DIABETES/METABOLISM RESEARCH AND REVIEWS Diabetes Metab Res Rev 2014; 30: 201–203. Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2505

CO M M E N TA R Y

Questions on therapy with DPP-4 inhibitors and bone homeostasis Nicola Napoli1,2*

Abstract

1

Division of Endocrinology and Diabetes, Università Campus BioMedico di Roma, Rome, Italy

2

Division of Bone and Mineral Diseases, Washington University in St Louis, St Louis, MO, USA *Correspondence to: Nicola Napoli, Division of Endocrinology and Diabetes, Università Campus BioMedico di Roma, Via Alvaro del Portillo, Rome, Italy. E-mail: [email protected]

Received: 28 November 2013 Accepted: 3 December 2013

Copyright © 2014 John Wiley & Sons, Ltd.

A recent study from Gallagher et al. aimed to investigate the effect of a new depeptidyl-peptidase-4 inhibitor, MK-0626, on bone turnover in a mouse model developing insulin resistance and diabetes (MKR mice). Authors have found that treatment with MK-0626 did not affect either MKR mice fasting glucose or parameters of bone metabolism. These data are not in accordance with previous findings, raising questions on the possible protective effect of depeptidyl-peptidase-4 inhibitors on bone loss. Given the negative effects on the bone caused by some antidiabetic drugs, results from this study may be disappointing, but a neutral effect on the bone is still reassuring. However, some aspects of this study should be considered in order to explain these results, and more studies are needed to better understand the effect of this class of drugs on the bone health in humans. Copyright © 2014 John Wiley & Sons, Ltd.

Obese and diabetic patients have generally been considered at low risk of osteoporosis with higher bone mass compared with healthy subjects. However, contrary to what has been thought, recent analyses from the Study of Osteoporotic Fractures have shown that women with type 2 diabetes (T2DM) have an increased risk of hip, humerus and foot fractures [1]. These results were thereafter confirmed in other studies. Further, two meta-analyses that included data on more than one million subjects have reported a relative risk of 1.4–1.7 for hip fractures in T2DM patients compared with non-diabetic patients [2,3]. Analysis, combining data from several large prospective studies, has also shown that for a given age and bone density, fracture risk is higher in diabetic patients than in non-diabetic patients [4]. In general, the effect of medications used to lower serum glucose on bone metabolism is uncertain. Most data suggest that metformin has a neutral or even a positive effect on bone. However, some studies have shown a negative effect of sulphonylureas on bone health and that insulin may increase risk of fractures [5,6]. The negative effects of sulphanilureas or insulin may also be explained by an increased risk of hypoglycaemic events that in turn increase the risk of falls. Inhibitors of depeptidyl-peptidase-4 (DPP-4) increase levels of the active form of glucagon-like peptide-1 (GLP-1) in the body by preventing its breakdown, and are promising new agents for treating T2DM patients [7]. GLP-1 is secreted rapidly from L cells in the small intestine in response to feeding. It stimulates pancreatic insulin secretion and also slows gastric emptying [8]. DPP-4 inhibitors have been reported to significantly improve glycaemic control without weight gain or increased risk of hypoglycaemia [7].

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A recent meta-analysis, including 28 trials enrolling 11 880 patients, on DPP-4 inhibitors showed a reduced risk of fractures (OR 0.60, 95% CI 0.37–0.99) in these patients compared with those on placebo [9]. These findings have encouraged optimism about positive effects of these drugs on bone and are leading to more studies in the field. In this issue of the journal, Gallagher et al. have investigated the effect of a DPP-4 inhibitor, MK-0626 on several parameters of bone turnover in MKR mice [10]. These mice are characterized by a muscle-specific functional blockade of the insulin-like growth factor-I receptor (IGF-IR), which results in a marked reduction in IGF-I-mediated glucose uptake into the skeletal muscle. This abrogates the normal function of these receptors. The MKR mice exhibit insulin resistance and pancreatic β-cell dysfunction leading to the onset of diabetes at early age. The Gallagher study found that MK-0626 did not affect MKR mice fasting glucose. Furthermore, the study did not confirm previous positive data, showing lack of efficacy of this DPP-4 inhibitor on bone resorption [11]. As the authors recognize, high-basal levels of GLP-1 may have impaired the glucose lowering abilities of MK-0626 in MKR mice, which present high glucose and insulin levels in response to MK-0626. These data will raise questions not only about the possible protective effect of DPP-4 inhibitors on bone loss but also more generally on the effect of intestinal peptides on bone health. In vitro and in vivo data show that GLP-1 receptors are expressed on bone marrow stromal cells and immature osteoblasts, and GLP-1 stimulates proliferation of mesenchymal stem cells and inhibits differentiation to adipocytes. GLP-1 receptor knockout mice have decreased cortical bone mass because of increased osteoclast number and activity and decreased calcitonin secretion from thyroid C cells [11]. In fact, GLP-1 receptors are also expressed on thyroid C cells and therefore, GLP-1 may increase the secretion of calcitonin, which could contribute to the postprandial decrease in bone resorption. Other studies have shown that GLP-1 treatment improves trabecular bone mass and micro-architecture, an effect likely mediated by a positive effect on bone formation and on OPG/RANKL ratio [12]. Effects on bone formation may be mediated by interference with WNT signalling, considering that incretin treatment has been reported to lower serum levels of sclerostin and increasing serum levels of osteocalcin [13]. According to the present data, osteoblastogenesis is not positively affected after treatment with this DPP-4

Copyright © 2014 John Wiley & Sons, Ltd.

N. Napoli

inhibitor. Therefore, previous findings showing a positive effect of GLP-1 on bone formation do not seem to be confirmed in this article. Although this result may be disappointing, a neutral effect on bone metabolism is still reassuring. There are some aspects of this study that should be considered in evaluating the implications of these findings for human patients who may be eventually treated with this drug. In this mouse model, the muscle-specific functional blockade of the IGF-IR with over-expression of GLP-1 has created a not physiological condition that has detrimental effect on bone metabolism. In fact, confirming previous studies from the same group, authors have shown that MKR mice have decreased BV/TV, trabecular thickness, trabecular number with increased trabecular space [14,15]. Taken together, data show that these mice have increased bone fragility, reduced bone stiffness and strength. These factors suggest uncertainty about the extent to which this animal model may mimic human physiology in diabetic patients. Alendronate has been shown to improve bone density and probably strength in diabetic patients [16]. In this study, alendronate treatment in MKR mice increased osteoclastic number and osteoclast and bone erosion perimeter despite an improvement in trabecular architecture. However, bisphosphonate treatment is known to increase osteoclast size, but osteoclast number and activity are both decreased [17]. The implications of these inconsistent results on bone strength are hard to predict. It is worth noting that in this study, treatment with MK-0626 did not result in further bone loss, and bone resorption parameters remain stable. Depeptidyl peptidase-4 inhibitors and GLP-1 analogs represent a new frontier of diabetes treatment, and their pleiotropic effects are particularly promising in terms of their long-term effects in diabetic patients. Fractures are still often neglected as a complication of diabetes, but use of medications that do not affect bone health would be preferred. In contrast with previous findings, this study raises questions about the effects of these drugs on bone. Therefore, further studies are needed to shed more light on their effect of DPP-4 inhibitors on bone health. Regardless of the results, future therapeutic decisions in diabetic patients may need to consider the balance between glucose and bone homeostasis as part of the clinical-decision making process.

Conflict of interest None declared.

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Diabetes Metab Res Rev 2014; 30: 201–203. DOI: 10.1002/dmrr

Questions on therapy with DPP-4 inhibitors and bone homeostasis.

A recent study from Gallagher et al. aimed to investigate the effect of a new depeptidyl-peptidase-4 inhibitor, MK-0626, on bone turnover in a mouse m...
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