Sustained hypophosphatemia after denosumab in a patient on hemodialysis.

An 81-year-old Caucasian man who had commenced thrice weekly hemodialysis (HD) three months earlier, presented with a hip fracture, two vertebral fractures and a bone mineral density T-score of -3.6. He had received weekly iron sucrose infusions for 6 weeks and alphacalcidol on dialysis days. Although he suffered from coeliac disease and cirrhosis, he was fully ambulatory and well-nourished. He was normocalcaemic with a marginally low plasma phosphate and the PTH was 11.8 pmol/L (<2-times the upper range of the assay). In view of his severe osteoporosis, it was decided to treat him with denosumab (dmab). Laboratory assessment 2 weeks post dmab showed severe hypophosphatemia and hypocalcemia; phosphate 0.11 mmol/L and ionized calcium 0.83 mmol/L, and he was admitted for intravenous phosphate infusion. Three months later he remained on a phosphate supplement. The case illustrates that, in addition to the risks of hypocalcemia in patients with kidney failure and high bone turnover, kidney failure patients without evidence of high bone turnover, can also be at risk of hypocalcemia and severe hypophosphatemia requiring acute hospitalization and phosphate infusion. The potential role of compromised phosphate absorption versus increased deposition will be discussed. We recommend a cautious approach to dmab therapy in patients on dialysis, with evaluation of bone turnover and serum phosphate levels prior to initiation of treatment.

Newly Diagnosed Celiac Disease and Bone Health in Young Adults: A Systematic Literature Review.

Celiac disease (CD), a gluten-induced autoimmune disease, is associated with low bone mineral density (BMD) among children. Unfortunately, it is often diagnosed in adulthood, which may lead to an increased risk of fragile bones. The aim of this systematic review was to report on BMD status among young adults newly diagnosed with CD, and to examine the effect of a gluten-free diet (GFD), nutritional supplements, such as vitamin D, or antiresorptive medications on BMD recovery. Databases searched were Medline, Embase, and Cochrane Library up to July 2nd, 2020. Both observational studies and clinical trials were considered, if patients were newly diagnosed and between 20 and 35 years of age and reported on BMD. We critically appraised the identified studies using ROBINS-I and summarized the findings narratively. Out of 3991 references, we identified 3 eligible studies: one cross-sectional study and two longitudinal studies. In total, 188 patients were included, and the study population consisted primarily of women with an age range between 29 and 37 years old. Compared to healthy controls, our target population had lower BMD. Moreover, a strict GFD may increase BMD during a follow-up period of up to 5 years. Newly diagnosed CD patients aged 20-35 years are at risk of lower BMD. Therefore, it may be crucial to assess BMD at time of diagnosis in young women. Whether the results can be extrapolated to young men is unknown. While strict GFD may improve BMD over time, there is a lack of robust evidence to demonstrate that nutritional supplements or antiresorptive agents are beneficial in the prevention of fragile bones in this age group.

Assessing Health Consequences of Vitamin D Fortification Utilizing a Societal Experiment Design: Methodological Lessons Learned from the D-Tect Project.

By utilizing historical changes in Danish legislation related to mandatory vitamin D fortification of margarine, which was implemented in the mid 1930s and abruptly abandoned in June 1985, the studies in the D-tect project investigated the effects of vitamin D on health outcomes in individuals, who during gestation were exposed or unexposed to extra vitamin D from fortified margarine. This paper reviews and narratively summarizes the analytic approaches alongside the results of the societal fortification experiment studies from the D-tect project and addresses the challenges in designing societal experiment studies and evaluating their results. The latter are discussed as lessons learned that may be useful for designers of similar studies, expected to be extensively utilized while researching the health consequences of the COVID-19 pandemic by comparing individuals born before and after the epidemic. In the D-tect project, 16 articles based on the societal fortification experiment were published analyzing 10 different outcomes and using different statistical approaches. Lessons learned included the detail of the analysis of the historical information on the exposure, availability and validity of the outcome data, variety of analytical approaches, and specifics concerning vitamin D effect evaluation, such as consideration of the influence of sunshine or season. In conclusion, the D-tect project clearly demonstrated the cost-effectiveness and research potential of natural- or societal-experiment-based studies.

The Latest Evidence from Vitamin D Intervention Trials for Skeletal and Non-skeletal Outcomes.

Vitamin D has long been considered a central part of the treatment paradigm for osteoporosis. Initial studies in high-risk populations with widespread vitamin D deficiency found a reduction of both vertebral and non-vertebral fractures. Subsequent studies in the general population have yielded mixed but mostly disappointing results both for skeletal and especially non-skeletal outcomes. Recent sequential trial meta-analyses suggest that future studies are likely to be futile given the overall disappointing result. However, mega-trials are still in progress, and additional results have been released. This narrative review aims to evaluate new literature to determine if there has been any substantial change in the message. In conclusion, there is no longer a strong case for initiating vitamin D alone trials in the general adult population, irrespective of age and gender, for significant health outcomes such as fractures, cardiovascular disease and cancer. New studies should focus on risk groups and take directions from the Heaney criteria for evaluation of threshold nutrients. Indeed, real benefits may still be reaped by directing vitamin D supplementation to persons with proven or likely vitamin D deficiency. Further, the role of dietary calcium as a critical co-nutrient remains controversial and could contribute to the discrepancy between studies in terms of cancer outcomes and possibly falls and fractures.

[Phytoestrogens as a dietary supplement].

Phytoestrogens (PE) are widely used as a dietary supplement. PE affect oestrogen receptors. PE have been investigated regarding menopausal hot flushes, bone mineral density and prostate hyperplasia/cancer. It seems consistent, that PE increase bone mineral density, whereas the effect on hot flushes is controversial. Due to the effect on oestrogen receptors, concerns exist on the risk of cancer and venous thromboembolism related to the intake of PE. To date, no studies with PE have been large enough to clarify their safety. Widespread use of PE should therefore be discouraged.

The calcium and vitamin D controversy.

Areas of the world where vitamin D levels are low for months of the year and intakes of calcium are high have a high prevalence of osteoporosis and cardiovascular disease. This suggests a public health message of avoiding calcium supplements and increasing vitamin D intake. No message could be more welcome as vitamin D can be given as a bolus while calcium must be taken daily and may be poorly tolerated. This approach is based on no evidence from intervention studies. Randomized controlled trials (RCTs) suggest that vitamin D given with calcium elicits a small reduction in fracture risk and deaths. This has not been demonstrated for D given alone. The cardiovascular safety of calcium and vitamin D (CaD) supplements is difficult to ascertain due to weaknesses in RCT designs and adjudication that cannot be remedied by subanalysis. Moreover, no major new RCTs are in process to provide better evidence. It remains unclear that calcium from dietary sources has health advantages over supplements. Benefits may be confined to patients with poor nutritional intake and the small effects at societal levels may be derived from large effects in a small number of patients. This has been impossible to confirm given the limited information about baseline vitamin D and calcium status at entry into trials. Future intervention studies should carefully capture baseline characteristics as these may determine the strength of the response, and make more efficient use of randomization strategies allowing subsequent disassembly or subanalyses while maintaining balancing. Though large clinical RCTs currently evaluate the effects of higher vitamin D doses (equivalent to 50-83 µg/d) there is no current research effort regarding the calcium controversy. In the absence of such studies it is not possible to provide clinicians with evidence-based recommendations regarding the best use of CaD supplementation.

Prenatal exposure to vitamin D from fortified margarine and risk of fractures in late childhood: period and cohort results from 222 000 subjects in the D-tect observational study.

Prenatal low vitamin D may have consequences for bone health. By means of a nationwide mandatory vitamin D fortification programme, we examined the risk of fractures among 10-18-year-old children from proximate birth cohorts born around the date of the termination of the programme. For all subjects born in Denmark during 1983-1988, civil registration numbers were linked to the Danish National Patient Registry for incident and recurrent fractures occurring at ages 10-18 years. Multiplicative Poisson models were used to examine the association between birth cohort and fracture rates. The variation in fracture rates across birth cohorts was analysed by fitting an age-cohort model to the data. We addressed the potential modification of the effect of vitamin D availability by season of birth. The risk of fractures was increased among both girls and boys who were born before the vitamin D fortification terminated in 1985 (rate ratio (RR) exposed v. non-exposed girls: 1·15 (95 % CI 1·11, 1·20); RR exposed v. non-exposed boys: 1·11 (95 % CI 1·07, 1·14). However, these associations no longer persisted after including the period effects. There was no interaction between season of birth and vitamin D availability in relation to fracture risk. The study did not provide evidence that prenatal exposure to extra vitamin D from a mandatory fortification programme of 1·25 µg vitamin D/100 g margarine was sufficient to influence the risk of fractures in late childhood, regardless of season of birth. Replication studies are needed.

Nutrient and food intakes in early life and risk of childhood fractures: a systematic review and meta-analysis.

BACKGROUND: The identification of detrimental dietary patterns early in life may contribute to reducing the high incidence of fracture among healthy children. However, information based on a systematic review of the effect of various dietary foods and nutrients on fracture risk is lacking. OBJECTIVE: We conducted a systematic review and meta-analysis of observational studies that examined the association between dietary intake or serum nutritional concentrations and childhood fractures. DESIGN: Studies published up until June 2015 were identified on the basis of a literature search in Medline, Web of Science, and Scopus databases and by hand searching references by first author based on predefined inclusion criteria. A meta-analysis was carried out for case-control studies that examined differences in mean calcium intake in the case compared with the control group. Random-effects analysis was performed on the basis of the effect estimates derived as the differences in mean calcium intakes between cases and controls. RESULTS: From a total of 1960 articles, we identified 18 observational studies, which were primarily case-control in design. Randomized controlled trials were absent, potentially because of unethical aspects related to the enrollment of children randomly assigned to certain dietary exposures and later fracture rates. Overall, fracture risk seemed to be associated with milk avoidance, high energy intake, high cheese intake, high intake of sugar-sweetened beverages, and no breastfeeding. The pooled effect size of the 9 case-control studies that examined mean calcium intake, which had appropriate data for the meta-analysis, showed no association (P = 0.99) with fair heterogeneity (I(2) = 69.3%, P = 0.001) with the use of the random-effects model. CONCLUSIONS: On the basis of a systematic review of studies that were judged to be of high or medium quality, there is an indication that some nutritional factors seem to be associated with an increased fracture risk among children. The results may be inflated by selection bias, bias in diet reporting, or residual confounding. More high-quality longitudinal observational or intervention studies are needed on the subject.

Vitamin D insufficiency is associated with increased risk of first-trimester miscarriage in the Odense Child Cohort.

BACKGROUND: Miscarriage is the most common negative outcome of pregnancy, and identification of modifiable risk factors is potentially of great importance for public health. Low vitamin D concentrations in pregnancy are widespread worldwide, and vitamin D deficiency is implicated in immune cell regulation at the feto-maternal interface and several diseases of pregnancy. OBJECTIVE: We investigated whether 25-hydroxyvitamin D serum concentration was a modifiable risk factor for early miscarriage. DESIGN: In a prospective cohort study of 1683 pregnant women donating serum before gestational week 22, we investigated the association between maternal serum concentrations of serum 25-hydroxyvitamin D [25(OH)D] and the risk of subsequent miscarriage (n = 58). RESULTS: The adjusted hazard of first-trimester miscarriage was lower with higher 25(OH)D concentrations (HR: 0.98; 95% CI: 0.96, 0.99). Concentrations of 25(OH)D <50 nmol/L were associated with a >2-fold increased adjusted HR for miscarriage (HR: 2.50; 95% CI: 1.10, 5.69). Concentrations of 25(OH)D were not associated with an increased risk of second-trimester miscarriage. CONCLUSIONS: We found an association between 25(OH)D and first-trimester miscarriages, suggesting vitamin D as a modifiable risk factor for miscarriage. To test this hypothesis, randomized controlled trials should investigate the possible effect of vitamin D supplementation to increase 25(OH)D concentrations in early pregnancy, or before conception, to decrease risk of miscarriage. This trial was registered at clinicaltrials.gov as NCT02434900.

Status of drug development for the prevention and treatment of osteoporosis.

INTRODUCTION: The metabolic bone disease osteoporosis is a growing health and health-economic problem worldwide. Bisphosphonates are the most widely used antiresorptive medication and the de facto gold standard in fracture prophylaxis all over the world, in conjunction with calcium and vitamin D supplementation. Several new medications for the treatment of postmenopausal osteoporosis are in the pipeline. AREAS COVERED: The authors present the most recent studies on new and current antiresorptive as well as anabolic drugs. Specifically, the authors present the current knowledge on drugs directed against cathepsin K and sclerostin as well as the new pathways of interest from preclinical studies. EXPERT OPINION: New scientific results have identified novel signaling pathways as potential targets for future development of anti-osteoporotic drugs. The treatments close to marketing at the moment are odanacatib and romosozumab and these are both promising new medications based on bone mineral density results, safety profile and administration. Theoretically, romosozumab may hold the potential to be a drug to 'cure' even advanced stages of osteoporosis with short-term treatment. However, safety, fracture data and cost are key elements that will determine the extent of use.

The influence of early exposure to vitamin D for development of diseases later in life.

BACKGROUND: Vitamin D deficiency is common among otherwise healthy pregnant women and may have consequences for them as well as the early development and long-term health of their children. However, the importance of maternal vitamin D status on offspring health later in life has not been widely studied. The present study includes an in-depth examination of the influence of exposure to vitamin D early in life for development of fractures of the wrist, arm and clavicle; obesity, and type 1 diabetes (T1D) during child- and adulthood. METHODS/DESIGN: The study is based on the fact that in 1961 fortifying margarine with vitamin D became mandatory in Denmark and in 1972 low fat milk fortification was allowed. Apart from determining the influences of exposure prior to conception and during prenatal life, we will examine the importance of vitamin D exposure during specific seasons and trimesters, by comparing disease incidence among individuals born before and after fortification. The Danish National databases assure that there are a sufficient number of individuals to verify any vitamin D effects during different gestation phases. Additionally, a validated method will be used to determine neonatal vitamin D status using stored dried blood spots (DBS) from individuals who developed the aforementioned disease entities as adults and their time and gender-matched controls. DISCUSSION: The results of the study will contribute to our current understanding of the significance of supplementation with vitamin D. More specifically, they will enable new research in related fields, including interventional research designed to assess supplementation needs for different subgroups of pregnant women. Also, other health outcomes can subsequently be studied to generate multiple health research opportunities involving vitamin D. Finally, the results of the study will justify the debate of Danish health authorities whether to resume vitamin D supplementation policies.

The role of vitamin D supplementation in patients with rheumatic diseases.

Vitamin D is a dietary vitamin that can also be synthesized in adequate amounts from cholesterol in most mammals exposed to sunlight. Vitamin D has classical roles in calcium and phosphate metabolism, and thus the skeleton; however, this molecule also has nonclassical effects that might influence the function of the immune, cardiovascular and endocrine systems. Vitamin D deficiency, due to insufficient sunlight exposure, dietary uptake and/or abnormalities in its metabolism, has been associated with rheumatic diseases, and both the classical and nonclassical effects of vitamin D might be of relevance to patients with rheumatic disease. However, conclusive data from intervention trials demonstrating the relationship between vitamin D levels and pathogenetic processes separate from classical effects of this molecule are lacking. Furthermore, the majority of studies linking vitamin D to health outcomes, harmful or beneficial, are observational in nature, linking clinical events to vitamin D exposure or serum levels of vitamin D metabolites. Evidence from high quality, prospective, double-blind, placebo-controlled, randomized trials should be obtained before vitamin D supplementation is recommended in the treatment of the many rheumatic conditions in which deficiency of this compound has been implicated. Herein, we review the evidence for vitamin D supplementation in the management of patients with rheumatic diseases.

[Diagnosing and treating osteoporosis in patients with chronic obstructive pulmonary disease]. / Udredning og behandling af osteoporose hos patienter med kronisk obstruktiv lungesygdom.

Patients with chronic obstructive pulmonary disease have a high risk of osteoporosis and fractures. We present an algorithm for the prevention and treatment of osteoporosis in patients with chronic obstructive pulmonary disease.

Technology evaluation: denosumab, Amgen.

Amgen, as part of its program targeting the RANK/RANKL/ osteoprotegerin pathway, is developing denosumab, a fully human monoclonal antibody, delivered subcutaneously, targeting the receptor activator of nuclear factor-kappaB ligand, for the potential treatment of diseases associated with bone loss, such as osteoporosis and bone metastases. The antibody is currently undergoing phase III clinical trials.

Are effects of MTHFR (C677T) genotype on BMD confined to women with low folate and riboflavin intake? Analysis of food records from the Danish osteoporosis prevention study.

We have previously found BMD and fracture risk to be significantly associated with the MTHFR (C677T) polymorphism in healthy postmenopausal women in the first years after menopause. Since then, other cohort studies have suggested that sufficient intake of riboflavin and/or folate may have the potential to prevent development of low BMD in women with the TT genotype. This could to some extent explain why this polymorphism is associated with low BMD or fracture in some study populations and not in others. It would also indicate that fractures associated with the TT genotype could be preventable by vitamin B supplementation. We have, therefore, reviewed baseline food record data from our original study to determine if BMD and fracture associations with the MTHFR genotype depended on the intake of folate, riboflavin, or other members of the vitamin B complex, associated with homocysteine metabolism. We analyzed genotype, BMD, and dietary records from 1700 healthy postmenopausal women who participated in the DOPS study. For the assessment of fracture risk, we used longitudinal observations from 854 women in the control group who remained compliant with their initial allocation of no treatment. Riboflavin intake was significantly correlated with femoral neck (FN) BMD in women with the TT genotype (r = 0.24, P < 0.01). FN and lumbar spine (LS) BMD were only associated with the MTHFR genotype in the lowest quartile of riboflavin intake. At the FN, similar threshold effects were shown for folate, vitamin B12, and vitamin B6. Among these vitamin B complex members, stepwise regression analysis identified riboflavin as the only significant predictor of FN BMD in the TT genotype. In conclusion, we confirm reports that BMD in the MTHFR TT genotype is only significantly reduced in the lowest quartile of riboflavin, B12, B6, and folate intake, at least at the time of menopause. Vitamin B supplementation would only be expected to benefit BMD in about 2% of the population, i.e., those with the TT genotype and low vitamin B intake.