High-resolution peripheral quantitative computed tomography in children with osteogenesis imperfecta.

Bone health in children with osteogenesis imperfecta is monitored using radiographs and dual-energy X-ray absorptiometry, which have limitations. High-resolution peripheral quantitative CT can non-invasively derive bone microarchitectural data. Children with severe osteogenesis imperfecta have fragile deformed bones, and positioning for this scan can be difficult. We assessed the feasibility of high-resolution peripheral quantitative CT in nine children aged 9-15 years with osteogenesis imperfecta and compared results with dual-energy X-ray absorptiometry and with healthy controls. All nine recruited children were successfully scanned and showed no preference for either modality. It therefore appears feasible to perform high-resolution peripheral quantitative CT in children with osteogenesis imperfecta aged 9 years and older. Future studies should focus on understanding the clinical implications of the technology in this patient cohort.

Effect of vitamin D supplementation on free and total vitamin D: A comparison of Asians and Caucasians.

OBJECTIVES: It is well established that UK Asians typically have lower vitamin D levels than Caucasians. It is also known that vitamin D binding protein (DBP) is lower in some races than Caucasians. To investigate how ethnicity, skin colour and genetic variation affect the response to vitamin D (15000 IU) administered to young Asian and Caucasian men. DESIGN: Prospective, single-centre clinical trial. PARTICIPANTS: Sixty young men (18-25 year) of Asian (n = 30) and Caucasian (n = 30) origin. MEASUREMENTS: We measured serum calcium, phosphate, magnesium, alkaline phosphatase, albumin, parathyroid hormone; total 25 hydroxyvitamin D (25OHD); calculated and directly measured free 25OHD; DBP at baseline and 4 weeks; DBP genotype, skin colour (Fitzpatrick scale), dietary vitamin D and calcium intake at baseline; and urine calcium:creatinine ratio at baseline, 1 and 4 weeks. RESULTS: At baseline, Asians had lower serum total 25OHD (26.4 [13.7] vs 34.1 [12.3] nmol/L P = 0.0272) and DBP (6.7 [3.4] vs 9.6 [4.4] nmol/L; P = 0.0065) but similar free 25OHD (16.7 [10.4] vs 17.8 [7.5] pmol/L P = 0.6530). After dosing, total 25OHD rose similarly in each group (≈56 nmol/L), but measured free 25OHD rose more in Asians (18.1 [9.4] vs 12.2 [13.3] pmol/L P = 0.0464). Lower DBP at baseline, possibly reflecting genotype differences, was associated with a greater change in measured free 25OHD in Caucasians, but not in Asians. CONCLUSIONS: Asian compared with Caucasian males had a larger increment in measured free 25OHD following 150 000 units vitamin D3, possibly reflecting differences in DBP affinity for 25OHD. Ethnicity should be considered when devising guidelines for the treatment of vitamin D deficiency.

Early life vitamin D depletion alters the postnatal response to skeletal loading in growing and mature bone.

There is increasing evidence of persistent effects of early life vitamin D exposure on later skeletal health; linking low levels in early life to smaller bone size in childhood as well as increased fracture risk later in adulthood, independently of later vitamin D status. A major determinant of bone mass acquisition across all ages is mechanical loading. We tested the hypothesis in an animal model system that early life vitamin D depletion results in abrogation of the response to mechanical loading, with consequent reduction in bone size, mass and strength during both childhood and adulthood. A murine model was created in which pregnant dams were either vitamin D deficient or replete, and their offspring moved to a vitamin D replete diet at weaning. Tibias of the offspring were mechanically loaded and bone structure, extrinsic strength and growth measured both during growth and after skeletal maturity. Offspring of vitamin D deplete mice demonstrated lower bone mass in the non loaded limb and reduced bone mass accrual in response to loading in both the growing skeleton and after skeletal maturity. Early life vitamin D depletion led to reduced bone strength and altered bone biomechanical properties. These findings suggest early life vitamin D status may, in part, determine the propensity to osteoporosis and fracture that blights later life in many individuals.

Osteogenesis imperfecta.

Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation.

Osteogenesis imperfecta in adults.

A 42-year-old premenopausal woman with osteogenesis imperfecta presents to the metabolic bone clinic. She has a daughter with osteogenesis imperfecta who is seen regularly in a specialist pediatric clinic, but the patient herself hasn't had a clinical consultation in years. She has pain and stiffness in her back and is worried for her future bone health. The patient asks, "Am I going to fall apart?" She had numerous fractures in childhood, including fractures of her femur and wrist; fractured her ankles several times in her late teens; and had occasional fractures in adulthood. Her last fracture was a comminuted fracture of her humerus three years ago, when she stumbled and fell forward onto her hands and knees. The woman is hyperextensible and thinks her ankles feel weak. Her bone mineral density T scores are -2.6 at the lumbar spine and -1.9 at the total hip, and spine imaging shows several vertebral endplate deformities, but overall preservation of vertebral height. What are the available pharmacological and nonpharmacological strategies to preserve her skeletal health and function?

The role of bone shape in determining gender differences in vertebral bone mass.

Dual-energy X-ray absorptiometry (DXA) measures of bone mineral density (BMD) in children fail to account for growth because bone depth is unmeasured. While multiple adjustment methods have been proposed using body or bone size, the effect of vertebral shape is relatively unknown. Our study aimed to determine gender differences in vertebral shape and their impact on areal BMD (aBMD). We recruited 189 children, including 107 boys, aged 4-17 years, who attended the emergency department due to trauma. None had fractured. Height, weight, Tanner stage, and DXA measurements of the lumbar spine (LS) and total body were obtained. Cylindrical models were used to predict relationships between vertebral width (VW) and areal density for a given vertebral area assuming uniform volumetric density. The actual relationships between VW, bone area, and aBMD for the LS in the children were then determined. The theoretical models predicted a positive relationship between width and areal density for a constant vertebral area. Actual vertebral measurements demonstrated that boys had greater VW for a given vertebral area but lower aBMD for a given VW than girls at any age. The most likely explanation for the apparent paradox was that vertebral cortical thickness relative to width was greater in girls. This difference remained after adjusting for lean mass, suggesting that bone's response to mechanical stimulation may vary between the sexes during growth with consequent evolutionary advantage for girls approaching reproductive age.

Aluminium exposure from parenteral nutrition in preterm infants and later health outcomes during childhood and adolescence.

Aluminium is the most common metallic element, but has no known biological role. It accumulates in the body when protective gastrointestinal mechanisms are bypassed, renal function is impaired, or exposure is high - all of which apply frequently to preterm infants. Recognised clinical manifestations of aluminium toxicity include dementia, anaemia and bone disease. Parenteral nutrition (PN) solutions are liable to contamination with aluminium, particularly from acidic solutions in glass vials, notably calcium gluconate. When fed parenterally, infants retain >75% of the aluminium, with high serum, urine and tissue levels. Later health effects of neonatal intravenous aluminium exposure were investigated in a randomised trial comparing standard PN solutions with solutions specially sourced for low aluminium content. Preterm infants exposed for >10 d to standard solutions had impaired neurologic development at 18 months. At 13-15 years, subjects randomised to standard PN had lower lumbar spine bone mass; and, in non-randomised analyses, those with neonatal aluminium intake above the median had lower hip bone mass. Given the sizeable number of infants undergoing intensive care and still exposed to aluminium via PN, these findings have contemporary relevance. Until recently, little progress had been made on reducing aluminium exposure, and meeting Food and Drug Administration recommendations (<5 µg/kg per d) has been impossible in patients <50 kg using available products. Recent advice from the UK Medicines and Healthcare regulatory Authority that calcium gluconate in small volume glass containers should not be used for repeated treatment in children <18 years, including preparation of PN, is an important step towards addressing this problem.

Official positions of the International Society for Clinical Densitometry (ISCD) on DXA evaluation in children and adolescents.

Dual-energy X-ray absorptiometry (DXA) is the most widely used technical instrument for evaluating bone mineral content (BMC) and density (BMD) in patients of all ages. However, its use in pediatric patients, during growth and development, poses a much more complex problem in terms of both the technical aspects and the interpretation of the results. For the adults population, there is a well-defined term of reference: the peak value of BMD attained by young healthy subjects at the end of skeletal growth. During childhood and adolescence, the comparison can be made only with healthy subjects of the same age, sex and ethnicity, but the situation is compounded by the wide individual variation in the process of skeletal growth (pubertal development, hormone action, body size and bone size). The International Society for Clinical Densitometry (ISCD) organized a Pediatric Position Development Conference to discuss the specific problems of bone densitometry in growing subjects (9-19 years of age) and to provide essential recommendations for its clinical use.

Aluminum exposure from parenteral nutrition in preterm infants: bone health at 15-year follow-up.

OBJECTIVE: Aluminum has known neurotoxicity and may impair short-term bone health. In a randomized trial, we showed reduced neurodevelopmental scores in preterm infants who were previously exposed to aluminum from parenteral nutrition solutions. Here, in the same cohort, we test the hypothesis that neonatal aluminum exposure also adversely affects long-term bone health, as indicated by reduced bone mass. METHODS: Bone area (BA) and bone mineral content (BMC) of lumbar spine, hip, and whole body were measured with dual radiograph absorptiometry in 13- to 15-year-olds who were born preterm and randomly assigned standard or aluminum-depleted parenteral nutrition solutions during the neonatal period. RESULTS: Fifty-nine children (32% of survivors) were followed. Those who were randomly assigned to standard parenteral nutrition solution had lower lumbar spine BMC, apparently explained by a concomitant decrease in bone size. In nonrandomized analyses, children who were exposed to neonatal aluminum intakes above the median (55 microg/kg) had lower hip BMC (by 7.6% [95% confidence interval: 0.12-13.8]; P = 0.02), [corrected] independent of bone (or body) size. CONCLUSIONS: Neonates who are exposed to parenteral aluminum may have reduced lumbar spine and hip bone mass during adolescence, potential risk factors for later osteoporosis and hip fracture. These findings need confirmation in larger, more detailed studies. Nevertheless, given our previous finding of adverse developmental outcome in these individuals and the sizeable number of contemporary infants who undergo intensive neonatal care and are still exposed to aluminum via parenteral feeding solutions, the potential adverse long-term consequences of early aluminum exposure now deserve renewed attention.

Prenatal and infant predictors of bone health: the influence of vitamin D.

Vitamin D is essential for the health of pregnant women and their infants. Vitamin D insufficiency and deficiency during pregnancy are reflected in lower maternal weight gain and biochemical evidence of disturbed skeletal homeostasis in the infant, with, in extreme situations, reduced bone mineralization, radiologically evident rickets, and fractures. Populations at risk for vitamin D deficiency are those for which, for environmental, cultural, or medical reasons, exposure to sunlight is poor and the dietary intake of vitamin D is low. The infants born in such populations have low vitamin D stores and may receive little additional vitamin D if they are breast-fed without supplements for long periods. In the short term, lack of vitamin D supplementation in infancy leads to biochemical disturbances, reduced bone mineralization, slower growth, and eventual alterations in bone shape and increased risk of fracture, the hallmarks of rickets. In the longer term, lack of vitamin D supplementation may result in reduced bone size and mass during childhood and an increased risk of type 1 diabetes mellitus. Clear recommendations are needed regarding the intake of vitamin D during pregnancy and infancy. Such recommendations should be based on functional outcomes, rather than biochemical measurements, so that the medical problems resulting from the lack of this essential nutrient can be overcome.