Advanced Glycation End Products and esRAGE Are Associated With Bone Turnover and Incidence of Hip Fracture in Older Men

Lamb, Lydia S; Alfonso, Helman; Norman, Paul; Davis, Timothy; Forbes, Josephine M.; Müench, Gerald; Irrgang, Felix; Almeida, Osvaldo P.; Golledge, Jonathan; Hankey, Graeme J.; Flicker, Leon; Yeap, Bu B.

doi:10.1210/jc.2018-00674

Cited by 34 publications

(28 citation statements)

References 39 publications

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“…Higher serum CML, a frequently studied AGE, was related to higher risk of incident hip fractures in two longitudinal cohort-studies in elderly subjects. (21,41) In one of these studies, in 3384 community-dwelling men aged 70 to 89 years, a nonlinear relation was found of CML with incident hip fractures, which is similar to our findings of a nonlinear relationship of SAF with prevalent hip fractures. (41) Compared to the other two cohorts with a longitudinal design, our subjects were relatively younger with fewer prevalent hip fractures, but we still observed the same trend ( Table 5).…”

Section: Discussionsupporting

confidence: 89%

“…(21,41) In one of these studies, in 3384 community-dwelling men aged 70 to 89 years, a nonlinear relation was found of CML with incident hip fractures, which is similar to our findings of a nonlinear relationship of SAF with prevalent hip fractures. (41) Compared to the other two cohorts with a longitudinal design, our subjects were relatively younger with fewer prevalent hip fractures, but we still observed the same trend ( Table 5). Urinary pentosidine was associated with incident long-bone and vertebral fractures in a linear fashion in Japanese subjects (n = 765), but no association was found in French (n = 396) postmenopausal women.…”

Section: Discussionsupporting

confidence: 89%

“…(12,13) In summary, our data primarily suggest that the influence of AGEs on fracture risk is not mediated by low BMD. (21) Lamb and colleagues (41) This study In contrast to our expectations, SAF was not associated with TBS, a recently developed 2D textural imaging technique related to bone microarchitecture and derived from DXA images. TBS has been shown by several but not all studies to predict fracture risk largely independent of BMD.…”

Section: Journal Of Bone and Mineral Researchcontrasting

confidence: 62%

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Skin Autofluorescence, a Noninvasive Biomarker for Advanced Glycation End-Products, Is Associated With Prevalent Vertebral and Major Osteoporotic Fractures: The Rotterdam Study

Waqas

Chen

Koromani

et al. 2020

Journal of Bone and Mineral Research

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Advanced glycation end-products (AGEs), which bind to type 1 collagen in bone and skin, have been implicated in reduced bone quality. The AGE reader™ measures skin autofluorescence (SAF), which might be regarded as a marker of long-term accumulation of AGEs in tissues. We investigated the association of SAF with bone mineral density (BMD) and fractures in the general population. We studied 2853 individuals from the Rotterdam Study with available SAF measurements (median age, 74.1 years) and with data on prevalent major osteoporotic (MOFs: hip, humerus, wrist, clinical vertebral) and vertebral fractures (VFs: clinical + radiographic Genant's grade 2 and 3). Radiographs were assessed 4 to 5 years before SAF. Multivariate regression models were performed adjusted for age, sex, BMI, creatinine, smoking status, and presence of diabetes and additionally for BMD with interaction terms to test for effect modification. Prevalence of MOFs was 8.5% and of VFs 7%. SAF had a curvilinear association with prevalent MOFs and VFs and therefore, age-adjusted, sex stratified SAF quartiles were used. The odds ratio (OR) (95% confidence interval [CI]) of the second, third and fourth quartiles of SAF for MOFs were as follows: OR 1.60 (95% CI, 1.08-2.35; p = .02); OR 1.30 (95% CI, 0.89-1.97; p = .20), and OR 1.40 (95% CI, 0.95-2.10; p = .09), respectively, with first (lowest) quartile as reference. For VFs the ORs were as follows: OR 1.69 (95% CI, 1.08-2.64; p = .02), OR 1.74(95% CI, 1.11-2.71; p = .01), and OR 1.73 (95% CI, 1.12-2.73; p = .02) for second, third, and fourth quartiles, respectively. When comparing the top three quartiles combined with the first quartile, the OR (95% CI) for MOFs was 1.43 (95% CI, 1.04-2.00; p = .03) and for VFs was 1.72 (95% CI, 1.18-2.53; p = .005). Additional adjustment for BMD did not change the associations. In conclusion, there is evidence of presence of a threshold of skin AGEs below which there is distinctly lower prevalence of fractures. Longitudinal analyses are needed to confirm our cross-sectional findings.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 89%

Section: Journal Of Bone and Mineral Researchcontrasting

confidence: 62%

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Skin Autofluorescence, a Noninvasive Biomarker for Advanced Glycation End-Products, Is Associated With Prevalent Vertebral and Major Osteoporotic Fractures: The Rotterdam Study

Waqas

Chen

Koromani

et al. 2020

Journal of Bone and Mineral Research

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“…Consistent with this possibility, low serum esRAGE levels is a risk factor for vertebral fractures [86]. Additionally, low serum sRAGE and S100A12 levels in juvenile idiopathic arthritis correlated with increased disease activity [87].…”

Section: Rage As a Biomarker For Bone Disease/osteoporosismentioning

confidence: 79%

RAGE Signaling in Skeletal Biology

Plotkin

Essex

Davis

2019

Curr Osteoporos Rep

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Purpose of review-The receptor for advanced glycation end products (RAGE) and several of its ligands have been implicated in the onset and progression of pathologies associated with aging, chronic inflammation, and cellular stress. In particular, the role of RAGE and its ligands in bone tissue during both physiological and pathological conditions has been investigated. However, the extent to which RAGE signaling regulates bone homeostasis and disease onset remains unclear. Further, RAGE effects in the different bone cells and whether these effects are cell-type specific is unknown. The objective of the current review is to describe the literature over RAGE signaling in skeletal biology as well as discuss the clinical potential of RAGE as a diagnostic and/or therapeutic target in bone disease. Recent findings-The role of RAGE and its ligands during skeletal homeostasis, tissue repair, and disease onset/progression is beginning to be uncovered. For example, detrimental effects of the RAGE ligands, advanced glycation end products (AGEs), have been identified for osteoblast viability/activity, while others have observed that low level AGE exposure stimulates osteoblast autophagy, which subsequently promotes viability and function. Similar findings have been reported with HMGB1, another RAGE ligand, in which high levels of the ligand are associated with osteoblast/osteocyte apoptosis, whereas low level/short-term administration stimulates osteoblast differentiation/bone formation and promotes fracture healing. Additionally, elevated levels of several RAGE ligands (AGEs, HMGB1, S100 proteins) induce osteoblast/osteocyte apoptosis and stimulate cytokine production, which is associated with increased osteoclast differentiation/activity. Conversely, direct RAGE ligand exposure in osteoclasts may have inhibitory effects. These observations support a conclusion that elevated bone resorption observed in conditions of high circulating ligands and RAGE expression are due to actions on osteoblasts/ osteocytes rather than direct actions on osteoclasts, although additional work is required to substantiate the observations.

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“…There are differences in the affinity of different AGEs for RAGE and its activation. Whether this underpins the variable relationship between different AGEs and fracture risk remains to be elucidated [19,24]. Although SAF predicts traditional diabetic complications independently of HbA 1c [12], whether it can help stratify for fracture risk in people with diabetes is unclear.…”

Section: Discussionmentioning

confidence: 99%

Association of glycaemic variables with trabecular bone score in post‐menopausal women with type 2 diabetes mellitus

2020

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Aim To determine the relationship between bone microarchitecture, as measured by trabecular bone score, and advanced glycation end-product accumulation, as assessed by skin autofluorescence. Methods This was a cross-sectional study. Participants were 64 post-menopausal women with type 2 diabetes and 175 post-menopausal women without diabetes. Trabecular bone score and skin autofluorescence data were obtained at time of bone density measurement. Results Trabecular bone score and skin autofluorescence were inversely correlated in women with type 2 diabetes (r =-0.34, P = 0.006); no correlation was seen in post-menopausal women without diabetes (r =-0.029, P = 0.707). After adjustment, neither skin autofluorescence nor a diagnosis of diabetes were associated with trabecular bone score, but HbA 1c and waist circumference were independently associated with trabecular bone score. Conclusion Skin autofluorescence did not predict trabecular bone score. In contrast, glycaemia, as reflected by HbA 1c , and visceral adiposity, as reflected by waist circumference, were independently associated with trabecular bone score.

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Advanced Glycation End Products and esRAGE Are Associated With Bone Turnover and Incidence of Hip Fracture in Older Men

Abstract: Glycemia associates positively with CML and reciprocally with esRAGE in older men. Circulating esRAGE modulates bone turnover in older men, whereas CML predicts incidence of hip fracture.

Cited by 34 publications

References 39 publications

Skin Autofluorescence, a Noninvasive Biomarker for Advanced Glycation End-Products, Is Associated With Prevalent Vertebral and Major Osteoporotic Fractures: The Rotterdam Study

Skin Autofluorescence, a Noninvasive Biomarker for Advanced Glycation End-Products, Is Associated With Prevalent Vertebral and Major Osteoporotic Fractures: The Rotterdam Study

RAGE Signaling in Skeletal Biology

Association of glycaemic variables with trabecular bone score in post‐menopausal women with type 2 diabetes mellitus

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