Dataset Information

A Novel Vitamin D Receptor Agonist, VS-105, Improves Bone Mineral Density without Affecting Serum Calcium in a Postmenopausal Osteoporosis Rat Model.

ABSTRACT:

Background and objectives

VS-105, a novel vitamin D receptor agonist with significantly less hypercalcemic side effects than calcitriol, is a useful tool to investigate whether or not a vitamin D receptor agonist at non-hypercalcemic doses could improve bone mineral density (BMD).

Methods

VS-105 and calcitriol were evaluated in an ovariectomized (OVX) osteoporosis rat model and in calvariae bone organ culture.

Results

Treatment of OVX rats by VS-105 (0.1, 0.2 or 0.5 μg/kg, intraperitoneal, 3×/week, for 90 days) significantly improved BMD in the L3 lumbar vertebra in a dose-dependent manner (sham vs. OVX/vehicle: 324 ± 14 vs. 279 ± 10 mg/cm²; VS-105 at 0.1, 0.2 and 0.5 μg/kg: 306 ± 9, 329 ± 12, and 327 ± 10 mg/cm², respectively) without affecting serum calcium (Ca). Calcitriol at 0.1 μg/kg significantly increased BMD but it also increased serum Ca. VS-105 and calcitriol at the test doses significantly suppressed serum parathyroid hormone and promoted tibia bone growth. With respect to biomarkers of bone remodeling, calcitriol and VS-105 both significantly elevated serum osteocalcin. In the calvariae bone organ culture, net Ca release was significantly less in VS-105-treated groups (vs. calcitriol).

Conclusions

VS-105 is efficacious in improving BMD in a dose range that does not affect serum Ca in OVX rats; the improvement in BMD by VS-105 is attributable to increased osteoblastic activity and reduced osteoclastic bone resorption.

SUBMITTER: Wu-Wong JR

PROVIDER: S-EPMC8478347 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:The study investigated the associations of rs9340799:A?>?G (XbaI) and rs2234693:T?>?C (PvuII) polymorphisms in the estrogen receptor 1 gene (ESR1) with femoral neck (BMD-FN) and lumbar spine bone mineral density (BMD-LS), biochemical markers of bone turnover, calcium and phosphate levels, fracture prevalence, and a response to two types of anti-osteoporotic therapy in postmenopausal women from southern Slovakia. METHODS:We analysed 343 postmenopausal Slovak women (62.40?±?0.46 years). The influence of rs9340799 (AA vs. AG?+?GG) and rs2234693 (TT vs. TC?+?CC) genotypes on BMD and biochemical markers was evaluated by covariance analysis adjusted for age and BMI. Binary logistic regression was used to evaluate the genotype effect on fracture prevalence. Pharmacogenetic part of the study included women who received a regular therapy of HT (17ß estradiol with progesterone; 1 mg/day for both; N?=?76) or SERMs/raloxifene (60 mg/day; N?=?64) during 48 months. The genotype-based BMD change was assessed by variance analysis for repeated measurements. RESULTS:Women with AA genotype of rs9340799 had higher BMD-FN (+?0.12?±?0.57 of T-score) and BMD-LS (+?0.17?±?0.08 of T-score) in comparison with AG?+?GG. The rs2234693 polymorphism did not affect any of the monitored parameters. No effect of any ESR1 polymorphisms was found on fracture prevalence. Both types of anti-osteoporotic therapy had a positive effect on BMD improvement in FN and LS sites. Considering the effect of the ESR1 gene within the HT, the subjects with rs9340799/AA genotype showed worse response than those with GG genotype (-?0.26?±?0.10 of BMD-FN T-score; -?0.35?±?0.10 of BMD-LS T-score) and also with AG genotype (-?0.22?±?0.08 of BMD-LS T-score). The rs2234693/TT genotype responded poorer in BMD-LS in comparison with TC (-?0.22?±?0.08 of T-score) and CC (-?0.35?±?0.09 of T-score). The effect of the ESR1 gene on raloxifene therapy was reported only in BMD-LS. Subjects with rs9340799/AA genotype had a?-?0.30?±?0.11 of T-score worse response compared to AG genotype. The rs2234693/TT genotype showed -?0.39?±?0.11 and?-?0.46?±?0.15 lower T-scores in comparison with TC and CC genotypes, respectively. CONCLUSIONS:The rs9340799 polymorphism may contribute to decreased BMD in postmenopausal women from southern Slovakia; however, this is not related to higher fracture prevalence. Concurrently, both polymorphisms affected a response to analysed anti-osteoporotic therapies.