Original Full Length ArticleIncreased serum sclerostin and decreased serum IGF-1 are associated with vertebral fractures among postmenopausal women with type-2 diabetes
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 (HbA1c%) 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.
Section snippets
Study Design
Between January 2008 and December 2010, a total of 926 patients visiting diabetic clinics at King Abdulaziz University Hospital, New Jeddah Clinic Hospital, Al-Khandra Clinic Hospital, Dr S Fakeeh Hospital, King Fahd General Hospital, and 40 primary health care centers in the Jeddah area were consecutively recruited and referred to the clinics at the Center of Excellence for Osteoporosis Research (CEOR), King Abdulaziz University for screening and study as part of a bone health survey campaign.
Subject Characteristics
Table 1 compares the basic characteristics of postmenopausal women with T2DM with sex- and age-matched non-T2DM controls. WHR (P = 0.011), parity (P = 0.011), fasting plasma glucose (FPG; P < 0.0001), and HbA1c (P < 0.0001) levels were significantly higher in T2DM women compared to controls. Serum sclerostin levels were significantly higher (P < 0.0001) in women with T2DM, but s-IGF-1 was significantly lower (P = 0.016) compared to controls. Levels of serum PTH, s-OC, s-P1NP, p-CTX, and u-NTX were
Discussion
We demonstrated that postmenopausal women with T2DM exhibited higher circulating sclerostin and lower serum levels of IGF-1 and PTH, which were accompanied by lower bone turnover as indicated by decreased levels of bone formation and resorption markers, even after adjusting for confounding factors. Multiple regression analysis suggested that the changes in serum sclerostin and s-IGF-1 levels among T2DM postmenopausal women could play a role in low bone turnover. The latter was evidenced by our
Conflict of Interest
The authors have no conflicts of interest.
Acknowledgments
We thank the Ministry of Higher Education for their financial support to the CEOR at King Abdulaziz University, Jeddah, Saudi Arabia (Grants # CEOR/001-08, CEOR/004-08, and CEOR/019-09). We also thank all the participants of the present study and all the staff members and our colleagues at the CEOR, King Abdulaziz University Hospital, New Jeddah Clinic Hospital, Al-Khandara Clinic Hospital, Dr. S Fakeeh Hospital, King Fahd General Hospital, and the Primary Care Health Centers for their
References (72)
- et al.
Diabetes and fragility fractures: a burgeoning epidemic?
Bone
(2008) - et al.
Wnt/β-catenin in mesencymal progenitor's controls osteoblast and chondrocyte differentiation during vertebrae skeletogenesis
Dev Cell
(2005) - et al.
Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling
J Biol Chem
(2005) - et al.
Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein
Am J Hum Genet
(2001) - et al.
Wnt signaling: relevance to β-cell biology and diabetes
Trends Endocrinol Metab
(2008) - et al.
Association of the gene encoding wingless-type mammary tumor virus integration-site family member 5B (WNT5B) with type 2 diabetes
Am J Hum Genet
(2004) - et al.
The insulin-like growth factor-1 gene and osteoporosis: a critical appraisal
Gene
(2005) - et al.
Low serum IGF-1 and occurrence of osteoporotic fractures in postmenopausal women
Lancet
(2000) - et al.
Mortality after all major types of osteoporotic fracture in men and women: an observational study
Lancet
(1999) - et al.
Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial
Bone
(2003)
The association between low bone mass at the menopause and cardiovascular mortality
Am J Med
Assessment methods for physical activity and physical fitness in population studies: report of a NHLBI workshop
Am Heart J
Reference intervals of biochemical bone turnover markers for Saudi Arabian women: a cross-sectional study
Bone
Bone metabolism is relation to alterations in systemic growth hormone
Growth Horm IGF Res
Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals and essential role of IGF signaling in bone matrix mineralization
J Biol Chem
Risk of fracture in women with type 2 diabetes: the women's health initiative observational study
J Clin Endocrinol Metab
Discrepancies in bone and mineral density and fracture risk in patients with type 1 and type 2 diabetes — a meta-analysis
Osteoporos Int
FRAX underestimates fracture risk in patients with diabetes
J Bone Miner Res
Study of osteoporotic fractures (SOC) research group; osteoporotic fractures in men (MrOS) research group; health, aging and body composition (Health ABC) research group. Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes
JAMA
The involvement of the wnt signaling pathway and TCF7L2 in diabetes mellitus: the current understanding, dispute, and perspective
Cell & Bioscience
Smad3-dependent nuclear translocation of β-catenin is required for TGF-β1 induced proliferation of bone marrow- derived adult human mesenchymal stem cells
Genes Dev
The influence of fluoride on the expression of inhibitors of Wnt/β-catenin signaling pathway in rat skin fibroblast cells
Biol Trace Elem Res
Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)
Hum Mol Genet
Sclerostin antibody treatment increases bone formation, bone mass and bone strength in a rat model of postmenopausal osteoporosis
J Bone Miner Res
Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength
J Bone Miner Res
Single-dose, placebo-controlled, randomized study of AMG785, a sclerostin monoclonal antibody
J Bone Miner Res
Distinct effects of pioglitazone and metformin on circulating sclerostin and biochemical markers of bone turnover in men with type 2 diabetes mellitus
Eur J Endocrinol
Circulating sclerostin levels and bone turnover in type 1 and type 2 diabetes
J Clin Endocrinol Metab
The anabolic effects of GH/IGF system on bone
Curr Pharm Des
Serum levels of insulin-like growth factor (IGF) 1, IGF-binding protein (IGFBP)-2, and IGFBP-3 in osteoporotic patients with and without spinal fractures
J Bone Miner Res
Serum levels of insulin-like growth factor (IGF); IGF-binding proteins-3, -4 and -5; and their relationships to bone mineral density and the risk of vertebral fractures in postmenopausal women
Calcif Tissue Int
Serum insulin-like growth factor-1 is associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes mellitus
Osteoporos Int
Serum insulin-like growth factor-1 is a marker for assessing the severity of vertebral fractures in postmenopausal women with type 2 diabetes mellitus
Osteoporos Int
Morphometric vertebral fractures of the lower thoracic and lumbar spine, physical function and quality of life in men
Osteoporos Int
Risk of mortality following clinical fractures
Osteoporos Int
Diagnosis and classification of diabetes mellitus
Diabetes Care
Cited by (139)
The role of sclerostin in lipid and glucose metabolism disorders
2023, Biochemical PharmacologyBone fragility in diabetes: novel concepts and clinical implications
2022, The Lancet Diabetes and EndocrinologyOsteoporosis and diabetes
2021, Medecine des Maladies MetaboliquesManagement of bone fragility in type 2 diabetes: Perspective from an interdisciplinary expert panel
2021, Nutrition, Metabolism and Cardiovascular Diseases