Nutrients are essential to the viability of all cells, including those in bone. Osteoporosis has been called a pediatric disorder because adult peak bone mass is largely determined during childhood. Bone mass is ultimately determined by genetics as modified by current and past mechanical loading and limited or permitted by nutrition. Recommended food patterns around the world attempt to meet national nutrient requirements and to promote health and reduce risk of disease. Bone health rests on a combination of mechanical loading and adequate intakes of a broad array of macro- and micronutrients. Three important essential nutrients for bone health are calcium, vitamin D, and protein. Optimal protection of bone requires a diet rich in all the essential nutrients. Mononutrient supplementation regimens will often be inadequate to ensure optimal nutritional protection of bone health. Some bioactive ingredients may improve bone health by reducing chronic inflammation.

Vitamin D deficiency has been shown to be associated with many adverse health problems. Studies have shown that patients with Crohn's disease who have low vitamin D levels have a poorer quality of life than those with more adequate levels. It has also been shown that patients with mal-absorption problems have a difficult time achieving normal vitamin D levels in spite of aggressive supplementation, and that exposure to UVB radiation may be the most effective treatment option for these patients. We present a case in which 25-hydroxyvitamin D levels were normalized within 2 weeks in a severely vitamin D deficient patient with Crohn's disease with mal-absorption and a new ileostomy, utilizing sublingually administered vitamin D2. A 58 year-old white female was admitted with a new ileostomy following partial bowel resection due to complications from Crohn's disease. She was found to be severely vitamin D deficient at the time of admission, with a level of 6.1 ng/ml on hospital day 3. Her treatment with vitamin D was delayed for a few days. She was initially treated with 5000 units of vitamin D3 orally twice a day for 3 days (days 7-10). After discussion with the patient and obtaining her consent, vitamin D3 was stopped, and she was then treated with a total of 8 doses of 50,000 units of vitamin D2 administered sublingually. She was given the first 3 doses on alternating days (days 11,13,15), and then 5 more doses on consecutive days (days 17-21). The rise in her 25-hydroxyvitamin D level in response to treatment with sublingual vitamin D2 was significant. On day 10, after receiving 3 days of orally administered vitamin D3, her level was 9.8 ng/ml. One week later, after receiving 3 sublingual doses of vitamin D2, it rose to 20.3 ng/ml. It was then measured on alternating days twice over the next 4 days, and it rose to 45.5 ng/ml, and then to 47.4 ng/ml on the day of discharge to home. The major finding of this study is that sublingual administration of vitamin D2 appears to work effectively when intestinal absorption is impaired. The optimal dosing regimen still needs to be determined for the average Crohn's disease patient. (C) 2017 Elsevier Ltd. All rights reserved.

In 1986, David Barker, a British epidemiologist, noted a connection between small infant birth size and risk of heart disease later in adult life.1 The theory that certain adult-onset diseases might have their roots in nutritional insults sustained in the perinatal period (either in utero or in the early months of infancy—or perhaps both) has since been known as “the Barker hypothesis” or sometimes “The Fetal Origins Hypothesis.” The original association between undernutrition in utero and late-life heart disease has been difficult to confirm, but the idea that early-life influences can have important downstream consequences is intuitively attractive and is supported by such concrete instances as perinatal thyroid function (and, its cognate, adequate dietary iodine), which is absolutely essential for early-life brain development and maturation. Perinatal iodine deficiency and hypothyroidism from any cause are recognized as important contributors worldwide to mental retardation and learning disabilities during childhood and adult life. In this example, iodine deficiency and its consequences certainly qualify as an outspoken instance of the Barker hypothesis in operation. A critical feature of diseases occurring by way of the Barker hypothesis is the nutritional irreversibility of the long-latency disorders that result. Beyond certain critical points in development, full nutrient repletion is not able to offset or reverse the early inadequacy. This irreversibility is the major stimulus for the better elucidation of these disorders, leading to emphasis on the imperative of early-life preventive nutrition. The Barker hypothesis has been elaborated and evaluated in several reviews,2–4 but to the best of my knowledge, there has been no attempt to evaluate the hypothesis specifically for vitamin D. Thus, what I propose to explore in this very brief review is the evidence relating unrecognized, perinatal vitamin D inadequacy to increased risk of certain chronic diseases later in life, that is, to ascertain whether any such effects might be an instance of the “Barker hypothesis.” I deliberately avoid use of labels such as “deficient” or “insufficient” in characterizing vitamin D status, as these terms are often linked to specific values for serum 25-hydroxyvitamin D [25(OH)D], about which there is considerable controversy. Instead, I use terms such as “low” or “inadequate,” referencing in each such use prevailing values for vitamin D status or input relative to values found in those individuals who do not manifest the disorders concerned. I defer until the end of this review consideration of the actual, numerical range of vitamin D status values that appears to permit avoidance of the Barker effect if it is present. Also, it is important to be clear that I am not including in this exploration the well-known downstream skeletal effects of classic rickets, for example, the pelvic deformation that is considered to have been a major factor in the evolution of pale skin for populations living in, or migrating to, high latitudes. Rickets in childhood is a serious disorder and fortunately is evident and both preventable and treatable. Instead, where I focus here is on the nonskeletal consequences both of untreated rickets and of lesser degrees of vitamin D inadequacy, often not clinically apparent and occurring at critical periods during maturation, in some instances well before the life stages when rickets is typically manifest. For most of the disorders concerned, etiology is almost always multi-factorial. The relation to vitamin D inadequacy should be understood simply as just one of the conditions that, when met, together lead to expression of the diseases concerned. Removing that single factor will not usually be expected completely to eradicate the disease of interest, but will reduce its expression at a population level. For the handful of diseases discussed in what follows, the extent of that risk reduction appears to be large enough to demand serious attention, including more research.

Sixteen years ago, the National Osteoporosis Foundation (NOF) published a review of peak bone mass and of the factors that influence it [1]. In the ensuing years, literally hundreds of studies have been published on the topics of peak bone mass, its timing, and its contributing factors. A recent article in this journal contains the results of NOF’s effort at bringing that earlier review up-to-date [2]. It is useful to recall, in 2016, that both the current and the earlier reviews were based on two premises: (1) other things being equal, a more massive bone is structurally stronger than a more flimsy bone; and (2) bone mass in the adult years is influenced by how much bone an individual has been able to acquire during growth. This accumulated mass is designated Bpeak^ because it is the highest value an individual will normally accumulate over the course of his or her life. Put together, these premises postulate that going into the adult years having a greater bone mass provides useful protection from late life fragility fractures. It is the conjunction of these two premises that undergirds the concern about maximizing bone mass during growth. An unexamined presumption in both reviews (and in many of the research studies they summarize) is that bone mineral density (BMD), as measured by dual energy absorptiometry (DXA), adequately captures the amount of bone (i.e., bone mass) an individual has. Accordingly, measured peak BMD is commonly treated as effectively equivalent to peak bone mass. As a moment’s reflection will suffice to show, and as has been pointed out elsewhere [3], that presumption is incorrect. Density is not mass, but is, rather, mass per unit volume [or, with DXA, mass per unit area of the X-Ray shadow cast by the bone(s) being measured]. It is true that measured values for mass and density are often positively correlated. But that is hardly surprising, as mass is formally incorporated into the definition and measurement of density (i.e., see above). But correlation does not establish identity. It is important to make this distinction, as bone growth during maturation involves both accumulations of bone mass and expansion of bone volume [3, 4], two processes not always occurring in parallel. Thus, density can appear to decrease during some phases of growth at the same time as mass is increasing [3, 4]. Clark and colleagues [5, 6], cited in the current review, are careful to dissect apart the components of BMD prior to searching for correlations with putative causes. Not all authors have been so careful. Of more than passing interest today is how little the principal factors currently identified as influencing accumulation of a high peak bone mass have changed from the earlier synthesis [1], i.e., nutrition and mechanical loading (exercise). So, what then is the appropriate action outcome going forward? What is to be done? In asking ourselves this question, we are forced to confront yet another poorly examined presumption. Both the reviewers and the investigators whose work they review assume that public policy is science-driven. If policy remains unchanged, then perhaps it is because the science is not convincing enough. And the solution for that, obviously, is more research. * R. P. Heaney rheaney@creighton.edu

Higher serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with lower risk of type 2 diabetes. This study compared incidence rates of type 2 diabetes among participants aged ≥20 years in two U.S. cohorts with markedly different median 25(OH)D concentrations. The median 25(OH)D concentration in the GrassrootsHealth (GRH) cohort was 41 ng/ml (N=4933) while in the 2005-6 National Health and Nutrition Examination Survey (NHANES) it was 22 ng/ml (N=4078) (P<0.0001). The adjusted annual incidence rate of type 2 diabetes was 3.7 per 1000 population (95% confidence interval=1.9, 6.6) in the GRH cohort, compared to 9.3 per 1000 population (95% confidence interval=6.7, 12.6) in NHANES. In the NHANES cohort, the lowest 25(OH)D tertiles (<17, 17-24 ng/ml) had higher odds of developing diabetes than the highest tertile (OR: 4.9, P=0.02 and 4.8, P=0.01 respectively), adjusting for covariates. Differences in demographics and methods may have limited comparability. Raising serum 25(OH)D may be a useful tool for reducing risk of diabetes in the population.

[This corrects the article DOI: 10.1371/journal.pone.0152441.].

Parathyroid hormone (PTH), vitamin D, and magnesium interact at several levels at the whole organism level. The classical actions of PTH on bone, kidney, and gut are dependent upon adequate status of both vitamin D and magnesium. At the same time, high PTH activity increases the requirement for vitamin D and low vitamin D status is commonly associated with both subclinical magnesium deficiency and increased PTH activity.

Letters19 May 2015Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion?Arthur B. Chausmer, MD, PhDArthur B. Chausmer, MD, PhDFrom Johns Hopkins University School of Medicine, Baltimore, Maryland.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L15-5095 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:We read Heaney and Armas' editorial (1) about the assessment of and need for vitamin D supplementation with great interest. The pathologic hallmark of vitamin D insufficiency is an increase in uncalcified osteoid organic matrix in bone. The clinical hallmarks of this condition are specific findings, such as Milkman fractures, or unmineralized osteoid on undecalcified bone biopsy specimens. Neither hypocalcemia nor osteoporosis—which causes uniform loss of organic and mineralized bone and is a disorder of architecture, not calcification—is a hallmark of vitamin D deficiency. Virtually no direct clinical evidence of vitamin D deficiency in the general U.S. ...References1. Heaney RP, Armas LA. Screening for vitamin D deficiency: is the goal disease prevention or full nutrient repletion? [Editorial]. Ann Intern Med. 2015;162:144-5. [PMID: 25420050] doi:10.7326/M14-2573 LinkGoogle Scholar2. LeFevre ML; U.S. Preventive Services Task Force. Screening for vitamin D deficiency in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2015;162:133-40. [PMID: 25419853] doi:10.7326/M14-2450 LinkGoogle Scholar Author, Article, and Disclosure InformationAuthors: Arthur B. Chausmer, MD, PhDAffiliations: From Johns Hopkins University School of Medicine, Baltimore, Maryland.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterest Forms.do?msNum=L15-0126. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoScreening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion? Robert P. Heaney and Laura A.G. Armas Screening for Vitamin D Deficiency in Adults: U.S. Preventive Services Task Force Recommendation Statement Michael L. LeFevre , on behalf of the U.S. Preventive Services Task Force* Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion? Robert P. Heaney Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion? Robert P. Heaney Metrics 19 May 2015Volume 162, Issue 10Page: 738-739KeywordsBloodBoneConflicts of interestDisclosureEpidemiologyHypocalcemiaMetabolitesNutrientsVitamin DVitamin D deficiency ePublished: 19 May 2015 Issue Published: 19 May 2015 Copyright & PermissionsCopyright © 2015 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...

Despite the Institute of Medicine's commitment to base its nutrient intake recommendations in evidence, the 2004/2005 Dietary Reference Intakes for sodium were not supported by evidence, as the subsequent 2013 Institute of Medicine review admitted. In this review, I suggest an approach to setting nutrient intake requirements based in physiology. Briefly, the requirement of a given nutrient can best be said to be the intake that calls for the least adaptation or compensation by the intact organism. For sodium, evidence indicates that such an intake is typically between 3000 and 5000 mg/d.

The World Health Organization's International Agency for Research on Cancer recommends avoiding outdoor activities at midday, wearing clothing to cover the whole body, and daily use of sunscreen on usually exposed skin [1]. The American Cancer Society advocates Slip! Slop! Slap! and Wrap! to make sure skin is covered in clothing or sunscreen and to avoid exposure to the sun between 10 am and 4 pm [2]. The U.S. Surgeon General has issued a Call to Action focused on reducing ultraviolet (UV) exposure, whether from indoor UV or from the sun [3]. Though these recommendations, all focused on reduction of skin cancer, are accompanied by brief acknowledgement of the importance of vitamin D for health, they persist in urging avoidance of the sun at the precise times when vitamin D can be synthesized in the skin—the hours between 10 am and 3 pm—and suggest that all necessary vitamin D can be obtained through food and dietary supplements. These recommendations are understandable from the viewpoint of preventing the 3.5 million new cases of and 2000 deaths from nonmelanoma skin cancer in the United States each year [4], but they neglect the fact that we have a long cultural history of appreciation of the sun and use of UV radiation for healing purposes. Moreover, they neglect that we have evolved with physiological adaptations to help protect the skin from the sun [5] when we are mindful of our exposure and do not burn. They neglect the fact that increased sun exposure, based on latitude, has been associated with protection from several different types of cancer [6–15], type 1 diabetes [16], multiple sclerosis [17,18], and other diseases [19–23]. They also neglect the fact that exposure to the sun induces beneficial physiological changes beyond the production of vitamin D. Though adherence to the current sun-protective recommendations would likely result in the reduction of nonmelanoma skin cancer, that reduction would likely be overshadowed by the potential reduction in deaths from other cancers and from cardiovascular disease, which could be achieved by doubling average blood concentrations of 25-hydroxyvitamin D (25(OH)D) to 40 ng/mL through a combination of sun exposure and supplements [24]. The potential harm of sun avoidance and the neglect of its positive effects on human health led to a seminar, Vitamin D for Public Health: Integrating Sunshine, Supplements and Measurement for Optimal Health, presented by GrassrootsHealth at the University of California San Diego to inform and to help initiate an action plan to restore a more balanced approach to solar radiation based on input by the conference speakers.

The amount of dietary protein needed to prevent deficiency in most individuals is defined in the United States and Canada by the Recommended Dietary Allowance and is currently set at 0.8 g protein · kg-1 · d-1 for adults. To meet this protein recommendation, the intake of a variety of protein food sources is advised. The goal of this article is to show that commonly consumed food sources of protein are more than just protein but also significant sources of essential nutrients. Commonly consumed sources of dietary protein frequently contribute substantially to intakes of nutrients such as calcium, vitamin D, potassium, dietary fiber, iron, and folate, which have been identified as nutrients of "concern" (i.e., intakes are often lower than recommended). Despite this, dietary recommendations to reduce intakes of saturated fat and solid fats may result in dietary guidance to reduce intakes of commonly consumed food sources of protein, in particular animal-based protein. We propose that following such dietary guidance would make it difficult to meet recommended intakes for a number of nutrients, at least without marked changes in dietary consumption patterns. These apparently conflicting pieces of dietary guidance are hard to reconcile; however, we view it as prudent to advise the intake of high-quality dietary protein to ensure adequate intakes of a number of nutrients, particularly nutrients of concern.

Bone health is not a mononutrient issue. Although predominant attention has been given to calcium in recent years (with vitamin D getting honorable mention), other nutrients are also known to affect calcium economy and bone status, even if they are less commonly factored into dietary recommendations for the prevention of osteoporosis or the support of antiosteoporosis therapy. This chapter discusses sodium, potassium, phosphorus, and magnesium, and overlaps with the previous two chapters in matters of the acid/alkaline ash characteristic of the diet. Taken together, these four minerals make up about 6% of the dry, fat-free mass of the human body. Table 1 (1) presents their contributions individually, together with that of chloride and calcium—the former because chloride accompanies sodium, both in extracellular fluid and in the diet, and the latter (which is the subject of other chapters in this book) for comparative purposes.

Recently Veugelers and Ekwaru published data [1] indicating that, in its dietary reference intakes for calcium and vitamin D, the Institute of Medicine (IOM) had made a serious calculation error [2]. Using the same data set as had the IOM panel, these investigators showed that the Recommended Dietary Allowance (RDA) for vitamin D had been underestimated by an order of magnitude. Veugelers and Ekwaru, using the IOM’s data, calculated an RDA of 8895 IU per day. They noted that there was some uncertainty in that estimate, inasmuch as this value required an extrapolation from the available data, which did not include individuals receiving daily vitamin D inputs above 2400 IU/day.[...]

Vitamin D enters the body through multiple routes and in a variety of chemical forms. Utilization varies with input, demand, and genetics. Vitamin D and its metabolites are carried in the blood on a Gc protein that has three principal alleles with differing binding affinities and ethnic prevalences. Three major metabolites are produced, which act via two routes, endocrine and autocrine/paracrine, and in two compartments, extracellular and intracellular. Metabolic consumption is influenced by physiological controls, noxious stimuli, and tissue demand. When administered as a supplement, varying dosing schedules produce major differences in serum metabolite profiles. To understand vitamin D's role in human physiology, it is necessary both to identify the foregoing entities, mechanisms, and pathways and, specifically, to quantify them. This review was performed to delineate the principal entities and transitions involved in the vitamin D economy, summarize the status of present knowledge of the applicable rates and masses, draw inferences about functions that are implicit in these quantifications, and point out implications for the determination of adequacy.

Cutaneous synthesis and traditional food sources do not fully account for unsupplemented vitamin D status. Non-traditional food sources may be an undiscovered input. In a cohort of 780 non-supplement-taking adults with a mean serum 25-hydroxyvitamin D [25(OH)D] of 33 (±14)ng/ml we assessed the relationship between vitamin D status and selected food sources. Serum 25(OH)D concentration was adjusted for season, UVB exposures, and body size. These adjusted values were then regressed against multiple food items and combinations. Whole milk cottage cheese, eggs, red meat, and total protein were positively associated with total 25(OH)D and/or 25(OH)D3 (P<0.05 for each), whereas fish and milk intake were not. The slope of the relationship was such that for every intake of 1serving/day, serum 25(OH)D rose by about 2ng/ml for eggs and 1ng/ml for meat and total protein. For every weekly serving of whole milk cottage cheese, serum 25(OH)D rose by about 1ng/ml. While some food sources were significant predictors of vitamin D status, their ability to explain inter-individual variability was limited. Supplementation will likely remain essential to improving vitamin D status on a population level. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.