Increase In Bone Fracture Risk Research Articles

EFFECT OF TYPE-2 DIABETES ON OSTEOPOROTIC TRABECULAR BONE MECHANICAL PROPERTIES AND MICRODAMAGE ACCUMULATION

Type-2 Diabetic (T2D) patients experience up to a 3-fold increase in bone fracture risk[1]. Paradoxically, T2D-patients have a normal or increased bone mineral density when compared to non-diabetic patients. This implies that T2D has a deleterious effect on bone quality, whereby the intrinsic material properties of the bone matrix are altered. Creating clinical challenges as current diagnostic techniques are unable to accurately predict the fracture probability in T2D-patients. To date, the relationship between cyclic fatigue loading, mechanical properties and microdamage accumulation of T2D-bone tissue has not yet been examined and thus our objective is to investigate this relationship.Ethically approved femoral heads were obtained from patients, with (n=8) and without (n=8) T2D. To obtain the mechanical properties of the sample, one core underwent a monotonic compression test to 10% strain, the other core underwent a cyclic compression test at a normalized stress ratio between 0.0035mm/mm and 0.016mm/mm to a maximum strain of 3%. Microdamage was evaluated by staining the tissue with barium sulfate precipitate [2] and conducting microcomputed tomography scanning with a voxel size of 10μm.The monotonically tested T2D-group showed no statistical difference in mechanical properties to the non-T2D-group, even when normalised against BV/TV. There was also no difference in BV/TV. For the cyclic test, the T2D-group had a significantly higher initial modulus (p<0.01) and final modulus (p<0.05). There was no difference in microdamage accumulation.Previous population-level studies have found that T2D-patients have been shown to have an increased fracture risk when compared to non-T2D-patients. This research indicates that T2D does not impair the mechanical properties of trabecular bone from the femoral heads of T2D-patients, suggesting that other mechanisms may be responsible for the increased fracture risk seen in T2D-patients.

Vitamin D and Calcium Supplementation and Urolithiasis: A Controversial and Multifaceted Relationship

Patients with urolithiasis, and particularly those with hypercalciuria, frequently have a marked reduction of bone mineral content up to the levels of osteoporosis, with a significant increase in bone fracture risk. For these reasons, the indication to prescribe vitamin D and/or calcium supplementations is very frequent in such patients. On the other hand, both calcium supplementation, and even more vitamin D therapy, can worsen the risk of developing urolithiasis by increasing calcium, phosphate, and oxalate urinary excretion. Despite the clinical and practical relevance of this issue, the evidence on this topic is scarce and contradictory. Therefore, some concerns exist about how and whether to prescribe such supplements to a patient with a history of kidney stones. In this narrative review, we resume some pivotal pathophysiological concepts strictly related to the dealt topic, and we draw some considerations and personal opinions on the pros and cons of such prescriptions. Finally, we share with the reader our pragmatic algorithm for handling the urolithiasis risk in patients who have strong indications to be prescribed vitamin D and calcium supplementations.

A steered molecular dynamics investigation on the role of glycation on the energy dissipation capacity of osteopontin at mineral interfaces in bone.

Type-2 Diabetes (T2D) is associated with a 3-fold increase in bone fracture risk. T2D impairs bone quality, whereby the intrinsic material properties of the bone matrix are altered, through glycation of collagenous and non-collagenous proteins (NCPs). There is a distinct lack of understanding of how altered protein configurations impair whole-bone biomechanics, particularly in the case of NCPs since their structural roles in bone are only now emerging. In this study, the effect of glycation on the energy dissipation behaviour of OPN, the most abundant NCP, on HydroxyApatite (HAp) mineral surfaces was investigated. The adsorption modes of OPN on the surface was obtained by conventional MD by comparing the residues residence time for each protein orientation with their average values. Then, energy dissipation of OPN was obtained through Steered Molecular Dynamics (SMD) by pulling simulations perpendicular to the surface. Two different glycation possibilities were considered whereby (a) Glycation occurred prior to Adsorption (GA) or (b) Adsorption took place before Glycation (AG). The simulation results showed that AG has the same adsorption modes as the healthy OPN, while the GA experienced a different mode. It was found that energy dissipation in absence of glycation was EOPN = 2646 kcal/mol. For glycated groups energy dissipation values were EOPN-AG = 2324 kcal/mol and EOPN-GA = 773 kcal/mol. The simulation results showed that OPN had reduced capacity for energy dissipation for either glycation case. However, it was notable that if OPN glycation occurred before its adsorption on HAp, its energy dissipation capacity was greatly reduced, which was caused by changes to the adsorption mode itself. The current study for the first time showed that the glycation sequence could negatively affects energy dissipation behaviour of OPN, which could have consequence for bone toughness.

Speculation on the pathophysiology of musculoskeletal injury with COVID-19 infection.

Coronavirus disease 2019 (COVID-19) primarily affects the respiratory tract, but also many other organs and tissues, leading to different pathological pictures, such as those of the musculoskeletal tissues. The present study should be considered as a speculation on the relationship between COVID-19 infection and some frequent musculoskeletal pathologies, in particular sarcopenia, bone loss/osteoporosis (OP) and fracture risk and osteoarthritis (OA), to hypothesize how the virus acts on these pathologies and consequently on the tissue regeneration/healing potential. The study focuses in particular on the modalities of interaction of COVID-19 with Angiotensin-Converting Enzyme 2 (ACE2) and on the “cytokine storm.” Knowing the effects of COVID-19 on musculoskeletal tissues could be important also to understand if tissue regenerative/reparative capacity is compromised, especially in elderly and frail patients. We speculate that ACE2 and serine proteases together with an intense inflammation, immobilization and malnutrition could be the responsible for muscle weakness, altered bone remodeling, increase in bone fracture risk and inflammatory joint pathologies. Future preclinical and clinical studies may focus on the regenerative/reparative properties of the musculoskeletal tissues after COVID-19 infection, toward a personalized treatment usually based on scaffolds, cells, and growth factors.

Prolonged Hyperglycemia Reduces Elasticity of Type II Diabetic Rat Bone.

An increase in bone fracture risk has been reported in patients with diabetes. To evaluate an early effect of glucose intolerance on bone homeostasis, we have characterized bones from spontaneously diabetic torii (SDT) rats, an animal model of type 2 diabetes in comparison with Sprague Dawley (SD) rats as healthy control. Focusing on early effects of diabetes on bone elasticity, longitudinal wave velocities of animal bones were first determined by a micro-Brillouin scattering technique in a non-destructive way. Wave velocities in the cortical and cancellous bones in the tibias of the SDT and SD rats were compared. In a pre-diabetic stage at approximately 10weeks of age, there seems no significant difference in wave velocities in bones from age-matched SDT and SD rats. By contrast, after the onset of diabetes at approximately 20weeks of age, the mean velocities of bones from SDT rats were lower than those of SD rat. In addition, the X-ray CT showed that the bone amounts of SDT rats were smaller than those of SD rats in an early diabetic stage at 20weeks of age. The current study demonstrated that the wave velocity decreased in bones of SDT rats in the early stages of diabetes. While a decrease of bone strength in an early stage of diabetes can be partially explained from decreases in bone amount as well as bone elasticity, further studies will be needed in understanding a detailed mechanism of bone deterioration due to diabetes.

Individuals with type 2 diabetes mellitus show dimorphic and heterogeneous patterns of loss in femoral bone quality.

Type 2 diabetes mellitus (T2DM), a metabolic disease on the rise, is associated with substantial increase in bone fracture risk. Because individuals with T2DM have normal or high bone mineral density (BMD), osteodensitometric measurements of BMD do not predict fracture risk with T2DM. Here, we aim to identify the underlying mechanism of the diabetes-induced fracture risk using a high-resolution multi-scale analysis of human cortical bone with special emphasis on osseous cellular activity. Specifically, we show increased cortical porosity in a subgroup of T2DM individuals accompanied by changed mineralization patterns and glycoxidative damage to bone protein, caused by non-enzymatic glycation of bone by reducing sugar. Furthermore, the high porosity T2DM subgroup presents with higher regional mineralization heterogeneity and lower mineral maturity, whereas in the T2DM subgroup regional higher mineral-to-matrix ratio was observed. Both T2DM groups show significantly higher carboxymethyl-lysine accumulation. Our results show a dimorphic pattern of cortical bone reorganization in individuals afflicted with T2DM and hence provide new insight into the diabetic bone disease leading to increased fracture risk.

Nanoindentation time-dependent deformation/recovery suggestive of methylglyoxal induced glycation in calcified nodules

Although empirical findings have indicated increase in bone fracture risk in type 2 diabetes patients, that has yet to be proven by results obtained at the material level. Here, we report evidence showing nanoscale time-dependent deformation/recovery of in vitro calcified nodules mimicking bone turnover in type 2 diabetes in respect to methylglyoxal (MG)-induced glycation. Nanoindentation test results revealed that calcified nodules cultured with MG did not show adequate dimensional recovery, despite a large creep rate during constant load indentation testing. This lesser recovery is likely based on the linear matrix polymerization network formed by advanced glycation end products (AGEs) as a secondary product of MG. Since elevated serum MG and abnormal bone turnover related to the amount of AGEs are observed in cases of type 2 diabetes, this time-dependent behavior may be one of the factors of the bone fracture mechanism at the material level in affected patients.

Multiscale alterations in bone matrix quality increased fragility in steroid induced osteoporosis

A serious adverse clinical effect of glucocorticoid steroid treatment is secondary osteoporosis, enhancing fracture risk in bone. This rapid increase in bone fracture risk is largely independent of bone loss (quantity), and must therefore arise from degradation of the quality of the bone matrix at the micro- and nanoscale. However, we lack an understanding of both the specific alterations in bone quality n steroid-induced osteoporosis as well as the mechanistic effects of these changes. Here we demonstrate alterations in the nanostructural parameters of the mineralized fibrillar collagen matrix, which affect bone quality, and develop a model linking these to increased fracture risk in glucocorticoid induced osteoporosis. Using a mouse model with an N-ethyl-N-nitrosourea (ENU)-induced corticotrophin releasing hormone promoter mutation (Crh−120/+) that developed hypercorticosteronaemia and osteoporosis, we utilized in situ mechanical testing with small angle X-ray diffraction, synchrotron micro-computed tomography and quantitative backscattered electron imaging to link altered nano- and microscale deformation mechanisms in the bone matrix to abnormal macroscopic mechanics. We measure the deformation of the mineralized collagen fibrils, and the nano-mechanical parameters including effective fibril modulus and fibril to tissue strain ratio. A significant reduction (51%) of fibril modulus was found in Crh−120/+ mice. We also find a much larger fibril strain/tissue strain ratio in Crh−120/+ mice (~1.5) compared to the wild-type mice (~0.5), indicative of a lowered mechanical competence at the nanoscale. Synchrotron microCT show a disruption of intracortical architecture, possibly linked to osteocytic osteolysis. These findings provide a clear quantitative demonstration of how bone quality changes increase macroscopic fragility in secondary osteoporosis.