Calcifediol Cornerstone of the Vitamin D Endocrine System.

It is likely that rickets has afflicted humanity since the dawn of time, but it was first described in great detail in the mid-17th century [...].

The One-Hundred-Year Anniversary of the Discovery of the Sunshine Vitamin D3: Historical, Personal Experience and Evidence-Based Perspectives.

The discovery of a fat-soluble nutrient that had antirachitic activity and no vitamin A activity by McCollum has had far reaching health benefits for children and adults. He named this nutrient vitamin D. The goal of this review and personal experiences is to give the reader a broad perspective almost from the beginning of time for how vitamin D evolved to became intimately involved in the evolution of land vertebrates. It was the deficiency of sunlight causing the devastating skeletal disease known as English disease and rickets that provided the first insight as to the relationship of sunlight and the cutaneous production of vitamin D3. The initial appreciation that vitamin D could be obtained from ultraviolet exposure of ergosterol in yeast to produce vitamin D2 resulted in the fortification of foods with vitamin D2 and the eradication of rickets. Vitamin D3 and vitamin D2 (represented as D) are equally effective in humans. They undergo sequential metabolism to produce the active form of vitamin D, 1,25-dihydroxyvitamin D. It is now also recognized that essentially every tissue and cell in the body not only has a vitamin D receptor but can produce 1,25-dihydroxyvitamin D. This could explain why vitamin D deficiency has now been related to many acute and chronic illnesses, including COVID-19.

Precarious adolescence: Adolescent rickets and anterior sacral angulation in two Dutch skeletal collections from the 18th-19th centuries.

OBJECTIVE: This project aims to provide an objective approach to suggesting cases of adolescent rickets using the presence of anterior sacral angulation and interglobular dentine. MATERIALS: Sacra from 49 individuals from Hattem and 150 individuals from Middenbeemster, and second and third molars from five individuals from Hattem were analyzed. Both sites date to the 17th to 19th centuries. METHODS: The sacra were visually assessed for sacral angulation and measured to quantify anterior sacral angulation. The sampled molars were thin sectioned to look for the presence of interglobular dentine. RESULTS: Metric analysis determined that seven individuals had significantly anteriorly angled sacra. Three of the five individuals with sampled molars had interglobular dentine formed during adolescence. CONCLUSIONS: Adolescent rickets may be associated with anterior sacral angulation. SIGNIFICANCE: Anterior sacral angulation may help identify possible cases of adolescent rickets in archaeological human remains. LIMITATIONS: The small sample size for the molars prevented the identification of more individuals with interglobular dentine present during adolescence. Several individuals with visibly angled sacra were unmeasurable due to post-mortem damage and lacked molars. SUGGESTIONS FOR FURTHER RESEARCH: Research on a larger sample would allow us to understand better the association between anterior sacral angulation and adolescent rickets.

Rickets, Vitamin D, and Ca/P Metabolism.

Rickets was a major public health problem dating from Roman times, and medical descriptions of rickets date from the 17th century. Sniadecki first advocated treatment by exposure to sunshine in 1822; contemporaneously, several British physicians advocated use of cod liver oil. Both approaches were successful. Work in 1924 showed that exposure to UV light endowed fats and other foods with antirachitic properties. Vitamins D2 and D3, the antirachitic agent in cod liver oil, were, respectively, produced by UV radiation of ergosterol and 7-dehydrocholesterol. Calcitriol (1,25[OH]2D3) was identified as the biologically active form of vitamin D in the early 1970s. The vitamin D 25-hydroxylase, 24-hydroxylase, and 1α-hydroxylase were cloned in the 1990s and their genetic defects were soon delineated. The vitamin D receptor was also cloned and its mutations identified in vitamin D-resistant rickets. Work with parathyroid hormone (PTH) began much later, as the parathyroids were not identified until the late 19th century. In 1925, James B. Collip (of insulin fame) identified PTH by its ability to correct tetany in parathyroidectomized dogs, but only in the 1970s was it clear that only a small fragment of PTH conveyed its activity. Congenital hypoparathyroidism with immune defects was described in 1968, eventually linked to microdeletions in chromosome 22q11.2. X-linked hypophosphatemic rickets was reported in 1957, and genetic linkage analysis identified the causative PHEX gene in 1997. Autosomal dominant hypophosphatemic rickets similarly led to the discovery of FGF23, a phosphate-wasting humoral factor made in bone, in 2000, revolutionizing our understanding of phosphorus metabolism.

La accidentada historia del descubrimiento de la vitamina D, en su primer centenario / The checkered history of the discovery of vitamin D, in its first centenary

El año 2022 marca el primer centenario del descubrimiento de la vitamina D, hallazgo que recompensó la prolongada búsqueda de la causa del raquitismo, su prevención y tratamiento. Al mismo tiempo puso en marcha importantes investigaciones relaciona-das con su biotransformación y el mecanismo de su acción antirraquítica, además de estudios sobre diversos efectos biológicos sin relación directa con su papel en la salud ósea. Esta breve revisión se limitará a delinear la prehistoria de la vitamina D y los diversos estudios, básicos y clínicos, que condujeron a su descubrimiento y caracterización química. (AU)

The year 2022 marks the centenary of the discovery of vitamin D, a breakthrough that rewarded the long search for the cause of rickets, its prevention and treatment. At the same time, it launched important investigations related to its biotransformation and the mechanism of its antirachitic action, as well as studies on various biological effects without direct relation to its role in bone health. This brief review will be limited to an outline of the prehistory of vitamin D and the various basic and clinical studies that led to its discovery and chemical characterization. (AU)

[Kurt Huldschinsky: A pioneer in the struggle against rickets]. / Kurt Huldschinsky: Ein Vorreiter im Kampf gegen Rachitis.

Kurt Huldschinsky (1883-1940) was a German pediatrician who was one of the international leaders in the field of rickets research between the two world wars. After his medical studies, he served at the Kaiserin-Auguste-Victoria-Haus in Berlin and at the University Children's Hospital in Vienna, among other places. After World War I, he worked with the famous orthopedist Konrad Biesalski at the Oskar-Helene-Heim for the healing and education of frail children in Berlin. Here he was the first to prove that exposure to ultraviolet (UV) radiation from mercury vapor lamps ("artificial sunlight") could cure rickets in young children, which is mostly caused by vitamin D deficiency. He published his discovery in this journal - the Deutsche Medizinische Wochenschrift [German Medical Weekly] - in 1919. For this groundbreaking scientific achievement and his further research into the prevention and treatment of rickets, Huldschinsky was awarded the Otto Heubner Prize of the German Association of Pediatrics in 1926. He was even nominated for the Nobel Prize in Medicine. As a Jew, however, he had to flee Germany from the National Socialists in 1933/34. Together with his wife and daughter, he emigrated to Egypt, where he died in Alexandria on October 31, 1940. As Huldschinsky was for many decades almost forgotten, this article recalls the life and work of a meritorious physician and scientist.

Differential diagnosis of metabolic disease in a commingled sample from 19th century Hisban, Jordan.

OBJECTIVE: This research attempts a differential diagnosis of skeletal lesions in a commingled sample from Hisban, Jordan, focusing on non-adults in the assemblage. MATERIALS: 2,883 well-preserved skeletal elements and 9 relatively complete skulls representing an MNI of 32 non-adults (<18 years old). METHODS: All skeletal elements were observed macroscopically and pathophysiological processes underlying any lesions or other anomalies were assessed, followed by a comparative approach to rule out potential diagnoses. RESULTS: The skeletal lesions observed were caused by inflammation due to chronic hemorrhaging, marrow hyperplasia due to an increase in hemopoiesis, rapid bone growth, and the impact of biomechanical strain on poorly mineralized elements. Rickets, scurvy, and acquired anemias best fit this pattern of lesions, although inflammation from other sources such as trauma or infection could not be definitively ruled out. CONCLUSIONS: The in utero and postnatal environments at Hisban were conducive to the development of vitamin C and D deficiencies from birth until 2 years of age. The analysis of commingled remains requires an ontological shift in the importance of the individual to the population in paleopathology. SIGNIFICANCE: This investigation demonstrates the efficacy of a combined biological and comparative approach in differential diagnosis in complicated commingled collections. In addition, it emphasizes the importance of the mother-infant dyad in understanding metabolic disease. LIMITATIONS: Histological and radiographic analyses were not included in this diagnostic study due to COVID-19 travel restrictions. SUGGESTIONS FOR FURTHER RESEARCH: Isotopic analysis to investigate childhood diet and histological and radiographic analyses to assess survival of deficiencies.

Arte, historia y endocrinología / Art, history and endocrinology

Las enfermedades han sido representadas en el arte desde tiempos remotos. Las obras pictóricas muchas veces nos muestran trastornos que aún no se constituían como una entidad. Observar estos cuadros a la luz de la historia de las enfermedades nos da una perspectiva enriquecedora que nos ayuda a entender mejor dichas patologías. Se comenta un caso clínico endocrinológico pediátrico, la historia probable y su descripción física. Se revisa la historia de cómo se llegó a dilucidar la enfermedad y las claves de su tratamiento.

Diseases have been represented in art since ancient times. Paintings often show us disorders that had not yet been described as a pathological entity. Looking at these pictures in the light of the history of the diseases gives us an enriching perspective that helps us to better understand those pathologies. On this background a pediatric endocrinological clinical case, the most probable history and the features of the physical examination are discussed. The history of how the disease was uncovered and the keys of its treatment are reviewed.

A brief history of rickets.

The review provides a historical perspective on the convergence of our understanding of the physiology and pathophysiology of bone, calcium, phosphorus, vitamin D, parathyroid hormone, and FGF-23 their impact on rickets.

Nutritional rickets: Historic overview and plan for worldwide eradication.

Rickets was first described in great detail in the mid 17th century and was affecting a great number of children in major European cities. The disease, however, existed already in the Roman times. The etiology of this disease remained enigmatic until the 1920s when two different mechanisms, lack of exposure to sunlight and lack of a dietary factor were finally solved by the discovery of vitamin D and its dual origin. Soon thereafter, the implementation of vitamin D supplementation for all infants and small children largely eliminated nutritional rickets in Europe and North America. It took nearly a century to elucidate the complex chemistry, metabolism, mode and spectrum of activity of the vitamin D endocrine system. Nutritional rickets, whether due to simple vitamin D or calcium deficiency or both, remains widely ravaging many infants and children around the world. Asian countries and the Middle East are mainly confronted with vitamin D deficiency whereas many African and some Asian countries face calcium deficiency rickets. Immigrants and refugees or in general people with a darker skin living in moderate climate zone are also confronted with this disease. There is great consensus how this disease could be prevented or cured. In collaboration with most international professional societies, we prepare a memorandum, in line with the successful battle against iodine deficiency disorders, to convince the World Health Organization and its member states to start an implementation program to eradicate nutritional rickets by 2030.

Micro-CT assessment of dental mineralization defects indicative of vitamin D deficiency in two 17th-19th century Dutch communities.

OBJECTIVES: This study investigates vitamin D deficiency patterns in individuals from birth to the beginning of adolescence. Microscopic computed tomography (micro-CT) evaluation of interglobular dentine (IGD) in teeth provides information on the age of disease onset and the number of deficient periods per individual, which will increase our understanding of factors influencing vitamin D deficiency prevalence, including sociocultural practices and latitude. MATERIALS AND METHODS: Beemster and Hattem, two Dutch 17th-19th century communities, yielded relatively high prevalences of rickets (15-24%) and residual rickets (15-24%). From the affected individuals, a subsample of 20 teeth were selected for micro-CT scanning. Thin sections were made of 17 teeth, consisting of 6 teeth with and 11 teeth without observable IGD on micro-CT that were included for method comparison. RESULTS: About 19 out of 29 (65.5%) individuals (one tooth was deemed unobservable) presented with IGD on micro-CT. Eight of the 11 (72.7%) individuals without IGD on micro-CT demonstrated histologically visible IGD. In 40.7% (11/27) of the affected individuals (combined micro-CT and histology results), vitamin D deficiency was recurrent, and in four individuals, some episodes occurred at approximately annual intervals suggesting vitamin D deficiency was seasonal. In three individuals, IGD occurred in the dentine formed around birth, suggesting maternal vitamin D deficiency. DISCUSSION: Micro-CT analysis of IGD is found to be a valuable non-destructive method that can improve our understanding of the influence of sociocultural practices and latitude on disease development within age and sex groups in past communities.

Vitamin D: part II; cod liver oil, ultraviolet radiation, and eradication of rickets.

PURPOSE: After Glisson's description of rickets, it took two centuries to realize that rickets was due to the absence of antirachitic nutrients in the diet or lack exposure of the skin to ultraviolet rays. This bone disease caused by vitamin D deficiency was one of the most common diseases of children 100 years ago. This paper explores how the definition, diagnosis, and treatment of rickets shifted in the first decades of the twentieth century. MATERIAL AND METHODS: Although benefits of cod liver oil as food were known as early as the seventh century, cod liver oil was only proposed as medicinal for rickets in Northern Europe at the end of the eighteenth century. The relationship between rickets and nutritional deficiency was suspected and demonstrated between 1880 and 1915, at the same time of the discovery of other vital substances (vitamins) needed to prevent beriberi, scurvy, and pellagra. Understanding that the lack of photosynthesized vitamin D or the lack of dietary vitamin D was a similar risk of rickets was an important turn in the comprehension of the disease. We look at the sequence and turn of events related to the discovery of vitamin D. RESULTS: Rickets has been recognized first as a disease of urban living people. Cod liver oil had been used since 1700 as a nonspecific treatment for a range of diseases. Generations of children in cities of the north of Europe had learned to hate the taste and smell of the black oily liquid and then grown up to be parents who, in turn, hated to force it down their children's throats. Occasional papers before 1900 pointed to its efficacy for rickets, and most textbooks of the early 1900s mentioned it only as a treatment option. The discovery in the early 1900s that artificial and natural ultraviolet rays had both antirachitic activity allowed to produce antirachitic foods just by food irradiation with artificial ultraviolet irradiation. Clinical guidelines were adopted to propose exposure to sunlight or to artificial ultraviolet radiation to prevent rickets in children. By the mid-1920s, rickets was promoted as universal, at times invisible to non-experts, but present to some degree in nearly every young child regardless of race or class. It was thus used to promote the young disciplines of preventive medicine, pediatrics, and public health. Innovative advances were made in the understanding of vitamin D synthesis from 1915 to 1935. A public health campaign of the 1930s was a success to eradicate rickets, using irradiated ergosterol from yeast to enrich milk and other foods with vitamin D, ensuring that the general population was consuming sufficient vitamin D. CONCLUSION: Rickets therefore provides an excellent window into the early politics of preventive health and the promotion of targeted interventions in the world. It is also a relevant historical counterpoint for current debates over the role of risk factors (absence of light or sun) for disease (today's so-called "lifestyle" diseases).

Analysis of patterning in the occurrence of skeletal lesions used as indicators of vitamin D deficiency in subadult and adult skeletal remains.

Paleopathological investigations of conditions linked to vitamin D deficiency have increased in the last twenty years, and a suite of skeletal lesions has been established to aid in the diagnosis of vitamin D deficiency disease in subadults and adults. This paper analyzes the occurrence of these lesions in a large skeletal series comprising 3541 Roman period individuals (1st-6th century AD). Sixteen lesions reported in rickets in subadults, and 13 associated with residual rickets and osteomalacia in adults, were analyzed. Among subadults, there were clear associations among post-cranial lesions. Porotic cranial changes were associated with each other, but not with post-cranial lesions. A range of conditions could have produced the cranial lesions. There was a general paucity of correlations between indicators found in adults, and the difficulty in recording bending deformities was clear. Pseudofractures appear to provide a useful means of investigating osteomalacia in adults. In general, a simple algorithmic approach using presence or absence of lesions is unlikely to provide an adequate means of diagnosing vitamin D deficiency in paleopathology. Knowledge and consideration of the underlying physiological mechanisms involved in lesion formation, combined with individual judgement, will be required to differentially diagnose cases.

Osteological evidence for juvenile vitamin D deficiency in a 19th century suburban population from Surrey, England.

Vitamin D deficiency rickets was considered endemic in the industrialized cities of 19th century England, but was rarely reported in more rural and suburban areas. The commercial excavation of St. John's Church, Redhill, Surrey, UK provided an opportunity to examine to what extent suburban children were affected by rickets and the factors responsible for its development. Seventy-nine non-adults (0-17 years) from St. John's Church were subjected to macroscopic and radiographic analysis to identify skeletal manifestations of vitamin D deficiency. Rachitic lesions were identified in 14/79 individuals (17.7%) aged from six months to six years. Active cases occurred from six months to two years of age with healed cases observed from three to six years. One seven month old infant also displayed healed lesions. The age-specific pattern of active and healed rickets suggests the population was vulnerable to the seasonal restriction of sunlight hours, with the considerably low vitamin D content of the infant diet unable to provide sufficient amounts to maintain metabolic functions. This research demonstrates that rickets was not simply a disease of industrialization but that a variety of factors contributed to its development in groups previously considered to be low risk.

Rare paleopathological insights into vitamin D deficiency rickets, co-occurring illnesses, and documented cause of death in mid-19th century London, UK.

Growing evidence suggests that vitamin D supports immune responses to infections, autoimmune conditions and cancers, although evidence from large-scale studies is limited. There is scope to better understand how vitamin D deficiency interacted with other diseases to affect health in past groups. This study investigated paleopathological evidence and documentary records of individual cause of death to examine disease co-occurrence in a group of mid-19th century child burials from London, UK. Twenty-one percent of children had vitamin D deficiency rickets (138/642) and 36 children with rickets had an identified cause of death. Cyclical episodes of metabolic and nutritional deficiencies (rickets and scurvy) had occurred during childhood. Active rickets co-occurred with respiratory and gastrointestinal infections in a small number of children, likely reflecting vitamin D's role in supporting immune function. Consideration of the stage of the vitamin D deficiency showed that the majority of children were affected by chronic disease loads indicative of multiple episodes of illness. Reconstructions of the wider health consequences of vitamin D deficiency in past groups are dependent on recognising whether the deficiency was active or healed. The variability of diseases identified illustrates the high disease burden that affected children in this socially disadvantaged group.

The epidemiology of rickets in the 17th-19th centuries: Some contributions from documentary sources and their value to palaeopathologists.

This article considers the nature of written sources on the epidemiology of rickets in the post-Mediaeval period, and examines the value of these sources for palaeopathologists. There is a progression from 17th-18th century sources, which generally make ex cathedra, qualitative statements on rickets frequency to, in the 19th century, semi-quantitative geographical surveys of its occurrence, through to reports of percentage prevalence in various groups. Of course, even these latter cannot be directly compared with prevalences calculated from excavated skeletal remains, but there are also considerable difficulties in comparing them with one another, and this effectively precludes synthesis to provide reliable information on geographic and temporal trends at anything more than a very broad-brush level. Their problematic nature mandates a cautious approach when using written sources to shed light on the epidemiology of rickets. For palaeopathologists, a useful way of incorporating these sources into a biocultural approach may be to use them in order to formulate hypotheses that can then be evaluated using skeletal evidence.