Original article
Clinical
Calcium-sensing Receptor Gene A986S Polymorphism and Bone Mass in Hypertensive Women

https://doi.org/10.1016/j.arcmed.2005.11.009Get rights and content

Background

The function of the calcium-sensing receptor (CaSR) is to maintain serum calcium concentration within a narrow physiological range. Two types of mutations have been described: activating that causes hypocalcemia and inactivating, which leads to hypercalcemia. The objective was to assess the effect of CaSR gene A986S polymorphism on the lumbar spine bone mass, calcium metabolism parameters and markers of bone remodeling in hypertensive women.

Methods

The study included 48 patients (mean age 59 ± 10 years) with mild-to-moderate hypertension, according to JNC VI and who did not present any associated diseases. We determined the following in all patients: Ca, P, Mg, PTHi, 25-vitamin D, 1,25-vitamin D, osteocalcin, deoxypyridinoline in urine, 24-h urine calcium. A bone densitometry of the lumbar spine was also performed. CaSR gene A986S polymorphism was also studied in all patients by PCR.

Results

Genotype frequency was 69% for AA, 27% for AS and 4% for SS, with a prevalence of 82% for allele A and 18% for allele S. Patients with a lack of allele S had lower levels of p (3.5 ± 0.5 vs. 4 ± 0.4, p = .034). No differences in calcium plasma levels, urinary calcium excretion and bone mass were observed.

Conclusions

We found no clinical significance in the parameters studied of the CaSR gene A986S polymorphism in hypertensive women.

Introduction

Hypertension and osteoporosis are clinically silent diseases with a financial and social cost determined by their consequences: vascular disease in hypertension and fractures in osteoporosis. The relationship between these two conditions is not clearly established, although numerous alterations of extracellular calcium metabolism have been described in connection with hypertension, possibly causing decreased bone mass in these patients. These alterations include decreased ionic calcium, increased calciuria and urinary cAMP, elevated serum concentrations of PTH and plasma calcitriol, and increased intestinal absorption of calcium, although only calciuria has been associated with decreased bone mass 1, 2, 3, 4, 5, 6 in this population group 7, 8.

The function of the calcium-sensing receptor (CaSR) is to maintain the serum calcium concentration within a narrow physiological range. This receptor is a member of the superfamily of G-protein-coupled receptors and is expressed predominantly in the principal parathyroid cells and renal tubular cells, although it has also been described in many other tissues and cells (lung, terminal ileum, colon, adrenal gland, thyroid, osteoclasts). Calcium regulation takes place through two mechanisms: increased PTH secretion by the parathyroid glands and calcium reabsorption in the renal tubules (9).

The receptor gene codes a polypeptide of 1078 Aa, which is composed of an extracellular domain of 600 Aa, seven characteristic transmembrane domains of G-protein-coupled receptors and a cytoplasmic tail of 200 Aa (10). Two types of mutations have been described: activating that causes hypocalcemia and inactivating that leads to hypercalcemia (11). Most research has focused on A986S polymorphism, located in exon 7, which results from an amino acid shift in codon 986 (alanine to serine). The polymorphism has a significant effect on extracellular calcium, and the presence of allele S is associated with increased serum calcium (12) related to a decrease of urinary calcium excretion (13).

The main determinant of bone mass in hypertensive women is calciuria associated with hypocalcemia 7, 8. On this basis, the purpose of our research was to assess the effect of the CaSR gene A986S polymorphism on bone mass and remodeling markers in hypertensive women and to determine if the presence of allele S has a protective effect on bone mass in this population.

Section snippets

Subjects and Study Protocol

According to the criteria of the Joint National Committee (JNC VI), 48 postmenopausal women with mild-to-moderate hypertension were included in the study. Patients were recruited from hypertensive women seen at the out-patient unit of the Department of Medicine of Hospital Rio Hortega, Valladolid, Spain. Exclusion criteria were alcoholism, neoplasm, secondary hypertension, chronic renal insufficiency, hyper- and hypocalcemia, diabetes, hyperparathyroidism and the use of drugs that affect bone

Results

Forty-eight women with a mean age of 59 ± 9 years and a body mass index of 28 ± 4 were studied. Mean intake of dietary calcium was 548 ± 288 mg/day. Smokers comprised 18%. Mean systolic blood pressure (SBP) was 155 ± 22 mmHg, and mean diastolic blood pressure (DBP) was 93 ± 10 mmHg. Mean values of patients were within normal limits. The bone mineral density (BMD), 1.070 ± 0.15, and the percentage of osteoporotic women (17%) are similar to those of the Spanish population of the same age (15).

Discussion

Only a few studies have analyzed the relationship between bone mass and hypertension, finding an inverse relationship between bone mineral density and hypercalciuria 7, 8. This alteration is the calcium metabolism disorder most frequently described in hypertensive individuals.

The cause of hypercalciuria is unknown. There are two hypotheses: a) the central blood volume hypothesis, which explains hypercalciuria as the result of the expanded central blood volume seen in these patients, and b) the

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