•The burden of “nutritional” rickets due to solar vitamin D and dietary calcium deficiency is increasing worldwide.•Nutritional osteomalacia co-exists with rickets in children, but also affects ...adults/adolescents who mostly remain undiagnosed.•Nutritional osteomalacia is a growing global public health concern and yet the true disease burden remains unexplored and neglected.•There is a pressing need for non-invasive diagnostic criteria and studies exploring osteomalacia’s true prevalence in vivo and post-mortem.•Further studies will inform public health policies relating to vitamin D and/or calcium supplementation and food fortification.
Osteomalacia and rickets result from defective mineralization when the body is deprived of calcium. Globally, the main cause of osteomalacia is a lack of mineral supply for bone modeling and remodeling due to solar vitamin D and/or dietary calcium deficiency. Osteomalacia occurs when existing bone is replaced by unmineralized bone matrix (osteoid) during remodeling in children and adults, or when newly formed bone is not mineralized in time during modeling in children. Rickets occurs when hypomineralization affects the epiphyseal growth plate chondrocytes and adjacent bone metaphysis in growing children. Hence, osteomalacia co-exists with rickets in growing children. Several reports in the last decade highlight the resurgence of so-called “nutritional” rickets in the dark-skinned population living in high-income countries. However, very few studies have ever explored the hidden iceberg of nutritional osteomalacia in the population.
Rickets presents with hypocalcaemic (seizures, tetany, cardiomyopathy), or hypophosphataemic complications (leg bowing, knock knees, rachitic rosary, muscle weakness) and is diagnosed on radiographs (cupping and fraying of metaphyses). In contrast, osteomalacia lacks distinctive, non-invasive diagnostic laboratory or imaging criteria and the clinical presentation is non-specific (general fatigue, malaise, muscle weakness and pain). Hence, osteomalacia remains largely undiagnosed, as a hidden disease in millions of dark-skinned people who are at greatest risk. Radiographs may demonstrate Looser’s zone fractures in those most severely affected, however to date, osteomalacia remains a histological diagnosis requiring a bone biopsy. Biochemical features of high serum alkaline phosphatase (ALP), high parathyroid hormone (PTH) with or without low 25 hydroxyvitamin D (25OHD) concentrations are common to both rickets and osteomalacia.
Here, we propose non-invasive diagnostic criteria for osteomalacia. We recommend a diagnosis of osteomalacia in the presence of high ALP, high PTH, low dietary calcium intake (<300 mg/day) and/or low serum 25OHD (<30 nmol/L). Presence of clinical symptoms (as above) or Looser’s zone fractures should be used to reaffirm the diagnosis.
We call for further studies to explore the true prevalence of nutritional osteomalacia in various populations, specifically the Black and Asian ethnic groups, in order to identify the hidden disease burden and inform public health policies for vitamin D/calcium supplementation and food fortification.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Bone material strength is determined by several factors, such as bone mass, matrix composition, mineralization, architecture and shape. From a clinical perspective, bone fragility is classified as ...primary (i.e., genetic and rare) or secondary (i.e., acquired and common) osteoporosis. Understanding the mechanism of rare genetic bone fragility disorders not only advances medical knowledge on rare diseases, it may open doors for drug development for more common disorders (i.e., postmenopausal osteoporosis). In this review, we highlight the main disease mechanisms underlying the development of human bone fragility associated with low bone mass known to date. The pathways we focus on are type I collagen processing, WNT-signaling, TGF-ß signaling, the RANKL-RANK system and the osteocyte mechanosensing pathway. We demonstrate how the discovery of most of these pathways has led to targeted, pathway-specific treatments.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The consequences of vitamin D and dietary calcium deficiency have become a huge public health concern in the UK. The burden of disease from these deficiencies includes rickets, and hypocalcaemic ...seizures, dilated cardiomyopathy and mostly occult myopathy and osteomalacia. The increasing burden of the disease is intrinsically linked to ethnicity and the population demographic changes in the UK. Three facts have led to the resurfacing of the English disease: (1) the UK has no ultraviolet sunlight for at least 6 months of the year, (2) dark skin produces far less vitamin D than white skin per unit ultraviolet light exposure, and (3) non-European Union immigration over the last century. To date, the UK government demonstrates incomplete understanding of these three facts, and its failure to adjust its prevention programmes to changing demographics is endangering the health and life of UK residents with dark skin, of whom infants are the most vulnerable. Establishing accountability through the implementation of monitored antenatal and infantile supplementation programmes and mandatory food fortification is overdue.
Early diagnosis, optimal therapeutic management and regular follow up of children with X-linked hypophosphatemia (XLH) determine their long term outcomes and future quality of life. Biochemical ...screening of potentially affected newborns in familial cases and improving physician's knowledge on clinical signs, symptoms and biochemical characteristics of XLH for de novo cases should lead to earlier diagnosis and treatment initiation. The follow-up of children with XLH includes clinical, biochemical and radiological monitoring of treatment (efficacy and complications) and screening for XLH-related dental, neurosurgical, rheumatological, cardiovascular, renal and ENT complications. In 2018, the European Union approved the use of burosumab, a humanized monoclonal anti-FGF23 antibody, as an alternative therapy to conventional therapy (active vitamin D analogues and phosphate supplements) in growing children with XLH and insufficiently controlled disease.
Diagnostic criteria of XLH and the principles of disease management with conventional treatment or with burosumab are reviewed in this paper.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Current guidelines use differing definitions of vitamin D deficiency based on serum 25-hydroxyvitamin D (25OHD) levels, which complicates clinical decision making on vitamin D doses used for the ...prevention and treatment. This study examined the natural relationship between serum 25OHD, parathyroid hormone (PTH), calcium, phosphate, and alkaline phosphatase.
Two-hundred and fourteen children routinely admitted without conditions affecting the natural relationship among metabolites, including 17 with radiologically confirmed vitamin D deficiency rickets, were studied. The frequency of abnormal bone metabolites was examined for different 25OHD thresholds.
The best fitting intersection point where PTH levels increased was a 25OHD level of 34 nmol/l (R(2) = 0.454; 95% confidence interval: 27-41 nmol/l). Seventy-three and 86% of the children demonstrated some biochemical abnormality below 25OHD levels of 41 and 27 nmol/l, respectively. All patients with rickets had 25OHD levels < 34 nmol/l. The vast majority of children with abnormal bone metabolites had 25OHD levels < 34 nmol/l and PTH levels > 50 ng/l.
Vitamin D deficiency, based on PTH elevation, was best defined by a 25OHD level of < 34 nmol/l. Because deficient calcium supply often coexists with vitamin D deficiency and both can independently cause nutritional rickets, a threshold for the skeletal effects of vitamin D should not be based purely on 25OHD levels.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Micronutrient deficiencies are common among household/family members due to shared lifestyle and dietary habits. The extent of biochemical abnormalities in household members of children ...presenting with symptomatic vitamin D deficiency remains unknown.
Aim
Investigate the prevalence of vitamin D deficiency and biochemical osteomalacia in the mothers and siblings of children presenting with symptomatic vitamin D deficiency.
Methods
All mothers and sibling of children referred to a single tertiary endocrine centre between January 2018 and December 2021, with symptomatic vitamin D deficiency were investigated prospectively for vitamin D deficiency defined as 25 hydroxyvitamin D (25OHD) < 30nmol/L and biochemical osteomalacia vitamin D deficiency and elevated alkaline phosphatase (ALP) and/or parathormone (PTH) as per clinical guidelines.
Reults
Ninety-seven family members (68 siblings and 29 mothers) of 29 index cases (median age 1.7 years, 55.5% male) were investigated. The majority (65.5%, n=19) were of Asian ethnic background. The mean (SD) 25OHD levels of the index, maternal and sibling cohorts were 15 (10), 15 (7) and 20 (10) nmol/L respectively. Vitamin D deficiency was noted in 93% of the maternal and 79% of the sibling cohorts. Biochemical osteomalacia was present in 72% of the maternal and 79% of the sibling cohorts. Mothers of infants had significantly lower mean 25OHD levels compared to mothers of older children 11 (n=12) vs 18 nmol/L (n=17) respectively, p=0.006), most of whom were symptomatic (66.6%, n=8/12). None of the mothers had hypocalcaemia. Among the 10% (n=7) of the siblings with hypocalcaemia, 86% (n=6/7) had concurrent dietary calcium deficiency and 71.4% (n= 5/7) reported symptoms in retrospect. Hypocalcaemic siblings had significantly lower 25OHD (7 vs 15 nmol/L, p<0.001), higher PTH (175 vs 58 ng/L, p<0.001) and ALP (846 vs 318 IU/L, p<0.001), respectively compared to normocalcaemic siblings.
Conclusions
In view of the substantial morbidity uncovered in household/family members of children diagnosed with symptomatic vitamin D deficiency, we recommend universal supplementation of all risk groups. Biochemical testing and treatment is indicated to replenish stores only in those at highest risk such as mothers of infants, individuals with concurrent dietary calcium deficiency and those with clinical symptoms.
Abstract
The last 2 decades have seen growing recognition of the need to appropriately identify and treat children with osteoporotic fractures. This focus stems from important advances in our ...understanding of the genetic basis of bone fragility, the natural history and predictors of fractures in chronic conditions, the use of bone-active medications in children, and the inclusion of bone health screening into clinical guidelines for high-risk populations. Given the historic focus on bone densitometry in this setting, the International Society for Clinical Densitometry published revised criteria in 2013 to define osteoporosis in the young, oriented towards prevention of overdiagnosis given the high frequency of extremity fractures during the growing years. This definition has been successful in avoiding an inappropriate diagnosis of osteoporosis in healthy children who sustain long bone fractures during play. However, its emphasis on the number of long bone fractures plus a concomitant bone mineral density (BMD) threshold ≤ −2.0, without consideration for long bone fracture characteristics (eg, skeletal site, radiographic features) or the clinical context (eg, known fracture risk in serious illnesses or physical-radiographic stigmata of osteoporosis), inappropriately misses clinically relevant bone fragility in some children. In this perspective, we propose a new approach to the definition and diagnosis of osteoporosis in children, one that balances the role of BMD in the pediatric fracture assessment with other important clinical features, including fracture characteristics, the clinical context and, where appropriate, the need to define the underlying genetic etiology as far as possible.
Calcium and phosphorus represent building material for bones. The supplier of these bone minerals is the hormone calcitriol, which originates from vitamin D, itself made by sunshine in human skin. ...Requirement for bone minerals is highest during phases of rapid growth, and no one grows faster than the foetus and the infant, making them particularly vulnerable. Deprivation of calcium, whether through low calcium intake or low vitamin D, leads to serious health consequences throughout life, such as hypocalcaemic seizures, dilated cardiomyopathy, skeletal myopathy, congenital and infantile rickets, and osteomalacia. These 5 conditions are often summarised as ‘symptomatic vitamin D deficiency’, are fully reversible but also fully preventable. However, the increasing prevalence of rickets and osteomalacia, and the deaths from hypocalcaemic cardiomyopathy, demand action from global health care providers. Clarification of medical and parental responsibilities is a prerequisite to deliver successful prevention programmes. The foetus and infant have the human right to be protected against harm, and vitamin D supplementation has the same public health priority as vaccinations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Pubertal induction in girls with ovarian insufficiency aims to mimic normal puberty, a highly complex process. Here we amalgamate the sparse global evidence and propose three options for pubertal ...induction regimens including oral ethinyloestradiol, and oral and transdermal 17β-oestradiol. The introduction of progestogens is discussed and the transition to hormone supplementation for adult women. The merits and disadvantages of the different options are detailed. The available evidence indicates that transdermal 17β-oestradiol has the most favourable efficacy, safety and cost profile but randomised controlled trials are urgently required to determine which regimen provides the best clinical outcomes.
Purpose
1. To determine the effect of vitamin D supplementation on bone age (BA), a marker of skeletal maturity, and Bone Health Index (BHI), a surrogate marker of bone density. 2. To characterise ...the differences in nutritional intake and anthropometry between children with advanced vs. delayed BA.
Methods
The current study is a post hoc analysis of radiographs obtained as part of a randomised controlled trial. In this double-blind, placebo-controlled trial, deprived Afghan children (
n
= 3046) aged 1–11 months were randomised to receive six doses of oral placebo or vitamin D3 (100,000 IU) every 3 months for 18 months. Dietary intake was assessed through semi-quantitative food frequency questionnaires at two time points. Anthropometric measurements were undertaken at baseline and 18 months. Serum 25OHD was measured at five time points on a random subset of 632 children. Knee and wrist radiographs were obtained from a random subset (
n
= 641), of which 565 wrist radiographs were digitised for post-hoc analysis of BA and BHI using BoneXpert version 3.1.
Results
Nearly 93% (522, male = 291) of the images were analysable. The placebo (
n
= 258) and vitamin D (
n
= 264) groups were comparable at baseline. The mean (± SD) age of the cohort was 2 (± 0.3) years. At study completion, there was no difference in mean 25-hydroxy vitamin D concentrations 47 (95% CI 41, 56) vs. 55 (95% CI 45, 57) nmol/L,
p
= 0.2, mean (± SD) BA SDS − 1.04 (1.36) vs. − 1.14 (1.26) years,
p
= 0.3 or mean (± SD) BHI SDS − 0.30 (0.86) vs. − 0.31 (0.80),
p
= 0.8 between the placebo and vitamin D groups, respectively. Children with advanced skeletal maturity (BA SDS ≥ 0) when compared to children with delayed skeletal maturity (BA SDS < 0), had consumed more calories mean (± SD) calories 805 (± 346) vs 723 (± 327) kcal/day, respectively, p < 0.05, were significantly less stunted (height SDS − 1.43 vs. − 2.32,
p
< 0.001) and underweight (weight SDS − 0.82 vs. − 1.45,
p
< 0.001), with greater growth velocity (11.57 vs 10.47 cm/ year,
p
< 0.05).
Conclusion
Deprived children have significant delay in skeletal maturation but no substantial impairment in bone health as assessed by BHI. BA delay was influenced by total calorie intake, but not bolus vitamin D supplementation.
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DOBA, EMUNI, FIS, FSPLJ, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
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