Vitamin C Prevents Hypogonadal Bone Loss

PLOS ONE, Dec 2019

Epidemiologic studies correlate low vitamin C intake with bone loss. The genetic deletion of enzymes involved in de novo vitamin C synthesis in mice, likewise, causes severe osteoporosis. However, very few studies have evaluated a protective role of this dietary supplement on the skeleton. Here, we show that the ingestion of vitamin C prevents the low-turnover bone loss following ovariectomy in mice. We show that this prevention in areal bone mineral density and micro-CT parameters results from the stimulation of bone formation, demonstrable in vivo by histomorphometry, bone marker measurements, and quantitative PCR. Notably, the reductions in the bone formation rate, plasma osteocalcin levels, and ex vivo osteoblast gene expression 8 weeks post-ovariectomy are all returned to levels of sham-operated controls. The study establishes vitamin C as a skeletal anabolic agent.

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Vitamin C Prevents Hypogonadal Bone Loss

Citation: Zhu L-L, Cao J, Sun M, Yuen T, Zhou R, et al. ( Vitamin C Prevents Hypogonadal Bone Loss Ling-Ling Zhu 0 Jay Cao 0 Merry Sun 0 Tony Yuen 0 Raymond Zhou 0 Jianhua Li 0 Yuanzhen Peng 0 Surinder S. Moonga 0 Lida Guo 0 Jeffrey I. Mechanick 0 Jameel Iqbal 0 Liu Peng 0 Harry C. Blair 0 Zhuan Bian 0 Mone Zaidi 0 Brenda Smith, Oklahoma State University, United States of America 0 1 School of Stomatology, Wuhan University , Wuhan, Hubei , China , 2 The Mount Sinai Bone Program, Mount Sinai School of Medicine , New York , New York, United States of America, 3 Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture , Grand Forks , North Dakota, United States of America, 4 Department of Pathology, University of Pittsburgh , Pittsburgh, Pennsylvania , United States of America Epidemiologic studies correlate low vitamin C intake with bone loss. The genetic deletion of enzymes involved in de novo vitamin C synthesis in mice, likewise, causes severe osteoporosis. However, very few studies have evaluated a protective role of this dietary supplement on the skeleton. Here, we show that the ingestion of vitamin C prevents the low-turnover bone loss following ovariectomy in mice. We show that this prevention in areal bone mineral density and micro-CT parameters results from the stimulation of bone formation, demonstrable in vivo by histomorphometry, bone marker measurements, and quantitative PCR. Notably, the reductions in the bone formation rate, plasma osteocalcin levels, and ex vivo osteoblast gene expression 8 weeks post-ovariectomy are all returned to levels of sham-operated controls. The study establishes vitamin C as a skeletal anabolic agent. - Funding: This work was supported in part by research grants from the National Institute of Health (DK0804590, AG023176 and AG040132) and from the USDA Agricultural Research Service CRIS program 5450-51000-046-00D. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. The diligent search for small molecules and biologics to treat osteoporosis resonates with the expanding definition of osteoporosis and the implication that many more individuals worldwide have fragile bones. In developing nations in particular, while disease prevalence is difficult to estimate short of bone density measurements, the growing incidence of fractures poses a heavy burden of healthcare costs. In China, for example, almost 69 million individuals are estimated to have osteoporosis [1]. The cost of non-generic medications becomes difficult to bear in such emerging economies, prompting the need for affordable osteoprotection. Vitamin C has long been known to affect the skeleton as gross deficiency causes the brittle bones of scurvy [2]. However, over the past decade, more subtle effects of vitamin C undernutrition have been gleaned. For example, low vitamin C intake is associated with low bone mass and a high fracture risk [3,4]. More importantly, persuasive epidemiological evidence suggests that higher vitamin C intake is associated with higher bone mass [5], as well as reduced fracture risk over a 17-year follow-up [6]. Likewise, the Womens Health Initiative found a statistical relationship between total vitamin C intake and bone mineral density at both the hip and spine in women receiving hormone therapy [7]. Thus, it appears that, while adequate vitamin C prevents scurvy, higher doses might protect against skeletal loss. Further evidence for an effect of vitamin C on bone mass comes from mouse genetic studies. The deletion of two key enzymes aldose reductase and aldehyde reductase, which results in absent de novo synthesis of ascorbic acid in mice, causes scorbutic bones [8]. While humans have lost the ability to synthesize vitamin C in vivo, and thus require nutritional supplementation, data in mice firmly establish an indispensible role for vitamin C in skeletal homeostasis. Both mouse and human osteoblasts require ascorbic acid to differentiate into mature mineralizing cells [9,10]. In addition, mice that genetically lack ascorbic acid have immature dysplastic osteoblasts [8]. Thus, a key target for vitamin C appears to be the osteoblast. However, vitamin C also alters the resorption of bone by osteoclasts [11]. Importantly, Chambers and colleagues found that intraperitoneally injected ascorbic acid (2 mmol/kg/day) prevented ovariectomy-induced hyper-resorption and bone loss [12]. This study provided proof-of-concept that vitamin C could potentially be used to prevent hypogonadal bone loss. Still, even with the passage of ,20 years, no clinical trials have evaluated the effect of vitamin C on skeletal integrity in humans. Here, we extend Chambers initial observation, and provide evidence that vitamin C, when ingested orally (...truncated)


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Ling-Ling Zhu, Jay Cao, Merry Sun, Tony Yuen, Raymond Zhou, Jianhua Li, Yuanzhen Peng, Surinder S. Moonga, Lida Guo, Jeffrey I. Mechanick, Jameel Iqbal, Liu Peng, Harry C. Blair, Zhuan Bian, Mone Zaidi. Vitamin C Prevents Hypogonadal Bone Loss, PLOS ONE, 2012, Volume 7, Issue 10, DOI: 10.1371/journal.pone.0047058