Relative Energy Deficiency in Sport (RED-S) refers to a syndrome of impaired physiological functioning caused by relative energy deficiency and includes, but is not limited to, impairments of metabolic rate, menstrual function, bone health, immunity, protein synthesis and cardiovascular health1. The term RED-S was introduced in 2014 by an International Olympic Committee (IOC) consensus statement to address growing evidence that the clinical phenomenon known as the female athlete triad–whose components include low energy availability (EA), menstrual dysfunction and low bone mineral density2–could also be conceptualized with low EA at the etiological center of a complex set of physiological consequences that includes menstrual dysfunction and low BMD, but also disruptions in immunological, gastrointestinal, cardiovascular, psychological, developmental, hematological, metabolic, and endocrine systems3. The term RED-S is also inclusive of male athletes1, though RED-S is thought to be more prevalent in women4 and more extensively studied as the Triad in the literature.

As components of the Triad, it is well-known that low EA and hypogonadism are major risk factors for bone stress injuries (BSIs)1,5, 6, 7. BSIs, including stress fractures and stress reactions, are overuse injuries that occur when excessive repetitive loads are introduced to bone such that microdamage accumulation is favored over its removal and replacement with new bone through remodeling, and can progress to a complete fracture.8 Bone health is so significantly disrupted by low EA and hypogonadism (as manifested by functional hypothalamic amenorrhea in the female athlete) that BSIs cannot be managed adequately without addressing those deficiencies.

In this review, we will first describe the conceptual model of RED-S and survey its broad physiological consequences. We will then review the diagnosis and management of bone stress injuries in the female athlete, with special considerations for the energy deficient state.

The crux of the RED-S model is the concept of energy availability (EA), which is the energy from dietary intake that is left over for the body to utilize for its physiological functions after accounting for energy expenditure through exercise. It is defined asEA=(EI−EEE)/FFM,where EA represents energy availability (kcal), EI represents the energy intake (kcal), EEE represents exercise energy expenditure (kcal), and FFM refers to fat free mass (kg)3. Rigorous laboratory evidence in women have suggested an optimal EA is achieved at a level of 45 kcal/kg FFM/day9,10, and an EA less than 30 kcal/kg FFM/day has been suggested as a threshold for low EA at which many body systems demonstrate substantial perturbation3.

While this operational definition serves as a useful working model to reason about RED-S, in clinical practice it has not been useful to target a numerical EA goal due to the impracticality of obtaining thermodynamically precise measurements of dietary intake, exercise expenditure, and fat free mass (which requires dual energy X-ray absorptiometry (DEXA)), as well as the significant discrepancies in field studies between EA calculations and RED-S symptoms11,12. Instead, imperfect surrogate markers such as target BMI and restoration of recent weight loss are often used, though it should be noted that weight stability often occurs in low EA states if the resting metabolic rate adapts and should not be used in isolation as a marker for adequate nutrition2.

The physiological effects of RED-S are myriad, with virtually every body system affected (Figure 1), though a comprehensive account is lacking and under active research3. A brief survey of these changes is provided below.

Figure 1: Health consequences of RED-S. The RED-S paradigm expands the concept of the Female Athlete Triad to acknowledge a wider range of outcomes and emphasizes low energy availability as the etiological center of the syndrome. Note that psychological problems can precede or be induced by RED-S.

Endocrine changes result as the body conserves energy for vital processes, leading to disruptions of the hypothalamic-pituitary-gonadal axis, thyroid hormones, and appetite hormones (including decreased leptin and oxytocin, and increased ghrelin, peptide YY, and adiponectin). There is also decreased insulin and insulin-like growth factor 1 (IGF-1), which is bone-trophic, as well as increased growth hormone (GH) resistance and cortisol levels13, 14, 15, 16.

Menstrual dysfunction occurs as a result of the disruption of the hypothalamic-pituitary-gonadal axis. Specifically, low EA alters the pulsatility of GnRH at the hypothalamus, altering LH and FSH release at the anterior pituitary and subsequently leading to a decrease in estradiol and progesterone levels17,18. This process is the underlying mechanism for the type of secondary amenorrhea known as functional hypothalamic amenorrhea (FHA) that is seen in female athletes with the Triad.

Active female athletes with oligomenorrhea/amenorrhea or low EA have decreased BMD, altered bone microarchitecture and turnover markers, decreased bone strength, and increased risk for bone stress injuries compared to eumenorrheic and energy replete athletes19, 20, 21, 22, 23. Anatomical sites with less bone loading or greater trabecular (as opposed to cortical) bone content, such as lumbar spine and radius, are at higher risk for low BMD and impaired microarchitecture in populations susceptible to low EA21,22,24, 25, 26. BMI, while an imperfect surrogate for low EA, has been shown to be associated with increased risk of low BMD in both sexes27, 28, 29. Risk of bone stress injury is increased as Triad factors of disordered eating, menstrual dysfunction, and low BMD are combined6,30,31. See below for further discussion of the pathophysiology of bone stress injuries and their relation to the energy deficient state.

Low EA is correlated with decreased resting metabolic rate (RMR) in female endurance athletes32. It has been shown prospectively that increasing training load while maintaining constant energy intake over four weeks in male and female elite rowers significantly reduces RMR33.

Indirect markers for low EA correlate with low ferritin and iron deficiency anemia in adolescent and young adult female athletes34. Iron deficiency can both contribute to, and be caused by, low EA. Low iron levels can disrupt bone health via dysregulation of the GH/IGF-1 axis, hypoxia, and hypothyroidism35.

Anorexia nervosa (AN), which by definition is a severely low EA state, slows linear growth in adolescents. However, “catch-up” growth occurs after recovery, though this is not always complete36, 37, 38. Amenorrheic athletes demonstrate similarly disordered GH and IGF-1 secretory patterns as in patients with AN, but more research is needed to understand the growth implications39,40.

Early atherosclerosis is associated with low estrogen and functional hypothalamic amenorrhea in young athletes41. It has been shown that resumption of menses leads to improvements in vascular endothelial function42. Amenorrheic athletes have lower heart rates and systolic blood pressure than eumenorrheic athletes and have disruption of the renin-angiotensin-aldosterone response to orthostatic challenge43. Anorexia nervosa can lead to valve abnormalities, pericardial effusion, severe bradycardia, hypotension, and arrhythmias44.

Severely low EA states can negatively influence the entire gastrointestinal tract and cause altered sphincter function, delayed gastric emptying, constipation, and increased intestinal transit time45. A negative correlation with EA and GI symptoms has been documented in Swedish and Danish athletes46, as well as in adolescent American female athletes34.

Low EA states appear to be associated with less robust immunity. For example, a study of 21 Japanese elite collegiate runners reported more upper respiratory infections and lower immunoglobulin A secretion rates in amenorrheic compared to eumenorrheic athletes47. Another study of elite Australian female athletes preparing for the 2016 Rio Olympics showed that rates of gastrointestinal infections and upper respiratory infections were correlated with higher scores on the low energy availability in females questionnaire (LEAF-Q), a tool developed to assess for low EA48,49.

Low EA in athletes correlates negatively with psychological well-being, and it appears that psychological problems can precede or be induced by low EA3. In female athletes, a higher drive for thinness (as measured by the Eating Disorder Inventory) has been associated with disordered physiology including low EA, lower T3 levels, and higher ghrelin levels50, as well as the personality traits of perfectionism, competitiveness, and pain tolerance51. Female adolescents with FHA have higher rates of depression, psychosomatic disorders, and decreased ability to manage stress52,53. Disordered eating is more prevalent in both sexes in weight-sensitive sports54, 55, 56, 57, 58, and is associated with coach-athlete relationships with high conflict and low support59.

A more extensive discussion of the systemic effects of RED-S can be found in the IOC's updated 2018 consensus statement on RED-S3. We will now turn our attention to bone stress injuries, focusing our discussion on the energy-deficient female athlete.