Implications of combined ovariectomy and glucocorticoid (dexamethasone) treatment on mineral, microarchitectural, biomechanical and matrix properties of rat bone

Abstract

Osteoporosis is one of the deleterious side effects of long-term glucocorticoid therapy. Since the condition is particularly aggressive in postmenopausal women who are on steroid therapy, in this study we have attempted to analyse the combined effect of glucocorticoid (dexamethasone) treatment and cessation of oestrogen on rat bone. The dual aim was to generate osteoporotic bone status in a short time scale and to characterise the combination of glucocorticoid-postmenopausal osteoporotic conditions. Sprague Dawley rats (N = 42) were grouped randomly into three groups: untreated control, sham-operated and ovariectomized-steroid (OVX-Steroid) rats. Control animals were euthanized with no treatment [Month 0 (M0)], while sham and OVX-Steroid rats were monitored up to 1 month (M1) and 3 months (M3) post laparotomy/post OVX-Steroid treatment. Histology, dual-energy X-ray absorptiometry (DXA), micro-computed tomography (micro-CT), and biomechanical and mRNA expression analysis of collagenous, non-collagenous matrix proteins and osteoclast markers were examined. The study indicated enhanced osteoclastogenesis and significantly lower bone mineral density (BMD) in the OVX-Steroid rats with Z-scores below -2.5, reduced torsional strength, reduced bone volume (BV/TV%), significantly enhanced trabecular separation (Tb.S), and less trabecular number (Tb.N) compared with sham rats. Osteoclast markers, cathepsin K and MMP 9 were upregulated along with Col1α1 and biglycan with no significant expression variation in fibronectin, MMP 14, LRP-5, Car II and TNC. These results show higher bone turnover with enhanced bone resorption accompanied with reduced torsional strength in OVX-Steroid rats; and these changes were attained within a short timeframe. This could be a useful model which mimics human postmenopausal osteoporosis that is associated with steroid therapy and could prove of value both in disease diagnosis and for testing generating and testing biological agents which could be used in treatment.

Variance of spinal osteoporosis induced by dexamethasone and methylprednisolone and its associated mechanism

“…Being consistent with our findings, previous studies [32][33][34][35][36] demonstrated GCs were able to generate deterioration of bone microarchitecture, which but rarely compared the effect of different types of GCs on bone microarchitecture. In our study comparing the influence of DEXA and MP, lower BS/BV, CONN.D, Tb.N and higher Tb.Sp were observed in DEXA group compared with MP group, and there are less transverse trabecular number and significantly higher trabecular separation in DEXA group than MP group ( figure 4j, k), accordingly, we could conclude that DEXA induced more deteriorative spinal microarchitecture than MP, making the spine be susceptible to fragile fracture.…”

“…These results seem to conflict with some of previous studies which reported that MMP9, Sclerostin, Cathepsink were up-regulated [16,32,50]. However, in fact, this confliction may attribute to multiple factors such as different duration of GCs intervention and varied site of bone sample.…”

“…Genetic polymorphisms of Col1a1 are associated with abnormal BMD. High Col1a1 expression cause an imbalance in the Col1a1:Col1a2 ratio leading to reduced integrity andincreased fracture risk [32,45].…”

The rational use of animal models in the evaluation of novel bone regenerative therapies

“…The first determinant depends on the availability of an animal model that mimics a human disease involving bone repair so that the data generated can be used to predict the drug efficacy and safety in patients. Examples of animal models with good predictability of clinical outcomes include models of postmenopausal osteoporosis [87][88][89][90][91][92], models of glucocorticoid induced bone loss [93][94][95][96], models of cancer metastasis to bone [97], disuse models [98,99], fracture healing models [100][101][102][103] and several others. The second determinant of successful experimentation relates to translational biomarkers of novel therapy efficacy and safety that can be accurately predicted and monitored in patients.…”

Age and Sex Features of Bone Mineral Density in Rats

“…Завдяки значному прогресу біології в останні роки існує мож-ливість аналізувати дію багатьох чинників, котрі впливають на метаболізм кісткової тканини, як in vivo, так і in vitro, що призвело до більш активного використання експери-ментального моделювання на тваринах [1][2][3][4][5][6]. Проте існуючі сучасні методи оцінки стану й метаболізму кісткової тканини є інвазивними (гістоморфометричне дослідження, визначен-ня біохімічних маркерів кісткового ремоде-лювання в сироватці крові тощо) і неінвазив-ними (комп'ютерна томографія, двофотонна рентгенівська денситометрія -ДРА), що може обмежувати оцінку результатів дослідження в динаміці експерименту [1,7,8].…”