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.
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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)