ME TAB O L IS M CL I N ICA L A N D EX PE R IM EN T AL 6 3 ( 2 0 14 ) 14 8 0 –14 9 0

Available online at www.sciencedirect.com

Metabolism www.metabolismjournal.com

Type 2 diabetes mellitus and fracture risk Anastasia D. Dede a,⁎, Symeon Tournis b , Ismene Dontas b , George Trovas b a b

Department of Endocrinology and Metabolism, Hippokrateion General Hospital, Vas. Sofias 114, 11527 Athens, Greece Laboratory for Research of Musculoskeletal System “Theodoros Garofalidis”, University of Athens, KAT Hospital, Athens, Greece

A R T I C LE I N FO

AB S T R A C T

Article history:

Increased fracture risk, traditionally associated with type 1 diabetes, has lately been of great

Received 28 June 2014

concern in patients with type 2 diabetes. A variable increase in fracture risk has been

Accepted 19 September 2014

reported, ranging from 20% to 3-fold, depending on skeletal site, diabetes duration and study design. Longer disease duration, the presence of diabetic complications, inadequate

Keywords:

glycemic control, insulin use and increased risk for falls are all reported to increase fracture

Diabetes

risk. Patients with type 2 diabetes display a unique skeletal phenotype with either normal

Bone fragility

or more frequently increased, bone mineral density and impaired structural and geometric

Fracture healing

properties. Recently, alterations in bone material properties seem to be the predominant

Advanced glycation end-products

defect leading to increased bone fragility. Accumulation of advanced glycation end-

Collagen cross-linking

products and changes in collagen cross-linking along with suppression of bone turnover seem to be significant factors impairing bone strength. FRAX score has been reported to underestimate fracture risk and lumbar spine BMD is inadequate in predicting vertebral fractures. Anti-diabetic medications, apart from thiazolidinediones, appear to be safe for the skeleton, although more data are needed. Optimal strategies to reduce skeletal fragility in type 2 diabetic patients are yet to be determined. © 2014 Elsevier Inc. All rights reserved.

1.

Introduction

Diabetes mellitus constitutes a modern epidemic affecting 382 million individuals worldwide [1]. Its prevalence is steadily rising, especially at younger age groups, and type 2 diabetes mellitus (T2DM) accounts for most of the observed increase [2]. T2DM is characterized by high morbidity and mortality rates due to a series of microvascular and macrovascular complications. Longer disease duration and inadequate glycemic control both contribute to the development of diabetic complications, namely diabetic nephropathy, retinopathy, neuropathy and cardiovascular disease.

Recent evidence suggests that the skeleton might be another casualty in the course of T2DM. We performed a literature search in PubMed database using the term “diabetes” in conjunction with the following keywords in variable combinations: “bone”, “fractures”, “osteoporosis”, “fracture healing”, “falls” and the term “bone” in conjunction with each of the following keywords: “advanced glycation end-products”, “metformin”, “sulphonylureas”, “thiazolidinediones”, “GLP-1 analogues”, “DPP-4 inhibitors”, “insulin”, “pramlintide”, “SGLT-2 inhibitors”. We limited our search only to English language articles and to the past 20 years. Occasionally, articles’ references were also

Abbreviations: T2DM, Type 2 Diabetes Mellitus; HbA1c, Glycated Hemoglobin; BMD, Bone Mineral Density; BMI, Body Mass Index; pQCT, peripheral Quantitative Computed Tomography; DXA, Dual-Energy X-ray Absorptiometry; TBS, Trabecular Bone Score; BMS, Bone Material Strength; AGE, Advanced Glycation End-product; MSC, Mesenchymal Stem Cell; TZD, Thiazolidinedione; PPARγ, Peroxisome Proliferator-Activated Receptor gamma; GLP-1, Glucagon-Like Peptide-1; DPP-4, Dipeptidyl Peptidase-4; SGLT2, Sodium-Glucose Cotransporter-2; RANKL, Receptor Activator of Nuclear Factor κB Ligand; GLP-2, Glucagon-Like Peptide-2; GIP, Gastric Inhibitory Polypeptide; P1NP, Amino-Terminal Propeptide of Type 1 Collagen; CTX, Carboxy-Terminal Collagen Cross-links. ⁎ Corresponding author at: Vas. Sofias 114, 11527 Athens, Greece. Tel.: +30 2132088369. E-mail address: [email protected] (A.D. Dede). http://dx.doi.org/10.1016/j.metabol.2014.09.002 0026-0495/© 2014 Elsevier Inc. All rights reserved.

ME TAB O L IS M CL I N ICA L A N D EX P ER IM EN T AL 6 3 ( 2 0 14 ) 14 8 0 –1 49 0

evaluated when considered relevant. About 12,200 titles, excluding case reports and reviews, were retrieved and about 800 were considered relevant and screened. Approximately 200 articles were finally reviewed in an attempt to examine the association between T2DM and fracture risk, to suggest possible risk factors, indicate relevant pathogenetic mechanisms and illustrate issues regarding prevention and treatment of increased bone fragility in patients with T2DM.

2.

Increased fracture risk

Type 1 diabetes has long been a well recognized risk factor for hip fractures [3]. More recently, an increase in fracture risk in patients with type 2 diabetes has been observed [3–8], at least in most studies. In the Women’s Health Initiative (WHI) study, postmenopausal women suffering from diabetes exhibited a 20% increase in fracture risk for all types of fractures. When each skeletal site was evaluated separately, the increase was prevalent in every skeletal site, except from the distal upper extremities [4]. Elevated overall fracture risk has been demonstrated in diabetic men in the Rotterdam study, although not at the wrist [5]. Janghorbani et al, in a metaanalysis of case-control and cohort studies confirmed a 1.7 relative risk for hip fracture in both men and women suffering from T2DM [8]. Vertebral fractures are quite difficult to evaluate in large observational studies; nevertheless, increase in vertebral fracture risk in type 2 diabetic patients has been reported, both for clinical vertebral fractures [4] and for morphometric deformities [9]. Given that T2DM often goes undiagnosed for many years, it is postulated that fracture risk, at least in some of these studies, may be attenuated due to ascertainment bias, since the diabetic state was demonstrated either from medical records or by self report. Thus, the true relative risk might be even higher. On the other hand, in large case-control studies, where data are collected though medical records, it is impossible to correct for all confounding factors affecting fracture risk. However, even though it is currently difficult to estimate its true magnitude, the elevated fracture risk seems to be a rather constant finding among studies.

3. Risk factors for fracture in diabetic patients (Table 1) Duration of diabetes seems to be an important risk factor for fractures. In the Nurses’ health study [3], duration longer than 11 years conveyed a relative risk for hip fracture of 3.1, comparing to disease duration shorter than 11 or 5 years, which conveyed a relative risk of 1.8 and 1.7 respectively. Melton et al demonstrated that although overall fracture risk was increased in diabetic patients, the incidence of hip fractures was elevated only 10 years after the diagnosis [6]. Other studies have likewise demonstrated an association between longer duration of diabetes and fracture risk [10]. Of note, some studies (although including both T1DM and T2DM) have demonstrated a biphasic pattern in the association between diabetes duration and fracture risk, with similar or

1481

even lower risk in newly diagnosed diabetic patients and increased risk with prolonged diabetes duration [11]. The lower risk in older newly diagnosed patients could be attributed to the increased weight usually observed in diabetic patients. It is quite clear that the negative effects of diabetes on skeletal fragility are time dependent. Nevertheless, it would be extremely difficult to estimate the latency period required to affect bone strength, since T2DM remains undiagnosed for many years and newly diagnosed patients in several studies do not necessarily represent recent onset diabetes, while all controls may not be truly non-diabetic. A correlation between fracture risk and insulin use has also been observed in some [3,6], albeit not all, studies [7]. Insulin is anabolic to bone and is unlikely to exert negative effects on skeletal health; however, insulin use is associated with increased risk for hypoglycemia that could induce falling and, also reflects a more advanced stage and longer duration of diabetes, both associated with the presence of complications. Increased risk of falls has been reported in older diabetic women [12,13]. Specifically, there is a higher number of falls per person among women with diabetes, compared with women without diabetes [12]. Furthermore, diabetes has been associated with an elevated risk for falls that result in serious injuries leading to hospitalization or death [14]. Patients using insulin display further increase in the risk for falls, either due to hypoglycemia or to the presence of diabetic complications [12]. There is evidence that hypoglycemic events are associated with increased risk for fall-related fractures, even after adjustments for confounding factors, such as the presence of microvascular complications, which are more prevalent among patients who exhibit more hypoglycemic events [15]. Complications associated with diabetes, such as peripheral neuropathy, orthostatic hypotension, vision impairment and cardiovascular disease could all in theory predispose to falling. The presence of peripheral neuropathy has been shown to increase the risk for falls in diabetic patients [12]. Complicated diabetes is associated with increased fracture risk. Ivers et al demonstrated an association between the presence of diabetic retinopathy and the risk for fractures, however, no other diabetic complications were evaluated [10]. The increase in fracture risk in the presence of diabetic complications has also been confirmed by Vestergaard et al [16]. An association between glycemic control and fracture risk has been difficult to demonstrate since glycated hemoglobin (HbA1c) levels are not constant, and in most epidemiological studies data concerning glycemic control are either unavailable, or lie solely on baseline HbA1c measurements. Nevertheless, in the Rotterdam study Oei et al [17] have demonstrated an association of fracture risk and baseline HbA1c levels above 7.5%, while they observed no elevation in fracture risk in patients with baseline HbA1c levels below 7.5%, indicating that inadequate glycemic control might be a risk factor for fractures. On the contrary, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, where longitudinal data concerning HbA1c levels were available, there was no difference in fracture risk between patients on conventional treatment and those on intensive glycemic control [18]. Notably, both patient groups had similar HbA1c at the beginning of the study and relatively good glycemic control during the study, since in both groups mean HbA1c values were below 7.5%. On the other hand, impaired glucose

1482

ME TAB O L IS M CL I N ICA L A N D EX PE R IM EN T AL 6 3 ( 2 0 14 ) 14 8 0 –14 9 0

Table 1 – Summary of studies evaluating risk factors for fracture in T2DM (T2DM: type 2 diabetes mellitus, M: male, F: female). Author/year

Study design

Gender N

Parameter

Result

Janghorbani M et al, 2006 Melton LJ 3rd et al, 2008 Ivers RQ et al, 2001 Leslie WD et al, 2007

Prospective observational cohort study Retrospective cohort study

F

8348 patients with T2DM/101,343 controls 1964 patients with T2DM

T2DM duration

Prospective observational cohort study Retrospective case-control study

M+F

216 patients with T2DM/3459 controls 82,094 patients with DM/236,682 controls

T2DM duration

Vestergaard P et al, 2009

Retrospective case-control study

M+F

124,655 fracture cases/373,962 controls

Complicated diabetes

Ivers RQ et al, 2001 Janghorbani M et al, 2006 Melton LJ 3rd et al, 2008 Vestergaard P et al, 2005 Oei et al, 2013

Prospective observational cohort study Prospective observational cohort study Retrospective cohort study

M+F

Complicated diabetes Insulin use

Retrospective case-control study Prospective observational cohort study

M+F

216 patients with T2DM/3459 controls 8348 patients with T2DM/101,343 controls 1964 patients with T2DM 124,655 fracture cases/373,962 controls 420 patients with T2DM

Schwartz AV et al, 2012

Prospective randomized parallel treatment trial

M+F

7287 patients with T2DM

Glycemic control

Longer T2DM duration increases hip fracture risk Increased hip fracture risk 10 years after diagnosis Longer T2DM duration increases overall fracture risk Biphasic pattern: longer DM duration increases overall fracture risk. Newly diagnosed DM is associated with decreased fracture risk The presence of diabetic complications is associated with increased overall fracture risk Diabetic retinopathy is associated with increased overall fracture risk History of insulin use is associated with increased risk for hip fracture Insulin use is associated with increased overall fracture risk Insulin use is not associated with increased overall fracture risk Patients with HbA1c ≥ 7.5% had increased overall fracture risk comparing to those with HbA1c < 7.5% No difference in fracture rates among patients on standard versus intensive glycemic control

M+F

M+F

F M+F

M+F

tolerance has not been associated with elevated fracture risk [19]. It is currently unknown whether there is a threshold in HbA1c levels below which there is no diabetes-associated increase in fracture risk to be used as a “target HbA1c” when treating diabetic patients, or whether intensive glycemic control during the early stages of diabetes may be protective at later stages, as observed for other diabetic complications (the so-called “metabolic memory” phenomenon). Vitamin D deficiency is a common finding among patients with T2DM. Zoppini et al demonstrated that circulating vitamin D (25OHD) levels in diabetic patients are inversely correlated with HbA1c levels, even after controlling for confounding factors, such as BMI and diabetes duration [20]. Moreover, a correlation between low vitamin D levels, namely below 20 ng/ml, and the risk for vertebral fractures in diabetic men, but not women, has been demonstrated [21].

4.

Pathogenesis of increased fragility in T2DM

4.1.

Bone mineral density

Most studies indicate that patients with T2DM exhibit higher lumbar spine and hip, but not forearm, bone mineral density (BMD) as compared with healthy, age-matched controls [22]. It is postulated that the increased BMD is related to the higher body mass index (BMI) observed in obese diabetic patients, however, correction for BMI does not completely eliminate the association [22]. Data on age-related bone loss in T2DM are conflicting with studies reporting lower rate [23], while in

T2DM duration

DM duration

Insulin use Insulin use Glycemic control

older white diabetic women, despite higher baseline BMD, accelerated hip bone loss has also been reported [24]. However, accelerated bone loss was accompanied by weight loss during follow-up, which might explain the reduction in hip BMD. Notably, weight loss associated with intensive lifestyle intervention in obese diabetic individuals results in more significant hip bone loss than standard diabetes support and education, at least in male subjects [25]. Bone loss is, as expected, correlated with the magnitude of weight loss in both men and women and is not prevented by increased physical activity. Accelerated bone loss and decreased BMD has been, however, described in poorly controlled T2DM, yet, only in conjunction with glycosuria, hypercalciuria and secondary hyperparathyroidism [26]. Paradoxically, a positive correlation between BMD and HbA1c, even after controlling for body weight, has been reported in some studies [17,22], indicating that elevated bone mass could be a consequence of poor glycemic control.

4.2.

Bone turnover

Most studies report lower levels of biochemical markers of bone turnover in patients with T2DM, as compared with nondiabetic controls [27,28], and an inverse correlation with the duration of T2DM [29]. The low bone turnover state has been confirmed by histomorphometry, showing reduced bone formation derived mainly from lower matrix apposition, rather than abnormal mineralization, coupled with low osteoclast activity [23].

1483

ME TAB O L IS M CL I N ICA L A N D EX P ER IM EN T AL 6 3 ( 2 0 14 ) 14 8 0 –1 49 0

Table 2 – Mineral density, structure and material properties of bones in T2DM. DXA

↑ or ↔ BMD, ↓ trabecular bone score ↓ composite strength indices

pQCT Trabecular sites

Cortical sites

↓total bone area, ↑ trabecular density

↓total bone area, ↔ cortical density

Sclerostin is a potent inhibitor of bone formation by inhibiting Wnt/β-catenin signaling. Sclerostin levels are elevated in patients with T2DM, and correlate positively with diabetes duration, HbA1c and paradoxically BMD [30]. Furthermore, increased sclerostin levels have been associated with the presence of vertebral fractures in diabetic patients [31]. The suppression of osteoblastic activity is of particular concern in T2DM and different mechanisms have been implicated as will be discussed later. Animal models are often used to study the pathophysiology of bone fragility and the effects of various interventions on bone. However, there are no ideal animal models to study the effects of type 2 diabetes on bone physiology, since most T2DM models display a skeletal phenotype that is considerably different from that encountered in humans; specifically, most T2DM animal models are characterized by reduced BMD and increased bone turnover [32]. Data from T2DM animal models should thus be interpreted with caution.

4.3. Structure, microarchitecture and material properties (Table 2) Alterations in bone geometry as well as defects in microarchitecture can both result in increased bone fragility, irrespective of BMD. Petit et al, using peripheral Quantitative Computed Tomography (pQCT), in male diabetic patients from the Osteoporotic Fractures in Men Study [33] demonstrated that men with T2DM displayed smaller total bone area at the weight bearing tibia, but only after adjusting for body weight. However, higher trabecular density at the distal tibia compensated for the reduced bone area, leading to similar compressive bone strength between diabetic patients and controls. On the contrary, at cortical sites, cortical density was similar between patients and controls, and thus, smaller bone area resulted in decrease in bending strength in diabetic patients. Of note, diabetic patients had larger muscle cross sectional area. Evaluation of bone structure with high resolution pQCT in postmenopausal women with T2DM demonstrated no significant differences in bone microarchitecture between patients and controls. However, after adjusting for multiple factors, including BMI, patients exhibited lower cortical area at the weight bearing tibia [27]. As expected, diabetic patients have increased muscle mass, correlating with their increased body weight. However, muscle quality is impaired in diabetic patients and correlates negatively with diabetes duration and poor glycemic control [34]. Taken together, these data suggest that diabetic patients may exhibit an impaired skeletal response to mechanical loading which might be attributed to muscle function defects.

HRpQCT

Microindentation

↓ cortical area, ↑ cortical porosity, ↔ trabecular microarchitecture

↓ bone material strength

An increase in cortical porosity has been observed in type 2 diabetic patients probably contributing to fracture risk [35]. This finding is particularly evident in diabetic patients who have already sustained a fragility fracture [36]. On the other hand, Ishii et al, using hip dual-energy X-ray absorptiometry (DXA) scans, demonstrated that diabetic women have lower values of composite strength indices than non-diabetic women, relative to their increased body weight, and that there is a negative correlation between strength parameters and insulin resistance [37]. Interestingly, Garg et al suggested that bone strength, as calculated by hip geometry indices, is lower in diabetic patients who use insulin, implying that longer disease duration and severity of T2DM are associated with weaker bones [38]. Trabecular bone score (TBS) is an indirect index of microarchitecture derived from DXA scans with low values being associated with increased fracture risk [39]. Patients with T2DM display lower TBS as compared with matched controls and in these patients TBS is a good predictor of fracture risk [40]. Of note, poor glycemic control (HbA1c > 7.5%) is associated with lower TBS [41]. It is rather unlikely that the alterations mentioned above may entirely explain the increased fracture risk in type 2 diabetic patients. These findings indicate that the material properties of bone, which are quite difficult to assess with current diagnostic modalities, might be the culprit leading to impaired bone strength in these patients. Microindentation constitutes a relatively new minimally invasive technique for assessing bone quality in vivo. A probe is inserted in the tibia after displacing the periosteum and bone strength, as well as susceptibility to micro-fractures, is directly measured [42]. Patients who have sustained osteoporotic fractures display higher indentation distance (ID) and indentation distance increase (IDI), both indicative of impaired bone strength, as compared with age-matched controls. Moreover, in cadaveric human bone samples indentation distance increase (IDI) exhibited inverse correlation with crack growth toughness [19]. Farr et al evaluated bone material strength (BMS) in vivo using microindentation in postmenopausal women with T2DM [28]. BMS was significantly lower in diabetic patients compared with age-matched controls. Of note, no correlation between BMS and duration of T2DM could be demonstrated, however, disease duration was longer than 10 years in all participating subjects. On the contrary, there was a negative correlation between BMS and the average HbA1c levels over the previous 10 years, indicating that long term poor glycemic control impairs bone strength. Pritchard et al [43], using human femoral neck trabecular bone specimens from T2DM patients and matched controls, demonstrated that patients with T2DM display higher

1484

ME TAB O L IS M CL I N ICA L A N D EX PE R IM EN T AL 6 3 ( 2 0 14 ) 14 8 0 –14 9 0

Table 3 – Pathophysiological mechanisms involved in increased fragility in T2DM (MSCs: mesenchymal stem cells, AGEs: advanced glycation end-products, TZDs: thiazolidinediones). Pathogenetic mechanism

Responsible alteration or agent

↓ differentiation of MSCs toward cells of osteoblastic lineage

• ↑ AGEs • ↑ glucose • Oxidative

↑ differentiation of MSCs toward adipocytes ↑ osteoblasts’ apoptosis ↓ ↓ ↑ ↓

osteoblasts’ action osteoblastic cells’ growth collagen stiffness collagen ductility

• • • • • • • •

stress TZDs ↑ glucose TZDs ↑ AGEs TZDs ↑ AGEs ↑ glucose ↑ AGEs

Result

↓ bone formation

↑ bone brittleness

calcium concentrations, indicative of increased mineralization, as compared with controls. Furthermore, mineralization in patients with T2DM appeared to be less heterogeneous. These findings might be attributed to the suppressed bone turnover in the diabetic state and might be associated with increased brittleness and reduced ductility, predisposing to mechanical failure. Advanced glycation end-products (AGEs) are non-enzymatic chemical modifications of proteins by aldose sugars, formed by the oxidation of products generated during the Maillard reaction. The accumulation of AGEs has been associated with diabetic complications as well as other degenerative diseases. Type I collagen is the major protein component in bone. Enzymatic cross-linking between collagen molecules is essential to the preservation of bone mechanical strength and is tightly regulated. In the presence of non-enzymatic glycation, formation of AGEs cross-linking occurs. In experimental studies, it has been demonstrated that the accumulation of AGEs in cortical and trabecular bone can increase the stiffness of the collagen network and reduce its ductility [44,45]. These alterations in biomechanical properties of the bone tissue can lead to modifications in microdamage formation and, thus, to increased fragility [46]. There is enough evidence that apart from their effects on collagen properties, AGEs can also affect the function of bone cells (Table 3). In vitro studies have demonstrated that AGEs can attenuate the differentiation of cells of the osteoblastic lineage [47] and that incubation of osteoblasts with AGEs can inhibit the expression of alkaline phosphatase and col IA1 gene and decrease mineralization [48]. Moreover, there is evidence that AGEs may induce osteoblasts' apoptosis [49], further impairing bone formation. On the other hand, AGEs have been shown to reduce osteoclastogenesis and osteoclastic activity [50], although increased bone resorption has been reported as well [51].

Apart from the indirect effects of high glucose on osteoblastic differentiation and activity through the formation of AGEs, glucose can also exert direct effects as evidenced by in vitro studies. High glucose is associated with a shift of the differentiation of mesenchymal stem cells (MSCs) toward adipocytes, rather than toward osteoblasts [52] and exposure of osteoblast-like cells to elevated glucose levels results in diminished cell growth [53]. Oxidative stress, a major mediator in the development of diabetic complications, has been associated with inhibition of mineralization [54] and of differentiation of osteoblastic cells [54], whereas, in animal models, oxidative stress in bone tissue, as assessed by immunohistochemical studies, is negatively correlated with bone formation indices [55]. Pentosidine is a well characterized non-enzymatic crosslink that accumulates in bone with aging and whose plasma levels are correlated in a linear manner to its concentration in cortical bone [56]. Pentosidine concentrations are negatively associated with compressive biomechanical properties of human lumbar vertebrae [57]. A reduction in enzymatic cross-linking and higher pentosidine content has been described in the femoral neck cancellous bone of patients who have sustained a hip fracture, comparing to controls [58]. It is suggested that increased urinary pentosidine levels might be a risk factor for the development of vertebral and long bones fractures in postmenopausal women [59]. Serum pentosidine levels have been associated with the presence of vertebral fractures in patients with T2DM, irrespective of BMD [60]. Moreover, while in diabetic patients urine pentosidine levels have been correlated with the presence of clinical fractures and prevalent vertebral fractures, a similar association was not observed in non-diabetic subjects. Interestingly, however, urine pentosidine levels were similar in previously and newly diagnosed patients with T2DM, patients with impaired glucose tolerance and normoglycemic subjects and did not correlate with HbA1c levels [61]. Plasma and urine pentosidine levels are dependent on bone turnover rate and renal function and might not accurately reflect its concentration on the skeleton, even though a good correlation between plasma levels and concentrations in cortical bone has been documented [56]. Thus, association studies examining circulating or urine levels of pentosidine levels in correlation with bone health in diabetic patients should be interpreted with caution.

5.

Effects of anti-diabetic agents on bone

The effect of anti-diabetic medications on skeletal health has lately received great interest. More data concern the use of thiazolidinediones (TZDs), an insulin sensitizing class of drugs that are peroxisome proliferator-activated receptor gamma (PPARγ) agonists. Activation of PPARγ results in stimulation of adipocyte differentiation and in inhibition of osteoblastogenesis [62]. Furthermore, TZDs induce osteoblast and osteocyte apoptosis [63,64] and upregulate the expression of sclerostin [63], a potent inhibitor of osteoblastogenesis. TZDs use has been associated with BMD reductions at both

ME TAB O L IS M CL I N ICA L A N D EX P ER IM EN T AL 6 3 ( 2 0 14 ) 14 8 0 –1 49 0

the lumbar spine and the hip, mainly in postmenopausal women [65], although there are reports for a similar effect in premenopausal women [66] and men [67]. There is increasing evidence that the use of TZDs increases the risk for any fracture in postmenopausal women, while no definite effect could be demonstrated in men [68,69]. It is postulated that longer medication use [69], as well as higher doses [68] might both increase the risk for fracture. It is estimated that treatment of 86 patients with a thiazolidinedione for 3 years would produce 1 additional peripheral fracture [69]. However, the overall increased fracture risk in T2DM could not be attributed to the use of TZDs alone, since the percentage of patients on TZDs in the large epidemiological studies demonstrating increased fracture risk was rather small and an increase in fracture risk was demonstrated in cohorts even before the introduction of these drugs. Apart from TZDs, the rest of anti-diabetic drugs probably have either a neutral or a positive effect on bone metabolism, as suggested by studies so far, even though it is perhaps too early to draw any definite conclusions about the newest drugs such as the glucagon-like peptide-1 (GLP-1) analogues, dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Sulphonylureas may have a beneficial impact on the risk for any fracture [7], as well as the risk for vertebral fractures [70], although a neutral role has also been suggested [6]. However, the pathogenetic mechanisms are quite difficult to explain and their effects are probably explained by their efficiency in improving glycemic control. Nevertheless, a possible anabolic effect through the increase in endogenous insulin release induced by sulphonylureas and a direct anabolic effect by stimulating proliferation and differentiation of osteoblasts, as demonstrated by in vitro studies [71], cannot be excluded. Metformin use has also been associated with a decrease in fracture risk [6,7], and it is likely that it exerts direct effects on bone metabolism, apart from those mediated through improved glycemic control. Metformin has been shown to produce direct osteogenic effects in vitro [72], to reduce receptor activator of nuclear factor κB ligand (RANKL) expression and thus inhibit osteoclast differentiation [73] and to protect from ovariectomy induced bone loss in vivo [73]. Moreover, in animal models, metformin has demonstrated an ability to protect from the deleterious effects of rosiglitazone on bone when administered in combination [74]. However, the latter finding was not confirmed in humans; the combination of metformin and rosiglitazone for 80 weeks in diabetic men and women resulted in significant decreases of 2.2% in lumbar spine and of 1.5% in total hip BMD, as compared with metformin monotherapy [75]. Of note, there was no difference in BMD reduction between men, premenopausal and postmenopausal women. Finally, there is evidence that metformin might protect from the adverse effects of AGEs on osteoblastic cells [76]. GLP-1 receptor knockout mice are shown to exhibit enhanced bone resorption accompanied by elevated osteoclasts numbers and cortical osteopenia, leading to increased bone fragility [77]. It is postulated that the effects of GLP-1 on bone homeostasis are mediated through its action in stimulating calcitonin secretion from the parafollicular cells of the

1485

thyroid. In animal studies, administration of GLP-1 or exendin-4 exerted osteogenic effects [77], however, administration of exenatide in diabetic patients for 44 weeks did not significantly affect BMD or bone turnover markers, comparing to the administration of insulin glargine [78]. Of note, patients treated with exenatide displayed a significant reduction in body weight which, however, had no negative effect on bone metabolism. Mabilleau et al, in a recent meta-analysis, demonstrated that the use of GLP-1 analogues does not have any impact on fracture risk, nevertheless, most studies were of short duration and not adequately powered to establish an association between GLP-1 analogues use and fractures [79]. DPP-4 inhibitors inhibit the degradation of endogenous incretins, namely GLP-1 and gastric inhibitory polypeptide (GIP), as well as other gastrointestinal peptides such as glucagon-like peptide-2 (GLP-2), increasing their plasma levels. GIP enhances osteoblasts’ function [80]. GIP receptor knockout mice (GIPR−/−) exhibit decreased bone size, mainly due to a reduction in bone formation, while GIP administration prevents the bone loss associated with ovariectomy [81]. Data about the effect of GLP-2 at the tissue level are limited. However, its administration in postmenopausal women resulted in suppression of bone resorption without affecting bone formation [82]. Prolonged administration, for four months, was associated with a significant increase in total hip BMD [83]. DPP-4 knockout male and female mice display normal skeletal phenotypes, however ovariectomized DPP-4 knockout models exhibited significantly reduced femoral size. Sitagliptin treatment resulted in significant improvements in trabecular architecture in female, but not in male, or ovariectomized mice [84]. Data regarding the effects of DPP-4 inhibitors in human skeletal health are quite scarce. In a retrospective population based cohort study, the use of DPP-4 inhibitors was not associated with increased risk for fractures, as compared with the use of other anti-diabetic medications, nevertheless, the duration of use was short [85]. A metaanalysis of randomized controlled trials with DPP-4 inhibitors suggested that the use of this class of medication could be associated with a reduction in fracture risk [86]. However, the duration of the studies included was quite short and fractures were not the primary end point, so larger studies concerning the effects of DPP-4 inhibitors on skeletal physiology are necessary in order to draw any definite conclusions. Dapagliflozin, a selective SGLT2 inhibitor, is a relatively new medication for diabetes and data concerning its effects on bone metabolism are therefore limited. In a 50 week trial, the addition of dapagliflozin on metformin produced neither changes on markers of bone turnover, namely amino-terminal propeptide of type 1 collagen (P1NP) and carboxy-terminal collagen crosslinks (CTX), nor any alterations in BMD [87]. More data on SGLT2 inhibitors on skeletal homeostasis are warranted. Pramlintide is an amylin analogue, with an indication for T2DM in patients who use mealtime insulin. Amylin enhances proliferation of osteoblasts, inhibits osteoclastic activity and osteoclastogenesis, while systemic administration in adult mice increases skeletal mass [81]. However, in a study regarding patients with T1DM, pramlintide administration for 12 months had no effect on BMD and bone turnover markers [88]. There are currently no available data concerning its effects on bone metabolism in T2DM patients.

1486

ME TAB O L IS M CL I N ICA L A N D EX PE R IM EN T AL 6 3 ( 2 0 14 ) 14 8 0 –14 9 0

6. Difficulties in assessing individual fracture risk There is increasing evidence that the FRAX algorithm with the use of hip bone mineral density probably underestimates fracture risk in patients with type 2 diabetes [89,90]. This is probably due to the high BMD values observed in diabetic patients. It is postulated that the diabetic state is not associated with effects in the clinical parameters incorporated in the FRAX algorithm, but rather exerts an independent additive effect in fracture risk, as calculated by FRAX, which is more pronounced in younger diabetic patients [91]. BMD in diabetes does not reflect fracture risk in a similar manner to the general population. Fracture risk seems to increase with decreased BMD at least for non-vertebral and hip fractures, however, for a given T-score, diabetic patients have a higher risk for fracture than non-diabetic controls [89]. In contrast, there is poor correlation between lumbar spine BMD and the risk for vertebral fractures, since diabetic patients with and without vertebral fractures exhibit similar BMD values [9], limiting its use for fracture prediction at least concerning vertebral fractures. Recently, T2DM has been included in the FRAX algorithm as a cause of secondary osteoporosis [92], increasing fracture risk in diabetic patients when hip bone mineral density is not available. Most causes of secondary osteoporosis are thought to increase fracture risk principally by decreasing BMD. In type 2 diabetic patients, however, this does not seem to be the case and using T2DM as a secondary cause of osteoporosis could result in treating patients, especially elderly, who could possibly have normal or slightly reduced BMD. The effectiveness and safety of treating such patients with current antiosteoporotic medications are largely unknown.

7. Treatment of osteoporosis in patients with T2DM Due to the unique pathogenetic mechanisms of bone fragility in T2DM, there is some concern about the effects of antiosteoporotic medication on skeletal integrity. Data on the efficacy of antiresorptive drugs in patients suffering from both osteoporosis and T2DM have been rather reassuring. Vestergaard et al [93] demonstrated that antiresorptive agents, such as bisphosphonates and raloxifene, are effective for fracture prevention in patients with low BMD, irrespective of their diabetes status, establishing that further suppression of bone turnover does not confer any deterioration of bone strength in diabetic patients with low bone mass. Moreover, in univariate analysis in the subset of patients with T2DM from the Multiple Outcomes of Raloxifene Evaluation (MORE) study, raloxifene proved to be more efficient in diabetic patients than in non-diabetics. However, diabetic patients constituted barely 2.5% of the study population [94]. In a subset analysis in diabetic patients from the Fracture Intervention Trial (FIT) study, alendronate was effective in increasing BMD at all skeletal sites, as compared with placebo, in a similar way to non-diabetic patients [95]. The reduction in fracture risk was not statistically significant, perhaps due to the small sample size (4.5% of study population).

There are no definite data on the effects of treatment in patients with T2DM who have normal or slightly decreased BMD values and who, in the absence of BMD evaluation, might be candidates for treatment according to the updated FRAX algorithm. In the Raloxifene Use for the Heart Trial study, raloxifene use was evaluated in postmenopausal women, not selected on the basis of osteoporosis. Raloxifene use resulted in 35% lower incidence of clinical vertebral fractures, comparing to placebo, but had no effect in nonvertebral fractures [96]. Notably, the baseline presence of diabetes did not alter the results and nearly half of the participants in the study suffered from diabetes. More data on the effects of osteoporotic medication in patients with diabetes are definitely warranted. Recent research has implicated a role for osteocalcin in the regulation of insulin secretion, raising concerns about the results of the suppression of bone turnover in glycemic control. Schwartz et al evaluated the effect of antiresorptive medication, namely alendronate, zoledronic acid and denosumab, on glucose metabolism. The reduction of bone turnover did not significantly affect fasting glucose, weight, or risk for diabetes incidence [97].

8.

Effects on fracture healing

T2DM has been associated with impaired fracture healing, such as delayed union or nonunion [98], which are much more common in diabetic patients suffering from various diabetic complications, comparing to diabetic patients without complications [99], and in patients with inadequate glycemic control (HbA1c > 7%) [100]. Moreover, diabetic patients exhibit more often serious complications during hospitalization for fractures. Increased in-hospital mortality, cardiac perioperative complications, infections and longer duration of hospitalization have all been described [101,102]. The pathogenetic mechanisms responsible for healing complications are quite difficult to study in humans and, thus, most information stems from animal models and predominantly from insulin deficient rodents. Experimental studies have demonstrated that the diabetic state is characterized by reduced cellularity in the fracture microenvironment during the first week post fracture, possibly stemming from an impairment in the recruitment of MSCs and a subsequent deficit in differentiation and proliferation of osteoblastic cells. At later stages, delayed and impaired cartilage differentiation and mineralization are observed. These defects may be prevented through strict glycemic control achieved by insulin therapy [103], at least in insulin deficient animal models. Although poorly controlled diabetes (as evidenced by elevated HbA1c levels) is a well known risk factor for healing complications, little is known about the effect of strict glycemic control throughout hospitalization and during the recovery period on healing outcomes in humans. There is enough evidence that adequate, but not strict, glycemic control during cardiac surgery, myocardial infarction and in the intensive care unit is associated with improved outcomes and current recommendations highlight the importance of

ME TAB O L IS M CL I N ICA L A N D EX P ER IM EN T AL 6 3 ( 2 0 14 ) 14 8 0 –1 49 0

insulin therapy and careful monitoring and titration for diabetic patients during hospitalization. A premeal glucose target of less than 140 mg/dl and a random glucose target of less than 180 mg/dl are recommended for most hospitalized patients [104]. Of note, adequate glycemic control following dental implant placement in type 2 diabetic patients is associated with improved outcomes during follow-up for 3 years [105]. It is possible that improved glycemic control in the post fracture period might attenuate the detrimental effects of hyperglycemia on healing, but prospective studies are needed.

9.

Conclusion

Increased fracture risk and impaired fracture healing are consistently associated with T2DM. Studies evaluating fracture risk in patients with T2DM may be based on associations and thus be unable to prove causality; however, the association is rather constant, irrespective of study design, and is unlikely to represent a coincidental finding. Longer disease duration seems to be an important determinant of fracture risk, as is the presence of diabetic complications. Nevertheless, data regarding the effect of glycemic control on skeletal fragility are sparse and it is still unknown whether improving glycemic control might be protective against skeletal complications. Impairment of bone material properties and architecture seem to be major determinants of reduced bone strength, which, coupled with increased risk of falls, might explain the elevated fracture risk. The evaluation and prediction of individual fracture risk represents a challenge due to limitations caused by increased BMD and FRAX prediction score. Moreover, even though T2DM is now considered a cause for secondary osteoporosis, important parameters such as diabetes duration and presence of complications are not taken into account. Certainly, more stringent data are necessary before any of these parameters becomes integrated in the evaluation of the risk for fracture of diabetic patients.

Authors’ contributions All authors substantially contributed to the conception, acquisition and interpretation of the data and drafting the manuscript.

Conflict of interest The authors have nothing to disclose.

REFERENCES [1] International Diabetes Federation. IDF Diabetes Atlas. 6th edn. Brussels, Belgium: International Diabetes Federation; 2013 [http://www.idf.org/diabetesatlas]. [2] Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010;87(1):4–14.

1487

[3] Janghorbani M, Feskanich D, Willett WC, Hu F. Prospective study of diabetes and risk of hip fracture: the Nurses’ Health Study. Diabetes Care 2006;29(7):1573–8. [4] Bonds DE, Larson JC, Schwartz AV, Strotmeyer ES, Robbins J, Rodriguez BL, et al. Risk of fracture in women with type 2 diabetes: the Women’s Health Initiative Observational Study. J Clin Endocrinol Metab 2006;91(9):3404–10. [5] de Liefde II, van der Klift M, de Laet CE, van Daele PL, Hofman A, Pols HA. Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. Osteoporos Int 2005;16(12):1713–20. [6] Melton III LJ, Leibson CL, Achenbach SJ, Therneau TM, Khosla S. Fracture risk in type 2 diabetes: update of a population-based study. J Bone Miner Res 2008;23(8): 1334–42. [7] Vestergaard P, Rejnmark L, Mosekilde L. Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk. Diabetologia 2005;48(7):1292–9. [8] Janghorbani M, Van Dam RM, Willett WC, Hu FB. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 2007;166(5):495–505. [9] Yamamoto M, Yamaguchi T, Yamauchi M, Kaji H, Sugimoto T. Diabetic patients have an increased risk of vertebral fractures independent of BMD or diabetic complications. J Bone Miner Res 2009;24(4):702–9. [10] Ivers RQ, Cumming RG, Mitchell P, Peduto AJ, Blue Mountains Eye Study. Diabetes and risk of fracture: the Blue Mountains Eye Study. Diabetes Care 2001;24(7):1198–203. [11] Leslie WD, Lix LM, Prior HJ, Derksen S, Metge C, O'Neil J. Biphasic fracture risk in diabetes: a population-based study. Bone 2007;40(6):1595–601. [12] Schwartz AV, Hillier TA, Sellmeyer DE, Resnick HE, Gregg E, Ensrud KE, et al. Older women with diabetes have a higher risk of falls: a prospective study. Diabetes Care 2002;25(10): 1749–54. [13] Gregg EW, Beckles GL, Williamson DF, Leveille SG, Langlois JA, Engelgau MM, et al. Diabetes and physical disability among older U.S. adults. Diabetes Care 2000;23 (9):1272–7. [14] Malmivaara A, Heliövaara M, Knekt P, Reunanen A, Aromaa A. Risk factors for injurious falls leading to hospitalization or death in a cohort of 19,500 adults. Am J Epidemiol 1993; 138(6):384–94. [15] Johnston SS, Conner C, Aagren M, Ruiz K, Bouchard J. Association between hypoglycaemic events and fall-related fractures in Medicare-covered patients with type 2 diabetes. Diabetes Obes Metab 2012;14(7):634–43. [16] Vestergaard P, Rejnmark L, Mosekilde L. Diabetes and its complications and their relationship with risk of fractures in type 1 and 2 diabetes. Calcif Tissue Int 2009;84(1):45–55. [17] Oei L, Zillikens MC, Dehghan A, Buitendijk GH, CastañoBetancourt MC, Estrada K, et al. High bone mineral density and fracture risk in type 2 diabetes as skeletal complications of inadequate glucose control: the Rotterdam Study. Diabetes Care 2013;36(6):1619–28. [18] Schwartz AV, Margolis KL, Sellmeyer DE, Vittinghoff E, Ambrosius WT, Bonds DE, et al. Intensive glycemic control is not associated with fractures or falls in the ACCORD randomized trial. Diabetes Care 2012;35(7):1525–31. [19] Diez-Perez A, Güerri R, Nogues X, Cáceres E, Peña MJ, Mellibovsky L, et al. Microindentation for in vivo measurement of bone tissue mechanical properties in humans. J Bone Miner Res 2010;25(8):1877–85. [20] Zoppini G, Galletti A, Targher G, Brangani C, Pichiri I, Negri C, et al. Glycated haemoglobin is inversely related to serum vitamin D levels in type 2 diabetic patients. PLoS One 2013;8 (12):e82733.

1488

ME TAB O L IS M CL I N ICA L A N D EX PE R IM EN T AL 6 3 ( 2 0 14 ) 14 8 0 –14 9 0

[21] Kim YJ, Park SO, Kim TH, Lee JH, Kim SH. The association of serum 25-hydroxyvitamin D and vertebral fractures in patients with type 2 diabetes. Endocr J 2013;60(2):179–84. [22] Ma L, Oei L, Jiang L, Estrada K, Chen H, Wang Z, et al. Association between bone mineral density and type 2 diabetes mellitus: a meta-analysis of observational studies. Eur J Epidemiol 2012;27(5):319–32. [23] Krakauer JC, McKenna MJ, Buderer NF, Rao DS, Whitehouse FW, Parfitt AM. Bone loss and bone turnover in diabetes. Diabetes 1995;44(7):775–82. [24] Schwartz AV, Sellmeyer DE, Strotmeyer ES, Tylavsky FA, Feingold KR, Resnick HE, et al. Diabetes and bone loss at the hip in older black and white adults. J Bone Miner Res 2005;20 (4):596–603. [25] Lipkin EW, Schwartz AV, Anderson AM, Davis C, Johnson KC, Gregg EW, et al. Bone loss at four-year follow-up in type 2 diabetes. Diabetes Care 2014;37(10):2822–9 [pii: DC_140762]. [26] Gregorio F, Cristallini S, Santeusanio F, Filipponi P, Fumelli P. Osteopenia associated with non-insulin-dependent diabetes mellitus: what are the causes? Diabetes Res Clin Pract 1994;23(1):43–54. [27] Shu A, Yin MT, Stein E, Cremers S, Dworakowski E, Ives R, et al. Bone structure and turnover in type 2 diabetes mellitus. Osteoporos Int 2012;23(2):635–41. [28] Farr JN, Drake MT, Amin S, Melton III LJ, McCready LK, Khosla S. In Vivo assessment of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res 2014;29(4):787–95. [29] Starup-Linde J, Eriksen SA, Lykkeboe S, Handberg A, Vestergaard P. Biochemical markers of bone turnover in diabetes patients-a meta-analysis, and a methodological study on the effects of glucose on bone markers. Osteoporos Int 2014;25(6):1697–708. [30] García-Martín A, Rozas-Moreno P, Reyes-García R, MoralesSantana S, García-Fontana B, García-Salcedo JA, et al. Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2012;97(1): 234–41. [31] Ardawi MS, Akhbar DH, Alshaikh A, Ahmed MM, Qari MH, Rouzi AA, et al. Increased serum sclerostin and decreased serum IGF-1 are associated with vertebral fractures among postmenopausal women with type-2 diabetes. Bone 2013;56 (2):355–62. [32] Fajardo RJ, Karim L, Calley VI, Bouxsein ML. a review of rodent models of type 2 diabetic skeletal fragility. J Bone Miner Res 2014;29(5):1025–40. [33] Petit MA, Paudel ML, Taylor BC, Hughes JM, Strotmeyer ES, Schwartz AV, et al. Bone mass and strength in older men with type 2 diabetes: the Osteoporotic Fractures in Men Study. J Bone Miner Res 2010;25(2):285–91. [34] Park SW, Goodpaster BH, Strotmeyer ES, de Rekeneire N, Harris TB, Schwartz AV, et al. Decreased muscle strength and quality in older adults with type 2 diabetes: the health, aging, and body composition study. Diabetes 2006;55(6): 1813–8. [35] Burghardt AJ, Issever AS, Schwartz AV, Davis KA, Masharani U, Majumdar S, et al. High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2010;95(11):5045–55. [36] Patsch JM, Burghardt AJ, Yap SP, Baum T, Schwartz AV, Joseph GB, et al. Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures. J Bone Miner Res 2013;28(2):313–24. [37] Ishii S, Cauley JA, Crandall CJ, Srikanthan P, Greendale GA, Huang MH, et al. Diabetes and femoral neck strength: findings from the Hip Strength Across the Menopausal Transition Study. J Clin Endocrinol Metab 2012;97(1):190–7.

[38] Garg R, Chen Z, Beck T, Cauley JA, Wu G, Nelson D, et al. Hip geometry in diabetic women: implications for fracture risk. Metabolism 2012;61(12):1756–62. [39] Hans D, Goertzen AL, Krieg MA, Leslie WD. Bone microarchitecture assessed by TBS predicts osteoporotic fractures independent of bone density: the Manitoba study. J Bone Miner Res 2011;26(11):2762–9. [40] Leslie WD, Aubry-Rozier B, Lamy O, Hans D. Manitoba Bone Density Program. TBS (trabecular bone score) and diabetesrelated fracture risk. J Clin Endocrinol Metab 2013;98(2): 602–9. [41] Dhaliwal R, Cibula D, Ghosh C, Weinstock RS, Moses AM. Bone quality assessment in type 2 diabetes mellitus. Osteoporos Int 2014;25(7):1969–73. [42] Hansma P, Yu H, Schultz D, Rodriguez A, Yurtsev EA, Orr J, et al. The tissue diagnostic instrument. Rev Sci Instrum 2009;80(5):054303. [43] Pritchard JM, Papaioannou A, Tomowich C, Giangregorio LM, Atkinson SA, Beattie KA, et al. Bone mineralization is elevated and less heterogeneous in adults with type 2 diabetes and osteoarthritis compared to controls with osteoarthritis alone. Bone 2013;54(1):76–82. [44] Tang SY, Zeenath U, Vashishth D. Effects of non-enzymatic glycation on cancellous bone fragility. Bone 2007;40(4): 1144–51. [45] Vashishth D, Gibson GJ, Khoury JI, Schaffler MB, Kimura J, Fyhrie DP. Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone 2001;28(2): 195–201. [46] Tang SY, Vashishth D. Non-enzymatic glycation alters microdamage formation in human cancellous bone. Bone 2010;46(1):148–54. [47] Okazaki K, Yamaguchi T, Tanaka K, Notsu M, Ogawa N, Yano S, et al. Advanced glycation end products (AGEs), but not high glucose, inhibit the osteoblastic differentiation of mouse stromal ST2 cells through the suppression of osterix expression, and inhibit cell growth and increasing cell apoptosis. Calcif Tissue Int 2012;91(4):286–96. [48] Sanguineti R, Storace D, Monacelli F, Federici A, Odetti P. Pentosidine effects on human osteoblasts in vitro. Ann N Y Acad Sci 2008;1126:166–72. [49] Alikhani M, Alikhani Z, Boyd C, MacLellan CM, Raptis M, Liu R, et al. Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone 2007;40(2):345–53. [50] Valcourt U, Merle B, Gineyts E, Viguet-Carrin S, Delmas PD, Garnero P. Non-enzymatic glycation of bone collagen modifies osteoclastic activity and differentiation. J Biol Chem 2007;282(8):5691–703. [51] Dong XN, Qin A, Xu J, Wang X. In situ accumulation of advanced glycation endproducts (AGEs) in bone matrix and its correlation with osteoclastic bone resorption. Bone 2011; 49(2):174–83. [52] Vanella L, Kim DH, Asprinio D, Peterson SJ, Barbagallo I, Vanella A, et al. HO-1 expression increases mesenchymal stem cell-derived osteoblasts but decreases adipocyte lineage. Bone 2010;46(1):236–43. [53] Terada M, Inaba M, Yano Y, Hasuma T, Nishizawa Y, Morii H, et al. Growth-inhibitory effect of a high glucose concentration on osteoblast-like cells. Bone 1998;22(1): 17–23. [54] Arai M, Shibata Y, Pugdee K, Abiko Y, Ogata Y. Effects of reactive oxygen species (ROS) on antioxidant system and osteoblastic differentiation in MC3T3-E1 cells. IUBMB Life 2007;59(1):27–33. [55] Hamada Y, Kitazawa S, Kitazawa R, Fujii H, Kasuga M, Fukagawa M. Histomorphometric analysis of diabetic osteopenia in streptozotocin-induced diabetic mice: a possible role of oxidative stress. Bone 2007;40(5):1408–14.

ME TAB O L IS M CL I N ICA L A N D EX P ER IM EN T AL 6 3 ( 2 0 14 ) 14 8 0 –1 49 0

[56] Odetti P, Rossi S, Monacelli F, Poggi A, Cirnigliaro M, Federici M, et al. Advanced glycation end products and bone loss during aging. Ann N Y Acad Sci 2005;1043:710–7. [57] Viguet-Carrin S, Roux JP, Arlot ME, Merabet Z, Leeming DJ, Byrjalsen I, et al. Contribution of the advanced glycation end product pentosidine and of maturation of type I collagen to compressive biomechanical properties of human lumbar vertebrae. Bone 2006;39(5):1073–9. [58] Saito M, Fujii K, Soshi S, Tanaka T. Reductions in degree of mineralization and enzymatic collagen cross-links and increases in glycation-induced pentosidine in the femoral neck cortex in cases of femoral neck fracture. Osteoporos Int 2006;17(7):986–95. [59] Tanaka S, Kuroda T, Saito M, Shiraki M. Urinary pentosidine improves risk classification using fracture risk assessment tools for postmenopausal women. J Bone Miner Res 2011;26 (11):2778–84. [60] Yamamoto M, Yamaguchi T, Yamauchi M, Yano S, Sugimoto T. Serum pentosidine levels are positively associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab 2008;93(3):1013–9. [61] Schwartz AV, Garnero P, Hillier TA, Sellmeyer DE, Strotmeyer ES, Feingold KR, et al. Pentosidine and increased fracture risk in older adults with type 2 diabetes. J Clin Endocrinol Metab 2009;94(7):2380–6. [62] Lecka-Czernik B, Moerman EJ, Grant DF, Lehmann JM, Manolagas SC, Jilka RL. Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiation. Endocrinology 2002;143(6):2376–84. [63] Mabilleau G, Mieczkowska A, Edmonds ME. Thiazolidinediones induce osteocyte apoptosis and increase sclerostin expression. Diabet Med 2010;27(8):925–32. [64] Sorocéanu MA, Miao D, Bai XY, Su H, Goltzman D, Karaplis AC. Rosiglitazone impacts negatively on bone by promoting osteoblast/osteocyte apoptosis. J Endocrinol 2004;183(1): 203–16. [65] Schwartz AV, Sellmeyer DE, Vittinghoff E, Palermo L, LeckaCzernik B, Feingold KR, et al. Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab 2006;91(9):3349–54. [66] Glintborg D, Andersen M, Hagen C, Heickendorff L, Hermann AP. Association of pioglitazone treatment with decreased bone mineral density in obese premenopausal patients with polycystic ovary syndrome: a randomized, placebo-controlled trial. J Clin Endocrinol Metab 2008;93(5):1696–701. [67] Yaturu S, Bryant B, Jain SK. Thiazolidinedione treatment decreases bone mineral density in type 2 diabetic men. Diabetes Care 2007;30(6):1574–6. [68] Bilik D, McEwen LN, Brown MB, Pomeroy NE, Kim C, Asao K, et al. Thiazolidinediones and fractures: evidence from translating research into action for diabetes. J Clin Endocrinol Metab 2010;95(10):4560–5. [69] Dormuth CR, Carney G, Carleton B, Bassett K, Wright JM. Thiazolidinediones and fractures in men and women. Arch Intern Med 2009;169(15):1395–402. [70] Kanazawa I, Yamaguchi T, Yamamoto M, Sugimoto T. Relationship between treatments with insulin and oral hypoglycemic agents versus the presence of vertebral fractures in type 2 diabetes mellitus. J Bone Miner Metab 2010;28(5):554–60. [71] Ma P, Gu B, Ma J, E L, Wu X, Cao J, et al. Glimepiride induces proliferation and differentiation of rat osteoblasts via the PI3-kinase/Akt pathway. Metabolism 2010;59(3): 359–66. [72] Cortizo AM, Sedlinsky C, McCarthy AD, Blanco A, Schurman L. Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture. Eur J Pharmacol 2006;536(1–2):38–46.

1489

[73] Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, et al. Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem 2011;112(10):2902–9. [74] Sedlinsky C, Molinuevo MS, Cortizo AM, Tolosa MJ, Felice JI, Sbaraglini ML, et al. Metformin prevents anti-osteogenic in vivo and ex vivo effects of rosiglitazone in rats. Eur J Pharmacol 2011;668(3):477–85. [75] Borges JL, Bilezikian JP, Jones-Leone AR, Acusta AP, Ambery PD, Nino AJ, et al. A randomized, parallel group, doubleblind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long-term glycaemic control and bone mineral density after 80 weeks of treatment in drug-naïve type 2 diabetes mellitus patients. Diabetes Obes Metab 2011;13(11):1036–46. [76] Schurman L, McCarthy AD, Sedlinsky C, Gangoiti MV, Arnol V, Bruzzone L, et al. Metformin reverts deleterious effects of advanced glycation end-products (AGEs) on osteoblastic cells. Exp Clin Endocrinol Diabetes 2008;116(6):333–40. [77] Yavropoulou MP, Yovos JG. Incretins and bone: evolving concepts in nutrient-dependent regulation of bone turnover. Hormones (Athens) 2013;12(2):214–23. [78] Bunck MC, Eliasson B, Cornér A, Heine RJ, Shaginian RM, Taskinen MR, et al. Exenatide treatment did not affect bone mineral density despite body weight reduction in patients with type 2 diabetes. Diabetes Obes Metab 2011;13(4):374–7. [79] Mabilleau G, Mieczkowska A, Chappard D. Use of glucagon-like peptide-1 receptor agonists and bone fractures: a meta-analysis of randomized clinical trials. J Diabetes 2014;6(3):260–6. [80] Bollag RJ, Zhong Q, Phillips P, et al. Osteoblast-derived cells express functional glucose-dependent insulinotropic peptide receptors. Endocrinology 2000;141(3):1228–35. [81] Wong IP, Baldock PA, Herzog H. Gastrointestinal peptides and bone health. Curr Opin Endocrinol Diabetes Obes 2010; 17(1):44–50. [82] Henriksen DB, Alexandersen P, Hartmann B, Adrian CL, Byrjalsen I, Bone HG, et al. Disassociation of bone resorption and formation by GLP-2: a 14-day study in healthy postmenopausal women. Bone 2007;40(3):723–9. [83] Henriksen DB, Alexandersen P, Hartmann B, Adrian CL, Byrjalsen I, Bone HG, et al. Four-month treatment with GLP-2 significantly increases hip BMD: a randomized, placebo-controlled, dose-ranging study in postmenopausal women with low BMD. Bone 2009;45(5):833–42. [84] Kyle KA, Willett TL, Baggio LL, Drucker DJ, Grynpas MD. Differential effects of PPAR-{gamma} activation versus chemical or genetic reduction of DPP-4 activity on bone quality in mice. Endocrinology 2011;152(2):457–67. [85] Driessen JHM, van Onzenoort HAW, Henry RMA, Lalmohamed A, van den Bergh JP, Neef C, et al. Use of dipeptidyl peptidase-4 inhibitors for type 2 diabetes mellitus and risk of fracture. Bone 2014. http://dx.doi.org/10. 1016/j.bone.2014.07.030 [Epub ahead of print]. [86] Monami M, Dicembrini I, Antenore A, Mannucci E. Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials. Diabetes Care 2011;34(11):2474–6. [87] Ljunggren Ö, Bolinder J, Johansson L, Wilding J, Langkilde AM, Sjöström CD, et al. Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab 2012; 14(11):990–9. [88] Borm AK, Klevesath MS, Borcea V, Kasperk C, Seibel MJ, Wahl P, et al. The effect of pramlintide (amylin analogue) treatment on bone metabolism and bone density in patients with type 1 diabetes mellitus. Horm Metab Res 1999;31(8): 472–5.

1490

ME TAB O L IS M CL I N ICA L A N D EX PE R IM EN T AL 6 3 ( 2 0 14 ) 14 8 0 –14 9 0

[89] Schwartz AV, Vittinghoff E, Bauer DC, Hillier TA, Strotmeyer ES, Ensrud KE, et al. Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. JAMA 2011;305(21):2184–92. [90] Giangregorio LM, Leslie WD, Lix LM, Johansson H, Oden A, McCloskey E, et al. FRAX underestimates fracture risk in patients with diabetes. J Bone Miner Res 2012;27(2):301–8. [91] Leslie WD, Morin SN, Lix LM, Majumdar SR. Does diabetes modify the effect of FRAX risk factors for predicting major osteoporotic and hip fracture? Osteoporos Int 2014. http:// dx.doi.org/10.1007/s00198-014-2822-2 [Epub ahead of print]. [92] Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY. Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2013;24(1):23–57. [93] Vestergaard P, Rejnmark L, Mosekilde L. Are antiresorptive drugs effective against fractures in patients with diabetes? Calcif Tissue Int 2011;88(3):209–14. [94] Johnell O, Kanis JA, Black DM, Balogh A, Poor G, Sarkar S, et al. Associations between baseline risk factors and vertebral fracture risk in the Multiple Outcomes of Raloxifene Evaluation (MORE) Study. J Bone Miner Res 2004;19(5):764–72. [95] Keegan TH, Schwartz AV, Bauer DC, Sellmeyer DE, Kelsey JL. Fracture intervention trial. Effect of alendronate on bone mineral density and biochemical markers of bone turnover in type 2 diabetic women: the fracture intervention trial. Diabetes Care 2004;27(7):1547–53. [96] Ensrud KE, Stock JL, Barrett-Connor E, Grady D, Mosca L, Khaw KT, et al. Effects of raloxifene on fracture risk in postmenopausal women: the Raloxifene Use for the Heart Trial. J Bone Miner Res 2008;23(1):112–20.

[97] Schwartz AV, Schafer AL, Grey A, Vittinghoff E, Palermo L, Lui LY, et al. Effects of antiresorptive therapies on glucose metabolism: results from the FIT, HORIZON-PFT, and FREEDOM trials. J Bone Miner Res 2013;28(6):1348–54. [98] Hernandez RK, Do TP, Critchlow CW, Dent RE, Jick SS. Patient-related risk factors for fracture-healing complications in the United Kingdom General Practice Research Database. Acta Orthop 2012;83(6):653–60. [99] Wukich DK, Joseph A, Ryan M, Ramirez C, Irrgang JJ. Outcomes of ankle fractures in patients with uncomplicated versus complicated diabetes. Foot Ankle Int 2011;32(2): 120–30. [100] Shibuya N, Humphers JM, Fluhman BL, Jupiter DC. Factors associated with nonunion, delayed union, and malunion in foot and ankle surgery in diabetic patients. J Foot Ankle Surg 2013;52(2):207–11. [101] Ganesh SP, Pietrobon R, Cecílio WA, Pan D, Lightdale N, Nunley JA. The impact of diabetes on patient outcomes after ankle fracture. J Bone Joint Surg Am 2005;87(8):1712–8. [102] Wang H, Lü YW, Lan L, Zhang Q, Chen HL, Zhang GY, et al. Impact of diabetes on the prognosis of hip fracture: a cohort study in the Chinese population. Chin Med J (Engl) 2013;126 (5):813–8. [103] Retzepi M, Donos N. The effect of diabetes mellitus on osseous healing. Clin Oral Implants Res 2010;21(7):673–81. [104] Umpierrez GE, Hellman R, Korytkowski MT, Kosiborod M, Maynard GA, Montori VM, et al. Endocrine Society. Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2012;97(1):16–38. [105] Gómez-Moreno G, Aguilar-Salvatierra A, Rubio Roldán J, Guardia J, Gargallo J, Calvo-Guirado JL. Peri-implant evaluation in type 2 diabetes mellitus patients: a 3-year study. Clin Oral Implants Res 2014. http://dx.doi.org/10. 1111/clr.12391 [Epub ahead of print].