Calcified Tissue International

, Volume 100, Issue 2, pp 122–132 | Cite as

Pathophysiology of Bone Fragility in Patients with Diabetes

  • Andrea Palermo
  • Luca D’Onofrio
  • Raffaella Buzzetti
  • Silvia Manfrini
  • Nicola NapoliEmail author


It has been well established that bone fragility is one of the chronic complications of diabetes mellitus, and both type 1 and type 2 diabetes are risk factors for fragility fractures. Diabetes may negatively affect bone health by unbalancing several pathways: bone formation, bone resorption, collagen formation, inflammatory cytokine, muscular and incretin system, bone marrow adiposity and calcium metabolism. The purpose of this narrative review is to explore the current understanding of pathophysiological pathways underlying bone fragility in diabetics. In particular, the review will focus on the peculiar cellular and molecular system impairment that may lead to increased risk of fracture in type 1 and type 2 diabetes.


Osteoporosis Diabetes Osteoblast Osteoclast Hyperglycaemia 


Recent findings have highlighted the importance of the skeleton as an endocrine organ which may regulate metabolic pathways such as glucose tolerance and insulin signalling [1, 2]. A crucial role for Osteocalcin in regulating insulin secretion has been largely investigated [2] while an intriguing role may be positively played by vitamin D even if epidemiological data are contrasting [3]. Conversely, diabetes may negatively affect bone health by unbalancing several processes and systems: bone formation, bone resorption, collagen formation and collagen cross-linking, secretion of inflammatory cytokines, skeletal muscle, incretin system, bone marrow adiposity, calcium metabolism, etc. Eventually, such alterations lead to an increased risk of fracture. In particular, in subjects with T1D there is an about sixfold increase in hip fracture risk and an about twofold increase in vertebral fracture risk compared to individuals without diabetes [1]. Although T1D negatively affects bone quality, it is also characterized by a significant reduction in bone mineral density (BMD), in particular at the femur [1]. Type 2 diabetes (T2D) is associated with an about two- and threefold increase in hip fracture risk compared with non-diabetic subjects, despite higher or normal BMD [1, 4]. The difference between these two bone phenotypes may reflect the peculiar pathophysiological background of the two types of diabetes. Indeed, although T1D and T2D share hyperglycaemia as their main hallmark, they are heterogeneous diseases whose aetiology and clinical presentation differ considerably.

This narrative review aims to explore the current understanding of the pathophysiological pathways underlying bone fragility in diabetic patients.

Materials and Methods

According to PRISMA guidelines, PubMed and MEDLINE were searched to identify published articles about diabetes mellitus and bone metabolism. In particular, we considered articles that investigated pathophysiological pathways underlying bone fragility due to diabetes, such as hyperglycaemia, insulin resistance, insulin “deficiency”, advanced glycation end-products (AGEs), inflammatory cytokines, bone marrow adiposity. Moreover, we took in consideration studies that analysed how diabetes may impair bone formation and resorption, collagen formation, calcium metabolism, skeletal muscle and the incretin system.

The name of different cells, genes and molecules (i.e. osteoblast, osteoclast, osteocyte, GIP, GLP-1, sclerostin, RUNX2, AGE, irisin, IGF-1, IRS, insulin, PTH, calcium) was matched with diabetes mellitus, hyperglycaemia and osteoporosis. Only publications in English were included.

From Type 1 to Type 2 Diabetes: Insulin Deficiency, Hyperinsulinaemia and the Other Way Around

Insulin Deficiency

Insulin has a pivotal role in bone metabolism; indeed, osteoblasts and osteoclasts express the insulin receptor (IR) on their surface. In particular, in vitro [5] and in vivo [6] studies show that insulin administration enhances osteoblast proliferation and osteoblast differentiation and, in turn, bone formation rate.

Insulin stimulation results in the activation of the insulin receptor substrate (IRS), followed by an activation of the intracellular MAPK and PI3-K/Akt pathways, necessary for osteoblast growth, osteoblast differentiation and osteoblast survival. Therefore, impairment of insulin signalling may lead to osteoblast dysfunction. Fulzele et al. have demonstrated that mice lacking the IR on osteoblasts have low circulating undercarboxylated OC and reduced bone acquisition due to decreased bone formation and reduced number of osteoblasts [7].

IRS-1 and IRS-2, but not IRS-3 and IRS-4, are also involved in bone metabolism [8, 9]. In vitro studies have demonstrated that the deletion of IRS-1, which is expressed only in osteoblasts, negatively affects osteoblast proliferation and differentiation [10], similar to bone IRS-2 knockout mice, mainly expressed in osteoclasts than in osteoblasts [11].

Insulin may also affect osteoclast function indirectly, through the insulin signalling pathway in the osteoblast. In particular, IRS-1 is needed to generate osteoclast differentiation factors such as the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoclast differentiation factor (ODF) [9].

MAPK and PI3K/Akt, two downstream intracellular insulin signal transduction pathways, can influence osteoblast development. Indeed, when these pathways are powered by insulin, there is an increase in the expression of osterix (osteoblast-specific transcriptional factor), while genetic deletion of PI3K/Akt decreases the expression of runt-related transcription factor 2 (RUNX2) [12].

There is in vivo evidence that insulin may restore the impairment of osteoclast and osteoblast function associated with diabetes. Indeed, in STZ-induced diabetic rats, up-regulation of osteoclastogenesis and down-regulation of osteoblastogenesis were reversed by insulin therapy [12]. Campos Pastor et al. have confirmed this observation in a study that included 62 patients with new onset T1D, in whom intensive insulin therapy for 7 years was associated with stabilization of bone mineral density (BMD) at all sites [13].


Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a protein encoded by the IGF-1 gene in humans. IGF-1 binds both the IGF-1 and the insulin receptor and, although a lower binding affinity to the insulin receptor, it triggers the insulin signalling pathway. Indeed, osteoblasts express the IGF receptor on their surface [14], and IRS-1 and IRS-2 are main mediators in the IGF signalling cascade [8].

Adolescent T1D patients have low levels of IGF-1 compared to healthy control subjects [15]; earlier age at diagnosis and poor metabolic control are predictive of lower IGF-1 [15]. Low IGF-1 levels are associated with low femoral and lumbar spine BMD in T1D patients [15] and with vertebral fractures in post-menopausal women with T2D [16].

Hyperinsulinaemia and Insulin Resistance

Hyperinsulinaemia and insulin resistance are the hallmarks of T2D. High levels of insulin might explain the relative increase in BMD observed in T2D patients compared to subjects without diabetes. Barrett-Connor [17] and Stolk [18] have shown in their cross-sectional evaluations that there is a positive correlation between insulin and BMD. Indeed, most of the conditions associated with hyperinsulinaemia, i.e. the metabolic syndrome, polycystic ovary syndrome or lipodystrophy, are characterized by high BMD levels [19].

On the other hand, animal models have shown that insulin resistance may play a negative effect on bone health, altering insulin signalling in osteoblasts [7, 9].

Moreover, “osteoblast insulin resistance” induced by increased levels of free saturated fatty acids is associated with decreased circulating levels of osteocalcin (OC), which in turn leads to a decrease in insulin sensitivity in skeletal muscle [20]. However, these preclinical data are in contrast with epidemiological funding showing either a protection [21] or a neutral effect [4] played by an insulin resistance state, like prediabetes, on risk fracture.

Diabetes Mellitus and Bone Health: Pathways to Bone Fragility

Glucose Toxicity

Bone Formation


Osteoblastogenesis Hyperglycaemia exerts detrimental effects on osteoblastogenesis starting from the first differentiation step. Osteoblasts derive from mesenchymal stem cells (MSC), and high glucose concentration may reduce MSC viability and clonogenicity [22]. Several in vitro studies have demonstrated that hyperglycaemia down-regulates bone marrow stromal cells (BMSC) proliferation, osteoblast gene expression, alkaline phosphatase (ALP) activity [23] and bone mineralization rate in BMSC isolated from streptozotocin (STZ)-induced diabetic rats [23].

Many studies have been conducted in T1D and T2D animal models suggesting a similar impairment in bone formation. In particular, these models were characterized by low rate of mineralization and decreased trabecular bone volume, probably due to the decreased RUNX2 gene expression [24, 25], reduced ALP activity [24, 26], down-regulated OC, osteoprotegerin (OPG) [27, 28] and Bone morphogenetic protein-2 expression [24, 26].

Wnt/β-catenin signalling Hyperglycaemia exerts a negative effect on Wnt/β-catenin signalling. In STZ diabetic rats, reduced β-catenin and increased expression of the Wnt signalling inhibitors SOST and Dickkopf-related protein 1 (Dkk1) have been reported [24].

Adipogenic pathway BMSC exposed to high glucose exhibit enhanced adipogenic rather than osteogenic pathway by the activation of peroxisome proliferator-activated receptor γ (PPARγ) and enhanced expression of cyclin D3 [29].

In particular, diabetes-associated hyperglycaemia is able to increase PPARγ 2 expression and decrease RUNX2 [30], ALP [31] and OC expression in osteoblasts. Adipogenesis seems to be triggered by chronic rather than acute hyperglycaemia. Other mechanisms that may explain the stimulation of adipogenesis over osteoblastogenesis involves the PI3K/Akt pathway, which is activated by reactive oxygen species (ROS) associated with hyperglycaemia.

Advanced glycation end-products Advanced glycation end-products (AGEs) due to prolonged hyperglycaemia may reduce RUNX2, OC and osterix expression [32]. Furthermore, AGEs can suppress endoplasmic reticulum function that is essential to osteoblast differentiation and activity [33] and increase osteoblast apoptotic death [32]. All these mechanisms lead to decreased mineralization [31, 34] and to bone quality impairment [30].


Several studies have highlighted an important contribution of osteocytes on bone fragility in DM. Sclerostin is produced by osteocytes and, antagonizing the WNT/β catenin canonical signalling pathway, is one of the main bone formation inhibitors.

Recently, it has been shown, in vitro, that hyperglycaemia, AGEs [35], ROS and TNFα [36] increase sclerostin production in MLO-Y4 cells. Increased serum levels of sclerostin have been observed in T2D patients while it is still controversial in T1D ones [37]. A central role of sclerostin in diabetic bone metabolism is also supported by the observation that treatment with sclerostin antibodies improves bone mass and strength in T2D rats and STZ diabetic mice.

Bone Resorption


Hyperglycaemia may play a negative role in osteoclastogenesis, resulting in impaired bone resorption.

Differentiation of embryonic stem cells (ESCs) into osteoclasts is promoted by physiological glucose levels, and hyperglycaemia could impair this process. This hypothesis is supported by impaired bone resorption due to the reduced levels of dendritic cell-specific trans-membrane protein [38] which are involved in osteoclast differentiation in STZ-induced diabetic mice [39].

Most of the in vitro studies have demonstrated that high glucose concentrations reduce RANKL concentration [35], nuclear factor κ B (NF-kB) activity [40, 41], cathepsin K and reduced tartrate-resistant acid phosphatase (TRAP) activity [41].

Although data have not been consistent, most of diabetic animal models show an increased osteoclast activity supported by elevated TRAP [26], cathepsin K activity [26] and RANKL levels [28], that may lead to impaired mineralization [42].

AGEs and “Diabetic Collagenopathy”

As diabetes may be characterized by a significant reduction in bone strength that is not fully explained by BMD, impairment of tissue material properties could play an important role in the development of bone fragility.

It is well known that bone elasticity, toughness and strength are dependent on the type of cross-links between adjacent collagen molecules, while the mineral component of the bone matrix provides stiffness.

Two types of covalent cross-links have been identified that are needed to stabilize the newly formed collagen fibres:

Enzymatic cross-links (lysyl oxidase (LOX)-mediated cross-linking) [43];

Non-enzymatic cross-links (glycation or oxidation-induced AGEs cross-linking) [44].

The amount of enzymatic cross-links in bone is strictly regulated by the expression of LOX, which prevents excessive accumulation of enzymatic cross-links in the physiological mineralization process [43]. It has been demonstrated that proper enzymatic cross-link formation is also needed to ensure osteoblastic differentiation [45]. Diabetes is one of the conditions that can indirectly affect LOX activity through the homocysteine pathway. Indeed, diabetes is associated with high plasma levels of homocysteine, which in turn may down-regulate gene expression and enzymatic activity of LOX [46].

Chronic hyperglycaemia is associated with the formation of AGEs. AGEs form spontaneously through non-enzymatic glycation or oxidation, and a large body of evidence suggests that formation of AGEs within collagen fibres negatively affects bone strength. Indeed, while enzymatic cross-links are essential to maintain bone strength, non-enzymatic AGEs cross-links impair bone quality [44].

Moreover, AGEs form irreversible cross-links between the fibres in the triple helix, and competitively inhibit enzymatic cross-link formation because AGEs cross-links are formed between Lys residues, which are essential sites of enzymatic cross-linking in collagen molecules. The slow turnover of collagen leads to the accumulation of a large quantity of altered type 1 collagen, which may determine biomechanical changes both in the cortical and trabecular bone [47].

Moreover, in vitro and in vivo animal and human studies demonstrated that cancellous bone is susceptible to the accumulation of non-enzymatic glycation, which increases its propensity to fracture and decreased post-yield strain and energy.

However, AGEs can also negatively affect bone health by determining cellular dysfunctions. Indeed, robust and quite clear evidence has been provided that the interaction of AGEs with their receptor RAGE (also expressed on osteoblasts and immune cells) impairs osteoblast activity [48].

While osteoblast function is negatively affected by AGEs, their impact on osteoclasts activity is controversial.

Some in vivo clinical studies have investigated the role of pentosidine, one of the most common non-enzymatic cross-links in bone and a specific marker of AGEs in bone. In animal models with diabetes [49, 50] and, importantly, in TD2 subjects [51], pentosidine levels are increased compared to healthy controls. Using an animal model of T2D, Saito and coll. demonstrated that pentosidine and the ratio of pentosidine/total enzymatic cross-links are negatively associated with some bone mechanical properties such as maximum load, energy absorption, stiffness and elastic modules, in the absence of changes in BMD [49]. A significant increase in pentosidine bone level, possibly responsible for reduced material properties, has been reported in STZ diabetic rats [50]. Based on these observations, plasma and/or urinary pentosidine has been investigated as a potential new marker of bone damage in diabetes. In particular, Yamamoto et al. have examined the association between serum pentosidine levels and vertebral fractures in Japanese patients with T2D; pentosidine levels were significantly higher in post-menopausal women with vertebral fractures compared to the control group [52]. Although plasma pentosidine levels are influenced by glycaemic control and renal function, in this cross-sectional study pentosidine was associated with fractures independent of BMD, risk factors for osteoporosis, diabetic status and renal function [52]. A similar finding was provided by a cross-sectional study conducted in 128 men and premenopausal women with T1D [53]. Multivariate logistic regression analysis adjusted for BMD and fracture risks showed that pentosidine levels and glycated haemoglobin (HbA1c) are independent factors associated with fractures. Endogenous secretory receptor for AGEs (RAGE) did not significantly differ between subjects with or without fractures.

Although these observations suggest that the impairment in collagen cross-links and AGE formation might explain the relation between bone fragility and diabetes, larger and more robust studies are needed to confirm this hypothesis. Moreover, the immunoassay needed to detect and measure pentosidine has a low grade of sensitivity and specificity due to numerous factors in blood and urine that interfere with immunoassay standardization [54], therefore it needs to be improved.

Incretin System

The incretin system includes a large number of peptides, although more than 90% of its physiological effects are accomplished by glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). Several studies have shown that the magnitude of nutrient-stimulated insulin secretion is reduced in subjects with T2D, which prompted investigations to ascertain whether endogenous secretion and/or incretin action is reduced in diabetic subjects. GIP plasma levels appear normal or even elevated in subjects with T2D, whereas meal-stimulated GLP-1 plasma levels, are modestly but considerably reduced in patients with impaired glucose tolerance or T2D. Conversely, T1D patients may have normal incretin responses to meals [55]. Normally, GIP and GLP-1 have short half-lives and are quickly degraded by dipeptidyl peptidase-4 (DPP-4).

GIP exerts its functions by activating a specific G protein-coupled receptor (GIPR) expressed by different cells, including pancreatic beta-cells and adipocytes and apparently also by osteoclasts [56], osteoblasts [57], osteocytes and chondrocytes [58]. GIP stimulates osteoblast proliferation, increasing the expression of collagen type I and the activity of alkaline phosphatase [55]. GIP appears to inhibit osteoclast activity through cyclic adenosine monophosphate (cAMP). As demonstrated by Zhong and coll., GIP increases both intracellular calcium and cAMP content [56], which may inhibit osteoclastic activity. However, evidence on the potential anti-resorptive effect of GIP is inconsistent. Indeed, Tsukiyama et al. have shown that GIP does not have a direct effect on osteoclast activity [59].

In vivo studies have confirmed the favourable effect of GIP on bone health. Mieczkowska et al. have shown that mice lacking the GIPR exhibit decrease of cortical mass and bone strength [60]. On the other hand, it has been reported that mechanical properties of the bone matrix, BMD and the ratio of mature/immature collagen cross-links are impaired in GIPR-knockout mice, despite an increased trabecular bone volume and trabecular number.

Nissen and coll. examined the effect of GIP administration on bone resorption in 10 healthy subjects. The concentrations of degradation products of C-terminal telopeptide (CTX) were measured during four different conditions: euglycaemic or hyperglycaemic glucose clamps with co-infusion of GIP or placebo. Hyperglycaemia itself resulted in a reduction in CTX levels, which were further lowered when GIP was added to the hyperglycaemic clamp, suggesting an interaction of GIP with a possible effect of hyperglycemia on bone resorption [57].

GLP-1 exerts its effects through interaction with the GLP-1 receptor found in pancreatic islets, lung, hypothalamus, stomach, heart and kidney. GLP-1 can interact directly and functionally with osteoblastic cells, possibly through a GPI/IPG-coupled receptor (GLP-1R), as well demonstrated for the first time by Nuche-Berenguer B et al. [61].

Although the effect of GLP-1 on osteoblasts has not been fully elucidated, there is some evidence suggesting that it may induce osteogenic differentiation in bone [62]. Indeed, Jeon et al. described the expression of GLP-1R during osteogenic differentiation of adipose-derived stem cells [62]. GLP-1 seems to be able to suppress osteoclasts through a calcitonin-dependent pathway [61].

Many in vivo studies, using different animal models, have shown a potential role for incretin hormones in bone metabolism, but there are only limited data regarding the impact of DPP-4 inhibitors and GLP-1 agonists on bone health in humans [63]. Administration of GLP-1 (or its analogue enzyme-resistant variant, such as exendin-4) to normal and diabetics rats has shown to increase trabecular bone mass and the expression of osteoblast markers. These data confirm the potential anabolic effect of GLP-1 on trabecular bone [64]. Moreover, the administration of GLP-1 to mice with T2D and insulin resistance had a positive effect on bone mass, whereas administration to WT mice had no effect on bone structure [64].Very recent data also suggest a positive effect of GIP and GLP-1 analogues on bone quality in T1D. In STZ diabetic mice, GIP and GLP-1 were able to preserve cortical microarchitecture and to prevent the loss of whole bone strength [65]. Unfortunately, clinical evidences are lacking and only indirect data from clinical trials (metanalisi exenatide vs liraglutide) or other contrasting results are available [66, 67].

Acute and Chronic Diabetic Complications

Recent large retrospective cohort studies have shown that hypoglycaemia is strictly associated with risk of falls in diabetics [68]. There is robust evidence supporting a relationship between chronic diabetes complications and risk of fracture in both T1D and T2D [69] by several mechanisms [70].

In particular, patients with retinopathy, vasculopathy and neuropathy are more at risk of falls and may present altered bone microstructure and altered bone material properties [70, 71].

In a recent cross-sectional study, Shanbhogue and coll. showed that only a subgroup of T2D patients affected by microvascular complications had deficits of cortical bone compared to T2D patients without microvascular complications or control subjects, but the authors were not able to explain this feature [72]. Instead, no significant difference in trabecular bone parameters and trabecular microarchitecture was evident in subjects with microvascular complications [72].

Calcium Metabolism

Both T1D and T2D are characterized by low levels of vitamin D, as supported by several case-control studies. However, calcitriol supplementation did not have any positive effects on bone turnover markers in T1D subjects [73].

Moreover, polyuria due to hyperglycaemia may cause urinary loss of calcium, phosphorus and magnesium [74] leading to an imbalance in the PTH/vitamin D axis. Yamamoto and coll. found that T2D subjects had decreased levels of PTH, which leads to low bone formation in conjunction with reduced bone resorption in both males and females. In addition, lower levels of PTH with lower levels of OC were associated with vertebral fractures, independent of BMD, in post-menopausal women. These findings indicate that reduced bone formation associated with low levels of PTH might increase the risk of vertebral fracture through bone quality deterioration [75]. Thakassinos et al. have described a “functional hypoparathyroidism” in T1D patients, likely associated to poor glycaemic control. Improvement of metabolic control positively affects serum calcium levels [76].


In different ways, both TD1 and TD2 may be considered as inflammatory diseases. Susceptibility to T1D involves a complex interplay between genetic and environmental factors, but there is now increasing evidence for a role of innate inflammation. Indeed, therapeutic targeting of innate inflammation has been proven effective in preventing and delaying T1D in rat models. In particular, IL-1, a pro-inflammatory cytokine central to innate immunity, and tumor necrosis factor-α (TNF-α) have been involved in T1D onset and beta cell damage impairing insulin bio-synthesis. Both cytokines can promote the osteoclastogenic process and enhance osteoclast activity by inducing the expression of RANKL and by exerting an anti-apoptotic effect, as shown in in vitro experiments [77].

It has been also demonstrated that TNF-α can down-regulate RUNX2 and osterix, thereby increasing the expression of sclerostin and Dkk1 [78]. Consistently, low concentrations of TNF-α or suppression of TNF-α by TNF soluble binding protein or an anti-TNF-α [79] reduces the RANKL-induced osteoclast formation, suppressing bone resorption.

It has been proposed that a low-grade chronic inflammation is involved in the pathogenic processes causing TD2 [80]. IL-6 is one of the cytokines more strictly linked to obesity and T2D, as it is released from the adipose tissue [80]. Indeed, both insulin resistance and hyperglycaemia are associated with high levels of IL-6 enhancing osteoclastogenesis [81]. Importantly, serum levels of CRP, a main inflammation marker, are higher in obese subjects and are independent predictors of low BMD [82].

Unbalanced adipokines concentration may play an important role in bone health in diabetic subjects; while the complex role of leptin on bone metabolism has been reviewed elsewhere, adiponectin production is downregulated in diabetics [83] and in turn negatively affecting both trabecular and cortical bone [84, 85].

Marrow Adiposity

Fat cells inhabit the bone marrow along with osteoblasts and their common mesenchymal precursors [86]. In the bone marrow, constitutional changes occur continuously with ageing and different environmental and health conditions [87]. Conversion of marrow adiposity is a physiological age-related phenomenon that consists in transformation of an active marrow (hematopoietic/red marrow, status at birth) into a less active one (fat/yellow).

Fig. 1

Physiopathological pathways leading to bone fragility due to diabetes. The figure represents the detrimental effects of Hyperglycaemia and AGEs, due to insulin deficiency, identification of T1D, and hyperinsulinemia/insulin resistance, hallmark of T2D, on different biological systems related on bone metabolism. Open image in new window : impairment; Open image in new window : stimulation; (*) most of the evidence may suggest a major effect on osteoclasts; (§) just few evidences support also the effects on osteoclasts

Fat bone marrow is considered an insulin-sensitive tissue, closely linked to systemic energy metabolism, because of the expression of genetic and metabolic traits of brown adipose tissue [86, 88].

Bone marrow fat might be abnormal in patients with osteoporosis and/or T2D [88], and an inverse correlation between bone marrow adiposity and BMD [88] has been found. Patsch et al., examining bone marrow fat content (by MRI) and composition in diabetic and non-diabetic women, found that fracture and T2D were associated with lower unsaturation of bone marrow lipids and high bone marrow lipids saturation levels independent of age, race and local BMD. Indeed, the prevalence of fragility fractures was associated with lower unsaturation levels [88].

Moreover, long-standing diabetes is linked to changes in bone marrow cellularity. These changes include an enhancement of adipogenesis from MSCs, as observed in both T1D and T2D [89, 90]. In insulin-deficient in vivo models, this process leads to a decrease in bone density (in particular loss of trabecular bone) and a reciprocal increase in marrow adiposity [29, 89, 90]. Furthermore, a positive correlation between bone marrow fat and sclerostin has been demonstrated in older men (but not in women). Diabetes also induces microvascular remodelling in bone marrow, which may be responsible for the impairment of angiogenic ability, vascular endothelial cell dysfunction and reduction of stem cells number seen in patients with diabetes [89]. Recent evidences have also proved that Sclerostin levels are directly related to higher vertebral marrow fat in diabetics [91].



In T1D, “diabetic myopathy” is characterized by reduced muscle growth and strength [92] and impaired stem cell differentiation toward the myogenic lineage [93]. Other Studies in humans have suggested a reduction in muscle mass and fibre size. Kim et al. have estimated that the risk of developing sarcopenia is threefold higher in T2D subjects compared to non-diabetic subjects after adjusting for many confounding risk factors [94]. It has been recognized that sarcopenia increases the risk of falls and fractures. Although the mechanism underlying the relationship between sarcopenia and diabetes has not been fully identified, chronic inflammation, reduction in muscle protein synthesis and an increase in protein degradation due to insulin resistance may play an important role [95]. Furthermore, a reduction of endogenous insulin secretion may lead to sarcopenia in diabetics. As skeletal muscle is the major site of glucose disposal, reduced muscle mass resulting in a lower number of available insulin receptors may further worsen glucose metabolism [95].

Finally, it has been found that pentosidine is inversely associated with relative skeletal muscle mass index and could represent an independent risk factor for low muscle mass. Muscle impairment and lower muscle strength induced by diabetes may increase the risk of falls [96].


Irisin might represent a further link among diabetes, skeletal muscle and increased risk of fracture. Irisin is an exercise-induced myokine that may trigger “browning” of white adipose tissue. There is consistent in vitro and some in vivo evidence that irisin can positively affect bone health. In particular, Grano and coll. demonstrated that the injection of irisin in male mice stimulates bone formation, reduces the number of osteoclasts and increases cortical bone mass and strength, [97]. As compared to control healthy individuals, patients with diabetes have lower irisin serum levels [98]. A few cross-sectional studies have confirmed that low levels of irisin are associated with vertebral fractures in post-menopausal women [99].


Both T1D and T2D are associated with impairment of bone health. The current understanding of the underlying bone fragility in diabetic patients includes several risk factors and the involvement of different pathways (Fig. 1).

Chronic Hyperglycaemia plays a central role, leading to impairment of osteoblast function trough detrimental effects on osteoblastogenesis and Wnt/β-catenin signalling. Furthermore, hyperglycaemia is the main drive to the formation of AGEs that impair collagen fibres flexibility causing lower bone strength. Accordingly, longer duration of the disease and worsened glucose control are associated with higher risk of fractures.

Bone metabolism may be also negatively affected by decreased GIP and GLP-1 levels (lowering bone formation) and a pro-inflammatory state (increasing bone resorption) that are hallmarks of type 2 diabetes. Increased bone marrow adiposity, low vitamin D and adipokines disregulation are also negative regulators of bone health in diabetes. Finally, diabetic patients have a higher risk of hypoglycaemic events that, in turn, increase the risk of falls and fractures. Falls are also caused by sarcopenia and chronic complications like poor balance, retinopathy and neuropathy.

Further preclinical and clinical studies are needed to confirm and better understand the different pathways that lead to bone fragility in diabetes mellitus.



The authors thank Anda Naciu, MD, for the valuable support given to the drafting of this work.

Compliance with Ethical Standards

Conflict of interest

Andrea Palermo, Luca D’Onofrio, Raffaella Buzzetti, Silvia Manfrini and Nicola Napoli declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This is a systematic review and we did not perform any animal or human experiments for this work. For this type of study formal consent is not required.


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Andrea Palermo
    • 1
  • Luca D’Onofrio
    • 2
  • Raffaella Buzzetti
    • 2
  • Silvia Manfrini
    • 1
  • Nicola Napoli
    • 1
    • 3
    Email author
  1. 1.Diabetes and Bone network, Department Endocrinology and DiabetesUniversity Campus Bio-Medico of RomeRomeItaly
  2. 2.Department of Experimental Medicine, Polo PontinoSapienza University of RomeRomeItaly
  3. 3.Division of Bone and Mineral DiseasesWashington University in St LouisSt LouisUSA

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