Nutrients 2023 , 15 , 2688
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neck, and total hip), plasma bone biomarkers, and other secondary outcomes, notably blood lipids and glucose homeostasis parameters. This beneficial impact on BMD is consistent with previous studies performed in the ovariectomized rat with standardized hop extract, which showed an increase in BMD fol- lowing 8 to 12 weeks of supplementation while using a daily dose of 8-PN from 6 to 27 times higher in a human dose equivalent [13,14]. Regarding the effects of other types of phy- toestrogens in humans, isoflavones are the most studied in terms of bone health effect in postmenopausal women. The recent meta-analysis by Sansai et al. included 63 RCTs and various types of isoflavone interventions [8]. A statistically significant increase in BMD was found at the lumbar spine, femoral neck, and distal radius with isoflavones. However, these favorable effects were predominantly associated with the use of genistein pure compounds and synthetic isoflavones, while the benefits of isoflavone extracts and dietary isoflavone supplements on BMD remain inconclusive (with up to 300 mg/day of isoflavone aglycone equivalents). This analysis did not reveal any significant effects on the total hip and the total body, which might be because no study has investigated the effects of genistein or synthetic isoflavones on those two sites. Bone turnover biochemical markers help clinicians to identify patients at high risk for fracture and to monitor the efficacy of osteoporosis treatments. However, no significant dif- ference between the HE and placebo groups was observed regarding the bone biochemical markers concentrations after 48 weeks of supplementation. Among the available biochemi- cal markers, pro-collagen type I N- terminal propeptide (PINP) and C- terminal telopeptide (CTX) have been recommended as reference biochemical markers of bone formation and bone resorption, respectively [41]. Surprisingly, CTX increased compared to baseline in both groups, while PINP remained stable. The marker of bone resorption TRAP5b and sclerostin, a marker known to increase in bone diseases, were both decreased in the HE and placebo groups compared to baseline. Finally, a decrease in serum undercarboxylated osteocalcin (uOC) was observed only in the HE group compared to baseline, which could be a sign of a beneficial impact on BMD in the HE group. Indeed, uOC concentration is a marker of bone turnover, increased serum uOC levels have been associated with an increased risk of hip fracture [42] and of low BMD of the hip and spine in postmenopausal women [43]. The magnitude of HE effects on bone density is not comparable to those of osteoporosis medications, but it could be of interest as a preventive measure for women with low bone mass that cannot be prescribed medication at this stage. Dawson-Hughes et al. have reported that after 3 years of vitamin D (700 IU) and calcium (500 mg) supplementation, a 1.1% net increase in total body BMD compared to placebo was associated with a relative risk reduction of 0.4 of first osteoporotic fracture in men and women [44]. Accordingly, in our study, the mean total body BMD increase of 1% and the significantly higher proportion of women with an increase ≥ 1% following HE consumption compared to placebo might point toward a similar relative risk reduction. Notably, considering that this 1% net increase is in addition to a 0.8% increase already observed in both groups in the context of CaD supplementation. Moreover, several studies have found reduced muscle strength, reduced physical capacity, and reduced quality of life among patients with low BMD [45–47]. Notably, in a cross-sectional study, 18 postmenopausal women with osteopenia and a healed wrist fracture had a lower score in the sub-scales on the SF-36 quality of life questionnaire for physical functioning, role limitation due to physical problem, bodily pain and vitality compared to a matched, healthy control group with no previous fracture [47]. Therefore, the increase in the physical functioning SF-36 sub-scale following HE supplementation compared to placebo may indicate an improved quality of life in women with osteopenia. Dawnson Hugues et al. have reported in older women without intervention an annual bone loss of about 1% in the total body and 0.8% in the lumbar spine region [44]. Furthermore, inadequate intakes of vitamin D and calcium lead to increased bone loss, and CaD supplementation has been demonstrated to be effective in reducing bone loss in postmenopausal women [48]. In our study, all women were supplemented with CaD,
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