Focus on Osteoporosis
Osteoporosis is a disease where decreased bone strength increases the risk of a broken bone and it is defined as a bone density of 2.5 standard deviations below that of a young adult (typically measured by dual-energy X-ray absorptiometry at the hip). Bones that commonly break include the back bones, the bones of the forearm, and the hip. Until a broken bone occurs there are typically no symptoms.
Bone loss increases after menopause due to lower levels of estrogen. Osteoporosis may also occur due to a number of diseases or treatments including alcoholism, anorexia, hyperthyroidism, surgical removal of the ovaries and kidney disease. Certain medications increase the rate of bone loss including some antiseizure medications, chemotherapy, proton pump inhibitors, selective serotonin reuptake inhibitors and steroids. Not enough exercise and smoking are also risk factors.
Focus on Diabetes Mellitus type 2
Diabetes mellitus type 2 (formerly noninsulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes) is a metabolic disorder that is characterized by hyperglycemia (high blood sugar) in the context of insulin resistance and relative lack of insulin.
Type 2 diabetes is due to insufficient insulin production from beta cells in the setting of insulin resistance. Insulin resistance, which is the inability of cells to respond adequately to normal levels of insulin, occurs primarily within the muscles, liver, and fat tissue. In the liver, insulin normally suppresses glucose release. However, in the setting of insulin resistance, the liver inappropriately releases glucose into the blood. The proportion of insulin resistance versus beta cell dysfunction differs among individuals, with some having primarily insulin resistance and only a minor defect in insulin secretion and others with slight insulin resistance and primarily a lack of insulin secretion.
Osteoporosis in patients with T2D
Many studies have noted the presence of an increased risk of fracture in patients with diabetes:
In T2D, bone mass per se may be increased, even though fracture risk is increased . Patients with T2D may thus not readily meet the criteria for osteoporosis, although their bone fragility may be increased.
[1] http://www.sciencedirect.com.offcampus.dam.unito.it/science/article/pii/S0026049514002844
[2] http://www-ncbi-nlm-nih-gov.offcampus.dam.unito.it/pubmed/26201005
[3] http://www-ncbi-nlm-nih-gov.offcampus.dam.unito.it/pubmed/26320532
What are the molecular mechanisms involved?
Advanced Glication End Products (AGEs)
At the tissue level, hyperglycemia affects the organic bone matrix through the accumulation of advanced glycation end products (AGEs) leading to inferior bone strength. Indeed, the contribution of AGEs to the development and progression of complications of diabetes is well demonstrated in the literature. In general, the pathological effects of AGEs are related the ability of these compounds to modify the chemical and functional properties of several biological structures. In all tissues, AGEs generate free radicals and promote oxidative stress, and increased expression of inflammatory mediators. In the skeleton, the accumulation of AGEs leads to more brittle bone with reduced toughness and therefore, less ability to deform before fracturing. The most studied AGE is pentosidine, the concentrations of which in cortical and trabecular bone are negatively associated with bone strength. Patients with fracture present higher concentrations of pentosidine than nonfractured controls. It was demonstrated in vitro that incubation of osteoblasts with pentosidine caused a significant decrease in alkaline phosphatase, collagen 1α1, osteocalcin, and RAGE gene expression. These data suggest a detrimental effect of AGEs on bone that leads to functional alterations in osteoblasts and in the bone mineralization process.
In addition, serum concentrations of pentosidine in T2D were shown to be higher than those in control subjects and were correlated with cortical bone pentosidine. One Japanese study evaluated serum pentosidine levels in postmenopausal women with diabetes and demonstrated an association with prevalent vertebral fractures, which was independent of BMD This study suggested that serum pentosidine was more sensitive than BMD in assessing the risk of prevalent vertebral fractures in women with diabetes.
Insulin and IGF-1
Insulin is an anabolic hormone which has effects on the skeleton. It acts on bone tissue through insulin receptors (IRS-1 and IRS-2) expressed by osteoblasts. In normal physiological conditions, stimulation of these receptors stimulates bone formation by increasing osteoblast proliferation and promoting collagen synthesis. In the same way, insulin growth factor-1 (IGF-1) is a key regulator of bone and acts to increase osteoblast recruitment and bone matrix deposition and reduce collagen degradation. Indeed, studies have demonstrated a positive correlation between IGF-1 and BMD and also a negative correlation with hip and vertebral fractures.
Bone Turnover
Studies have shown that serum markers of bone turnover (BTM), especially the formation markers (osteocalcin and P1NP) are decreased in patients with diabetes. Moreover, bone histomorphometry has demonstrated that remodeling parameters such as bone formation rate and mineralizing surface are significantly lower in T2D than controls indicating a low turnover state. In this regard, sclerostin a regulator of bone formation, has emerged as an important player in this scenario. Sclerostin is an osteocyte product which inhibits the wnt B-catenin pathway by binding to LRP5 or 6 and, thereby, negatively regulates bone formation. Patients with T2D have been shown to have higher levels of circulating sclerostin that were associated with time and control of the disease.
A Chinese study evaluated 265 postmenopausal women with T2D and showed that the serum sclerostin level was significantly higher than that in a non-diabetic control group (48.2 ± 19.4 vs. 37.2 ± 18.6 pmol/L, p < 0.001). Serum sclerostin concentration was positively correlated with hemoglobin A1c level and negatively associated with biochemical bone turnover markers, intact parathyroid hormone and bone-specific alkaline phosphatase. In addition, sclerostin levels were associated with increased risk of vertebral fractures, independent of BMD,15 indicating that the low bone formation caused by high levels of sclerostin impaired bone quality. A significant association between bone formation markers and IGF-1 was demonstrated and confirmed that IGF-1 is linked to osteoblast function. Moreover, an inverse association of IGF-1 and sclerostin was demonstrated in postmenopausal women with T2D and vertebral fractures. It, therefore, appears that the association of low IGF-1 and high sclerostin levels contribute to the bone fragility observed in T2D patients.
Osteocalcin is a non-collagenous matrix protein that is linked to glucose metabolism. It is a 49-amino acid peptide synthesized exclusively by the osteoblasts and stored in matrix. In its undercarboxylated form, it has some hormonal features and has been associated with glucose metabolism and fat mass. Osteocalcin stimulates insulin secretion and enhances insulin sensitivity in adipose tissue and muscle . A negative association between osteocalcin and markers of metabolic syndrome, such as serum glucose, insulin, high-sensitivity C reactive protein, interleukin-6, body fat and body mass index (BMI) has been demonstrated, suggesting that reduced osteocalcin levels may play a role in the pathophysiology of bone fragility in T2D.
[4]: http://www.sciencedirect.com.offcampus.dam.unito.it/science/article/pii/S8756328213002470
Obesity
Obesity was once believed to be protective for osteoporosis. An elevated BMI is very frequent in T2D patients and is strongly associated with higher BMD, however obesity is not protective against fractures. Indeed, results from the GLOW study (Global Longitudinal study of Osteoporosis in Women) demonstrate that obesity is not protective against fracture in postmenopausal women and is associated with increased risk of ankle and upper leg fractures.
Conclusion
There is an increased risk of fracture in patients with T2D, we must take into account during diagnosis of osteoporosis.
As we have seen, a great number of features play a role in the impairment of bone quality in T2D. An adequate glycemic control is important and might help reduce the risk of bone fragility, since it may decrease the accumulation of AGEs in bone matrix. In addition, a new class of drug, sclerostin inhibitors, might be a promising therapeutic option in diabetic patients with bone fragility.
[5] http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0101-28002015000400490&lng=en&nrm=iso&tlng=en
