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Carboxylated Osteocalcin Levels in Cystic Fibrosis

Low bone density and its sequelae, fractures and kyphosis, are very common among adults with cystic fibrosis (1). Recently, Elkin and colleagues reported low bone formation by bone histomorphometry in 20 adults with cystic fibrosis (2). This finding was somewhat surprising because most noninvasive studies of bone formation (i.e., measurement of the serum bone formation markers, osteocalcin and bone-specific alkaline phosphatase) have suggested that formation would be normal or high in cystic fibrosis (3, 4). Osteocalcin undergoes a vitamin K–dependent, posttranscriptional -carboxylation of the glutamic acid residues, which results in a greater mineral binding coefficient with the calcium ions in the hydroxyapatite [Ca₁₀(PO₄)₆(OH)₂] matrix at the mineralization front of new bone (5). Because vitamin K insufficiency may be common in patients with cystic fibrosis, we hypothesized that lower levels of carboxylated osteocalcin may be present. Lower levels of carboxylated osteocalcin result in abnormal bone maturation, decreased bone density, and increased fractures in cohorts without cystic fibrosis (5, 6). Reduced carboxylated osteocalcin levels may help explain the discordance between the bone histomorphometry and the bone marker data in cystic fibrosis.

Adults with cystic fibrosis (n = 52) and age- and sex-matched healthy control subjects (n = 44) were recruited in a study approved by the Committee on Human Research. Exclusionary criteria were bisphosphonate, corticosteroid or antibiotic use or hospitalization within 2 months, liver disease, and pregnancy. Fasting serum samples were measured for osteocalcin with a radioimmunoassay (CIS-US, Bedford, MA). To determine the amount of carboxylated osteocalcin, levels were also measured after treatment with hydroxyapatite (7.5 mg incubated with 250 µL serum for 1 hour at 4°C) (6). The patients with cystic fibrosis were 29.0 ± 1.0 years old and had a reduced body mass index (20.0 ± 0.5 kg/m²), FEV₁ (47 ± 3%), and spine (-1.74 ± 0.12) and femur (-1.57 ± 0.12) T scores. Total osteocalcin levels did not differ between the groups, but the patients with cystic fibrosis had significantly lower carboxylated osteocalcin levels (16.0 ± 1.0 versus 19.6 ± 1.0 ng/ml, p = 0.02). There were no significant associations between the carboxylated osteocalcin and age, sex, body mass index, FEV₁%, pancreatic function, and genotype. The spine, but not the femur, T scores showed a significant relation with the level of carboxylated osteocalcin (r = 0.33, p = 0.035). Also, there was a moderate association between carboxylated osteocalcin and prothrombin time, a surrogate for vitamin K deficiency (r = -0.44, p = 0.01).

Adults with cystic fibrosis have significantly lower carboxylated osteocalcin levels than healthy control subjects. At the cellular level, reduced carboxylated osteocalcin may alter the protein composition of bone and lead to abnormal bone formation. Vitamin K deficiency may play an important role in bone health in patients with cystic fibrosis.

Robert M. Aris, David A. Ontjes, Sue A. Brown, Worakij Chalermskulrat, Isabel Neuringer and Gayle E. Lester

University of North Carolina Chapel Hill, North Carolina

FOOTNOTES

Conflict of Interest Statement: R.M.A., D.A.O., S.A.B., W.C., I.N., and G.E.L. have no declared conflict of interest.

Dr. Elkin was given an opportunity to respond to this letter but declined to do so.

REFERENCES

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3. Haworth CS, Selby PL, Webb AK, Dodd ME, Musson H, McL Niven R, Economou G, Horrocks AW, Freemont AJ, Mawer EB, et al. Low bone mineral density in adults with cystic fibrosis. Thorax 1999;54:961–967.[Abstract/Free Full Text]
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