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 Women's 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, can prevent bone loss following ovariectomy through an anabolic action. We show, in a model of low-turnover osteoporosis, that this in vivo action results from the stimulation of bone formation noted in histomorphometric, bone marker, and quantitative PCR (qPCR) studies. Together with prior epidemiologic evidence showing a relationship between dietary intake and bone mass, our data provide compelling evidence for a therapeutic potential for vitamin C.
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