Strategies to reverse bone loss in women with functional hypothalamic amenorrhea: a systematic review of the literature

Osteoporos Int. 2008 Apr;19(4):465-78. doi: 10.1007/s00198-007-0518-6. Epub 2008 Jan 8.


Functional hypothalamic amenorrhea (FHA) impairs the attainment of peak bone mass and as such can increase the risk of fractures later in life. To document available treatment strategies, we conducted a systematic review of the literature. We report that hormonal therapies have limited effectiveness in increasing bone mass, whereas increased caloric intake resulting in weight gain and/or resumption of menses is an essential strategy for restoring bone mass in women with FHA.

Introduction: Women with functional hypothalamic amenorrhea (FHA) may not achieve peak bone mass (PBM), which increases the risk of stress fractures, and may increase the risk of osteoporotic fractures in later life.

Methods: To identify effective treatment strategies for women with FHA, we conducted a systematic review of the literature. We included randomized controlled trials (RCTs), cross-sectional studies, and case studies that reported on the effects of pharmacological and non-pharmacological interventions on bone mineral density (BMD) or bone turnover in women with FHA.

Results: Most published studies (n=26) were designed to treat the hormonal abnormalities observed in women with FHA (such as low estrogen, leptin, insulin-like growth factor-1, and DHEA); however none of these treatments demonstrated consistent improvements in BMD. Therapies containing an estrogen given for 8-24 months resulted in variable improvements (1.0-19.0%) in BMD, but failed to restore bone mass to that of age-matched controls. Three studies reported on the use of bisphosphonates (3-12 months) in anorexic women, which appear to have limited effectiveness to improve BMD compared to nutritional treatments. Another three investigations showed no improvements in BMD after androgen therapy (DHEA and testosterone) in anorexic women. In contrast, reports (n=9) describing an increase in caloric intake that results in weight gain and/or the resumption of menses reported a 1.1-16.9% increase in BMD concomitant with an improvement in bone formation and reduction in bone resorption markers.

Conclusions: Our literature review indicates that the most successful, and indeed essential strategy for improving BMD in women with FHA is to increase caloric intake such that body mass is increased and there is a resumption of menses. Further long-term studies to determine the persistence of this effect and to determine the effects of this and other strategies on fracture risk are needed.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Adolescent
  • Adult
  • Amenorrhea / complications
  • Amenorrhea / pathology*
  • Anorexia Nervosa / complications*
  • Energy Intake / physiology
  • Epidemiologic Methods
  • Female
  • Fractures, Bone / diet therapy
  • Fractures, Bone / prevention & control*
  • Humans
  • Hypothalamic Diseases / complications
  • Hypothalamic Diseases / pathology*
  • Middle Aged
  • Osteoporosis / diet therapy
  • Osteoporosis / physiopathology
  • Osteoporosis / prevention & control*
  • Treatment Outcome
  • Weight Gain / physiology