Increased serum sclerostin and decreased serum IGF-1 are associated with vertebral fractures among postmenopausal women with type-2 diabetes

Highlights

• Sclerostin levels were significantly higher in T2DM women.

• Serum IGF-1 levels were significantly lower in T2DM women.

• Sclerostin and IGF-1 levels were increased and decreased in relation to VFs number.

• Sclerostin and/or IGF-1 maybe involved in increased osteofragility of T2DM.

Abstract

Insulin-like growth factor 1 (IGF-1) is a determinant of bone mass and is inversely associated with vertebral fractures (VFs). Sclerostin regulates bone formation by inhibiting Wnt/β-catenin signaling. Currently, there is little information on circulating sclerostin levels among postmenopausal women with type-2 diabetes mellitus (T2DM) with VFs in relation to serum IGF-1 (s-IGF-1). We investigated the relationships between serum sclerostin, s-IGF-1, and VFs in postmenopausal women with T2DM. We assessed cross-sectionally 482 postmenopausal women with T2DM and 482 age-matched postmenopausal women without T2DM who were recruited at diabetic clinics and primary health care centers for inclusion in a bone health survey. The main outcome measures were serum sclerostin, s-IGF-1, bone mineral density (BMD), and bone turnover markers. Lateral X-rays of the thoracic and lumbar spine were taken to diagnose VFs. Serum sclerostin levels were increased, whereas s-IGF-1 levels were decreased when T2DM women were stratified by the number of VFs (P < 0.0001). Multiple logistic regression analysis showed that serum sclerostin levels were positively associated with 1 VF (odds ratio [OR] = 1.27, (95%CI:1.01–2.03), P = 0.016), 2 VFs (OR = 1.41, (95%CI:1.03–2.36), P = 0.006), and ≥ 3 VFs (OR = 1.54, (95%CI:1.12–2.44) P = 0.005). s-IGF-1 levels were inversely associated with 1 VF (OR = 0.58, (95%CI:0.39–0.88), P = 0.041), 2 VFs (OR = 0.42, (95%CI:0.21–0.90), P = 0.012), and ≥ 3 VFs (OR = 0.19, (95%CI: 0.14–0.27), P < 0.001). Increased serum sclerostin and decreased s-IGF-1 were associated with VFs among postmenopausal women with T2DM, suggesting that sclerostin and/or IGF-1 may be involved in increased bone fragility in T2DM and could be potential markers of VF severity.

Introduction

There is accumulating evidence that type-2 diabetes mellitus (T2DM) is associated with an increased risk of bone fragility [1], [2], [3] despite higher bone mineral density (BMD) compared to non-T2DM controls [4], [5]. Evidence implicates Wnt signaling in this association [6]. The Wnt/β-catenin pathway is essential for normal osteogenesis [7], [8], [9] and is modulated by several factors, including sclerostin. The latter competes with Wnt/β-catenin for binding to low-density lipoprotein receptor-related protein (LRP) -5 and -6 to prevent colocalization of these receptors with frizzled protein, resulting in decreased Wnt signaling, osteoblastogenesis, and bone formation [10], [11], [12]. Recent studies have demonstrated that anti-sclerostin-neutralizing antibodies are promising for treating low bone mass disorders in both experimental animals and humans [13], [14], [15]. Several studies have demonstrated the importance of Wnt signaling in regulating insulin secretion and viability [16], and a single polymorphism locus in the WNT5B gene is associated with T2DM susceptibility among Japanese subjects [17]. Patients with T2DM showed higher levels of circulating sclerostin that were associated with disease duration and glycated hemoglobin A1c (HbA_1c%) but inversely related to bone turnover markers (BTMs) [18], [19].

IGF-1 is a key regulator of bone; it increases bone matrix deposition, decreases collagen degradation, and enhances osteoblast recruitment [20]. Experimental animal studies demonstrated that IGF-1 modulates bone mineralization and both linear and transverse bone growth [21]. In humans, there is a significant correlation between serum IGF-1 (s-IGF-1) and BMD, and lower s-IGF-1 levels are inversely associated with the risk of hip [22] and vertebral fractures (VFs) [23], [24] among postmenopausal women. It was suggested that s-IGF-1 levels could be used to predict bone mass and VF risk among postmenopausal women [25]. Kanazawa et al. reported that s-IGF-1 levels were inversely associated with VFs independent of BMD among postmenopausal women with T2DM [26]. Conversely, no association between s-IGF-1 and VFs were observed in men with T2DM [26].

VFs adversely affect quality of life [27] and result in increased morbidity and mortality among the elderly [28], [29], [30]. Furthermore, a prior VF is a strong independent risk factor for future fractures [30]. Finally, increased mortality due to cardiovascular diseases is related to the number of VFs [31]. Thus, it is imperative to examine the effect of multiple VFs on prognosis of patients at risk of and/or with osteoporosis.

Currently, there is limited information on circulating sclerostin levels among postmenopausal women with T2DM with VFs or in relation to s-IGF-1. Hence, the objectives of the present study were to: 1) examine whether VFs were associated with changes in serum sclerostin levels in relation to s-IGF-1 levels; and 2) examine relationships among serum sclerostin, s-IGF-1, and BMD with that of BTMs in postmenopausal women with T2DM.