Physiologic Transdermal Estradiol Replacement Mimics Effects of Endogenous Estrogen on Bone Outcomes in Hypoestrogenic Women with Anorexia Nervosa
Abstract
:1. Introduction
2. Participants and Methods
2.1. Participant Selection
2.2. Study Protocol
2.3. Areal Bone Mineral Density (aBMD) and Body Composition Assessments
2.4. Volumetric Bone Mineral Denisty (vBMD), Bone Geometry and Structure Assessment
2.5. Laboratory Measures
2.6. Statistical Analysis
3. Results
3.1. Baseline Characteristics and Changes in Clinical Characteristics, and Body Composition over 12 Months
3.2. Baseline Characteristics and 12-Month Change in Biochemical Parameters
3.3. Baseline Characteristics and 12-Month Changes in DXA Measures of Areal BMD
3.4. Baseline Characteristics and 12-Month Change in HRpQCT Bone Parameters
- Radius:
- Tibia:
3.5. Adverse Events
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AN | Anorexia Nervosa |
DSM | Diagnostic and Statistical manual of Mental Disorders |
BMD | Bone Mineral Density |
vBMD | Volumetric Bone Mineral Density |
aBMD | Areal Bone Mineral Density |
HC | Healthy Control |
17βE2 | 17-beta Estradiol |
BMI | Body Mass Index |
% mBMI | Percentage Median Body Mass Index |
% mBW | Percentage Median Body Weight |
% mBW-Ht | Percentage Median Body Weight for Height |
FSH | Follicle Stimulating Hormone |
TSH | Thyroid Stimulating Hormone |
DXA | Dual X-ray Absorptiometry |
HRpQCT | High Resolution Peripheral Quantitative Computed Tomography |
TMD | Tissue Mineral Density |
ECA | Extended Cortical Analysis |
µFEA | Micro Finite Element Analysis |
SEM | Standard Error Mean |
25OHD | 25-hydroxy Vitamin D |
P1NP | N-terminal Propeptide of Type 1 Procollagen |
NTX | N-terminal Cross-linking Telopeptide |
PTH | Parathyroid Hormone |
IGF-1 | Insulin-like Growth Factor-1 |
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Clinical Characteristics | Baseline Measures | p Value | Change over 12 Months | p-Value | ||
---|---|---|---|---|---|---|
AN-E+ (n = 23) | HC (n = 27) | AN-E+ (n = 23) | HC (n = 27) | |||
Age (years) | 19.29 ± 0.51 | 19.40 ± 0.47 | 0.876 | – | – | – |
Age at AN Diagnosis (years) | 16.23 ± 0.48 | – | – | – | – | – |
Duration of Amenorrhea since Last Menses (months) | 7.77 ± 2.72 | – | – | – | – | – |
Age of Menarche (years) | 13.17 ± 0.35 | 12.51 ± 0.24 | 0.117 | – | – | – |
Race (White/African American/Others) (%) | 21/0/2 | 45/3/10 | 0.004 | – | – | – |
Height (cm) | 165.14 ± 1.28 | 164.40 ± 1.32 | 0.830 | 0.04 ± 0.14 | 0.37 ± 0.10 * | 0.065 |
Weight (kg) | 50.90 ± 1.37 | 59.35 ± 1.57 | 0.0002 | 1.78 ± 0.82 * | 0.80 ± 0.42 | 0.305 |
BMI (kg/m2) | 18.75 (17.53, 19.97) | 21.27 (20.20, 24.43) | <0.0001 | 0.48 (−0.49, 1.83) * | 0.16 (−0.41, 0.64) | 0.066 |
BMI z-score | −1.13 (−1.58, −0.38) | −0.08 (−0.40, 0.84) | <0.0001 | 0.30 (−0.05, 0.80) * | −0.02 (−0.20, 0.05) | 0.100 |
% Median BMI | 86.83 (81.97, 94.58) | 98.85 (94.04, 115.46) | <0.0001 | 2.26 (−2.19, 8.77) * | −0.22 (−2.36, 1.0) | 0.019 |
Total Weight Bearing Activity (hours/week) | 4.79 (1.64, 7.85) | 1.13 (0, 3.18) | 0.001 | −0.48 (−3.99, 2.71) | 0 (−0.56, 0.92) | 0.630 |
Body Composition (by DXA) | ||||||
Total Lean Mass (kg) | 37.69 ± 0.84 | 40.41 ± 1.06 | 0.0553 | 1.32 ± 0.44 * | −0.30 ± 0.28 | 0.003 |
% Lean Mass | 72.90 ± 1.02 | 66.50 ± 0.91 | <0.0001 | −1.32 ± 1.11 | −1.04 ± 0.48 | 0.803 |
Total Fat Mass (kg) | 12.42 ± 0.76 | 18.40 ± 0.87 | <0.0001 | 1.41 ± 0.83 | 0.84 ± 0.39 | 0.528 |
% Fat Mass | 23.89 ± 1.03 | 33.31 ± 1.07 | <0.0001 | 1.12 ± 1.27 | −2.26 ± 0.80 * | 0.026 |
Biochemical Parameters | Baseline Measures | p-Value | Change over 12 Months | p-Value | ||
---|---|---|---|---|---|---|
AN-E+ (n = 23) | HC (n = 27) | AN-E+ (n = 23) | HC (n = 27) | |||
P1NP (ug/L) | 100.99 ± 10.28 | 79.06 ± 7.13 | 0.068 | −10.39 ± 9.47 | −12.07 ± 4.45 * | 0.983 |
NTX (nM BCE) | 15.69 ± 5.56 | 16.62 ± 8.82 | 0.672 | −3.40 ±1.43 * | −2.43 ± 1.24 | 0.610 |
Calcium (mg/dL) | 9.44 ± 0.06 | 9.07 ± 0.09 | 0.002 | −0.16 ± 0.08 * | 0.39 ± 0.08 * | <0.0001 |
25OHD (ng/mL) | 41.04 ± 3.75 | 25.93 ± 2.44 | 0.0002 | −9.27 ± 3.42 * | 3.53 ± 2.41 | 0.002 |
PTH (pg/mL) | 21.69 ± 2.13 | 31.30 ± 2.53 | 0.006 | 0.16 ± 2.59 | −1.44 ± 3.29 | 0.725 |
IGF-1 (ng/mL) | 260.0 ± 17.5 | 286.0 ± 18.8 | 0.318 | −30.2 ± 14.7 | −30.1 ± 14.8 | 0.994 |
IGF-1 Z-score | −0.42 ± 0.24 | −0.05 ± 0.12 | 0.193 | −0.08 ± 0.17 | −0.09 ± 0.16 | 0.973 |
Areal Bone Mineral Density (by DXA) | Baseline Measures | p-Value | Change over 12 Months | p-Value Adjusted for Baseline Age and Race | p-Value Adjusted for Baseline Age, Race and Change in Weight | ||
---|---|---|---|---|---|---|---|
AN-E+ (n = 23) | HC (n = 27) | AN-E+ (n = 23) | HC (n = 27) | ||||
Femoral Neck BMD (g/cm2) | 0.74 ± 0.02 | 0.84 ± 0.02 | 0.0016 † | 0.01 ± 0.008 | 0.003 ± 0.004 | 0.501 | 0.417 |
Femoral Neck Z-score | −1.40 ± 0.23 | −0.37 ± 0.18 | 0.0006 † | 0.37 ± 0.09 * | 0.09 ± 0.05 | 0.009 | 0.017 |
Total Hip BMD (g/cm2) | 0.85 ± 0.03 | 0.96 ± 0.02 | 0.0005 † | 0.020 ± 0.007 * | 0.006 ± 0.004 | 0.072 | 0.084 |
Total Hip Z-score | −0.82 ± 0.22 | 0.004 ± 0.16 | 0.0030 † | 0.15 ± 0.07 * | 0.04 ± 0.03 | 0.081 | 0.119 |
Lumbar BMD (g/cm2) | 0.84 ± 0.03 | 0.97 ± 0.02 | 0.0006 † | 0.042 ± 0.008 * | 0.008 ± 0.005 | 0.001 | 0.004 |
Lumbar BMD Z-Score | −1.60 ± 0.24 | −0.53 ± 0.20 | 0.0013 † | 0.28 ± 0.08 * | 0.04 ± 0.06 | 0.023 | 0.054 |
Whole Body BMD (g/cm2) | 0.97 ± 0.01 | 1.05 ± 0.02 | 0.0002 † | 0.020 ± 0.001 * | −0.002 ± 0.004 | 0.011 | 0.0003 |
Whole Body BMD Z-score | −1.57 ± 0.19 | −0.64 ± 0.17 | 0.0006 † | 0.12 ± 0.07 | −0.11 ± 0.06 | 0.057 | 0.004 |
HRpQCT Variables | Baseline Measures | p Value | Change over 12 Months | p Value Adjusted for Baseline Age and Race | p Value Adjusted for Baseline Age, Race and Change in Weight | ||
---|---|---|---|---|---|---|---|
Radius | AN-E+ -17β-E2 (n = 21) | HC (n = 26) | AN-E+ -17β-E2 (n = 21) | HC (n = 26) | |||
Cortical Area (mm2) | 44.10 (35.50, 50.9) | 56.45 (47.23, 62.90) | 0.012 † | 2.25 (−0.25, 7.00) * | 1.35 (−0.18, 2.33) * | 0.719 | 0.891 |
Trabecular area (mm2) | 222.6 (199.5, 239.5) | 206.8 (171.8, 247.7) | 0.634 | −2.00 (−3.70, −0.05) * | −1.30 (−2.63, 0.60) * | 0.647 | 0.715 |
Cortical Thickness (mm) | 0.68 (0.54, 0.84) | 0.84 (0.71, 0.94) | 0.012 † | 0.05 (0.00, 0.11) * | 0.02 (−0.003, 0.04) * | 0.595 | 0.746 |
Cortical vBMD (mgHA/cm3) | 816.3 (770.9, 842.6) | 862.5 (820.3, 881.9) | 0.005 | 16.80 (6.45, 37.85) * | 10.40 (3.88, 16.53) * | 0.018a | 0.029a |
Cortical TMD (mgHA/cm3) | 918.6 (884.6, 949.1) | 948.1 (907.4, 974.2) | 0.048 | 19.8 (10.7, 30.4) * | 10.2 (6.0, 14.0) * | 0.015 | 0.010 |
Trabecular vBMD (mgHA/cm3) | 153.7 (124.1, 176.8) | 174.1 (145.1, 199.8) | 0.047 † | 3.20 (−4.45, 4.85) | −0.35 (−1.78, 2.63) | 0.904 | 0.554 |
Number of Trabeculae (1/mm) | 1.90 ± 0.04 | 2.02 ± 0.05 | 0.065 | −0.04 ± 0.04 | −0.02 ± 0.03 | 0.312 | 0.399 |
Trabecular Thickness (mm) | 0.06 (0.06, 0.08) | 0.07 (0.06, 0.08) | 0.130 | 0.003 (−0.003, 0.006) | 0.002 (−0.002, 0.005) | 0.564 | 0.360 |
Trabecular Separation (mm) | 0.46 ± 0.01 | 0.43 ± 0.01 | 0.042 | 0.009 ± 0.011 | 0.004 ± 0.008 | 0.302 | 0.377 |
Cortical Porosity (%) | 1.0 (0.7, 1.3) | 0.7 (0.4, 1.3) | 0.040 | −0.1 (−0.3, 0.1) | 0.1 (−0.1, 0.5) | 0.122 | 0.198 |
Failure Load (kN) | 3.32 (2.56, 4.18) | 4.05 (3.66, 4.59) | 0.011 † | 0.14 (−0.05, 0.32) * | 0.04 (−0.03, 0.14) * | 0.004a | 0.008a |
Tibia | AN-E+ -17β-E2 (n = 23) | HC (n = 27) | AN-E+ -17β-E2 (n = 23) | HC (n = 27) | |||
Cortical Area (mm2) | 102.7 (88.8, 120.1) | 125.0 (105.9, 139.1) | 0.001 † | 0.7 (−0.6, 3.3) | 0.5 (0.0, 1.4) * | 0.769 | 0.774 |
Trabecular Area (mm2) | 554.1 (474.7, 585.9) | 545.3 (457.4, 583.5) | 0.718 | 0.1 (−1.3, 1.0) | −0.5 (−1.2, 0.3) * | 0.728 | 0.796 |
Cortical Thickness (mm) | 1.06 ± 0.03 | 1.24 ± 0.04 | 0.004 † | 0.01 ± 0.04 | 0.00 ± 0.00 | 0.968 | 0.980 |
Cortical vBMD (mgHA/cm3) | 859.8 ± 7.2 | 884.4 ± 7.4 | 0.023 † | 9.6 ± 1.9 * | 9.2 ± 2.7 * | 0.900 | 0.985 |
Cortical TMD (mgHA/cm3) | 954.4 (916.4, 983.1) | 981.9 (959.1, 1006.2) | 0.009 | 8.1 (3.5, 22.5) * | 4.8 (−0.4, 11.2) * | 0.120 | 0.917 |
Trabecular vBMD (mgHA/cm3) | 174.9 (153.9, 194.7) | 184.0 (167.8, 216.4) | 0.119 | 1.0 (−2.1, 2.1) | 0.2 (−2.0, 2.2) | 0.941 | 0.940 |
Number of Trabeculae (1/mm) | 1.73 (1.62, 1.84) | 1.92 (1.81, 2.12) | 0.002 † | 0.03 (−0.06, 0.08) | −0.04 (−0.16, 0.04) | 0.514 | 0.975 |
Trabecular Thickness (mm) | 0.08 (0.07, 0.09) | 0.08 (0.07, 0.10) | 0.601 | −0.002 (−0.006, 0.003) | 0.001 (−0.003, 0.004) | 0.415 | 0.267 |
Trabecular Separation (mm) | 0.49 (0.46, 0.54) | 0.43 (0.40, 0.48) | 0.003 † | −0.01 (−0.02, 0.02) | 0.01 (−0.01, 0.04) | 0.485 | 0.966 |
Cortical Porosity (%) | 2.5 (1.9, 3.4) | 1.4 (0.9, 2.6) | 0.010 | −0.1 (−0.3, 0.2) | 0.3 (−0.1, 1.3) * | 0.194 | 0.306 |
Failure Load (kN) | 9.68 (8.74, 11.07) | 10.79 (9.80, 12.04) | 0.091 | −0.03 (−0.23, 0.18) | 0.12 (−0.01, 0.25) * | 0.177 | 0.368 |
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Singhal, V.; Nimmala, S.; Slattery, M.; Eddy, K.T.; Miller, K.K.; Klibanski, A.; Misra, M. Physiologic Transdermal Estradiol Replacement Mimics Effects of Endogenous Estrogen on Bone Outcomes in Hypoestrogenic Women with Anorexia Nervosa. Nutrients 2022, 14, 2557. https://doi.org/10.3390/nu14132557
Singhal V, Nimmala S, Slattery M, Eddy KT, Miller KK, Klibanski A, Misra M. Physiologic Transdermal Estradiol Replacement Mimics Effects of Endogenous Estrogen on Bone Outcomes in Hypoestrogenic Women with Anorexia Nervosa. Nutrients. 2022; 14(13):2557. https://doi.org/10.3390/nu14132557
Chicago/Turabian StyleSinghal, Vibha, Supritha Nimmala, Meghan Slattery, Kamryn T. Eddy, Karen K. Miller, Anne Klibanski, and Madhusmita Misra. 2022. "Physiologic Transdermal Estradiol Replacement Mimics Effects of Endogenous Estrogen on Bone Outcomes in Hypoestrogenic Women with Anorexia Nervosa" Nutrients 14, no. 13: 2557. https://doi.org/10.3390/nu14132557