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Mineral density differences between femoral cortical bone and trabecular bone are not explained by turnover rate alone

ABSTRACT: Bone mineral density distributions (BMDDs) are a measurable property of bone tissues that depends strongly on bone remodelling and mineralisation processes. These processes can vary significantly in health and disease and across skeletal sites, so there is high interest in analysing these processes from experimental BMDDs. Here, we propose a rigorous hypothesis-testing approach based on a mathematical model of mineral heterogeneity in bone due to remodelling and mineralisation, to help explain differences observed between the BMDD of human femoral cortical bone and the BMDD of human trabecular bone. Recent BMDD measurements show that femoral cortical bone possesses a higher bone mineral density, but a similar mineral heterogeneity around the mean compared to trabecular bone. By combining this data with the mathematical model, we are able to test whether this difference in BMDD can be explained by (i) differences in turnover rate; (ii) differences in osteoclast resorption behaviour; and (iii) differences in mineralisation kinetics between the two bone types. We find that accounting only for differences in turnover rate is inconsistent with the fact that both BMDDs have a similar spread around the mean, and that accounting for differences in osteoclast resorption behaviour leads to biologically inconsistent bone remodelling patterns. We conclude that the kinetics of mineral accumulation in bone matrix must therefore be different in femoral cortical bone and trabecular bone. Although both cortical and trabecular bone are made up of lamellar bone, the different mineralisation kinetics in the two types of bone point towards more profound structural differences than usually assumed. Highlights • Compare bone mineral density distributions in trabecular bone and in cortical bone• Analyse data for differences in turnover, resorption, and mineralisation kinetics• Hypothesis testing suggests skeletal sites differ by more than their turnover rate• Hypothesis testing suggests mineralisation kinetics is coupled to turnover ratec

SUBMITTER: Lerebours C

PROVIDER: S-EPMC7772649 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Project description:Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n?=?5,878) followed by replication (n?=?1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p?=?3.6×10?¹?; LOC285735, rs271170, p?=?2.7×10?¹²; OPG, rs7839059, p?=?1.2×10?¹?; and ESR1/C6orf97, rs6909279, p?=?1.1×10??). The trabecular vBMD GWA meta-analysis (n?=?2,500) followed by replication (n?=?1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p?=?1.9×10??). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n?=?729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.

Project description:ObjectiveThe objectives of this study were to describe the trajectories of bone mineral density (BMD) and trabecular bone score (TBS) changes throughout pre-menopause (reproductive phase and menopausal transition) and post-menopause (early and late menopause) in women with HIV (WWH) undergoing different antiretroviral therapies (ARTs) and explore the risk factors associated with those changes.MethodsThis was an observational longitudinal retrospective study in WWH with a minimum of two DEXA evaluations comprising BMD and TBS measurements, both in the pre-menopausal and post-menopausal periods. Menopause was determined according to the STRAW+10 criteria, comprising four periods: the reproductive period, menopausal transition, and early- and late-menopausal periods. Mixed-effects models were fitted to estimate the trajectories of the two outcomes (BMD and TBS) over time. Annualized lumbar BMD and TBS absolute and percentage changes were calculated in each STRAW+10 time window. A backward elimination procedure was applied to obtain the final model, including the predictors that affected the trajectories of BMD or TBS over time.ResultsA total of 202 WWH, all Caucasian, were included. In detail, 1954 BMD and 195 TBS data were analyzed. The median number of DEXA evaluations per woman was 10 (IQR: 7, 12). The median observation periods per patient were 12.0 years (IQR = 8.9-14.4) for BMD and 6.0 years (IQR: 4.3, 7.9) for TBS. The prevalence of osteopenia (63% vs. 76%; p < 0.001) and osteoporosis (16% vs. 36%; p < 0.001) increased significantly between the pre-menopausal and post-menopausal periods. Both BMD (1.03 (±0.14) vs. 0.92 (±0.12) g/cm2; p < 0.001) and TBS (1.41 (IQR: 1.35, 1.45) vs. 1.32 (IQR: 1.28, 1.39); p < 0.001) decreased significantly between the two periods. The trend in BMD decreased across the four STRAW+10 periods, with a slight attenuation only in the late-menopausal period when compared with the other intervals. The TBS slope did not significantly change throughout menopause. The delta mean values of TBS in WWH were lower between the menopausal transition and reproductive period compared with the difference between menopause and menopausal transition.ConclusionsBoth BMD and TBS significantly decreased over time. The slope of the change in BMD and TBS significantly decreased in the menopausal transition, suggesting that this period should be considered by clinicians as a key time during which to assess bone health and modifiable risk factors in WWH.

Project description:BackgroundSevere gonadal steroid deficiency induces bone loss in adult men; however, the specific roles of androgen and estrogen deficiency in hypogonadal bone loss are unclear. Additionally, the threshold levels of testosterone and estradiol that initiate bone loss are uncertain.MethodsOne hundred ninety-eight healthy men, ages 20-50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone. Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men.ResultsAs testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites. Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men.ConclusionsEstrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton.Trial registrationClinicalTrials.gov, NCT00114114.FundingAbbVie Inc., AstraZeneca Pharmaceuticals LP, NIH.

Project description:ObjectiveThis study used microcomputed tomography (micro-CT) to evaluate the effects of ovariectomy on the trabecular bone microarchitecture and cortical bone morphology in the femoral neck and mandible of female rats.Materials and methodsTwelve female Wister rats were divided into two groups: the control and ovariectomized groups. The rats in the ovariectomized group received ovariectomy at 8 weeks of age; all the rats were sacrificed at 20 weeks of age, and their mandibles and femurs were removed and scanned using micro-CT. Four microstructural trabecular bone parameters were measured for the region below the first mandibular molar and the femoral neck region: bone volume fraction (BV/TV), trabecular thickness (TbTh), trabecular separation (TbSp), and trabecular number (TbN). In addition, four cortical bone parameters were measured for the femoral neck region: total cross-sectional area (TtAr), cortical area (CtAr), cortical bone area fraction (CtAr/TtAr), and cortical thickness (CtTh). The CtTh at the masseteric ridge was used to assess the cortical bone morphology in the mandible. The trabecular bone microarchitecture and cortical bone morphology in the femoral necks and mandibles of the control group were compared with those of the ovariectomized group. Furthermore, Spearman's correlation (rs) was conducted to analyze the correlation between the osteoporosis conditions of the mandible and femoral neck.ResultsRegarding the trabecular bone microarchitectural parameters, the BV/TV of the trabecular bone microarchitecture in the femoral necks of the control group (61.199±11.288%, median ± interquartile range) was significantly greater than that of the ovariectomized group (40.329±5.153%). Similarly, the BV/TV of the trabecular bone microarchitecture in the mandibles of the control group (51.704±6.253%) was significantly greater than that of the ovariectomized group (38.486±9.111%). Furthermore, the TbSp of the femoral necks in the ovariectomized group (0.185±0.066 mm) was significantly greater than that in the control group (0.130±0.026mm). Similarly, the TbSp of the mandibles in the ovariectomized group (0.322±0.047mm) was significantly greater than that in the control group (0.285±0.041mm). However, the TbTh and TbN trends for the mandibles and femoral necks were inconsistent between the control and ovariectomized groups. Regarding the cortical bone morphology parameters, the TtAr of the femoral necks in the ovariectomized group was significantly smaller than that in the control group. There was no significant difference in the TtAr, CtAr, or CtTh of the femoral necks between the control and ovariectomized groups, and no significant difference in the CtTh of the mandibles between the control and ovariectomized groups. Moreover, the BV/TV and TbSp of the mandibles were highly correlated with those of the femurs (rs = 0.874 and rs = 0.755 for BV/TV and TbSp, respectively). Nevertheless, the TbTh, TbN, and CtTh of the mandibles were not correlated with those of the femoral necks.ConclusionAfter the rats were ovariectomized, osteoporosis of the trabecular bone microarchitecture occurred in their femurs and mandibles; however, ovariectomy did not influence the cortical bone morphology. In addition, the parametric values of the trabecular bone microarchitecture in the femoral necks were highly correlated with those of the trabecular bone microarchitecture in the mandibles.

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Mineral density differences between femoral cortical bone and trabecular bone are not explained by turnover rate alone

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