The Negative Impact of Selective Activation of Retinoic Acid Receptors on Bone Metabolism and Bone Mechanical Properties in Rats

Abstract

hibitors, androgen deprivation therapy, heparin, calcineurin inhibitors and some chemotherapies are among the drugs increasing the risk of osteoporotic fractures [1].The mechanisms of the regulation of bone turnover involved in the etiology and pathology of osteoporosis seem to be very complex. Recent papers have revealed that various nuclear receptors are involved in the regulation of bone metabolism, its physiology and pathology. Many studies suggest Osteoporosis is defined as pathological bone microarchitecture making bones prone to low-energy fractures. In recent decades it has become one of the major health and socio-economic problems in many countries. Drug-induced osteoporosis is a significant health problem, as many drugs have deleterious effects on bone metabolism. Glucocorticoids, proton pump inhibitors, selective serotonin receptor inhibitors, thiazolidinediones, anticonvulsants, medroxyprogesterone acetate, aromatase in- AbstractBackground. Drug-induced osteoporosis is a significant health problem, as many drugs have deleterious effects on bone metabolism. Data from several studies concerning the influence of retinol on bone homeostasis are inconsistent. Objectives. The purpose of this study was to investigate the influence of tazarotene, a selective agonist of the retinoic acid receptor (RAR), on bone metabolism and bone mechanical properties in rats. Material and Methods. Sixteen male Wistar rats were assigned either to the group receiving tazarotene or to the control group. Serum biochemical markers of bone turnover (osteocalcin: OC, tartrate resistant acid phosphatase 5: TRACP5b, and osteoprotegerin: OPG) and the mechanical properties of bones were analyzed. Results. The mean Young's modulus was 24% higher (p < 0.05) in the control group than in the group receiving tazarotene. The stiffness of femur bones was 25% lower (p < 0.05) in rats receiving tazarotene. Flexural yield stress was slightly (2%) decreased in the tazarotene group, but the difference was not statistically significant. In the tazarotene group significantly lower serum concentration of bone turnover markers were obeserved (TRACP5b: 0.86 ± 0.30 ng/mL vs. 2.17 ± 0.67 ng/mL, OC: 7.77 ± 2.28 ng/mL vs. 13.04 ± 3.54 ng/mL and OPG: 0.09 ± 0.04 ng/mL vs. 0.27 ± 0.10) than in the control group. Conclusions. Tazarotene worsened bone mechanical properties and inhibited bone turnover in rats. These results suggest that tazarotene has a negative impact on bone metabolism and that it exerts osteoporotic activity (Adv Clin Exp Med 2016, 25, 2, 213-218).

The safety of isotretinoin treatment in patients with bone fractures

“…Recently, rats receiving intragastrically tazarotene (0.075 mg/kg) in sesame oil (4 ml/kg) daily were demonstrated to have worse bone mechanical properties than control animals. Both mean Young’s modulus and the stiffness were significantly impaired at the femur in tazarotene-treated rats suggesting osteoporotic nature of the drug [29]. Previously, Hotchkiss et al also demonstrated an unfavorable effect of retinoids in long bones.…”

“…Enhanced bone resorption was manifested by a significant increase in serum tartrate-resistant acid phosphatase in the study of Saadi et al [21], whereas other markers (serum pyridinoline, urine deoxypyridinoline, urine hydroxyproline) were elevated insignificantly [19, 20, 22, 29]. Surprisingly, Trifiro and Norbiato found even a decrease in urine N-terminal telopeptide of type I collagen (NTx) level on isotretinoin treatment.…”

Effect of osteoporosis treatment agents on the cortical bone osteocyte microenvironment in adult estrogen-deficient, osteopenic rats

“…Although a large effect size, given the precision with which Young's modulus is estimated, such a difference corresponds to ~10.5% difference in means. A recent article found a 24% difference in Young's modulus between groups when testing drug effects on Young's modulus ( Nowak et al, 2016 ). Since we have power to detect a difference less than half their observed difference and a 10.5% difference in Young's modulus would be clinically meaningful, our study design with eight groups and N = 5/group was justified.…”