Bone mineral density in response to increased energy intake in exercising women with oligomenorrhea/amenorrhea: the REFUEL randomized controlled trial

Abstract

Background: Energy deficiency can result in menstrual disturbances and compromised bone health in women, a condition known as the Female Athlete Triad.

Objectives: The REFUEL randomized controlled trial assessed the impact of increased energy intake on bone health and menstrual function in exercising women with menstrual disturbances.

Methods: Exercising women with oligomenorrhea/amenorrhea (Oligo/Amen) were randomly assigned to an intervention group (Oligo/Amen + Cal, n = 40, mean ± SEM age: 21.3 ± 0.5 y; weight: 55.0 ± 1.0 kg; BMI: 20.4 ± 0.3 kg/m2) who increased energy intake 20%-40% above baseline energy needs for 12 mo or a control group (Oligo/Amen Control, n = 36; mean ± SEM age: 20.7 ± 0.5 y; weight: 59.1 ± 1.3 kg; BMI: 21.3 ± 0.4 kg/m2). Energy intake and expenditure, metabolic and reproductive hormones, body composition, and areal bone mineral density (aBMD) were assessed.

Results: Oligo/Amen + Cal improved energy status [increased body mass (2.6 ± 0.4 kg), BMI (0.9 ± 0.2 kg/m2), fat mass (2.0 ± 0.3 kg), body fat percentage (2.7% ± 0.4%), and insulin-like growth factor 1 (37.4 ± 14.6 ng/mL)] compared with Oligo/Amen Control and experienced a greater likelihood of menses (P < 0.05). Total body and spine aBMD remained unchanged (P > 0.05). Both groups demonstrated decreased femoral neck aBMD at month 6 (-0.006 g/cm2; 95% CI: -0.011, -0.0002 g/cm2 ; time main effect P = 0.043) and month 12 (-0.011 g/cm2; 95% CI: -0.021, -0.001 g/cm2; time main effect P = 0.023). Both groups demonstrated a decrease in total hip aBMD at month 6 (-0.006 g/cm2; 95% CI: -0.011, -0.002 g/cm2; time main effect P = 0.004).

Conclusions: Although higher dietary energy intake increased weight, body fat, and menstrual frequency, bone mineral density was not improved, compared with the control group. The 12-mo intervention may have been too short and the increase in energy intake (∼352 kcal/d), although sufficient to increase menstrual frequency, was insufficient to increase estrogen or improve aBMD. Future research should refine the optimal nutritional and/or pharmacological interventions for the recovery of bone health in athletes and exercising women with Oligo/Amen.This trial was registered at clinicaltrials.gov as NCT00392873.

Keywords: Female Athlete Triad; amenorrhea; bone mineral density; exercising women; nutrition.

© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1

Abbreviated study design with measures pertinent to this analysis. Modified from Williams NI, Mallinson RJ, and De Souza MJ. “Rationale and study design of an intervention of increased energy intake in women with exercise-associated menstrual disturbances to improve menstrual function and bone health: The REFUEL study.” Contemporary Clinical Trials Communications, 14 (2019); with permission from Elsevier. BMD, bone mineral density; body comp, body composition; Oligo/Amen, oligomenorrhea/amenorrhea; Oligo/Amen + Cal, oligomenorrheic/amenorrheic intervention group; OV Reference, ovulatory reference group.

FIGURE 2

Flowchart of subject enrollment during the study for this sample and reasons for dropout during the study. OC, oral contraceptive; Oligo/Amen + Cal, oligomenorrheic/amenorrheic intervention group; Oligo/Amen Control, oligomenorrheic/amenorrheic control group; OV Reference, ovulatory reference group; UT, University of Toronto.

FIGURE 3

Estimated marginal means and SEMs from the intent-to-treat analysis for BMD (baseline n = 40, Oligo/Amen + Cal; n = 36, Oligo/Amen Control). Dotted P value lines indicate differences within OV Reference. Solid P value lines indicate differences within the Oligo/Amen groups combined. Total body BMD increased in OV Reference from baseline to months 6 and 12. Femoral neck BMD decreased in the Oligo/Amen groups from baseline to months 6 and 12. Total hip BMD decreased in the Oligo/Amen groups from baseline to month 6. Baseline BMI was associated with all BMD outcomes in the Oligo/Amen groups, but not the OV Reference control. BMD, bone mineral density; Oligo/Amen + Cal, oligomenorrheic/amenorrheic intervention group; Oligo/Amen Control, oligomenorrheic/amenorrheic control group; OV Reference, ovulatory reference group.

FIGURE 4

Individual changes in BMD z scores from baseline to post in study completers. At the total body, 2 of 17 women in Oligo/Amen + Cal had low BMD (z score < −1.0) at baseline. Both improved to have normal BMD at post. One of 16 women in Oligo/Amen Control had low BMD at baseline. She improved to have normal BMD at post. At the lumbar spine, 9 of 17 women in Oligo/Amen + Cal had low BMD at baseline. Three of 9 improved to have normal BMD at post, whereas 6 of 9 maintained low BMD. Six of 16 women in Oligo/Amen Control had low BMD at baseline. Three of 6 improved to have normal BMD at post, whereas 3 of 6 maintained low BMD. At the femoral neck, 2 of 11 women in Oligo/Amen + Cal had low BMD at baseline. Both maintained low BMD at post. No women in Oligo/Amen Control had low BMD at baseline or post. At the total hip, 3 of 14 women in Oligo/Amen + Cal had low BMD at baseline. One of 3 improved to have normal BMD at post, whereas 2 of 3 maintained low BMD. No women in Oligo/Amen Control had low BMD at baseline. One woman in Oligo/Amen Control who was missing a z score at baseline had low BMD at post. BMD, bone mineral density; Oligo/Amen + Cal, oligomenorrheic/amenorrheic intervention group; Oligo/Amen Control, oligomenorrheic/amenorrheic control group.

FIGURE 5

Estimated marginal means and SEMs from the intent-to-treat analysis for E1G and PdG AUC and mean concentrations (baseline n = 40, Oligo/Amen + Cal; n = 36, Oligo/Amen Control). There were no significant group, time, or study group*time interaction effects in the Oligo/Amen groups and no time effects in OV Reference. E1G, estrone-1-glucuronide; Oligo/Amen + Cal, oligomenorrheic/amenorrheic intervention group; Oligo/Amen Control, oligomenorrheic/amenorrheic control group; OV Reference, ovulatory reference group; PdG, pregnanediol glucuronide.