See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/323974154

Influence of diabetes on tissue healing in orthopedic injuries

Article  in  Clinical and Experimental Pharmacology and Physiology · March 2018

DOI: 10.1111/1440-1681.12939

CITATION READS

1 69

4 authors:

Artur Stolarczyk Sylwia Sarzyńska

Medical University of Warsaw Medical University of Warsaw
29 PUBLICATIONS   70 CITATIONS    16 PUBLICATIONS   6 CITATIONS   

SEE PROFILE SEE PROFILE

Agata Gondek Agnieszka Cudnoch - Jedrzejewska

Medical University of Warsaw Medical University of Warsaw
15 PUBLICATIONS   9 CITATIONS    77 PUBLICATIONS   387 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Takotsubo View project

Apelin and hypertension View project

All content following this page was uploaded by Agata Gondek on 29 March 2018.

The user has requested enhancement of the downloaded file.

 MISS AGATA GONDEK (Orcid ID : 0000-0003-4060-7037)
Accepted Article
Article type : Review Article

Influence of diabetes on tissue healing in orthopedic injuries

Artur Stolarczyk1, Sylwia Sarzyńska2, Agata Gondek3, Agnieszka Cudnoch- Jędrzejewska3

1
Department of Clinical Rehabilitation, Second Faculty of Medicine, Medical University of

Warsaw, Kondratowicza 8, 03-242 Warsaw, Poland

2
Department of Orthopaedics and Traumatology, Medical University of Warsaw, Lindleya 4,

02-005 Warsaw, Poland

3
Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical

Research, Medical University of Warsaw, Banacha 1b, 02-097 Warsaw, Poland

Short title: Diabetes and orthopedic injuries

Corresponding author: Agata Gondek

Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical

Research, Medical University of Warsaw, Banacha 1b, 02-097 Warsaw, Poland; phone: +48

22 116 6113; fax: +48 22 116 6201; e-mail address: agata.gondek@wum.edu.pl

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/1440-1681.12939
This article is protected by copyright. All rights reserved.
 The authors declare no conflict of interest.
Accepted Article
ABSTRACT

Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from the

defective action or secretion of insulin. Chronic hyperglycemia can lead to the damage,

dysfunction and failure of various organs. In the context of complications of healing and

orthopedic rehabilitation, vascular (microangiopathy) and nerve (neuropathy) disorders

deserve particular attention. About 12% of the patients admitted to orthopedic departments

have diabetes. Studies indicate that there is an indisputable link between diabetes and: an

increased risk of fractures, the difficult healing of injuries of bones, ligaments and

musculotendinous. It appears that one of the main reasons for this is non-enzymatic

glycosylation (glycation) of collagen molecules, a phenomenon observed in the elderly and

diabetic populations, as it leads to the formation of advanced glycation end products (AGEs).

Collagen is one of the major connective tissue components, and is therefore part of ligaments,

tendons and bones. AGEs affect the weakening of its structure and biomechanical properties,

and thus also affects the weakening of the structure and properties of the above mentioned

tissues.

The aim of the study was to undertake an overview of the current knowledge of the impact of

diabetes on the risk of some injuries and subsequent healing and rehabilitation of patients

following orthopedic injuries.

KEY WORDS: advanced glycation end products, AGEs, bone fractures, diabetes,

ligament, orthopedic injuries, tissue healing

This article is protected by copyright. All rights reserved.

 INTRODUCTION

Diabetes mellitus (DM) is a group of metabolic diseases characterized by

Accepted Article
hyperglycemia resulting from the defective action or secretion of insulin. Chronic

hyperglycemia in diabetes is associated with the injury, dysfunction, and failure of various

organs. Complications may be divided into microvascular and macrovascular. The most

prevalent complications from the first group are blindness, amputations and kidney disease.

Among macrovascular complications, cerebrovascular events, heart failure, myocardial

infarctions, and atherosclerosis should be mentioned (1, 2). In the context of orthopedics,

vascular and nerve disorders deserve particular attention. Diabetic neuropathy is one of the

most common chronic complications of DM. According to the data, more than 50% of

patients with DM develop neuropathic changes. The risk of amputation due to neuropathic

and microvascular changes may be as high as 15% in some populations (1). The most

common form of neuropathy is peripheral, symmetrical lower limb neuropathy affecting both

sensory and motor functions (3). Motor neuropathy leads to muscular atrophy that interferes

with the cooperation of rectifiers and flexors and to foot deformation (1). It should be noted

that neuropathic changes affect various structures: vessels, nerves, skin, muscles, and bones.

There is also a problem of lower limb ischemia, which is important in the process of healing

injured tissues. Ischemia is the combined result of microangiopathic and neuropathic

disorders. Sensory neuropathy, leading to pain, temperature and touch disturbances, results in

repeated uncontrolled injuries promoting foot and leg ulceration, which in the end may result

in amputations (1).

It is recognized that significant morphological changes in diabetes are closely related

to its late complications (positive correlation with morbidity and mortality). The onset of

these changes is very individual and depends on the degree of diabetes control by the patient.

This article is protected by copyright. All rights reserved.

 However, in most patients after 10–15 years from diagnosis, morphological changes in the

arteries (atherosclerosis), kidneys (diabetic nephropathy), retina (retinopathy), nerves

Accepted Article
(neuropathy) and other tissues should be expected (3).

Diabetes occurs in about 12% of the patients of orthopedic departments (4). It is a

problem both with regard to the increased risk of injury and with regard to the subsequent

healing and rehabilitation process. The available data show the negative effect of diabetes on

the outcome of various orthopedic procedures. In addition, more frequent occurrences of

musculotendinous injuries in this patient population are observed (5). Considering the

orthopedic complications in people with diabetes, there is an increased incidence of the

following disorders: fractures, Charcot neuroarthropathy, dorsiflexion of the digits of the

hands and toes, plantar ulcerations and postoperative infections (6). It should also be noted

that diabetes has a significant effect on the increased risk of infection after orthopedic

procedures (6, 7). One of the main pathomechanisms involved in joint and bone changes in

DM is non-enzymatic glycosylation of collagen (glycation) resulting from chronic

hyperglycemia accompanying diabetes. As a result, so-called advanced glycation end

products (AGEs) are formed. Because collagen is one of the main connective tissue

components, it is therefore also part of ligaments, tendons, and bones. AGEs cause the

weakening of its structure and biomechanical properties, and this weakens the above-

mentioned tissues and contributes to increasing skeletal fragility (8). Further clinical studies

of this issue are required, as the research results indicate that there is a link between diabetes

and the injuries of bones, ligaments and musculotendinous. These issues will be discussed in

this paper.

This article is protected by copyright. All rights reserved.

 In the context of the complications of healing and orthopedic rehabilitation, we

focused on disorders of the vessels (microangiopathy) and nerves (neuropathy). Detailed

Accepted Article
characteristics of the pathogenesis and complications of diabetes exceed the framework of

this study. Only aspects that directly affect the rehabilitation and healing of orthopedic

injuries are described.

SKELETON AND DIABETES

An increased risk of fractures in DM patients may seem paradoxical, especially in

DM type 2, as in general they have a bone mineral density (BMD) within normal limits and a

rather high body mass index. In type 1 diabetes, BMD has been reported as being lower

compared with healthy controls (6). In general, these two factors have been correlated with a

decreased risk of fractures (8, 9). It has been suggested that an increased risk of fractures in

DM patients is multifactorial and includes an increased risk of falling, microvascular

complications and alterations due to chronic hyperglycemia (Fig. 1) (10). Moreover, skeletal

fragility in DM patients is a result of morphological and architectural bone changes such as a

smaller cortical area, increased porosity and impaired strength (6). According to the data, in

type 2 DM skeletal dynamics are reduced, assessed on the basis of decreased biochemical

markers level of bone metabolism and reduced bone formation rate in histomorphometric

studies (11, (11, 12). Furthermore, it has been reported that osteoblast function and

maturation may be impaired due to increased circulating levels of molecules such as

transforming growth factor β (TGF-β) (13).

It has been suggested that a crucial impact on the fragility of the skeleton in DM

patients may be due to the accumulation of AGEs (8). Studies have revealed that AGEs

decrease the activity of osteoblasts via impairing the adhesion of these cells to the collagen

This article is protected by copyright. All rights reserved.

 matrix, inhibiting differentiation and proliferation. Furthermore, a decrease in the mRNA of

crucial osteoblast products has been noted (8). According to the results, there is a negative
Accepted Article
correlation between AGEs and mechanical bone properties, especially with ultimate strain,

stress and fracture toughness. Moreover, in vitro studies have revealed that crack-like micro

damage is positively correlated with high AGEs levels (8). The level of pentosidine (one of

the AGEs) has been reported as 30% higher in DM patients compared with nondiabetic (8).

In terms of increased severity of osteoarthritis (OA) in DM patients, it has been suggested

that it may be explained by the catabolic effect of hyperinsulinemia and hyperglycemia on

cartilage (14, 15). Furthermore, not only cartilage degeneration but also subchondral bone

changes are exacerbated in DM patients. Chen et al. (16) reported microstructural

deterioration, abnormal bone remodeling and decreased strength in DM patients assessed on

the basis of tibial plateaus, compared with non-DM patients and controls (cadavers).

In experimental studies in animal models with type 1 diabetes and type 2 diabetes, it

has been observed that the biomechanical properties of the diabetic animals worsened when

compared with the control animals (17-19). Follak et al. (17) demonstrated that femur

fractures of type 1 diabetic rats had worse biomechanical properties (defined as stiffness,

energy, and the force required to break the bone) after 6 weeks from fracture compared with

similar properties in the control animals after 2 weeks from fracture. Although the extreme

values of hyperglycemia and hypoinsulinemia observed in animals in the type 1 diabetes

model poorly reflect clinical reality, they directly indicate the contribution of these factors to

the healing process of the fracture. In the model of type 2 diabetes, more common clinically,

deterioration of the biomechanical properties (torsional strength) was observed not before 35

days of intervention without significant difference after 2 weeks (19).

This article is protected by copyright. All rights reserved.

 According to data, the risk of hip fracture in DM patients is increased. For type 1 diabetes the

incidence is 6-7 times higher and for type 2 DM the incidence is 1.4-1.8. It has been
Accepted Article
suggested, that the reason may be due to the increased risk of falling and antidiabetic drugs,

acting both directly on bone metabolisms and indirectly inducing hypoglycemia, which may

result in falls (6). Ankle fractures are another common injury. It has been suggested that, in a

diabetic woman (20) and patients treated with insulin (21), the risk of ankle fractures is

increased, although these results are inconsistent. (6) Nevertheless, if a fracture occurs, the

risk of infection, nonunion or amputation is significantly increased compared with

nondiabetic patients. According to the results, in 90% of nondiabetic patients, treatment

results are reported as good, whereas in DM patients it is 70% (6). In a study by Kline et al.

(22), intraarticular fracture of the distal tibial plateau (pilon type) in diabetic patients was

complicated by the lack of or delayed bone fusion in 43% of the patients as compared with

11% of healthy individuals. Shibuya et al. (23), in a retrospective analysis of 177 cases

involving intervention of foot and shin bones (osteotomy, arthrodesis, fracture setting),

looked for a link between pre- and postoperative factors affecting complications that were

defined as: delay of bone fusion, absence of bone fusion or abnormal bone fusion. Statistical

significance was found for the following: the presence of neuropathy, glycated hemoglobin

(HbA1c) above 7%, and length of surgery. It should be noted that the most important

prognostic factor was neuropathy.

The question arises - of which predictors are the most accurate in the assessment of

the risk of potential fractures in this group of patients. It seems that bone turnover markers

may be an important tool. According to the Starup-Linde and Vestergaard (11) study, the

level of bone turnover markers is lowered in patients with diabetes. The authors evaluated the

concentration of C-terminal telopeptide of type I collagen (CTX), insulin-like growth factor 1

(IGF-1) and sclerostin, procollagen type 1 N-terminal propeptide (P1NP), osteocalcin and

This article is protected by copyright. All rights reserved.

 bone-specific alkaline phosphatase (ALP). The results seem promising, but researchers

underline the need for further research in this area (11, 24).
Accepted Article
Coexisting diabetes is a problem not only because it increases the risk of fractures, but

also because it affects the subsequent healing and rehabilitation process. According to the

data, blood viscosity in DM patients is increased, leading to hypoxia of tissues. As a result,

inflammatory reactions are slowed down, impairing wound healing and increasing infection

risk (25,26). Pollock et al. (27), in a retrospective study of 1486 patients, reported a risk of

hospital re-admission for patients with fractures of the proximal end of the femur (femoral

neck fractures, intertrochanteric and subtrochanteric fractures) within 30 days of discharge

after primary surgery. According to the results, the rate of re-admission was 9.35%. There

was a positive correlation between patients requiring re-hospitalization and the coexistence of

either diabetes or respiratory diseases (27). According to Gortler et al. (26) coexisting DM

significantly impair healing in lower extremity fractures. In a review, it has been reported

that the rate of infections, re-operations, malunions and nonunions is significantly higher in

DM patients.

In shin bone fractures, Bibbo et al. (25) observed an extended wound healing period

in people with diabetes (over 50% longer). There is also an increased incidence of

complications (28), especially in patients treated with insulin compared with those treated

with oral antidiabetic drugs or diabetic diets (22). Patients with advanced complications of

late diabetes are more likely to develop an infection during treatment, bone healing problems

and the longer use of orthopedic orthoses after fractures (29). Interestingly, the complications

described above did not depend on the method of treatment – surgical or nonsurgical. Factors

that directly correlate with bone healing disorders are neurogenic neuroarthropathy in the

medical history, nephropathy, neuropathy, longer duration of illness, and insulin treatment.

This article is protected by copyright. All rights reserved.

 IMPACT OF ANTIDIABETIC DRUGS ON BONES

Although DM itself impairs bone mechanical properties, it should be noted that some
Accepted Article
drugs administered for DM may negatively impact bone metabolism as well. Table 1 presents

the mechanism of action of antidiabetic drugs and their effect on risk of fractures.

The most commonly prescribed drug for increased insulin sensitivity is metformin,

which is a biguanide (30). This drug activates AMP-activated protein kinase (AMPK),

causing the reduction of glucose production in the liver and increased glucose uptake in the

muscles (31, 32). It appears, that it is neutral in terms of the risk of fractures and some studies

showed a reduced risk of fractures in patients treated with metformin (30). According to

studies on animal models, the beneficial effects of metformin on bone metabolism may be

due to increased osteoblast differentiation via activating osteoblast-specific runt-related

transcription factor 2 (Runx2) with AMPK/USF-1/SHP regulatory cascade (33). Metformin

has also been shown to have an adverse effect on osteoclastogenesis in ovariectomized rats

by reducing the expression of the receptor activator for nuclear factor kappa-Β ligand

(RANKL) and increasing the level of osteoprotegerin also known as osteoclastogenesis

inhibitory factor (34).

Sulfonylureas are other drugs commonly used in DM type 2 patients. Drugs from this

group stimulate the pancreatic cells to secrete insulin. It was shown that one of sulfonylureas

drug glimepiride has a positive effect on rat osteoblast cells and promotes their proliferation

and differentiation (35). The ADOPT and Rochester studies indicated that therapy with

glibenclamide does not affect bone mass nor increases the risk of fractures (36, 37).

However, another study showed that glibenclamide therapy decreased the level of the serum

P1NP, a marker of bone formation (38). It has also been revealed that in the elderly with type

This article is protected by copyright. All rights reserved.

 2 diabetes these drugs have an adverse effect on bones and are associated with an increased

risk of hip fractures in both sexes over the age of 65 years (39).
Accepted Article
Glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-

4) inhibitors are relatively new incretin-based drugs for the treatment of T2DM. In response

to nutrients, the endocrine cells of the intestine release incretins – gastric inhibitory peptide

(GIP) and glucagon-like peptide 1 (GLP-1) (40). Incretins are quickly inactivated by DPP-4

(41) and these antidiabetic medications are intended to prolong the effect of the incretins by

stimulating the release of insulin by the pancreatic cells and inhibiting the production of

glucagon in the liver. Most of the animal studies reviewed by Gilbert and Pratley (42) or

Charandran (43) indicate a neutral or positive effect of these drugs on bones. The findings of

Sun et al. (44) show an anabolic effect of GLP-1 receptor agonist to the skeleton in

spontaneous diabetic rats. Regarding the clinical data, incretin-based antidiabetic drugs seem

to have a neutral effect (45, 46) or a positive effect (47, 48) on reducing the risk of bone

fracture.

Thiazolidinediones (TZDs) are antidiabetic drugs that increase insulin sensitivity by

activating peroxisome proliferator-activated receptor γ (PPARγ). Due to the many side

effects, their use has decreased significantly (43). Rosiglitazone and pioglitazone, the most

well-known TZDs, have been proven to negatively affect the skeleton. According to the

review by Gilbert and Pratley (42), thiazolidinediones increase the rate of bone loss and the

risk of fractures in the population of patients with diabetes (42). Chen et al. (49) found that

TZDs caused an increased risk of fractures particularly in women under 64 years of age. It

seems that thiazolidinediones impair the function of osteoblasts and activate

osteoclastogenesis. Moreover, these drugs negatively impact osteoblastogenesis via

decreased activity of osteoblast-specific signaling pathways and decreased activity of

osteoblast-specific transcription factors. These processes result in a more intense bone loss

This article is protected by copyright. All rights reserved.

 (30). By activating PPARγ, TZDs stimulate the differentiation of mesenchymal cells towards

adipocytes, increase RANKL expression and osteoclastogenesis, and reduce

Accepted Article
osteoblastogenesis (50, 51). Pioglitazone treatment has been shown to reduce the expression

of osteoblast-specific Runx2 and ALP and to stimulate the transdifferentiation of human

mesenchymal bone marrow stem cells into adipocytes in vitro (51). Bone loss as a result of

the action of TZDs may also be associated with a reduced amount of insulin-like growth

factor 1 (IGF-1) and therefore reduced bone formation (52).

The sodium/glucose cotransporter 2 inhibitors (SGLT2 inhibitors or gliflozins) is

another DM drug class, which may negatively affect bone metabolism. Due to the mechanism

of action, they may alter the hemostasis of calcium and phosphate, thus inducing secondary

hyperparathyroidism. It may potentially affect bone mass and increase the risk of fractures

(30). However, the mechanisms by which SGLT2 inhibitors cause bone loss are not clear

(43).

LIGAMENT AND TENDON INJURIES IN PATIENTS WITH DM

It is known that diabetes affects changes in the joints and ligaments. According to the

available data, collagen glycation appears to be crucial. The process of production of the final

form of collagen is regulated by the formation of numerous cross bonds between individual

filaments that stabilize its structure. Regulation of bond formation may occur in an enzymatic

and non-enzymatic manner. It is considered that enzymatic cross-linking of collagen is

crucial in connective tissue regeneration (53). This affects the achievement of proper

stiffness, resistance to load, and resistance to injury by the healing tissue. In turn, the process

of non-enzymatic cross-linking is a negative phenomenon observed in both elderly and

diabetic patients. These bonds are the result of oxidative, non-enzymatic reactions between

This article is protected by copyright. All rights reserved.

 glucose and collagen (53). As a result, AGEs are formed. The healing tissues in this

mechanism are less resistant to injuries, load and stretching.

Accepted Article
Data about the healing process of ligaments in patients with diabetes are limited.

There is, however, research on animal models related to the healing process of tendons in

diabetes-induced mice. Since the histological structure of the ligaments is similar to the

tendon structure, they may be the basis for the study and analysis of ligament healing

disturbances in diabetes-inflicted individuals. Disorders of healing are observed at the

structural, biochemical and molecular level. Healing tendons in diabetic individuals exhibit

worse biomechanical properties: reduced stiffness, reduced tensile stress, reduced maximum

load, decreased Young’s modulus (54-57). Young’s modulus is also known as the elastic

modulus and is defined as the quotient of stress (MPa) and strain (proportional deformation)

in a material. In the inflammatory phase of healing, significant reduction of neutrophil and

macrophage infiltration at the lesion site was observed (58). In turn, the proliferative phase is

characterized by decreased amounts of fibroblast and lymphocyte infiltration (54, 56),

therefore, cell proliferation is limited. There is also a decrease in vascularization in the early

proliferative phase (evaluated on the 7th day after injury, unchanged on the 28th day) (56,

58). Another deviation in the healing process is the decrease of collagen type I, collagen type

III and biglycan synthesis within 2 weeks of injury (55). Molecular studies have shown an

increased amount of insulin receptors in the lesion site in both the control group and the

group with induced diabetes (34). Decrease mRNA expression of growth factors, such as

vascular endothelial growth factor (VEGF), thymosin β-4 (Tβ-4) and metalloproteinase 3

(MMP-3), has also been detected (55, 59).

One of the most common orthopedic problems is Achilles tendon injury. Recently, an

attempt has been made to find a link between diabetes (type 1 and type 2) and changes in the

Achilles tendon structure that can be observed in ultrasonography (USG). Achilles tendon

This article is protected by copyright. All rights reserved.

 changes have been shown to correlate with the risk of tendinopathy. It is worth noting that a

direct association of the body mass index (BMI) of a diabetic patient with the occurrence of
Accepted Article
changes in USG was more likely than diabetes alone (5). The structure of the tendon unit in

diabetic patients is generally impaired. Thinning, shortening, and increasing stiffness of

tendons are observed. The pathomechanisms of these changes have not yet been fully

explained. Non-enzymatic glycosylation of collagen is most likely responsible for increased

tendon stiffness in individuals with diabetes (5). There are numerous studies on animal

models.

Boivin et al. (60) compared the biomechanical and histological structure of the

Achilles tendon in db/db diabetic mice to nondiabetic control mice. In mice with diabetes, the

following changes were observed: tendon diameter increase, decrease of maximum load,

decrease of tensile stress, decrease of tendon stiffness, and decrease of tendon elastic

modulus. In addition, 25% of the diabetic mice were evaluated with the infiltration of the

tendon by inflammatory cells (neutrophils). In summary, hyperglycemia and obesity had a

significant effect on the occurrence of pathological lesions within the Achilles tendon in mice

(60). It is likely that similar changes occur in humans, but further research is needed.

Ahmed et al. (61) hypothesized that impaired healing in DM may be due to abnormal

expression of neurotrophic and angiotrophic factors, as neurotrophins play a prominent role

in angiogenesis and re-innervation within connective tissue, which is crucial for regeneration

and homeostasis. Indeed, in a study on rats with injured Achilles tendons, the authors

observed significantly lower levels of nerve growth factor (NGF) and brain-derived

neurotrophic factor (BDNF) in rats with induced DM versus healthy controls.

This article is protected by copyright. All rights reserved.

 According to the results of Oliveira et al. (62), the Achilles tendon in DM rats

displays significant differences in morphology compared with the control group without DM.
Accepted Article
The tendons were assessed with MRI and Atomic Force Microscopy. The authors observed a

significant increase in the coronal and transverse dimensions of the tendon in the DM group.

Furthermore, irregularity in the fiber bundles was noted (62). In the previous study, the

authors reported vascular hyperplasia in the vessels of the Achilles tendons and an increase in

VEGF, type 1 collagen, and NF-κB expression and mast cell number in comparison with

healthy controls (63).

In the study by Mohsenifar et al. (57), the animals underwent tenotomy of the

Achilles tendon. According to the study, the healthy control group displayed significantly

higher Young's modulus and stress tensile load. In the group with streptozotocin induced type

2 DM, the authors noted intensified inflammation and diminished fibrosis.

Also, in vitro studies can be useful in understanding the mechanisms of tendon

healing disorders in diabetes. Lin et al. (64) determined the effect of various glucose

concentrations on tendon-derived stem cells (TDSCs) in vitro. It has been shown that high

glucose concentration inhibits the proliferation of these cells, induces apoptosis and reduces

the expression of markers associated with the tendons (sclerosis and collagen type 1 alpha 1

chain).

Another common orthopedic injury in the population of people affected by diabetes is

rotator cuff disease (65). In the reconstruction of the rotator cuff, diabetes was one of the

preoperative predictors that negatively affected the mobility of the shoulder joint at 3 months

postoperatively. However, in the same study, there was no statistically significant difference

when lifting the hand forward after one year of observation (66). Dhar et al. (67) conducted a

study evaluating the outcome of arthroscopic reconstruction of rotator cuff damage after one

This article is protected by copyright. All rights reserved.

 year of observation and showed improvement in movement range and higher scores on the

American Shoulder and Elbow Score (ASES) and the Penn Shoulder Score (PSS) in patients
Accepted Article
with diabetes and in the control group. Similar results were obtained by Chen et al. (68) in a

study in which, after an open repair operation, progressive improvement in locomotive

performance was observed at the 6th week, the 6th month and the 34th month. It is worth

noting that in both studies, patients from the control group had a significantly greater range of

movement in postoperative evaluation (forward elevation of the shoulder, external rotation,

internal rotation) compared with patients with diabetes, although the difference was not

significant in the preoperative evaluation (67, 68). In patients with diabetes, recurrent damage

after rotator cuff repair occurs significantly more often and, importantly, correlates with

glycemia. Among individuals with poorly controlled diabetes (HbA1c > 7%), as many as

43.2% were injured again (69). In an experimental study of tendon attachment of

supraspinatus muscle healing in a diabetic mouse model, diabetes was associated with the

deterioration of the biomechanical properties, namely – stiffness and maximum load, in DM

rats when compared to the controls (70).

Mubark et al. (71) conducted a study evaluating the results of frozen shoulder

treatment by the arthroscopic release of the articular capsule. There were 40 patients in the

experimental group. Excellent results were noted in 22 patients, good results in 14 patients,

and fair results in 4 patients. All of the patients with the fair results (i.e., the worst results in

the study) were diagnosed with type 2 diabetes.

This article is protected by copyright. All rights reserved.

 IMPACT OF DIABETES ON TOTAL KNEE ARTHROPLASTY (TKA) AND TOTAL

HIP ARTHROPLASTY (THA) RESULTS

Accepted Article
As mentioned previously, DM impairs bone and cartilage metabolism and

biomechanical properties. As a result, severe osteoarthritis and eventually arthroplasty may

be expected. It has been reported that DM is a risk factor in patients undergoing arthroplasties

and increase the risk for vascular disease, wound infection and myocardial infarction

compared with nondiabetic patients (72). Gharaibeh et al. (73) reported a positive correlation

between diabetes and acute kidney injury in patients after THA. In terms of direct

orthopedics complications the following are mentioned: periprosthetic fractures, dislocations,

aseptic loosening, persistent pain, revision risk and increased readmission rates (72, 74-76).

Martinez - Huedo et al. (72) report higher rates of mortality in patients with DM versus non-

DM after TKAs and THAs. According to Webb et al. (77), patients with insulin-dependent

DM were found to be at a greater risk for adverse effects after TKA than the group with non-

insulin dependent DM and the group without DM. Patients with DM are more likely to be

readmitted and discharged to a location other than home (77-79). DM and preoperative

hyperglycemia have been considered an important predictor and a risk factor for surgical side

infections (SSI) (80). Moreover, in orthopedics, it is a well-known risk factor for

postoperative complications (81). Kremers et al. (82) reported an increased risk of surgical

side infection after TKA and THA in one year postoperatively in patients with DM and

preoperative hyperglycemia, although these effects did not remain statistically significant

after adjusting for BMI, operative time and ASA score.

Severe complications of lower limb arthroplasty procedures are venous

thromboembolisms (VTE), including deep vein thrombosis (DVT) and pulmonary embolism

(PE). It is hypothesized that DM may increase the risk of these complications as DM has

been associated with decreased fibrinolysis, increased blood coagulability and endothelial

This article is protected by copyright. All rights reserved.

 damage (83). According to Zhao et al. (84), DVT after TKA was significantly more common

in patients with DM.

Accepted Article
Not only are the primary THA and TKAs results affected in patients with DM.

According to the study by Lopez-de-Andres et al. (85), hospital postoperative complications

were significantly more common in patients with DM after revision TKA or revision THA. In

the first group, the incidence of acute post hemorrhagic anemia and urinary tract infections

was higher. Postoperative infection, acute post-hemorrhagic anemia, mean length of hospital

stay and in-hospital mortality were significantly higher in patients with T2DM after revision

THA.

SUMMARY

Microvascular disorders (microangiopathy) and nerve disorders (neuropathy) deserve

particular attention when considering the complications of healing and orthopedic

rehabilitation. The research we have reviewed reveals an indisputable link between diabetes

and: an increased risk of fractures, difficulty in bone healing, difficulty in the healing of

ligaments and tendons, and difficulty in the healing of musculotendinous injuries. It seems

that the non-enzymatic glycosylation of collagen molecules (a phenomenon observed in the

elderly and diabetic populations), leading to the formation of AGEs is essential. It should be

noted, however, that most of the research on this problem was conducted on animal models.

Due to the small number of clinical trials in this area, further studies are needed to understand

the exact etiology of changes at the cytological and histological level.

This article is protected by copyright. All rights reserved.

 DISCLOSURE

The authors declare no conflict of interest.

Accepted Article
FIGURE LEGEND

Figure 1. Factors that increased risk of fractures in diabetes mellitus.

Abbreviations: AGEs, advanced glycation end products

REFERENCES

1. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013;93:137-

88.

2. Forbes JM, Fotheringham AK. Vascular complications in diabetes: old messages, new

thoughts. Diabetologia. 2017;60:2129-38.

3. Kumar V, Cotran RS, Robbins SL. Robbins basic pathology. 7th ed. Philadelphia, PA:

Saunders; 2003. xii, p. 873.

4. Kurup H, Thomas M. Orthopaedics and diabetes. Acta Orthop Belg. 2013;79:483-7.

5. de Jonge S, Tol JL, Weir A, Waarsing JH, Verhaar JA, de Vos RJ. The Tendon Structure

Returns to Asymptomatic Values in Nonoperatively Treated Achilles Tendinopathy but Is

Not Associated With Symptoms: A Prospective Study. Am J Sports Med. 2015;43:2950-8.

6. Gehling DJ, Lecka-Czernik B, Ebraheim NA. Orthopedic complications in diabetes. Bone.

2016;82:79-92.

7. Brophy RH, Wright RW, Huston LJ, Nwosu SK, Group MK, Spindler KP. Factors associated

with infection following anterior cruciate ligament reconstruction. J Bone Joint Surg Am.

2015;97:450-4.

This article is protected by copyright. All rights reserved.

 8. Karim L, Bouxsein ML. Effect of type 2 diabetes-related non-enzymatic glycation on bone

biomechanical properties. Bone. 2016;82:21-7.

Accepted Article
9. Ma L, Oei L, Jiang L, Estrada K, Chen H, Wang Z, et al. Association between bone mineral

density and type 2 diabetes mellitus: a meta-analysis of observational studies. Eur J

Epidemiol. 2012;27:319-32.

10. Leslie WD, Rubin MR, Schwartz AV, Kanis JA. Type 2 diabetes and bone. J Bone Miner

Res. 2012;27:2231-7.

11. Starup-Linde J, Vestergaard P. Biochemical bone turnover markers in diabetes mellitus - A

systematic review. Bone. 2016;82:69-78.

12. Krakauer JC, McKenna MJ, Buderer NF, Rao DS, Whitehouse FW, Parfitt AM. Bone loss

and bone turnover in diabetes. Diabetes. 1995;44:775-82.

13. Ehnert S, Freude T, Ihle C, Mayer L, Braun B, Graeser J, et al. Factors circulating in the

blood of type 2 diabetes mellitus patients affect osteoblast maturation - description of a novel

in vitro model. Exp Cell Res. 2015;332:247-58.

14. Laiguillon MC, Courties A, Houard X, Auclair M, Sautet A, Capeau J, et al. Characterization

of diabetic osteoarthritic cartilage and role of high glucose environment on chondrocyte

activation: toward pathophysiological delineation of diabetes mellitus-related osteoarthritis.

Osteoarthritis Cartilage. 2015;23:1513-22.

15. Ribeiro M, Lopez de Figueroa P, Blanco FJ, Mendes AF, Carames B. Insulin decreases

autophagy and leads to cartilage degradation. Osteoarthritis Cartilage. 2016;24:731-9.

16. Chen Y, Huang YC, Yan CH, Chiu KY, Wei Q, Zhao J, et al. Abnormal subchondral bone

remodeling and its association with articular cartilage degradation in knees of type 2 diabetes

patients. Bone Res. 2017;5:17034.

17. Follak N, Kloting I, Merk H. Influence of diabetic metabolic state on fracture healing in

spontaneously diabetic rats. Diabetes Metab Res Rev. 2005;21:288-96.

This article is protected by copyright. All rights reserved.

 18. Beam HA, Parsons JR, Lin SS. The effects of blood glucose control upon fracture healing in

the BB Wistar rat with diabetes mellitus. J Orthop Res. 2002;20:1210-6.

Accepted Article
19. Brown ML, Yukata K, Farnsworth CW, Chen DG, Awad H, Hilton MJ, et al. Delayed

fracture healing and increased callus adiposity in a C57BL/6J murine model of obesity-

associated type 2 diabetes mellitus. PLoS One. 2014;9:e99656.

20. Holmberg AH, Johnell O, Nilsson PM, Nilsson J, Berglund G, Akesson K. Risk factors for

fragility fracture in middle age. A prospective population-based study of 33,000 men and

women. Osteoporos Int. 2006;17:1065-77.

21. Schwartz K, Chang SI. Clinical inquiries. What is the best approach to prevention and

treatment of osteoporosis? J Fam Pract. 2001;50:1024-5.

22. Kline AJ, Gruen GS, Pape HC, Tarkin IS, Irrgang JJ, Wukich DK. Early complications

following the operative treatment of pilon fractures with and without diabetes. Foot Ankle

Int. 2009;3:1042-7.

23. Shibuya N, Humphers JM, Fluhman BL, Jupiter DC. Factors associated with nonunion,

delayed union, and malunion in foot and ankle surgery in diabetic patients. J Foot Ankle

Surg. 2013;52:207-11.

24. Rubin MR. Bone cells and bone turnover in diabetes mellitus. Curr Osteoporos Rep.

2015;13:186-91.

25. Bibbo C, Lin SS, Beam HA, Behrens FF. Complications of ankle fractures in diabetic

patients. Orthop Clin North Am. 2001;32:113-33.

26. Gortler H, Rusyn J, Godbout C, Chahal J, Schemitsch EH, Nauth A. Diabetes and Healing

Outcomes in Lower Extremity Fractures: A Systematic Review. Injury. 2017. DOI:

10.1016/j.injury.2017.11.006 [Epub ahead of print].

27. Pollock FH, Bethea A, Samanta D, Modak A, Maurer JP, Chumbe JT. Readmission within 30

days of discharge after hip fracture care. Orthopedics. 2015;38:e7-13.

This article is protected by copyright. All rights reserved.

 28. McCormack RG, Leith JM. Ankle fractures in diabetics. Complications of surgical

management. J Bone Joint Surg Br. 1998;80:689-92.

Accepted Article
29. Jones KB, Maiers-Yelden KA, Marsh JL, Zimmerman MB, Estin M, Saltzman CL. Ankle

fractures in patients with diabetes mellitus. J Bone Joint Surg Br. 2005;84:489-95.

30. Meier C, Schwartz AV, Egger A, Lecka-Czernik B. Effects of diabetes drugs on the skeleton.

Bone. 2016;82:93-100.

31. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber

T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein

kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167-74.

32. An H, He L. Current understanding of metformin effect on the control of hyperglycemia in

diabetes. J Endocrinol. 2016;228:R97-106.

33. Jang WG, Kim EJ, Bae IH, Lee KN, Kim YD, Kim DK, et al. Metformin induces osteoblast

differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone.

2011;48:885-93.

34. Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, et al. Metformin stimulates

osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J

Cell Biochem. 2011;112:2902–9.

35. Ma P, Gu B, Ma J, E L, Wu X, Cao J, Liu H. Glimepiride induces proliferation and

differentiation of rat osteoblasts via the PI3-kinase/Akt pathway. Metabolism. 2010;59:359-

66.

36. Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, Kravitz BG, Yu D,

Heise MA, Aftring RP, Viberti G. Rosiglitazone-associated fractures in type 2 diabetes: an

Analysis from A Diabetes Outcome Progression Trial (ADOPT) Diabetes

Care. 2008;31:845–851.

This article is protected by copyright. All rights reserved.

 37. Melton LJ 3rd, Leibson CL, Achenbach SJ, Therneau TM, Khosla S. Fracture risk in type 2

diabetes: update of a population-based study. J Bone Miner Res. 2008;23:1334-42.

Accepted Article
38. Zinman B, Haffner SM, Herman WH, Holman RR, Lachin JM, Kravitz BG, Paul G, Jones

NP, Aftring RP, Viberti G, Kahn SE. Effect of rosiglitazone, metformin, and glyburide on

bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab. 2010;95:134–142.

39. Rajpathak SN, Fu C, Brodovicz KG, Engel SS, Lapane K. Sulfonylurea use and risk of hip

fractures among elderly men and women with type 2 diabetes. Drugs Aging. 2015;32:321-7.

40. Holst JJ, Gribble F, Horowitz M, Rayner CK. Roles of the Gut in Glucose Homeostasis.

Diabetes Care. 2016;39:884-92.

41. Deacon CF. Circulation and degradation of GIP and GLP-1. Horm Metab Res. 2004;36:761–

765.

42. Gilbert MP, Pratley RE. The impact of diabetes and diabetes medications on bone health.

Endocr Rev. 2015;36:194-213.

43. Chandran M. Diabetes Drug Effects on the Skeleton. Calcif Tissue Int. 2017; 100:133–149.

44. Sun HX, Lu N, Luo X, Zhao L, Liu JM. Liraglutide, the glucagon-like peptide-1 receptor

agonist, has anabolic bone effects in diabetic Goto-Kakizaki rats. J Diabetes 2015;7:584–8.

45. Mamza J, Marlin C, Wang C, Chokkalingam K, Idris I. DPP-4 inhibitor therapy and bone

fractures in people with Type 2 diabetes–A systematic review and meta-analysis. Diabetes

Res Clin Pract 2016;116:288–98.

46. 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.

47. Mabilleau G, Mieczkowska A, Chappard D. Use of glucagon-like peptide-1 receptor agonists

and bone fractures: a meta-analysis of randomized clinical trials. J Diabetes 2014;6:260–6.

This article is protected by copyright. All rights reserved.

 48. Driessen JH, Henry RM, van Onzenoort HA, Lalmohamed A, Burden AM, Prieto-Alhambra

D, et al. Bone fracture risk is not associated with the use of glucagon-like peptide-1 receptor
Accepted Article
agonists: a population-based cohort analysis. Calcif Tissue Int. 2015;97:104-112.

49. Chen HH, Horng MH, Yeh SY, Lin IC, Yeh CJ, Muo CH, Sung FC, Kao CH. Glycemic

Control with Thiazolidinedione Is Associated with Fracture of T2DM Patients. PLoS One.

2015;10:e0135530.

50. Wang L, Li L, Gao H, Li Y. Effect of pioglitazone on transdifferentiation of preosteoblasts

from rat bone mesenchymal stem cells into adipocytes. J Huazhong Univ Sci Technol Med

Sci. 2012;32:530–533.

51. Beck GR, Khazai NB, Bouloux GF, Camalier CE, Lin Y, Garneys LM et al. The effects of

thiazolidinediones on human bone marrow stromal cell differentiation in vitro and in

thiazolidinedione-treated patients with type 2 diabetes. Transl Res. 2013;161:145–155.

52. Lecka-Czernik B, Ackert-Bicknell C, Adamo ML, Marmolejos V, Churchill GA, Shockley

KR et al. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by

rosiglitazone suppresses components of the insulin-like growth factor regulatory system in

vitro and in vivo. Endocrinology. 2007;148:903–911.

53. Snedeker JG, Gautieri A. The role of collagen crosslinks in ageing and diabetes - the good,

the bad, and the ugly. Muscles Ligaments Tendons J. 2014;4:303-8.

54. David MA, Jones KH, Inzana JA, Zuscik MJ, Awad HA, Mooney RA. Tendon repair is

compromised in a high fat diet-induced mouse model of obesity and type 2 diabetes. PLoS

One. 2014;9:e91234.

55. Ahmed AS, Schizas N, Li J, Ahmed M, Ostenson CG, Salo P, et al. Type 2 diabetes impairs

tendon repair after injury in a rat model. J Appl Physiol (1985). 2012;113:1784-91.

This article is protected by copyright. All rights reserved.

 56. Egemen O, Ozkaya O, Ozturk MB, Sen E, Akan M, Sakiz D, et al. The biomechanical and

histological effects of diabetes on tendon healing: experimental study in rats. J Hand

Accepted Article
Microsurg. 2012;4:60-4.

57. Mohsenifar Z, Feridoni MJ, Bayat M, Masteri Farahani R, Bayat S, Khoshvaghti A.

Histological and biomechanical analysis of the effects of streptozotocin-induced type one

diabetes mellitus on healing of tenotomised Achilles tendons in rats. Foot Ankle Surg.

2014;20:186-91.

58. Chbinou N, Frenette J. Insulin-dependent diabetes impairs the inflammatory response and

delays angiogenesis following Achilles tendon injury. Am J Physiol Regul Integr Comp

Physiol. 2004;286:R952-7.

59. Ahmed AS, Li J, Schizas N, Ahmed M, Ostenson CG, Salo P, et al. Expressional changes in

growth and inflammatory mediators during Achilles tendon repair in diabetic rats: new

insights into a possible basis for compromised healing. Cell Tissue Res. 2014;357:109-17.

60. Boivin GP, Elenes EY, Schultze AK, Chodavarapu H, Hunter SA, Elased KM.

Biomechanical properties and histology of db/db diabetic mouse Achilles tendon. Muscles

Ligaments Tendons J. 2014;4:280-4.

61. Ahmed AS, Li J, Abdul AM, Ahmed M, Ostenson CG, Salo PT, et al. Compromised

Neurotrophic and Angiogenic Regenerative Capability during Tendon Healing in a Rat

Model of Type-II Diabetes. PLoS One. 2017;12:e0170748.

62. Oliveira RR, Mattos RM, Magalhaes Rebelo L, Ferreira FGM, Tovar-Moll F, Nasciutti LE, et

al. Experimental Diabetes Alters the Morphology and Nano-Structure of the Achilles Tendon.

PLoS One. 2017;12:e0169513.

63. Oliveira RR, Martins CS, Rocha YR, Braga AB, Mattos RM, Hecht F, et al. Experimental

diabetes induces structural, inflammatory and vascular changes of Achilles tendons. PLoS

One. 2013;8:e74942.

This article is protected by copyright. All rights reserved.

 64. Lin YC, Li YJ, Rui YF, Dai GC, Shi L, Xu HL, Ni M, Zhao S, Chen H, Wang C, Li G, Teng

GJ. The effects of high glucose on tendon-derived stem cells: implications of the
Accepted Article
pathogenesis of diabetic tendon disorders. Oncotarget. 2017; 8:17518–17528.

65. Titchener AG, White JJ, Hinchliffe SR, Tambe AA, Hubbard RB, Clark DI. Comorbidities in

rotator cuff disease: a case-control study. J Shoulder Elbow Surg. 2014;23(9):1282-8.

66. Namdari S, Green A. Range of motion limitation after rotator cuff repair. J Shoulder Elbow

Surg. 2010;19:290-6.

67. Dhar Y, Anakwenze OA, Steele B, Lozano S, Abboud JA. Arthroscopic rotator cuff repair:

impact of diabetes mellitus on patient outcomes. Phys Sportsmed. 2013;41:22-9.

68. Chen AL, Shapiro JA, Ahn AK, Zuckerman JD, Cuomo F. Rotator cuff repair in patients

with type I diabetes mellitus. J Shoulder Elbow Surg. 2003;12:416-21.

69. Cho NS, Moon SC, Jeon JW, Rhee YG. The influence of diabetes mellitus on clinical and

structural outcomes after arthroscopic rotator cuff repair. Am J Sports Med. 2015;43:991-7.

70. Bedi A, Fox AJ, Harris PE, Deng XH, Ying L, Warren RF, et al. Diabetes mellitus impairs

tendon-bone healing after rotator cuff repair. J Shoulder Elbow Surg. 2010;19:978-88.

71. Mubark IM, Ragab AH, Nagi AA, Motawea BA. Evaluation of the results of management of

frozen shoulder using the arthroscopic capsular release. Ortop Traumatol Rehabil.

2015;17:21-8.

72. Martinez-Huedo MA, Jimenez-Garcia R, Jimenez-Trujillo I, Hernandez-Barrera V, Del Rio

Lopez B, Lopez-de-Andres A. Effect of Type 2 Diabetes on In-Hospital Postoperative

Complications and Mortality After Primary Total Hip and Knee Arthroplasty. J Arthroplasty.

2017;32:3729-34 e2.

73. Gharaibeh KA, Hamadah AM, Sierra RJ, Leung N, Kremers WK, El-Zoghby ZM. The Rate

of Acute Kidney Injury After Total Hip Arthroplasty Is Low but Increases Significantly in

Patients with Specific Comorbidities. J Bone Joint Surg Am. 2017;99:1819-26.

This article is protected by copyright. All rights reserved.

 74. Yang Z, Liu H, Xie X, Tan Z, Qin T, Kang P. The influence of diabetes mellitus on the post-

operative outcome of elective primary total knee replacement: a systematic review and meta-
Accepted Article
analysis. Bone Joint J. 2014;96-B:1637-43.

75. Rajamaki TJ, Jamsen E, Puolakka PA, Nevalainen PI, Moilanen T. Diabetes is associated

with persistent pain after hip and knee replacement. Acta Orthop. 2015;86:586-93.

76. Paxton EW, Inacio MC, Khatod M, Yue E, Funahashi T, Barber T. Risk calculators predict

failures of knee and hip arthroplasties: findings from a large health maintenance organization.

Clin Orthop Relat Res. 2015;473:3965-73.

77. Webb ML, Golinvaux NS, Ibe IK, Bovonratwet P, Ellman MS, Grauer JN. Comparison of

Perioperative Adverse Event Rates After Total Knee Arthroplasty in Patients With Diabetes:

Insulin Dependence Makes a Difference. J Arthroplasty. 2017;32:2947-51.

78. Keswani A, Tasi MC, Fields A, Lovy AJ, Moucha CS, Bozic KJ. Discharge Destination

After Total Joint Arthroplasty: An Analysis of Postdischarge Outcomes, Placement Risk

Factors, and Recent Trends. J Arthroplasty. 2016;31:1155-62.

79. Saucedo JM, Marecek GS, Wanke TR, Lee J, Stulberg SD, Puri L. Understanding

readmission after primary total hip and knee arthroplasty: who's at risk? J Arthroplasty.

2014;29:256-60.

80. Marchant MH, Jr., Viens NA, Cook C, Vail TP, Bolognesi MP. The impact of glycemic

control and diabetes mellitus on perioperative outcomes after total joint arthroplasty. J Bone

Joint Surg Am. 2009;91:1621-9.

81. Schwartz FH, Lange J. Factors That Affect Outcome Following Total Joint Arthroplasty: a

Review of the Recent Literature. Curr Rev Musculoskelet Med. 2017;10:346-55.

82. Maradit Kremers H, Lewallen LW, Mabry TM, Berry DJ, Berbari EF, Osmon DR. Diabetes

mellitus, hyperglycemia, hemoglobin A1C and the risk of prosthetic joint infections in total

hip and knee arthroplasty. J Arthroplasty. 2015;30:439-43.

This article is protected by copyright. All rights reserved.

 83. Jones EW, Mitchell JR. Venous thrombosis in diabetes mellitus. Diabetologia. 1983;25:502-

5.
Accepted Article
84. Zhao Z, Wang S, Ma W, Kong G, Zhang S, Tang Y, et al. Diabetes mellitus increases the

incidence of deep vein thrombosis after total knee arthroplasty. Arch Orthop Trauma Surg.

2014;134:79-83.

85. Lopez-de-Andres A, Hernandez-Barrera V, Martinez-Huedo MA, Villanueva-Martinez M,

Jimenez-Trujillo I, Jimenez-Garcia R. Type 2 diabetes and in-hospital complications after

revision of total hip and knee arthroplasty. PLoS One. 2017;12:e0183796.

This article is protected by copyright. All rights reserved.

 Table 1 Impact of antidiabetic drugs on risk of fractures and their mode of action.
Accepted Article
Impact on
Class of drugs Action risk of
fractures
Biguanides Metformin increased osteoblast differentiation. Neutral /
Metformin has an adverse effect on osteoclastogenesis. decreased

Sulfonylureas Glimepiride stimulates proliferation and differentiation of Neutral /

rat osteoblast cells via PI3K/Akt signaling pathway decreased
activation.
Incretine-based Mechanism of action of GLP-1 receptor agonists and Neutral /
drugs DPP-4 inhibitors on a risk of fractures is not clear. decreased /
increased
Thiazolidinediones TZDs stimulate adipogenesis via PPARγ activation, Increased
increase RANKL expression and osteoclastogenesis, and
reduce osteoblastogenesis.
SGLT-2 inhibitors SGLT-2 inhibitors may alter the hemostasis of calcium Neutral /
and phosphate, thus inducing secondary increased
hyperparathyroidism.
The mechanisms by which SGLT2 inhibitors cause bone
loss are not clear.

Abbreviations: GLP-1, glukagon-like peptide 1; DPP-4, dipeptidyl peptidase 4; TZDs,

thiazolidinediones; PPARγ, peroxisome proliferator-activated receptor γ; RANKL, receptor activator
for nuclear factor kappa-Β ligand; SGLT-2, sodium/glucose cotransporter 2

This article is protected by copyright. All rights reserved.

Accepted Article

This article is protected by copyright. All rights reserved.

View publication stats