Citation

Meier C, Schwartz AV, Egger A, Lecka-Czernik B. Bone 2015; 82: 93-100.

Affiliation

Department of Orthopedic Surgery, Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, USA; Department of Physiology, Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, USA; Department of Pharmacology, Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, USA.

Copyright

(Copyright © 2015, Elsevier Publishing)

DOI

10.1016/j.bone.2015.04.026

PMID

25913633

Abstract

Type 2 diabetes is associated with increased fracture risk and the mechanisms underlying the detrimental effects of diabetes on skeletal health are only partially understood. Anti-diabetic drugs are indispensable for glycemic control in most type 2 diabetics, however, they may, at least in part, modulate fracture risk in exposed patients. Preclinical and clinical data clearly demonstrate an unfavorable effect of thiazolidinediones on the skeleton with impaired osteoblast function and activated osteoclastogenesis. The negative effect of thiazolidinediones on osteoblastogenesis includes decreased activity of osteoblast-specific transcription factors (e.g. Runx2, Dlx5, osterix) and decreased activity of osteoblast-specific signaling pathways (e.g. Wnt, TGF-β/BMP, IGF-1). In contrast, metformin has a positive effect on osteoblast differentiation due to increased activity of Runx2 via the AMPK/USF-1/SHP regulatory cascade resulting in a neutral or potentially protective effect on bone. Recently marketed anti-diabetic drugs include incretin-based therapies (GLP-1 receptor agonists, DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2)-inhibitors. Preclinical studies indicate that incretins (GIP, GLP-1, GLP-2) play an important role in the regulation of bone turnover. Clinical safety data are limited, however, meta-analyses of trials investigating the glycemic-lowering effect of both, GLP-1 receptor agonists and DPP4-inhibitors, suggest a neutral effect of incretin-based therapies on fracture risk. For SGLT2-inhibitors recent data indicate that due to their mode of action they may alter calcium and phosphate homeostasis (secondary hyperparathyroidism induced by increased phosphate reabsorption) and thereby potentially affect bone mass and fracture risk. Clinical studies are needed to elucidate the effect of SGLT2-inhibitors on bone metabolism. Meanwhile SGLT2-inhibitors should be used with caution in patients with high fracture risk, which is specifically true for the use of thiazolidinediones. Type 2 diabetes is associated with increased fracture risk despite the fact that patients with diabetes have higher bone mineral density as compared to non-diabetic individuals [1-3]. The mechanisms underlying the detrimental effects of diabetes on skeletal health are only partially understood. It is assumed that determinants of fracture risk are multifactorial including diabetes-related microvascular complications, fall risk and alterations associated with chronic hyperglycemia [4]. As documented in preclinical models hyperglycemia may alter calcium and vitamin D metabolism resulting in impaired bone mineralization [5, 6]. Furthermore, chronic hyperglycemia may result in deposition of advanced glycosylation end-products in bone collagen (such as pentosidine) contributing to impaired bone quality [7, 8] and higher fracture risk [9, 10]. Several studies suggest that skeletal dynamics are reduced in type 2 diabetes [4] with decreased osteoblast function as documented by reduced biochemical markers of bone formation [11] and lower bone formation rate in a histomorphometric study [12]. Several pathophysiological changes in diabetics might contribute to decreased bone formation. They include interference of advanced glycosylation end-products with osteoblast development [13], function [14] and attachment to collagen matrix [15], increased levels of osteocyte-derived sclerostin [16-18], and hyperglycemia-induced suppression of osteogenic differentiation of marrow-derived progenitor cells diverting osteoblastic precursor cells to a metabolically stressed adipogenic pathway that induces synthesis of a hyaluronan matrix that recruits inflammatory cells and establishes an inflammatory process contributing to bone demineralization [19]. Anti-diabetic drugs are indispensable for glycemic control in most type 2 diabetics. However before discussing potential benefits or risks of anti-diabetic drugs on bone metabolism it seems evident that optimal glycemic control per se is an important contributing factor for improvement of skeletal integrity in diabetic patients. This notion is supported by several studies showing increased fracture risk in patients with poor glycemic control and reduced risk in patients on intensive glycemic control. A recent cohort study explored the association between glycemic control as measured by serum hemoglobin A1c (HbA1c) levels and the risk of hip fracture in type 2 diabetics aged over 65 years and observed a linear relationship between HbA1c and hip fracture risk. After adjustment for various contributing factors hip fracture risk was 24-31% higher among diabetics with HbA1c levels above 9% than among patients with HbA1c levels of 6-7% [20]. These data are in line with some but not all previous studies confirming a detrimental effect of poor glycemic control on fracture risk [21-23]. In contrast, however, this relationship could not be observed in the ACCORD trial, a clinical trial investigating type 2 diabetics randomized either to intensive or standard treatment strategies. The lack of significant effect of glycemic control on the occurrence of non-vertebral fractures (and falls) might be attributed to the small difference in effective diabetes control between patients with intensified treatment strategy (HbA1c 6.4%) and standard treatment (HbA1c 7.5%) [24]. Although reducing hyperglycemia is mandatory not only for skeletal health but also to decrease the onset and progression of microvascular complications, individualized treatment is necessary, balancing the benefits and risks of glycemic control based on the patient's age and health status [25]. Drug-induced hypoglycemic episodes need to be avoided which in addition to diabetic complications (neuropathy, retinopathy) may increase the risk of falls and fractures. This review summarizes the effects of anti-diabetic drugs on bone metabolism and fracture risk (Table 1). Preclinical and clinical data of both, insulin sensitizers (metformin, thiazolidinediones) and insulin secretagogues are discussed with specific focus on the skeletal effects of recently marketed drugs such as incretin-based therapies (GLP-1 receptor agonists, DPP-4 inhibitors) and SGLT2-inhibitors.

Language: en