More than metabolic: Considering the broader paleoepidemiological impact of vitamin D deficiency in bioarchaeology

Vitamin D deficiency has traditionally been viewed as a metabolic bone disease by bioarchaeologists and considered primarily in terms of the development of specific musculoskeletal changes used for diagnosis in paleopathological research. These skeletal manifestations are usually interpreted as representing general ill‐health. Clinical research shows that vitamin D is also integral to a number of extra‐skeletal physiological processes including immunoregulation, blood pressure homeostasis, cell division, and programmed cell death. Vitamin D deficiency and sub‐clinical insufficiency are thought to be risk factors for infectious and autoimmune diseases, as well as certain cancers and cardiovascular diseases. Epidemiological work indicates that the skeletal manifestations of vitamin D deficiency represent the extreme end of a spectrum of morbidity associated with negative health outcomes, including increased risk for secondary tuberculosis. This article provides a review of clinical research on the extra‐skeletal roles of vitamin D and the pathological consequences of poor vitamin D status. Additionally, it presents an interpretive model for bioarchaeological analyses of rickets and osteomalacia for consideration of the whole‐body impact of poor vitamin D nutriture and possible comorbidities that may have affected the wider population. Am J Phys Anthropol 160:183–196, 2016. © 2016 Wiley Periodicals, Inc.     

Growth in an English population from the Industrial Revolution

The rapid urbanization of the Industrial Revolution in 18th-19th century England presented new health challenges. Our aim is to investigate using English skeletal remains whether the living conditions for an urban working class group in the Industrial Revolution negatively impacted upon their skeletal growth compared with a population from a rural agrarian parish. The Industrial Revolution skeletal material is from St Martin's Churchyard, Birmingham (SMB), West Midlands. It dates primarily from the first half of the nineteenth century when Birmingham was a major manufacturing center. The rural group is from Wharram Percy (WP), North Yorkshire, and dates from 10th-19th century AD. The methodology involves plotting diaphyseal bone lengths versus dental age for subadults. No overall difference was found between the two populations in bone length-for-age among the 2- to 18-year cohort. However the younger parts of the SMB cohort were smaller than at WP; the opposite was true of the older parts of the cohort. Growth rate, as inferred from crosssectional data, appeared greater at SMB than at WP. The only result consistent with expectations is the larger bone dimensions in young children from WP, but this likely reflects prolonged breastfeeding at WP not differences in urban and rural environments. That the deleterious health effects that we know accompanied the major transition in human society from a rural agrarian to an urban industrialized living environment should be little manifest in skeletal endochondral growth data is discouraging for those who would use such methodology to monitor health in earlier populations.     

Paleopathological and biomolecular study of tuberculosis in a medieval skeletal collection from England

Nine human skeletons of medieval date from a rural English burial site show signs of skeletal tuberculosis. They were subject to polymerase chain reaction (PCR) assays aimed at detecting traces of DNA from infecting mycobacteria, with the purpose both of confirming the paleopathological diagnosis of tuberculosis and determining in individual cases whether disease was due to M. tuberculosis or M. bovis. In all nine cases, evidence for M. tuberculosis complex DNA was found, and in all instances it appeared that disease was due to M. tuberculosis rather than M. bovis. The significance of the findings for understanding tuberculous infection in rural agrarian communities in medieval England is discussed.     

Rickets and Osteomalacia in the Glasgow Pakistani Community, 1961-71

The prevalence of vitamin D deficiency was reassessed in April and May 1971, 10 years after the discovery of widespread late rickets and osteomalacia in the Glasgow Pakistani community. Evidence of vitamin D deficiency was found in 28 out of 115 adults and children examined (24%). Children at the age of puberty were most severely affected by rickets, whereas most infants and younger children in the survey were protected by vitamin D supplements. Mild biochemical osteomalacia was common in Pakistani women.A total of 21 Pakistani and Indian children with rickets were admitted to Glasgow hospitals during 1968-70. These comprised 10 children with infantile rickets and 11 with late rickets. Four of the latter group required osteotomy for severe rachitic deformity.Late rickets and osteomalacia in Pakistani and Indian immigrants are not primarily due to nutritional deficiency of vitamin D, though the high phytate content of their diet may be of aetiological importance. A combination of environmental, social, and endogenous factors, the relative importance of which is not at present clear, may also be involved. Advice on the prophylaxis of vitamin D deficiency should be given to all Pakistani and Indian communities in the United Kingdom.     

Critical role of vitamin D in sulfate homeostasis: regulation of the sodium-sulfate cotransporter by 1,25-dihydroxyvitamin D3

As the fourth most abundant anion in the body, sulfate plays an essential role in numerous physiological processes. One key protein involved in transcellular transport of sulfate is the sodium-sulfate cotransporter NaSi-1, and previous studies suggest that vitamin D modulates sulfate homeostasis by regulating NaSi-1 expression. In the present study, we found that, in mice lacking the vitamin D receptor (VDR), NaSi-1 expression in the kidney was reduced by 72% but intestinal NaSi-1 levels remained unchanged. In connection with these findings, urinary sulfate excretion was increased by 42% whereas serum sulfate concentration was reduced by 50% in VDR knockout mice. Moreover, levels of hepatic glutathione and skeletal sulfated proteoglycans were also reduced by 18 and 45%, respectively, in the mutant mice. Similar results were observed in VDR knockout mice after their blood ionized calcium levels and rachitic bone phenotype were normalized by dietary means, indicating that vitamin D regulation of NaSi-1 expression and sulfate metabolism is independent of its role in calcium metabolism. Treatment of wild-type mice with 1,25-dihydroxyvitamin D3 or vitamin D analog markedly stimulated renal NaSi-1 mRNA expression. These data provide strong in vivo evidence that vitamin D plays a critical role in sulfate homeostasis. However, the observation that serum sulfate and skeletal proteoglycan levels in normocalcemic VDR knockout mice remained low in the absence of rickets and osteomalacia suggests that the contribution of sulfate deficiency to development of rickets and osteomalacia is minimal.     

Vitamin D deficiency in children with cerebral palsy: A narrative review of epidemiology,contributing factors,clinical consequences and interventions

Sufficient vitamin D levels are necessary, not only for mineralization, normal growth and development of bones, but also for the prevention of fatal chronic diseases like diabetes mellitus, metabolic syndrome and cancer. This is of particular importance in children with neuro- and musculoskeletal disorders, especially cerebral palsy (CP). CP is a heterogeneous group of childhood developmental disability disorders described by uncharacteristic posture, balance, and movement. Patients with CP are at an increased risk of vitamin D deficiency and as a result reduced bone mineral density, bone fragility, osteopenia, and rickets. The present review aims to combine and summarize available evidence, regarding the epidemiology, underlying contributing factors, clinical consequences, and treatment interventions of vitamin D deficiency in children with CP.     

Technical note: The use and misuse of threshold diagnostic criteria in paleopathology

Weighted threshold diagnostic criteria approaches have emerged for diseases that involve skeletal/bony tissue that are readily diagnosed in the field of paleopathology such as Vitamin C deficiency (scurvy), Vitamin D deficiency (rickets) and treponemal disease. These criteria differ from traditional differential diagnosis in that they involve standardized inclusion criteria based on the lesion's specificity to the disease. Here I discuss the limitations and benefits of threshold criteria. I argue that while these criteria will benefit from further revision such as inclusion of lesion severity, and the incorporation of exclusion criteria, threshold diagnostic approaches have considerable value in the future of diagnosis in the field.     

Age-related cortical bone loss in women from a 3rd-4th century AD population from England

Age-dependent cortical bone loss in adult females from a skeletal assemblage from 3rd-4th century AD England was studied using metacarpal radiogrammetry. Results showed reduced peak cortical bone thickness compared with modern subjects, and the magnitude of cortical bone loss in older females compared with their younger counterparts was greater than that documented for a modern reference population. An elevated prevalence of fractures classically associated with osteoporosis was also observed in the over-50-year cohort. The severity of osteoporosis in this group is difficult to explain in terms of extraneous factors relating to 3rd-4th century lifestyles. Given the important genetic component in osteoporosis, the results may indicate some inherent susceptibility in this particular population to the disease, and ways in which this possibility might be further explored are suggested.     

Interrelationships of vitamin D,bone metabolism and blood calcium concentration in the chick

It is not known if the effects of vitamin D deficiency on chick bone are due to direct actions of the vitamin or if they are secondary to other changes, such as hypocalcemia. Day-old cockerels were fed either a rachitogenic diet containing no Ca (−D-Ca), 1.4% Ca (−D), or 3% Ca (−DHiCa) and given corn oil (−D groups) or vitamin D₃ in corn oil (+D and + D-Ca) p.o. for up to 21 days. Radii were harvested and incubated for 6–8 h in a defined medium. Medium samples were taken every 2 h and analysed for Ca, P₁ and lactate. Some bones were incubated in a respirometer to measure O₂ consumption. Compared to +D, −D birds showed evidence of D deficiency by decreased plasma Ca concentration (33%), bone and body weight (43%) and Ca release from bone (70%) and by histological changes in bone characteristic of rickets. Increases were seen in total and bone alkaline phosphatase activity in plasma (270 and 706%, respectively), P_i release (23%), O₂ consumption (23%) and lactate production (52%) by the −D radii. The marked hypocalcemia seen in the −D chicks did not occur in −DHiCa birds. Nevertheless, bone and body weights were decreased in this group and bone lactate production, O₂ consumption and total and bone alkaline phosphatase in plasma were increased. Rachitic bone lesions were only partially corrected by the high-Ca diet. Release of Ca and P_i from the −DHiCa bone? was not different than from +D radii. Comparing +D-Ca and −D-Ca groups with +D chicks, both were hypocalcemic with decreased bone weight, body weight and bone Ca release, while showing elevated lactate production and P_i release. The only difference between the +D-Ca and −D-Ca groups was a 50% decrease in Ca release by −D-Ca bone. The results suggest that in chicks: (1) some, but not all, of the effects of vitamin D deficiency on bone can be corrected by normalizing plasma Ca and (2) evaluation of the effects of vitamin D deficiency on bone may require hypocalcemia, since some responses are masked by normocalcemia.     

骨密度检测对婴幼儿佝偻病早期诊断的临床意义

目的:探讨骨密度检测在佝偻病早期诊断中的应用价值。方法:收集衡水市哈励逊国际和平医院门诊诊治的600例婴幼儿,以血清维生素D327.5 nmol/L为判定标准分为非佝偻病组和佝偻病组,比较两组婴幼儿维生素D3、骨碱性磷酸酶和骨密度,绘制维生素D3、骨碱性磷酸酶、骨密度诊断结果的ROC曲线图,对骨密度检测结果进行评价。结果:佝偻病组婴幼儿维生素D3和骨密度Z值明显低于非佝偻病组,骨碱性磷酸酶显著高于非佝偻病组(P0.05)。维生素D3诊断佝偻病的ROC曲线下面积为0.951,灵敏度为0.973,特异度为0.840;骨碱性磷酸酶诊断佝偻病的ROC曲线下面积为0.866,灵敏度为0.824,特异度为0.747;骨密度Z值诊断佝偻病的ROC曲线下面积为0.923,灵敏度为0.826,特异度为0.875,骨密度指标诊断佝偻病的曲线下面积和维生素D3比较无统计学意义(P0.05),但骨密度指标诊断佝偻病的曲线下面积大于骨碱性磷酸酶(P0.05)。结论:超声骨密度检测在婴幼儿佝偻病早期诊断中具有一定价值,其诊断敏感性、特异性、准确率与维生素D3诊断基本相当,且骨密度检测存在无创、可重复性高等优点。     

An image analysis protocol for the quantification of interglobular dentine in anthropological tooth sections

The histological identification of interglobular dentine (IGD) in archeological human remains with macroscopic evidence of rickets has opened a promising new avenue for the investigation of metabolic disease in the past. Recent paleopathological studies have shown that histological analysis of archeological human teeth may allow the identification of periods of vitamin D deficiency occurring within very narrow developmental windows, yielding new information on the seasonality or even maternal‐fetal transmission of this disease. However, currently available techniques for recording IGD rely on subjective scoring systems or visual estimations, potentially leaving them open to inter and intra‐observer error and rendering comparisons of datasets difficult. Here we describe a new imaging protocol that utilizes open access software and may yield more objective and quantitative data on the amount of IGD present within a dentinal region of interest. We demonstrate that grayscale histograms in FIJI®/ImageJ® might be used to provide less subjective estimates of the percentage of a region of interest affected by IGD. Application of this technique may enable more accurate comparison of datasets between researchers.     

CHRONIC RENAL FAILURE—Its Effect on Calcium,Phosphorus and Osseous Metabolism; A Unified Approach

The renal osteodystrophies represent the metabolic consequences of (1) vitamin D resistance, (2) secondary hyperplasia of the parathyroids, and (3) the changes in serum PO₄= and Ca++ secondary to the renal insufficiency per se.The osseous lesion in any given patient with chronic renal failure may be osteitis fibrosa, rickets (osteomalacia), calcium deficiency osteoporosis or any combination of these. The concentration of Ca++ and PO₄= in the serum is determined by the degree of renal failure and the skeletal response to parathyroid hormone.     

Medieval trabecular bone architecture: the influence of age, sex, and lifestyle

Osteoporosis has become a growing health concern in developed countries and an extensive area of research in skeletal biology. Despite numerous paleopathological studies of bone mass, few studies have measured bone quality in past populations. In order to examine age- and sex-related changes in one aspect of bone quality in the past, a study was made of trabecular bone architecture in a British medieval skeletal sample. X-ray images of 5-mm-thick coronal lumbar vertebral bone sections were taken from a total of 54 adult individuals divided into three age categories (18-29, 30-49, and 50+ years), and examined using image analysis to evaluate parameters related to trabecular bone structure and connectivity. Significant age-related changes in trabecular bone structure (trabecular bone volume (BV/TV), trabecular number (Tb.N), trabecular separation (Tb.Sp), and anisotropic ratio (Tb.An)) were observed to occur primarily by middle age with significant differences between the youngest and two older age groups. Neither sex showed continuing change in trabecular structure between the middle and old age groups. Age-related changes in bone connectivity (number of nodes (N.Nd) and node-to-node strut length (Nd.Nd)) similarly indicated a change in bone connectivity only between the youngest and two older age groups. However, females showed no statistical differences among the age groups in bone connectivity. These patterns of trabecular bone loss and fragility contrast with those generally found in modern populations that typically report continuing loss of bone structure and connectivity between middle and old age, and suggest greater loss in females. The patterns of bone loss in the archaeological samples must be interpreted cautiously. We speculate that while nutritional factors may have initiated some bone loss in both sexes, physical activity could have conserved bone architecture in old age in both sexes, and reproductive factors such as high parity and extended periods of lactation could have played a key role in female bone maintenance in this historic population. The study of qualitative elements (such as trabecular architecture) is vital if we are to understand bone maintenance and fragility in the past.     

Urban–rural differences in Roman Dorset,England: A bioarchaeological perspective on Roman settlements

In the Roman period, urban and rural ways of living were differentiated philosophically and legally, and this is the first regional study of these contrasting life‐ways. Focusing on frailty and mortality risk, we investigated how these differed by age, sex, and status, using coffin type as a proxy for social status. We employed skeletal data from 344 individuals: 150 rural and 194 urban (1st–5th centuries A.D.) from Dorset, England. Frailty and mortality risk were examined using indicators of stress (cribra orbitalia, porotic hyperostosis, nonspecific periostitis, and enamel hypoplastic defects), specific metabolic and infectious diseases (rickets, scurvy, and tuberculosis), and dental health (carious lesions and calculus). These variables were studied using Chi‐square, Siler model of mortality, Kaplan–Meier analysis, and the Gompertz model of adult mortality. Our study found that overall, mortality risk and survivorship did not differ between cemetery types but when the data were examined by age, mortality risk was only significantly higher for urban subadults. Demographic differences were found, with urban cemeteries having more 0–10 and >35 year olds, and for health, urban cemeteries had significantly higher frequencies of enamel hypoplastic defects, carious lesions, and rickets. Interestingly, no significant difference in status was observed between rural and urban cemeteries. The most significant finding was the influence of the skeletal and funerary data from the Poundbury sites, which had different demographic profiles, significantly higher frequencies of the indicators of stress and dental health variables. In conclusion, there are significant health, demographic, and mortality differences between rural and urban populations in Roman Britain. Am J Phys Anthropol 157:107–120, 2015. © 2015 Wiley Periodicals, Inc.     

Is Vitamin D the Fountain of Youth?

ObjectiveTo review the role of vitamin D deficiency for both classic and “nonclassic” effects and raise the caution that association does not prove causation.MethodsThe pertinent literature regarding vitamin D and its effects on bone, muscle function, immune function, glucose tolerance, cancer risk, and development of cardiovascular disease and other conditions is reviewed. In addition, the limitations of observational studies are discussed.ResultsVitamin D inadequacy is common worldwide and classically causes osteomalacia and rickets. More recently, the contribution of low vitamin D status to increased falls and fracture risk has become appreciated. Additionally, nonclassic effects of vitamin D inadequacy are being recognized, and low vitamin D status is being potentially associated with a multitude of conditions (including Alzheimer disease, osteoarthritis, multiple sclerosis, and hypertension) and higher overall mortality. It is important to recognize that associations in observational studies can be due to chance, bias, or confounders or may be indicative of causality.ConclusionBecause vitamin D deficiency has been established to have adverse musculoskeletal consequences, optimization of vitamin D status, for both the individual patient and the overall population, is indicated. (Endocr Pract. 2009;15:590-596)     

Vestibular dysfunction in vitamin D receptor mutant mice

The vitamin D endocrine system is essential for calcium and bone homeostasis. Vitamin D deficits are associated with muscle weakness and osteoporosis, whereas vitamin D supplementation may improve muscle function, body sway and frequency of falls, growth and mineral homeostasis of bones. The loss of muscle strength and mass, as well as deficits in bone formation, lead to poor balance. Poor balance is one of the main causes of falls, and may lead to dangerous injuries. Here we examine balance functions in vitamin D receptor deficient (VDR−/−) mice, an animal model of vitamin D-dependent rickets type II, and in 1α-hydroxylase deficient (1α-OHase−/−) mice, an animal model of pseudovitamin D-deficiency rickets. Recently developed methods (tilting box, rotating tube test), swim test, and modified accelerating rotarod protocol were used to examine whether the absence of functional VDR, or the lack of a key vitamin D-activating enzyme, could lead to mouse vestibular dysfunctions. Overall, VDR−/− mice, but not 1α-OHase−/− mice, showed shorter latency to fall from the rotarod, smaller fall angle in the tilting box test, and aberrant poor swimming. These data suggest that VDR deficiency in mice is associated with decreased balance function, and may be relevant to poorer balance/posture control in humans with low levels of vitamin D.     

Effect of vitamin D deficiency on skeletal development during early growth in the rat

To define the role of vitamin D in early development, female weanling rats were grown to maturity on a vitamin D-deficient diet and mated with normal males. At Day 20 of pregnancy the weight and total body calcium of fetuses were determined. At various times after parturition, pups were sacrificed. Plasma samples were analyzed for calcium and phorphorus, and femurs were characterized as to volume, dry weight, ash weight, and total calcium. The results indicate that vitamin D deficiency with its accompanying hypocalcemia does not impair placental transfer of calcium nor weight gain of the fetus. Vitamin D deficiency does appear to increase calcium accumulation in the fetus. After parturition vitamin D is functional in maintaining a normocalcemia as early as 3 days postpartum and its importance increases with age of the neonate. Bone mineralization is clearly disrupted by Day 14 as judged by calcium content per unit bone volume and the severity of the defect increases with age. Both vitamin D and normal concentrations of calcium and phosphorus appear to be essential for proper skeletal development during early growth postpartum.     

Vitamin-D-deficient rickets in Manitoba, 1972-84.

Vitamin-D-deficient rickets still exists in children in Manitoba and adjacent areas. Between 1972 and 1984, 48 cases were documented at Winnipeg Children''s Hospital. The patients ranged in age from 1 to 49 months; 40 were Canadian natives (38 Indians and 2 Inuit), most of whom lived in the Island Lake area of northern Manitoba. Of the 48, 16 had clinical signs of rickets, 12 had tetany due to hypocalcemia and 38 had radiologic evidence of rickets. Hypocalcemia was found in 27, and hypophosphatemia in 19; hyperaminoaciduria was found in 7 of 20. All 48 had elevated serum alkaline phosphatase levels. In addition to rickets, 16 patients aged 12 months or more had evidence of malnutrition. Climate and lifestyle in northern areas of the Canadian midwest result in little or no biosynthesis of vitamin D by solar radiation; therefore, adequate dietary vitamin D intake is essential to prevent deficiency. The diets of pregnant women and infants in these areas are deficient in vitamin D. The authors recommend vitamin D supplements for all pregnant women and infants in areas of risk to eradicate this preventable disease.     

Vitamin D and aging: old concepts and new insights

Aging is a complex biological process driven by a selective class of molecules and pathways that affect overall deterioration of physiological functions to increase the risk of age-related diseases. A role of vitamin D in mammalian aging is well documented. Since vitamin D has an essential role in bone formation and mineralization, its deficiency results in impaired bone mineralization, such as rickets in children, osteomalacia in adults and osteoporosis in the aged population. Vitamin D replacement therapy therefore is one of the most commonly prescribed treatments for the elderly. Recent studies using genetically altered mouse models, such as in Fgf-23^−/− and klotho mutant mice, that exhibit altered mineral ion metabolism due to high vitamin D activities showed features of premature aging that include atherosclerosis, emphysema, osteopenia/osteoporosis, hypogonadism, soft tissue calcifications and generalized atrophy of organs; the pathologic effects of vitamin D in these mouse models are obvious, as diminution or genetic ablation of the vitamin D pathway ameliorated most of the above-mentioned phenotypes, by reversing mineral ion metabolism, and the resultant effect being prolonged survival of the mutant mice. These in vivo mouse studies, although subject to further molecular characterization, add new insights into the role of vitamin D in aging.