Bone mineral content in patients with congenital generalized lipodystrophy is unaffected by metreleptin replacement therapy

Abstract

Context: Leptin alters bone and mineral metabolism in rodents, but this has not been verified in humans. PATIENTS with congenital generalized lipodystrophy (CGL) have low leptin due to deficient adipose mass and serve as models of leptin deficiency and replacement.

Objective: To study the effects of recombinant human methionyl leptin (metreleptin) on bone mineral content (BMC) and mineral metabolism.

Design and setting: An open-label nonrandomized study at the National Institutes of Health.

Patients: Thirty-one patients with CGL (ages 4.3 to 46.7 y).

Intervention: Metreleptin (0.06 to 0.24 mg/kg/d) for 6 months to 11 years.

Outcome measures: BMC was assessed by dual-energy x-ray absorptiometry. SD scores (SDS) for BMC were calculated based on height, race, sex, and age using population normative data. Calcium, phosphorus, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were measured at baseline and follow-up.

Results: At baseline, patients demonstrated significantly increased total body less head BMC (mean SDS, 1.8 ± 0.7), height (mean SDS, 1.3 ± 1.3), and lean mass index, defined as lean body mass per height squared (mean SDS, 1.5 ± 0.83), vs population normative data. No change in total body less head BMC was observed after metreleptin. Lean mass index decreased with metreleptin. Serum calcium decreased with metreleptin, but remained within normal limits. No changes were seen in phosphorus, PTH, or vitamin D.

Conclusions: In contrast to rodent models, CGL patients have increased BMC in the leptin-deficient state, which does not change with leptin replacement. The high BMC in these patients is partially explained by high lean mass and tall stature.

Trial registration: ClinicalTrials.gov NCT00025883.

Figures

Figure 1.

Box-and-whisker plots showing mean SDS. SDS were calculated based on population normative data for age, sex, and race. A, SDS of height and LMI (lean body mass in kilograms per square meter of height) (open squares) of CGL patients at baseline. B, TBLH BMC SDS of CGL patients at baseline (left, black circles) and further adjusted for height (right, open squares). All measures were significantly (P < .001) elevated from the population mean, defined as an SDS of zero.

Figure 2.

Mean TBLH BMC SDS of CGL patients during metreleptin replacement therapy. SDS were calculated based on population normative data for age, sex, race, and height. A, Mean ± SD. B, Individual patients plotted over time. No significant change in BMC SDS from baseline values was observed with metreleptin.

Figure 3.

SDS of congenital generalized lipodystrophy patients during metreleptin replacement therapy. SDS were calculated based on population normative data for age and sex for BMI, and age, sex, and race for LMI (defined as lean body mass in kilograms per square meter of height). A, Mean BMI SDS. B, Mean LMI SDS. Both BMI and LMI significantly decreased over time with metreleptin replacement (P < .0001 and P = .0012, respectively).

Figure 4.

Site-specific bone density. A–C, Site-specific BMD SDS of CGL patients during metreleptin therapy. SDS were calculated based on population normative data for age, sex, race, and height. A, AP spine BMD SDS. B, Total hip BMD SDS. C, 1/3 Radius BMD SDS. AP spine and total hip BMD SDS were significantly elevated from the population mean at baseline. D, Relative amounts of trabecular and cortical bone as assessed by a ratio of BMC of the appendicular skeleton (arms and legs) to the axial skeleton (trunk). No significant change was observed with metreleptin in the AP spine, total hip, or 1/3 radius BMD SDS, or in the appendicular:axial BMC ratio.