Parathyroid hormone changes in infants investigated for inflicted injury; an observational retrospective single centre cohort study.

BACKGROUND: Biochemical and haematological testing is recommended in the United Kingdom when inflicted injury is suspected. We examined the associations of test results with radiologically-confirmed fracture(s), and between test results, in a large retrospective observational cohort. METHODS: Infants up to age two years presenting with suspected inflicted injury, without clinically or radiologically apparent bone disease, and where a skeletal survey was undertaken during the period 1st August 2013 to 31st December 2020, were included. Biochemical parameters: corrected calcium (cCa); phosphate (P); alkaline phosphatase (ALP); parathyroid hormone (PTH); 25-hydroxyvitamin D (25D); and haematological parameters: haemoglobin (Hb); mean corpuscular haemoglobin (MCH); mean corpuscular haemoglobin content (MCHC); mean corpuscular volume (MCV); platelet count were collated together with the results of the radiological assessments. FINDINGS: Of 332 eligible infants (190 male), 142 (84 male) had fracture(s) and/or intracranial injury. Mean PTH in the non-fracture group (n measured 50/190) was 27.3 ng/l; in those with intracranial injury alone (n measured 9/23) was 39.4 ng/l; in those with fracture alone (n measured 62/84) was 45.0 ng/l; and in those with fracture and intracranial injury (n measured 20/35) 51.8 ng/l. F-test of multiple means = 0.0369. There was no difference in 25D between the groups. INTERPRETATION: PTH was raised in infants who had fracture(s), intracranial injury or both. A single raised PTH may not necessarily be an indicator of prior disturbed skeletal health in these circumstances. The relevance of vitamin D status and interpretation of data from biochemical testing should be informed by the overall presentation in suspected inflicted injury cases. A single raised PTH may be a consequence of the child's injuries rather than prior disturbed bone health.

Monitoring Skull Base Abnormalities in Children with Osteogenesis Imperfecta - Review of Current Practice and a Suggested Clinical Pathway.

OBJECTIVES: In the context of a lack of national consensus on the benefits of skull base imaging in children with osteogenesis imperfecta (OI), this study aims to analyse and correlate the clinical symptoms and radiological images of children with severe OI. METHODS: A retrospective case notes and image analysis was carried out on children with complex OI between 2012 and 2018 at a specialist tertiary centre. Data were collected on patient demographic factors, clinical data, imaging findings (presence of Wormian bones, platybasia, basilar impression (McGregor's technique) and basilar invagination (McRae's technique)), and clinical features at the time of imaging. RESULTS: Of the 127 patients in the OI database, 94 were included. A total of 321 radiographs, 21 CT scans and 39 MRI scans were analysed. Average frequency of radiographs was 8 per 10 years. Of the 94 patients, 58 (62%), 10 (11%), 1 (1%) demonstrated platybasia, basilar impression, and basilar invagination, respectively. Of the radiographs analysed, platybasia, basilar impression, basilar invagination, and the presence of Wormian bones, could not be evaluated in 71 (22.3%), 48 (15.2%), 61 (19.5%) and 28 (9.4%) radiographs respectively (due to poor positioning, anatomical abnormalities, and poor image quality). Of the 140 radiographs with platybasia, 17 (12%) also demonstrated basilar impression compared to only 3 (2.9%) out of the 99 without platybasia (p = 0.03). No significant associations were seen between the presence of Wormian bones and basilar impression. Of the 39 MRIs, additional information on CSF flow rate, spinal cord signal and cerebellar morphology was reported in 14 (36%). There was a lack of concordance between MRI and matched radiographs in 7.1% (1/14) and 36% (5/14) for platybasia and basilar impression respectively, with full concordance for basilar invagination. Fewer than 5% had positive clinical symptoms/signs at the time of imaging; 2% (7/321) had macrocephaly, 0.6% (2/321) headache, all other neurological features were absent). Clinical features were not documented in >85% of patients. CONCLUSION: The apparent low prevalence of clinical symptoms and signs and of radiologically identified cranio-cervical abnormalities, suggests that current levels of serial imaging may be excessive. Until larger prospective studies clarify these issues, we suggest a clinical pathway for base of skull imaging which proposes a risk stratification approach to radiographic frequency and suggests parameters for proceeding to MRI.

High bone mass phenotype in a cohort of patients with Osteogenesis Imperfecta caused due to BMP1 and C-propeptide cleavage variants in COL1A1.

OBJECTIVES: Osteogenesis Imperfecta (OI) is a heterogeneous condition mainly characterised by bone fragility; extra-skeletal features in OI include blue sclerae, dentinogenesis imperfecta, skin laxity and joint hyper-extensibility. Most patients with OI are thought to have a low bone mass but contrary to expectations there are certain forms of OI with high bone mass which this study explores in further detail. METHOD: A cohort of n = 6 individuals with pathogenic variants in BMP1 and the C-propeptide cleavage variants in COL1A1 were included in this study. Detailed clinical and radiological phenotyping was done and correlated with genotype to identify patterns of clinical presentation and fracture history in this cohort of patients. This data was compared to previously reported literature in this group. RESULTS: 2 patients with BMP1 and 4 patients with pathogenic variants in C-propeptide region in COL1A1 were deep-phenotyped as part of this study and 1 patient with C-propeptide variant in COL1A1, showed low bone mineral density. In those with an elevated bone mineral density, this became even more apparent on bisphosphonate therapy. Patients in this cohort had variable clinical presentation ranging from antenatal presentation to more of an insidious course resulting in later confirmation of genetic diagnosis up to 19 years of age. CONCLUSIONS: Patients with pathogenic variants in the C-propeptide region of COL1A1/A2 and BMP1 appear to have a high bone mass phenotype with increased sensitivity to bisphosphonate therapy. It is important to closely monitor patients with these genotypes to assess their response to therapy and tailor their treatment regime accordingly.

Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment.

This article provides an overview of the current knowledge on hypophosphatasia-a rare genetic disease of very variable presentation and severity-with a special focus on adolescents and adults. It summarizes the available information on the many known mutations of tissue-nonspecific alkaline phosphatase (TNSALP), the epidemiology and clinical presentation of the disease in adolescents and adults, and the essential diagnostic clues. The last section reviews the therapeutic approaches, including recent reports on enzyme replacement therapy (EnzRT).

Latent Profiles of Macronutrient Density and their Association with Mobility Limitations in an Observational Longitudinal Study of Older U.S. Adults.

OBJECTIVES: Our first objective was to estimate empirically-derived subgroups (latent profiles) of observed carbohydrate, protein, and fat intake density in a nationally representative sample of older U.S. adults. Our second objective was to determine whether membership in these groups was associated with levels of, and short term change in, physical mobility limitations. DESIGN AND SETTING: Measures of macronutrient density were taken from the 2013 Health Care and Nutrition Study, an off-year supplement to the Health and Retirement Study, which provided indicators of physical mobility limitations and sociodemographic and health-related covariates. PARTICIPANTS: 3,914 community-dwelling adults age 65 years and older. MEASUREMENTS: Percent of daily calories from carbohydrate, protein, and fat were calculated based on responses to a modified Harvard food frequency questionnaire. Latent profile analysis was used to describe unobserved heterogeneity in measures of carbohydrate, protein, and fat density. Mobility limitation counts were based on responses to 11 items indicating physical limitations. Poisson regression models with autoregressive controls were used to identify associations between macronutrient density profile membership and mobility limitations. Sociodemographic and health-related covariates were included in all Poisson regression models. RESULTS: Four latent subgroups of macronutrient density were identified: "High Carbohydrate", "Moderate with Fat", "Moderate", and "Low Carbohydrate/High Fat". Older adults with the lowest percentage of daily calories coming from carbohydrate and the greatest percentage coming from fat ("Low Carbohydrate/High Fat") were found to have greater reported mobility limitations in 2014 than those identified as having moderate macronutrient density, and more rapid two-year increases in mobility limitations than those identified as "Moderate with Fat" or "Moderate". CONCLUSION: Older adults identified as having the lowest carbohydrate and highest fat energy density were more likely to report a greater number of mobility limitations and experience greater increases in these limitations than those identified as having moderate macronutrient density. These results suggest that the interrelation of macronutrients must be considered by those seeking to reduce functional limitations among older adults through dietary interventions.

Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcome and patient benefit. REPORT: Whole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (neuroblastoma amplified sequence). Patient 1: NBAS c.5741G>A p.(Arg1914His); c.3010C>T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G>A p.(Arg1914His); c.2032C>T p.(Gln678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency. DISCUSSION: Homozygous missense NBAS variants cause SOPH syndrome (short stature; optic atrophy; Pelger-Huet anomaly), the same missense variant was found in our patients on one allele and a nonsense variant in the other allele. Recent literature suggests a multi-system phenotype. In this study, patient fibroblasts have shown reduced collagen expression, compared to control cells and RNAseq studies, in bone cells show that NBAS is expressed in osteoblasts and osteocytes of rodents and primates. These findings provide proof-of-concept that NBAS mutations have mechanistic effects in bone, and that NBAS variants are a novel cause of bone fragility, which is distinguishable from 'Classical' OI. CONCLUSIONS: Here we report on variants in NBAS, as a cause of bone fragility in humans, and expand the phenotypic spectrum associated with NBAS. We explore the mechanism underlying NBAS and the striking skeletal phenotype in our patients.

The aetiology of rickets-like lower limb deformities in Malawian children.

UNLABELLED: Debilitating rickets-like lower limb deformities are common in children throughout the world, particularly in Malawi, Africa where the causes are unknown. We have identified that Blount disease and calcium deficiency rickets are the likely causes of these deformities and propose calcium supplementation as a potential treatment of Malawian rickets. INTRODUCTION: Surgical correction of rickets-like lower limb deformities is the most common paediatric operation performed at Beit Cure Orthopaedic Hospital, Malawi. The aim of this study was to investigate the aetiology of these deformities. METHODS: Children with a tibio-femoral angle of deformity >20° were enrolled (n = 42, 3.0-15.0 years). Anthropometric and early life and well-being data were collected. Early morning serum and urine samples were collected on the morning of the operation for markers of calcium and phosphate homeostasis. Knee radiographs were obtained, and the children were diagnosed with either Blount (BD, n = 22) or evidence of rickets disease (RD, n = 20). As BD is a mechanical rather than metabolic disease, BD were assumed to be biochemically representative of the local population and thus used as a local reference for RD. RESULTS: There were no differences in anthropometry or early life experiences between BD and RD. Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, total alkaline phosphatase and urinary phosphate were significantly higher and serum phosphate, 25-hydroxyvitamin D (25OHD) and tubular maximal reabsorption of phosphate significantly lower in RD than BD. There was no difference in serum calcium, fibroblast growth factor 23 or markers of iron status between groups. All children had 25OHD > 25 nmol/L. CONCLUSIONS: Vitamin D deficiency is not implicated in the aetiology of RD or BD in Malawian children. The cause of RD in Malawi is likely to be dietary calcium deficiency leading to elevated PTH resulting in increased losses of phosphate from the bone and glomerular filtrate. The causes of BD remain unclear; there was no evidence in support of previously suggested risk factors such as being overweight or starting to walk early. Prior to surgical intervention, supplementation with calcium should be considered for children with RD.

Osteogenesis imperfecta: Ultrastructural and histological findings on examination of skin revealing novel insights into genotype-phenotype correlation.

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. Over 90% of patients with OI have a mutation in COL1A1/COL1A2, which shows an autosomal dominant pattern of inheritance. In-depth phenotyping and in particular, studies involving manifestations in the skin connective tissue have not previously been undertaken in OI. The aims of the study were to perform histological and ultrastructural examination of skin biopsies in a cohort of patients with OI; to identify common and distinguishing features in order to inform genotype-phenotype correlation; and to identify common and distinguishing features between the different subtypes of OI. As part of the RUDY (Rare Diseases in Bone, Joints and/or Blood Vessels) study, in collaboration with the NIHR Rare Diseases Translational Research Collaboration, we undertook a national study of skin biopsies in patients with OI. We studied the manifestations in the skin connective tissue and undertook in-depth clinical and molecular phenotyping of 16 patients with OI. We recruited 16 patients: analyses have shown that in type 1 collagen mutation positive patients (COL1A1/ COL1A2) (n-4/16) consistent findings included: variable collagen fibril diameter (CFD) and presence of collagen flowers. Histological examination in these patients showed an increase in elastic fibers that are frequently fragmented and clumped. These observations provide evidence that collagen flowers and CFD variability are consistent features in OI due to type 1 collagen defects and reinforce the need for accurate phenotyping in conjunction with genomic analyses.

Acute bone response to whole body vibration in healthy pre-pubertal boys.

The skeleton responds to mechanical stimulation. We wished to ascertain the magnitude and speed of the growing skeleton's response to a standardised form of mechanical stimulation, vibration. 36 prepubertal boys stood for 10 minutes in total on one of two vibrating platforms (high (>2 g) or low (<1 g) magnitude vibration) on either 1, 3 or 5 successive days (n=12 for each duration); 15 control subjects stood on an inactive platform. Blood samples were taken at intervals before and after vibration to measure bone formation (P1NP, osteocalcin) and resorption (CTx) markers as well as osteoprotegerin and sclerostin. There were no significant differences between platform and control groups in bone turnover markers immediately after vibration on days 1, 3 and 5. Combining platform groups, at day 8 P1NP increased by 25.1% (CI 12.3 to 38.0; paired t-test p=0.005) and bone resorption increased by 10.9% (CI 3.6 to 18.2; paired t-test p=0.009) compared to baseline. Osteocalcin, osteoprotogerin and sclerostin did not change significantly. The growing skeleton can respond quickly to vibration of either high or low magnitude. Further work is needed to determine the utility of such "stimulation-testing" in clinical practice.

Collagen gene polymorphisms influence fracture risk and bone mass acquisition during childhood and adolescent growth.

Fractures are common in childhood with incidence maximal during puberty, around the time of peak height velocity. The relationships between single nucleotide polymorphisms (SNPs) in COL1A1 and COL1A2, bone mass acquisition, and childhood fractures are unclear. We recruited 394 children and adolescents aged 4 to 16 years into a noninterventional case control study. All had suffered an episode of trauma leading to hospital presentation; 205 had sustained a fracture. We determined the frequency of COL1A1 Sp1 and COL1A2 PvuII SNPs. Lumbar spine dual-energy X-ray absorptiometry (DXA) measurements were compared between fracture and control groups according to genotype. Subgroup analyses were performed according to sex, pubertal status, and site of injury. We found that the COL1A2 'PP' genotype approximately halved the odds of fracture in the study group as a whole (OR=0.45 [95% CI=0.24-0.82], p=0.01). In particular, possession of the same genotype by subjects who had not yet progressed beyond midpuberty was associated with reduced odds of fracture (OR=0.38 [95% CI=0.19-0.79], p=0.01) and significantly increased lumbar spine bone mineral content (p=0.03) and areal bone mineral density (p=0.007). The COL1A1 Sp1 binding site 's' allele was associated with a trebling of the odds of fracture in prepubertal children (OR=3.1 [95% CI=1.43-6.61], p=0.004), but there was no association with any DXA measures. This is the first paediatric study to our knowledge that shows an association of the COL1A2 PvuII restriction site 'PP' genotype with a reduced risk of fracture and of the COL1A1 Sp1 binding site 's' allele with an increased risk. The association of these variants with fracture risk is greatest during periods of predominantly appendicular bone growth.

Special report on the 2007 adult and pediatric Position Development Conferences of the International Society for Clinical Densitometry.

The International Society for Clinical Densitometry (ISCD) conducts Position Development Conferences (PDCs) for the purpose of establishing standards and guidelines in the field of bone densitometry. Topics for consideration are selected according to clinical relevance, a perceived need for standardization, and the likelihood of achieving agreement. Questions regarding nomenclature, indications, acquisition, analysis, quality control, interpretation, and reporting of bone density tests for each topic area are assigned to task forces for a comprehensive review of the scientific literature. The findings of the review and recommendations are then presented to an international panel of experts at the PDC. The expert panel votes on potential Official Positions for appropriateness, necessity, quality of the evidence, strength of the recommendation, and applicability (worldwide or variable according to local requirements). Recommendations that are approved by the ISCD Board of Directors become Official Positions. The first Pediatric PDC was 20-21 June 2007 in Montreal, QC, Canada. The most recent Adult PDC was held 20-22 July 2007, in Lansdowne, VA, USA. This Special Report summarizes the methodology of the ISCD PDCs and presents selected Official Positions of general interest.

Two doses of pamidronate in infants with osteogenesis imperfecta.

INTRODUCTION: Current regimens of intravenous pamidronate for infants and children with osteogenesis imperfecta (OI) typically deliver 3-12 mg/kg/year of drug. We wished to ascertain the effect of pamidronate at 6 or 12 mg/kg/year on skeletal health in infants with OI. METHODS: We recruited 12 infants over a period of 4 years. Infants received either 6 or 12 mg/kg/year of pamidronate. Bone outcomes were assessed by skeletal surveys and DXA bone density measurements at baseline and at 12 months. RESULTS: Bone mass increased in both groups. Infants receiving 12 as opposed to 6 mg/kg/year pamidronate had increased spine bone density after adjusting for covariates at study entry (p = 0.04). Crush fractures improved or remained unchanged in all but one infant. Biochemical markers of bone turnover fell but remained within or above the normal range for age. Metaphyseal remodelling was not impaired. CONCLUSIONS: Pamidronate dose in infants may influence lumbar spine bone acquisition. Pamidronate improved vertebral size after prior crush fracturing and did not over-suppress bone turnover.

Bisphosphonate treatment of bone disease.

In 1997 a review article on bisphosphonates in this journal identified 24 published articles relating to children at that time. Since then there has been a considerable increase in their use in clinical paediatric practice and research with there being nearly a further one hundred articles published at the time of writing.

Chemically modified tetracyclines act through multiple mechanisms directly on osteoclast precursors.

Chemically modified tetracyclines (CMTs) are thought to inhibit bone resorption primarily through their ability to inhibit matrix metalloproteinases (MMPs). We have previously demonstrated that some tetracycline compounds (TCs) induce apoptosis in mature rabbit osteoclasts and inhibit osteoclastic resorption in mouse osteoblast/marrow co-cultures in vitro. In this report, we now show that non-antibiotic analogues of doxycycline (CMT-3) and minocycline (CMT-8) are potent inhibitors of osteoclastogenesis in vitro from human peripheral blood mononuclear cells (PBMC) stimulated with macrophage colony stimulating factor (MCSF) and receptor activator of NF-kappaB ligand (RANKL), through an action that is independent of osteoblast-osteoclast interactions. Osteoclast formation over 20 days was completely abrogated when CMT-3 or CMT-8 were included in PBMC cultures at a concentration of 250 ng/ml, although doxycycline at this concentration reduced osteoclast formation to ca. 50% of control. CMT-3 and CMT-8 also significantly induced apoptosis over 24 h in mature osteoclasts generated over 20 days when added to cultures at 5 microg/ml or more. In a time-course experiment, apoptosis was evident after a delay of 1-2 h following treatment of mature osteoclasts with CMT-3 at 20 microg/ml. The broad-spectrum MMP inhibitor BB94 (Batimastat) did not recapitulate the apoptosis induced by CMT-3, even at a concentration where MMP-13 activity was completely inhibited. There was no evidence for an anabolic effect of any of the TCs on osteoblast lineage cells in a calcifying fibroblastic colony (CFU-f) formation assay, where CMT-3 partially inhibited CFU-f formation at 5 microg/ml. Our data indicate that inhibition of osteoclast formation and induction of osteoclast apoptosis are pharmacologically significant actions of CMTs in inhibiting bone resorption, and that osteoclast apoptosis cannot be attributed to the ability of CMTs to inhibit MMPs or to actions mediated by osteoblastic lineage cells.

Male sex and low physical activity are associated with reduced spine bone mineral density in survivors of childhood acute lymphoblastic leukemia.

Survivors of acute lymphoblastic leukemia (ALL) are at risk of osteoporosis and obesity. We studied bone mineral density (BMD), percent of fat mass (%FM), and activity levels in survivors of ALL treated without radiotherapy. Lumbar and total areal BMD (g/cm2) and %FM were measured in 28 survivors (aged 5.7-14.7 years) of childhood ALL by dual-energy X-ray absorptiometry (DXA) scan (GE Lunar, Prodigy) an average of 5 years after completion of chemotherapy (UK Medical Research Council randomized trial protocol XI [UKALL XI]). One boy fractured his arm during treatment. Apparent volumetric lumbar BMD (BMD(vol); g/cm3) was calculated and %FM was adjusted for sex and age (%FM(adj)). Physical activity was measured by accelerometer and questionnaire. The results were compared with 28 sex- and age-matched healthy controls. Total body and lumbar areal BMD (g/cm2) were not different between the ALL group and the control group. However, mean lumbar BMD(vol) in survivors of ALL was significantly lower than in controls (0.303 +/- 0.036 g/cm3 vs. 0.323 +/- 0.03 g/cm3; p < 0.01), which mostly was caused by the difference in boys (0.287 +/- 0.032 g/cm3 vs. 0.312 +/- 0.027 g/cm3; p < 0.05). Weekly activity score by questionnaire was significantly lower in the ALL group than in the control group (geometric mean 50 vs. geometric mean 74; p < 0.05). Male gender, low activity levels and an intravenous (iv) high dose of methotrexate were associated with low lumbar BMD(vol). Patients who received an iv high dose of methotrexate (n = 18) had significantly higher %FM(adj) than those with intrathecal methotrexate only (n = 10; 141 +/- 70% vs. 98 +/- 37%;p < 0.05). In conclusion, male survivors of childhood ALL have reduced lumbar BMD(vol), whereas no such difference was seen in girls. Overall, survivors of ALL were physically less active than their healthy controls and lower activity correlated with lower lumbar BMD(vol) and higher %FM(adj).

Clinical management of childhood osteoporosis.

A current working definition of osteoporosis in children is 'fragility fractures in association with low bone mass'. This review illustrates the determinants of bone mass and fracture risk. We elucidate the pathophysiology and causes of osteoporosis in various childhood disorders, with a particular focus on the commonest iatrogenic problem, glucocorticoid-induced osteoporosis. We discuss clinical evaluation, investigation and multidisciplinary management including lifestyle advice, diet, physiotherapy and occupational therapy, drug treatments and monitoring for children with osteoporosis. We also emphasise the important concepts of bone mass assessment and interpretation in children.