Nutrients 2023 , 15 , 2688
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which placed favorable conditions of bone loss prevention, therefore potentially limiting the ability to detect an effect of the HE alone. In the placebo group, supplementation with 1000 mg of calcium and 800 UI of vitamin D resulted in a mean net increase of 0.8% at the total body, 2.2% at the femoral neck, and no change at the lumbar spine observed after 48 weeks. Similar total body BMD increase has been previously reported with CaD supplementation [49–52]. Notably, an open-label, randomized, controlled trial investigated in 590 postmenopausal women the effect of a similar CaD supplementation or no intervention over 3 years [50]. A significant increase in total body BMD of 0.8% was observed in the intervention group compared to control group (0.2%), but no significant differences were observed at the lumbar spine, femoral neck, trochanter, and total proximal. In compliant women (those who took at least 80% of their supplementation), greater effect was observed with a significant increase in BMD at the total body (1.3%, i.e., around 0.4% per year) and all specific sites investigated. Interestingly, these women had a mean baseline serum 25OHD level of 50 nmol/L, which suggests that they were moderately vitamin D insufficient. It is known that vitamin insufficient women benefit more from a higher CaD intake [53]. In our study, following a subgroup analysis, according to vitamin D status, we observed that vitamin D-insufficient women (defined here as <75 nmol/L) might have benefited more from the CaD supplements, as in the placebo group, an increase of 0.8% was observed in these women, while a decrease of 1% was observed in vitamin D-sufficient women. Moreover, we observed that vitamin D-sufficient women seemed to have a more beneficial impact of HE supplementation compared to vitamin D-insufficient women, as an increase of the lumbar spine BMD (+2.3% HE vs. placebo) was observed primarily in this vitamin D-sufficient population. The main mechanism of action of HE is the estrogenic activity of 8-PN, which has been demonstrated in vitro and in vivo and which has been recently extensively reviewed [9–11,54]. Along with its metabolites, 8-PN was only detected in the plasma and urine of women supplemented with HE, confirming adherence to treatment and an exposition to these active compounds in this group only. No correlation was found between the levels of total 8-PN and change in total body BMD after 48 weeks. However, the samples were collected 24 h after the last capsule ingestion and therefore are not representative of the acute levels of metabolites circulating after HE consumption. Another potential mechanism of action could be the antioxidant properties of the standardized hop extract. Indeed, changes in reactive oxygen species (ROS) and/or antioxidant systems seem to be involved in the patho- genesis of bone loss. Additionally, a marked decrease in plasma antioxidants was found in osteoporotic women, and recent data suggest that diet supplementation with antioxidants could be an effective strategy to prevent bone loss [55]. Hops prenylflavonoids, and particu- larly xanthohumol (X), are known to exert diverse antioxidant and free-radical-scavenging properties and therefore might have beneficially impacted BMD of postmenopausal women supplemented with HE [56]. Despite the fact that volunteers were asked to maintain a similar diet throughout the study, significantly higher changes from baseline at week 48 were observed for fat, vitaminK 2 , and calcium in the HE group compared to the placebo group. No difference was observed between groups in terms of weight, fat mass, and blood lipids, suggesting that the small difference of fat intake (around 11 g) had no impact on these parameters. The minimum efficacy dose of vitamin K 2 for osteopenia and osteoporosis is known to be of 45 mg/d; therefore, the differential amount of +2.3 µ g/d (20,000 times less) observed here is unlikely to be responsible for the effect on BMD [57]. Finally, the difference of calcium between groups does not take into account the calcium supplementation, i.e., an additional 1000 mg/d of calcium in all women in addition to the initial reported mean intake of 1170 mg/d at baseline. Therefore, it is also unlikely that the differential amount of calcium of +112 mg/d could have contributed to the observed effect.
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