Dataset Information

Postmenopausal osteoporotic fracture-associated COLIA1 variant impacts bone accretion in girls.

ABSTRACT: Over the past two decades, a low frequency variant (rs1800012) within the first intron of the type I collagen alpha 1 (COLIA1) gene has been implicated in lower areal BMD (aBMD) and increased risk of osteoporotic fracture. This association is particularly strong in postmenopausal women, in whom net bone loss arises in the context of high bone turnover. High bone turnover also accompanies childhood linear growth; however, the role of rs1800012 in this stage of net bone accretion is less well understood. Thus, we assessed the association between rs1800012 and aBMD and bone mineral content (BMC) Z-scores for the 1/3 distal radius, lumbar spine, total hip, and femoral neck total body less head in the Bone Mineral Density in Childhood Study, a mixed-longitudinal cohort of children and adolescents (total n?=?804 girls and 771 boys; n?=?19 girls and 22 boys with the TT genotype). Mixed effects modeling, stratified by sex, was used to test for associations between rs1800012 and aBMD or BMC Z-scores and for pubertal stage interactions. Separately, SITAR growth modeling of aBMD and BMC in subjects with longitudinal data reduced the complex longitudinal bone accrual curves into three parameters representing a-size, b-timing, and c-velocity. We tested for differences in these three parameters by rs1800012 genotype using t-tests. Girls with the TT genotype had significantly lower aBMD and BMC Z-scores prior to puberty completion (e.g. spine aBMD-Z P-interaction?=?1.0?×?10-6), but this association was attenuated post-puberty. SITAR models revealed that TT girls began pubertal bone accrual later (b-timing; e.g. total hip BMC, P?=?0.03). BMC and aBMD Z-scores also increased across puberty in TT homozygous boys. Our data, along with previous findings in post-menopausal women, suggest that rs1800012 principally affects female bone density during periods of high turnover. Insights into the genetics of bone gain and loss may be masked during the relatively quiescent state in mid-adulthood, and discovery efforts should focus on early and late life.

SUBMITTER: Cousminer DL

PROVIDER: S-EPMC6800229 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Postmenopausal osteoporotic fracture-associated COLIA1 variant impacts bone accretion in girls.

Cousminer Diana L DL McCormack Shana E SE Mitchell Jonathan A JA Chesi Alessandra A Kindler Joseph M JM Kelly Andrea A Voight Benjamin F BF Kalkwarf Heidi J HJ Lappe Joan M JM Shepherd John A JA Oberfield Sharon E SE Gilsanz Vicente V Zemel Babette S BS Grant Struan F A SFA

Bone 20190131

Over the past two decades, a low frequency variant (rs1800012) within the first intron of the type I collagen alpha 1 (COLIA1) gene has been implicated in lower areal BMD (aBMD) and increased risk of osteoporotic fracture. This association is particularly strong in postmenopausal women, in whom net bone loss arises in the context of high bone turnover. High bone turnover also accompanies childhood linear growth; however, the role of rs1800012 in this stage of net bone accretion is less well unde ...[more]

PMID: 30711642

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Project description:The study examined long-term direct and indirect economic burden of osteoporotic fractures among postmenopausal women. Healthcare costs among fracture patients were substantial in first year after fracture and remained higher than fracture-free controls for 5 years which highlight needs for early detection of high-risk patients and continued management for osteoporosis.IntroductionThis study compared direct and indirect healthcare costs between postmenopausal women and demographically matched controls in the 5 years after incident non-traumatic fracture, and by fracture type in commercially insured and Medicare populations.MethodsTwo hundred twenty-six thousand one hundred ninety women (91,925 aged 50-64 years; 134,265 aged ≥ 65 years) with incident non-traumatic fracture (hip, vertebral, and non-hip non-vertebral (NHNV)) from 2008 to 2017 were identified. Patients with fracture were directly matched (1:1) to non-fracture controls based on demographic characteristics. Direct healthcare costs were assessed using general linear models, adjusting for baseline costs, comorbidities, osteoporosis diagnosis, and treatment. Indirect costs associated with work loss due to absenteeism and short-term disability (STD) were assessed among commercially insured patients. Costs were standardized to 2019 US dollars.ResultsOsteoporosis diagnosis and treatment rates prior to fracture were low. Patients with fracture incurred higher direct costs across 5-year post-index compared with non-fracture controls, regardless of fracture type or insurance. For commercially insured hip fracture patients, the mean adjusted incremental direct healthcare costs in years 1, 3, and 5 were $59,327, $6885, and $3241, respectively. Incremental costs were lower, but trends were similar for vertebral and NHNV fracture types and Medicare-insured patients. Commercially insured patients with fracture had higher unadjusted indirect costs due to absenteeism and STD in year 1 and higher adjusted indirect costs due to STD at year 1 (incremental cost $5848, $2748, and $2596 for hip, vertebral, and NHNV fracture).ConclusionsA considerable and sustained economic burden after a non-traumatic fracture underscores the need for early patient identification and continued management.

Project description:Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a "one-size-fits-all" approach to diagnosis and management of osteoporosis may not be suitable. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides additive information by capturing information about volumetric density and microarchitecture, but interpretation is challenging because of the complex interactions between the numerous properties measured. In this study, we propose that there are common combinations of bone properties, referred to as phenotypes, that are predisposed to different levels of fracture risk. Using HR-pQCT data from a multinational cohort (n = 5873, 71% female) between 40 and 96 years of age, we employed fuzzy c-means clustering, an unsupervised machine-learning method, to identify phenotypes of bone microarchitecture. Three clusters were identified, and using partial correlation analysis of HR-pQCT parameters, we characterized the clusters as low density, low volume, and healthy bone phenotypes. Most males were associated with the healthy bone phenotype, whereas females were more often associated with the low volume or low density bone phenotypes. Each phenotype had a significantly different cumulative hazard of major osteoporotic fracture (MOF) and of any incident osteoporotic fracture (p < 0.05). After adjustment for covariates (cohort, sex, and age), the low density followed by the low volume phenotype had the highest association with MOF (hazard ratio = 2.96 and 2.35, respectively), and significant associations were maintained when additionally adjusted for femoral neck aBMD (hazard ratio = 1.69 and 1.90, respectively). Further, within each phenotype, different imaging biomarkers of fracture were identified. These findings suggest that osteoporotic fracture risk is associated with bone phenotypes that capture key features of bone deterioration that are not distinguishable by aBMD. © 2021 American Society for Bone and Mineral Research (ASBMR).

Dataset Information

Postmenopausal osteoporotic fracture-associated COLIA1 variant impacts bone accretion in girls.

Publications

Postmenopausal osteoporotic fracture-associated COLIA1 variant impacts bone accretion in girls.

Similar Datasets

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