The Role of Trace Elements and Minerals in Osteoporosis: A Review of Epidemiological and Laboratory Findings

Abstract

The objective of the present study was to review recent epidemiological and clinical data on the association between selected minerals and trace elements and osteoporosis, as well as to discuss the molecular mechanisms underlying these associations. We have performed a search in the PubMed-Medline and Google Scholar databases using the MeSH terms "osteoporosis", "osteogenesis", "osteoblast", "osteoclast", and "osteocyte" in association with the names of particular trace elements and minerals through 21 March 2023. The data demonstrate that physiological and nutritional levels of trace elements and minerals promote osteogenic differentiation through the up-regulation of BMP-2 and Wnt/β-catenin signaling, as well as other pathways. miRNA and epigenetic effects were also involved in the regulation of the osteogenic effects of trace minerals. The antiresorptive effect of trace elements and minerals was associated with the inhibition of osteoclastogenesis. At the same time, the effect of trace elements and minerals on bone health appeared to be dose-dependent with low doses promoting an osteogenic effect, whereas high doses exerted opposite effects which promoted bone resorption and impaired bone formation. Concomitant with the results of the laboratory studies, several clinical trials and epidemiological studies demonstrated that supplementation with Zn, Mg, F, and Sr may improve bone quality, thus inducing antiosteoporotic effects.

Keywords: bone mineral density; bone resorption; fluoride; minerals; osteoporosis; selenium; strontium; trace elements; zinc.

Figure 1

The proposed mechanism of antiresorptive effects of Se. Se is transported to the bone by selenoprotein P (SELENOP), where it is used for synthesis of antioxidant selenoproteins (SEPs) including GPX and TXNRD. Antioxidant activity of selenoproteins inhibits RANKL/RANK/tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) signaling-associated ROS overproduction, thus inhibiting activation of redox sensitive NF-κB, resulting in down-regulation of nuclear factor of activated T-cells (NFATc1)-dependent osteoclastogenesis.

Figure 2

The proposed mechanisms involved in adverse effects of Fe overload in the bone. Fe overaccumulation is associated with increased ROS production via Fenton chemistry as well as Fe-induced mitochondrial dysfunction, which also contributes to ROS generation. In the presence of elevated intracellular Fe levels, ROS induce lipid peroxidation (LPO), in turn triggering ferroptosis. In addition to ferroptosis, Fe-induced mitochondrial dysfunction results in increased cytochrome c leakage and apoptosis, altogether resulting in osteocyte and osteoblast damage. Excessive ROS production due to Fe overload also interferes with canonical Wnt signaling, leading to reduced β-catenin levels and inhibiting osteoblastogenesis. In turn, ROS was also shown to induce excessive RANKL secretion, which promotes osteoclastogenesis. Taken together, Fe overload promotes osteocyte/osteoblast damage, reduced osteoblast differentiation, as well as excessive osteoclastogenesis with induction of bone resorption through ROS-dependent mechanisms.

Figure 3

The role of miRNA in mediation of the effects of fluoride in the bone. F-induced modulation of miR-486-3p expression up-regulates cyclin D1 through TGF-β1/Smad2/3, resulting in increased osteoblast proliferation. Let-7c-5p also modulates cyclin D1 upon fluoride exposure. miR-200c-3p was shown to mediate proliferative effects of fluoride via up-regulation of BMP4/Smad pathway. Finally, F-induced increase in miR-21-5p expression promotes Wnt signaling through LRP5/6 and subsequent dissociation of a destruction complex consisting of Axin, GSK3β, and adenomatous polyposis coli (APC), leading to β-catenin accumulation. The impact of miR-21-5p on canonic Wnt signaling may also be mediated by its inhibitory effect on PTEN and DKK. Upward arrow is indicative of stimulation.

Figure 4

Biphasic effect of fluoride on osteoclastogenesis and bone resorption. Micromolar fluoride concentrations were shown to reduce RANKL production, resulting in decreased RANKL/OPG ratio and down-regulation of osteoclastogenesis, as well as inhibition of bone resorption. In contrast, excessive doses of fluoride up-regulate RANKL production with an increase in RANKL/OPG production, which promotes osteoclast formation and bone resorption. Upward and downward arrows are indicative of stimulation and inhibition, respectively. Green color of the arrows is indicative of positive effect on bone health, whereas red arrows demonstrate effect leading to bone resorption.