Level and change in bone microarchitectural parameters and their relationship with previous fracture and established bone mineral density loci

Fuggle, Nicholas R.; Westbury, Leo D.; Bevilacqua, Gregorio; Titcombe, Philip; Ó. Breasail, Mícheál; Harvey, Nicholas C.; Dennison, Elaine M.; Cooper, Cyrus; Ward, Kate A.

Affiliations

¹MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK

²The Alan Turing Institute, London, UK

³MRC Nutrition and Bone Health Research Group, Cambridge, UK

⁴NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK

⁵Victoria University of Wellington, Wellington, New Zealand

⁶NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK

Abstract and keywords

Background: Osteoporosis is characterised by a reduction of bone mineral density (BMD) and predisposition to fracture. Bone microarchitecture, measured by high resolution peripheral quantitative computed tomography (HR-pQCT), has been related to fragility fractures and BMD and has been the subject of large-scale genome-wide analysis. We investigated whether fracture was related to baseline values and longitudinal changes in bone microarchitecture and whether bone microarchitecture was associated with established BMD loci.

Methods: 115 males and 99 females (aged 72–81 at baseline) from the Hertfordshire Cohort Study (HCS) were analysed. Fracture history was determined in 2011–2012 by self-report and vertebral fracture assessment. Participants underwent HR-pQCT scans of the distal radius and tibia in 2011–2012 and 2017. Previous fracture in relation to baseline values and changes in tibial HR-pQCT parameters was examined using sex-adjusted logistic regression with and without adjustment for age, sociodemographic, lifestyle and clinical characteristics; baseline values and changes in parameters associated with previous fracture were then examined in relation to four established BMD loci after adjustment for sex and age.

Results: Previous fracture was related to: higher trabecular area (fully-adjusted odds ratio [95% CI] per SD greater baseline value: 2.18 [1.27,3.73], p = 0.005); lower total volumetric BMD (0.53 [0.34,0.84], p = 0.007), cortical area (0.53 [0.30,0.95], p = 0.032), cortical BMD (0.56 [0.36,0.88], p = 0.011) and cortical thickness (0.45 [0.27,0.77], p = 0.004); and greater declines in trabecular BMD (p = 0.001). Associations were robust in sex- and fully-adjusted analysis. Relationships between BMD loci and these HR-pQCT parameters were weak: rs3801387 (WNT16) was related to decline in trabecular BMD (p = 0.011) but no other associations were significant (p > 0.05).

Conclusion: Baseline values of HR-pQCT parameters and greater decline in trabecular BMD were associated with fracture. Change in trabecular BMD was associated with WNT16 which has been demonstrated to influence bone health in murine models and human genome-wide association studies (GWAS).

Keywords: Osteoporosis; Epidemiology; Fracture; Quantitative computed tomography; Loci

Links

DOI: 10.1016/j.bone.2021.115937

PubMed: 33766802

WoS: 000643707100005

History

Received: 2020-12-18

Revised: 2021-03-18

Accepted: 2021-03-18

Online: 2021-03-22

Cited Works (15)

Year	Entry
2006	Khosla S, Riggs BL, Atkinson EJ, Oberg AL, McDaniel LJ, Holets M, .Peterson JM, Melton LJ III. Effects of sex and age on bone microstructure at the ultradistal radius: a population-based noninvasive in vivo assessment. J Bone Miner Res. January 2006;21(1):124-131.
2007	MacNeil JA, Boyd SK. Accuracy of high-resolution peripheral quantitative computed tomography for measurement of bone quality. Med Eng Phys. December 2007;29(10):1096-1105.
2008	Boutroy S, Van Rietbergen B, Sornay-Rendu E, Munoz F, Bouxsein ML, Delmas PD. Finite element analysis based on in vivo HR-pQCT images of the distal radius is associated with wrist fracture in postmenopausal women. J Bone Miner Res. March 2008;23(3):392-399.
1998	Laib A, Häuselmann HJ, Rüegsegger P. In vivo high resolution 3D-QCT of the human forearm. Technol Health Care. 1998;6(5-6):329-337.
2005	Boutroy S, Bouxsein ML, Munoz F, Delmas PD. In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography. J Clin Endocrinol Metab. December 2005;90(12):6508-6515.
1993	Genant HK, Wu CY, van Kuijk C, Nevitt MC. Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res. September 1993;8(9):1137-1148.
2017	Sornay‐Rendu E, Boutroy S, Duboeuf F, Chapurlat RD. Bone microarchitecture assessed by HR‐pQCT as predictor of fracture risk in postmenopausal women: the OFELY study. J Bone Miner Res. June 2017;32(6):1243-1251.
2010	Burghardt AJ, Buie HR, Laib A, Majumdar S, Boyd SK. Reproducibility of direct quantitative measures of cortical bone microarchitecture of the distal radius and tibia by HR-pQCT. Bone. September 2010;47(3):519-528.
2011	Vilayphiou N, Boutroy S, Szulc P, van Rietbergen B, Munoz F, Delmas PD, Chapurlat R. Finite element analysis performed on radius and tibia HR‐pQCT images and fragility fractures at all sites in men. J Bone Miner Res. May 2011;26(5):965-973.
2020	Whittier DE, Boyd SK, Burghardt AJ, Paccou J, Ghasem-Zadeh A, Chapurlat R, Engelke K, Bouxsein ML. Guidelines for the assessment of bone density and microarchitecture in vivo using high-resolution peripheral quantitative computed tomography. Osteoporos Int. September 2020;31(9):1607-1627.
2017	Kemp JP, Morris JA, Medina-Gomez C, Forgetta V, Warrington NM, Youlten SE, Zheng J, Gregson CL, Grundberg E, Trajanoska K, Logan JG, Pollard AS, Sparkes PC, Ghirardello EJ, Allen R, Leitch VD, Butterfield NC, Komla-Ebri D, Adoum A-T, Curry KF, White JK, Kussy F, Greenlaw KM, Xu C, Harvey NC, Cooper C, Adams DJ, Greenwood CMT, Maurano MT, Kaptoge S, Rivadeneira F, Tobias JH, Croucher PI, Ackert-Bicknell CL, Bassett JHD, Williams GR, Richards JB, Evans DM. Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Nat Genet. October 2017;49(10):1468-1475.
2018	Biver E, Durosier-Izart C, Chevalley T, van Rietbergen B, Rizzoli R, Ferrari S. Evaluation of radius microstructure and areal bone mineral density improves fracture prediction in postmenopausal women. J Bone Miner Res. February 2018;33(2):328-337.
2012	Estrada K, Styrkarsdottir U, Evangelou E, Hsu Y-H, Duncan EL, Ntzani EE, Oei L, Albagha OME, Amin N, Kemp JP, Koller DL, Li G, Liu C-T, Minster RL, Moayyeri A, Vandenput L, Willner D, Xiao S-M, Yerges-Armstrong LM, Zheng H-F, Alonso N, Eriksson J, Kammerer CM, Kaptoge SK, Leo PJ, Thorleifsson G, Wilson SG, Wilson JF, Aalto V, Alen M, Aragaki AK, Aspelund T, Center JR, Dailiana Z, Duggan DJ, Garcia M, Garcia-Giralt N, Giroux S, Hallmans G, Hocking LJ, Husted LB, Jameson KA, Khusainova R, Kim GS, Kooperberg C, Koromila T, Kruk M, Laaksonen M, Lacroix AZ, Lee SH, Leung PC, Lewis JR, Masi L, Mencej-Bedrac S, Nguyen TV, Nogues X, Patel MS, Prezelj J, Rose LM, Scollen S, Siggeirsdottir K, Smith AV, Svensson O, Trompet S, Trummer O, van Schoor NM, Woo J, Zhu K, Balcells S, Brandi ML, Buckley BM, Cheng S, Christiansen C, Cooper C, Dedoussis G, Ford I, Frost M, Goltzman D, González-Macías J, Kähönen M, Karlsson M, Khusnutdinova E, Koh J-M, Kollia P, Langdahl BL, Leslie WD, Lips P, Ljunggren Ö, Lorenc RS, Marc J, Mellström D, Obermayer-Pietsch B, Olmos JM, Pettersson-Kymmer U, Reid DM, Riancho JA, Ridker PM, Rousseau F, Slagboom PE, Tang NLS, Urreizti R, Van Hul W, Viikari J, Zarrabeitia MT, Aulchenko YS, Castano-Betancourt M, Grundberg E, Herrera L, Ingvarsson T, Johannsdottir H, Kwan T, Li R, Luben R, Medina-Gómez C, Palsson ST, Reppe S, Rotter JI, Sigurdsson G, van Meurs JBJ, Verlaan D, Williams FMK, Wood AR, Zhou Y, Gautvik KM, Pastinen T, Raychaudhuri S, Cauley JA, Chasman DI, Clark GR, Cummings SR, Danoy P, Dennison EM, Eastell R, Eisman JA, Gudnason V, Hofman A, Jackson RD, Jones G, Jukema JW, Khaw K-T, Lehtimäki T, Liu Y, Lorentzon M, McCloskey E, Mitchell BD, Nandakumar K, Nicholson GC, Oostra BA, Peacock M, Pols HAP, Prince RL, Raitakari O, Reid IR, Robbins J, Sambrook PN, Sham PC, Shuldiner AR, Tylavsky FA, van Duijn CM, Wareham NJ, Cupples LA, Econs MJ, Evans DM, Harris TB, Kung AWC, Psaty BM, Reeve J, Spector TD, Streeten EA, Zillikens MC, Thorsteinsdottir U, Ohlsson C, Karasik D, Richards JB, Brown MA, Stefansson K, Uitterlinden AG, Ralston SH, Ioannidis JPA, Kiel DP, Rivadeneira F. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. April 15, 2012;44(5):491-501.
2012	Pauchard Y, Liphardt A-M, Macdonald HM, Hanley DA, Boyd SK. Quality control for bone quality parameters affected by subject motion in high-resolution peripheral quantitative computed tomography. Bone. June 2012;50(6):1304-1310.
2006	Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. December 2006;17(12):1726-1733.

Cited By (2)

Year	Entry
2022	Tuck SP, Hanusch B, Prediger M, Walker JA, McNally R, Datta HK. Reduced trabecular bone mineral density and thinner cortices in men with distal forearm fractures. Bone. November 2022;164:116513.
2023	Lu S, Fuggle NR, Westbury LD, Ó. Breasail M, Bevilacqua G, Ward KA, Dennison EM, Mahmoodi S, Niranjan M, Cooper C. Machine learning applied to HR-pQCT images improves fracture discrimination provided by DXA and clinical risk factors. Bone. March 2023;168:116653.