Extraskeletal benefits and risks of calcium, vitamin D and anti-osteoporosis medications

Drugs used for the prevention and the treatment of osteoporosis exert various favourable and unfavourable extra-skeletal effects whose importance is increasingly recognized notably for treatment selection. INTRODUCTION: The therapeutic armamentarium for the prevention and the treatment of osteoporosis is increasingly large, and possible extra-skeletal effects of available drugs could influence the choice of a particular compound. METHODS: The present document is the result of a national consensus, based on a systematic and critical review of the literature. RESULTS: Observational research has suggested an inverse relationship between calcium intake and cardiovascular diseases, notably through an effect on blood pressure, but recent data suggest a possible deleterious effect of calcium supplements on cardiovascular risk. Many diverse studies have implicated vitamin D in the pathogenesis of clinically important non-skeletal functions or diseases, especially muscle function, cardiovascular disease, autoimmune diseases and common cancers. The possible effects of oral or intravenous bisphosphonates are well-known. They have been associated with an increased risk of oesophageal cancer or atrial fibrillation, but large-scale studies have not found any association with bisphosphonate use. Selective oestrogen receptor modulators have demonstrated favourable or unfavourable extra-skeletal effects that vary between compounds. Strontium ranelate has a limited number of non-skeletal effects. A reported increase in the risk of venous thromboembolism is not found in observational studies, and very rare cases of cutaneous hypersensitivity reactions have been reported. Denosumab has been introduced recently, and its extra-skeletal effects still have to be assessed. CONCLUSION: Several non-skeletal effects of bone drugs are well demonstrated and influence treatment choices

On order and disorder during the COVID-19 pandemic

Funding: Canadian Institute for Advanced Research.In this paper, we analyse the conditions under which the COVID‐19 pandemic will lead either to social order (adherence to measures put in place by authorities to control the pandemic) or to social disorder (resistance to such measures and the emergence of open conflict). Using examples from different countries (principally the United Kingdom, the United States, and France), we first isolate three factors which determine whether people accept or reject control measures. These are the historical context of state‐public relations, the nature of leadership during the pandemic and procedural justice in the development and operation of these measures. Second, we analyse the way the crisis is policed and how forms of policing determine whether dissent will escalate into open conflict. We conclude by considering the prospects for order/disorder as the pandemic unfolds.Publisher PDFPeer reviewe

Efficacy of teriparatide compared with risedronate on FRAX®-defined major osteoporotic fractures. results of the VERO clinical trial

Summary: FRAX® calculates the 10-year probability of major osteoporotic fractures (MOF), which are considered to have a greater clinical impact than other fractures. Our results suggest that, in postmenopausal women with severe osteoporosis, those treated with teriparatide had a 60% lower risk of FRAX®-defined MOF compared with those treated with risedronate. Introduction: The VERO trial was an active-controlled fracture endpoint clinical trial that enrolled postmenopausal women with severe osteoporosis. After 24 months, a 52% reduction in the hazard ratio (HR) of clinical fractures was reported in patients randomized to teriparatide compared with risedronate. We examined fracture results restricted to FRAX®-defined major osteoporotic fractures (MOF), which include clinical vertebral, hip, humerus, and forearm fractures. Methods: In total, 1360 postmenopausal women (mean age 72.1 years) were randomized to receive subcutaneous daily teriparatide (20 μg) or oral weekly risedronate (35 mg). Patient cumulative incidence of ≥ 1 FRAX®-defined MOF and of all clinical fractures were estimated by Kaplan-Meier analyses, and the comparison between treatments was based on the stratified log-rank test. Additionally, an extended Cox model was used to estimate HRs at different time points. Incidence fracture rates were estimated at each 6-month interval. Results: After 24 months, 16 (2.6%) patients in the teriparatide group had ≥ 1 low trauma FRAX®-defined MOF compared with 40 patients (6.4%) in the risedronate group (HR 0.40; 95% CI 0.23–0.68; p = 0.001). Clinical vertebral and radius fractures were the most frequent FRAX®-defined MOF sites. The largest difference in incidence rates of both FRAX®-defined MOF and all clinical fractures between treatments occurred during the 6- to 12-month period. There was a statistically significant reduction in fractures between groups as early as 7 months for both categories of clinical fractures analyzed. Conclusion: In postmenopausal women with severe osteoporosis, treatment with teriparatide was more efficacious than risedronate, with a 60% lower risk of FRAX®-defined MOF during the 24-month treatment period. Fracture risk was statistically significantly reduced at 7 months of treatment. Clinical trial information: ClinicalTrials.gov Identifier: NCT01709110 EudraCT Number: 2012-000123-41

The role of bisphosphonates in breast cancer: The present and future role of bisphosphonates in the management of patients with breast cancer

At least 25% of patients with breast cancer develop skeletal metastases, with bone the site of disease producing the greatest morbidity. It is apparent that the bisphosphonates present an important component of the treatment strategy. They are now the treatment of choice in tumour-induced hypercalcaemia, and they can reduce bone pain and skeletal complications such as pathological fractures. In addition, bisphosphonates are being increasingly evaluated in the prevention of bone metastases and to prevent and treat cancer therapy-induced osteoporosis. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate

Additive growth inhibitory effects of ibandronate and antiestrogens in estrogen receptor-positive breast cancer cell lines

INTRODUCTION: Bisphosphonates are inhibitors of osteoclast-mediated tumor-stimulated osteolysis, and they have become standard therapy for the management of bone metastases from breast cancer. These drugs can also directly induce growth inhibition and apoptosis of osteotropic cancer cells, including estrogen receptor-positive (ER+) breast cancer cells. METHODS: We examined the anti-proliferative properties of ibandronate on two ER+ breast cancer cell lines (MCF-7 and IBEP-2), and on one ER negative (ER-) cell line (MDA-MB-231). Experiments were performed in steroid-free medium to assess ER regulation and the effect of ibandronate in combination with estrogen or antiestrogens. RESULTS: Ibandronate inhibited cancer cell growth in a dose- and time-dependent manner (approximate IC(50): 10(-4 )M for MCF-7 and IBEP-2 cells; 3 × 10(-4 )M for MDA-MB-231 cells), partly through apoptosis induction. It completely abolished the mitogenic effect induced by 17β-estradiol in ER+ breast cancer cells, but affected neither ER regulation nor estrogen-induced progesterone receptor expression, as documented in MCF-7 cells. Moreover, ibandronate enhanced the growth inhibitory action of partial (4-hydroxytamoxifen) and pure (ICI 182,780, now called fluvestrant or Faslodex™) antiestrogens in estrogen-sensitive breast cancer cells. Combination analysis identified additive interactions between ibandronate and ER antagonists. CONCLUSION: These data constitute the first in vitro evidence for additive effects between ibandronate and antiestrogens, supporting their combined use for the treatment of bone metastases from breast cancer

Morpho-syntactic processing of Arabic plurals after aphasia: dissecting lexical meaning from morpho-syntax within word boundaries

Within the domain of inflectional morpho-syntax, differential processing of regular and irregular forms has been found in healthy speakers and in aphasia. One view assumes that irregular forms are retrieved as full entities, while regular forms are compiled on-line. An alternative view holds that a single mechanism oversees regular and irregular forms. Arabic offers an opportunity to study this phenomenon, as Arabic nouns contain a consonantal root, delivering lexical meaning, and a vocalic pattern, delivering syntactic information, such as gender and number. The aim of this study is to investigate morpho-syntactic processing of regular (sound) and irregular (broken) Arabic plurals in patients with morpho-syntactic impairment. Three participants with acquired agrammatic aphasia produced plural forms in a picture-naming task. We measured overall response accuracy, then analysed lexical errors and morpho-syntactic errors, separately. Error analysis revealed different patterns of morpho-syntactic errors depending on the type of pluralization (sound vs broken). Omissions formed the vast majority of errors in sound plurals, while substitution was the only error mechanism that occurred in broken plurals. The dissociation was statistically significant for retrieval of morpho-syntactic information (vocalic pattern) but not for lexical meaning (consonantal root), suggesting that the participants' selective impairment was an effect of the morpho-syntax of plurals. These results suggest that irregular plurals forms are stored, while regular forms are derived. The current findings support the findings from other languages and provide a new analysis technique for data from languages with non-concatenative morpho-syntax

Joint analysis of left ventricular expression and circulating plasma levels of Omentin after myocardial ischemia

BACKGROUND: Omentin-1, also known as Intelectin-1 (ITLN1), is an adipokine with plasma levels associated with diabetes, obesity, and coronary artery disease. Recent studies suggest that ITLN1 can mitigate myocardial ischemic injury but the expression of ITLN1 in the heart itself has not been well characterized. The purpose of this study is to discern the relationship between the expression pattern of ITLN1 RNA in the human heart and the level of circulating ITLN1 protein in plasma from the same patients following myocardial ischemia. METHODS: A large cohort of patients (n = 140) undergoing elective cardiac surgery for aortic valve replacement were enrolled in this study. Plasma and left ventricular biopsy samples were taken at the beginning of cardiopulmonary bypass and after an average of 82 min of ischemic cross clamp time. The localization of ITLN1 in epicardial adipose tissue (EAT) was also further characterized with immunoassays and cell fate transition studies. RESULTS: mRNA expression of ITLN1 decreases in left ventricular tissue after acute ischemia in human patients (mean difference 280.48, p = 0.001) whereas plasma protein levels of ITLN1 increase (mean difference 5.24, p \u3c 0.001). Immunohistochemistry localized ITLN1 to the mesothelium or visceral pericardium of EAT. Epithelial to mesenchymal transition in mesothelial cells leads to a downregulation of ITLN1 expression. CONCLUSIONS: Myocardial injury leads to a decrease in ITLN1 expression in the heart and a corresponding increase in plasma levels. These changes may in part be due to an epithelial to mesenchymal transition of the cells that express ITLN1 following ischemia. Trial Registration Clinicaltrials.gov ID: NCT00985049