Background: Skeletal complications of HH have been reported, to include osteopenia and osteoporosis. However, systematic assessments of bone density and bone metabolism in healthy HH subjects have not been performed, nor have such results been compared prospectively with an appropriate control group.Methods: Thirty-five C282Y +/+ HH subjects (25M, 10 F) were compared with 35 demographically-matched whole blood (WB) donor (non-HH) controls. HH was diagnosed by biochemical and genetic testing. Liver biopsy (n=12) was restricted to subjects at high risk for advanced liver disease Mean initial ferritin level was 1400 ± 1100 ng/mL and transferrin saturation 80 ± 15% in the HH cohort. BMD was measured 4.8 ± 6 (range 0 to 22) yrs after diagnosis using dual energy x-ray absorptiometry (Delphi Advanced Instrument, Hologic, MA), and reported according to absolute bone density (g/cm2), T score (number of SD from peak BMD of persons of the same gender/race) and Z score (number of SD from mean BMD of age-matched persons of the same gender/race). Additional laboratory assessments were performed at the time of BMD testing.Results: HH and WB subjects had similar age (53 vs 54 yr), weight (88 vs 86 kg), gender (71% M), and racial (100% Caucasian) distributions. There were 6 post-menopausal women in each group (8 vs 5 yrs post, p = 0.46). 89% of HH subjects (21/25 men, 10/10 women) and 100% of WB subjects met eligibility criteria for allogeneic blood donation. Mean Z scores were ≥ zero (above age, gender and race adjusted mean values of a reference database maintained by the instrument manufacturer) in both groups at all sites assessed. Absolute BMD values (g/cm2) were similar at the AP spine (1.06 vs 1.04), femoral neck (0.83 vs 0.81), hip trochanteric region (0.77 vs 0.77), total hip (1.00 vs 1.01) and distal radius (0.76 vs 0.75) in HH vs WB subjects (p > 0.25 for all). Respective Z scores at these sites were also similar (0.41 vs 0.39, 0.20 vs 0.08, 0.19 vs 0.49, 0.19 vs 0.46 and 0.45 vs 0.12). Z scores were significantly lower in HH than in WB subjects only at the hip intertrochanteric region (0.14 vs 0.51, p = 0.03); absolute BMD levels at this site were similar (1.16 vs 1.20 g/cm2, p = 0.2). Two HH subjects, including one with cirrhosis, and one WB subject had osteoporosis (T score ≤ −2.5), while 7 HH (20%) and 14 WB (40%) had osteopenia (T score ≤ −1.0) Higher ferritin levels at diagnosis were associated with lower BMD Z scores in univariate logistic regression analysis (p<0.03, all sites tested), however this association remained statistically significant in multivariate analysis only at the total hip region (p=0.008) There were no significant differences in bone specific alkaline phosphatase (65 vs 67 ug/L), osteocalcin (5.5 vs 5.1 ng/mL), ionized and total calcium (1.30 vs 1.30, 2.31 vs 2.31 mmol/L), parathyroid hormone (39 vs 35 pg/mL), 25 OH vitamin D (28 vs 24 ng/mL) or free and total testosterone (113 vs 93 and 313 vs 334 ng/dL, p=0.41 and 0.45, male subjects only) in the HH vs WB study groups.Conclusion: In this study, there was no evidence of clinically significant abnormalities in bone mineral density or in chemical measures of bone metabolism in healthy HH subjects when compared with appropriate age, gender, and racially matched control populations.