Hypophosphatemic Hypovitaminosis D Induces Osteomalacia in the Adult Female Rat.

Osteomalacia is a bone-demineralizing disease of adulthood, often caused by hypovitaminosis D. Current animal models of the disease mimic osteomalacia as a consequence of gastric bypass or toxic exposure to metals, but a relevant model of diet-induced osteomalacia is lacking. For that purpose, 7-month-old female Sprague Dawley rats were randomly assigned into 2 weight-stratified groups and maintained for 4 months on synthetic diets containing negligible or normal levels of vitamin D. The dietary regimen resulted in vitamin D deficiency as measured by 25-hydroxyvitamin D serum levels; however, hypovitaminosis D per se did not affect biomarkers of calcium metabolism and bone turnover, nor did it result in increased osteoid. Thus, vitamin D depletion through the diet was found to be insufficient to induce an osteomalacia-like phenotype in the adult rat. After 4 months, the phosphate content of the vitamin D-depleted diet had decreased to 0.16% (calcium:phosphorus ratio of 5.85), resulting in an osteomalacic-like condition (trabecular osteoid surface/bone surface constituted 33%; CI, 26-40). The diet change also affected both metabolic and bone turnover biomarkers, including significantly suppressing serum fibroblast growth factor 23. Furthermore, decreased dietary phosphate in a vitamin D-depleted diet led to microarchitectural changes of trabecular and cortical bone, lower bone mass density, lower bone mass content and decreased bone strength, all indicating reduced bone quality. Taken together, our results show that osteomalacia can be induced in the adult female rat by depleting vitamin D and lowering phosphate content in the diet.

Evaluation of the reported rates of hypersensitivity reactions associated with iron dextran and ferric carboxymaltose based on global data from VigiBase™ and IQVIA™ MIDAS® over a ten-year period from 2008 to 2017.

Objectives: It is hypothesized that the risk of hypersensitivity reactions (HSRs) may be lower with ferric carboxymaltose than iron dextran because of its non-dextran carbohydrate moiety. This study compares the risk of HSRs between iron dextran and ferric carboxymaltose.Methods: This was a retrospective pharmacoepidemiological study with a case-population design covering 2008-2017. Global exposure data were estimated using IQVIA™ sales data. Spontaneously reported HSR data were retrieved from the World Health Organization database (VigiBase™) using different search criteria including: the Standardized MedDRA® Query (SMQ) 'Anaphylactic reaction'; type I-IV HSR terms; narrow terms for anaphylactic/anaphylactoid reactions; and cases with a fatal outcome.Results: Total exposure in 100 mg doses was 117.3 million for iron dextran and 84.2 million for ferric carboxymaltose. The relative risk (with 95% confidence interval) for ferric carboxymaltose versus iron dextran was 4.18 (3.88-4.50) for SMQ Anaphylactic reaction; 12.9 (9.90-16.7) for type I-IV HSRs; 1.72 (1.45-2.04) for anaphylactic/anaphylactoid reactions; and 1.92 (1.24-2.99) for death.Conclusion: The risk of spontaneously reported HSRs was consistently higher with ferric carboxy-maltose than with iron dextran over the period 2008-2017. Thus, this study does not support that dextran-free intravenous irons are associated with fewer HSRs than iron dextran.

Vitamin D levels and cancer incidence in 217,244 individuals from primary health care in Denmark.

Vitamin D has been linked to cancer development in both pre-clinical and epidemiological studies. Our study examines the association between serum levels of vitamin D and cancer incidence in the Capital Region of Denmark. Individuals who had vitamin D analyzed at The Copenhagen General Practitioners Laboratory between April 2004 and January 2010 were linked to Danish registries with end of follow-up date at Dec 31st 2014, excluding individuals with pre-existing cancer. Cox regression models adjusted for age in one-year intervals, sex, month of sampling, and Charlson Comorbidity Index were applied. The study population of 217,244 individuals had a median vitamin D level of 46 nmol/L (IQR 27-67 nmol/L). Non-melanoma skin cancer was the most frequent form of cancer, followed by breast-, lung-, and prostate cancers. No associations were found between increments of 10 nmol/L vitamin D and incidence of breast, colorectal, urinary, ovary or corpus uteri cancer. However, higher levels of vitamin D were associated with higher incidence of non-melanoma (HR 1.09 [1.09-1.1]) and melanoma skin cancer (HR 1.1 [1.08-1.13]) as well as prostate (HR 1.05 [1.03-1.07]) and hematological cancers (HR 1.03 [1.01-1.06]), but with lower incidence of lung cancer (HR 0.95 [0.93-0.97]). In our study, vitamin D levels are not associated with the incidence of several major cancer types, but higher levels are significantly associated with a higher incidence of skin, prostate, and hematological cancers as well as a lower incidence of lung cancer. These results do not support an overall protective effect against cancer by vitamin D.

Inflammatory eye reactions with bisphosphonates and other osteoporosis medications: what are the risks?

Inflammatory eye reactions (IERs) are rare but have been associated with medications to treat osteoporosis. The aim of this review is to summarize the current literature on the association between IERs and specific medications to treat osteoporosis (bisphosphonates, selective estrogen receptor modulators, strontium, denosumab and teriparatide). We cover the known epidemiology, potential pathogenic mechanisms and a resume of unanswered questions. Briefly, this review highlights that none of the existing randomized clinical trials were powered to identify these rare adverse events, and the majority of the information available is from spontaneous case reports and case series reporting associations between bisphosphonates and IERs. No case reports describe IERs after other anti-osteoporosis medications. Importantly, some case reports describe recurrence of the IER after affected patients were rechallenged with the same or another bisphosphonate, and that no reported cases resolved without discontinuation of the bisphosphonate. However, three large population-based cohort studies have shown conflicting results between osteoporosis treatments and IERs, but overall these studies suggest that IERs may actually be part of underlying inflammatory disease processes that also cause osteoporosis, rather than due to the medications used to treat osteoporosis themselves. There are no clear pathogenic mechanisms for how bisphosphonates could potentially cause IERs. However, the drug is secreted into the tears by the lacrimal gland and could cause irritation to the mucous membranes with subsequent release of inflammatory mediators, similar to the systemic response typically seen after infusion of bisphosphonates. However, in summary it is still not known whether there is a true causal association between bisphosphonates or other anti-osteoporosis medications and IERs, or whether it is confounding by indication and is actually due to underlying inflammatory diseases that cause both osteoporosis and IERs.

A Reverse J-Shaped Association Between Serum 25-Hydroxyvitamin D and Cardiovascular Disease Mortality: The CopD Study.

CONTEXT: Cardiovascular disease is the major cause of death in the Western world, but the association between 25-hydroxyvitamin D [25(OH)D] levels and the risk of cardiovascular disease mortality remains unclear. OBJECTIVE: The objective of the study was to determine the association between cardiovascular, stroke, and acute myocardial infarct mortality and serum levels of 25(OH)D. DESIGN: This was an observational cohort study, the Copenhagen vitamin D study, data from a single laboratory center in Copenhagen, Denmark. Follow-up was from 2004 to 2011. SETTING: Serum 25(OH)D was analyzed from 247 574 subjects from the Copenhagen general practice sector. PARTICIPANTS: Examination of the association 25(OH)D levels and mortality from cardiovascular disease, stroke, and acute myocardial infarct was performed among 161 428 women and 86 146 men. MAIN OUTCOME MEASURES: A multivariate Cox regression analysis was used to compute hazard ratios for cardiovascular, stroke, and acute myocardial infarct mortality. RESULTS: Of 247 574 subjects, a total of 16 645 subjects died in the ensuing 0-7 years. A total of 5454 died from cardiovascular disease including 1574 from stroke and 702 from acute myocardial infarct. The 25(OH)D level of 70 nmol/L was associated with the lowest cardiovascular disease mortality risk. Compared with that level, the hazard ratio for cardiovascular disease mortality was 2.0 [95% confidence interval (CI) 1.8-2.1] at the lower extreme (∼ 12.5 nmol/L) with a higher risk for men [2.5 (95% CI 2.2-2.9)] than for women [1.7 (95% CI 1.5-1.9)]. At the higher extreme (∼ 125 nmol/L), the hazard ratio of cardiovascular disease mortality was 1.3 (95% CI 1.2-1.4), with a similar risk among men and women. Results were similar for stroke and acute myocardial subgroups. CONCLUSIONS: In this large observational study, low and high levels of 25(OH)D were associated with cardiovascular disease, stroke, and acute myocardial mortality in a nonlinear, reverse J-shaped manner, with the highest risk at lower levels. Whether this was a causal or associational finding cannot be determined from our data. There is a need for randomized clinical trials that include information on the effects of 25(OH)D levels greater than 100 nmol/L.

Attributable hospital cost and length of stay associated with health care-associated infections caused by antibiotic-resistant gram-negative bacteria.

Determination of the attributable hospital cost and length of stay (LOS) are of critical importance for patients, providers, and payers who must make rational and informed decisions about patient care and the allocation of resources. The objective of the present study was to determine the additional total hospital cost and LOS attributable to health care-associated infections (HAIs) caused by antibiotic-resistant, gram-negative (GN) pathogens. A single-center, retrospective, observational comparative cohort study was performed. The study involved 662 patients admitted from 2000 to 2008 who developed HAIs caused by one of following pathogens: Acinetobacter spp., Enterobacter spp., Escherichia coli, Klebsiella spp., or Pseudomonas spp. The attributable total hospital cost and LOS for HAIs caused by antibiotic-resistant GN pathogens were determined by comparison with the hospital costs and LOS for a control group with HAIs due to antibiotic-susceptible GN pathogens. Statistical analyses were conducted by using univariate and multivariate analyses. Twenty-nine percent of the HAIs were caused by resistant GN pathogens, and almost 16% involved a multidrug-resistant GN pathogen. The additional total hospital cost and LOS attributable to antibiotic-resistant HAIs caused by GN pathogens were 29.3% (P < 0.0001; 95% confidence interval, 16.23 to 42.35) and 23.8% (P = 0.0003; 95% confidence interval, 11.01 to 36.56) higher than those attributable to HAIs caused by antibiotic-susceptible GN pathogens, respectively. Significant covariates in the multivariate analysis were age >or=12 years, pneumonia, intensive care unit stay, and neutropenia. HAIs caused by antibiotic-resistant GN pathogens were associated with significantly higher total hospital costs and increased LOSs compared to those caused by their susceptible counterparts. This information should be used to assess the potential cost-efficacy of interventions aimed at the prevention of such infections.