As expected, subjects in the PHPT group had high levels of calcium, PTH, bone remodelling markers and low BMD at the three studied sites. We found BMI corresponding to overweight in the PHPT group consistent with previous studies [32
] although the nature of this relationship remains uncertain. We found no differences in vitamin D levels between patients and control subjects, as Vignali had also found in postmenopausal PHPT women [34
], and, in contrast with previous data [35
] showing lower vitamin D levels in PHPT patients than in control subjects, we did not find such a difference between the study groups although we did not evaluate seasonal factors as the aforementioned study did. OPG serum levels were three times higher in our PHPT patients than in a previous study on men and women aged 62 with PHPT [36
] and our PHPT subjects had lower levels than a group of postmenopausal women [37
]. Despite there being no established reference values, OPG serum levels appear to be higher in postmenopausal women than in other conditions as PHPT.
There were no differences in the allelic distribution between PHPT and control groups, this means that none of the studied SNPs appears to be a genetic factor which predisposes for PHPT.
The main purpose of this study was to analyze the relationship between BMD, or fractures, and three SNPs of the OPG
and the rs2277438 SNP of the RANKL
in PHPT. We did not find any differences in frequency of fractures between genotypes in control nor in PHPT subjects in all the SNPs studied according to data of previous studies of OPG
rs3102735 (163 A/G) [27
] and of OPG
rs2073618 (1181 G/C) [27
] on postmenopausal women. These two studies neither did find any differences in BMD. A study of OPG
rs2073618 (1181 G/C) described a 26% higher risk of hip fractures and 52% higher of femoral neck fractures in CC homozygote than GG homozygote women independent of BMD [24
]. There are no fracture data related to RANKL
rs2277438 SNP in the literature. The genetic variation that causes SNPs appear not to have main influence on a clinical event as relevant as fractures in PHPT and in non PHPT population.
Significantly lower BMD in the 1/3 distal radius with similar PTH levels were found in the minor homozygotes (GG) compared to heterozygotes and major allele homozygotes in both OPG
rs3102735 (163 A/G) and OPG
rs3134070 (245 T/G) SNPs in PHPT but not in control subjects. This could mean that these minor homozygote individuals suffer from more specific cortical BMD loss not mediated by PTH or creatinine serum levels in PHPT. An association between the G allele of the OPG rs3102735 (163 A/G) SNP and low BMD in the forearm, low heel broadband ultrasound attenuation (BUA) and low heel speed of sound (SOS) were described in Danish women with and without hip or forearm fractures [16
]. In Hungarian women the GG genotype of the OPG
rs3102735 (163 A/G) was associated with low hip BMD [17
]. Nevertheless, Hsu reported that males with the GG genotype of the OPG
rs3102735 (163 A/G) had very low risk of having extremely low BMD in the hip [30
]. Regarding the OPG
rs3134070 (245 T/G) SNP, an association between the GG genotype and low BMD has already been reported in the radius and femoral neck in postmenopausal women [18
]. Several other studies failed to show this association between OPG
rs3102735 (163 A/G) or OPG
245 T/G [19
We did not find any difference between genotypes of the OPG
rs2073618 (1181 G/C) SNP regarding BMD in the PHPT subjects, a finding in accordance with previous studies on menopausal women [27
]. However, we did find higher BMD in the lumbar spine in the CC than in the GG genotype group in the healthy control subjects, also in accordance with previous findings in the general or postmenopausal osteoporotic populations [15
]. These findings could mean that the bone loss in PHPT, mainly cortical, and in the osteoporotic condition, mainly cancellous, is modulated by different genetic factors. Some possible factors could be the G allele of the OPG
rs2073618 (1181 G/C) SNP favouring lumbar spine bone loss in osteoporosis, or the G allele of the OPG
rs3134070 (245 T/G) and rs3102735 (163 A/G) favouring cortical bone loss in PHPT. But it should be also considered that the wrist is a non-weight bearing site and therefore is free of external factors or remodelling due to body weight or physical activity.
Consistent with studies in the non-PHPT population [19
] we did not find any significant difference between genotypes of the RANKL
rs2277438 SNP in PHPT or in the control group.
The main limitations of our study are the low frequency of the GG genotype in both the OPG rs3102735 (163 A/G) and rs3134070 (245 T/G) SNPs and that there was a trend (not statistically significant) to difference in age between the GG and the rest of the groups. Otherwise, our results are supported by the fact that they are not reproducible in control subjects and that these two SNPs are located in the same haplotype block (promoter).