Elsevier

Bone

Volume 82, January 2016, Pages 93-100
Bone

Review
Effects of diabetes drugs on the skeleton

https://doi.org/10.1016/j.bone.2015.04.026Get rights and content

Highlights

  • Antidiabetic drugs may modulate fracture risk in type 2 diabetics.

  • Thiazolidinedione use results in accelerated bone loss and increased fracture risk.

  • Skeletal safety data for incretin-based therapies and SGLT2-inhibitors are limited.

  • Metformin, sulfonylureas, liraglutide and DPP4-inhibitors do not increase fracture risk.

  • SGLT2-inhibitors may increase fracture risk by provoking hyperparathyroid state.

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. Antidiabetic 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 antidiabetic 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, and 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.

Introduction

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], [2], [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], [17], [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].

Antidiabetic drugs are indispensable for glycemic control in most type 2 diabetics. However before discussing potential benefits or risks of antidiabetic 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], [22], [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 in decreasing 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 antidiabetic 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.

Section snippets

Metformin

Metformin is most commonly used to increase insulin sensitivity in diabetic patients. Biguanides decrease hepatic glucose production and increase glucose uptake in muscle. Metformin is considered by the World Health Organization an essential medicine satisfying the criteria of the public health relevance, evidence on efficacy and safety, and comparative cost effectiveness (www.who.int/medicines). Metformin mechanism of insulin sensitization includes activation of hepatic and muscle

Thiazolidinediones

TZDs increase insulin sensitivity via activation of peroxisome proliferator-activated receptor (PPARγ). Two TZDs, rosiglitazone and pioglitazone, have been used clinically since 1999. A number of studies showed superior efficacy of TZDs over other available antidiabetic therapies in the control of diabetic hyperglycemia [41]. However, their prolonged use is associated with several adverse effects. Strong clinical evidence points to the connection between rosiglitazone use and a significant

Sulfonylureas

Although sulfonylureas are widely used for many years in type 2 diabetics, data on their skeletal safety are scarce. Nevertheless, based on epidemiological studies with adjustments for covariables, sulfonylureas seem to have a beneficial effect on fracture risk irrespective of the duration of treatment [34], [89]. Evidence from both the ADOPT studies and the Rochester studies indicates that glibenclamide (glyburide) therapy does not have an effect on bone mass and fracture risk [32], [41].

Incretin-based therapies

Nearly 10 years ago glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors have been approved for the treatment of type 2 diabetes and are widely used as second-line agents in case of inadequate glycemic control [25].

Incretins are gut-derived hormones which exert their actions through activation of incretin receptor signaling. Glucagon-like peptides (GLP-1, GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) are related hormones released from intestinal

SGLT-2 inhibitors

Recently, a new class of glucose-lowering agents, the sodium-glucose co-transporter 2 (SGLT2) inhibitors have become available [25], [120]. Sodium-glucose co-transporters are responsible for renal glucose reabsorption with SGLT2 accounting for approximately 90% of reabsorbed glucose. SGLT2 actively transports glucose across the proximal nephron, an action which is independent of insulin [121]. Inhibition of SGLT2 results in increasing urinary excretion of glucose, thereby decreasing serum HbA1c

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