Original Full Length ArticleHigh serum total homocysteine levels accelerate hip bone loss in healthy premenopausal women and men
Highlights
► Serum tHcy level was significantly higher in men than women, and, among women, in postmenopausal women than premenopausal women. ► Higher serum tHcy concentrations were independently associated with accelerated hip bone loss in premenopausal women and men. ► In contrast, there was no relationship between serum tHcy levels and hip bone loss in postmenopausal women. ► First clinical evidence demonstrating that the detrimental effects of tHcy on bone loss are predominant in relatively younger subjects.
Introduction
Many lines of evidence now indicate that elevation of homocysteine and its disulfide derivatives (tHcy) has direct detrimental effects on bone metabolism. Homocysteine may interfere with bone collagen cross-links, thereby increasing bone fragility [1]. In a murine experimental model, rats with elevated tHcy demonstrated severe trabecular bone loss, altered microarchitectural parameters, and decreased mechanical strength in the femoral neck [2]. In addition, our in vitro studies have reported that homocysteine induces apoptosis in bone marrow stromal cells via the reactive oxygen species (ROS)-mediated mitochondrial pathway and NF-kappa B activation [3], whereas it promotes bone resorption by stimulating p38 mitogen-activated protein kinase (MAPK) activity and the generation of intracellular ROS in osteoclasts [4]. The first clinically relevant evidence of these in vitro and animal findings was observed in patients with homocystinuria due to cystathionine beta-synthase deficiency, an inborn error of metabolism that is characterized by very high plasma concentrations of tHcy and, among several clinical manifestations, premature osteoporosis and fractures [5].
Based on these findings, numerous epidemiological studies have been performed to assess the role of serum tHcy as a risk factor for osteoporosis-related phenotypes. All prospective trials that enrolled > 1000 patients found a significant positive relationship between tHcy and osteoporotic fractures [6], [7], [8], [9]. In contrast, studies on the association between tHcy and bone mineral density (BMD) have yielded inconsistent results [10]. However, because almost all of these studies were cross-sectional in design [11], [12], the role of tHcy in bone mass could not be appropriately investigated. Furthermore, the only two studies of longitudinal bone loss that have been previously reported were based on data from elderly patients > 75 years of age on average and had contradictory findings [13], [14]. Thus, the effects of tHcy on bone density are still equivocal.
It is well known that the biologic differences between men and women, as well as menopause status, are important factors that influence bone metabolism, implying that the effects of various risk factors on bone health could be different depending on the sex and menopause status of the individual patient. Actually, several epidemiological studies have reported different relationships of serum tHcy levels with osteoporosis-related phenotypes in men and women [7], [9], [12]. In the present study, we performed a longitudinal study on healthy pre- and postmenopausal women and men in order to investigate the association between serum tHcy concentrations and annualized changes in BMD.
Section snippets
Study participants
This was a 3-year longitudinal health promotion center-based study. The study population consisted of subjects ≥ 30 years of age who had undergone comprehensive routine health examinations at the Asan Medical Center (AMC, Seoul, Republic of Korea) in 2007 and had returned for follow-up examinations in 2010; BMD and serum tHcy concentrations were measured during these examinations. The examinations consisted of extensive screening tests for the early detection of malignancy, diabetes, osteoporosis,
Results
The baseline characteristics of the 460 study subjects are shown in Table 1. The mean ages of the pre- and postmenopausal women and men were 45.6 ± 3.5 years (range: 30–54 years), 55.6 ± 6.2 years (range: 44–80 years), and 55.0 ± 8.4 years (range: 35–80 years), respectively. BMI and the percentage of current smokers and drinkers were significantly higher in men than in women, whereas the percentage of subjects who consumed dairy products was higher in women than in men. Women demonstrated significantly
Discussion
In this longitudinal study of 460 healthy Koreans, we found that the rates of bone loss over 3 years at multiple proximal femur sites significantly accelerated in a dose–response manner as the tHcy concentration increased, even after adjusting for potential confounding factors in premenopausal women and men. These data provide the first clinical evidence that increased tHcy levels could be an independent risk factor for future deterioration of bone mass in premenopausal women and men.
Although
Acknowledgments
This study was supported by grants from the Korea Health Technology R&D Project and the National Project for Personalized Genomic Medicine, Ministry of Health & Welfare, Republic of Korea (project nos. A110536 and A111218-GM03, respectively).
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Moderate hyperhomocysteinemia induced by short-term dietary methionine overload alters bone microarchitecture and collagen features during growth
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