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Annual Changes of Bone Density over 12 Years in an Amenorrheic Athlete

ZANKER, CATHY L.1; COOKE, CARLTON B.1; TRUSCOTT, JOHN G.2; OLDROYD, BRIAN2; JACOBS, HOWARD S.3

Medicine & Science in Sports & Exercise: January 2004 - Volume 36 - Issue 1 - p 137-142
doi: 10.1249/01.MSS.0000106186.68674.2C
APPLIED SCIENCES: Physical Fitness and Performance
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ZANKER, C. L., C. B. COOKE, J. G. TRUSCOTT, B. OLDROYD, and H. S. JACOBS. Annual Changes of Bone Density over 12 Years in an Amenorrheic Athlete. Med. Sci. Sports Exerc., Vol. 36, No. 1, pp. 137–142, 2004.

Purpose To link annual changes of bone mineral density (BMD) over 12 consecutive years to pharmacological intervention and to fluctuations of body mass and body composition in an amenorrheic athlete.

Methods BMD of the lumbar spine (LS) and total proximal femur (PF) were measured using dual energy x-ray absorptiometry (DXA), every 11–13 months between ages 24.8 and 36.9 yr. Body composition was assessed every 3–4 yr from a whole body DXA scan. Body mass was recorded every 3 months. For the first 5 yr of study, the subject used oral contraceptives (OC). For the subsequent 7 yr, she used estradiol skin patches (EP) with oral norethisterone.

Results The first DXA scan (age 24.8 yr) revealed a low BMD at both LS and PF, with T-scores of −1.4 and −2.8, respectively. During the next 5 yr, while adhering to OC, the BMD of her LS and PF declined by 9.8% and 12.1%, respectively. Concomitantly, her body mass fell from 45.1 to 41.4 kg, her body mass index (BMI) from 16.4 to 15.0 kg·m−2, and her percent body fat from 8.3 to <4.0%. While treated with EP and norethisterone (age 29.8-33.5 yr), her LS BMD gradually increased by 9.4%, despite a further 0.8 kg decline of body mass. From age 33.8 to 36.9 yr, voluntary weight gain (2–3 kg·yr−1; total: 8.1 kg) was accompanied by an increase of her PF BMD (16.9%), with no further increase at the LS.

Conclusion Changes of BMD at the total proximal femur reflected changes of body mass in this subject. At the lumbar spine, BMD declined with weight loss but increased in association with transdermal estradiol treatment in the absence of weight gain.

1School of Leisure and Sport Studies, Leeds Metropolitan University, UNITED KINGDOM;

2Centre for Bone and Body Composition Research, University of Leeds, UNITED KINGDOM; and

3The London Diabetes and Lipid Centre, London, UNITED KINGDOM

Address for correspondence: Dr. Cathy L. Zanker, School of Leisure and Sport Studies, Leeds Metropolitan University, Beckett Park Campus, Leeds LS6 3QS, United Kingdom; E-mail: c.zanker@lmu.ac.uk.

Submitted for publication February 2003.

Accepted for publication July 2003.

The “female athlete triad” is a syndrome of disordered eating, amenorrhea, and osteoporosis that has been documented in women training for sports in which there is an emphasis on a low body mass, such as distance running (25). Certain metabolic features of this syndrome resemble those of anorexia nervosa and are characteristic of protracted energy restriction (6,25). Despite the potential for physical activity to enhance or protect bone mass (20,27,31), this beneficial effect may be counteracted by a negative energy balance, a low body mass, and associated endocrine disturbances (26,34,38,39). Furthermore, it is well established that only those activities that involve load bearing and/or high-impact movements provide an osteogenic stimulus (20,27,31). This stimulus is localized to the bones that are specifically stressed by the activity (20,27,31) and is therefore unlikely to protect the entire skeleton from the systemic effects of energy restriction and a low body mass. Decrements of bone mass in women with the female athlete triad have been shown to be positively related to the duration of their menstrual disturbance (23,26,28).

To date, prospective studies of bone mineral density (BMD) in women with the female athlete triad have been short term (<2 yr) and have shown that bone loss continues, or fails to increase, while a low body mass and amenorrhea persist (8,18,35). However, weight gain may be accompanied by significant increments of BMD, particularly if there is an associated resumption of menses (8,18,35). There have been few controlled trials that have investigated the efficacy of combined estrogen and progestogen treatment for the protection of bone mass in young, active women with a low body mass and amenorrhea (10,12,14,19,22), and the majority have shown no beneficial effect. We report here annual changes of BMD within the lumbar spine and total proximal femur over a 12-yr period (24.8–36.9 yr) in a female athlete with a history of energy-restricting behavior dating back to childhood. All measurements of BMD were made on GE/Lunar absorptiometers operating in the same scan mode. Three different absorptiometers were used throughout the study, with a change of machine after the first five scans and the subsequent four scans. Before measurement with a different absorptiometer, a cross-calibration procedure was undertaken to enable accurate comparisons to be made. To prevent drift in measurements made by the same absorptiometer over time, the machine was subjected to a daily quality assurance and a weekly quality control procedure as recommended by the manufacturers. Accompanying measures of body mass and composition, physical activity, and selected hormone concentrations, in conjunction with sex hormone treatment, are discussed.

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CASE REPORT

The subject of this report was referred to the Reproductive Endocrinology clinic at the Middlesex Hospital, London, UK, for investigation of amenorrhea and suspected osteoporosis at age 24.8 yr. She provided a detailed retrospective account of her lifestyle and physical characteristics from childhood. She has given informed consent for her clinical data to be presented in this report.

She began to train seriously for distance running at age 10 yr, before menarche and significant pubertal development. At age 11, she eliminated high fat and carbohydrate foods from her diet with the belief that this would improve her running performance and by age 12 had established restrictive eating behavior. She ensured high energy expenditure through rigorous exercising, without resorting to purging. She harbored a routine of restrictive eating to age 22 yr while competing for her county. At age 22 yr, she added cycling and swimming to her exercise program, and by age 24, her typical weekly training regime comprised 90–100 km of running, 100–120 km of cycling, and 5–6 km of swimming. Her 10-km personal best time was 33.8 min, and a laboratory test of maximal oxygen consumption (O2max) demonstrated a high cardiorespiratory fitness (3.05 L·min−1; 67.8 mL·kg−1·min−1). She sought medical advice when she began to suffer repeated bilateral stress fractures to the tibia and metatarsals.

On initial referral, her stature and body mass were 166.0 cm and 45.1 kg, respectively (BMI 16.3 kg·m−2). She had never menstruated. A medical examination excluded physical or pathological abnormalities, except for a low BMI. A full blood count was normal, as were serum levels of cholecalciferol, calcium, PTH, thyroxine, TSH, albumin, and liver enzymes. However, her serum estradiol concentration (43 pmol·L−1) was depressed relative to the normal range for the early follicular phase of the menstrual cycle (108–180 pmol·L−1), and her serum levels of gonadotropins were also reduced [FSH, 1.8 U·L−1 (normal range: 4.1–9.5 U·L−1) and LH, 0.7 U·L−1 (normal range: 1.4–11.6 U·L−1)]. Dual-energy x-ray absorptiometry (DXA) scans of her lumbar spine (mean L1–L4: anteroposterior view) and total proximal femur, using a GE Lunar absorptiometer (GE/Lunar Co., Madison, WI), revealed values that were 16% (spine) and 35% (femur) below the age-matched mean values for the respective UK reference populations provided by the manufacturer (women, aged 20–40 yr). These values equated to T-scores of −2.8 (proximal femur) and −1.4 (lumbar spine) (where T-scores indicate the deviation of a BMD measure from the mean value for young adults of a given sex, stature, and body mass from the reference population provided by the absorptiometer). Her percent body fat measured by total body DXA on the same absorptiometer was 8.3% of total mass. She was advised to increase her energy intake and to reduce her training volume in order to gain weight. She was also prescribed a combined estrogen-progestogen oral contraceptive containing 30 μg ethinylestradiol and 150 μg desogestrel (Marvelon, Organon Ltd., Cambridge, UK), for 21 d of a 28-d cycle. Thereafter, she reported to the clinic every 3 months. DXA scans were repeated every 11–13 months.

From age 24.8 to 29.8 yr, she adhered to the prescribed oral contraceptive regimen and continued to cycle (120–140 km·wk−1) and swim (8–10 km·wk−1). She abandoned running training at age 25.2 yr because of further stress fractures in the lower limbs. Her body mass slowly fell to 41.4 kg at age 29.8 yr (BMI 15.0 kg·m−2; body fat content by DXA < 4.0%). Concomitantly, the BMD of her proximal femur and lumbar spine declined progressively (Table 1 and Fig. 1), by 12.1% and 9.8%, respectively, resulting in T-scores of −3.6 and −2.2 at age 29.8 yr. Between age 29 and 30 yr, she suffered multiple rib fractures on three separate occasions after minimal trauma. She also fell from her bicycle, while stationary, and fractured her left superior and inferior pubic rami.

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

At age 29.8 yr, in place of oral contraceptives, she was prescribed estradiol skin patches (Estraderm TTS 100; Novartis Pharmaceuticals UK Ltd., Camberley, UK) providing 100-μg estradiol per 24 h, to be given with and an oral progestogen, norethisterone (Micronor HRT; Janssen-Cilag Ltd., High Wycombe, UK) at a dose of 1 mg·d−1 for 12 consecutive days of a 28-d cycle. This treatment increased her measured serum estradiol concentration to between 300 and 400 pmol·L−1. She resumed her exercise regimen, and during the following 4 yr, her body mass declined by a further 0.8 kg. Nevertheless, annual DXA scans revealed a gradual increase of BMD at her lumbar spine that amounted to 9.4% (Table 1 and Fig. 1). There was no significant change of BMD at her proximal femur. At age 33.4 yr (BMI 14.8 kg·m−2; body fat content < 4.0%), a fasting serum sample revealed concentrations of nutritionally dependent hormones that were either below, or at the lower end of, the normal reference ranges for sex and age: IGF-1, 115 μg·L−1 (normal range: 120–280 μg·L−1), total T3, 98 ng·dL−1 (normal range: 84–208 μg·L−1) and leptin, <0.5 ng·mL−1 (normal range for women, BMI 20–25 kg·m−2: 15–20 ng·mL−1).

At age 33.5 yr, she made a personal decision to gain weight. This presented a physical and emotional challenge; however, she progressively increased her energy intake, primarily through the consumption of full-fat milk drinks between meals. She continued to exercise daily for 50–60 min and adhered to the prescribed estrogen-progestogen regimen. Her body mass increased gradually, by 8.1 kg over 36 months (BMI from 14.9 to 17.6 kg·m−2). A whole-body DXA scan revealed a 4.9-kg increase of body fat, a 3.2-kg increment of lean tissue, and an increase of percent body fat from <4.0% to 11.8% of total mass. Figure 2 illustrates the distribution of fat storage that accompanied the 6.1-kg increment of body mass between ages 34.6 and 36.9 yr. A consistent increase of BMD at her proximal femur was observed that amounted to 16.9% of her lowest recorded value at 32.8 yr (Table 1 and Fig. 1). Meanwhile, the BMD of her lumbar spine remained stable. She has continued to gain weight and has sustained no further fractures.

FIGURE 2

FIGURE 2

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DISCUSSION

The subject of this case study displayed characteristic features of the “female athletic triad” as manifested by dietary restriction, a high level of physical activity, amenorrhea, and osteoporosis (25). She had begun to restrict her energy intake shortly after commencing regular training for distance running, in early puberty, and had sustained energy-restricting behaviors for over 20 yr. By the age of 29 yr, her osteoporosis was advanced and symptomatic.

This woman’s low BMD at her first DXA scan (age 24.8 yr) probably reflected an impaired acquisition of bone mass during childhood. In girls, normal pubertal progression is accompanied by a 30–50% increment of bone mass, with an attainment of a peak value within 4 yr postmenarche (2,36). The deleterious effects of energy restriction and gonadal suppression on the acquisition of bone mass during this phase of development are well documented (1,15,19). The very low BMD measured within this woman’s proximal femur (T-score −2.8) at age 24.8 yr contrasted with previous observations of the distribution of BMD within adult amenorrheic runners, which have reported a significantly reduced BMD at the lumbar spine (T-score −1 to −2), with either a normal, or marginal, reduction of BMD at the proximal femur (T-score > −1.0) (11,23,26). However, the amenorrheic runners of these previous studies had experienced shorter intervals of menstrual disturbance than our subject, their amenorrhea had generally been secondary rather than primary, and their BMI had usually exceeded 17.5 kg·m−2 (11,23,26). The distribution of BMD reported in our subject displayed a closer resemblance to that seen in women with anorexia nervosa, who usually show significant deficits of cortical as well as trabecular bone (1,15).

The most plausible explanation for the progressive reduction of BMD within this woman’s lumbar spine and total proximal femur from age 24.8 to 29.7 yr was a gradual loss of body mass (total, 3.7 kg) that lowered her BMI from 16.4 to 15.0 kg·m−2. Retrospective and short-term prospective studies (<2 yr) of changes of BMD in young women with anorexia nervosa suggest that trabecular and cortical bone loss accelerate when BMI falls below a “threshold” value, which is often in the order of 16–17 kg·m−2 (1,15). It is proposed that this “threshold” marks a turning point, below which bone turnover is uncoupled, as exemplified by reduced serum levels of markers of bone formation and an elevated urinary excretion of markers of bone resorption (1,16,38). The suggested stimuli for this uncoupling are endocrine disturbances that accompany energy restriction and a reduced BMI (16,19,37,39). These disturbances include a raised serum concentration of cortisol (9,24), with reduced serum concentrations of sex hormones (6,38), insulin-like growth factor I (IGF-1) (16,37), 3,5,3′ triiodothyronine (T3) (6,37), and leptin (33,34). Recent research suggests that a reduction of serum IGF-1 concentration is particularly pertinent, because of a strong link between the magnitude of reduction of the serum concentration of IGF-1 and markers of bone formation under conditions of energy restriction (16,19,38,39). At age 33.4 yr, our subject displayed subnormal serum concentrations of IGF-1, leptin, and T3, which concurs with previous observations in women with the female athlete triad (33,38). It is also noteworthy she had discontinued her running training at age 25 yr yet persisted to expend large amounts of energy through the practice of mainly nonweight-bearing or low-impact activities. This practice would tend to contribute to a negative energy balance without offering an osteogenic stimulus.

The influence of oral contraceptives on the acquisition and maintenance of bone mass in young women is currently debatable (3). The few controlled trials that have investigated the efficacy of these drugs for the protection of bone mass in active, underweight women with amenorrhea have produced equivocal findings, with the majority indicating little benefit (10,12,14,19,22). Of importance, is that recent research suggests that oral contraceptive use in adolescence and early adulthood may impair bone gain, or induce untimely bone loss, even when combined with regular exercise (5,37). Consequently, it is possible that the sustained use of oral contraceptives by our subject had a detrimental rather than a beneficial effect on her bone mass.

An interesting observation in this study was an increase of BMD within the lumbar spine during treatment with estradiol skin patches and oral norethisterone. This increase occurred in the absence of weight gain and was recorded using the same absorptiometer. To date, there have been no published trials of the skeletal effects of estradiol administered by the transdermal route in women with the female athlete triad or with anorexia nervosa. However, such treatment has been shown to induce significant gains of bone mass at the lumbar spine in other estrogen deficient states (7,13). There is also evidence to suggest that the progestogen norethisterone exerts an anabolic action in bone (4). To attempt to explain the apparent positive influence of estradiol skin patches on BMD within this woman’s lumbar spine is beyond the scope of the present study. Nevertheless, it was noted that this treatment greatly increased her serum estradiol concentration (to between 300 and 400 pmol·L−1). Although speculative, it is possible that very lean and active women require a higher circulating concentration of estradiol to preserve bone mass than sedentary women with greater stores of body fat. Previous research has shown that a paucity of body fat and endurance exercise both appear to favor the metabolism of endogenous estrone, via 2-hydroxylation, to catechol-estrogens with antiestrogenic properties (30). Concomitantly, the synthesis of biologically active estriol (via the 16α-hydroxylase pathway) is reduced. On this premise, the administration of high doses of exogenous estradiol may be required to mediate an anabolic effect in responsive tissues (17).

The substantial increase of BMD measured within this woman’s total proximal femur with progressive weight gain was recorded using the same absorptiometer. This finding is consistent with observations made in previous studies of women recovering from the female athlete triad or anorexia nervosa (8,15,18,19,35). These previous studies also showed that significant increments of bone mass accompany weight gain even before the resumption of regular menses. It is of interest that repeated, whole-body DXA scans of our subject illustrated a preferential gain of fat mass within the femoral region. Adipocytes within this region possess a high capacity for leptin synthesis in estrogen replete women (21,29). The possible implications of these observations are that leptin appears to act both locally and systemically to increase bone formation, by enhancing the differentiation of marrow stromal cells to osteoblasts (32). Consequently, it might be speculated that the pattern of fat storage with weight gain in this woman assisted a site-specific increase of BMD.

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CONCLUSION

Longitudinal observations of BMD in a female athlete with premature osteoporosis linked to disordered eating since childhood showed that bone loss accompanied weight loss while adhering to oral contraceptives. In the absence of weight gain, treatment with physiological doses of estradiol, delivered transdermally, was accompanied by a progressive increase of BMD at the lumbar spine, with no change at the proximal femur. However, with an increase of energy intake and weight gain, there was a gradual increase of BMD at the total proximal femur, which started at the age of 33 yr, after 22 yr of energy-restricting behavior. The originalities of this study relate primarily to its long duration and the regularity of DXA scans, which enabled changes of BMD to be associated with both pharmacological and lifestyle intervention. Our observations are consistent with a link between energy balance, body mass, and bone density in young women. However, it is clearly not possible to make recommendations for the treatment or prevention of osteoporosis in active, amenorrheic women on the basis of observations made in a single subject. Also, the absence of repeated measures of selected hormones or markers of bone turnover in this subject precludes an explanation of the observed changes of BMD. Although this woman has continued to gain weight, given the pre-/peri-pubertal onset of her nutritional disturbance, the prognosis for achieving a normal adult BMD is uncertain.

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Keywords:

ENERGY RESTRICTION; AMENORRHEA; ESTROGEN; RUNNING; OSTEOPOROSIS; BODY MASS

©2004The American College of Sports Medicine