HDCN Abstract:  Am Soc Nephrol Ann Mtg -- Miami  

Cruz D, Simon D, Lifton R

Inactivating mutations in the Na-Cl cotransporter are associated with high bone density

Am Soc Nephrol Ann Mtg -- Miami
J Am Soc Nephrol (Sep) 10:597A 1999

Gitelman's syndrome (GS) is an autosomal recessive disorder characterized by hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria. It is caused by homozygous inactivating mutations in the thiazide-sensitive Na-Cl co-transporter gene (NCCT), and results in hypocalciuria analogous to that produced by thiazide diuretics. NCCT is also expressed in human osteoblast-like cell lines. Recent data support a direct effect of thiazide diuretics on these cells. Chronic thiazide therapy has been reported to improve bone mineral density (BMD) in patients with osteoporosis and to reduce the incidence of hip fractures.

To determine the effect of NCCT mutations on BMD, we studied 18 GS patients, and 28 unaffected family members from 3 extended Gitelman's kindreds. The unaffected relatives were classified as heterozygous for NCCT mutations (n=18), or wild type (n=10). BMD was measured by DEXA. To control for differences in age, sex and race, BMD Z-scores were evaluated. Biochemical markers of bone turnover and calcium homeostasis were measured. The 3 groups were compared using ANOVA.

BMD Z-scores Affected Heterozygote Wild Type P
Spine +1.31 ± 0.30 +0.64 ± 0.22 -0.22 ± 0.24 0.009
Femoral Neck +0.68 ± 0.19 +0.14 ± 0.21 -0.36 ± 0.19 0.014
Total Hip +0.86 ± 0.30 +0.25 ± 0.17 -0.38 ± 0.22 0.006
Total Body +1.42 ± 0.79 +1.09 ± 0.33 -0.07 ± 0.37 0.079
Urine Ca/Cr 0.18 ± 0.04 0.26 ± 0.03 0.34 ± 0.05 0.020


All subjects had normal serum calcium and phosphorus levels. Dietary calcium intake, PTH, 1,25 (OH)2 vitamin D, osteocalcin, and urine pyridinoline and deoxypyridinoline levels were similar in all groups. These data indicate that the inactivation of the NCCT is associated with a lower urinary calcium excretion, and a higher BMD. Whether the latter reflects lifelong hypocalciuria or a direct effect on osteoblasts remains to be determined.

Copyright © 1999 American Society of Nephrology