Nutrition, Metabolism & Cardiovascular Diseases (2014) 24, 1151e1157
Available online at www.sciencedirect.com
Nutrition, Metabolism & Cardiovascular Diseases journal homepage: www.elsevier.com/locate/nmcd
REVIEW
Bone damage in type 2 diabetes mellitus V. Carnevale a,*, E. Romagnoli b, L. D’Erasmo c, E. D’Erasmo c a
Unit of Internal Medicine, “Casa Sollievo della Sofferenza” Hospital, IRCCS, Viale dei Cappuccini snc, 71013 San Giovanni Rotondo, FG, Italy Department of Experimental Medicine, “Sapienza” University, Viale del Policlinico 155, 00161 Rome, Italy c Department of Internal Medicine and Medical Specialties, “Sapienza” University, Viale del Policlinico 155, 00161 Rome, Italy b
Received 28 February 2014; received in revised form 18 June 2014; accepted 30 June 2014 Available online 27 July 2014
KEYWORDS Type 2 diabetes mellitus; Bone mineral density; Bone quality; Fractures; Clinical risk factors
Abstract This review focuses on the mechanisms determining bone fragility in patients with type 2 diabetes mellitus (T2DM). Despite bone mineral density (BMD) is usually normal or more often increased in these patients, fracture incidence is high, probably because of altered bone ”quality”. The latter seems to depend on several, only partly elucidated, mechanisms, such as the increased skeletal content of advanced glycation end-products causing collagen deterioration, the altered differentiation of bone osteogenic cells, the altered bone turnover and microarchitecture. Disease duration, its severity and metabolic control, the type of therapy, the presence or absence of complications, as like as the other known predictors for falls, are all relevant contributing factors affecting fracture risk in T2DM. In these patients the estimate of fracture risk in the everyday clinical practice may be challenging, due to the lower predictive capacity of both BMD and risk factors-based algorithms (e.g. FRAX). ª 2014 Elsevier B.V. All rights reserved.
Type 1 and type 2 diabetes mellitus are both associated to bone damage [1,2]. However, the heavy epidemiological impact of type 2 diabetes on Western and developing Countries amplifies the interest on this latter condition. Type 2 diabetes mellitus (T2DM) now affects at least 285 million people worldwide, and this number will raise to 438 million by the year 2030 [3]. Such an increase will mainly occur in people aged over 60 years [3]. On the other hand, osteoporosis affects over 200 million people worldwide, concerning one out of ten women in their 60ies, 40% of women aged 80 and two-thirds of women aged 90 years [4]. Osteoporosis causes about 9 million fractures per year worldwide [5] and by 2050 the incidence of hip fracture is projected to increase by 240% in women and by 310% in men [4]. These epidemiological * Corresponding author. Tel.: þ39 0882 410285; fax: þ39 06 45549053. E-mail address: [email protected] (V. Carnevale). http://dx.doi.org/10.1016/j.numecd.2014.06.013 0939-4753/ª 2014 Elsevier B.V. All rights reserved.
data underlines as T2DM and osteoporosis are rapidly expanding among older people, that is in a growing proportion of the general population. This in turn will translate not only in staggering financial costs for the communities, but it will also impact on the daily clinical practice of most physicians, who will increasingly deal with elderly patients in whom diabetes and osteoporosis coexist [6]. Moreover, despite T2DM and osteoporosis have been traditionally viewed as separate entities, accumulating evidence indicates that these diseases are tightly linked. Recent reports even advanced the hypothesis that common genetic determinants may contribute to both diseases [7]. Anyhow, although the pathogenesis of bone involvement in diabetes is complex and still not fully elucidated, patients with T2DM have an increased propensity to fracture [1,2], only partly depending on their increased risk of falls due to complications as retinopathy, neuropathy, and macrovascular disease [1,8] (Fig. 1). Qualitative, more than quantitative, alterations of bone
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Figure 1 Proposed pathogenetic mechanism of bone fragility and fractures in type 2 diabetes mellitus. Insulin resistance results in higher levels of both insulin (which induce increased aBMD due to its anabolic action on bone) and glucose (which promote the skeletal accumulation of AGEs). Both insulin resistance and AGEs accumulation alter bone quality, microarchitecture (increased cortical porosity), and osteoblast differentiation and turnover (the related decrease of osteocalcin levels in turn worsens insulin-resistance). The consequently increased skeletal fragility, together with extraskeletal factors predisposing to fall, justifies the higher fracture rate of these patients. (L Z liver; AT Z adipose tissue; M Z muscle; P Z pancreas; MAT Z marrow adipose tissue; aBMD Z areal bone mineral density; MSC Z mesenchymal stem cells; PPARg Z peroxisome proliferator-activated receptor gamma pathway; Wnt Z Wingless integrase-1 pathway).
probably account for the increased skeletal fragility of patients with T2DM. The current review mainly focuses on evidence from human studies, but these results are largely consistent with those obtained in animal models [9].
Bone mineral density and fractures Patients with T2DM, as an apparent paradox, usually have relatively high bone mineral density (BMD), associated to an increased propensity to fracture. Despite some contrasting data [1], most reports on this topic indicated that these patients have normal or higher BMD values in respect to control subjects [1,2,10,11]. Discrepant results from literature probably relate to the non homogeneous composition of the investigated samples, since T2DM patients often differ for body weight, body mass index (BMI), insulin levels, clinical presentation or disease duration, presence or absence of complications, type and duration of anti-diabetic therapy [1]. All the mentioned factors actually could be as many confounders, because previous studies showed significant associations between BMD and obesity, BMI [12], serum insulin levels, drugs [13]. It is worth noting as most studies on this topic have been carried out by the DXA measurement of BMD. However, body or skeletal size affects the results obtained by DXA, which assesses areal instead of “true” volumetric BMD because of its two-dimensional geometry. Moreover, areal
BMD assessment by dual-energy X-ray absorptiometry (DXA) in patients with T2DM could be often affected by vascular calcium deposits, osteophytes, and diffuse idiopathic skeletal hyperostosis (DISH) [1]. Even considering these concerns, recent meta-analyses of BMD data [11,14] confirmed that BMD values are increased in patients with T2DM. In particular, Ma and co-workers [11], pooling 15 observational studies, analyzed DXA-BMD of 3437 patients and 19 139 control subjects. The BMD values measured at lumbar spine, femoral neck and total hip were higher in the whole sample of T2DM patients, as like as in male and female patients separately. The higher BMD associated with younger age, male sex, higher BMI, and glycated hemoglobin levels. Although normal or higher BMD values should portend preserved or increased bone strength, patients with T2DM, counter-intuitively, have an increased fracture risk [1,2,15e20], showing a higher rate both of “classical” osteoporotic fractures, as those of the forearm, vertebrae, humerus, and hip, and of so-called fatigue fractures (i.e. tarsal and metatarsal fractures). In patients with T2DM the risk of hip fracture, which carries the heaviest burden of morbidity and mortality, is significantly increased [21], attaining a relative risk (RR) between 1.80 and 2.66 [16,18]. Although a recent paper reported no elevation in risk in men with T2DM, and only a minimal increase (RR 1.05) of fracture risk in T2DM women [22], a recent meta-analysis of 12 studies
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demonstrated a RR of 1.7, without significant gender difference [19]. Patients taking oral anti-diabetic drugs seem to have lower risk, whereas the highest risk has been found in those with long-lasting or insulin-treated T2DM (being insulin a marker of more severe and long standing disease) and/or in those with complications of the disease [16,23]. Actually, patients with impaired glucose tolerance or recently diagnosed disease have lower or similar risk to non-diabetic subjects [24]. On the other hand, patients with T2DM have accelerated bone loss at the hip [24,25]. It has been hypothesized that the high insulin levels due to insulin resistance may initially play a protective role on bone, while protracted or complicated disease may induce qualitative and (less apparent) quantitative effects compromising skeletal integrity [2]. Vertebral fractures, though may severely impact on activities of daily living and on overall quality of life, are worldwide under-diagnosed, about two-thirds of them going clinically unrecognized. This explains some apparently contrasting results. Schwartz et al. in elderly women with diabetes found that the RR for vertebral fracture was 1.06e1.09 [15]. Instead, a recent study on Korean women, systematically utilizing vertebral morphometry to identify significant deformities, found that 43.3% of patients with T2DM had morphometric vertebral fractures. Such a risk was in turn associated to older age, history of fragility fracture and increased cardiovascular risk [26]. Similarly, in a small sample of Italian patients with T2DM vertebral fractures were found in 46% of patients, versus 17% of controls, through the use of the Spinal Deformity Index (SDI) [27]. Available data challenge the ability of BMD to identify patients with T2DM at higher risk for fracture, in comparison to the predictive capacity that this tool displays in the general population. In general, for a given BMD and age, patients with T2DM have a higher risk of fracture than those without the disease, and T2DM seems to represent an independent determinant of fracture risk [10,28]. The lower predictive capacity of BMD mandates the research of alternative tools for fracture prediction in patients with diabetes. A growing attention is paid to test the predictive capacity of algorithms based on clinical risk factors, among which the FRAX tool is the most diffused worldwide. It predicts the ten-year probability of either major osteoporotic (a composed endpoint of femur, spine, humerus and forearm fractures) or hip fracture [29]. Noteworthy, T2DM is not included among the primary entry variables of FRAX. Two recent reports tested the clinical performances of FRAX in T2DM patients, retrospectively examining the series of two prospective North American studies [28,30]. Schwartz et al. [28] found that in older patients with diabetes both lower femoral neck BMD T-score and higher FRAX score were associated with hip and nonspine fracture risk. However, the two reports consistently indicated that FRAX underestimates fracture risk in patients T2DM [28,30]. Also a multicentric Italian study on a prospectively enrolled sample of 974 patients with T2DM and 777 control subjects [31] showed that the FRAX scores of patients was not higher than those of control subjects, despite the
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higher number of previous fractures. Interestingly, some complications of diabetes were significantly related to the FRAX scores. Such associations might delineate specific clinical profiles, possibly destined to sustain a heavier burden of the disease, due to the sum of additive risk factors [31]. Overall, according to current data, the fracture risk of diabetic patients is not entirely captured by the current FRAX algorithm. However, the attracting hypothesis of adding diabetes to the FRAX algorithm deserves the preliminary collection of additional data from large population-based cohorts [10]. Interestingly, T2DM has been included as a binary variable (Y/N) in the statistically robust algorithm QFracture, derived by a cohort of 3 142 673 and validated on a cohort of 1 583 373 British patients [32]. But, at variance with FRAX, this algorithm has not been validated outside UK, so that its clinical utility in other Countries has not been demonstrated.
Bone structure/strength/turnover and quality Modified bone geometry, structure, turnover and biochemical features can all contribute to alter bone quality, which finally results in compromised biomechanical properties of the skeleton [10]. Through high resolution peripheral quantitative computed tomography (HR-pQCT), Petit and co-workers showed that older men with diabetes had similar cortical volumetric BMD (vBMD) but smaller bone area (possibly due to smaller periosteal expansion), which determined low bone bending strength at mid-shaft sites of the radius and tibia [21]. Also perimenopausal women with T2DM, despite the higher areal BMD of the femoral neck, had lower strength indices for compression and bending, which in turn inversely correlated with the homeostasis model-assessed insulin resistance [33]. Accordingly, women with diabetes have higher mechanical stress (evaluated by an engineering beam analysis, incorporating dimension and geometry obtained by hip structural analysis) despite higher femoral neck BMD [34]. This reflects weaker femoral geometry for a given load, and in turn suggests that bone fragility derives from an impaired adaptive response of the skeleton to load [34]. The defective mechanical competence has been also related to poor metabolic control of diabetes. In inadequately controlled diabetic patients, skeletal fragility may occur in the presence of higher femoral neck BMD and thicker femoral cortices, in narrower bones. These features of bone geometry have been speculatively traced back to an impaired bone repair, resulting in microcracks accumulation and cortical porosity [35]. Bone microstructure has been largely investigated non invasively by HR-pQCT. Through this technique, in T2DM it has been consistently shown that increased vBMD of trabecular bone is associated with increased cortical porosity, mainly at peripheral skeletal sites [36]. Moreover, postmenopausal women with T2DM and fragility fractures showed higher cortical porosity of the distal radius and ultradistal and distal tibia than those without fractures [37]. In short, the reported higher areal bone density is
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confounded by bone size, and faces to higher trabecular vBMD but unchanged cortical vBMD. Such inefficient redistribution of bone mass could partly explain the apparent inconsistency between the increased fracture rate and the higher areal BMD, as well as the occurrence of fracture in skeletal sites rich of cortical tissue [10,38]. Recently Leslie et al. utilized the Trabecular Bone Score (TBS) (a software-generated texture parameter, capable to detect pixel gray-level variations from the DXA scan of the spine, and to indirectly provide information about bone microarchitecture) in patients with diabetes. In keeping with results obtained in different conditions [39], they showed that TBS values may be an independent predictor of major osteoporotic fractures (hip, clinical spine, forearm, and humerus fractures) even more accurate than BMD [40]. Independent of geometry and micro-structure, factors related to hyperglycemia itself may play a detrimental role on the mechanical properties of the skeleton. Chronic hyperglycemic state, together with oxidative stress, may induce the accumulation of Advanced Glycation EndProducts (AGEs) into various bone proteins, including type 1 collagen. This in turn translates in altered bone quality and increased susceptibility to fracture [1,10], probably because higher AGEs levels worsens the effects of increased cortical bone porosity [41]. Among the AGEs, the most investigated moiety is pentosidine, resulting from the non enzymatic glycation of cross-links of type 1 collagen, and accumulating in bone with aging and in diabetes [42]. Higher urine and serum pentosidine levels were found to be associated to increased incidence and prevalence of vertebral and nonspine fractures in T2DM [43]. Increased AGEs may decrease bone formation by interfering with osteoblast differentiation and function [10]. Also circulating osteogenic precursor cells are decreased in T2DM [44], even because mesenchymal stem cells seem to be preferentially committed toward preadypocytes rather than toward the osteogenic lineage [45]. Actually, women with poorly controlled T2DM have higher levels of marrow adipose tissue than those with normal glycated hemoglobin levels [46]. Such an interference on bone formation is also mirrored by the reduced concentration of osteocalcin, a biochemical marker bone formation, whose undecarboxylated form in turn affects glucose metabolism [47]. Among 123 men and 123 postmenopausal women with T2DM, Yamamoto et al. found lower values of PTH and osteocalcin in those with higher fracture risk [48]. However, it should be stressed that the relationship between osteocalcin (or its undecarboxylated form) and glucose homeostasis in human beings is complex and still conflicting, coming most evidence from animal models. Furthermore, recent “in vitro” and “in vivo” studies are disclosing a complex network among adipose tissue, the liver, and the skeleton, whose cytokine-mediated crosstalk may influence bone tissue. In this context a possible role for adipokines (leptin and adiponectin) [49], fetuin-A [50], and retinol-binding protein 4 [51] has been identified.
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A relevant role in the pathogenesis of skeletal involvement in T2DM has been recently assigned to sclerostin, a substance produced by the osteocyte, that is capable to inhibit the anabolic Wnt pathway in bone. Its levels are increased in patients with T2DM [52], directly correlate with disease duration and glycated hemoglobin levels, whereas negatively correlate with some biomarkers of bone turnover [53]. Moreover, elevated sclerostin levels have been found in diabetic patients having higher BMD, vertebral fractures, and atherosclerotic vascular involvement (i.e. abnormal intima-media thickness, carotid plaques, and aortic calcifications) [54,55]. On the other hand, reduced levels of other biochemical markers of bone formation (e.g. bone-specific alkaline phosphatase), as well as of bone resorption (e.g. the carboxy-terminal peptide of type 1 collagen) have been reported in T2DM [49]. Although the evidence on bone turnover is sparse, available data on average suggest that skeletal turnover in T2DM tend to be decreased [1,2], and this would affect bone quality, too. A contributing role might also be played by the modified PTH secretion and electrolyte renal handling [56]. Extra-skeletal factors In T2DM, several disease-related factors may increase the risk of fall and, consequently, of fracture (particularly of the hip). The increased fall risk is pronounced in older patients with long-lasting diabetes, or with complications of the disease, such as disturbed vision (due to retinopathy or cataracts), cardiac arrhythmia (due to cardiovascular complications), poor balance and poorer walking performances (due to diabetic neuropathy), nicturia (due to glycosuria and associated hypercalciuria), associated therapies, and even intensive glycemic control [1,8,16,19]. Growing attention has been recently paid to sarcopenia and frailty [57]. The vast majority of older patients with T2DM have vitamin D deficiency [58], which induces muscle weakness and increased risk of falls. At this regard, the results of a previous meta-analysis [59] are in line with those of a recent Cochrane review of data from community-dwelling older people [60], showing that, besides exercise programmes (including Tai-chi), vitamin D supplementation may reduce the rate of falls and falling risk in people with lower vitamin D levels before treatment. Pharmacologic treatments Recent data indicate that several drugs employed for diabetes treatment may affect skeletal metabolism [61]. Despite the anabolic effect of insulin on bone, some studies reported that insulin treatment was associated to a higher rate of falls and an increased risk of fracture [8,20,62]. This could merely reflect the fact that insulin therapy is usually employed in T2DM patients with severe disease of longer duration, and/or bearing multiple complications. Interestingly, a higher rate of falls has been
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found in insulin-treated patients with glycated hemoglobin 6% [8], which from this perspective underlines the risk of a too tight control of the disease. Thiazoledinediones have been shown to exert detrimental effects on bone. These drugs ameliorate the insulin sensitivity of muscle and adipose tissue, by acting as agonists of the PPAR-g. Via the same mechanism, however, they promote the preferential differentiation of mesenchymal stem cells into adipocytes rather than osteoblasts, also through the decreased expression of IGF-I in bone tissue [47,62]. In postmenopausal non-osteoporotic diabetic women, rosiglitazone therapy after 52 weeks increased bone turnover markers and decreased vertebral and femoral BMD, though these effects were reversible with the withdrawal of the drug [63]. Thiazoledinediones significantly increase the incidence of fracture, at least in postmenopausal women, whereas less conclusive results were obtained in men [10,61,64,65]. Since pioglitazone exert similar skeletal effects, bone damage appears as a “class effect” of the thiazoledinediones [65]. These skeletal, together with the cardiovascular side effects, may considerably narrow the benefit/risk window of these drugs in older people with diabetes. Sparse results suggest a preventive effects of sulfonylureas on fractures, but available data still suffer from limitations in study population and design, outcome definition, confounding adjustment, and further studies are needed to define the effect sulfonylureas on falls and fractures [66]. In vitro and animal studies indicated that metformin could inhibit adipocyte differentiation and stimulate osteoblast differentiation, through the inhibition of PPARg and the transactivation of Runx-2. This way, the drug could play a protective role on osteoblasts, against the detrimental effects of AGEs. Metformin would also stimulate osteoblastic expression of osteoprotegerin and depress that of RANK-L, so inhibiting osteoclast function and bone loss [13]. Such mechanisms would account for the reduced risk of fracture found in patients treated with metformin. Finally, the administration of agonists of glucacon-like peptide 1 (GLP-1) (as exenatide and liraglutide), or of inhibitors of the enzyme dipeptidyl peptidase-4 (DPP-4) (as sitagliptin and valdagliptin) increases the bioavailability of the gastrointestinal peptides (GIP, GLP-1 and GLP-2). Available data from animal models (mainly) and small studies in humans indicate that these drugs could positively modify the balance of bone turnover, increasing bone formation and reducing nocturnal bone resorption [61,67]. Moreover, a meta-analysis of relatively short-term studies [68] suggests that therapy with DPP-4 inhibitors might be associated with reduced fracture risk. If confirmed on large and prospectively followed samples of patients with T2DM, these results would have relevant therapeutic implications. Few notes on anti-osteoporotic therapy Therapy of osteoporosis in patients with T2DM at the moment simply follows the schemes approved for
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osteoporosis treatment, because specific clinical trials for these patients are still not available. A nationwide Danish cohort study comparing 103 562 users of anti-resorptive drugs (bisphosphonates or raloxifene) to 310 683 control subjects from the general population did not show differences in the anti-fracture efficacy between patients with and without T2DM, or between patients with type 1 and type 2 diabetes [69]. Thus, it is conceivable that patients with and without T2DM should receive the same treatment for osteoporosis, but formal guidelines on this topic are still lacking. Conceptual concerns remain on possible detrimental effects on bone quality of anti-resorptive drugs, due to the mentioned mechanisms underlying skeletal involvement in T2DM. Conclusions In conclusion, patients with T2DM on average have increased fracture risk, despite having higher BMD values. This seemingly paradoxical evidence relies on the fact that altered microarchitecture, accumulation of AGEs (mainly pentosidine), modified bone turnover (and in particular depressed osteoblastic differentiation and action) significantly affect bone quality. All these aspects exert detrimental effects on the mechanical properties of the skeleton, and increase bone fragility, in a way that is poorly captured by both BMD measurement and algorithms based on clinical risk factors. On the other hand, extraskeletal factors as frailty, muscle weakness, complications of the disease, and some anti-diabetic therapy, translate in increased rate of fall. The combination of bone fragility and increased tendency to fall in turn accounts for the significantly higher fracture rate of these patients. Declaration of interest The authors declare that they have no conflict of interest. References [1] Carnevale V, Romagnoli E, D’Erasmo E. Skeletal involvement in patients with diabetes mellitus. Diabetes Metab Res Rev 2004; 20:196e204. [2] Merlotti D, Gennari L, Dotta F, Lauro D, Nuti R. Mechanisms of impaired bone strength in type 1 and 2 diabetes. Nutr Metab Cardiovasc Dis 2010;20:683e90. [3] Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011;94:311e21. [4] International Osteoporosis Foundation. Facts and statistics. www. iofbonehealth.org/facts-statistics. [5] Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006;17:726e1733. [6] Gerber Y, Melton III LJ, McNallan SM, Jiang R, Weston SA, Roger VL. Cardiovascular and noncardiovascular disease associations with hip fractures. Am J Med 2013;126:169. e19e169.e26. [7] Billings LK, Hsu YH, Ackerman RJ, Dupuis J, Voigt BF, RasmussenTorvik LJ, et al. Impact of common variation in bone-related genes on type 2 diabetes and related traits. Diabetes 2012;61: 2176e86. [8] Schwartz AV, Vittinghof E, Sellmeyer DE, Feingold KR, de Rekeneire N, Strotmeyer ES, et al. Diabetes-related complications,
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in men and women with and without type 2 diabetes mellitus: a cross-sectional study. Diabetes Metab Res Rev 2014;30:313e22. Hippisley-Cox J, Coupland C. Derivation and validation of updated QFracture algorithm to predict risk of osteoporotic fracture in primary care in the United Kingdom: prospective open cohort study. Brit Med J 2012;344:e3427. http: //dx.doi.org/10.1136/bmj.e3427. Ishii S, Cauley JA, Crandall CJ, Srikanthan P, Greendale GA, Huang MH, et al. Diabetes and femoral neck strength: finding from the hip strength across the menopausal transition study. J Clin Endocrinol Metab 2012;97:190e7. Hamilton CJ, Jamal SA, Beck TJ, Khaled AS, Adachi JD, Brown JP, et al. Evidence for impaired skeletal load adaptation among Canadian women with type 2 diabetes mellitus: insight into the BMD and bone fragility paradox. Metabolism 2013;62:1401e5. Oei L, Zillikens MC, Dehghan A, Buitendijk GHS, CastanoBetancourt MC, Estrada K, et al. High bone mineral density and fracture risk in type 2 diabetes as skeletal complications of inadequate glucose control. Diabetes Care 2013;36:1619e28. 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 micro-architecture in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2010;95:5045e55. 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 Min Res 2013; 28:313e24. Melton III LJ, Riggs BL, Leibson CL, Achenbach SJ, Camp JJ, Bouxsein ML, et al. A bone structural basis for fracture risk in diabetes. J Clin Endocrinol Metab 2008;93:4804e9. Romagnoli E, Cipriani C, Nofroni I, Castro C, Angelozzi M, Scarpiello A, et al. “Trabecular bone score” (TBS): an in direct measure of bone micro-architecture in postmenopausal patients with primary hyperparathyroidism. Bone 2013;53:154e9. Leslie WD, Aubry-Rozier B, Lami O, Hans D, Manitoba Bone Density Program. TBS (Trabecular Bone Score) and diabetesrelated fracture risk. J Clin Endocrinol Metab 2013;98:602e9. Tang SY, Vashishth D. The relative contributions of nonenzymatic glycation and cortical porosity on the fracture toughness of aging bone. J Biomech 2011;44:330e6. Saito M, Marumo K. Collagen cross-links as a determinant of bone quality: a possible explanation of bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int 2010;21: 195e214. Schwartz AV, Garnero P, Hillier TA, Sellmeyer ES, Feingold K, Resnick HE, et al. Pentosidine and increased fracture risk in older adults with type 2 diabetes. J Clin Endocrinol Metab 2009;94: 2380e6. Manavalan JS, Cremers S, Dempster DW, Zhou H, Dworakowsky E, Kode A, et al. Circulating osteogenic precursor cells in type 2 diabetes mellitus. J Clin Endocrinol Metab 2012;97: 3240e50. Kawai M, de Paula FJA, Rosen CJ. New insights into osteoporosis: the bone-fat connection. J Intern Med 2012;272:317e29. Fazeli PK, Horowitz MC, MacDougald OA, Scheller EL, Rodeheffer MS, Rosen CJ, et al. Marrow fat and bone-New perspectives. J Clin Endocrinol Metab 2013;98:935e45. Clements T, Karsenty G. The osteoblast: an insulin target cell controlling glucose homeostasis. J Bone Min Res 2011;26: 677e80. Yamamoto M, Yamaguchi T, Nawata K, Yamauchi M, Sugimoto T. Decreased PTH levels accompanied by low bone formation are associated with vertebral fractures in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab 2012;97:1277e84. Naot D, Cornish J. Citokines and hormones that contribute to the positive association between fat and bone. Front Endocrinol 2014;5:70. eCollection 2014. Musso G, Paschetta E, Gambino R, Cassader M, Molinaro F. Interactions among bone, liver, and adipose tissue predisposing to diabesity and fatty liver. Trends Mol Med 2013;19:522e35. Högström M, Nordström A, Nordström P. Retinol, retinol-binding protein 4, abdominal fat mass, peak bone mineral density, and markers of bone metabolism in men: the northern osteoporosis and obesity (NO2) study. Eur J Endocrinol 2008;158:765e70.
Bone damage in type 2 diabetes mellitus [52] Gaudio A, Privitera F, Battaglia K, Troisi V, Sidoti MH, Pulvirenti I, et al. Sclerostin levels associated with inhibition of the Wnt betacatenin signaling and reduced bone turnover in type 2 diabetes mellitus. J Clin Endocrinol Metab 2012;97:3744e50. [53] Gennari L, Merlotti D, Valenti R, Ceccarelli R, Ruvio M, Pietrini MG, et al. Circulating sclerostin levels in type 1 and type 2 diabetes. J Clin Endocrinol Metab 2012;97:1737e44. [54] Yamamoto M, Yamauchi M, Sugimoto T. Elevated sclerostin levels are associated with vertebral fractures in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2013;98:4030e7. [55] Morales-Santana S, Garcia-Fontana B, Garcia-Martin A, RozasMoreno P, Garcia-Salced JA, Reyes-Garcia R, et al. Atheroscleroic disease in type 2 diabetes is associated with an increase in sclerostin levels. Diabetes Care 2013;36:1667e74. [56] Carnevale V, Inglese M, Annese MA, De Matthaeis A, Santini SA, Frusciante V, et al. Vitamin D and parameters of calcium homeostasis in inpatients with and without type 2 diabetes mellitus. J Endocrinol Invest 2012;35:853e8. [57] Balducci S, Sacchetti M, Orlando G, Salvi L, Pugliese L, Salerno G, et al., Study on the Assessment of Determinants of Muscle and Bone Strength Abnormalities in Diabetes SAMBA Investigators. Correlates of muscle strength in diabetes: the study on the assessment of determinants of muscle and bone strength abnormalities in diabetes (SAMBA). Nutr Metab Cardiovasc Dis 2014;24:18e26. [58] Muscogiuri G, Sorice GP, Ajjan R, Mezza T, Pilz S, Prioletta A, et al. Can vitamin D deficiency cause diabetes and cardiovascular diseases? Present evidence and future perspectives. Nutr Metab Cardiovasc Dis 2012;22:81e7. [59] Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, Staehelin HB, Bazemore MG, Zee RY, et al. Effect of vitamin D on falls: a metaanalysis. J Am Med Assoc 2004;291:1999e2006.
1157 [60] Gillespie LD, Robertson MC, Gillespie WJ, Sherrington C, Gates S, Clemson LM, et al. Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev 2012 Sep 12;2012:9. http://dx.doi.org/10.1002/14651858. CD007146. [61] Montagnani A, Gonnelli S. Antidiabetic therapy effects on bone metabolism and fracture risk. Diabetes Obes Metab 2013;15: 784e91. [62] Lipscombe LL, Jamal SA, Booth GL, Hawker GA. The risk of hip fractures in older individuals with diabetes: a population-based study. Diabetes Care 2007;30:835e41. [63] Bilezikian JP, Josse RG, Eastell R, Lewiecki EM, Miller CG. Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus. J Clin Endocrinol Metab 2013;98:1519e28. [64] Lake YK, Singh S, Furberg CD. Long-term Use Thiazolidinediones Fractures Type 2 Diabetes: A Meta-analysis. Can Med Assoc J 2009;180:32e9. [65] Meier C, Kraenzlin ME, Bodmer M, Jick SS, Jick H, Meier CR. Use of thiazolidinediones and fracture risk. Arch Intern Med 2008;168: 820e5. [66] Lapane KL, Yang S, Brown MJ, Jawahar R, Pagliasotti C, Rajpathak S. Sulfonylureas and risk of falls and fractures: a systematic review. Drugs Aging 2013;30:527e47. [67] Yavopoulou MP, Yovos JG. Incretins and bone: evolving concepts in nutrient-dependent regulation o bone turnover. Hormones 2013;12:214e23. [68] Monami M, Dicembrini I, Antenore A, Mannucci E. Dipeptidyl peptidase-4 inhibitors and bone fractures. Diabetes Care 2011; 34:2474e6. [69] Vestergaard P, Rejnmark L, Mosekilde L. Are antiresorptive drugs effective against fractures in patients with diabetes? Calcif Tissue Int 2011;88:209e14.
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Nutrition, Metabolism & Cardiovascular Diseases journal homepage: www.elsevier.com/locate/nmcd
REVIEW
Bone damage in type 2 diabetes mellitus V. Carnevale a,*, E. Romagnoli b, L. D’Erasmo c, E. D’Erasmo c a
Unit of Internal Medicine, “Casa Sollievo della Sofferenza” Hospital, IRCCS, Viale dei Cappuccini snc, 71013 San Giovanni Rotondo, FG, Italy Department of Experimental Medicine, “Sapienza” University, Viale del Policlinico 155, 00161 Rome, Italy c Department of Internal Medicine and Medical Specialties, “Sapienza” University, Viale del Policlinico 155, 00161 Rome, Italy b
Received 28 February 2014; received in revised form 18 June 2014; accepted 30 June 2014 Available online 27 July 2014
KEYWORDS Type 2 diabetes mellitus; Bone mineral density; Bone quality; Fractures; Clinical risk factors
Abstract This review focuses on the mechanisms determining bone fragility in patients with type 2 diabetes mellitus (T2DM). Despite bone mineral density (BMD) is usually normal or more often increased in these patients, fracture incidence is high, probably because of altered bone ”quality”. The latter seems to depend on several, only partly elucidated, mechanisms, such as the increased skeletal content of advanced glycation end-products causing collagen deterioration, the altered differentiation of bone osteogenic cells, the altered bone turnover and microarchitecture. Disease duration, its severity and metabolic control, the type of therapy, the presence or absence of complications, as like as the other known predictors for falls, are all relevant contributing factors affecting fracture risk in T2DM. In these patients the estimate of fracture risk in the everyday clinical practice may be challenging, due to the lower predictive capacity of both BMD and risk factors-based algorithms (e.g. FRAX). ª 2014 Elsevier B.V. All rights reserved.
Type 1 and type 2 diabetes mellitus are both associated to bone damage [1,2]. However, the heavy epidemiological impact of type 2 diabetes on Western and developing Countries amplifies the interest on this latter condition. Type 2 diabetes mellitus (T2DM) now affects at least 285 million people worldwide, and this number will raise to 438 million by the year 2030 [3]. Such an increase will mainly occur in people aged over 60 years [3]. On the other hand, osteoporosis affects over 200 million people worldwide, concerning one out of ten women in their 60ies, 40% of women aged 80 and two-thirds of women aged 90 years [4]. Osteoporosis causes about 9 million fractures per year worldwide [5] and by 2050 the incidence of hip fracture is projected to increase by 240% in women and by 310% in men [4]. These epidemiological * Corresponding author. Tel.: þ39 0882 410285; fax: þ39 06 45549053. E-mail address: [email protected] (V. Carnevale). http://dx.doi.org/10.1016/j.numecd.2014.06.013 0939-4753/ª 2014 Elsevier B.V. All rights reserved.
data underlines as T2DM and osteoporosis are rapidly expanding among older people, that is in a growing proportion of the general population. This in turn will translate not only in staggering financial costs for the communities, but it will also impact on the daily clinical practice of most physicians, who will increasingly deal with elderly patients in whom diabetes and osteoporosis coexist [6]. Moreover, despite T2DM and osteoporosis have been traditionally viewed as separate entities, accumulating evidence indicates that these diseases are tightly linked. Recent reports even advanced the hypothesis that common genetic determinants may contribute to both diseases [7]. Anyhow, although the pathogenesis of bone involvement in diabetes is complex and still not fully elucidated, patients with T2DM have an increased propensity to fracture [1,2], only partly depending on their increased risk of falls due to complications as retinopathy, neuropathy, and macrovascular disease [1,8] (Fig. 1). Qualitative, more than quantitative, alterations of bone
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Figure 1 Proposed pathogenetic mechanism of bone fragility and fractures in type 2 diabetes mellitus. Insulin resistance results in higher levels of both insulin (which induce increased aBMD due to its anabolic action on bone) and glucose (which promote the skeletal accumulation of AGEs). Both insulin resistance and AGEs accumulation alter bone quality, microarchitecture (increased cortical porosity), and osteoblast differentiation and turnover (the related decrease of osteocalcin levels in turn worsens insulin-resistance). The consequently increased skeletal fragility, together with extraskeletal factors predisposing to fall, justifies the higher fracture rate of these patients. (L Z liver; AT Z adipose tissue; M Z muscle; P Z pancreas; MAT Z marrow adipose tissue; aBMD Z areal bone mineral density; MSC Z mesenchymal stem cells; PPARg Z peroxisome proliferator-activated receptor gamma pathway; Wnt Z Wingless integrase-1 pathway).
probably account for the increased skeletal fragility of patients with T2DM. The current review mainly focuses on evidence from human studies, but these results are largely consistent with those obtained in animal models [9].
Bone mineral density and fractures Patients with T2DM, as an apparent paradox, usually have relatively high bone mineral density (BMD), associated to an increased propensity to fracture. Despite some contrasting data [1], most reports on this topic indicated that these patients have normal or higher BMD values in respect to control subjects [1,2,10,11]. Discrepant results from literature probably relate to the non homogeneous composition of the investigated samples, since T2DM patients often differ for body weight, body mass index (BMI), insulin levels, clinical presentation or disease duration, presence or absence of complications, type and duration of anti-diabetic therapy [1]. All the mentioned factors actually could be as many confounders, because previous studies showed significant associations between BMD and obesity, BMI [12], serum insulin levels, drugs [13]. It is worth noting as most studies on this topic have been carried out by the DXA measurement of BMD. However, body or skeletal size affects the results obtained by DXA, which assesses areal instead of “true” volumetric BMD because of its two-dimensional geometry. Moreover, areal
BMD assessment by dual-energy X-ray absorptiometry (DXA) in patients with T2DM could be often affected by vascular calcium deposits, osteophytes, and diffuse idiopathic skeletal hyperostosis (DISH) [1]. Even considering these concerns, recent meta-analyses of BMD data [11,14] confirmed that BMD values are increased in patients with T2DM. In particular, Ma and co-workers [11], pooling 15 observational studies, analyzed DXA-BMD of 3437 patients and 19 139 control subjects. The BMD values measured at lumbar spine, femoral neck and total hip were higher in the whole sample of T2DM patients, as like as in male and female patients separately. The higher BMD associated with younger age, male sex, higher BMI, and glycated hemoglobin levels. Although normal or higher BMD values should portend preserved or increased bone strength, patients with T2DM, counter-intuitively, have an increased fracture risk [1,2,15e20], showing a higher rate both of “classical” osteoporotic fractures, as those of the forearm, vertebrae, humerus, and hip, and of so-called fatigue fractures (i.e. tarsal and metatarsal fractures). In patients with T2DM the risk of hip fracture, which carries the heaviest burden of morbidity and mortality, is significantly increased [21], attaining a relative risk (RR) between 1.80 and 2.66 [16,18]. Although a recent paper reported no elevation in risk in men with T2DM, and only a minimal increase (RR 1.05) of fracture risk in T2DM women [22], a recent meta-analysis of 12 studies
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demonstrated a RR of 1.7, without significant gender difference [19]. Patients taking oral anti-diabetic drugs seem to have lower risk, whereas the highest risk has been found in those with long-lasting or insulin-treated T2DM (being insulin a marker of more severe and long standing disease) and/or in those with complications of the disease [16,23]. Actually, patients with impaired glucose tolerance or recently diagnosed disease have lower or similar risk to non-diabetic subjects [24]. On the other hand, patients with T2DM have accelerated bone loss at the hip [24,25]. It has been hypothesized that the high insulin levels due to insulin resistance may initially play a protective role on bone, while protracted or complicated disease may induce qualitative and (less apparent) quantitative effects compromising skeletal integrity [2]. Vertebral fractures, though may severely impact on activities of daily living and on overall quality of life, are worldwide under-diagnosed, about two-thirds of them going clinically unrecognized. This explains some apparently contrasting results. Schwartz et al. in elderly women with diabetes found that the RR for vertebral fracture was 1.06e1.09 [15]. Instead, a recent study on Korean women, systematically utilizing vertebral morphometry to identify significant deformities, found that 43.3% of patients with T2DM had morphometric vertebral fractures. Such a risk was in turn associated to older age, history of fragility fracture and increased cardiovascular risk [26]. Similarly, in a small sample of Italian patients with T2DM vertebral fractures were found in 46% of patients, versus 17% of controls, through the use of the Spinal Deformity Index (SDI) [27]. Available data challenge the ability of BMD to identify patients with T2DM at higher risk for fracture, in comparison to the predictive capacity that this tool displays in the general population. In general, for a given BMD and age, patients with T2DM have a higher risk of fracture than those without the disease, and T2DM seems to represent an independent determinant of fracture risk [10,28]. The lower predictive capacity of BMD mandates the research of alternative tools for fracture prediction in patients with diabetes. A growing attention is paid to test the predictive capacity of algorithms based on clinical risk factors, among which the FRAX tool is the most diffused worldwide. It predicts the ten-year probability of either major osteoporotic (a composed endpoint of femur, spine, humerus and forearm fractures) or hip fracture [29]. Noteworthy, T2DM is not included among the primary entry variables of FRAX. Two recent reports tested the clinical performances of FRAX in T2DM patients, retrospectively examining the series of two prospective North American studies [28,30]. Schwartz et al. [28] found that in older patients with diabetes both lower femoral neck BMD T-score and higher FRAX score were associated with hip and nonspine fracture risk. However, the two reports consistently indicated that FRAX underestimates fracture risk in patients T2DM [28,30]. Also a multicentric Italian study on a prospectively enrolled sample of 974 patients with T2DM and 777 control subjects [31] showed that the FRAX scores of patients was not higher than those of control subjects, despite the
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higher number of previous fractures. Interestingly, some complications of diabetes were significantly related to the FRAX scores. Such associations might delineate specific clinical profiles, possibly destined to sustain a heavier burden of the disease, due to the sum of additive risk factors [31]. Overall, according to current data, the fracture risk of diabetic patients is not entirely captured by the current FRAX algorithm. However, the attracting hypothesis of adding diabetes to the FRAX algorithm deserves the preliminary collection of additional data from large population-based cohorts [10]. Interestingly, T2DM has been included as a binary variable (Y/N) in the statistically robust algorithm QFracture, derived by a cohort of 3 142 673 and validated on a cohort of 1 583 373 British patients [32]. But, at variance with FRAX, this algorithm has not been validated outside UK, so that its clinical utility in other Countries has not been demonstrated.
Bone structure/strength/turnover and quality Modified bone geometry, structure, turnover and biochemical features can all contribute to alter bone quality, which finally results in compromised biomechanical properties of the skeleton [10]. Through high resolution peripheral quantitative computed tomography (HR-pQCT), Petit and co-workers showed that older men with diabetes had similar cortical volumetric BMD (vBMD) but smaller bone area (possibly due to smaller periosteal expansion), which determined low bone bending strength at mid-shaft sites of the radius and tibia [21]. Also perimenopausal women with T2DM, despite the higher areal BMD of the femoral neck, had lower strength indices for compression and bending, which in turn inversely correlated with the homeostasis model-assessed insulin resistance [33]. Accordingly, women with diabetes have higher mechanical stress (evaluated by an engineering beam analysis, incorporating dimension and geometry obtained by hip structural analysis) despite higher femoral neck BMD [34]. This reflects weaker femoral geometry for a given load, and in turn suggests that bone fragility derives from an impaired adaptive response of the skeleton to load [34]. The defective mechanical competence has been also related to poor metabolic control of diabetes. In inadequately controlled diabetic patients, skeletal fragility may occur in the presence of higher femoral neck BMD and thicker femoral cortices, in narrower bones. These features of bone geometry have been speculatively traced back to an impaired bone repair, resulting in microcracks accumulation and cortical porosity [35]. Bone microstructure has been largely investigated non invasively by HR-pQCT. Through this technique, in T2DM it has been consistently shown that increased vBMD of trabecular bone is associated with increased cortical porosity, mainly at peripheral skeletal sites [36]. Moreover, postmenopausal women with T2DM and fragility fractures showed higher cortical porosity of the distal radius and ultradistal and distal tibia than those without fractures [37]. In short, the reported higher areal bone density is
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confounded by bone size, and faces to higher trabecular vBMD but unchanged cortical vBMD. Such inefficient redistribution of bone mass could partly explain the apparent inconsistency between the increased fracture rate and the higher areal BMD, as well as the occurrence of fracture in skeletal sites rich of cortical tissue [10,38]. Recently Leslie et al. utilized the Trabecular Bone Score (TBS) (a software-generated texture parameter, capable to detect pixel gray-level variations from the DXA scan of the spine, and to indirectly provide information about bone microarchitecture) in patients with diabetes. In keeping with results obtained in different conditions [39], they showed that TBS values may be an independent predictor of major osteoporotic fractures (hip, clinical spine, forearm, and humerus fractures) even more accurate than BMD [40]. Independent of geometry and micro-structure, factors related to hyperglycemia itself may play a detrimental role on the mechanical properties of the skeleton. Chronic hyperglycemic state, together with oxidative stress, may induce the accumulation of Advanced Glycation EndProducts (AGEs) into various bone proteins, including type 1 collagen. This in turn translates in altered bone quality and increased susceptibility to fracture [1,10], probably because higher AGEs levels worsens the effects of increased cortical bone porosity [41]. Among the AGEs, the most investigated moiety is pentosidine, resulting from the non enzymatic glycation of cross-links of type 1 collagen, and accumulating in bone with aging and in diabetes [42]. Higher urine and serum pentosidine levels were found to be associated to increased incidence and prevalence of vertebral and nonspine fractures in T2DM [43]. Increased AGEs may decrease bone formation by interfering with osteoblast differentiation and function [10]. Also circulating osteogenic precursor cells are decreased in T2DM [44], even because mesenchymal stem cells seem to be preferentially committed toward preadypocytes rather than toward the osteogenic lineage [45]. Actually, women with poorly controlled T2DM have higher levels of marrow adipose tissue than those with normal glycated hemoglobin levels [46]. Such an interference on bone formation is also mirrored by the reduced concentration of osteocalcin, a biochemical marker bone formation, whose undecarboxylated form in turn affects glucose metabolism [47]. Among 123 men and 123 postmenopausal women with T2DM, Yamamoto et al. found lower values of PTH and osteocalcin in those with higher fracture risk [48]. However, it should be stressed that the relationship between osteocalcin (or its undecarboxylated form) and glucose homeostasis in human beings is complex and still conflicting, coming most evidence from animal models. Furthermore, recent “in vitro” and “in vivo” studies are disclosing a complex network among adipose tissue, the liver, and the skeleton, whose cytokine-mediated crosstalk may influence bone tissue. In this context a possible role for adipokines (leptin and adiponectin) [49], fetuin-A [50], and retinol-binding protein 4 [51] has been identified.
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A relevant role in the pathogenesis of skeletal involvement in T2DM has been recently assigned to sclerostin, a substance produced by the osteocyte, that is capable to inhibit the anabolic Wnt pathway in bone. Its levels are increased in patients with T2DM [52], directly correlate with disease duration and glycated hemoglobin levels, whereas negatively correlate with some biomarkers of bone turnover [53]. Moreover, elevated sclerostin levels have been found in diabetic patients having higher BMD, vertebral fractures, and atherosclerotic vascular involvement (i.e. abnormal intima-media thickness, carotid plaques, and aortic calcifications) [54,55]. On the other hand, reduced levels of other biochemical markers of bone formation (e.g. bone-specific alkaline phosphatase), as well as of bone resorption (e.g. the carboxy-terminal peptide of type 1 collagen) have been reported in T2DM [49]. Although the evidence on bone turnover is sparse, available data on average suggest that skeletal turnover in T2DM tend to be decreased [1,2], and this would affect bone quality, too. A contributing role might also be played by the modified PTH secretion and electrolyte renal handling [56]. Extra-skeletal factors In T2DM, several disease-related factors may increase the risk of fall and, consequently, of fracture (particularly of the hip). The increased fall risk is pronounced in older patients with long-lasting diabetes, or with complications of the disease, such as disturbed vision (due to retinopathy or cataracts), cardiac arrhythmia (due to cardiovascular complications), poor balance and poorer walking performances (due to diabetic neuropathy), nicturia (due to glycosuria and associated hypercalciuria), associated therapies, and even intensive glycemic control [1,8,16,19]. Growing attention has been recently paid to sarcopenia and frailty [57]. The vast majority of older patients with T2DM have vitamin D deficiency [58], which induces muscle weakness and increased risk of falls. At this regard, the results of a previous meta-analysis [59] are in line with those of a recent Cochrane review of data from community-dwelling older people [60], showing that, besides exercise programmes (including Tai-chi), vitamin D supplementation may reduce the rate of falls and falling risk in people with lower vitamin D levels before treatment. Pharmacologic treatments Recent data indicate that several drugs employed for diabetes treatment may affect skeletal metabolism [61]. Despite the anabolic effect of insulin on bone, some studies reported that insulin treatment was associated to a higher rate of falls and an increased risk of fracture [8,20,62]. This could merely reflect the fact that insulin therapy is usually employed in T2DM patients with severe disease of longer duration, and/or bearing multiple complications. Interestingly, a higher rate of falls has been
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found in insulin-treated patients with glycated hemoglobin 6% [8], which from this perspective underlines the risk of a too tight control of the disease. Thiazoledinediones have been shown to exert detrimental effects on bone. These drugs ameliorate the insulin sensitivity of muscle and adipose tissue, by acting as agonists of the PPAR-g. Via the same mechanism, however, they promote the preferential differentiation of mesenchymal stem cells into adipocytes rather than osteoblasts, also through the decreased expression of IGF-I in bone tissue [47,62]. In postmenopausal non-osteoporotic diabetic women, rosiglitazone therapy after 52 weeks increased bone turnover markers and decreased vertebral and femoral BMD, though these effects were reversible with the withdrawal of the drug [63]. Thiazoledinediones significantly increase the incidence of fracture, at least in postmenopausal women, whereas less conclusive results were obtained in men [10,61,64,65]. Since pioglitazone exert similar skeletal effects, bone damage appears as a “class effect” of the thiazoledinediones [65]. These skeletal, together with the cardiovascular side effects, may considerably narrow the benefit/risk window of these drugs in older people with diabetes. Sparse results suggest a preventive effects of sulfonylureas on fractures, but available data still suffer from limitations in study population and design, outcome definition, confounding adjustment, and further studies are needed to define the effect sulfonylureas on falls and fractures [66]. In vitro and animal studies indicated that metformin could inhibit adipocyte differentiation and stimulate osteoblast differentiation, through the inhibition of PPARg and the transactivation of Runx-2. This way, the drug could play a protective role on osteoblasts, against the detrimental effects of AGEs. Metformin would also stimulate osteoblastic expression of osteoprotegerin and depress that of RANK-L, so inhibiting osteoclast function and bone loss [13]. Such mechanisms would account for the reduced risk of fracture found in patients treated with metformin. Finally, the administration of agonists of glucacon-like peptide 1 (GLP-1) (as exenatide and liraglutide), or of inhibitors of the enzyme dipeptidyl peptidase-4 (DPP-4) (as sitagliptin and valdagliptin) increases the bioavailability of the gastrointestinal peptides (GIP, GLP-1 and GLP-2). Available data from animal models (mainly) and small studies in humans indicate that these drugs could positively modify the balance of bone turnover, increasing bone formation and reducing nocturnal bone resorption [61,67]. Moreover, a meta-analysis of relatively short-term studies [68] suggests that therapy with DPP-4 inhibitors might be associated with reduced fracture risk. If confirmed on large and prospectively followed samples of patients with T2DM, these results would have relevant therapeutic implications. Few notes on anti-osteoporotic therapy Therapy of osteoporosis in patients with T2DM at the moment simply follows the schemes approved for
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osteoporosis treatment, because specific clinical trials for these patients are still not available. A nationwide Danish cohort study comparing 103 562 users of anti-resorptive drugs (bisphosphonates or raloxifene) to 310 683 control subjects from the general population did not show differences in the anti-fracture efficacy between patients with and without T2DM, or between patients with type 1 and type 2 diabetes [69]. Thus, it is conceivable that patients with and without T2DM should receive the same treatment for osteoporosis, but formal guidelines on this topic are still lacking. Conceptual concerns remain on possible detrimental effects on bone quality of anti-resorptive drugs, due to the mentioned mechanisms underlying skeletal involvement in T2DM. Conclusions In conclusion, patients with T2DM on average have increased fracture risk, despite having higher BMD values. This seemingly paradoxical evidence relies on the fact that altered microarchitecture, accumulation of AGEs (mainly pentosidine), modified bone turnover (and in particular depressed osteoblastic differentiation and action) significantly affect bone quality. All these aspects exert detrimental effects on the mechanical properties of the skeleton, and increase bone fragility, in a way that is poorly captured by both BMD measurement and algorithms based on clinical risk factors. On the other hand, extraskeletal factors as frailty, muscle weakness, complications of the disease, and some anti-diabetic therapy, translate in increased rate of fall. The combination of bone fragility and increased tendency to fall in turn accounts for the significantly higher fracture rate of these patients. Declaration of interest The authors declare that they have no conflict of interest. References [1] Carnevale V, Romagnoli E, D’Erasmo E. Skeletal involvement in patients with diabetes mellitus. Diabetes Metab Res Rev 2004; 20:196e204. [2] Merlotti D, Gennari L, Dotta F, Lauro D, Nuti R. Mechanisms of impaired bone strength in type 1 and 2 diabetes. Nutr Metab Cardiovasc Dis 2010;20:683e90. [3] Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011;94:311e21. [4] International Osteoporosis Foundation. Facts and statistics. www. iofbonehealth.org/facts-statistics. [5] Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006;17:726e1733. [6] Gerber Y, Melton III LJ, McNallan SM, Jiang R, Weston SA, Roger VL. Cardiovascular and noncardiovascular disease associations with hip fractures. Am J Med 2013;126:169. e19e169.e26. [7] Billings LK, Hsu YH, Ackerman RJ, Dupuis J, Voigt BF, RasmussenTorvik LJ, et al. Impact of common variation in bone-related genes on type 2 diabetes and related traits. Diabetes 2012;61: 2176e86. [8] Schwartz AV, Vittinghof E, Sellmeyer DE, Feingold KR, de Rekeneire N, Strotmeyer ES, et al. Diabetes-related complications,
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