Elsevier

Bone

Volume 55, Issue 2, August 2013, Pages 458-460
Bone

Commentary
Dancing with sex hormones, could iron contribute to the gender difference in osteoporosis?

https://doi.org/10.1016/j.bone.2013.03.008Get rights and content

Introduction

It may not be fair, but it's true. Women are automatically at greater risk of developing osteoporosis than men. Why are there gender differences? First, women start with lower bone mineral density (BMD) than their male peers. Heritability of skeletal traits has been demonstrated and many common single nucleotide polymorphisms (SNPs) have pointed to genes accounting for variability in BMD and fracture risk [1]. These observations led to an investigation whether gene variation affects the female skeleton differently than it does the male. The gene-by-gender interactions could identify new signals not detected in the sex-combined analyses and indicate important gender-dependent skeletal biology. Yet, a recent report shows that no gender differences in the effects of autosomal SNPs on BMD were found in analyses of more than 50,000 men and women [2]. Although other genetic features beyond SNPs and BMD can be explored [1], postnatal factors are important to be considered.

Indeed, women lose bone mass more quickly than men as they age. Estrogen deficiency has been regarded as the main causative factor in postmenopausal osteoporosis, which is characterized by an increase in bone turnover rate and a remodeling imbalance of bone resorption exceeding bone formation. Is estrogen deficiency the sole factor or other factor(s) involved in accelerating postmenopausal bone loss? If estrogen deficiency is the sole factor, the exact mechanism as to why bone resorption outpaces bone formation remains unexplained.

One factor that has long been overlooked is that while estrogen decreases by 90% during menopausal transition, levels of serum ferritin, an iron storage protein with a capacity of storing up to 4500 atoms of iron per molecule of ferritin and an indicator of body iron status [3], are increased 2 to 3-fold from premenopause to postmenopause. Based on this observation, it has been hypothesized that in addition to estrogen deficiency, increased iron as a result of menopause could contribute to bone loss in postmenopausal women [4]. It is known that individuals with pathological iron overload, such as those with hereditary hemochromatosis and β-thalassemia, have decreased BMD. Yet, one cannot rule out the possibility that the disease itself, e.g., hemochromatosis Fe (HFE) gene mutation but not iron overload has an effect on bone metabolism. Although extensive animal evidence has emerged about the detrimental effects of iron on bone metabolism [5], [6], [7], [8], [9], association of iron with bone loss in healthy adults has not been demonstrated until recently.

That changed with the work from a team of scientists in Seoul. They used a 3-year longitudinal health promotion center-based study, which included 789 men and 940 women who were aged 40 years or older. Individuals who might have had inflammatory diseases were excluded, since inflammation has been suggested to play a role in the pathogenesis of osteopenia and osteoporosis and serum ferritin levels are known to be elevated in the inflammatory state. Serum ferritin levels and BMD of the total femur, femur neck and trochanter were measured at baseline and at follow-up in all study participants. They found that serum ferritin levels were positively correlated with accelerated bone loss at all three sites in both men and women in a dose-dependent manner [10]. This is the first large population study which shows an association of higher levels of ferritin with bone loss in healthy individuals. Yet, the finding of the study poses another question about the role of iron in bone metabolism. Despite lower ferritin levels, the effect of body iron stores on bone loss appears more striking in postmenopausal women than in middle-aged men. Moreover, the researchers did not find a significant association between fracture risk and serum ferritin levels in men; however, in women, a dose-dependent increase in the risk of fracture was evident. Why does a lower ferritin level have a greater impact on the bones of postmenopausal women than that of middle-aged men? Here we looked at the changes of iron with sex hormones over time. The difference in timing and pattern of changes may explain the more damaging effects of iron on bone in women and the resulting gender difference in osteoporosis incidence.

Section snippets

Iron tangoes with estrogen in women

Menstruation is a unique physiological phenomenon in women, characterized by the periodic high levels of estrogen and endometrium shedding in the form of blood. As a result of this monthly blood loss, iron deficiency in young premenopausal women is highly prevalent [11]. As women age, iron is no longer lost through menstruation, and body iron level is significantly increased in postmenopausal women [12], [13]. By compiling separate large population studies on iron and estrogen, we found a

Iron waltzes with androgen in men

It is known that iron also increases in men during their adolescent years. When we searched for changes in iron and testosterone levels in men, we found that significant differences exist. The timing and pattern of changes in sex hormones and iron levels are not the same at all. Iron levels rise in men in conjunction with the increase of testosterone from 20 to 40 years old, then reverse between ages 40 and 50 years old, and gradually decrease in tandem thereafter (Fig. 1b) [13], [14]. If they

Do the differences in iron and sex hormones contribute to the gender differences in osteoporosis incidence?

It is well established that estrogen deficiency enhances bone resorption and testosterone increases bone mass by promoting bone formation [15], [16], [17]. According to our previous results [8], increased iron could be a risk factor for osteoporosis by mainly inhibiting bone formation. Therefore, simultaneous increases in testosterone and iron could neutralize each other's effects on bone formation. In young men, the promoting effects of testosterone slightly supersede the inhibiting effects of

Systemic interaction of estrogen with iron

Before testing the above hypothesis, one important question must be answered: Is increased iron a downstream effect of estrogen deficiency? If it is, estrogen replacement therapy should ease the iron loading concern. Thus, clarification of the mechanism may have important clinical implications. By examining the effects of estrogen on hepcidin, a key negative regulator of iron absorption [18], it has been found that transcription of hepcidin was suppressed by estrogen treatment, suggesting that

Perspective for future research

It has been well established that estrogen deficiency mainly promotes bone resorption and lack of testosterone inhibits bone formation [15], [16], [17]. The mode of action of iron accumulation needs to be determined precisely. Iron is a well-known transition metal producing reactive oxygen species (ROS) that could affect both bone resorption and bone formation [22]. ROS has been reported to antagonize Wnt signaling in osteoblast precursors by diverting β-catenin from T cell factor to Forkhead

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  • Cited by (46)

    • Development of a novel polysaccharide-based iron oxide nanoparticle to prevent iron accumulation-related osteoporosis by scavenging reactive oxygen species

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      Upon treatment of the NPs, although serum Fe did not seem to differ, osteoporosis did not occur. In addition, estrogen is another an important factor contributing to the incidence of osteoporosis, and it has been reported that postmenopausal women are more likely to have osteoporosis induced by iron accumulation [8,44,45]. Thus, we prepared OVX models to test the bone protection effect of the NPs in an estrogen-deficient environment.

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    Disclosure: All authors state that they have no conflict of interest.

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