Disturbed bone marrow adiposity in patients with Cushing’s syndrome and glucocorticoid- and postmenopausal- induced osteoporosis

Abstract

BackgroundSkeletal stem/progenitor cells (SSPCs) in the bone marrow can differentiate into osteoblasts or adipocytes in response to microenvironmental signalling input, including hormonal signalling. Glucocorticoids (GC) are corticosteroid hormones that promote adipogenic differentiation and are endogenously increased in patients with Cushing´s syndrome (CS). Here, we investigate bone marrow adiposity changes in response to endogenous or exogenous GC increases. For that, we characterize bone biopsies from patients with CS and post-menopausal women with glucocorticoid-induced osteoporosis (GC-O), compared to age-matched controls, including postmenopausal osteoporotic patients (PM-O).MethodsTransiliac crest bone biopsies from CS patients and healthy controls, and from postmenopausal women with GC-O and matched controls were analysed; an additional cohort included biopsies from women with PM-O. Plastic-embedded biopsies were sectioned for histomorphometric characterization and quantification of adipocytes. The fraction of adipocyte area per tissue (Ad.Ar/T.Ar) and marrow area (Ad.Ar/Ma.Ar), mean adipocyte profile area (Ad.Pf.Ar) and adipocyte profile density (N.Ad.Pf/Ma.Ar) were determined and correlated to steroid levels. Furthermore, the spatial distribution of adipocytes in relation to trabecular bone was characterized and correlations between bone marrow adiposity and bone remodeling parameters investigated.ResultsBiopsies from patients with CS and GC-O presented increased Ad.Ar/Ma.Ar, along with adipocyte hypertrophy and hyperplasia. In patients with CS, both Ad.Ar/Ma.Ar and Ad.Pf.Ar significantly correlated with serum cortisol levels. Spatial distribution analyses revealed that, in CS, the increase in Ad.Ar/Ma.Ar near to trabecular bone (<100 µm) was mediated by both adipocyte hypertrophy and hyperplasia, while N.Ad.Pf/Ma.Ar further into the marrow (>100 µm) remained unchanged. In contrast, patients with GC-O only presented increased Ad.Ar/Ma.Ar and mean Ad.Pf.Ar>100 µm from trabecular bone surface, highlighting the differential effect of increased endogenous steroid accumulation. Finally, the Ad.Ar/Ma.Ar and Ad.Ar/T.Ar correlated with the canopy coverage above remodeling events.ConclusionIncreased cortisol production in patients with CS induces increased bone marrow adiposity, primarily mediated by adipocyte hypertrophy. This adiposity is particularly evident near trabecular bone surfaces, where hyperplasia also occurs. The differential pattern of adiposity in patients with CS and GC-O highlights that bone marrow adipocytes and their progenitors may respond differently in these two GC-mediated bone diseases.

Association of serum sclerostin levels with marrow adiposity in postmenopausal women with glucocorticoid-induced osteoporosis

“…The correlation between vertebral marrow fat fraction in our study cohort and BMD values demonstrated an inverse relationship, consistent with previously published data highlighting the negative association between bone marrow adipocytes and BMD in GIO [ 6 ]. While numerous studies, particularly those conducted clinically and in vivo with rodents, have highlighted an augmentation in bone marrow adipose tissue in response to glucocorticoids [ 6 , 34 – 36 ], it's crucial to note that this phenomenon is not universally observed. For instance, a study on outbred Swiss mice, exposed to short-term glucocorticoid excess at two different doses (2.8 and 5.4 mg/kg/d), revealed no significant impact on adipocyte volume density.…”

“…The regulatory influence of the Wnt pathway intricately shapes the differentiation process of bone marrow mesenchymal stem cells (BMSCs) [ 5 ]. Glucocorticoids promote the differentiation of BMSCs towards adipocytes rather than osteoblasts, and both endogenous and exogenous glucocorticoids may induce the accumulation of bone marrow adipose tissue (BMAT) [ 6 , 7 ]. Central to the pathogenesis of glucocorticoid-induced osteoporosis (GIO) is the suppression of bone formation.…”

Association of serum sclerostin levels with marrow adiposity in postmenopausal women with glucocorticoid-induced osteoporosis

“…The correlation between vertebral marrow fat fraction in our study cohort and BMD values demonstrated an inverse relationship, consistent with previously published data highlighting the negative association between bone marrow adipocytes and BMD in GIO [5]. The primary discovery from our study reveals a negative association between sclerostin serum concentrations and marrow adiposity in postmenopausal females with GIO.…”

“…The regulatory in uence of the Wnt pathway intricately shapes the differentiation process of bone marrow mesenchymal stem cells (BMSCs) [4]. Glucocorticoids promote the differentiation of BMSCs towards adipocytes rather than osteoblasts, and both endogenous and exogenous glucocorticoids may induce the accumulation of bone marrow adipose tissue (BMAT) [5,6]. Prior research has indicated that inhibiting Wnt signaling could potentially play a crucial role in glucocorticoid-induced osteoporosis (GIO) [7].…”

Effectiveness of Corticosteroid Therapy in Enhancing Early Postoperative Recovery in Lumbar Spinal Stenosis Patients: A Retrospective Study

“…Nevertheless, corticosteroid use is not devoid of risk and can lead to other complications. Some literature suggests that corticosteroids might precipitate hyperglycemia in patients with diabetes [ 28 ], induce immune suppression, with a subsequent heightened risk of perioperative infection [ 29 ], and exacerbate osteoporosis [ 30 ], potentially culminating in fusion failure. Hence, it is incumbent upon physicians to judiciously assess patient-specific variables when considering postoperative corticosteroid use and to implement stringent monitoring and risk mitigation strategies.…”