Seong Hee Ahn

Iron overload accelerates bone loss in healthy postmenopausal women and middle‐aged men: A 3‐year retrospective longitudinal study

Despite extensive experimental and animal evidence about the detrimental effects of iron and its overload on bone metabolism, there have been no clinical studies relating iron stores to bone loss, especially in nonpathologic conditions. In the present study, we performed a large longitudinal study to evaluate serum ferritin concentrations in relation to annualized changes in bone mineral density (BMD) in healthy Koreans. A total of 1729 subjects (940 postmenopausal women and 789 middle‐aged men) aged 40 years or older who had undergone comprehensive routine health examinations with an average 3 years of follow‐up were enrolled. BMD in proximal femur sites (ie, the total femur, femur neck, and trochanter) was measured with dual‐energy X‐ray absorptiometry using the same equipment at baseline and follow‐up. The mean age of women and men in this study was 55.8 ± 6.0 years and 55.5 ± 7.8 years, respectively, and serum ferritin levels were significantly higher in men than in women (p < 0.001). The overall mean annualized rates of bone loss in the total femur, femur neck, and trochanter were −1.14%/year, −1.17%/year, and −1.51%/year, respectively, in women, and −0.27%/year, −0.34%/year, and −0.41%/year, respectively, in men. After adjustment for potential confounders, the rates of bone loss in all proximal femur sites in both genders were significantly accelerated in a dose‐response fashion across increasing ferritin quartile categories (p for trend = 0.043 to <0.001). Consistently, compared with subjects in the lowest ferritin quartile category, those in the third and/or highest ferritin quartile category showed significantly faster bone loss in the total femur and femur neck in both genders (p = 0.023 to <0.001). In conclusion, these data provide the first clinical evidence that increased total body iron stores could be an independent risk factor for accelerated bone loss, even in healthy populations.

Plasma periostin associates significantly with non-vertebral but not vertebral fractures in postmenopausal women: Clinical evidence for the different effects of periostin depending on the skeletal site

BACKGROUND Periostin is preferentially expressed by the periosteum, which mainly covers the long bones. Therefore, the role of periostin in osteoporotic fracture (OF) may differ depending on bone type. We performed a case-control study to investigate whether periostin can serve as a predictor of OF risk, particularly after dividing OFs into non-vertebral and vertebral fractures. METHODS Among 532 consecutive postmenopausal women not taking any drug or without any disease that could affect bone metabolism, 133 cases with OF (i.e., non-vertebral and/or vertebral fractures) and 133 age- and body mass index-matched controls were enrolled. Non-vertebral (i.e., forearm, humerus, hip, and pelvis; n=81) and morphological vertebral (n=62) fractures were identified by an interviewer-assisted questionnaire and lateral thoracolumbar radiographs, respectively. Bone mineral density (BMD) and plasma periostin levels were also measured. RESULTS Plasma periostin was markedly higher in subjects with non-vertebral fracture than their controls even after adjustment for BMD and potential confounders (P=0.006). Each standard deviation increment of plasma periostin was associated with a multivariable-adjusted odds ratio of 1.59 for non-vertebral fracture. The odds for non-vertebral fracture were 2.48-fold higher in subjects in the highest periostin tertile compared with those in the lowest periostin tertile (95% confidence interval=1.10-5.61). However, associations between plasma periostin and vertebral fracture were not observed, regardless of the adjustment model used. Consistently, plasma periostin levels were inversely associated with proximal femur BMD (P=0.007 to 0.030) but not lumbar spine BMD. In subgroup analyses, plasma periostin had no correlation with the levels of classical bone turnover markers. CONCLUSIONS Plasma periostin may be a potential biomarker of the risk of OF, especially in non-spinal skeletal sites, such as the limbs, rather than spine.

Multiple gene polymorphisms can improve prediction of nonvertebral fracture in postmenopausal women.

Clinical risk factors (CRFs), with or without bone mineral density (BMD), are used to determine the risk of osteoporotic fracture (OF), which has a heritable component. In this study we investigated whether genetic profiling can additionally improve the ability to predict OF. Using 1229 unrelated Korean postmenopausal women, 39 single‐nucleotide polymorphisms (SNPs) in 30 human genomic loci were tested for association with osteoporosis‐related traits, such as BMD, osteoporosis, vertebral fracture (VF), nonvertebral fracture (NVF), and any fracture. To estimate the effects of genetic profiling, the genetic risk score (GRS) was calculated using five prediction models: (Model I) GRSs only; (Model II) BMD only; (Model III) CRFs only; (Model IV) CRFs and BMD; and (Model V) CRFs, BMD, and GRS. A total of 21 SNPs within 19 genes associated with one or more osteoporosis‐related traits and were included for GRS calculation. GRS associated with BMD before and after adjustment for CRFs (p ranging from <0.001 to 0.018). GRS associated with NVF before and after adjustment for CRFs and BMD (p ranging from 0.017 to 0.045), and with any fracture after adjustment for CRFs and femur neck BMD (p = 0.049). In terms of predicting NVF, the area under the receiver operating characteristic curve (AUC) for Model I was 0.55, which was lower than the AUCs of Models II (0.60), III (0.64), and IV (0.65). Adding GRS to Model IV (in Model V) increased the AUC to 0.67, and improved the accuracy of NVF classification by 11.5% (p = 0.014). In terms of predicting any fracture, the AUC of Model V (0.68) was similar to that of Model IV (0.68), and Model V did not significantly improve the accuracy of any fracture classification (p = 0.39). Thus, genetic profiling may enhance the accuracy of NVF predictions and help to delineate the intervention threshold.

High serum total homocysteine levels accelerate hip bone loss in healthy premenopausal women and men

INTRODUCTION Despite extensive evidence demonstrating the direct, detrimental role of homocysteine on bone metabolism, the effects of serum total homocysteine (tHcy) on bone loss are still equivocal. In the present study, we performed a longitudinal study on healthy participants of various ages of both sexes in order to investigate the association between serum tHcy concentrations and annualized changes in bone mineral density (BMD). METHODS A total of 460 Koreans ≥ 30 years of age received comprehensive, routine health examinations for an average period of 3 years. The BMD at proximal femur sites was measured with dual-energy X-ray absorptiometry using the same equipment at baseline and follow-up. RESULTS After adjusting for potential confounders, the rates of bone loss at the proximal femur sites were significantly accelerated in a dose-response fashion across increasing tHcy concentrations in premenopausal women and men, but not in postmenopausal women. Consistently, compared with subjects in the lowest tHcy quartile, premenopausal women in the third and/or highest tHcy quartile and men in the highest tHcy quartile showed significantly higher rates of bone loss at all proximal femur sites (p=0.015-0.048) and at the total femur and femur neck (p=0.008-0.013), respectively. In contrast, there were no differences in terms of bone loss among the tHcy quartiles for postmenopausal women. CONCLUSION These data provide the first clinical evidence that increased tHcy levels could be an independent risk factor for the future deterioration of bone mass in premenopausal women and men.

Prediction of Future Osteoporotic Fracture Occurrence by Genetic Profiling: A 6-Year Follow-Up Observational Study

CONTEXT Heredity is an important risk factor for osteoporotic fracture, but it remains unclear whether genetic factors improve the predictability of future fracture occurrence. OBJECTIVE To compare an integration model of genetic profiling with the current model for predicting future fracture occurrence. DESIGN AND SETTING A retrospective observational cohort study. PARTICIPANTS Postmenopausal women aged 45-93 years who were untreated (n = 117), hormone-treated (n = 491), or bisphosphonate (BP)-treated (n = 415), with a mean 6.1-year follow-up. MAIN OUTCOMES MEASURES The main outcome was incident fractures. Ninety-five single nucleotide polymorphisms were genotyped. We calculated the Korean-specific genetic risk score 35 (GRS35) from 35 single nucleotide polymorphisms associated with osteoporosis-related traits at the baseline visit. RESULTS Osteoporotic fracture occurred more frequently in the highest GRS35 tertile group than in the lower two tertile groups after adjustments for confounders (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.17-2.55). The associations of the GRS35 with incident fracture were only significant in the BP group (HR, 2.25; 95% CI, 1.28-3.95) and not in the untreated (HR, 1.26; 95% CI, 0.34-4.66) and hormone-treated (HR, 1.21; 95% CI, 0.62-2.36) groups. Integration of the GRS35 into the current model further improved its predictability for incident fracture occurrence by 6.3% (P = .010). CONCLUSIONS Genetic profiling can more accurately predict future fracture risk, especially in individuals taking BPs.

Common and Rare Variants in the Exons and Regulatory Regions of Osteoporosis-Related Genes Improve Osteoporotic Fracture Risk Prediction

CONTEXT Osteoporotic fracture risk is highly heritable, but genome-wide association studies have explained only a small proportion of the heritability to date. Genetic data may improve prediction of fracture risk in osteopenic subjects and assist early intervention and management. OBJECTIVE To detect common and rare variants in coding and regulatory regions related to osteoporosis-related traits, and to investigate whether genetic profiling improves the prediction of fracture risk. DESIGN AND SETTING This cross-sectional study was conducted in three clinical units in Korea. PARTICIPANTS Postmenopausal women with extreme phenotypes (n = 982) were used for the discovery set, and 3895 participants were used for the replication set. MAIN OUTCOME MEASURE We performed targeted resequencing of 198 genes. Genetic risk scores from common variants (GRS-C) and from common and rare variants (GRS-T) were calculated. RESULTS Nineteen common variants in 17 genes (of the discovered 34 functional variants in 26 genes) and 31 rare variants in five genes (of the discovered 87 functional variants in 15 genes) were associated with one or more osteoporosis-related traits. Accuracy of fracture risk classification was improved in the osteopenic patients by adding GRS-C to fracture risk assessment models (6.8%; P < .001) and was further improved by adding GRS-T (9.6%; P < .001). GRS-C improved classification accuracy for vertebral and nonvertebral fractures by 7.3% (P = .005) and 3.0% (P = .091), and GRS-T further improved accuracy by 10.2% (P < .001) and 4.9% (P = .008), respectively. CONCLUSIONS Our results suggest that both common and rare functional variants may contribute to osteoporotic fracture and that adding genetic profiling data to current models could improve the prediction of fracture risk in an osteopenic individual.

Different Relationships Between Body Compositions and Bone Mineral Density According to Gender and Age in Korean Populations (KNHANES 2008–2010)

CONTEXT Fat and muscle are linked to bone metabolism. OBJECTIVE The objective of the study was to investigate the association of fat mass (FM) and lean mass (LM) with bone mineral density (BMD) according to gender and age. DESIGN AND SETTING This was a population-based, cross-sectional study from Korea National Health and Nutrition Examination Surveys. PARTICIPANTS 15,036 Koreans (6692 men and 8344 women) aged 10-95 years. MAIN OUTCOME MEASURES BMD and body compositions were measured using dual-energy X-ray absorptiometry. BMD was determined at the femoral neck, total hip, and lumbar spine. Body compositions included total FM (TFM), percentage FM (PFM), truncal FM (TrFM), total LM (TLM), and appendicular skeletal muscle mass/weight (ASM/Wt). RESULTS We categorized each man and woman into one of three age groups, based on changes in age-related BMD and the hormonal status. In all gender and age groups, TFM, PFM, and TrFM associated inversely with BMD (P < .001-.034), whereas TLM and ASM/Wt associated positively (P < .001-.037) after adjusting for confounders. The negative contribution of FM (P < .001-.034), and the positive contribution of LM (P < .001-.035) on BMD were significantly stronger in men than in women. The associations were strongest in men of growing age (P = .003-.040). When we subdivided the subjects into four groups based on the median values of PFM and TLM, FM had a greater effect than LM on BMD in men (P < .001-.006). CONCLUSION These results demonstrate that the effects of FM and LM on BMD may be based on gender and age.

Association Between Metabolic Syndrome and Incident Fractures in Korean Men: A 3-Year Follow-Up Observational Study Using National Health Insurance Claims Data

CONTEXT Although the prevalence of both metabolic syndrome (MetS) and fractures increases with advancing age, studies on possible associations between these conditions in men are limited and the results are inconsistent. OBJECTIVE The objective of the study was to clarify the impact of MetS on the male risk of incident fractures. DESIGN AND SETTING This was a large, longitudinal study with an average 3-year follow-up period. PARTICIPANTS Korean men (n = 16 078) aged 50 years or older who had undergone comprehensive routine health examinations participated in the study. MAIN OUTCOME MEASURES Incident fractures found after baseline examinations were identified using selected International Classification of Diseases, tenth revision, codes in the nationwide claims database of the Health Insurance Review and Assessment Service of Korea. RESULTS In total, 158 men (1.0%) developed incident fractures. The fracture event rates for subjects with and without MetS were 26.2 and 35.7 per 10 000 person-years, respectively. After adjustment for potential confounders, subjects with MetS had a much lower risk of incident fractures than subjects without MetS (hazard ratio 0.662, 95% confidence interval 0.445-0.986). Furthermore, subjects with three and four or more MetS components had a 49.4% and 50.4% lower risk, respectively, of incident fractures compared with the subjects without any MetS components. Importantly, additional adjustment for body mass index eliminated the statistical significance of these associations. CONCLUSION Our current results indicate that the beneficial effects of MetS in reducing fracture risk could be explained by the general obesity that accompanies MetS, although other related factors, such as greater padding effect, peripheral aromatization, or adipokine changes, may also contribute.

Validation of pathological grading systems for predicting metastatic potential in pheochromocytoma and paraganglioma.

Purpose The Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP) was proposed for predicting the metastatic potential of pheochromocytoma and paraganglioma to overcome the limitations of the Pheochromocytoma of the Adrenal Scaled Score (PASS). However, to date, no study validating the GAPP has been conducted, and previous studies did not include mutations in the succinate dehydrogenase type B (SDHB) gene in the score calculation. In this retrospective cohort study, we validated the prediction ability of GAPP and assessed whether it would be improved by inclusion of the loss of SDHB immunohistochemical staining. Methods We divided the tumors into non-metastatic and metastatic groups based on the presence of synchronous or metachronous metastases. The GAPP score and PASS at the initial operation were measured. Moreover, we combined some GAPP parameters with the immunohistochemical staining of SDHB to obtain a modified GAPP (M-GAPP) score. Results Metastasis occurred in 15/72 (20.8%) patients, with a mean follow-up of 43.5 months. Loss of SDHB staining was more frequent (P = 0.044) in the metastatic group. The GAPP score (P = 0.006), PASS (P = 0.003), and M-GAPP score (P<0.001) were all higher in the metastatic group. Twelve of 40 (30.0%) moderately or poorly differentiated tumors, as defined by the GAPP score, and 12/34 (35.3%) tumors with a PASS ≥4 were metastatic. Conversely, 10/19 (52.6%) tumors with an M-GAPP score ≥3 were metastatic. The area under the curve of the M-GAPP score (0.822) was significantly higher than that of the GAPP (0.728) (P = 0.012), but similar to that of the PASS (0.753) (P = 0.411). The GAPP (P = 0.032) and M-GAPP scores (P = 0.040), but not PASS (P = 0.200), negatively correlated with metastasis-free survival. Conclusion The GAPP was validated, and M-GAPP, a combination of some GAPP parameters and loss of SDHB staining, might be useful for the prediction of the metastatic potential of pheochromocytoma and paraganglioma.

New diagnostic criteria for subclinical hypercortisolism using postsurgical hypocortisolism: the Co-work of Adrenal Research study.

There is no consensus on the biochemical diagnostic criteria for subclinical hypercortisolism (SH). Using parameters related to the hypothalamic–pituitary–adrenal axis, we aimed to develop a diagnostic model of SH for predicting postsurgical hypocortisolism and metabolic complications.