A Surprising Comorbidity of Diabetes: Decrease in Bone Quality

Bone Mass & Density Decrease have Debilitating Effects on the Quality of Life of Diabetic Patients

Mankind has reached a stage wherein the prevalence of diabetes as a social health epidemic is widely understood but sadly not much steps have been taken to curb its radical proliferation among adults and kids alike. Diabetes mellitus is becoming an epidemic with diabetes-related complications accounting for 60-70% of the health-care costs related to diabetes. Almost 420 million adults suffered from diabetes in 2015 and the statistics are said to reach 200.5 million by 2040. Almost 5.1 million people died due to diabetes in 2013, one person dies due to the disease every six seconds. Besides being an economic burden due to higher morbidity and mortality rates the comorbidities associated with the disease are quite high. I am sure that we do know about many of the macrovascular and microvascular complications such as stroke, coronary artery disease, neuropathy, renal complications and peripheral vascular disease but what remains a surprise find is that altered blood glucose levels alter bone health too. This has been evident since the last 50 years with more evidence showing that diabetics are at an increased risk of bone fracture due to decrease in bone quality.

Type 1 diabetes mellitus (T1DM) has low bone mineral density and 6-7-fold higher risk of fracture while type 2 diabetes mellitus (T2DM) has high bone mineral density and up to 3-fold higher fracture risk. Both T1DM and T2DM affect individuals with different pathophysiological mechanisms but both of their underlying reason for poor bone strength is not completely clear.

T1DM
Hyperglycaemia is the root cause for many of the disease’s complications and T1DM patients have accumulation of harmful advanced glycation end products (AGEs). AGEs cause apoptosis of mesenchymal stem cells in individuals preventing differentiation of osteoblasts, adipocytes and cartilage. Osteoblastic synthesis of protein osteocalcin is inhibited by high serum glucose concentration paving way for poor bone formation when the patient is repeatedly victimized to this condition. We also have a study linking AGEs to osteoclastic activity which is instrumental for bone loss activation. With all this, it has been deciphered that almost 20% of T1DM patients between 20 and 56 years are at a risk of being osteoporotic. T1DM impairs bone by decreasing bone mass density (BMD) and this is evident from numerous studies. BMD occupies 70% role in bone strength related to fracture risk and BMD measurements plays a pivotal role in evaluating fracture risk. This is due to lack of absolute insulin action which in turn increases risk of fracture. Albright et al. was the first group to impart knowledge on the relationship between diabetes and bone metabolism as a loss of bone mass in diabetes patients with poor glycemic control in 1948. Meta-analysis shows that risk of hip fracture increases 6.94 times in patients with T1DM and 1.38 times in those with T2DM compared to normal individuals.

T2DM
Contrary to T1DM, T2DM increases BMD of patients as shown by Ma et al. which probed into 15 observational studies with more than 3000 T1DM and 19,100 T2DM patients. So, what’s wrong when BMD is higher, isn’t it? But higher BMD is linked to decreased overall bone turnover which affects overall bone health. Another reason for higher BMD could also be due to hyperinsulinemia. A study by Schwartz et al. showed that lower T-score of BMD in the femoral neck was linked to increased risk of hip fracture in older T2DM patients. Fu et al. showed that trabeculae of the distal femur was thinner and less connected while the cortical bone was more connected in mice with type 2 diabetes. Such deterioration in bone strength increases the risk of fracture.

Negative calcium balance present in those whose diabetes rates are not under control experience more bone mineral content (BMC) loss. Li et al. reported higher HbA1c levels to be linked to higher risk of hip fracture un T2DM. Insulin hormone has been linked to bone remodelling and Kawaguchi et al. suggested that insulin signals are linked to bone formation. Fulzele et al. showed that mice lacking insulin receptors in osteoblasts showed reduced bone formation and bone mass. Certain proteins have also been associated with bone formation and are used as markers for bone turnover. Osteoblastogenesis is supressed by hyperglycaemia and osteocalcin levels are lower in diabetic patients. Glycemic control improved blood osteocalcin levels and this helps in maintaining BMD levels. This definitely shows the importance of maintaining blood sugar levels for preventing fracture in those with type 2 diabetes.

Patients with type 2 diabetes are especially at risk for hip, wrist and feet fracture and fracture risk increases with disease duration, insulin duration and poor control of hyperglycaemia. Studies show that biomechanical integrity of the skeleton is compromised in patients with T2DM. T2DM not only affects porosity but alters bone collagen as well and one important alteration is the formation of AGEs. AGE levels increase in those with hyperglycaemia altering protein properties resulting in increased brittleness of the elastic collagen fibres. AGE also has an upper hand on affecting bone material properties and bone turnover in T2DM.

Bone Fragility
T2DM affects differentiation and functioning of bone cells leading to negative effects on these cells such as reduced blood flow in bone, increased presence of fat in the marrow and inflammation. Osteoblasts are needed for bone formation and its differentiation is promoted by insulin. Mouse models show that glucose acts as a critical energy source for osteoblasts to produce collagen fibres. But higher glucose presence in T2DM decreases osteoblast differentiation. T2DM also negatively impacts osteoblasts via different molecular mechanisms, encourages mesenchymal stromal cells (MSCs) to turn into adipocytes which impairs osteoblast function, bone formation and bone mass.

Effect on Bone Cells
Bone marrow fat has been involved in impacting energy homeostasis and bone turnover via secretion of adiponectin. Men with type 2 diabetes and postmenopausal women show a higher marrow adipose tissue (MAT) compared to controls. MAT, in general is negatively associated with bone mineral density and positively associated with visceral adipose tissue and HbA1c values. While two studies proved MATs link with Hb1Ac and fractures two other studies on T2DM patients did not show any difference in MAT effects.

Osteoporosis
Studies show that the link between diabetes and hip fracture risk is stronger in T1DM than T2DM. T2DM increase risk of nonspine fracture. One of the most famous studies, the Nurses’ Health Study with more than 1,00,000 women aged between 34 and 59 years followed up for 22 years showed that both type 1 and type 2 diabetes are associated with an increased risk of hip fracture. Diabetic osteopathy is a general comorbidity of diabetes (both types) which is expressed with decrease in bone quality that thereby increases risk of bone fracture in both types of diabetes.

Studies show that high fracture risk is more in patients with T1D than for patients with T2D compared with controls. We also have a number of studies reporting high risk of fracture in female patients with T1D and T2D compared to male patients with the disease. But age seems to be quite surprising with fracture risk being higher in those of younger age compared with controls without diabetes but lower in older age individuals. One study showed that women with T2D had increased mortality risks following fracture and both men and women with T2DM had higher number of postfracture complications compared to those without diabetes. But yet another study showed that diabetes did not increase mortality nor duration of hospital stay. But all studies showed that diabetes patients who became victims to fracture suffered from decreased quality of life. A study by Vokó showed that osteoporotic fracture victimised diabetic patients as equally as complications such as blindness and amputation.

Aiding Diabetes Patients to Help them Manage Bone Diseases
Diabetes treatment primarily involves prescription of metformin but when this is not beneficial the physician tries several other treatment methods such as Thiazolidinediones (TZDs). But we have studies showing the disadvantages linked to the use of TZDs-higher risk of fracture, nonspine fracture, which were resolved once the individuals stopped using the medications. There are several other drugs prescribed each of them having a safety clause on their own.

Exercise has always been the best treatment course for those with elevate blood sugar levels along with a well-planned diet and we do have potential studies showing its benefits. There are few studies that show the impact of exercise on bone properties such as BMD or bone quality in diabetes mellitus. Studies by several research groups have revealed that jumping training increased BMD, cortical and total BMC in the femur and also periosteal bone formation and bone strength. A clinical research reported that resistance training and walking exercise helped preserve BMD and walking increased the BMD of femoral neck. Wu et al. showed that treadmill running exercise improved BMD of the femur while Hamrick et al. showed that it increased the BMD of the distal metaphysis of the femur. There are several other studies also supporting the fact that exercises such as jumping and walking stimulated the bones, promotes bone formation and supresses bone resorption in non-diabetics.

A study by Bello et al. looking into training programs involving walking, resistance and aquatic exercise in postmenopausal women with T2DM showed an increase in BMD. Hinton et al. showed that voluntary wheel running by obese type 2 diabetes animals was beneficial to both BMD of the femur and to increased properties of the femur. Ortinau et al. showed that voluntary wheel running for 36 weeks was beneficial not only to glycemic control and prevention of body fat accumulation but also tissue-level stiffness and strength of the femur in these species. Running as an exercise prevented increase in blood glucose, HbA1c levels and insulin levels which improved glucose tolerance and this directly or indirectly contributed to BMD and bone strength in diabetes patients.

Inflammation has been associated with bone deterioration and creative protein (CRP), one of the markers of inflammation, has been inversely linked to BMD and could also be considered a tool for screening osteoporosis. Kasapis et al. showed that physical activity was inversely linked to serum CRP levels while de Lemos et al. showed that swimming for 12 weeks decreased serum CRP levels compared to being sedentary.
​
Hence, the studies above clearly prove one thing-blood glucose, insulin sensitivity, inflammation and oxidative stress are associated with bone fragility in diabetes mellitus. There are studies also confirming the fact that exercise does have a positive effect on diabetes patients suffering from decreased bone quality. Exercise with low, long duration loading and long term is effective for bone metabolism. It needs to be seen further with multiple other studies to come up with the most effective exercise program for preventing fracture risk in those with diabetes mellitus. There are also suggestions that diet could be combined with exercise as a primary treatment strategy for dealing with osteoporosis and fractures in individuals with diabetes.