Department of Geriatrics, Internal Medicine and Metabolic Bone Diseases, Centre of Postgraduate Medical Education, Warsaw
Head of Department: Associate Professor Marek Tałałaj, MD, PhD
The prevalence of osteoporosis and diabetes mellitus is alarming. In the United States, 50% of elderly individuals are osteoporotic and 20% of population have either diabetes or prediabetic condition. It was found that both diseases had similar features including molecular mechanisms and genetic predispositions (1). Bone and energy homeostasis are under the control of the same regulatory factors, including insulin, bone derived hormone – osteocalcin, peroxisome proliferator-activated receptor-γ (PPAR-γ), as well as gastrointestinal hormones, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP).
Insulin exerts an anabolic effect on bone tissue due to its structural homology to insulin-like growth factor-I (IGF-I), interacting with the IGF-I receptor present on osteoblasts (2). It was shown that lower serum IGF-I concentrations are associated with a higher number of vertebral fractures in postmenopausal women with type 2 diabetes (3, 4). On the other hand insulin increases bone resorption by reducing an expression of osteoprotegerin (OPG) – a decoy receptor for receptor activator of nuclear factor kB ligand (RANKL) and stimulates bone turnover (5-8).
A complex and heterogenous molecular pathophysiology seems to underlie osteoporosis and fracture risk in diabetes-related bone disease. Diabetes mellitus (DM) was found to induce the overexpression of many cytokines and hormones, such as sclerostin, gremlin, angiotensin II (Ang-II), parathyroid hormone (PTH), interleukin-6 (IL-6) and tumor necrosis factors (TNFs) but it also sequesters the over expression of vitamin D and neurotransmitters required for growth of osteoblasts (1). DM is responsible for the upregulation of PPAR-γ, fatty acid binding protein, tumor necrosis factor-α (TNF-α) and for increased availability of mesenchymal stem cells for adipocyte formation at the cost of osteoblast formation (9-12). For this reason DM is considered responsible for the deposition of lipids in the bone marrow, expansion of marrow cavity, diminishing of bone microcirculation, and the reduction of osteoblast number available for bone formation (13-15).
Serum osteocalcin concentration has been reported to be negatively correlated with hemoglobin A1c (HbA1c) level (16). In patients with DM osteocalcin, both in bone and serum, has been found to be incompletely carboxylated, and undercarboxylated osteocalcin has been negatively implicated in energy metabolism and glucose control (17, 18). Higher levels of undercarboxylated osteocalcin were suggested to be linked to increased risk of hip fractures (19).
Recent human cross-sectional studies confirm that bone turnover is attenuated in type 2 diabetes mellitus (T2DM). Sclerostin, an inhibitor of bone formation, was shown to be increased in patients with T2DM, independent of gender and age. Positive correlation was documented between sclerostin level and both duration of T2DM and HbA1c, and negative correlations between sclerostin and bone turnover markers (13).
Decreased bone quality in patients with T2DM is partly combined with advanced glycation end products (AGEs) – highly reactive glucose metabolites, which are implicated in forming additional cross-links between collagen fibres in bone. It results in excessive stiffness and in fragility of bone tissue (20, 21). AGEs accumulate in various tissues including bone, interfere with normal tissue function, as well as increase inflammation and cellular damage. AGEs have been identified as a biomarkers of increased fracture risk. Accumulation of pentosidine, one of the AGEs, in cortical and trabecular bone tissues was reported to exert negative impact on bone strength (22-24), while higher levels of the endogenous secretory receptor for AGEs (esRAGE) – a decoy AGE receptor – have protective effects on fracture risk in diabetes (25).
Significant associations between diabetes mellitus and fracture risk were documented. Patients with T1DM are characterized by reduced BMD, which may partly explain increased fracture risk. Most patients with T2DM show normal or increased BMD (at the spine and femoral neck) but, in spite of this, higher fracture risk (26). The meta-analysis of the published data showed that younger age, higher body mass index, male gender, and higher HbA1c were positively associated with higher BMD values in patients with T2DM (27). The results of 16 studies performed in the US and Europe revealed that T2DM was associated with over two-fold increase in risk of hip fractures in men (relative risk [RR] = 2.8) and women (RR = 2.1) (1). Studies conducted on a Japanese population indicated that T2DM patients, both men and women have increased rate of vertebral fractures (28). The results of Rotterdam Study documented that individuals with T2DM were characterized by 69% higher risk of non-vertebral fractures compared to those without diabetes, despite having higher BMD at the femoral neck and lumbar spine (29). It was shown that glycemic control at the HbA1c level of 7.5% was associated with higher BMD but also with higher risk of all types of osteoporotic fractures (30). Obese Japanese men with T2DM and HbA1C of 9% and above had three times increased risk of vertebral fractures compared with men with diabetes and normal BMI, despite equal or even higher BMD values (16). Human histomorphometric studies revealed that bone turnover in older T2DM patients was diminished. Low bone turnover could result in higher BMD together with decreased bone quality (31).
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