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Bone Health and Linear Growth in Children With Familial Hypoparathyroidism Treated With Human Parathyroid Hormone 1-34
Abstract
Context:
Our study explores the impact of human PTH 1-34 injections (PTH therapy) on growth, areal bone mineral density (BMD), and bone quality (measured by trabecular bone score, TBS) in hypoparathyroidism due to autoimmune polyendocrine syndrome type 1 (APS-1) or an activating variant of the calcium sensing receptor (CaR).
Objective:
To assess associations of 1) age and PTH therapy duration with age-standardized Z-scores for height (HAZ), BMD (BMD-Z), and TBS (TBS-Z) in CaR or APS-1, and 2) APS-1 disease severity with BMD-Z and TBS-Z.
Methods:
This secondary analysis pooled linear growth and lumbar spine (LS) DXA data from studies of hypoparathyroidism with mean baseline age of 13.7±5.5y. Comparing the two diagnostic etiologies (18 APS-1 and 9 CaR), we examined the impact of age and PTH duration on HAZ, LS-BMD-Z, and LS-TBS-Z using longitudinal mixed-effects modeling.
Results:
During PTH therapy, mean HAZ remained below zero in the APS-1 group at all ages, whereas HAZ increased in the CaR group (age by group interaction p<0.0001). Mean LS-BMD-Z were normal (BMD-Z:0±1) for both groups. Mean LS-TBS-Z were near or above zero and differed by group; CaR showed an upward trajectory according to time on PTH whereas the APS-1 group maintained a LS-TBS-Z of approximately 0 (time by group interaction p=0.02). The APS-1 group with greater disease severity (≥7 manifestations) had lower LS-BMD-Z and LS-TBS-Z compared to the less severe APS-1 or CaR groups.
Conclusion:
Our study highlights distinct growth and BMD patterns in APS-1 and CaR and underscores the need for careful monitoring and tailored treatment strategies to optimize growth and bone health.
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Osteogenesis imperfecta (OI) is a hereditary skeletal disease characterized by bone fragility. Areal bone mineral density (BMD), evaluated by dual-energy X-ray absorptiometry (DXA), is used to assess bone brittleness. The height-adjusted BMD Z-score (BMDHAZ) is calculated in children and adolescents with OI to reduce the confounding factor of short stature. However, even with the BMDHAZ, severity evaluation in children and adolescents with OI is challenging because certain abnormalities in bone quality cannot be accurately assessed by BMD analysis. The trabecular bone scores (TBS) and bone mineral apparent density (BMAD), which represent the structural integrity of bone and bone-size-associated BMD, respectively, are associated with fracture risk. Recently, age- and sex-specific reference ranges have been reported, enabling the calculation of Z-scores for children. To evaluate which density measurements show the highest correlation with fracture risk, we analyzed the associations between the Z-scores of TBS, BMAD, and BMDHAZ, fracture rate, and genetic variants. We retrospectively reviewed 42 participants with OI aged 5 to 20 years who underwent DXA. COL1A1/2 pathogenic variants were detected in 41 of the 42 participants. In participants with nonsense and frameshift variants (n = 17) resulting in haploinsufficiency and mild phenotype, the TBS Z-score was negatively correlated with fracture rate (FR) (r = -0.50, p = 0.042). In participants with glycine substitution (n = 9) causing the severe phenotype, the BMAD Z-scores were negatively correlated with FR (r = -0.74, p = 0.022). No correlation between the BMDHAZ and FR was observed in both groups. These findings suggest that the TBS and BMAD are useful in assessing children and adolescents with OI with specific genetic variants.
Unlabelled:
Areal-bone mineral density (aBMD) of lumbar-spine dual energy X-ray absorptiometry (DXA) scan is the most frequently used tool in evaluating BMD in pediatric patients, however its size dependency have significant impact on measurements accuracy in children with chronic kidney disease (CKD). This study aimed to evaluate the usefulness of trabecular bone score (TBS) computed during lumbar-spine DXA scan in assessing bone status in children on maintenance hemodialysis (HD). Ninety-three children on HD (aged 9-18 years) were subjected to lumbar-spine DXA-scan to obtain aBMD (g/cm2) and TBS.Z-scores of aBMD for chronological-age (aBMDZ-CA), height-age (aBMDZ-HA), and TBSZ-score were calculated using mean and SD values of 442 healthy controls. aBMD and TBS were significantly lower in short-for-age and normal height-for-age patients compared to the corresponding values of controls (p < 0.05 for all). Degraded vertebral microarchitecture (TBSZ-score < -2) was detected in 48% and 44% of male and female patients respectively. There were no significant differences in median TBSZ-score between short-for-age and normal height-for-age HD patients in male (p = 0.425) and in female (p = 0.316) patients. TBSZ-score correlated significantly with aBMDZ-CA (r = 0.234; p = 0.024) but not with aBMDZ-HA (r = 0.077; p = 0.462). Patients with history of fractures (5 patients only) had significantly lower TBS scores compared to those without fracture history (p = 0.016).
Conclusion:
TBS is significantly reduced in children on maintenance HD and is associated with increased fracture incidence. TBS has shown to be a promising tool in assessing bone quality (trabecular microarchitecture) in children with CKD being not size-dependent as is a-BMD, for further evaluation of its potential role in therapeutic and follow-up decisions.
What is known:
• In children with CKD, bone demineralization starts as early as CKD stage 2, so assessment of bone health is mandatory for follow up and therapeutic decisions. • aBMD of lumbar-spine DXA scan is the most used tool in evaluating BMD in pediatric patients, however its size dependency have significant impact on measurements made in children with CKD.
What is new:
• TBS is significantly reduced in children on maintenance HD and associated with increased fracture incidence. • TBS has shown to be a promising tool in assessing bone quality (trabecular microarchitecture) in children with CKD being not size-dependent as is a-BMD.
Glucocorticoids (GC) are an important risk factor for bone fragility in children with serious illnesses, largely due to their direct adverse effects on skeletal metabolism. To better appreciate the natural history of fractures in this setting, over a decade ago the Canadian ST eroid-associated O steoporosis in the P ediatric P opulation (“ STOPP ”) Consortium launched a 6 year, multi-center observational cohort study in GC-treated children. This study unveiled numerous key clinical-biological principles about GC-induced osteoporosis (GIO), many of which are unique to the growing skeleton. This was important, because most GIO recommendations to date have been guided by adult studies, and therefore do not acknowledge the pediatric-specific principles that inform monitoring, diagnosis and treatment strategies in the young. Some of the most informative observations from the STOPP study were that vertebral fractures are the hallmark of pediatric GIO, they occur early in the GC treatment course, and they are frequently asymptomatic (thereby undetected in the absence of routine monitoring). At the same time, some children have the unique, growth-mediated ability to restore normal vertebral body dimensions following vertebral fractures. This is an important index of recovery, since spontaneous vertebral body reshaping may preclude the need for osteoporosis therapy. Furthermore, we now better understand that children with poor growth, older children with less residual growth potential, and children with ongoing bone health threats have less potential for vertebral body reshaping following spine fractures, which can result in permanent vertebral deformity if treatment is not initiated in a timely fashion. Therefore, pediatric GIO management is now predicated upon early identification of vertebral fractures in those at risk, and timely intervention when there is limited potential for spontaneous recovery. A single, low-trauma long bone fracture can also signal an osteoporotic event, and a need for treatment. Intravenous bisphosphonates are currently the recommended therapy for pediatric GC-induced bone fragility, typically prescribed to children with limited potential for medication-unassisted recovery. It is recognized, however, that even early identification of bone fragility, combined with timely introduction of intravenous bisphosphonate therapy, may not completely rescue the osteoporosis in those with the most aggressive forms, opening the door to novel strategies.
The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism.
Objective: Immunological abnormalities, the resulting endocrinopathies and their treatments may impact bone health in patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED, APS1). The aim of the present study was to describe skeletal characteristics in patients with APECED and the prevalence and risk factors of compromised bone health. Patients and methods: We performed a cross-sectional study on 44 patients (27 females) with APECED and 82 age-, gender- and ethnicity-matched control subjects (54 females). We determined the prevalence of osteoporosis by dual-energy X-ray absorptiometry and skeletal characteristics by peripheral quantitative computed tomography at radius and tibia. Results: Patients were examined at the median age of 37.8 years (range, 7.0–70.1). Dual-energy X-ray absorptiometry indicated osteoporosis in four adult patients (9%); radiographs showed vertebral fractures in three patients. The prevalence of multiple non-spinal fractures was higher in patients than in controls. On peripheral quantitative computed tomography, bone characteristics at distal and proximal radius did not differ between the groups. At distal tibia, patients had lower total (p = 0.009) and trabecular (p = 0.033) volumetric bone mineral density. At the proximal tibia, patients had lower cortical thickness (p < 0.001) than controls. Severity of APECED phenotype influenced both radial and tibial characteristics: cortical thickness and total and trabecular volumetric bone mineral density were lower in patients with ≥7 disease manifestations as compared with more mildly affected patients, whose values were similar to controls. Conclusions: APECED associated with bone structural alterations, especially in patients with a high number of disease manifestations. This may increase the risk of fractures with aging, but symptomatic osteoporosis was rare.
Importance
Bone health in early life is thought to influence the risk of osteoporosis in later life.
Objective
To examine whether puberty timing is associated with bone mineral density accrual up to adulthood.
Design, Setting, and Participants
This cohort study used data from the Avon Longitudinal Study of Parents and Children, a prospective population-based birth cohort initiated in 1991 to 1992 in southwest England. The participants were 6389 healthy British people who underwent regular follow-up, including up to 6 repeated bone density scans from ages 10 to 25 years. Data analysis was performed from June 2018 to June 2019.
Exposures
Age at puberty from estimated age at peak height velocity (years).
Main Outcomes and Measures
Gains per year in whole-body bone mineral density (grams per square centimeter), assessed by dual-energy x-ray absorptiometry at ages 10, 12, 14, 16, 18, and 25 years and modeled using linear splines.
Results
A total of 6389 participants (3196 [50.0%] female) were included. The mean (SD) age at peak height velocity was 13.5 (0.9) years for male participants and 11.6 (0.8) years for female participants. Male participants gained bone mineral density at faster rates than did female participants, with the greatest gains in both male participants (0.139 g/cm²/y; 95% CI, 0.127-0.151 g/cm²/y) and female participants (0.106 g/cm²/y; 95% CI, 0.098-0.114 g/cm²/y) observed between the year before and 2 years after peak height velocity. When aligned by chronological age, per 1-year older age at puberty was associated with faster subsequent gains in bone mineral density; the magnitudes of faster gains were greatest between ages 14 and 16 years in both male participants (0.013 g/cm²/y; 95% CI, 0.011-0.015 g/cm²/y) and female participants (0.014 g/cm²/y; 95% CI, 0.014-0.015 g/cm²/y), were greater in male participants (0.011 g/cm²/y; 95% CI, 0.010-0.013 g/cm²/y) than in female participants (0.003 g/cm²/y; 95% CI, 0.003-0.004 g/cm²/y) between ages 16 and 18 years, and were least in both male participants (0.002 g/cm²/y; 95% CI, 0.001-0.003 g/cm²/y) and female participants (0.000 g/cm²/y; 95% CI, −0.001 to 0.000 g/cm²/y) between ages 18 and 25 years. Despite faster gains, older age at puberty was associated with persistently lower bone mineral density, changing from 0.050 g/cm² (95% CI, −0.056 to −0.045 g/cm²) lower at age 14 years to 0.047 g/cm² (95% CI, −0.051 to −0.043 g/cm²) lower at age 25 years in male participants and from 0.044 g/cm² (95% CI, −0.046 to −0.041 g/cm²) to 0.034 g/cm² (95% CI, −0.036 to −0.032 g/cm²) lower at the same ages in female participants.
Conclusions and Relevance
People with older pubertal age should be advised on how to maximize bone mineral density and minimize its decrease in later life to help prevent fracture and osteoporosis.
Background:
Later puberty associates with lower areal bone mineral density (aBMD), and both are risk factors for osteoporosis. However, the association between puberty timing-associated genetic variants and aBMD during development, and the causal relationship between puberty timing and aBMD, remain uncharacterized.
Methods:
We constructed sex-specific polygenic risk scores (GRS) consisting of 333 genetic variants associated with later puberty in European-descent children in the Bone Mineral Density in Childhood Study (BMDCS), consisting of a longitudinal cohort with up to seven assessments (n = 933) and a cross-sectional cohort (n = 486). These GRS were tested for associations with age- and sex-specific aBMD Z-scores at the lumbar spine (LS), femoral neck (FN), total hip, and distal radius, accounting for clinical covariates using sex-stratified linear mixed models. The causal relationship between puberty timing and aBMD was tested in the BMDCS and in publicly available adult data (GEFOS consortium) using two-sample Mendelian randomization (MR).
Results:
The puberty-delaying GRS was associated with later puberty and lower LS-aBMD in the BMDCS in both sexes (combined beta (SE) = -0.078 (0.024), P = 0.0010). In the MR framework, the puberty-delaying genetic instrument also supported a causal association with lower LS-aBMD and FN-aBMD in adults of both sexes.
Conclusions:
Our results suggest that pubertal timing is causal for diminished aBMD in a skeletal site-and sex-specific manner that tracks throughout life, potentially impacting later risk for osteoporosis, which should be tested in future studies. This article is protected by copyright. All rights reserved.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous AIRE mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common AIRE mutation was c.967_979del13. All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic AIRE mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4(+) T cells and CD21(lo)CD38(lo) B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications.
Context:
In children, bone mineral content (BMC) and bone mineral density (BMD) measurements by dual-energy x-ray absorptiometry (DXA) are affected by height status. No consensus exists on how to adjust BMC or BMD (BMC/BMD) measurements for short or tall stature.
Objective:
The aim of this study was to compare various methods to adjust BMC/BMD for height in healthy children.
Design:
Data from the Bone Mineral Density in Childhood Study (BMDCS) were used to develop adjustment methods that were validated using an independent cross-sectional sample of healthy children from the Reference Data Project (RDP).
Setting:
We conducted the study in five clinical centers in the United States.
Participants:
We included 1546 BMDCS and 650 RDP participants (7 to 17 yr of age, 50% female).
Intervention:
No interventions were used.
Main outcome measures:
We measured spine and whole body (WB) BMC and BMD Z-scores for age (BMC/BMD(age)), height age (BMC/BMD(height age)), height (BMC(height)), bone mineral apparent density (BMAD(age)), and height-for-age Z-score (HAZ) (BMC/BMD(haz)).
Results:
Spine and WB BMC/BMD(age)Z and BMAD(age)Z were positively (P < 0.005; r = 0.11 to 0.64) associated with HAZ. Spine BMD(haz) and BMC(haz)Z were not associated with HAZ; WB BMC(haz)Z was modestly associated with HAZ (r = 0.14; P = 0.0003). All other adjustment methods were negatively associated with HAZ (P < 0.005; r = -0.20 to -0.34). The deviation between adjusted and BMC/BMD(age) Z-scores was associated with age for most measures (P < 0.005) except for BMC/BMD(haz).
Conclusions:
Most methods to adjust BMC/BMD Z-scores for height were biased by age and/or HAZ. Adjustments using HAZ were least biased relative to HAZ and age and can be used to evaluate the effect of short or tall stature on BMC/BMD Z-scores.
This report presents the revised growth charts for the United States. It summarizes the history of the 1977 National Center for Health Statistics (NCHS) growth charts, reasons for the revision, data sources and statistical procedures used, and major features of the revised charts.
Data from five national health examination surveys collected from 1963 to 1994 and five supplementary data sources were combined to establish an analytic growth chart data set. A variety of statistical procedures were used to produce smoothed percentile curves for infants (from birth to 36 months) and older children (from 2 to 20 years), using a two-stage approach. Initial curve smoothing for selected major percentiles was accomplished with various parametric and nonparametric procedures. In the second stage, a normalization procedure was used to generate z-scores that closely match the smoothed percentile curves.
The 14 NCHS growth charts were revised and new body mass index-for-age (BMI-for-age) charts were created for boys and girls (http://www.cdc.gov/growthcharts). The growth percentile curves for infants and children are based primarily on national survey data. Use of national data ensures a smooth transition from the charts for infants to those for older children. These data better represent the racial/ethnic diversity and the size and growth patterns of combined breast- and formula-fed infants in the United States. New features include addition of the 3rd and 97th percentiles for all charts and extension of all charts for children and adolescents to age 20 years.
Created with improved data and statistical curve smoothing procedures, the United States growth charts represent an enhanced instrument to evaluate the size and growth of infants and children.
Background:
Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood.
Methods:
We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses.
Results:
Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients.
Conclusions:
Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
Trabecular bone score (TBS) derived from secondary analysis of lumbar spine DXA scans improves fracture prediction independent of BMD in adults. The utility of TBS to assess fracture risk in younger patients has not been established because pediatric norms have been lacking. Robust TBS reference data from the Bone Mineral Density in Childhood Study (BMDCS) have been published. TBS values for the BMDCS study were derived using an algorithm that accounts for tissue thickness (TBSTH ) rather than the commercially-available algorithm that adjusts for BMI (TBSBMI ). We examined the magnitude of differences in TBSTH and TBSBMI in a cohort of 189 healthy youth. TBS values using both algorithms increased with age and pubertal development in a similar pattern. However,TBSBMI values were systematically and significantly higher than TBSTH (mean=0.06, p<0.0001). The difference between calculated TBSBMI and TBSTH was not uniform. Differences were greater at lower TBS values, in males, in older individuals, in those at later Tanner stages and in those with a greater BMI Z-score. These systematic differences preclude the development of a simple formula to allow conversion of TBSBMI to TBSTH "equivalents". Because of these systematic differences in these two algorithms, using an individual's TBSBMI to calculate a Z-score using the BMDCS TBSTH reference values results in a falsely higher TBS Z-score (differences mean=0.73, IQR=0.3 to 1.6). Until TBSTH software for Hologic DXA equipment becomes commercially available, BMDCS TBS reference norms should not be used. This article is protected by copyright. All rights reserved.
Trabecular bone score (TBS) is used for fracture prediction in adults, but its utility in children is limited by absence of appropriate reference values. We aimed to develop reference ranges for TBS by age, sex and population ancestry for youth ages 5 to 20 years. We also investigated the association between height, BMI and TBS, agreement between TBS and lumbar spine areal bone mineral density (aBMD) and bone mineral apparent density (BMAD) Z‐scores, tracking of TBS Z‐scores over time, and precision of TBS measurements. We performed secondary analysis of spine DXA scans from the Bone Mineral Density in Childhood Study (BMDCS), a mixed longitudinal cohort of healthy children (n=2014) evaluated at 5 U.S. centers. TBS was derived using a dedicated TBS algorithm accounting for tissue thickness rather than BMI. TBS increased only during ages corresponding to pubertal development with an earlier increase in females than males. There were no differences in TBS between African Americans and non‐African Americans. We provide sex‐specific TBS reference ranges and LMS values for calculation of TBS Z‐scores by age and means and SD for calculation of Z‐scores by pubertal stage. TBS Z‐scores were positively associated with height Z‐scores at some ages. TBS Z‐scores explained only 27% and 17% of the variance of spine aBMD and BMAD Z‐scores. Tracking of TBS Z‐scores over 6 years was lower (r=0.47) than for aBMD or BMAD Z‐scores (r=0.74 to 0.79), and precision error of TBS (2.87%) was greater than for aBMD (0.85%) and BMAD (1.22%). In sum, TBS Z‐scores provide information distinct from spine aBMD and BMAD Z‐scores. Our robust reference ranges for TBS in a well‐characterized pediatric cohort and precision error estimates provide essential tools for clinical assessment using TBS, and determination of its value in predicting bone fragility in childhood and adolescence. This article is protected by copyright. All rights reserved.
In this meta-analysis, we analyzed 7 observational studies for assessing the fracture risk in patients with hypoparathyroidism (hypoPT). We found that the risk of vertebral fractures is increased by almost 2-fold, especially those with nonsurgical hypoPT.PurposePatients with hypoPT have higher bone mineral density than age- and sex-matched controls. This would theoretically translate into a lower risk of fractures, although available clinical evidence is contradictory. Hence, the present systematic review and meta-analysis was undertaken to collate and provide a precise summary of fracture risk in hypoPT.Methods
PubMed, Scopus, and Web of Science databases were systematically searched using appropriate keywords till March 8, 2021, to identify observational studies reporting the rate of occurrence of fractures among hypoPT patients (nonsurgical and/or postsurgical) compared to non-hypoPT subjects (controls). Study quality was assessed using Newcastle-Ottawa Scale. Pooled odds ratio (OR) with 95% confidence intervals (CI) was calculated. Subgroup analyses of nonsurgical and postsurgical hypoPT patients were also conducted.ResultsWe identified 7 observational studies of high-quality pooling data retrieved from 1470 patients with hypoPT. When stratified based on the skeletal site, pooled analyses showed that hypoPT patients were at an increased risk of vertebral fractures compared to non-hypoPT controls (OR 2.22, 95% CI: 1.23, 4.03, p = 0.009, I2 = 49%, random-effects model). The increased risk of vertebral fractures was seen only in patients with nonsurgical hypoPT (OR 2.31, 95% CI: 1.32, 4.03, p = 0.003, I2 = 3%, random-effects model) but not in those with postsurgical hypoPT. hypoPT patients were not at an increased or decreased risk of any, humerus, or proximal femur/hip fractures than controls.Conclusions
Nonsurgical hypoPT patients are at an almost 2-fold increased risk of vertebral fractures and thus need to be actively screened irrespective of the underlying BMD.
Objective
Hypoparathyroidism has heterogeneous genetic and acquired etiologies with a broad spectrum of severity. Herein we describe the clinical outcomes of the largest cohort of hypoparathyroid patients reported to date, who were followed over 27-years.
Design
Pooled analysis of current and past studies describing the differential responses to PTH 1-34 injections vs conventional therapy among the varied hypoPT etiologies.
Methods
192 participants (ages 2-74 years) with hypoparathyroidism who received either calcitriol and calcium or PTH 1-34 by subcutaneous injection.
Results
Among the 4 main etiologic categories of hypoparathyroidism (autoimmune polyglandular failure type 1, activating mutation of the calcium receptor, surgical, and idiopathic hypoparathyroidism), we reveal significant differences in PTH 1-34 dose requirements, prevalence of nephrocalcinosis, biomarkers of mineral homeostasis, and pharmacodynamic profiles. Serum 1,25-dihydroxyvitamin D3 increased significantly (P<0.001) and 25-hydroxyvitamin D levels decreased during PTH 1-34 injections compared to calcitriol therapy (P<0.01). Post-surgical patients achieved consistently lower urine calcium excretion over long-term PTH 1-34 therapy compared to conventional therapy (p<0.001), but this was not achieved in the other etiologies. At study entry, patients had a high prevalence of renal insufficiency and nephrocalcinosis which were directly related to the duration of hypoparathyroidism (P<0.03). Renal function remained stable during participation in our studies for both PTH 1-34 and conventional therapies.
Conclusions
We conclude that the effects and dose-response of PTH 1-34 treatment differ according to the etiology of hypoparathyroidism. Postsurgical hypoPT maintained mean serum calcium levels in the mid- to low-normal range while concurrently maintaining normal mean urine calcium during long-term twice-daily PTH 1-34 therapy.
Gain-of-function mutations of the calcium-sensing receptor (CaSR) lead to disordered mineral homeostasis with disproportionate calcium excretion associated with small increases in blood calcium. Patients with this form of hypoparathyroidism have intractable hypercalciuria leading to nephrocalcinosis and renal damage which may appear, in the more severe cases, during early childhood. This case of severe hypoparathyroidism in a child with a sporadic activating mutation in the CaSR illustrates the overall benefit of parathyroid hormone replacement therapy in managing children with this disorder. Despite early diagnosis during the neonatal period, control of mineral homeostasis was never achieved in infancy and early childhood. This case report describes our 10-year experience treating a child who was referred to us at age 6 years old because of failure to thrive and worsening renal function while receiving conventional therapy with calcitriol, calcium, and thiazide diuretics. Synthetic human parathyroid hormone PTH(1–34) therapy improved her clinical status but reducing urine calcium to normal levels remained a challenge. In an effort achieve normal mineral homeostasis, she was placed first on twice daily then thrice daily injections and finally received PTH delivered by pump which led to the normalization of both serum and urine calcium excretion.
Objective:
To determine whether multiple daily injections of parathyroid hormone (PTH) 1-34 are safe and effective as long-term therapy for children with hypoparathyroidism.
Study design:
Linear growth, bone accrual, renal function, and mineral homeostasis were studied in a long-term observational study of PTH 1-34 injection therapy in 14 children.
Methods:
Subjects were 14 children with hypoparathyroidism attributable to autoimmune polyglandular syndrome type 1 (N = 5, ages 7-12 years) or calcium receptor mutation (N = 9, ages 7-16 years). Mean daily PTH 1-34 dose was 0.75 ± 0.15 µg/kg/day. Treatment duration was 6.9 ± 3.1 years (range 1.5-10 years). Patients were evaluated semiannually at the National Institutes of Health Clinical Center.
Results:
Mean height velocity and lumbar spine, whole body, and femoral neck bone accretion velocities were normal throughout the study. In the first 2 years, distal one-third radius bone accrual velocity was reduced compared with normal children (P < .003). Serum alkaline phosphatase correlated with PTH 1-34 dose (P < .006) and remained normal (235.3 ± 104.8 [SD] U/L, N: 51-332 U/L). Mean serum and 24-hour urine calcium levels were 2.05 ± 0.11 mmol/L (N: 2.05-2.5 mmol/L) and 6.93 ± 1.3 mmol/24 hour (N: 1.25-7.5 mmol/24 hour), respectively-with fewer high urine calcium levels vs baseline during calcitriol and calcium treatment (P < .001). Nephrocalcinosis progressed in 5 of 12 subjects who had repeated renal imaging although renal function remained normal.
Conclusions:
Twice-daily or thrice-daily subcutaneous PTH 1-34 injections provided safe and effective replacement therapy for up to 10 years in children with hypoparathyroidism because of autoimmune polyglandular syndrome type 1 or calcium receptor mutation.
Context
Dual-energy X-ray absorptiometry (DXA) is a cornerstone of pediatric bone health assessment, yet differences in height-for-age confound the interpretation of areal bone mineral density (aBMD) measures. To reduce the confounding of short stature on spine bone density, use of bone mineral apparent density (BMAD) and height-for-age Z-score (HAZ) adjusted aBMD (aBMDHAZ) are recommended. However, spine BMAD reference data are sparse, and the degree to which BMAD and aBMDHAZ account for height-related artifacts in bone density remains unclear.
Objective
We developed age-, sex-, and population ancestry-specific spine BMAD reference ranges; compared height-adjustment methods in accounting for shorter stature; and assessed the stability of these measures over time.
Design
Secondary analysis of data from a previous longitudinal study.
Participants
Children and adolescents ages 5-19 years at baseline (n=2014; 922 males, 22% African American) from the Bone Mineral Density in Childhood Study.
Main Outcome Measures
Lumbar spine BMAD and aBMDHAZ from DXA.
Results
Spine BMAD increased non-linearly with age and was greater in African Americans and females (all P<0.001). Age-specific spine BMAD Z-score reference curves were constructed for African American and non-African American males and females. Overall, both BMAD and aBMDHAZ Z-scores reduced the confounding influence of shorter stature, but neither were consistently unbiased across all age ranges. Both BMAD and aBMDHAZ Z-scores tracked strongly over 6 years (r=0.70-0.80, all P<0.001).
Conclusion
This study provides robust spine BMAD reference ranges and demonstrates that BMAD and aBMDHAZ partially reduce the confounding influence of shorter stature on bone density.
Precis
Adjusting for effects of short stature on childhood bone density is important. Spine bone mineral apparent density and height adjusted aBMD Z-scores reduced stature-related artifacts at most ages.
Osteoporosis is a common bone disease characterized by low bone mass and altered bone microarchitecture, resulting in decreased bone strength with an increased risk of fractures. In clinical practice, physicians can assess the risk of fracture for a patient based on several risk factors. Some such as age, weight, and history of fractures after 50 years of age, parental fracture, smoking status, and alcohol intake are incorporated into FRAX, an assessment tool that estimates the 10-year probability of hip fracture and major osteoporotic fractures based on the individual's risk factors profile. The diagnosis of osteoporosis is currently based on bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry scans. Among other widely recognized limitations of BMD is that BMD considers only the density of the bone and fails in measuring bone microarchitecture, for which novel techniques, such as trabecular bone score (TBS), have been developed. TBS is a texture parameter related to bone microarchitecture that may provide skeletal information that is not captured from the standard BMD measurement. Several studies have examined the value of TBS on predicting osteoporotic fractures. Our study aimed to summarize a review of the current scientific literature with focus on fracture risk assessment and to present both its findings and its conclusions regarding how and when TBS should be used. The existing literature indicates that low lumbar spine TBS is associated with a history of fracture and the incidence of new fracture. The effect is largely independent of BMD and of sufficient magnitude to enhance risk stratification with BMD. The TBS effect is also independent of FRAX, with likely greatest utility for those individuals whose BMD levels lie close to an intervention threshold. The clinical and scientific evidence supporting the use of TBS, with the ability of this technology to be seamlessly integrated into a daily workflow, makes TBS an attractive and useful clinical tool for physicians to improve patient management in osteoporosis. Further research is ongoing and necessary to further clarify the role of TBS in additional specific disorders.
Chronic inflammation and malabsorption in gastrointestinal disease can cause bone metabolism alterations and bone mineral loss in children and adults. Gastrointestinal disease is often forgotten as a cause of osteoporosis, osteopenia, or osteomalacia. The etiology of pathologic bone alterations in gastrointestinal disease is multifactorial. Bone alterations were thought to result simply from intestinal malabsorption, but a more complex interaction between cytokines and local/systemic factors influencing bone formation and resorption is envisaged. This review provides an updated discussion on bone alterations in patients with malabsorption due to celiac disease or inflammatory bowel disease. © Thieme Medical Publishers333 Seventh Avenue, New York, NY 10001, USA
The risk of fragility fractures is increased in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Although BMD is decreased in T1DM, BMD in T2DM is often normal or even slightly elevated compared with an age-matched control population. However, in both T1DM and T2DM, bone turnover is decreased and the bone material properties and microstructure of bone are altered; the latter particularly so when microvascular complications are present. The pathophysiological mechanisms underlying bone fragility in diabetes mellitus are complex, and include hyperglycaemia, oxidative stress and the accumulation of advanced glycation endproducts that compromise collagen properties, increase marrow adiposity, release inflammatory factors and adipokines from visceral fat, and potentially alter the function of osteocytes. Additional factors including treatment-induced hypoglycaemia, certain antidiabetic medications with a direct effect on bone and mineral metabolism (such as thiazolidinediones), as well as an increased propensity for falls, all contribute to the increased fracture risk in patients with diabetes mellitus. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
Hypoparathyroidism (HypoPT) is an uncommon endocrine disorder characterized by chronic deficiency or absence of parathyroid hormone (PTH), which leads to a profound reduction in bone remodeling. Subjects with HypoPT typically have bone mineral densities (BMDs) by dual-energy X-ray absorptiometry (DXA) above average at all skeletal sites, with greatest scores observed at the lumbar spine. Trabecular bone score (TBS), an indirect measure of bone microarchitecture, also appears to be normal in HypoPT. By peripheral quantitative computed tomography (pQCT) of the radius, volumetric BMD at cancellous and cortical compartments, as well as cortical area and thickness, are greater in hypoparathyroid subjects than in controls. The use of high-resolution pQCT (HRpQCT) confirmed the increase in cortical volumetric BMD but demonstrated reduced cortical thickness, associated with lower cortical porosity in HypoPT. Trabeculae tend to be more numerous but thinner in hypoparathyroid subjects. It is not clear whether these structural and the dynamic skeletal abnormalities in HypoPT affect bone strength or fracture risk. Treatment of HypoPT with PTH leads to improvement in bone remodeling rate, variable changes in bone density, and a transient increase in estimated bone strength. The effect of PTH therapy on fracture risk remains unknown. This article reviews skeletal involvement and the effect of PTH treatment in patients with HypoPT, as assessed by DXA, TBS, QCT, and HRpQCT. Data on bone strength and fracture risk in HypoPT are also reviewed here.
Altered bone micro-architecture is an important factor in accounting for fragility fractures. Until recently, it has not been possible to gain information about skeletal microstructure in a way that is clinically feasible. Bone biopsy is essentially a research tool. High-resolution peripheral Quantitative Computed Tomography, while non-invasive, is available only sparsely throughout the world. The trabecular bone score (TBS) is an imaging technology adapted directly from the Dual Energy X-Ray Absorptiometry (DXA) image of the lumbar spine. Thus, it is potentially readily and widely available. In recent years, a large number of studies have demonstrated that TBS is significantly associated with direct measurements of bone micro-architecture, predicts current and future fragility fractures in primary osteoporosis, and may be a useful adjunct to BMD for fracture detection and prediction. In this review, we summarize its potential utility in secondary causes of osteoporosis. In some situations, like glucocorticoid-induced osteoporosis and in diabetes mellitus, the TBS appears to out-perform DXA. It also has apparent value in numerous other disorders associated with diminished bone health, including primary hyperparathyroidism, androgen-deficiency, hormone-receptor positive breast cancer treatment, chronic kidney disease, hemochromatosis, and autoimmune disorders like rheumatoid arthritis. Further research is both needed and warranted to more clearly establish the role of TBS in these and other disorders that adversely affect bone.
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 (9–19years of age)
and to provide essential recommendations for its clinical use.
Deficits in bone acquisition during growth may increase fracture risk. Assessment of bone health during childhood requires appropriate reference values relative to age, sex, and population ancestry to identify bone deficits.
The objective of this study was to provide revised and extended reference curves for bone mineral content (BMC) and areal bone mineral density (aBMD) in children.
The Bone Mineral Density in Childhood Study was a multicenter longitudinal study with annual assessments for up to 7 yr.
The study was conducted at five clinical centers in the United States.
Two thousand fourteen healthy children (992 males, 22% African-Americans) aged 5-23 yr participated in the study. Intervention: There were no interventions.
Reference percentiles for BMC and aBMD of the total body, lumbar spine, hip, and forearm were obtained using dual-energy x-ray absorptiometry for Black and non-Black children. Adjustment factors for height status were also calculated.
Extended reference curves for BMC and aBMD of the total body, total body less head, lumbar spine, total hip, femoral neck, and forearm for ages 5-20 yr were constructed relative to sex and age for Black and non-Black children. Curves are similar to those previously published for 7-17 year olds. BMC and aBMD values were greater for Black vs. non-Black children at all measurement sites.
We provide here dual-energy x-ray absorptiometry reference data on a well-characterized cohort of 2012 children and adolescents. These reference curves provide the most robust reference values for the assessment and monitoring of bone health in children and adolescents in the literature to date.
Current evidence points to suboptimal bone health in children and adolescents with inflammatory bowel disease (IBD) when compared with their healthy peers. This compromise is evident from diagnosis. The clinical consequences and long-term outcome of this finding are still unknown. The mechanism of suboptimal bone health in children and adolescents with IBD lays mainly in reduced bone formation, but also reduced bone resorption, processes necessary for bone growth. Factors contributing to this derangement are inflammation, delayed growth and puberty, lean mass deficits, and use of glucocorticoids. We recognize that evidence is sparse on the topic of bone health in children and adolescents with IBD. In this clinical guideline, based on current evidence, we provide recommendations on screening and monitoring bone health in children and adolescents with IBD, including modalities to achieve this and their limitations; monitoring of parameters of growth, pubertal development, and reasons for concern; evaluation of vitamin D status and vitamin D and calcium intake; exercise; and nutritional support. We also report on the current evidence of the effect of biologics on bone health in children and adolescents with IBD, as well as the role of bone active medications such as bisphosphonates. Finally, we summarize the existing numerous gaps in knowledge and potential subjects for future research endeavors.
Hypoparathyroidism is among the few hormonal insufficiency states not treated with replacement of the missing hormone. This is the first randomized controlled study in children comparing treatment with synthetic human PTH 1-34 and calcitriol.
The primary objective was to assess the efficacy and safety of long-term PTH 1-34 vs. calcitriol treatment in the maintenance of normal serum calcium values and renal calcium excretion in children with hypoparathyroidism.
The study was conducted at a clinical research center.
Subjects included 12 children aged 5-14 yr with chronic hypoparathyroidism and without severe renal or hepatic insufficiency.
The study was a 3-yr randomized parallel trial comparing twice-daily calcitriol (plus calcium and cholecalciferol in four daily doses) vs. s.c. PTH 1-34 treatment, with weekly or biweekly monitoring of serum and urine calcium.
Mean predose serum calcium levels were maintained at, or just below, the normal range, and urine calcium levels remained in the normal range throughout the 3-yr study, with no significant differences between treatment groups. Creatinine clearance, corrected for body surface area, did not differ between groups and remained normal throughout the study. Markers of bone turnover were mildly elevated during PTH 1-34 therapy and remained within the normal range during calcitriol therapy. Mean bone mineral density Z-scores at the anterior-posterior lumbar spine, femoral neck, distal radius, and whole body remained within the normal range and did not differ between groups throughout the study. Similarly, height and weight percentiles did not differ between treatment groups and remained normal throughout the 3-yr follow-up.
We conclude that PTH 1-34 therapy is safe and effective in maintaining stable calcium homeostasis in children with hypoparathyroidism. Additionally, PTH 1-34 treatment allowed normal skeletal development because there were no differences in bone mineral accrual, linear growth, or weight gain between the two treatment arms over the 3-yr study period.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is characterized by chronic mucocutaneous candidiasis and autoimmune destruction of endocrine organs. The resulting endocrinopathies and their treatment may impact bone health. The purpose of our study was to assess bone health and its correlates in adult patients with APECED.
Twenty-five adults (12 males) with APECED were prospectively assessed. Data on their previous medical history were collected from hospital records. Areal bone mineral density (aBMD) for the lumbar spine (L1-L4), femoral neck and whole body as well as volumetric BMD (vBMD) for the lumbar spine (L2-L4) were measured with dual-energy X-ray absorptiometry (DXA).
Mean age was 34 years (range 21-59 years). All patients had 1-4 autoimmune endocrinopathies, the most common being adrenocortical failure (20 patients) and hypoparathyroidism (18 patients). Osteopaenia or osteoporosis was present in 28%. The median (range) aBMD Z-scores were for the lumbar spine -0.3 (-2.3 to +3.3) and for the femoral neck, -0.1 (-2.2 to +2.0). The BMD Z-scores tended to be higher in patients with hypoparathyroidism than in patients with normal parathyroid function (at the lumbar spine +0.4 vs.-1.2, P = 0.016, and at the femoral neck +0.3 vs.-0.4, P = 0.090). Adrenocortical failure had a negative impact on BMD. Six patients had had low-impact fractures and three were diagnosed with compression fractures.
Despite the complex endocrine problems, the overall prevalence of symptomatic osteoporosis is low in adults treated for APECED. Osteopaenia is frequently observed and warrants follow-up. Treated hypoparathyroidism may have a positive, and adrenocortical failure a negative, impact on bone health.
Hypoparathyroidism [published correction appears in Nat Rev Dis Primers. 2017 Oct 05;3:17080. doi: 10.1038/nrdp.2017.80]
- Mannstadt