Age-associated Iron Accumulation in Bone: Implications for Postmenopausal Osteoporosis and a New Target for Prevention and Treatment by Chelation

Abstract

Iron accumulation in tissues is believed to be a characteristic of aged humans and a risk factor for some chronic diseases. However, it is not known whether age-associated iron accumulation is part of the pathogenesis of postmenopausal osteoporosis that affects approximately one out three women worldwide. Here, we confirmed that this accumulation of iron was associated with osteopenia in ovariectomized (OVX) rats (a model of peri- and postmenopausal osteoporosis due to estrogen deficiency). To further investigate whether the increased iron level plays a causal role in the onset of bone loss, we treated OVX rats with an orally active and bone targeted chelator that prevented iron accumulation in their skeletal tissues. The results showed that this treatment mitigated the loss of bone mass and the deterioration of bone micro-architecture. We also found that one possible mechanism of the protective action of iron chelation was to significantly reduce bone resorption. Thus, these findings provide a novel target and a potentially useful therapeutic strategy for the prevention and treatment of postmenopausal osteoporosis and perhaps other age-related diseases.

Estrogen regulates iron homeostasis through governing hepatic hepcidin expression via an estrogen response element

“…Precious epidemiological studies have demonstrated that the postmenopausal women harbor a higher level of body iron than premenopausal women (Jian et al, 2009). Similar to clinical observations, Liu and his colleagues documented iron accumulation in the ovariectomized (OVX) rats, a model of postmenopausal osteoporosis (Liu et al, 2006). In contrast, a pilot study suggested that iron chelator could prevent bone loss induced by excess iron in OVX rats (G. Liu et al, 2008).…”

“…The major reason for choosing this time point is because biological effects induced by estrogen deficiency need at least 4-6 weeks to be reflected in animals. For example, most studies in evaluating the ovariectomized models for postmenopausal osteoporosis are performed over 1 month after ovariectomy (G. Liu et al, 2006Liu et al, , 2008Sottile et al, 2004;Thompson et al, 1995). Considering iron metabolism upon certain chronic physiological alternation, the end-point of iron-related studies are normally set over 1 month after ovariectomy when using ovariectomized models (Ikeda et al, 2012;Liu et al, 2006;Mattace Raso et al, 2009).…”

“…For example, most studies in evaluating the ovariectomized models for postmenopausal osteoporosis are performed over 1 month after ovariectomy (G. Liu et al, 2006Liu et al, , 2008Sottile et al, 2004;Thompson et al, 1995). Considering iron metabolism upon certain chronic physiological alternation, the end-point of iron-related studies are normally set over 1 month after ovariectomy when using ovariectomized models (Ikeda et al, 2012;Liu et al, 2006;Mattace Raso et al, 2009). Moreover, a previous study by Ramos et al has demonstrated that hepcidin expression were distinct in response to long-term (3 weeks) or acute (1 day) iron loading (Ramos et al, 2011).…”

Iron and Menopause: Does Increased Iron Affect the Health of Postmenopausal Women?

“…By searching for factor(s) other than estrogen deficiency in osteoporosis, we found that both dietary iron deficiency and overload affect bone in animal studies (8,18,19,21,23,29). One recent report showed that osteoporosis patients are slightly iron deficient, having lower serum iron and higher transferrin as compared with the control group (7).…”

Excess iron undermined bone load-bearing capacity through tumor necrosis factor-α-dependent osteoclastic activation in mice

“…Ovariectomized rats with an increased iron level showed a higher tendency to have osteoporosis (6). Tsay et al (7) reported that the iron overload (IO)-induced bone loss in mice was correlated with the inflammatory bone resorption and oxidative stress.…”