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Effect of Subcutaneous Leptin Replacement Therapy on Bone Metabolism in Patients with Generalized Lipodystrophy

Division of Nutrition and Metabolic Diseases, Center for Human Nutrition (V.S., A.G.), and Division of Mineral Metabolism (J.E.Z., K.S.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Address all correspondence and requests for reprints to: Abhimanyu Garg, M.D., Division of Nutrition and Metabolic Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Y3-222, Dallas, Texas 75390-9052. E-mail: abhimanyu.garg{at}utsouthwestern.edu.

Abstract

The adipocyte-derived hormone leptin, which plays an important role in energy homeostasis, has been suggested to have an influence on bone development and remodeling. However, it is not clear from animal studies whether leptin is a stimulator or an inhibitor of bone growth. Cross-sectional studies in humans suggest that serum leptin levels are positively associated with bone mineral density (BMD), but these observations are not consistent, and whether this relationship is independent of obesity remains unclear. We therefore examined the effect of sc leptin administration on BMD and markers of bone turnover in two women, one with congenital generalized lipodystrophy and the other with acquired generalized lipodystrophy. Both patients had regular menstrual cycles. At baseline, the BMD for both patients, measured at the lumbar spine and total hip, was within 1 SD of the peak bone mass. There was no significant change in BMD in both patients after 16–18 months of leptin therapy. Similarly, concentrations of serum osteocalcin and bone-specific alkaline phosphatase or urinary excretion of deoxypyridinoline and N-telopeptides remained unchanged after 6–8 months of leptin therapy, suggesting no effects of leptin on osteoblastic or osteoclastic activity. Our preliminary data suggest that sc leptin replacement in hypoleptinemic patients with generalized lipodystrophy has no effect on the mature adult skeleton.

THE ADIPOCYTE-DERIVED hormone leptin plays an important role in the regulation of food intake, energy expenditure, and body weight (1). Recent data suggest that leptin may regulate a variety of other physiological processes, such as insulin action (2), hemopoiesis (3), immune function (4), reproduction (5), angiogenesis (6), and bone development and remodeling (7). However, it is not clear from the animal studies whether leptin is a stimulator or an inhibitor of bone growth, as intracerebroventricular infusion of leptin has been reported to reduce bone mass in both wild-type and leptin-deficient (ob/ob) mice (8), whereas systemic administration has been reported to increase bone growth in ob/ob mice (9) and reduce bone loss in ovariectomized rats (10). Whether hyperleptinemia contributes to the higher bone mass seen in obese humans (11, 12, 13) is also not clear. Some investigators noted a positive relationship between serum leptin levels and bone mineral density (BMD) (14, 15, 16), whereas others failed to observe such a relationship (17, 18). Further, it is controversial whether the relationship between serum leptin levels and BMD is independent of adiposity (14, 15). Therefore, we examined the effects of sc leptin replacement therapy on BMD and markers of bone formation and resorption in two hypoleptinemic women with generalized lipodystrophy who participated in a recent collaborative trial (19).

Subjects and Methods

Patients

Two patients, one with congenital generalized lipodystrophy (CGL) and another with acquired generalized lipodystrophy, participated in the leptin trial at the University of Texas Southwestern Medical Center. The clinical characteristics of both patients are briefly summarized below.

Patient 1 (UTSW1, belonging to the pedigree CG 800) was a 31-yr-old African-American woman with CGL who has been reported previously (20, 21), and the pedigree shows linkage to the CGL1 locus on chromosome 9q34 (22). Our recent data also showed that she had compound heterozygous mutations, IVS4–2AG (Gln196fsX228) and 377insT (L126fsX146) in the 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) gene (23). One of her sisters also has CGL. She had extreme lack of body fat and a muscular appearance at birth. Roentgenograms of the skeleton at ages 4 months and 5 yr revealed normal bones, but at age 13 yr she suffered a pathological fracture of the right capitellum due to a lytic bone lesion from extensive vascular proliferation. She also has other skeletal anomalies, including focal lytic lesions in both humeri and left femur and diffuse signal intensity alteration on magnetic resonance imaging of the appendicular skeleton, even in roentgenographically normal bone (21). Diabetes mellitus was diagnosed at age 15 yr, and extreme hypertriglyceridemia with tubero-erruptive xanthomas was also noted at the same time. She was being treated with 700 U insulin/d and fenofibrate, besides receiving levothyroxine replacement for postsurgical hypothyroidism. The dose of levothyroxine had been stable for many years, and her serum TSH levels remained in the normal range throughout the study period. She was also taking captopril and hydrochlorthiazide for hypertension. She had regular menstrual periods and was not taking oral contraceptives. Physical examination revealed a height of 1.67 m and a weight of 67.5 kg, and was remarkable for generalized loss of fat from the face, trunk, and extremities; coarse, acromegaloid features; marked acanthosis nigricans over the neck, axillae, and abdominal wall; umbilical hernia; and hepatosplenomegaly. At the time of enrollment in the trial, the pooled serum leptin level was low at 0.73 ng/ml.

Patient 2 (UTSW2) was a 33-yr-old non-Hispanic white woman with acquired generalized lipodystrophy. She had juvenile dermatomyositis at age 8 yr and received treatment with systemic glucocorticoids, azathioprine and cyclophosphomide, besides plasmapheresis. She had been asymptomatic for the last 10 yr, requiring no therapy for dermatomyositis, including steroids. She had dystrophic calcium deposits, but no bone pain or pathological fractures. Fat loss was first noticed from the extremities by age 12 yr, and it soon spread to involve the face and trunk. She did not have diabetes, but has had hypertriglyceridemia for over 15 yr, treated with gemfibrozil. Primary hypothyroidism has been adequately treated with stable replacement doses of levothyroxine. She had normal menstruation and was not taking oral contraceptives. Physical examination revealed a height of 1.62 m, a weight of 47.6 kg, and marked loss of sc adipose tissue from the face and extremities, including the palms and soles. She also had marked loss of sc fat from the trunk, except from the anterior abdomen. She had acanthosis nigricans over the axilla and neck, and mild hepatomegaly. A few irregular, hard, calcified deposits were palpable in the muscles of her arm, forearm, and abdomen. Her pooled serum leptin concentration was 2.35 ng/ml.

Study design

The details of the study design have been published previously (19). Informed written consent was obtained, and the study protocol was approved by the institutional review board. Both patients were admitted to the General Clinical Research Center at University of Texas Southwestern Medical Center (Dallas, TX) for initial evaluation before leptin treatment and subsequently after 1, 2, 4, and 8 months of leptin therapy. BMD and markers of bone formation and resorption were measured at baseline and after 6 months of leptin therapy in patient 1 and after 8 months in patient 2. BMD was also measured after 18 months of leptin therapy in patient 1 and after 16 months of leptin therapy in patient 2. Fasting blood samples were obtained on at least 2 consecutive days for measurement of serum calcium, phosphorous, magnesium, intact PTH, bone-specific alkaline phosphatase (BAP), and osteocalcin. Twenty-four-hour urine samples were also collected for measurement of pH, calcium, phosphorous, sodium, creatinine, N-telopeptides (NTX), and deoxypyridinoline (DPD) levels. Except for hypoglycemic drugs, which were tapered and then discontinued in patient 1 during the study, none of their other concomitant medications were changed during the study period.

Human recombinant leptin (r-metHuLeptin) was provided by Amgen, Inc. (Thousand Oaks, CA). It was administered sc every 12 h to achieve near-physiological concentrations of plasma leptin. Patients were treated with 0.02 mg/kg·d r-metHuLeptin for the first month, 0.04 mg/kg·d during the second month, and 0.08 mg/kg·d subsequently. However, the dosage in patient 2 was reduced to 0.04 mg/kg·d after the eighth month.

Dual energy x-ray absorptiometry. A whole body, dual energy x-ray absorptiometry scan was performed with a multiple detector fan-beam QDR-4500 densitometer (Hologic, Inc., Waltham, MA) for measurement of body composition. BMD was calculated at the lumbar spine (L2–L4), total hip, and lower third of the radius and for the whole body. The coefficient of variation for these measures was 1%.

Biochemical analyses. Serum calcium, phosphorous, and magnesium were measured as part of the systematic multichannel analysis using automated equipment (Beckman, Fullerton, CA). Serum leptin was measured using a commercial RIA for human leptin (Linco Research, Inc., St. Charles, MO). Serum PTH and osteocalcin were measured using commercially available RIA kits (Nichols Institute Diagnostics, San Juan, CA; and Immunotopics, Capistrano, CA). Serum BAP was measured by ELISA (Alkphase-B, Quidel, San Diego, CA). Bone resorption was assessed by urinary levels of DPD (Quidel, San Diego, CA) and NTX (Osteomark, Ostex International, Inc., Seattle, WA). Both markers were expressed relative to urinary creatinine levels. Urinary pH, sodium, calcium, phosphorous, and creatinine were measured as described previously (24).

Results

The baseline characteristics of both the patients and the effect of 4 months of r-metHuLeptin therapy on physical and metabolic parameters have been described previously (19). Briefly, in patient 1, leptin replacement resulted in a weight loss of 3 kg, a decrease in the blood hemoglobin A_1c concentration from 9.5% to 7.3%, and a reduction in fasting serum triglycerides from 11.23 to 2.09 mmol/liter. Similarly, in patient 2 body weight decreased from 47.6 kg at baseline to 45.6 kg at 4 months. Her blood hemoglobin A_1c concentration did not change, whereas fasting serum triglycerides decreased slightly from 5.05 mmol/liter at baseline to 4.79 mmol/liter at 4 months. The serum leptin level increased from 0.73 to 3.27 ng/ml in patient 1 and from 2.35 to 8.45 ng/ml in patient 2. Continued leptin therapy caused further improvements in the metabolic parameters in both patients at the end of 8 months.

Table 1 shows the effect of r-metHuLeptin therapy on BMD in both patients. At baseline, both patients had normal bone densities. The T scores at the lumbar spine and total hip were 0.1 and 0.9, respectively, for patient 1, and –0.1 and –0.8, respectively, for patient 2. Similarly, the BMD at the distal third of the radius was also within 2 SD of peak bone mass in both patients. After 6 months of leptin therapy in patient 1 and 8 months in patient 2, there were no significant changes in BMD at any of the sites measured. Repeat measurements after 18 months of leptin therapy in patient 1 and 16 months in patient 2 also did not show any significant changes in BMD.

In the current study we examined the effect of sc r-metHuLeptin therapy on bone metabolism in two patients with generalized lipodystrophies and hypoleptinemia. Although limited by the small number of patients, this is the first longitudinal study in humans examining the effect of leptin treatment on bone density and bone turnover. In both patients leptin therapy did not cause any significant change in either BMD or markers of bone formation and resorption after 6–8 months of sc leptin administration. Follow-up measurements of BMD after 16–18 months of therapy also did not reveal any significant changes. Previous studies using other agents that affect bone turnover, such as estrogen, raloxifene, or bisphosphonates, and bone formation, such as sodium fluoride, have reported significant changes in BMD during a similar intervention period (25, 26, 27, 28).

There are limited human data on the effect of leptin administration on bone density. Leptin therapy in a severely obese 9-yr-old girl with congenital leptin deficiency for 12 months was reported to increase bone mineral mass by 0.15 kg despite a decrease in total body weight by 16.4 kg (29). However, given the patient’s age, it is difficult to exclude the contribution of ongoing skeletal growth to the increase in bone mineral mass. Leptin therapy, at a dose of 0.028 mg/kg lean mass, raised serum leptin levels from undetectable to 23.2 and 19.8 ng/ml after 8 and 10 months of therapy, respectively. The serum leptin levels attained in our patients with therapy were much lower at 3.3 and 8.5 ng/ml in patients 1 and 2, respectively. This raises the possibility that there may be a higher threshold for effects of serum leptin concentration on bone. However, it must be noted that in the earlier report (29), the patient had developed significant titers of antileptin antibodies, which may have resulted in the high serum leptin concentrations. Leptin concentrations were also measured by different assays in the two studies. In fact, patients in the present study received a higher dose of 0.08 mg/kg body weight of leptin, whereas Farooqi et al. (29) administered only 0.028 mg/kg lean mass of leptin. Despite the significant improvement in hyperglycemia and hypertriglyceridemia in our patients (19), we did not notice any change in their bone densities.

Furthermore, we examined whether sc leptin administration caused any change in the dynamic biochemical markers of bone formation and resorption after 6–8 months of therapy. Previous studies in postmenopausal women receiving estrogen or bisphosphonates have demonstrated rapid decreases in biochemical markers of bone turnover, preceding any observable change in BMD (25, 27). However, we noted no change in the levels of serum BAP and osteocalcin, which serve as markers of bone formation. Similarly, urinary DPD and NTX levels, which are specific markers for bone resorption, did not change with leptin therapy. These results are consistent with earlier observations of Goulding and Taylor (14), who did not notice any association between plasma leptin levels and either plasma osteocalcin or urinary DPD excretion in 54 postmenopausal women. Similarly, Rauch et al. (18) reported no relationship between circulating leptin levels and biochemical markers of either osteoblastic or osteoclastic activity in 60 premenopausal and 34 postmenopausal women. However, Ogueh et al. (30) noted a significant negative correlation between fetal blood levels of leptin and cross-linked carboxyl-terminal telopeptide of type 1 collagen (a marker of bone resorption). A modest negative correlation was also noted between leptin levels and the concentration of carboxyl-terminal pro-peptide of type 1 collagen (a marker of bone formation), but the researchers speculated that the overall effect of leptin on fetal bone metabolism is to increase bone mass by decreasing bone resorption (30). It is therefore possible that leptin may have a greater influence on the growing skeleton than on the mature skeleton. Similarly, the effect of sc leptin therapy on bone formation and resorption in postmenopausal women, who have high levels of bone turnover, remains to be investigated. Further, as we studied only two patients, our results should be considered preliminary, and confirmation of the lack of leptin’s effect on bone metabolism will require a large-scale clinical trial with adequate power.

We did not notice any significant changes in serum levels of PTH, calcium, phosphorous, and magnesium after leptin therapy. Patient 1 had low urinary calcium excretion, but she was also taking hydrochlorothiazide. Even though she continued to take hydrochlorothiazide, urinary calcium excretion increased with leptin treatment. As an increase in sodium excretion was also noted, it could account in part for the increased calciuresis. A modest natriuresis and calciuresis were also observed in patient 2. Leptin has been reported previously to cause significant natriuresis in normotensive rats (31). It is therefore likely that the slight increases in calcium excretion were secondary to increased natriuresis, and leptin administration may not primarily affect calcium metabolism. A small increase in urinary pH was noted in both patients after leptin therapy, the mechanisms for which need to be studied in future studies.

In summary, we observed no change in bone density or markers of bone turnover in two hypoleptinemic women with generalized lipodystrophy after 16–18 months of sc leptin replacement therapy. Our data suggest that sc leptin replacement therapy may not have a significant influence on the mature skeleton in these patients.

Acknowledgments

We are grateful to Anthony Wagner, Ph.D., and Alex DePaoli, M.D., from Amgen, Inc., for providing human recombinant leptin for the trial and for their review of the manuscript; to Angela Osborn, Peggy Boyd, Rebecca Aricheta, and Rita Millsaps for technical assistance; and to the nursing and dietetic services of the General Clinical Research Center for patient care.

Footnotes

This work was supported in part by NIH Grants R01-DK-54387 and M01-RR-00633 and grants from the Southwest Medical Foundation and Amgen, Inc.

Abbreviations: BAP, Bone-specific alkaline phosphatase; BMD, bone mineral density; CGL, congenital generalized lipodystrophy; DPD, deoxypyridinoline; NTX, N-telopeptides.

Received May 22, 2002.

Accepted August 14, 2002.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Simha, V. Articles by Garg, A. Search for Related Content PubMed PubMed Citation Articles by Simha, V. Articles by Garg, A.