Elsevier

Metabolism

Volume 60, Issue 9, September 2011, Pages 1211-1221
Metabolism

Clinical Science
Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women

https://doi.org/10.1016/j.metabol.2011.05.016Get rights and content

Abstract

Strenuously exercising young women with hypothalamic amenorrhea are hypoleptinemic and have low bone mineral density (BMD) and content (BMC), which predispose them to increased fracture risk. Short-term leptin replacement in these women corrects many neuroendocrine abnormalities and increases circulating levels of bone formation markers. Whether treatment with recombinant methionyl human leptin (metreleptin) for a long period improves BMD and BMC remains unknown. We studied 20 strenuously exercising young women with hypoleptinemia (leptin concentration <5 ng/mL) and hypothalamic amenorrhea of at least 6 months' duration. Eleven were randomized to metreleptin (initial dose, 0.08 mg/[kg·d] for 3 months; altered thereafter to 0.12 mg/kg for lack of efficacy or 0.04 mg/[kg d] for more than 5% weight loss) and 9 were randomized to placebo for 9 months. After a 3-month washout period, subjects were reexamined at the 1-year time point. Six subjects elected to continue on open-label metreleptin treatment for another 12 months. Two subjects dropped out after 18 months, and 4 completed the entire 2-year study. The BMD and BMC of the total body, lumbar spine (L1-L4), hip, and radius were assessed by using dual-energy x-ray absorptiometry at baseline and at 3, 6, 9, 12, 18, and 24 months of treatment. Metabolic and hormonal parameters and bone markers were measured in blood and urine. Metreleptin significantly increased BMC (P = .034) and tended to increase BMD (P = .069) at the lumbar spine at 9 months in the entire study group (intention-to-treat analysis). In subjects who completed the entire 2-year study (n = 4), metreleptin significantly increased BMD (P = .024) and BMC (P = .049) at the lumbar spine by 4% to 6%. Changes were not significant at the whole body, hip, and radius. Changes in hormonal and metabolic parameters and bone markers were moderate during the first year of treatment, but metreleptin further increased insulin-like growth factor 1 and decreased cortisol and cross-linked C-terminal telopeptide of type 1 collagen concentrations in serum during the second year of treatment (P < .05). The incremental area under the estradiol concentration curve over the 2-year course of the study correlated positively with the corresponding increase in lumbar spine BMD (ρ = 0.42, P = .039). Long-term metreleptin administration in strenuously exercising young women with hypothalamic amenorrhea and hypoleptinemia increases lumbar spine BMD and BMC and alters bone remodeling milieu to favor bone accretion. Results from this pilot study should be confirmed by future, larger clinical trials and need to be extended by studying bone microarchitecture and fracture risk.

Introduction

Chronic energy deficiency and the resulting hypoleptinemia are closely linked to hypothalamic amenorrhea, a condition encompassing a clinical spectrum ranging from hormonal abnormalities in strenuously exercising women athletes to anorexia nervosa [1], [2], [3], [4], [5]. Hypothalamic amenorrhea is caused by suppressed gonadotropin-releasing hormone pulsatility, and endocrine evaluation of these patients often reveals not only suppression of the midcycle gonadotropin surge with decreased downstream gonadal sex steroid production but also decreased serum leptin because of low adipose tissue mass [1], [2], [3], [4], [6]. An imbalance between energy intake and exercise-induced energy expenditure results in the female athletic triad of decreased energy availability, amenorrhea with anovulatory infertility, and decreased bone mineral density (BMD) that increases risk for osteoporosis and stress fractures.

Women with hypothalamic amenorrhea have low BMD and bone mineral content (BMC) and may not attain optimal peak bone mass [6], [7], [8], [9], [10]. Many of the therapies designed to improve the hormonal abnormalities associated with this condition (estrogen, insulin-like growth factor 1 [IGF-1], and dehydroepiandrosterone), isolated or in combination [11], have no consistent or only mild favorable effects on BMD [12], [13]. Thus, the search remains for a treatment that resolves both the reproductive dysfunction and the increased risk of osteoporosis in these women, possibly involving a molecule upstream of all neuroendocrine abnormalities.

Low body weight and adipose tissue mass in strenuously exercising women with hypothalamic amenorrhea raise the possibility that the relative lack of molecules normally secreted from adipose tissue could be responsible, at least in part, for the endocrine- and bone-related abnormalities associated with this condition. Leptin, a pleiotropic, adipocyte-secreted hormone, the circulating levels of which reflect the amount of energy stored in adipose tissue, has recently emerged as a key player in the complex system that regulates bone metabolism [14], [15], [16], [17]. Low leptin concentrations (hypoleptinemia) are frequently observed in young women with hypothalamic amenorrhea, the female athlete triad, and/or anorexia nervosa [1], [2], [3], [4]. We have previously shown that increasing leptin concentrations in women with hypothalamic amenorrhea by administering exogenous recombinant methionyl human leptin (metreleptin) leads to resumption of ovulatory menses and improves many of the underlying metabolic and neuroendocrine abnormalities [18], [19]. In addition, we found that metreleptin treatment significantly increases circulating levels of bone formation markers and/or decreases circulating levels of bone resorption markers [18], [19]. The duration of metreleptin treatment in our previous studies was probably too short to allow for changes in BMD to manifest [18], [19]. In this proof-of-concept, pilot study, we examined the effects of metreleptin treatment for 2 years on BMD, BMC, hormonal profile, and circulating markers of bone metabolism in lean, hypoleptinemic women with hypothalamic amenorrhea.

Section snippets

Subjects

Eligible subjects were strenuously exercising lean women between the ages of 18 and 35 years, with hypothalamic amenorrhea for at least 6 months and hypoleptinemia (fasting morning leptin concentrations <5 ng/mL at screening), recruited through advertisements in the community. At the time of screening, all subjects' body weights had been stable for at least 6 months before and were within 15% of their ideal body weight. Participants were free of any significant coexisting medical conditions,

Body weight and composition

During the first 9 months of the study, metreleptin treatment tended to reduce body weight and significantly decreased fat mass (Fig. 2, left panels). For the subjects who participated in both phases of the study (intention-to-treat: n = 6, Fig. 2, middle panels; on-treatment: n = 4, Fig. 2, right panels), body weight and fat mass appeared to decrease during the first 6 months of metreleptin treatment, stabilize between months 6 and 9 (possibly because of adjustment of metreleptin dosing),

Discussion

We found that increasing leptin concentrations in strenuously exercising, hypoleptinemic lean young women with hypothalamic amenorrhea through metreleptin administration for a prolonged period (2 years) increases lumbar spine BMC and BMD by 4% to 6% but does not significantly affect total body BMC and BMD, or BMC and BMD of the hip and forearm. The increase in lumbar BMD and BMC manifested slowly over the first year of treatment and became more evident after 18 to 24 months. Accordingly, we

Funding

The Mantzoros group is supported by National Institute of Diabetes and Digestive and Kidney Diseases grants 58785, 79929, and 81913 and AG032030. Funding was also received from the National Institutes of HealthNational Center for Research Resources grant M01-RR-01032 (Harvard Clinical and Translational Science Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National

Conflict of Interest

There are no conflicts of interest associated with this manuscript.

Acknowledgment

We would like to thank Jean Chan, MD, for contributions during initial phases of the study and Holly Kilim, MD, and Florencia Ziemke, MD, for their help in the performance of the study.

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    Clinical trial registration: clinicaltrials.gov, registration no. NCT00130117.

    Author contributions: ES and FM contributed to data collection and analysis, data interpretation, and manuscript writing. KNA contributed to data analysis and data interpretation. MB and JPC contributed to data collection and analysis. SC, KMA, and CG contributed to the design and conduct of the study. AK contributed to manuscript writing. CSM contributed to the conduct of the study, data collection and analysis, data interpretation, and manuscript writing.

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