Spain and throughout Europe. Furthermore, some authors have established a possible PPI link to the risk of fracture. In this paper, we make an initial approach to knowledge into PPI consumption and analyze what indication is prescribed. We also studied the drugs‘ possible association with increased risk of fragility fracture in users.
Material and method: An observational, transversal, open and descriptive study in which a number of randomly-chosen patients were interviewed. These patients had been treated in outpatient, emergency and primary care centers. Some had also been treated in hospital wards.
Results: Of the 411 patients interviewed, 54% received PPIs. The average age was 63.3 years, compared with 46% that did not take them and who were younger presenting a mean age of 50.9 years. Gender distribution was similar. PPIs were mainly used as a “gastric protector”, in 39.8% of the patients, with no indication appearing in the technical specifications for this group of drugs. Consumers of PPIs presented a higher prevalence of all fragility fractures.
Conclusions: More than half of the population surveyed consumed PPI. Of this group, about 40% did so without proper medical advice. Therefore, in addition to the higher prevalence of fragility fractures that suggest a possible increased risk of fracture among its users, we consider the need for a more rational use of these drugs. These preliminary findings point to a need for further studies to confirm the relationship between PPIs and the risk of osteoporotic fracture.

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General and bone pain syndrome in a patient treated with tenofovir

Tenofovir (TDF), is the only nucleotide analogue reverse transcriptase inhibitor for treating human immunodeficiency virus (HIV). Occasionally, it may cause acute renal failure and Fanconi syndrome.
We report the case of a 64-year-old male diagnosed with HIV infection 22 years previous and treated with tenofovir. In outpatient follow-up, the patient complained of progressive fatigue and diffuse aching bones. In several check-ups, increased alkaline phosphatase and parathyroid hormone (PTH) were observed. Over the past month, his condition worsened and he was admitted to hospital. Analytical data included marked glycosuria, hypophosphatemia, hyperphosphaturia and hypouricemia. All changes were resolved when TDF was discontinued.This illustrates the importance of clinical evaluations that include possible TDF-induced proximal tubulopathy in patients with general bone pain syndrome or mineral metabolism disturbances.

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Review of the incidence of hip fracture in Spain

The aging of the world population is an indicator of improving health worldwide. In developed countries, increased longevity has been accompanied by a so-called “compression of morbidity” , that is, although people live longer, they do not spend more years suffering a poor health status. However, hip fracture itself may reduce life expectancy in almost two years and one in five patients will require permanent health care.
Epidemiological studies reporting the incidence of hip fracture in Spain are numerous. In most cases, they are retrospective and short-term studies, and their results have shown variations across regions. The overall incidence of hip fracture in our country, in subjects older than 65 years, have varied between 301 and 897/105 inhabitants, lower figures than reported in other European countries or in the USA.
In this paper, we critically review the main published studies in Spain on the incidence of hip fracture.

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Secular trend in the incidence of hip fractures in the world

Osteoporosis is the most common metabolic bone disease and the main effector of the development of fractures in people over 50 years. When analyzing the evolution of the incidence of hip fracture it is important to consider the effects of the implementation of the strategies undertaken to prevent and treat early forms of disease and falls.
In most chronic diseases with an environmental etiological component, identified or not, an interval of several decades occurs between initial exposure to the main causative agent and the clinical onset of the disease. The systematic study of the secular trend of a disease shows different phenomena that help to understand its pathogenesis. At the same time, it constitutes an activity of surveillance that allows warn about its future relevance.
The evolution of the incidence rate of hip fractures has not been uniform over time in different countries. It is a matter of great interest to identify whether the observed temporal changes in rates are associated with an aging population or the result of a large number of circumstances of the same population over time.
In this paper we review the main studies published around the world that explore, in greater or lesser extent, in the analysis of the secular trend in the incidence of hip fracture in order to bring this concept to the reader and offer an overview on the evolution of the incidence of hip fracture and the causes of this evolution.

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Summary Annual Congress of American Society for Bone and Mineral Research 2015. A subjective overview

Introduction
This past October 2015, the annual congress of the American Society for Bone and Mineral Research (ASBMR) was held in Seattle, USA.
Those in attendance observed a constant through all the conference sessions: research aimed at finding new interrelationships in bone mineral metabolism beyond the bone itself or to better understand the patho-physiology or obtain new therapeutic resources.
SEIOMM and the Journal of Osteoporosis and Mineral Metabolism consider it interesting to provide our readers with a personal overview of the proceedings with a summary of the issues that seem most relevant and representative of current research trends in bone metabolism, as I explain below.

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