Abstract
Diabetes is a highly prevalent disease with complications that impact most bodily systems. However, the impact of diabetes on bone health is frequently ignored or underestimated. Both type 1 (T1D) and type 2 diabetes (T2D) are associated with a higher risk of fractures, albeit through different mechanisms. T1D is characterized by near total insulinopenia, which affects the anabolic tone of bone and results in reduced bone mineral density (BMD). Meanwhile, patients with T2D have normal or high BMD, but carry an increased risk of fractures due to alterations of bone microarchitecture and a local humoral environment that stimulates osteoclast activity. Chronic hyperglycemia induces non-enzymatic glycation of collagen in both types of diabetes. Epidemiological evidence confirms a largely increased fracture risk in T1D and T2D, but also that it can be substantially reduced by opportune monitoring of fracture risk and appropriate treatment of both diabetes itself and osteopenia or osteoporosis if they are present. In this review, we summarize the mechanistic, epidemiological, and clinical evidence that links diabetes and bone fragility, and describe the impact of available diabetes treatments on bone health.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Both type 1 and type 2 diabetes are associated with bone abnormalities and increased fracture risk, especially at the hip |
The mechanisms involved in type 1 diabetes involve reduced BMD as a consequence of insufficient anabolic tone from insulin |
Meanwhile, patients with type 2 diabetes usually have normal/increased BMD but have microarchitectural bone alterations that increase their risk of fracture |
Fracture risk should be taken into account when selecting antidiabetic medications for a patient |
Fracture risk should be routinely assessed and addressed in patients with diabetes |
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13154408.
Introduction
There is a strong interaction between insulin action and bone metabolism [1]. Therefore, both type 1 (T1D) and type 2 diabetes (T2D) are associated with a higher risk of fractures. Nonetheless, the mechanisms of the effects on bone in T1D and T2D may be different and do not necessarily involve a reduction in bone mineral density (BMD) [2]. Several studies show that BMD is lower among patients with T1D than healthy controls, while among patients with T2D BMD is equal or higher than in controls [2,3,4].
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Pathophysiology of Bone Alterations in Diabetes
Pathophysiology of Bone Alterations in Type 1 Diabetes
Compared to controls matched by age, sex, and body mass index (BMI), patients with T1D usually have a lower BMD in dual-energy X-ray absorptiometry (DEXA) [5]. T1D is characterized by almost absolute insulin deficiency [6], a key anabolic hormone not only in hepatocytes, adipocytes, and myocytes but also in osteoblasts [4]. Insulin action in osteoblasts stimulates mitosis, inhibits apoptosis, and prevents the deleterious effects of hyperglycemia on bone formation [4, 7]. Research shows that the stimulation of insulin receptors in immature mice osteoblasts promotes their proliferation and differentiation [4, 8]. Mature osteoblasts in culture also express insulin receptors [9]. Three signaling pathways are responsible for the effects of insulin in osteoblasts. First, insulin inhibits p27 (an inhibitor of cyclin-dependent kinases), de-repressing proliferation (Fig. 1) [10]. Second, insulin activates phosphatidylinositol 3-kinase, which phosphorylates BAD (BCL2-associated death promoter), blocking its pro-apoptotic effect (Fig. 2) [11, 12]. Third, insulin stimulates IGFR-1 (insulin-like growth factor 1 receptor), leading to anabolic effects [1]. Indeed, intensive insulin therapy stabilizes bone mass in T1D by restoring the anabolic activity of bone [13].
Not only lack of insulin but also hyperglycemia per se may have a negative effect on bone quality. In hyperglycemic states, non-enzymatic glycation of proteins, phospholipids, and nucleic acids leads to the formation of advanced glycation end products (AGE) [14]. Type 1 collagen is not exempt from this process [15]. The aggregation of AGEs causes non-enzymatic cross-linking of collagen, disrupting the adhesion of osteoblasts to the extracellular matrix and resulting in bone fragility [16] (Fig. 3). These alterations of extracellular matrix also reduce alkaline phosphatase (ALP) activity in mature osteoblasts, affecting bone mineralization [16]. The receptor for AGEs (RAGE) is expressed in human bone cells and its stimulation drives the activation of nuclear factor kappa-B (NF-kB) in osteoclasts, increasing the production of cytokines and reactive oxygen species (ROS) [17]. High proinflammatory cytokine and ROS levels trigger osteoclastogenesis and stop osteoblast differentiation [18, 19]. Hence, accumulation of AGEs promotes chronic inflammation and bone resorption among patients with diabetes. The autoimmune destruction of pancreatic islets decreases the co-secretion of insulin and amylin. Amylin inhibits osteoclasts and stimulates osteoblasts [20]. Thus, amylin deficiency may also affect BMD in patients with T1D.
Pathophysiology of Bone Alterations in Type 2 Diabetes
As mentioned previously, T2D is characterized by normal or high BMD, but an increased risk of fractures. This phenomenon is known as “the diabetic paradox of bone fragility”, suggesting that other independent factors aside from BMD may influence fracture risk. Consequently, the National Bone Health Alliance proposed that osteoporosis in T2D should be diagnosed on the basis of bone strength parameters like changes in trabecular microstructure or cortical bone porosity [21]. For instance, high-resolution peripheral quantitative computed tomography (HR-pQCT) has shown that postmenopausal women with T2D have greater cortical porosity than controls without T2D [22]. A greater cortical porosity results in less bone strength and more fragility fractures in this population [23].
The insulin resistance typical of T2D occurs also in bone tissue, where insulin does not exert its full anabolic effect. There is an inverse relationship between bone strength and insulin resistance measured by Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) in perimenopausal women [24]. In addition, all the mechanisms connecting hyperglycemia to bone injury are equally active in both T1D and T2D (Fig. 3) [25].
Methods for Evaluation of Bone Quality in Diabetes
DEXA (Dual-Energy X-Ray Absorptiometry)
To perform this technique, the patient is placed in a supine position above a C-arm X-ray machine which emits photons at two different energy levels specific for cortical bone and soft tissue [26]. The difference between these two energy photon emissions is detected to create a planar image used to determine BMD in units of bone mass per unit of area (g/cm2), with the help of associated computer software. Compared to other imaging techniques, DEXA is relatively inexpensive and has a short scan time and less radiation exposure. Even though BMD can be measured in the lumbar spine, hip, forearm, or in the whole body, lumbar spine and hip are the sites usually evaluated with DEXA [27]. Despite its many advantages, DEXA assesses BMD but not bone quality, which is also a relevant predictor of fragility [28].
HR-pQCT (High-Resolution Peripheral Quantitative Computed Tomography)
Quantitative computed tomography (QCT) measures real bone density in Hounsfield units without reference to other tissues. Hence, it requires an external bone mineral reference phantom to be scanned with the patient in order to obtain the volumetric BMD in milligrams per cubic centimeter [29]. In contrast to DEXA, QCT assesses both trabecular and cortical bone [28]. QCT can be performed using conventional whole-body CT scanners for the spine, or with a smaller CT device for the radius, ulna, tibia, and fibula. This last technique is known as peripheral QCT. Regular CT scanners have a spatial resolution of about 400 µm and a slice thickness of 1 mm. As trabeculae dimensions are 100–400 µm and trabecular spaces 200–2000 µm [30], standard QCT is unable to distinguish morphological parameters of trabecular bone. Therefore, a more sophisticated method (HR-pQCT) has arisen. HR-pQCT makes an in vivo 3D characterization of bone, preferably in the peripheral skeleton (distal radius and tibia), and has a higher resolution (200 µm) and thinner slice images (500 µm). These properties give HR-pQCT the ability to evaluate the microarchitectural, geometrical, and mechanical features of cortical and trabecular bone [22].
µFEA (Micro-Finite Element Analysis)
This technique is a computerized simulation of the stresses and strains induced by mechanical loading on a bone segment. It is used to estimate bone strength and compartment-specific changes in load distribution from HR-pQCT images. By quantifying strength deficits and changes associated with cortical porosity [31], µFEA serves to predict load conditions that increase fracture risk. HR-pQCT combined with µFEA can be used in fracture models to estimate fracture strength, initiation site, and direction as well as a fracture’s association with microarchitectural parameters [32].
Spinal X-Ray Images
Although the fracture risk algorithm (FRAX) score may be adapted in patients with diabetes, additional images aside from BMD are needed to assess bone quality. Spinal X-ray images may be a useful tool to detect patients at a higher risk of fracture [33]. A cross-sectional study in Japan found a higher proportion of vertebral fractures in thoracic and spinal radiographs among patients with T2D (31.4% in women and 37.9% in men) compared to controls (24.9% in women and 14.5% in men) [34]. Even though vertebral fractures are associated with consequent fractures in elderly woman [35], there is a lack of prospective evidence among patients with diabetes.
Evidence of Impact of Diabetes on Bone Quality
Evidence of Impact of T1D on Bone Quality
A host of evidence demonstrates that T1D negatively impacts bone quality. An observational study followed radius BMD in patients with T1D and patients with T2D over a 12-year period, documenting a faster slope of decline for T1D [36]. A cross-sectional study compared BMD in 75 patients with T1D and 140 controls matched by sex, age, and BMI. Patients presented significantly lower BMD in total body and lumbar spine. Furthermore, poor glycemic control, lower physical activity, lower plasma IGF-1, and celiac disease were predictors of worse BMD in T1D [37]. A meta-analysis of 16 studies found a slight difference in femoral neck BMD for individuals with versus without T1D (− 0.055 g/cm2) [38], whereas the difference in lumbar spine BMD was not significant. This highlights the fact that the large increase in fracture risk (2-fold to 4-fold) in T1D cannot be explained solely by BMD [39].
A recent study of patients with T1D from all age groups found that femoral neck and hip BMD were lower than in controls without diabetes only among postmenopausal women [40]. Thus, T1D accelerates the expected process of postmenopausal bone loss. This also manifests as increased concentrations of bone resorption markers in postmenopausal women with T1D [41].
When Do Bone Effects of T1D Become Manifest?
In a study of 99 pediatric patients recently diagnosed with T1D, BMD was unchanged over the first year after diagnosis [42]. Interestingly though, osteocalcin and P1NP (bone formation markers) decreased, while CTX (bone resorption marker) increased during the same period, revealing that bone turnover disturbances are present since very early stages of the disease.
The Canadian study of longevity in T1D compared BMD in 75 patients with long-standing T1D and 75 age- and sex-matched controls [43]. Despite no significant difference in BMD in lumbar spine, hip, or femoral neck, fragility fractures were more frequent among women with T1D. Therefore, fragility fractures in T1D may be related to other alterations of bone quality, probably resulting from a modified microarchitecture.
Importance of Glycemic Control
In a longitudinal study, 62 patients with T1D were assessed before and 7 years after starting intensive insulin therapy. The improved glycemic control stabilized BMD and reduced circulating tartrate-resistant alkaline phosphatase (TRAP, a bone resorption marker) and parathyroid hormone (PTH). Retinopathy was a correlate of osteopenia or osteoporosis, independently of HbA1c [13]. Similarly, poor control of T1D during childhood affects bone quality by increasing cortical porosity and decreasing trabecular number and density. This was proven in a study of girls with T1D, in which significant disruptions of cortical and trabecular microarchitecture were found only among those with HbA1c > 8.5% [44].
Evidence of Impact of T2D on Bone Quality
Despite the relative increase in BMD in T2D, this does not translate into a lower risk of fractures. On the contrary, absolute risk is comparable between patients with type 1 or type 2 diabetes. Potential mechanisms include changes in bone mechanical properties due to non-enzymatic glycation, mineralization disturbances, and bone microdamage [25].
In a case–control study of 80 postmenopausal women, morphological changes in cortical and trabecular bone were studied using HR-pQCT, while bone strength of the distal radius and tibia was assessed using µFEA. Participants were classified into four groups: diabetes and previous fracture (D-Fr), diabetes and no previous fracture (D-nFr), no diabetes and previous fracture (nD-Fr), and no diabetes and no previous fracture (nD-nFr). In the D-Fr group, there was a 27.8% higher cortical pore volume in the ultradistal radius compared to that in the nD-Fr group [24].
Even though patients with T2D have on average a higher BMD, their bone resorption marker levels have the same correlation with BMD as in the general population. In a cross-sectional study of 1499 patients with T2D, bone resorption markers were negatively correlated with lumbar, femoral neck, and total hip BMD [45].
Metabolic Syndrome and Bone Density
A high BMI is a protective factor against age-associated bone loss. However, there is uncertainty about how mechanisms induced by obesity may have a negative effect on bone [46]. A cross-sectional study assessed central obesity, hyperinsulinemia, inflammatory markers, and bone health (BMD and bone turnover markers) among 114 postmenopausal women with T2D [47]. Femoral BMD was positively associated with BMI, waist circumference, plasma insulin, and PAI-1 (plasminogen activator inhibitor 1). A high BMI is known to increase BMD by decreasing bone turnover [48], whereas chronic inflammation has a pro-resorptive effect on bone and promotes bone fragility [49]. Nonetheless, this increased BMD in obese patients with T2D does not provide any protection against fractures, as explained in the next section.
Diabetes and Risk of Fracture
Patients with diabetes have a higher risk of fracture, especially at the hip. In addition, patients with diabetes have a poorer prognosis after a fracture because of delayed healing [50], more frequent infections [51], and increased mortality [52]. Likewise, patients with diabetes and hip fracture have on average longer hospital stays and more postoperative cardiovascular events [53].
Risk of Fracture in T1D
A meta-analysis of more than 140,000 patients found a significant association between T1D and any fracture (RR 3.16), hip fracture (RR 3.78), and vertebral fracture (RR 2.88) [39]. The relative risk of any fracture differed by sex, being 4.1 for women and 1.8 for men [39]. In the THIN (The Health Improvement Network) cohort, the age-related increase in risk of fracture occurred 10 years earlier in patients with T1D relative to controls without the disease [54]. Even though patients with T1D have lower BMD, this difference does not completely explain their increased risk of fracture [55].
Diabetes complications may also influence the risk of fracture. Diabetic retinopathy and neuropathy increase the likelihood of falls [56, 57], while nephropathy may induce secondary hyperparathyroidism and osteodystrophy [58]. Similarly, autoimmune diseases associated with T1D (Graves’ disease, celiac disease, and rheumatoid arthritis) may have a negative effect on bone health [59].
Risk of Fracture in T2D
The relative risk of hip fracture in patients with T2D has been estimated at 2.8 for men and 2.1 for women, both statistically significant [60]. These findings position hip fracture as an unrecognized chronic complication of T2D [61]. Despite a higher BMD, patients with T2D have an increased risk of fracture, an apparent paradox. For instance, the risk of hip fracture at a T score of − 1.9 in a woman with T2D is equivalent to the risk at a T score of − 2.5 in a woman without diabetes [61]. Thus, risk of fracture in T2D must be influenced by other factors like trabecular bone quality or cortical bone porosity. The impact of T2D on fracture risk seems to be larger in Caucasians than in other ethnicities [62]. A simple rule to estimate the risk of fracture in patients with T2D consists in adding 10 years to age or replacing rheumatoid arthritis by diabetes in the FRAX [61,62,63].
T2D complications have also been associated with a higher risk of fractures. In a Danish study retinopathy (OR 2.1), nephropathy (OR 2.0), neuropathy (OR 1.9), and even macrovascular complications (OR 1.9) were associated with fracture risk [64]. It is likely then, that this increased risk results not from an intrinsic effect of each complication, but as part of a systemic deterioration process that negatively affects bone. Peripheral neuropathy in T2D is associated with fracture risk by means of more frequent falls [65]. Fractures are also more common with a T2D duration longer than 10 years [66].
Drug treatment of T2D comorbidities may influence fracture risk in these patients. A post hoc analysis of a clinical trial showed that therapy with thiazide diuretics, calcium channel blockers, or angiotensin-converting enzyme (ACE) inhibitors slightly lowered fracture risk (HR 0.97, p = 0.04). By contrast, the relationship between beta-blockers and the incidence of orthostatism-associated falls is still controversial [67].
Type 2 Diabetes, Sarcopenia, Falls, and Risk of Fracture
Sarcopenia is defined as a decline in muscle mass and function. This condition is highly prevalent among patients with T2D [68]. The association is bidirectional: diabetes-related mechanisms like insulin resistance, inflammation, accumulation of AGEs, and oxidative stress negatively affect muscle health; while low muscle mass decreases metabolic rate and glucose disposal, resulting in accelerated progression of T2D [68]. In a Brazilian cross-sectional study, 15.6% of adults with T2D met criteria for sarcopenia, compared to 2.4% of healthy controls [69]. Evidence from multiple observational studies has documented a positive association between sarcopenia and risk of both falls (pooled OR 1.60, 95% CI 1.37–1.86 in cross-sectional studies; pooled OR 1.89, 95% CI 1.33–2.68 in prospective studies) and fractures (pooled OR 1.84, 95% CI 1.30–2.62 in cross-sectional studies; pooled OR 1.71, 95% CI 1.44–2.03 in prospective studies) [70]. Consequently, sarcopenia may be considered as an extraskeletal factor that increases the risk of falls and fractures in patients with T2D [71].
Vitamin D Deficiency and Fracture Risk in Type 2 Diabetes
Vitamin D deficiency results in secondary hyperparathyroidism, increased osteoclastic activity, and reduced bone mass [72] and has been proven to increase the risk of falls [73], hip fractures [74], vertebral fractures [75], and major osteoporotic fractures [76]. A cross-sectional study reported that men with T2D and a serum 25-hydroxyvitamin D below 20 ng/mL had increased odds of vertebral fractures (OR 7.87, 95% CI 1.69–36.71), compared to sex- and diabetes status-matched controls with normal 25-hydroxyvitamin D [77]. This association was not significant among women.
Impact of Antidiabetic Medications on Bone Health
Metformin
Metformin is considered the first-line therapy for T2D, hence its impact on bone health is highly relevant. In vitro studies show that metformin induces osteoblast differentiation and expression of osteogenesis markers such as osteopontin, alkaline phosphatase, and bone morphogenic protein 2 (BMP-2). These effects are mediated by the activation of AMP-dependent kinase [78]. Multiple clinical trials and long-term observational studies have evaluated the impact of chronic metformin use on BMD and fracture risk among patients with T2D, finding neutral or slightly beneficial effects [79].
Sulfonylureas (SU)
Even though their use has declined, SU still play an important role in the therapeutic arsenal against T2D in several countries. Observational studies have found a neutral effect of SU on biological markers of bone resorption [80]. It should also be considered, nonetheless, that SU may increase the risk of hypoglycemia and subsequent falls, which are associated with fractures [1].
Thiazolidinediones (TZD)
After rosiglitazone was withdrawn from the market because of its adverse cardiovascular profile, the use of TZD has decreased markedly. Despite that, pioglitazone is still in use in several countries. By binding to and activating the nuclear receptor PPAR-gamma, TZD induce the preferential differentiation of mesenchymal precursor cells towards adipocytes instead of osteoblasts [81]. A meta-analysis including more than 250,000 patients found that the use of TZD was associated with a higher risk of fractures, though only among women. Such risk was not significantly different between rosiglitazone and pioglitazone, did not vary with age, and was not associated to changes in BMD [82]. Results from the ACCORD study follow-up suggest that fracture risk went back to normal after TZD were suspended [83].
Dipeptidyl Peptidase 4 Inhibitors (DPP4i)
DPP4i have become widely used for the treatment of T2D. A meta-analysis of 28 clinical trials and 220,000 patients found a lower risk of fractures among DPP4i users (OR 0.60, 95% CI 0.37–0.99) [84]. Given that SU and TZD might be associated with a higher fracture risk, the authors performed a sensitivity analysis excluding studies in which SU or TZD were the comparators. The results were the same (OR 0.56, 95% CI 0.33–0.93). Thus, the impact of DPP4i on fracture risk seems to be at least neutral and perhaps favorable.
Glucagon-Like Peptide 1 Agonists (GLP-1a)
GLP-1a are an attractive choice of treatment for many patients with T2D with cardio-metabolic comorbidities. A meta-analysis of studies designed to assess glycemic control evidenced a favorable or neutral effect of GLP-1a on fracture risk [85]. An interesting mechanistic study submitted 37 women (mean age 46) to a diet-induced 12% weight loss, and then randomized them to receive 1.8 mg/day of liraglutide or placebo for 1 year [86]. Measures were taken to maintain a constant weight in both groups throughout the study. Surprisingly, at the end of follow-up the loss of bone mineral content was four times higher in the placebo than in the liraglutide group. The bone formation marker P1NP increased only in the liraglutide group. Hence, GLP-1a might aid in the prevention of bone mass reduction related to weight loss, although these findings should be confirmed in larger studies.
Sodium–Glucose Co-Transporter 2 Inhibitors (SGLT2i)
SGLT2i are a novel group of oral antidiabetics with positive effects on many diabetes outcomes. In the CANVAS study, a cardiovascular endpoint trial, the cumulative incidence of fracture was 4.0% in the canagliflozin group and 2.6% in the placebo group [87]. However, a review of randomized trials with canagliflozin did not show a higher rate of fractures compared to other therapies (1.7% in canagliflozin group vs. 1.5% in comparators, OR 1.09, 95% CI 0.71–1.66) [87]. A meta-analysis of 20 studies with SGLT2i (canagliflozin, dapagliflozin, and empagliflozin) reported a pooled fracture risk ratio of 0.67 (95% CI 0.42–1.07) between SGLT2i and comparators [88]. The pooled risk ratio was not different among SGLT2i (canagliflozin 0.66 [95% CI 0.37–1.19], dapagliflozin 0.84, [95% CI 0.22–3.18], and empagliflozin 0.57, [95% CI 0.20–1.59]).
Insulin
So far, no clinical trial has assessed specifically the effect of insulin treatment on bone health and fracture risk. Observational studies have shown a higher risk of fracture for patients on insulin therapy [79]. Some factors frequently found in patients on insulin therapy may contribute to the risk of fracture, such as a longer disease duration, presence of chronic complications, and hypoglycemia-induced falls [79]. In a nested case–control study of more than 12,000 participants in Spain, insulin therapy was associated with a higher risk of fracture, even after adjustment by age and time since T2D diagnosis (aOR 1.63, 95% CI 1.30–2.04) [89].
Bariatric Surgery
Recently, bariatric surgery has been positioned as an effective therapy in patients with obesity-induced T2D. Evidence shows that malabsorptive procedures increase fracture risk, particularly biliopancreatic diversion [79]. A nested case–control study in Canada found an increased relative risk of fracture in upper limbs (1.64, 95% CI 1.40–1.93), spine (1.78, 95% CI 1.08–2.93), and hip or femur (2.52, 95% CI 1.78–3.59) after bariatric surgery [90]. Most of the excess risk was accounted for by 21% of participants, who underwent biliopancreatic diversion. Unexpectedly, the relative risk of lower limb fracture was reduced (0.66, 95% CI 0.56–0.78). Similar findings have been reported in Taiwan [91].
The effect on antidiabetic interventions on bone health is summarized in Table 1.
Should Osteoporosis Treatment Be Different for Patients with Diabetes?
Anti-osteoporotic therapies seem to have a similar effect on fracture risk reduction for patients with and without diabetes [92]. Consequently, international guidelines recommend the same therapeutic approach for osteoporosis regardless of diabetes status [79]. In a sub-analysis of the FREEDOM study (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) and its 7-year extension, the incidence of fractures was compared between denosumab (n = 266) and placebo (n = 242) in patients with diabetes [93]. The rate of vertebral fractures was drastically lower with denosumab compared with placebo (1.6% vs. 8.0%, RR 0.20, 95% CI 0.07–0.61). By contrast, the rate of non-vertebral fractures was higher in the denosumab group (11.7% vs. 5.9% in the placebo group, RR 1.94, 95% CI 1.00–3.77). Therefore, denosumab seems to be particularly effective against vertebral fractures among patients with diabetes. Furthermore, denosumab seems to have a positive effect on insulin resistance, as it slightly reduces fasting serum glucose in postmenopausal woman with diabetes who are not using antidiabetic medications [94]. In the DANCE (Direct Analysis of Nonvertebral Fractures in the Community Experience) study, treatment with teriparatide (a synthetic peptide comprising the first 34 amino acids of parathyroid hormone) for 6–24 months [95] showed a similar reduction in the incidence of non-vertebral fractures and back pain, and a similar increase in BMD in participants with or without diabetes [96]. A promising approach to osteoporosis treatment in diabetes is blocking the hormone sclerostin with monoclonal antibodies, positively impacting bone health through different pathophysiological mechanisms (Fig. 4). Animal and human studies of sclerostin blockade with the monoclonal antibody romosozumab show an anabolic effect on bone mass and significant improvements of bone microarchitecture and strength [97, 98]. In the FRAME study (The Fracture Study in Postmenopausal Women with Osteoporosis), romosozumab treatment reduced the risk of fracture and increased BMD among women with osteoporosis [99]. In 2019, the US Food and Drugs Administration and the European Medicines Agency approved romosozumab for treatment of osteoporosis in postmenopausal women at high risk of fractures. However, the specific impact of romosozumab in humans with T1D or T2D warrants further investigation. Regarding in-hospital management, patients with diabetes and fracture should be treated with insulin to achieve appropriate glycemic control, avoiding oral antidiabetics until the acute stress of fracture is overcome [100].
Conclusion
Bone fragility is a frequent and underdiagnosed condition among patients with diabetes. A host of pathophysiological, clinical, and epidemiological evidence supports early detection and proper treatment of bone fragility in patients with diabetes. Future research directions include the differential effects of osteoporosis therapies in patients with T2D, and the study of the impact of fracture prevention on long-term mortality and quality of life among patients with T2D.
References
Napoli N, Chandran M, Pierroz DD, et al. Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol. 2017;13:208–19.
Räkel A, Sheehy O, Rahme E, LeLorier J. Osteoporosis among patients with type 1 and type 2 diabetes. Diabet Metab. 2008;34:193–205.
Dennison E, Syddall H, Sayer A, Craighead S, Phillips DIW, Cooper C. Type 2 diabetes mellitus is associated with increased axial bone density in men and women from the Hertfordshire Cohort Study: evidence for an indirect effect of insulin resistance? Diabetologia. 2004;47:1963–8.
Thrailkill K, Lumpkin C, Bunn R, Kemp S, Fowlkes J. Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. Am J Physiol Endocrinol Metab. 2005;289:E735–45.
Joshi A, Varthakavi P, Chadha M, Bhagwat N. A study of bone mineral density and its determinants in type 1 diabetes mellitus. J Osteopor. 2013a;2013:1–8.
Sierra I, Mendivil CO, editors. Hacia el manejo práctico de la diabetes mellitus tipo 2. Universidad Nacional de Colombia, 2009.
Mieczkowska A, Mansur S, Irwin N, Flatt P, Chappard D, Mabilleau G. Alteration of the bone tissue material properties in type 1 diabetes mellitus: a Fourier transform infrared microspectroscopy study. Bone. 2015;76:31–9.
Thrailkill K, Liu L, Wahl E, et al. New bone formation is impaired in a model of type 1 diabetes mellitus. Diabetes. 2003;54:2875–81.
Thomas D, Hards D, Rogers S, Ng K, Best J. Insulin receptor expression in bone. J Bone Miner Res. 1996;11:1312–20.
Uchida T, Nakamura T, Hashimoto N, et al. Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice. Nat Med. 2005;11:175–82.
White MF. Insulin signaling pathway. Science. 2003;302:1710–1.
Fang X, Yu S, Eder A, et al. Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene. 1999;18:6635–40.
Campos Pastor M, López-Ibarra P, Escobar-Jiménez F, Serrano Pardo M, García-Cervigón A. Intensive insulin therapy and bone mineral density in type 1 diabetes mellitus: a prospective study. Osteoporos Int. 2000;11:455–9.
Tang SY, Allen MR, Philipps R, Burr D, Vashishth D. Changes in non-enzymatic glycation and its association with altered mechanical properties following 1 year treatment with risedronate or alendronate. Osteoporos Int. 2009;20:887–94.
Poundarik A, Wu P, Evis Z, et al. A direct role of collagen glycation in bone fracture. J Mech Behav Biomed Mater. 2015;52:120–30.
McCarthy A, Etcheverry S, Bruzzone L, Lettieri G, Barrio D, Cortizo A. Non-enzymatic glycosylation of a type I collagen matrix: effects on osteoblastic development and oxidative stress. BMC Cell Biol. 2001;2:16.
Hein GE. Glycation endproducts in osteoporosis—is there a pathophysiologic importance? Clin Chim Acta. 2006;371:32–6.
Gilbert L, He X, Farmer P, et al. Inhibition of osteoblast differentiation by tumor necrosis factor-α. Endocrinology. 2000;141:3956–64.
Glantschnig H, Fisher J, Wesolowski G, Rodan G, Reszka A. M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell Death Differ. 2003;10:1165–77.
Horcajada-Molteni MN, Chanteranne B, Lebecque P, et al. Amylin and bone metabolism in streptozotocin-induced diabetic rats. J Bone Miner Res. 2001;16:958–65.
Siris ES, Adler R, Bilezikian J, et al. The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group. Osteoporos Int. 2014;25:1439–43.
Burghardt AJ, Issever AS, Schwartz AV, et al. High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2010;95:5045–55.
Patsch JM, Burghardt AJ, Yap SP, et al. Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures. J Bone Miner Res. 2013;28:313–24.
Ishii S, Cauley J, Crandall C, Karlamangla A. Diabetes and femoral neck strength: findings from the hip strength across the menopausal transition study. J Clin Endocrinol Metab. 2012;97:190–7.
Saito M, Marumo K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int. 2010;21:195–214.
Krugh M, Langaker MD. Dual energy X-ray absorptiometry (DEXA) (Updated 2020 Jun 19). In: StatPearls (Internet). Treasure Island (FL): StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK519042/. Accessed 10 Nov 2020.
Ward R, Roberts C, Bencardino J, et al. ACR appropriateness criteria osteoporosis and bone mineral density. J Am Coll Radiol. 2017;14:S189–202.
D’Elia G, Caracchini G, Cavalli L, Innocenti P. Bone fragility and imaging techniques. Clin Cases Miner Bone Metab. 2009;6:234–46.
Gordon CL, Lang TF, Augat P, Genant HK. Image-based assessment of spinal trabecular bone structure from high-resolution CT images. Osteoporos Int. 1998;8:317–25.
Genant H, Engelke K, Prevrhal S. Advanced CT bone imaging in osteoporosis. Rheumatology. 2008;47:iv9–16.
Burghardt AJ, Kazakia GJ, Ramachandran S, Link TM, Majumdar S. Age- and gender-related differences in the geometric properties and biomechanical significance of intracortical porosity in the distal radius and tibia. J Bone Miner Res. 2010;25:983–93.
Varga P, et al. Validation of an anatomy specific finite element model of Colles’ fracture. J Biomech. 2009;42:1726–31.
Poiana C, Capatina C. Fracture risk assessment in patients with diabetes mellitus. J Clin Densitom. 2017;20:432–43.
Yamamoto M, Yamaguchi T, Yamauchi M, Kaji H, Sugimoto T. Diabetic patients have an increased risk of vertebral fractures independent of BMD or diabetic complications. J Bone Miner Res. 2009;24:702–9.
Black DM, Arden NK, Palermo L, Pearson J, Cummings SR. Prevalent vertebral deformities predict hip fractures and new vertebral deformities but not wrist fractures. Study of Osteoporotic Fractures Research Group. J Bone Miner Res. 1999;14:821–8.
Krakauer J, Mckenna M, Fenn Buderer N, Rao D, Whitehouse F, Parfitt A. Bone loss and bone turnover in diabetes. Diabetes. 1995;44:775–82.
Joshi A, Varthakavi P, Chadha M, Bhagwat N. A study of bone mineral density and its determinants in type 1 diabetes mellitus. J Osteoporosis. 2013b;2013:397814.
Shah V, Harrall K, Shah C, et al. Bone mineral density at femoral neck and lumbar spine in adults with type 1 diabetes: a meta-analysis and review of the literature. Osteoporos Int. 2017;28:2601–10.
Shah V, Shah C, Snell-Bergeon J. Type 1 diabetes and risk of fracture: meta-analysis and review of the literature. Diabet Med. 2015;32:1134–42.
Halper-Stromberg E, Gallo T, Champakanath A, et al. Bone mineral density across the life-span in patients with type 1 diabetes. J Clin Endocrinol Metab. 2020;105:1–8.
Christensen J, Svendsen O. Bone mineral in pre- and postmenopausal women with insulin-dependent and non-insulin-dependent diabetes mellitus. Osteoporos Int. 1999;10:307–11.
Madsen J, Herskin C, Zerahn B, et al. Bone turnover markers during the remission phase in children and adolescents with type 1 diabetes. Pediatr Diabetes. 2020;21:366–76.
Alhuzaim O, Lewis E, Lovblom L, et al. Bone mineral density in patients with longstanding type 1 diabetes: results from the Canadian Study of Longevity in Type 1 Diabetes. J Diabetes Complicat. 2019;33:107324.
Mitchell D, Caksa S, Joseph T, Bouxsein M, Misra M. Elevated HbA1c is associated with altered cortical and trabecular microarchitecture in girls with type 1 diabetes. J Clin Endocrinol Metab. 2020;105:dgz221.
Zhao C, Liu G, Zhang Y, et al. Association between serum levels of bone turnover markers and bone mineral density in men and women with type 2 diabetes mellitus. J Clin Lab Anal. 2019;2019:e23112.
Felson D, Zhang Y, Hannan M, Anderson J. Effects of weight and body mass index on bone mineral density in men and women: the Framingham study. J Bone Miner Res. 2009;8:567–73.
Bilić-Ćurčić I. Bone mineral density in relation to metabolic syndrome components in postmenopausal women with diabetes mellitus type 2. Acta Clin Croat. 2017;56:58–63.
Mashavi M, Menaged M, Shargorodsky M. Circulating osteoprotegerin in postmenopausal osteoporotic women. Menopause. 2017;24:1264–8.
Schett G. High-sensitivity C-reactive protein and risk of nontraumatic fractures in the Bruneck study. Arch Intern Med. 2006;166:2495.
Hernandez RK, Do TP, Critchlow CW, Dent RE, Jick SS. Patient-related risk factors for fracture-healing complications in the United Kingdom General Practice Research Database. Acta Orthop. 2012;83:653–60.
Humphers JM, Shibuya N, Fluhman BL, Jupiter D. The impact of glycosylated hemoglobin and diabetes mellitus on wound-healing complications and infection after foot and ankle surgery. J Am Podiatr Med Assoc. 2014;104:320–9.
Hu F, Jiang C, Shen J, Tang P, Wang Y. Preoperative predictors for mortality following hip fracture surgery: a systematic review and meta-analysis. Injury. 2012;43:676–85.
Norris R, Parker M. Diabetes mellitus and hip fracture: a study of 5966 cases. Injury. 2011;42:1313–6.
Weber DR, Haynes K, Leonard MB, Willi SM, Denburg MR. Type 1 diabetes is associated with an increased risk of fracture across the life span: a population-based cohort study using The Health Improvement Network (THIN). Diabetes Care. 2015;38:1913–20.
Starup-Linde J, Hygum K, Harsløf T, Langdahl B. Type 1 diabetes and bone fragility: links and risks. Diabetes Metab Syndr Obes. 2019;12:2539–47.
Gupta P, Aravindhan A, Gand ATL, et al. Association between the severity of diabetic retinopathy and falls in an Asian population with diabetes: the Singapore epidemiology of eye diseases study. JAMA Ophthalmol. 2017;135:1410–6.
Richardson J, Hurvitz E. Peripheral neuropathy: a true risk factor for falls. J Gerontol A Biol Sci Med Sci. 1995;50:M211–5.
Moe SM. Renal osteodystrophy or kidney-induced osteoporosis? Curr Osteoporos Rep. 2017;15:194–7.
Witek PR, Witek J, Pankowska E. Type 1 diabetes-associated autoimmune diseases: screening, diagnostic principles and management. Med Wieku Rozwoj. 2012;16:23–34.
Janghorbani M, Van Dam RM, Willett WC, Hu FB. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol. 2007;166:495–505.
Ferrari SL, Abrahamsen B, Napoli N, et al. Diagnosis and management of bone fragility in diabetes: an emerging challenge. Osteoporos Int. 2018;29:2585–96.
Sellmeyer DE, Civitelli R, Hofbauer LC, Khosla S, Lecka-Czernik B, Schwartz AV. Skeletal metabolism, fracture risk, and fracture outcomes in type 1 and type 2 diabetes. Diabetes. 2016;65:1757–66.
Looker AC, Eberhardt MS, Saydah SH. Diabetes and fracture risk in older U.S. adults. Bone 2016;82:9–15.
Vestergaard P, Rejnmark L, Mosekilde L. Diabetes and its complications and their relationship with risk of fractures in type 1 and 2 diabetes. Calcif Tissue Int. 2009;84:45–55.
Strotmeyer E, Cauley J, Schwartz A, et al. Nontraumatic fracture risk with diabetes mellitus and impaired fasting glucose in older white and black adults: the health, aging, and body composition study. Arch Intern Med. 2005;165:1612–7.
Ivers R, Cumming R, Mitchell P, et al. Diabetes and risk of fracture: the blue mountains eye study. Diabetes Care. 2001;24:1198–203.
Barzilay J, Davis B, Pressel S, et al. The impact of antihypertensive medications on bone mineral density and fracture risk. Curr Cardiol Rep. 2017;19:76.
Mesinovic J, Zengin A, De Courten B, Ebeling PR, Scott D. Sarcopenia and type 2 diabetes mellitus: a bidirectional relationship. Diabetes Metab Syndr Obes. 2019;12:1057–72.
Trierweiler H, Kisielewicz G, Hoffmann Jonasson T, Rasmussen Petterle R, Aguiar Moreira C, Zeghbi Cochenski Borba V. Sarcopenia: a chronic complication of type 2 diabetes mellitus. Diabetol Metab Syndr. 2018;10:25.
Yeung SSY, Reijnierse EM, Pham VK, et al. Sarcopenia and its association with falls and fractures in older adults: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle. 2019;10(3):485–500.
Sarodnik C, Bours SPG, Schaper NC, van den Bergh JP, van Geel TACM. The risks of sarcopenia, falls and fractures in patients with type 2 diabetes mellitus. Maturitas. 2018;109:70–7.
Holick M. Vitamin D deficiency. N Engl J Med. 2007;357:266–81.
Bischoff-Ferrari H, Dawson-Hughes B, Staehelin H, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ. 2009;339:b3692.
Nuti R, Martini G, Valenti R, et al. Vitamin D status and bone turnover in women with acute hip fracture. Clin Orthop Relat Res. 2004;422:208–13.
Zhang L, Chun C, Yang Y, et al. Vitamin D deficiency/insufficiency is associated with risk of osteoporotic thoracolumbar junction vertebral fractures. Med Sci Monit. 2019;25:8260–8.
Looker A. Serum 25-hydroxyvitamin D and risk of major osteoporotic fractures in older U.S. adults. J Bone Miner Res. 2013;28:997–1006.
Kim Y, Park S, Kim T, Lee J, Kim S. The association of serum 25-hydroxyvitamin D and vertebral fractures in patients with type 2 diabetes. Endocr J. 2013;60:179–84.
Kanazawa I, Yamaguchi T, Yano S, Yamauchi M, Sugimoto T. Metformin enhances the differentiation and mineralization of osteoblastic MC3T3-E1 cells via AMP kinase activation as well as eNOS and BMP-2 expression. Biochem Biophys Res Commun. 2008;375:414–9.
Paschou SA, Dede AD, Anagnostis PG, Vryonidou A, Morganstein D, Goulis DG. Type 2 diabetes and osteoporosis: a guide to optimal management. J Clin Endocrinol Metab. 2017;102:3621–34.
Zinman B, Haffner SM, Herman WH, et al. Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab. 2010;95:134–42.
Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.
Zhu ZN, Jiang YF, Ding T. Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials. Bone. 2014;68:115–23.
Schwartz AV, Chen H, Ambrosius WT, et al. Effects of TZD use and discontinuation on fracture rates in ACCORD bone study. J Clin Endocrinol Metab. 2015;100:4059–66.
Monami M, Dicembrini I, Antenore A, Mannucci E. Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials. Diabetes Care. 2011;34:2474–6.
Su B, Sheng H, Zhang M, et al. Risk of bone fractures associated with glucagon-like peptide-1 receptor agonists’ treatment: a meta-analysis of randomized controlled trials. Endocrine. 2015;48:107–15.
Iepsen EW, Lundgren JR, Hartmann B, et al. GLP-1 receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women. J Clin Endocrinol Metab. 2015;100:2909–17.
Watts NB, Bilezikian JP, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2016;101:157–66.
Ruanpeng D, Ungprasert P, Sangtian J, Harindhanavudhi T. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: a meta-analysis. Diabetes Metab Res Rev. 2017;33:e2903.
Losada E, Soldevila B, Ali MS, et al. Real-world antidiabetic drug use and fracture risk in 12,277 patients with type 2 diabetes mellitus: a nested case–control study. Osteoporosis Int. 2018;29:2079–86.
Rousseau C, Jean S, Gamache P, et al. Change in fracture risk and fracture pattern after bariatric surgery: nested case–control study. BMJ. 2016;354:i3794.
Lu CW, Chang YK, Chang HH, et al. Fracture risk after bariatric surgery: a 12-year nationwide cohort study. Medicine (Baltimore). 2015;94:e2087.
Anagnostis P, Paschou SA, Gkekas NN, et al. Efficacy of anti-osteoporotic medications in patients with type 1 and 2 diabetes mellitus: a systematic review. Endocrine. 2018;60:373–83.
Ferrari S, Eastell R, Napoli N, et al. Denosumab in postmenopausal women with osteoporosis and diabetes: subgroup analysis of FREEDOM and FREEDOM extension. Bone. 2020;134:115268.
Napoli N, Pannacciulli N, Vittinghoff E, et al. Effect of denosumab on fasting glucose in women with diabetes or prediabetes from the FREEDOM trial. Diabetes Metab Res Rev. 2018;34:e2991.
Silverman S, Miller P, Sebba A, et al. The direct assessment of nonvertebral fractures in community experience (DANCE) study: 2-year nonvertebral fragility fracture results. Osteoporos Int. 2013;24:2309–17.
Schwartz AV, Pavo I, Alam J, et al. Teriparatide in patients with osteoporosis and type 2 diabetes. Bone. 2016;91:152–8.
Hamann C, Rauner M, Höhna Y, et al. Sclerostin antibody treatment improves bone mass, bone strength, and bone defect regeneration in rats with type 2 diabetes mellitus. J Bone Miner Res. 2013;28:627–38.
McClung M. Sclerostin antibodies in osteoporosis: latest evidence and therapeutic potential. Ther Adv Musculoskel Dis. 2017;9:263–70.
Cosman F, Crittenden D, Adachi J, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375:1532–43.
Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2020;63:221–8.
Acknowledgements
We wish to thank Universidad de los Andes for its administrative support.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authorship Contributions
All authors meet the criteria for authorship and no deserving authors have been omitted. All authors contributed equally to the conception and execution of the work presented in this manuscript.
Disclosures
Camila Romero-Díaz, Daniela Duarte-Montero and Sebastián A. Gutiérrez-Romero have nothing to disclose. Carlos O. Mendivil is a member of the journal’s Editorial Board.
Compliance with Ethics Guidelines
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Data Availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
About this article
Cite this article
Romero-Díaz, C., Duarte-Montero, D., Gutiérrez-Romero, S.A. et al. Diabetes and Bone Fragility. Diabetes Ther 12, 71–86 (2021). https://doi.org/10.1007/s13300-020-00964-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13300-020-00964-1