BON-10693; No. of pages: 8; 4C: Bone xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Bone

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Review

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Effects of diabetes drugs on the skeleton

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Christian Meier a,⁎, Ann V. Schwartz b, Andrea Egger a, Beata Lecka-Czernik c,d

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Article history: Received 19 March 2015 Revised 13 April 2015 Accepted 16 April 2015 Available online xxxx

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Keywords: Diabetes mellitus Metformin TZDs Incretins DPP-4 inhibitors SGLT2 inhibitors

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journal homepage: www.elsevier.com/locate/bone

Division of Endocrinology, Diabetes and Metabolism, University Hospital, Basel, Switzerland Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA c Department of Orthopedic Surgery, Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, OH, USA d Department of Physiology and Pharmacology, Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, OH, USA

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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. © 2015 Published by Elsevier Inc.

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Contents

Introduction . . . . . . . . . . . . . . . . Metformin . . . . . . . . . . . . . . . . . Thiazolidinediones . . . . . . . . . . . . . Mechanism of TZD-induced bone loss . . Novel selective PPARγ modulators with Sulfonylureas . . . . . . . . . . . . . . . . Incretin-based therapies . . . . . . . . . . . GLP-1 receptor agonist . . . . . . . . . DPP-4 inhibitors . . . . . . . . . . . . SGLT-2 inhibitors . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .

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⁎ Corresponding author at: Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Missionsstrasse 24, CH-4055 Basel, Switzerland. Fax: +41 61 264 97 96. E-mail address: [email protected] (C. Meier).

http://dx.doi.org/10.1016/j.bone.2015.04.026 8756-3282/© 2015 Published by Elsevier Inc.

Please cite this article as: Meier C, et al, Effects of diabetes drugs on the skeleton, Bone (2015), http://dx.doi.org/10.1016/j.bone.2015.04.026

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Metformin

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Table 1 Antidiabetic drugs and their effect on fracture risk.

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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 AMP-activated protein kinase (AMPK), which results in suppression of fatty acid synthesis and stimulation of fatty acid oxidation in liver and increase in muscle glucose uptake [26]. AMPK also decreases expression of sterol-regulatory element-binding-protein 1 (SREBP-1), a transcription factor involved in adipocyte differentiation and pathogenesis of insulin resistance, dyslipidemia and diabetes. Animal studies indicate that metformin has a positive effect on osteoblast differentiation due to increased activity of osteoblast-specific Runx2 transcription factor via AMPK/USF-1/SHP regulatory cascade [27] and it has a negative effect on osteoclast differentiation and bone loss after ovariectomy by decreasing RANKL and increasing osteoprotegerin levels [28]. Interestingly, in rodent models metformin can prevent the adverse effects of TZDs on bone by either inducing re-ossification of bone after rosiglitazone treatment or preventing rosiglitazone effects when applied in combination with rosiglitazone [29]. There are few clinical studies investigating the effect of metformin on bone and fracture risk. Metformin was compared with a sulfonylurea (glyburide) and with a thiazolidinedione (rosiglitazone) in the ADOPT trial, discussed in more detail in the section on thiazolidinediones [30]. The primary endpoint of this trial was time to monotherapy failure. Fractures were identified as adverse events. Fracture incidence was similar in those assigned to metformin or glyburide. One-year changes in the bone resorption marker CTX were similar in women (difference in 12-month change: + 2.0%) and modestly greater in men (− 8.4%) in those assigned to metformin compared with a sulfonylurea [31]. The metformin group had greater decreases in levels of the bone formation marker P1NP (difference in 12-month change: −9.4% women; −19.5% men), compared with the sulfonylurea group. Most observational studies on metformin have found no effect on fracture risk although three studies have reported reduced risk [32–34]. Metformin use was associated with lower fracture risk,

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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 osteocytederived 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]. 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 [21–23]. 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

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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.

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Secretagogues

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α-glucosidase inhibitors Amylin analog SGLT2 inhibitors

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Mechanism of TZD-induced bone loss

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PPARγ, an essential regulator of lipid, glucose, and insulin metabolism [62], is a target for TZDs. The PPARγ protein is expressed in mice and humans in two isoforms, PPARγ1 and PPARγ2. PPARγ1 is expressed in a variety of cell types, including cells of mesenchymal and hematopoietic lineage, whereas PPARγ2 expression is restricted to cells of mesenchymal lineage adipocytes. In bone, PPARγ2 plays an important role in regulation of mesenchymal stem cell (MSC) differentiation toward osteoblasts and adipocytes, and the maintenance of bone mass. In marrow MSCs, PPARγ2 activated with rosiglitazone induces adipocyte differentiation, suppresses osteoblast differentiation, and increases RANKL expression and support for osteoclastogenesis [63–65]. In contrast, PPARγ1 expressed in hematopoietic stem cells promotes osteoclast differentiation and bone resorption [66]. It controls an expression of c-fos protein, an important determinant of osteoclast lineage commitment and development, and activates Pgc1β, an important co-

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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 increase in risk of myocardial infarction and death from cardiovascular causes [42]. This association resulted in a recent review of rosiglitazone safety by the FDA and recommendation for its restricted use in the US. Interestingly, pioglitazone use is associated with a significantly lower risk of death and lower number of myocardial infarction and stroke incidence [43], indicating that cardiovascular effects of TZDs are not a drug class effect, but rather specifically associated with the TZD type. However, increased risk of bladder cancer in long-term pioglitazone users resulted in recent restriction of its use by FDA. Both TZDs exhibit drug class properties of fluid retention and weight gain [44]. Although the use of both rosiglitazone and pioglitazone is currently restricted, new TZDs with better safety profile are in development. Therefore, understanding TZDs mechanism of action on bone is needed in respect to improvement of safety for bone of new line of TZDs. Clinical studies of rosiglitazone and pioglitazone use have identified adverse effects on the skeleton [45,46]. The first demonstration of increased fracture risk was reported from ADOPT (A Diabetes Outcome Progression Trial), designed to compare time to monotherapy failure of rosiglitazone, metformin and glyburide in recently diagnosed T2DM patients [41]. The trial included 2511 men and 1840 women with an average age of 56 (SD 10) years. In a post hoc analysis of fracture rates, using adverse event reports to identify fractures, fracture incidence in men did not differ across treatment groups [30,41]. However, in women, fracture incidence with rosiglitazone was approximately doubled compared with the other two treatments. The hazard ratios for fractures in women were 1.81 (95% CI 1.17–2.80) and 2.13 (95% CI 1.30–3.51) for rosiglitazone compared with metformin and glyburide, respectively. Increased fracture rates were seen in the lower and upper limbs. Hip and vertebral fractures did not differ across treatment assignments, but only 4 hip and 3 vertebral fractures were reported in women. The other prescribed TZD, pioglitazone, is also associated with increased fracture risk in women, but not men. This finding was first reported by the manufacturer based on a meta-analysis of pioglitazone trials [47]. Two subsequent meta-analyses of randomized trials have supported these initial findings of increased fracture risk with rosiglitazone and pioglitazone use in women without evidence of elevated risk in men [48,49]. The more recent meta-analysis, based on 22 RCTs, reported that effects in women were similar for rosiglitazone (OR = 2.10; 95% CI 1.61–2.51) and pioglitazone (OR = 1.73; 95% CI 1.18–2.55) [49]. The TZD trials included few participants over 70 years old, the age range when hip fractures become more common. The numbers of hip fractures in the trials are not sufficient to assess them separately. Observational studies have reported increased risk of hip fracture with TZD use. A recent study using registry data in Scotland found increased hip

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fracture with greater cumulative TZD use among those with any use (OR per year of exposure 1.18; 95% CI 1.09–1.28) [38]. Results were similar for pioglitazone and rosiglitazone considered separately. In contrast to reports from randomized trials, increased hip fracture risk was found in men (OR per year of exposure 1.20; 95% CI 1.03–1.41) as well as in women (OR per year of exposure 1.18; 95% CI 1.07–1.29). Two large observational studies using data from the UK also reported that TZD use increased hip fracture [34,50]. Most [45,51–56], but not all [57,58], randomized trials testing the effects of TZD use on bone density have found more rapid bone loss under therapy. A recent meta-analysis of ten randomized clinical trials that assessed change in BMD reported greater bone loss at the lumbar spine, total hip and femoral neck in women randomized to TZD treatment compared with placebo or other antidiabetic medication [49]. Assessments of changes in bone turnover markers with TZD treatment in clinical trials have not been entirely consistent but suggest modest increase in resorption and possibly decrease in formation. In the largest study to date, 12-month changes in serum markers were assessed in 1605 participants in the ADOPT trial [31]. Among women, rosiglitazone use was associated with increases in the resorption marker C-terminal telopeptide (CTX) compared with glyburide (10.7% difference, p = 0.002) or metformin (7.3% difference, p = 0.029). In men, CTX was elevated in the rosiglitazone group compared with metformin (12.2%, p b 0.001) but not compared with glyburide. Women and men had modest reductions in the bone formation marker P1NP (women − 4.4%, men − 14.4%), but those in the metformin arm experienced greater reductions. For women, changes in P1NP did not differ between the rosiglitazone and glyburide groups while in men losses were greater in the rosiglitazone group. Smaller trials of rosiglitazone treatment have also reported relative increases in markers of bone resorption compared to placebo [57,59] and to metformin [55]. These results indicate that increases in bone resorption may explain at least in part the increased fracture rate in women on TZD therapy [31]. Some smaller trials have reported a relative reduction in bone formation markers with rosiglitazone treatment, compared with placebo [60] or with diet only treatment [53], and others have reported no difference [54]. For pioglitazone, the largest trial included 156 postmenopausal women with pre-diabetes and found no differences in bone turnover markers after 12 months compared with placebo [58]. In contrast, a trial in 71 diabetic men reported relative increases in markers of bone resorption (CTX) and formation (P1NP) in the pioglitazone group compared with metformin [61] while a trial in 86 diabetic men and women found a relative increase in a formation but not a resorption marker with pioglitazone treatment compared with placebo [56]. In summary, clinical studies have found that TZD use is associated with increased fracture risk in women and possibly in men. This increased risk appears to be a class effect of both rosiglitazone and pioglitazone. More rapid bone loss seems to be the underlying mechanism.

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compared with non-diabetic residents, in a Danish population [33]. In the Rochester MN population metformin use was associated with a lower rate of fracture compared with T2DM patients who were not using metformin (adjusted hazard ratio 0.7; 95% CI 0.6–0.96) [32]. On the other hand, several studies have reported no difference in fracture risk with metformin use [35–40]. A recent report on diabetes and hip fracture found that metformin tends to be prescribed to patients with a lower overall risk of fracture [38]. This prescribing pattern may account for some of the reduced fracture risk associated with metformin use in observational studies.

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The PPARγ ligand-binding domain contains a large binding pocket capable of encompassing a variety of ligands. This provides a wide array of potential contact points that can result in various PPARγ post-translational modifications (PTMs), including phosphorylation, acetylation and sumoylation, and differential recruitment of coactivators, which determine specific activities of this nuclear receptor [78]. The molecular studies provide evidence for distinct mechanisms regulating the proadipocytic, antiosteoblastic, and insulin sensitizing activities of PPARγ and include the levels of Serine 273 and Serine 112 phosphorylation and functional interaction with other proteins such as β-catenin and molecular chaperons FKBP51 and PP5 [79–82]. The concern of TZDs' adverse effects has prompted pharmaceutical efforts to develop selective PPARγ modulators which will retain high potency to treat diabetic disease with minimal adverse effects [83]. The PPARγ selective activators, with a decreased proadipocytic activity but intact insulin sensitizing activity such as netoglitazone, INT131, MSDC-0602 and telmisartan do not affect bone mass in mice treated with the therapeutic doses [84–87]. A new class of insulin sensitizers with structural similarities to telmisartan, which block Serine 273 phosphorylation but do not stimulate PPARγ transcriptional proadipocytic activity, has been recently developed [79,88], however their safety for bone is not as yet determined.

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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]. Within the ADOPT trial the cumulative incidence of fractures was comparable in glibenclamide and metformin users and significantly lower as compared to rosiglitazone users [30]; however, glibenclamide treatment decreased serum levels of bone formation markers (P1NP) in the ADOPT study [90,91]. Hypoglycemia is a frequent complication of sulfonylurea use, specifically in elderly patients treated with glibenclamide. In the UK Prospective Diabetes Study up to 18% of type 2 diabetics on sulfonylureas experienced hypoglycemia [92]. As hypoglycemia may lead to falls, occurrence of fall-related, osteoporotic fractures in elderly is assumed. A systematic review with the purpose to review the literature regarding the use of sulfonylurea and falls or fall-related fractures among older type 2 diabetics was recently published [93]. Lapane et al. conclude that data available from existing studies suffer methodological limitations, because these studies were not designed to evaluate the risk of sulfonylureas on fractures and falls in elderly adults. Hence, the risk of falls and fractures may be underestimated in users of sulfonylureas [93].

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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 cells in response to nutrient intake. Although GLP-1 and GLP-2 are synthesized and secreted together from enteroendocrine cells they exhibit different biological functions. GLP-1 receptors are highly expressed on islet β cells, but also widely in non-islet cells promoting metabolic effect in various organs including bone [94]. In contrast, the GLP-2 receptors are expressed within the gastrointestinal tract. The predominant role for GLP-2 is its promotion of growth and function of intestinal mucosa, including gut barrier function and cytoprotective functions in the small bowel [95,96]. Bioactivity of incretin hormones is limited by their rapid degradation and inactivation by dipeptidyl peptidase-4, a serine protease that is present in a soluble form in plasma and is expressed in most tissues [97]. This has led to the development of degradationresistant GLP-1 receptor agonists and DPP-4 inhibitors. As GLP-1 receptors are found in various tissues, their functional effects are multifactorial. Favorable metabolic effects of GLP-1 include enhancement of glucose-stimulated insulin secretion, inhibition of glucose-dependent glucagon secretion and control of appetite and body weight [98,99]. Bone cells, including osteoblasts and osteoclasts have been shown to express receptors for both GIP and GLP incretins. A number of studies indicate that GLP-2 acts mainly as an anti-resorptive [100], whereas GIP can act as an anti-resorptive and anabolic hormone [101,102]. Furthermore, GLP-1 receptor has been shown to be essential for control of bone resorption as mice deficient in GLP-1 receptor present with cortical porosity as a result of increased osteoclastic bone resorption activity. In contrast to direct inhibitory effects of GIP and GLP-2 on bone resorption, the effect of GLP-1 is indirect through a calcitonindependent pathway [103].

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factor for energy utilization by the osteoclast [67]. PPARγ1 is also expressed in osteoblasts and negatively regulates their differentiation through suppression of mTOR signaling [68]. An essential role of PPARγ in maintenance of bone homeostasis was demonstrated in several animal models of either bone accrual or bone loss depending on the status of PPARγ activity [69–74]. In models of bone accrual, a decrease in PPARγ activity in either heterozygous PPARγ-deficient mice or mice carrying a hypomorphic mutation in the PPARγ gene locus or mice with targeted PPARγ deletion in either mesenchymal cells or osteoblasts led to increased bone mass due to increased quantity of osteoblasts [68,72,74,75]. Interestingly, mice deficient in PPARγ expression in cells of hematopoietic lineage develop osteopetrosis and are less sensitive to the TZD-induced bone loss than control mice [66]. In contrast, PPARγ activation with full agonist rosiglitazone resulted in significant decreases in BMD, bone volume and changes in bone microarchitecture [65,69–71,73]. Observed bone loss was associated with changes in the structure and function of bone marrow, which included decreased number of osteoblasts, and increased number of osteoclasts and adipocytes. The degree of bone loss in response to rosiglitazone correlated with the animal age and the level of PPARγ expression. In younger animals with less PPARγ, bone loss was less extensive than in older animals [65]. Moreover, age determined the mechanism by which bone loss occurred. In younger animals it occurred due to decreased bone formation, whereas in older animals due to increased bone resorption [65]. Interestingly, estrogen deficiency predisposes to the rosiglitazone-induced bone loss due to increased bone resorption [70]. In conclusion, animal studies suggest that aging and estrogen deficiency confound TZD-induced bone loss and determine its mechanism. The negative effect of TZDs on osteoblastogenesis includes decreased activity of Runx2, Dlx5, and Osterix, which are osteoblastspecific transcription factors, and decreased activity of osteoblastspecific signaling pathways controlling bone homeostasis, among them Wnt, TGF-β/BMP and IGF-1 [64,76]. The effect of TZDs on the expression of genes essential for osteoblast development is strikingly similar to changes observed during aging. Due to the type of bone loss and similarities to aging, some speculate that TZDs may accelerate the aging of bone [65,77].

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Exendin-4 is a peptide analogue of GLP-1 and has similar properties to GLP-1. It is resistant to degradation by DPP-4 and is characterized by a high in vivo potency and a prolonged duration of action due to its longer plasma half-life compared to GLP-1 [107]. While exenatide shares about 53% of its amino acid sequence with human naive GLP-1, the long-acting human GLP-1 analog liraglutide is characterized by a much higher homology with human naive GLP-1 (97% homogeneity) (33, 34). Ma et al. evaluated the effects of exendin-4 on ovariectomy-induced osteoporosis in old rats. Sixteen weeks of treatment with exendin-4 enhanced bone strength and prevented the deterioration of trabecular microarchitecture. Gene expression results showed that exendin-4 not only inhibited bone resorption by increasing OPG/RANKL ratio, but also promoted bone formation by increasing the expression of osteoblast-specific transcription factors [108]. Preclinical data are documenting that GLP-1 receptor is present on MLO-Y4 cells and osteocytes of rat femurs further supporting the osteoanabolic effect of GLP-1. Exendin-4 reduced the mRNA expression and protein production of SOST/sclerostin in MLO-Y4 cells and reduced serum levels of sclerostin in type 2 diabetic OLEF rats [109]. Clinical data on the safety of incretins on human bone are limited. In contrast to the above mentioned preclinical studies in rats a 44-week treatment with exendin-4 (exenatide) in patients with type 2 diabetes did not have an effect on serum levels of bone turnover markers and did not result in a significant change in BMD although exendin-4 decreased body weight by 6% [110]. Recently, two meta-analyses investigated the association between use of GLP-1 receptor agonists and fracture incidence [111,112]. Mabilleau et al. identified seven randomized clinical trials investigating the effect of GLP-1 agonists on glycemic control in which the occurrence of a fracture was disclosed as a serious adverse event. The use of GLP-1 receptor agonists (exenatide, liraglutide) did not modify the risk of fracture in type 2 diabetics as compared to

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Dipeptidyl peptidase-4 (DPP-4) degrades incretin hormones to inactive metabolites. As the pharmacological effect of DPP-4 inhibitors is to prolong the action of GLP-1, their effect on bone is assumed to be similar to that of GLP-1. A recent preclinical study evaluated the effect of DPP-4 inhibitor sitagliptin on bone in normal and streptozotocin-induced diabetic rats. As shown by in vivo μCT trabecular bone loss, the decrease in trabecular number and the increase in trabecular spacing were attenuated through sitagliptin treatment in diabetic rats most likely through the reduction of bone resorption. Furthermore sitagliptin prevented cortical bone growth stagnation in diabetic rats resulting in stronger femora. All these effects were independent of glycemic control [114]. Human studies investigating the effect of DPP-4 inhibitors on bone are scarce. A neutral role of vildagliptin was demonstrated in drug naive type 2 diabetics. Postprandial circulating levels of bone resorption markers and calcium homeostasis were unaffected as compared with baseline and placebo [115]. Recently, two studies were published investigating the association between use of DPP-4 inhibitors and fracture risk [116,117]. A meta-analysis by Monami et al. of 28 clinical trials enrolling over 21,000 type 2 diabetics showed that treatment with DPP-4 inhibitors was associated with a reduced fracture risk (OR 0.60, 95% CI 0.37–0.99) compared with placebo or other antidiabetic treatments [116]. A retrospective population based cohort study using data from the Clinical Practice Research Datalink (CPRD) database, however, observed no different risk of fracture comparing current users of DPP-4 inhibitors to non-diabetic controls. In addition, fracture risk was not elevated in type 2 diabetics after adjusting for the use of other antidiabetic drugs (metformin, sulfonylurea, TZDs, and insulin) [117]. Differences between these two studies can be explained by several factors [118]. First, in the meta-analysis fractures were not routinely collected but were defined as severe side-effects in enrolled randomized trials whereas in the retrospective studies fractures were identified with high accuracy. Secondly, duration of follow-up was different with short follow-up time in the meta-analysis (mean duration, 35 weeks) and longer duration in the cohort study (median duration, 5 years). As pointed out by Driessen et al. [117], the results of their study are in keeping with a large randomized placebo-controlled study comparing cardiovascular outcomes of saxagliptin [119]. This study, not included in the meta-analysis by Monami et al. [116], showed no significant difference in the number of fractures between saxagliptin and placebo treated diabetics. In summary, incretin-based therapies seem to have an anabolic effect on bone, attenuating bone loss and potentially reducing fracture risk in type 2 diabetics. However, currently available data are not conclusive and further studies are needed to prove a potential

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placebo or the use of other antidiabetic medications (glimepiride, sitagliptin, and insulin) [111]. The second meta-analysis by Su et al. included 16 published or unpublished RCTs of variable duration (12 to 104 weeks) comparing the effects of exenatide or liraglutide with comparators. Separate pooled analysis was performed for exenatide and liraglutide, respectively. This meta-analysis demonstrated a divergent risk of bone fractures associated with different GLP-1 receptor agonists with exenatide increasing the risk of fractures (OR 2.09, 95% CI 1.03– 4.21) and liraglutide reducing the risk of non-vertebral fractures (OR 0.38, 95% CI 0.17–0.87), respectively (Table 1) [112]. Both studies, however, are preliminary and further studies are needed to clarify potential beneficial or detrimental effects of GLP-1 receptor agonist on fracture risk. Several methodological aspects limit the generalization of these results: both studies included randomized trials which were not designed for assessment of fracture risk and included only small numbers of fractures [113]. Furthermore, studies included in the meta-analyses were of short duration and therefore not long enough to study the treatment-effects on bone fractures.

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Incretins play an important role in the regulation of bone turnover in response to feeding. Nutritional intake modulates bone turnover in favor of bone formation and, in contrast, fasting blunts the diurnal variation as documented by an increase of bone resorption markers. From a physiological point of view these responses are likely to have evolved to maximize skeletal strength when nutrition is abundant and to control and maintain calcium homeostasis in fasting conditions [104]. Evidence that incretins play a regulatory role in bone turnover was provided by Henriksen et al. After subcutaneous administration of GLP-2 in postmenopausal women a dose-related reduction in serum CTX levels and an increase in serum osteocalcin levels suggest a stimulatory effect of GLP-2 on bone formation [105]. In subsequent studies, nocturnal bone resorption decreased after daily administration of GLP-2 at bedtime, an effect that persisted for 2 weeks [100] and for 4 months [106]. In this double-blind placebocontrolled study 160 postmenopausal women were randomized to receive daily doses of 0.4, 1.6, and 3.2 mg of GLP-2 or placebo for 120 days. GLP-2 treatment resulted in a sustained decrease in bone resorption (in the presence of unaffected bone formation) and, most importantly, resulted in a dose-dependent increase in hip BMD for women randomized to the higher doses of daily GLP-2 [106]. These experimental studies indicate that incretins have a beneficial effect on bone mass and protective effects on bone quality. Therefore, it is conceivable that antidiabetic therapies which increase GIP and GLP hormone levels either as GLP-1 receptor agonists or inhibitors of DPP-4 might exert beneficial effects on bone [91]. From a clinical perspective incretin-based therapies seem to be an ideal treatment alternative in diabetics with high risk of falls and fractures due to their bone sparing potential, and most importantly, due to their low risk of hypoglycemia.

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Recently, a new class of glucose-lowering agents, the sodiumglucose 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 levels to a similar extent as most oral antidiabetic drugs. Treatment with SGLT2-inhibitors (canagliflozin, dapagliflozin) is associated with modest weight loss and a decrease in blood pressure; however, genital mycotic infections and volume depletion resulting from its diuretic effect are reported side-effects [25]. Due to their mechanism of action SGLT2-inhibitors may alter calcium and phosphate homeostasis and potentially affect bone mass and fracture risk. Preliminary clinical data have shown no changes in serum calcium or 25OH-vitamin D levels, but indicate that serum phosphate, magnesium and PTH levels are increased during dapagliflozin treatment as compared to placebo [122,123]. To further elucidate the role of SGLT2-inhibitors on bone metabolism, Ljunggren et al. performed a double-blind, placebo-controlled study in adults with type 2 diabetes whose glycemia was inadequately controlled with metformin [124]. The study confirmed small increases in serum phosphate and magnesium levels from baseline, but found no changes in serum calcium or 25OH-vitamin D and PTH levels. In addition and compared with placebo, no significant changes in bone turnover markers (P1NP, CTX) and BMD were observed during the course of 50 weeks of dapagliflozin treatment [124]. These data, however, are in contrast with recently published skeletal safety data with increased fracture incidence associated with the use of dapagliflozin [125] and canagliflozin [126]. In a double-blind, placebocontrolled study in which the long-term effects of dapagliflozin on glycemic control in 252 patients with inadequately controlled type 2 diabetes and moderate renal impairment were evaluated, only patients in the dapagliflozin groups experienced a low-trauma fracture (n = 13, 7.7%, follow-up 104 weeks). Seven of 13 patients who sustained fracture had a history of diabetic neuropathy or exhibited orthostatic hypotension [125]. An increase in fractures by about 30% was observed in patients receiving canagliflozin in a pooled analysis of eight clinical trials (mean duration 68 weeks) [126]. Potential mechanisms of a detrimental effect of SGLT2 inhibitors on bone metabolism have recently brought forward by Taylor et al. [127]. By blocking the sodium-glucose co-transporter 2 in the proximal tubule epithelial cell SGLT2 inhibitors may reduce sodium transport which increases the availability of sodium to drive cotransport of phosphate and sodium. Increased serum phosphate is likely to provoke secretion of PTH by parathyroid glands thereby enhancing bone resorption. Furthermore, serum PTH increases the secretion of FGF23 by osteocytes which has been associated with bone disease [128]. The exact mechanisms for increased magnesium levels in patients on SGLT2-inhibitors remain unclear. Consistent with the above mentioned hypothesis, data from the FDA report on canagliflozin indicate that canagliflozin increases bone turnover as suggested by increased levels of biochemical markers of bone resorption and formation [126]. In addition, a decrease in BMD, both at the lumbar spine and the hip was detected after 52 weeks of therapy with canagliflozin [126,127]. As these data are preliminary, further studies are needed to elucidate the effect of SGLT2 inhibitors on bone metabolism and, specifically, to clarify whether such a detrimental effect follows a drug class-effect or whether it is compound-specific.

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