A Metabolic Screen in Adolescents Reveals an Association Between Circulating Citrate and Cortical Bone Mineral Density

Kemp, John P.; Sayers, Adrian; Fraser, William D.; Smith, George Davey; Ala‐Korpela, Mika; Evans, David M.; Tobias, Jonathan H

doi:10.1002/jbmr.3697

Cited by 5 publications

(4 citation statements)

References 23 publications

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“…Human osteoblasts can produce citrate; it is hypothesized that citrate is incorporated into bone directly from osteoblast secretion, and that, as bone is resorbed and both bone collagen and mineral are degraded, citrate is released into the circulation generating the major source of plasma citrate . This concurs with the positive relationships we observed between citrate and both age and bone resorption and an inverse association recently identified between β‐CTX and citrate in a smaller sample from the ALSPAC adolescent population . Due to its suggested association with bone mineral, we hypothesize that plasma citrate may provide information on turnover of bone mineral during bone resorption.…”

Section: Discussionsupporting

confidence: 92%

“…25 This concurs with the positive relationships we observed between citrate and both age and bone resorption and an inverse association recently identified between β-CTX and citrate in a smaller sample from the ALSPAC adolescent population. 26 Due to its suggested association with bone mineral, we hypothesize that plasma citrate may provide information on turnover of bone mineral during bone resorption.…”

Section: Discussionmentioning

confidence: 99%

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Metabolomics analysis in adults with high bone mass identifies a relationship between bone resorption and circulating citrate which replicates in the general population

Hartley

Paternoster

Evans

et al. 2019

Clinical Endocrinology

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Objective: Bone turnover, which regulates bone mass, may exert metabolic consequences, particularly on markers of glucose metabolism and adiposity. To better understand these relationships, we examined cross-sectional associations between bone turnover markers (BTMs) and metabolic traits.Design: β-C-terminal telopeptide of type-I collagen (β-CTX), procollagen type-1 amino-terminal propeptide (P1NP) and osteocalcin were assessed by electrochemiluminescence immunoassays. Metabolic traits, including lipids and glycolysis-related metabolites, were measured using nuclear magnetic resonance spectroscopy.Associations of BTMs with metabolic traits were assessed using Generalized Estimating Equation linear regression, accounting for within-family correlation, adjusting for potential confounders (age, sex, height, weight, menopause, bisphosphonate and oral glucocorticoid use).Patients: 198 adults with high bone mass (HBM, BMD Z-score>+3.2), mean [SD] age 61.6 [13.7] years; 77% female. Results:Of 23 summary metabolic traits, citrate was positively related to all BTMs: adjusted β β-CTX = 0.050 (95% CI 0.024, 0.076), P = 1.71 × 10 −4 , β osteocalcin = 6.54 × 10 −4 (1.87 × 10 −4 , 0.001), P = .006 and β P1NP = 2.40 × 10 −4 (6.49 × 10 −5 , 4.14 × 10 −4 ), P = .007 (β = increase in citrate (mmol/L) per 1 µg/L BTM increase). Inverse relationships of β-CTX (β = −0.276 [−0.434, −0.118], P = 6.03 × 10 −4 ) and osteocalcin (−0.004 [−0.007, −0.001], P = .020) with triglycerides were also identified. We explored the generalizability of these associations in 3664 perimenopausal women (age 47.9 [4.4] years) from a UK family cohort. We confirmed a positive, albeit lower magnitude, association between β-CTX and citrate (adjusted β women = 0.020 [0.013, 0.026], P = 1.95 × 10 −9 ) and an inverse association of similar magnitude between β-CTX and triglycerides (β = −0.354 [−0.471, −0.237], P = 3.03 × 10 −9 ).This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Metabolomics analysis in adults with high bone mass identifies a relationship between bone resorption and circulating citrate which replicates in the general population

Hartley

Paternoster

Evans

et al. 2019

Clinical Endocrinology

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“…The weight percentages of the different metabolic acids in the bone vary according to animal age: fetal bone, which is much softer than adult bone, contains very large quantities of lactate, [32] whereas in adult bone, the quantity of citrate is directly related to bone mineral quality. [33] Currently, the role and characterization of metabolic acids in the bone is very poorly understood as well as their underlying role in biomineralization.…”

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confidence: 99%

A ⁴³Ca nuclear magnetic resonance perspective on octacalcium phosphate and its hybrid derivatives

Laurencin

Duer

et al. 2021

Magnetic Reson in Chemistry

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Ca nuclear magnetic resonance (NMR) spectroscopy has been extensively applied to the detailed study of octacalcium phosphate (OCP), Ca 8 (HPO 4 ) 2 (PO 4 ) 4 .5H 2 O, and hybrid derivatives involving intercalated metabolic acids (viz., citrate, succinate, formate, and adipate). Such phases are of importance in the development of a better understanding of bone structure. High-resolution 43 Ca magic angle spinning (MAS) experiments, including double-rotation (DOR) 43 Ca NMR, as well as 43 Ca{ 1 H} rotational echo DOR (REDOR) and 31 P{ 43 Ca} REAPDOR NMR spectra, were recorded on a 43 Calabeled OCP phase at very high magnetic field (20 T), and complemented by ab initio calculations of NMR parameters using the Gauge-Including Projector Augmented Wave-density functional theory (GIPAW-DFT) method. This enabled a partial assignment of the eight inequivalent Ca 2+ sites of OCP.Natural-abundance 43 Ca MAS NMR spectra were then recorded for the hybrid organic-inorganic derivatives, revealing changes in the 43 Ca lineshape. In the case of the citrate derivative, these could be interpreted on the basis of computational models of the structure. Overall, this study highlights the advantages of combining high-resolution 43 Ca NMR experiments and computational modeling for studying complex hybrid biomaterials.

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“…The roles of citrate and lactate in bone mineral structure have been much less studied than those of carbonate. In adult humans, bone mineral density correlates positively with the concentration of blood plasma citrate, 12 whilst foetal bone, which is typically much softer than mature bone, contains considerable quantities of lactate. 13 We have shown that the citrate chemical environment in bone is similar to that in octacalcium phosphate (OCP)-citrate by SSNMR spectroscopy.…”

Section: Introductionmentioning

confidence: 99%

Metabolic acids impact bone mineral maturation

Reid

et al. 2022

Preprint

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Bone mineral has a complex 3D architecture that is essential to its mechanical properties. It is a complex calcium phosphate phase related to hydroxyapatite that also contains significant quantities of cell respiration metabolites, in particular: carbonate, citrate and lactate. An as-yet unanswered question is what, if any, role do these metabolites collectively play in determining the 3D architecture of bone mineral? Here we synthesize apatitic materials by transformation from precursor mineral phases containing citrate, lactate or carbonate so that the synthesis environment mimics the densely-packed ionic environment within which bone mineral forms in vivo, and so that we can understand the mineral factors that may direct bone mineral 3D architecture. We show that incorporating citrate and lactate leads to complex mineral architectures reminiscent of those in bone mineral, including curvature of the mineral crystals. Our results suggest that metabolic acids may assist the moulding of bone mineral to restricted spaces available for mineral in in vivo bone. We find that the incorporation of lactate creates a softer material and inhibits the transformation towards apatitic structures, which may help to explain why foetal bone, necessarily soft, contains considerable quantities of lactate. High levels of plasma citrate have been previously found to correlate with high bone mineral density. Here we find that citrate incorporation leads to mineral crystal curvature modelling that in in vivo bone mineral suggesting its importance in mineral morphology. We conclude that metabolic anions may play an important role in controlling bone mineral physicochemical properties and 3D architecture.

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A Metabolic Screen in Adolescents Reveals an Association Between Circulating Citrate and Cortical Bone Mineral Density

Cited by 5 publications

References 23 publications

Metabolomics analysis in adults with high bone mass identifies a relationship between bone resorption and circulating citrate which replicates in the general population

Metabolomics analysis in adults with high bone mass identifies a relationship between bone resorption and circulating citrate which replicates in the general population

A ⁴³Ca nuclear magnetic resonance perspective on octacalcium phosphate and its hybrid derivatives

Metabolic acids impact bone mineral maturation

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A Metabolic Screen in Adolescents Reveals an Association Between Circulating Citrate and Cortical Bone Mineral Density

Cited by 5 publications

References 23 publications

Metabolomics analysis in adults with high bone mass identifies a relationship between bone resorption and circulating citrate which replicates in the general population

Metabolomics analysis in adults with high bone mass identifies a relationship between bone resorption and circulating citrate which replicates in the general population

A 43Ca nuclear magnetic resonance perspective on octacalcium phosphate and its hybrid derivatives

Metabolic acids impact bone mineral maturation

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A ⁴³Ca nuclear magnetic resonance perspective on octacalcium phosphate and its hybrid derivatives