Circulating osteogenic progenitors and osteoclast precursors are associated with long-term glycemic control, sex steroids, and visceral adipose tissue in men with type 2 diabetes mellitus

Abstract

IntroductionType 2 diabetes mellitus (T2DM) is well-known to be associated with normal bone density but, concurrently, low bone turnover and increased risk for fracture. One of the proposed mechanisms is possible derangement in bone precursor cells, which could be represented by deficiencies in circulating osteogenic progenitor (COP) cells and osteoclast precursors (OCP). The objective of our study is to understand whether extent of glycemic control has an impact on these cells, and to identify other factors that may as well.MethodsThis was a secondary analysis of baseline data from 51 male participants, aged 37-65 in an ongoing clinical trial at Michael E. DeBakey VA Medical Center, Houston, Texas, USA. At study entry serum Hemoglobin A1c was measured by high-performance liquid chromatography osteocalcin (OCN) and C-terminal telopeptide of type 1 collagen (CTx) were measured by ELISA, and testosterone and estradiol by liquid-chromatography/mass-spectrometry. Areal bone mineral density (BMD), trabecular bone score and body composition were measured by dual energy x-ray absorptiometry, while COP and OCP were measured by flow cytometry.ResultsWhen adjusted for serum testosterone, parathyroid hormone, and 25-hydroxyvitamin D, those with poor long-term glycemic control had significantly higher percentage of COP (p = 0.04). COP correlated positively with visceral adipose tissue (VAT) volume (r = 0.37, p = 0.01) and negatively with free testosterone (r = -0.28, p = 0.05) and OCN (r = -0.28, p = 0.07), although only borderline for the latter. OCP correlated positively with age, FSH, lumbar spine BMD, and COP levels, and negatively with glucose, triglycerides, and free estradiol. Multivariable regression analyses revealed that, in addition to being predictors for each other, another independent predictor for COP was VAT volume while age, glucose, and vitamin D for OCP.ConclusionOur results suggest that high COP could be a marker of poor metabolic control. However, given the complex nature and the multitude of factors influencing osteoblastogenesis/adipogenesis, it is possible that the increase in COP is a physiologic response of the bone marrow to increased osteoblast apoptosis from poor glycemic control. Alternatively, it is also likely that a metabolically unhealthy profile may retard the development of osteogenic precursors to fully mature osteoblastic cells.

Causal relationship between type 2 diabetes mellitus and bone mineral density: a Mendelian randomization study in an East Asian population

“…Given the cross-talk between osteoblasts and osteoclasts with abnormal microstructural repair in these T2DM patients, it is expected that reduction in bone resorption follows with resultant low bone turnover — the dynamic process of resorption followed by replacement by new bone [ 52 , 53 ]. A balance between osteoclast-dependent bone resorption and osteoblast-dependent bone formation is essential for the maintenance of bone material quality.…”

The complex pathophysiology of bone fragility in obesity and type 2 diabetes mellitus: therapeutic targets to promote osteogenesis

“…Given that obesity is a risk for T2DM, it would be hard to separate out the effect of obesity from diabetes on the bone. Clinical studies ( 54 – 57 ), including from our group ( 58 , 59 ) demonstrated suppressed bone formation maker OCN, P1NP ( 48 ) and bone resorption marker (CTX) in patients with T2DM. Additionally, Vigevano et al.…”

“…Our recent studies showed that in patients with poorly-controlled T2DM had significantly higher circulating osteogenic precursor cells (COPs) compared to well-controlled diabetics. This could mean that COPs are markers of poor metabolic control or the possibility for uncontrolled hyperglycemia results in retardation of differentiation of COPs into mature osteoblasts ( 59 ). Studies from our lab also confirmed, that poor glycemic control over 1year is associated with poor bone microarchitecture and strength in men with T2DM ( 59 , 111 ).…”

“…This could mean that COPs are markers of poor metabolic control or the possibility for uncontrolled hyperglycemia results in retardation of differentiation of COPs into mature osteoblasts ( 59 ). Studies from our lab also confirmed, that poor glycemic control over 1year is associated with poor bone microarchitecture and strength in men with T2DM ( 59 , 111 ). On the other hand, alteration in crucial genes of myogenesis can promote development of osteoprogenitor cells.…”