Aging Clin Exp Res DOI 10.1007/s40520-014-0258-3


The prevention of fragility fractures in diabetic patients Stefano Gonnelli • Carla Caffarelli Nicola Giordano • Ranuccio Nuti

Received: 25 January 2014 / Accepted: 1 July 2014 Ó Springer International Publishing Switzerland 2014

Abstract Patients with diabetes mellitus (DM) are at greater risk of fractures mostly due to not only extraskeletal factors, such as propensity to falls, but also to bone quality alteration, which reduces bone strength. In people with DM, insulin deficit and hyperglycemia seem to play a role in determining bone formation alteration by AGE accumulation which directly influences osteoblast activity. Although there are conflicting data in the literature, adequate glycemic control with hypoglycemic treatment may be an important element in preventing bone tissue alterations in both type 1 and type 2 DM. Diabetes status is a predictive of future hip and major osteoporosis fractures independently of BMD and FRAX probability. Attention should be paid to the use of thiazolidinediones, especially in older women, because the direct negative effect on bone could exceed the positive effect of glycemic control. Systematic screening for complications and fall prevention efforts, along with calcium and vitamin D repletion and adequate physical activity, represents the mainstay of fracture prevention in DM patients. All anticatabolic drugs (raloxifene, bisphosphonates, denosumab) seem to be effective in DM patients. On the basis of pathophysiological evidence that suggests low bone formation in DM patients, osteoanabolic therapies such as teriparatide might represent an important therapeutic option for DM patients with severe osteoporosis and/or multiple fractures. The search for better methods for the identification of fragility fracture risk in the growing population of adult and elderly subjects with DM might be considered a clinical priority

S. Gonnelli (&)  C. Caffarelli  N. Giordano  R. Nuti Department of Medicine, Surgery and Neuroscience, University of Siena, Policlinico Le Scotte, Viale Bracci 2, 53100 Siena, Italy e-mail: [email protected]

which could improve the prevention of fracture in DM patients. Keywords Osteoporosis  Diabetes mellitus  Fragility fractures  Prevention

Diabetes and bone fragility: an increasingly close relationship The number of patients with osteoporosis or type 2 diabetes mellitus (T2DM) is increasing in aging and westernized societies. Both disorders may lead to conditions of disability in the elderly by causing fractures and vascular complications, respectively. Although osteoporosis and T2DM are traditionally viewed as separate disease entities, accumulating evidence indicates that they could be linked by similar pathophysiological mechanisms. Moreover, fragility fractures due to low bone strength have become increasingly recognized as skeletal complications of diabetes [1–5]. Bone mineral density (BMD) by dual X-ray absorptiometry (DXA) is a strong predictor of fracture risk, even though it does not encompass all aspects of bone strength. In patients with type 1 diabetes (T1DM) the majority of studies have reported a reduction of BMD at both lumbar spine and proximal femur [6]. Insufficient skeletal mineralization during puberty seemingly due to the lack of the anabolic action of insulin on bone may explain the lower BMD in T1DM. Osteopenia at the onset of T1DM indicates that autoimmune and inflammatory phenomena, which precede T1DM onset, may contribute to bone loss and altered mineralization [7]. Also the reduced levels of insulin-like growth factor-1 (IGF-1) may play a role in the impairment of bone status in T1DM subjects [8]. In T1DM


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an increased risk of hip fracture was observed, whereas for other types of fracture the number of studies was too scarce for a meta-analysis, although most studies revealed a trend towards an increase [2]. Instead, many studies have reported that in T2DM patients BMD was increased or unchanged in comparison with the general population [2, 9, 10]. Cumulative evidence shows that patients with T2DM in spite of normal or increased BMD present a high fracture rate for hip, foot and possibly all fractures, while an increase in spine, forearm, or ankle fractures was less evident [1, 2]. In particular, diabetes has been reported to increase hip fracture risk by 18 % in men and by 11 % in women, after adjustment for potential confounding factors, including age, comorbidities and medications that increase the risk of falls [11]. Moreover, two large meta-analyses that assessed studies involving 1.3 million participants reported odds ratio (OR) for hip fractures of 6.3–6.9 in patients with T1DM and of 1.4–1.7 in those with T2DM [1, 2]. The risk of all clinical fractures also increases in T2DM patients and a recent meta-analysis reported a relative risk (RR) of 1.2 (95 % CI 1.0–1.5) [1]. In a case–control study of about 120,000 patients, the OR for any fracture was 1.3 and 1.2 for T1DM and T2DM patients, respectively; whereas, the OR for hip fracture was 1.4 and 1.7 for T1DM and T2DM patients, respectively [12]. Therefore, the fact that in T2DM BMD is normal or increased in the face of an increased fracture risk strongly suggests that, other than the increased rate of falls, a lower bone quality due to both the diabetes itself and the antidiabetic treatments could play a role in determining fracture risk [13]. Mechanisms of interaction between diabetes and bone metabolism Despite emerging evidence that links diabetes mellitus and fragility fractures the mechanisms underlying alterations of bone metabolism and turnover in DM remain not completely understood. Several observations evidenced a condition of low bone turnover and decreased bone formation both in T1DM and in T2DM [1]. Recent experimental studies have reported that hyperglycemia would lead to non-enzymatic glycosylation of various proteins in advanced glycosylation end products (AGEs) which could play a role in impaired bone quality, especially in T2DM [14]. Hemoglobin A1c is a common example of an earlystage glycation product. The accumulation of AGEs in the collagen components of bone matrix is considered of crucial importance for the pathogenesis of bone alterations in DM patients. In fact, some in vitro studies have reported that AGEs stimulate interleukin-6 production by bone cells, increase osteoclastic bone resorption and inhibit osteoblastic activity and maturation [15, 16]. Pentosidine, the best known AGE, when measured in urine has been


reported to be associated with a 42 % increase in clinical fracture incidence in T2DM patients [17]. Furthermore, in a recent clinical study Yamamoto et al. [18] observed that in postmenopausal women with T2DM pentosidine serum levels were associated with the presence of vertebral fractures and that this association was independent of BMD. Nevertheless, the role of AGEs in determining bone fragility in diabetic patients remains not completely defined and no consensus exists on the validity of AGEs measurement in determining the risk of fracture in diabetic patients. Wnt signaling is also thought to be a common mechanism in the pathogenesis of osteoporosis and diabetes. Mani et al. [19] showed that a single missense mutation in low-density lipoprotein receptor-related protein 6 (LRP6), the co-receptor for the Wnt-signaling pathway, was genetically linked to osteoporosis as well as diabetes, hyperlipidemia, and early coronary artery disease. Moreover, two recent studies have found a marked increase in circulating sclerostin levels in T2DM patients, which were associated with inhibition of Wnt/beta-catenin signaling and reduced bone formation and bone turnover [20, 21]. Recently, peroxisome proliferator-activated receptorgamma (PPARc) has emerged as a further important factor in bone metabolism. In fact, osteoblasts and adipocytes share a common progenitor in mesenchymal stem cells, which give rise to osteoblasts, adipocytes and other cell types [22]. An increased PPARc expression was detected in mice with T1DM, suggesting that insulin-dependent diabetes contributes to bone loss through an adipose accumulation in bone marrow in place of mature osteoblasts. Similarly, it has been observed that thiazolidinediones, PPARc activators, convert cells of osteoblastic lineage into terminally differentiated adipocytes while simultaneously and irreversibly suppressing the osteoblastic phenotype [23].

The prevention and the treatment of fragility fractures Glycemic control and diabetes therapy In theory, the therapeutic regimens able to ensure normal fasting and postprandial glucose levels and maintain the percentage of HbA1c below the threshold of 6.5–7.0 % are expected to minimize most of the adverse effects of glucose on bone. In animal models an improvement of diabetes control has resulted in a reversal of the histomorphometric bone changes induced by diabetes [24]. Observational studies have pointed out the reversal of loss of calcium in the urine and an improvement of BMD when blood glucose levels were better controlled [25]. Moreover, human data support the concept that insulinopenia in

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T1DM patients may impair osteoblast function. This hypothesis seems to be supported by the results of a study carried out in 62 patients with T1DM and low BMD who started intensive insulin treatment and who were followed for 7 years [26]. In this study insulin treatment was associated with the stabilization of BMD at all sites, as well as a significant decrease in bone resorption markers [26]. Likewise, Vestergaard et al. [3] reported that in both T1DM and T2DM patients the risk of fracture may decline over time together with an improved metabolic control. However, the same author [2] in one observational study failed to show any association between HbA1c and BMD. This finding should be interpreted with caution; in fact, HbA1c reflects blood glucose levels within the last 6–8 weeks, whereas bone turnover is a process which requires more time. Also, as previously underlined, BMD may not adequately reflect bone biomechanical competence in patients with diabetes. At present, the effects of glycemic control on BMD and fracture risk remain not clearly understood. In fact, in the ACCORD randomized trial, there was no difference in the rate of fractures and falls between the intensive and standard glycemic control groups, suggesting that an intensive management of glycemia does not improve bone strength in patients with diabetes [27]. However, the two groups in the ACCORD study were both well controlled (6.4 and 7.5 % of HbA1c in intensive and standard glycemic control protocol), and the use of thiazolidinediones was higher in the intensive group justifying no difference between the groups [27]. Concerning the relationship between strict glycemic control and fragility fracture risk two important epidemiological studies have provided conflicting and inconsistent results [12, 28]. In the Danish case–control study [12] insulin treatment did not seem to affect the incidence of bone fracture, whereas in an Italian case–control study [28] insulin treatment was seen to have caused a significant increase in bone fracture in women but not in men. Moreover, when the same Authors performed a long-term analysis, taking into account only patients with an exposure of more than 3 years, both agreed on not having found any insulin effects on bone fracture [12, 28]. An increased incidence of vertebral fractures in T2DM patients treated with insulin has been reported in another study [29]; this finding is probably due to the fact that T2DM patients on insulin therapy may be likely to have longer duration of diabetes, more complications and a higher risk of hypoglycemic events. However, the risk of hypoglycemic episodes, which represent a not entirely eliminable problem in these patients, should be minimized by accurate titration of the antidiabetic drugs dosage, frequent self-monitoring of glucose levels and, when necessary, using specific devices such as sensors and microinfusors. Also, the more recent observational studies have reported discordant findings

about the relationship between glycemic control and fracture risk. A case–control study carried out on a Chinese population of T2DM elderly patients reported that in T2 DM patients a tight glycemic control (HbA1c \7 %) was associated with an increased risk of hip fracture [30]. On the contrary, data from the Rotterdam study, a prospective population-based cohort, showed that a poor glycemic control (HbA1c C7.5 %) was associated with an increased fracture risk [31]. Also, the results of the Atherosclerosis Risk in Communities (ARIC) study have suggested that diabetic patients who also had poor glucose control, as defined by HbA1c C8 % or who used insulin, were at particularly high risk of fracture-related hospitalization [32]. Considering other oral antidiabetic drugs, several clinical studies have demonstrated that long-term therapy with thiazolidinediones causes a reduction in BMD and a greater risk of fractures, particularly in postmenopausal women, and that this effect increases with age [33]. Therefore, thiazolidinediones should not be given to postmenopausal women or to any patients with a history of fragility fractures. Since data on fracture risk associated with thiazolidinediones use in men and premenopausal women are less conclusive, in such cases treatment decisions should be made on an individual basis [4]. The skeletal effects of other oral antidiabetic drugs remain less known, even though some clinical evidence suggests a reduced risk of fractures in patients treated with metformin or sulfonylurea [12]. In fact, the A Diabetes Outcome Progression Trial (ADOPT) study reported that T2DM patients treated with metformin or sulfonylurea presented a reduced fracture risk with respect to those treated with thiazolidinediones and that there was no differences in fracture rates between patients treated with metformin or sulfonylurea [34]. Although preliminary data on animals and in humans suggest the hypothesis that GLP-1 analogs and DPP-4 inhibitors could have a positive effect on bone metabolism, their efficacy in the reduction of fracture risk has not yet been confirmed in large clinical trials [35, 36]. The effects of antidiabetic drugs on BMD and fragility fractures are summarized in Table 1. Moreover, many T2DM patients are overweight or obese and necessitate weight reduction to improve glycemic control and reduce cardiovascular risk. Literature data have reported that in older adults without DM intentional weight loss is associated with bone loss which may be prevented by increased physical activity [37]. Recently, data of the Look AHEAD trial have evidenced that 1 year of intentional weight loss in overweight and obese T2DM patients resulted in greater, though modest bone loss at the total hip and femoral neck, but not at the spine or whole body [38]. This latter study also evidenced that in the intervention group increased physical activity during weight loss did not prevent bone loss at proximal femur [38]. On the other hand, a previous


Aging Clin Exp Res Table 1 Effects of antidiabetic drugs on BMD and risk of fractures Antidiabetic drug

Effect on BMD

Risk of fracture



Controversial data



Probably reduced


Probably positive

Probably reduced




GLP-1 analogs


Potentially reduced

DPP-4 analogs

Positive or neutral

Potentially reduced

BMD bone mineral density, GLP-1 glucon-like peptide 1, DPP-4 dipeptidyl peptidase-4

Table 2 Diabetes-related risk factors for fractures Diagnosis of T1DM Intensive insulin therapy in T2DM Diabetic nephropathy Diabetic neuropathy Thiazolidinediones in PM women with T2DM Disease duration [10 years High serum levels of pentosidine Recurrent hypoglycemias

randomized trial of intervention to reduce falls in community-dwelling older people have found that falls can be prevented through exercise programs that included a combination of strength, endurance, balance and flexibility; they also reported that group and home-based exercise programs and home safety intervention reduced the right of falls and risk of falling [43]. Therefore, it is likely that exercise programs shown to reduce falls in broader population will also be effective in diabetic patients. Moreover, a systematic review by Gordon et al. [44] suggested that a combination of strength and aerobic exercise training may reduce fracture risk in T2DM patients. These findings indicate that systematic screening for complications and fall prevention efforts should be taken into consideration in the management of DM patients, in particular if elderly women. Within the systematic screening for DM complications the crucial points are as follows; (a) an intense therapy for hypertension with ACE inhibitors and ARBs; (b) an adequate control of hypercholesterolemia with statins; (c) periodic screening for albuminuria and retinopathy and (d) annual testing for vibration sensitivity [45].

T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus

Calcium and vitamin D supplementation study carried out on older T2DM individuals reported that high-intensity resistance training reduced the effects of weight loss on whole-body BMD [39]. However, to date the effect of weight loss on fragility fracture risk in T2DM individuals remains to be defined (Table 2). Prevention of diabetic complications Diabetic complications, such as nephropathy, retinopathy, polyneuropathy, macroangiopathy and microangiopathy, have been reported to be associated with reduced BMD and an increased risk of falls and fragility fractures [5, 40]. A prospective cohort study carried out in 9,249 postmenopausal women reported that diabetes was associated with an increased risk of falls also in patients not treated with insulin [41]. Moreover, patients with diabetes are more likely to have additional risk factors such as poor balance, arthritis, cardiovascular disease, depression, poor vision, and use of benzodiazepines [40]. However, several studies have reported that in DM patients the fracture risk is significantly reduced, but not annulled, after controlling for any diabetic complications predisposing to trauma, suggesting that the disease itself is closely connected with an impaired bone strength and an increased fracture risk. In turn, the propensity of DM patients toward falls because of visual reduction, peripheral neuropathy and reduced muscle strength may contribute to the amplifying of such a risk [42]. The Cochrane Collaboration reviews of the


In DM patients any deficiencies in calcium and vitamin D should be prevented and treated before specific osteoporosis drugs are started; however, at present, there are no specific guidelines for calcium/vitamin D supplementation in diabetic patients. The National Institutes of Health (NIH) in the USA propose a recommended dietary allowance for calcium of 1,000 mg in men aged 50–70 years and 1,200 mg in men older than 70 years and women older than 50 years. The concurrent use of loop diuretics or proton-pump inhibitors and the presence of malabsorption or diabetic nephropathy might increase the daily calcium requirement [4]. The recommended daily calcium intake should be ideally reached through the diet and calcium supplementation should be restricted to whenever the dietary intake is inadequate or, for whatever reason, cannot be optimized with the diet. In fact, recent studies have reported that high doses of calcium supplementation may increase the deposit of calcium at the level of atherosclerotic plaques and may represent a risk factor for myocardial infarction and other cardiovascular diseases [46, 47]. The potential risk connected to calcium supplementation could be increased by the contemporary presence of high phosphate levels, as happens in chronic kidney disease. The cardiovascular risk associated with calcium supplements has been put into doubt due to more recent studies [48, 49]. On the other hand, it is important to consider that DM patients often present scarce gastrointestinal tolerance to calcium supplements, which could be overcome by taking

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supplements during meals. However, calcium supplementation has been reported to have only a modest effect on BMD and fracture incidence and that these benefits do not persist once calcium supplements are stopped [49]. In fact, calcium supplementation has shown significant effects on fracture risk only when given together with vitamin D in high-risk populations. Vitamin D deficiency is common among elderly subjects and is thought to contribute to bone loss by stimulating parathyroid hormone (PTH) secretion with consequent increased bone resorption. Vitamin D supplementation should ensure a serum 25-OH-hydroxyvitamin D levels of 75 nmol/L (=30 ng/mL) since previous studies have reported that bone mineralization defects were not seen if serum 25-OH-hydroxyvitamin D levels were above 75 nmol/L [50]. As the majority of subjects cannot reach the threshold of 30 ng/mL by consuming foods rich in vitamin D or sun exposure, a supplementation of 800–2,000 IU of vitamin D per day is recommended. Obese patients with T2DM require higher doses of vitamin D ([3,000 IU daily) because of a larger volume of distribution and the accumulation of vitamin D in the adipose tissue. Since the adherence to daily regimens of vitamin D supplementation may be low, higher intermittent doses (25,000 IU monthly or 100,000 every 4 months) have been proposed, which should improve treatment adherence [51]. However, recent studies have reported that the use of vitamin D bolus exceeding 100,000–300,000 IU may be associated with an unexpected increase in bone resorption and in fracture rate [52, 53]. The ability of vitamin D in reducing falls in the elderly has been observed in several studies and in a double-blind, randomized controlled trial by Bischoff et al. [54] carried out in a cohort of 122 elderly women without DM (mean age 85.3 years). In this study the participants were randomized to receive 1,200 mg calcium plus 800 IU cholecalciferol or 1,200 mg per day over a 12-week treatment period. The results showed that the vitamin D plus calcium supplementation reduced the number of falls per person by 49 %, improved musculoskeletal function and decreased PTH levels and bone resorption markers. These findings support the necessity for all DM patients to have adequate serum levels of vitamin D assured. Pharmacological treatment: anticatabolic drugs In recent years, the therapeutic alternatives for the prevention and treatment of osteoporotic fractures have notably increased in number and today comprise numerous drugs with different mechanisms of action. However, studies specifically designed to evaluate the antifracture efficacy of different drugs in DM patients are not available. The need for information on this latter point has been

stimulated by the observation that DM is a condition characterized by low bone turnover and impaired bone formation. Therefore, this pattern appears to be different with respect to that of the populations on whom the registrative studies of antiosteoporotic drugs were carried out, who were generally postmenopausal osteoporotic women with high bone turnover and increased bone resorption. A few post hoc and retrospective studies reported that the effect of alendronate and raloxifene on BMD was similar in postmenopausal osteoporotic women with or without DM [55–59]. However, these studies, due to the small sample sizes, were lacking in statistical power for fracture incidence. In particular, it has been reported that the reduction in BMD in postmenopausal women on dialysis with or without T2DM was suppressed by raloxifene therapy [55]. Moreover, Johnell et al. [56] in a subgroup analysis of the MORE trial reported that 3-year treatment with raloxifene significantly reduced vertebral fracture risk in postmenopausal osteoporotic women with T2DM. An analysis of the Fracture Intervention Trial (FIT) to compare changes in BMD during 3 years of alendronate treatment versus placebo in postmenopausal women with low BMD and T2DM showed that the increase in BMD, at both lumbar spine and total hip in the alendronate group relative to placebo, was similar for women with or without T2DM; also, the tolerability profile was similar in diabetic and nondiabetic women [57]. Similar findings have been more recently reported in a small retrospective Japanese study [58]. Instead, Dagdelen et al. [59] suggested that postmenopausal osteoporotic women with T2DM were resistant to long-term alendronate (4.8 years) at the hip and forearm regions compared with the lumbar spine. A large Danish retrospective cohort study, carried out in 103,562 patients exposed to drugs against osteoporosis, assessed whether antiresorptive drugs were effective in patients with DM as well as in those without [60]. The conclusion of this study was that diabetes does not seem to affect the fracture preventive potential of bisphosphonates (alendronate, clodronate and etidronate) and raloxifene; therefore, the low bone turnover state of DM does not seem a hindrance to the antifracture effects of anticatabolic drugs [60]. A potential limitation of this latter study is the lack of data for more recent bisphosphonates, such as risedronate, ibandronate and zoledronate. However, it is generally considered that antifracture efficacy in DM patients is a class characteristic and so extendible to all bisphosphonates [60]. In recent years there has been a growing interest for the use of intravenous bisphosphonates, such as zoledronic acid (5 mg yearly) and ibandronate (3 mg every 3 months). Moreover, intravenous bisphosphonates, namely zoledronic acid, are being revealed as useful also in the treatment of Charcot arthropathy, an uncommon complication of DM patients with diabetic polyneuropathy. When using


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parenteral bisphosphonates in patients with DM it is important to consider that they should not be administered to patients with a glomerular filtration rate \45 mL/min/ 1.73 m and that DM is considered a risk factor for the osteonecrosis of the jaw [61]. In fact, diabetic patients were nearly five times more likely to be diagnosed with osteonecrosis of the jaw compared to the total population receiving bisphosphonates for osteoporosis [62]. Therefore, an accurate oral hygiene should be recommended to all diabetic patients treated with bisphosphonates, who undergo invasive dental procedures, since oral hygiene has been proved to markedly reduce the risk of the osteonecrosis of the jaw. Denosumab, the first inhibitor of the receptor activator of nuclear factor k-B ligand (RANKL), represents a novel strategy for treating osteoporosis. In fact denosumab, (60 mg) given subcutaneously once every 6 months, has been reported to markedly increase BMD at both trabecular and cortical sites and to reduce vertebral and non-vertebral fractures. The peculiar activity of denosumab on cortical bone could be useful in DM patients who present a preferential impairment of the cortical compartment with intracortical porosity. However, clinical data on the usefulness of denosumab for treating bone fragility in DM patients are lacking. Since rat models indicate that osteocalcin (OC) stimulates insulin sensitivity and insulin secretion by the pancreas, in hypothesis, a limitation to the use of anticatabolic drugs in DM patients could be the risk of an increased insulin resistance. In fact, potent anticatabolic drugs, such as bisphosphonates and denosumab, reduce both OC and undercarboxylated OC by 30–50 %. However, a recent large post hoc analysis of the registrative trials of alendronate, zoledronate and denosumab has reported that the above-mentioned antirsorptive drugs do not affect fasting glucose levels, weight or diabetes incidence [63]. Pharmacological treatment: anabolic drugs On the basis of pathophysiological evidence that suggests low bone formation in DM patients osteoanabolic therapies, such as parathyroid hormone 1–34 (teriparatide) or the full-length PTH 1–84, are particularly interesting. At present, there are no reports examining the efficacy of PTH treatment in the prevention of fragility fracture in patients with diabetes. However, in T1-diabetic mice PTH treatment has been reported to counteract bone loss and to stimulate osteoblastic bone formation [64]. Some clinical reports indicate that teriparatide may also favor the fracture healing in DM patients. In fact, DM patients who suffer fractures are at increased risk of delayed fracture healing and a high incidence of non-union or pseudoarthrosis. On this basis teriparatide might represent an important therapeutic option for DM patients with severe osteoporosis and/


or multiple fractures. One possible weakness for the using of teriparatide in DM patients could be the fact that teriparatide presents a mild increase in insulin resistance, which, however, tends to subside when teriparatide is continued on a chronic basis [65]. Among the osteoanabolic drugs, one interesting perspective is represented by the near availability of sclerostin antibodies, at present object of phase 3 trials. In fact, an increase in circulating sclerostin levels in T2DM patients has been reported to be associated with a reduction in bone formation and bone turnover [20, 21]. Recently, it has been reported that sclerostin antibody treatment reverses the adverse effects of T2DM on bone mass and strength, and improves bone defect regeneration in rats [66]. Also strontium ranelate, due to its combined anabolic and anticatabolic effects, could be an interesting therapeutic option for the treatment of bone fragility in T2DM patients. Moreover, strontium ranelate has been reported to improve fracture healing and ameliorate implant osseointegration. However, at present, the use of strontium ranelate in T2DM patients raises concerns about its cardiovascular safety in such patients. Since in T2DM patients osteoporosis is primarily secondary to an impairment of bone formation, anabolic therapies may be preferable but their effectiveness needs to be assessed and it is not known whether they are more effective than antiresorptive agents. The evaluation of bone fragility in diabetic patients The identification of diabetic patients at high fragility fracture risk before they have fractures might be considered a clinical priority which could improve the prevention of fractures. However, there is growing awareness of the inadequacy of current methods to predict fracture risk in DM patients who constitute a substantial portion of the older population. In general, in the evaluation of fracture risk in DM patients, we may use similar diagnostic tools as are used in other forms of secondary osteoporosis. Physical examination might help to identify the presence of diabetic complications (e.g. nephropathy, retinopathy, polyneuropathy, macroangiopathy and microangiopathy) and other risk factors for falls and fractures (e.g. malnutrition, low body weight, thoracic kyphosis, muscular atrophy, gait disturbances, etc.). The history should be focused on a comprehensive drug review to identify medications that reduce bone strength (e.g. thiazolidinediones, glucocorticoids, aromatase inhibitors, etc.) or increase the risk of falls (e.g. benzodiazepines, sleeping medications, antidepressants, etc.). In DM patients laboratory assessment does not offer any extra information but is essential for a comprehensive evaluation of the fracture risk. In addition to standard lab

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tests, it is important to assess the level of glycemic control by blood glucose profiles and HbA1c measurement, the urinary excretion of albumin, the serum levels of 25-hydroxyvitamin D and to calculate the glomerular filtration rate. The measurement of markers of bone turnover, namely bone-specific alkaline phosphatase and serum cross laps, could be useful in differential diagnosis and for the monitoring of treatment response [4]. In the general population, in the absence of previous fragility fractures, the diagnosis of osteoporosis has been based on low bone mass, defined by the World Health Organization (WHO) as a femoral neck BMD T score of -2.5 or lower. The suboptimal performance of BMD as the sole predictor of fracture risk and treatment decision making has led to the development of risk prediction algorithms that estimate fracture probability using multiple risk factors for fracture. The WHO Fracture Risk Algorithm (FRAX) score combines age, sex, body mass index, glucocorticoid use, current smoking, alcohol intake of three or more units per day, secondary osteoporosis, rheumatoid arthritis, prior fragility fractures, and BMD T score to estimate the probability for major osteoporotic and hip fractures over 10 years. FRAX score has been reported to improve fracture prediction over BMD T score alone. The FRAX score was designed to provide an estimate of absolute fracture risk in older adults that could be used in combination of country-specific cost-effectiveness data to set intervention thresholds. Diabetes is not a primary entry variable of FRAX; only T1DM is indirectly considered in FRAX as one of the secondary causes of osteoporosis. As T2DM is paradoxically characterized by higher BMD and increased facture risk, there are concerns about the usefulness of these established methods for predicting fragility fractures in T2DM patients. Schwartz et al. [67] by analyzing data from three prospective observational studies found that femoral neck BMD T score and FRAX score were associated with hip and non-spine fracture risk in older adults with T2DM and appeared to be useful for clinical evaluation of fracture risk. However, in these patients compared with participants without DM, the fracture risk was higher for a given T score and age, or for a given FRAX score; in particular, a T score in a woman with DM is associated with hip fracture risk equivalent to a woman without DM with a T score of approximately 0.6 units lower [67]. More recently, Giangregorio et al. [68] using a large clinical database from Manitoba, CA, reported that FRAX underestimated observed major osteoporotic and hip fracture risk in diabetics, but demonstrated good concordance with observed fractures for nondiabetics, suggesting that diabetes confers an increased risk of fracture that is independent of FRAX derived score with BMD. The inadequacy of commonly used diagnostic tools to pick up fracture risk in DM patients could be attributed to ‘‘the unresolved paradox of increased

fracture risk with higher bone density’’ as reported by Leslie [69]. In particular, the FRAX-based intervention thresholds (e.g., [20 % probability of a major osteoporotic fracture or [3 % probability of hip fracture in following 10 years) are certainly too high for DM patients and should be reduced. Unfortunately, at present no data are available to supply any information regarding the entity of such a reduction. Another possible alternative to overcome this problem could be to model the potential impact of DM on FRAX in a similar way to that proposed by Kanis [70] when considering the effects of glucocorticoid dosage or lumbar spine BMD on fracture probability. Moreover, divergent opinions are present in the literature about the opportunity that future prediction algorithms should consider including diabetes as an independent risk factor [68, 69]. However, since the current data suggest that women with T1DM are at higher risk of fracture it would be reasonable to screen these women at menopause instead of waiting until age 65, as generally suggested. X-ray evaluation of thoraco-lumbar spine should be considered in case of progressive back pain, kyphosis or substantial height loss to check for possible vertebral fractures. In fact, the presence of vertebral fractures may be expected to increase the risk of further vertebral, nonvertebral and hip fractures. The question of whether similar data could be more easily obtained with DXA-based vertebral fracture assessment, a tool associated with wider clinical applicability and less radiation and cost, remains not totally defined. Also, quantitative ultrasonography (QUS) at both calcaneus and phalanxes has been reported to be a promising alternative for the evaluation of fragility fracture risk in men and in women [71, 72]. In DM patients QUS measurements might be suggested as a screening tool or whenever BMD evaluation by DXA is not available. In conclusion, as the prevalence of diabetes continues to increase, it is necessary to understand the increased fracture risk in these patients. Therefore, the search for better methods for the identification of fragility fracture risk in the growing population of adult and elderly subjects with DM might be considered a clinical priority which could improve the prevention of fracture in DM patients who appear to benefit from the treatments for osteoporosis in the same way as nondiabetic patients. Conflict of interest On behalf of all authors, I declare no conflict of interest.

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The prevention of fragility fractures in diabetic patients.

Patients with diabetes mellitus (DM) are at greater risk of fractures mostly due to not only extraskeletal factors, such as propensity to falls, but a...
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