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Analysis of the prenylflavonoids concentrations in urine and plasma confirmed the good adherence to the treatment. Indeed, X, IX, 6-PN, 8-PN, and their metabolites (glu- curonide and sulfated forms) were present after 48 weeks in both urine and plasma of the HE group, while absent or negligible in the placebo group. In urine samples from the HE group, total 8-PN was detected in 94% of the participants with a mean concentration of 13.96 ± 19.11 ng/mL; total 8-PN was detected in 76% of participant plasma samples of the HE group at a mean concentration of 1.09 ± 0.92 ng/mL (Table S2). Regarding safety, there were a total of 127 TEAEs reported during the trial, of which 55 were noted in the HE group and 77 in the placebo group ( p = 0.21; Table S3). Among these, only 15 and 22 were suspected to be related to the IP in the HE and placebo group, re- spectively. Two participants in the HE group versus three in the placebo group discontinued IP and withdrew from trial due to an AE suspected to be related to the IP. Six participants experienced serious TEAEs, two occurred in the HE group and four in the placebo group. These serious TEAEs were unexpected and not related to the IP. Laboratory results were generally unremarkable (Table S4). There were no notable or clinically meaningful changes in participants’ anthropometrics or vitals detected during the study. CONSORT 2010 Flow Diagram
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Assessed for eligibility (n= 221)
Enrollment
Excluded (n=121) – Not meeting inclusion criteria (n=109) – Declined to participate (n=6) – Unable to get a DXA scan due to im- planted jewellery (n= 1) – No longer needed for the study as 100 eligible participants were met (n=5)
Randomized (n= 100)
Allocation
Allocated to intervention (n= 50) – Received allocated intervention (n= 50) – Did not receive allocated intervention (n= 0)
Allocated to placebo (n= 50) – Received allocated intervention (n= 50) – Did not receive allocated intervention (n= 0)
Follow-Up
Lost to follow-up (n= 0) Discontinued intervention (n= 3)
Lost to follow-up (n= 0) Discontinued intervention (n= 2)
Analysis
Analysed: – FAS (n=47) – Excluded from analysis: no post baseline efficacy value (n=3) – SS (n=50)
Analysed: – FAS (n=50) – SS (n=50)
Figure 1. CONSORT flow diagram. FAS: full analysis set, SS: safety set. Figure1. CONSORT flow diagram. FAS: full analysis set, SS: safety set. 3.3. DXA Parameters Baseline data of the FAS population are presented in Table 1. Both groups were bal- anced on all the parameters presented. The participant mean age was 62.2 ± 6.3 y (range: 50; 77 y), and time since menopause was 12.6 ± 7.1 y (range: 1.1–31.8 y) with a slightly higher prevalence of women > 10 years post-menopause in the placebo group, 70% com- pared to 48% in the HE group (no statistical test performed). Mean BMI was 24.9 ± 3.1 (range: 18.6; −31.9), with 54% of the participants within normal range and 46% in an over- weight and obese range. Mean serum 25-OH D3 concentration was 79.2 ± 27.7 nmol/L (range: 21; 155). The vitamin D status was considered sufficient if serum 25-OH D3 ≥ 75 nmol/L versus insufficient if <75 nmol/L [40]. A slightly lower prevalence of vitamin D insufficient women was observed in the HE group, 42% compared to 52% in the placebo group (no statistical test performed). All participants had osteopenia with an average T- score at the lowest site of −1.64 ± 0.41 g/cm 2 (range: −2.4; −1.0). Two participants (n = 1 HE; n = 1 placebo) were enrolled despite that they met the exclusion criteria regarding signifi- For the primary outcome, mean change in BMD at L2-L4 lumbar spine, from baseline after 48 weeks, revealed a slight but not statistically significant increase in the HE group (0.0063 ± 0.0371 g/cm 2 ) compared to no change in the placebo group (0.0002 ± 0.0002 g/cm 2 ). Additionally, there was no statistically significant difference detected between groups (0.0091 ± 0.0089 g/cm 2 and0.88 ± 0.85 in relative %).
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