Metformin and Bone Metabolism in Endogenous Glucocorticoid Excess: An Exploratory Study

ContextGlucocorticoid excess exhibits multiple detrimental effects by its catabolic properties. Metformin was recently suggested to protect from adverse metabolic side-effects of glucocorticoid treatment. Whether metformin is beneficial in patients with endogenous glucocorticoid excess has not been clarified.ObjectiveTo evaluate the phenotype in patients with endogenous Cushing’s syndrome (CS) treated with metformin at the time of diagnosis.Patients and MethodsAs part of the German Cushing’s Registry we selected from our prospective cohort of 96 patients all 10 patients who had been on pre-existing metformin treatment at time of diagnosis (CS-MET). These 10 patients were matched for age, sex and BMI with 16 patients without metformin treatment (CS-NOMET). All patients had florid CS at time of diagnosis. We analyzed body composition, metabolic parameters, bone mineral density and bone remodeling markers, muscle function and quality of life.ResultsAs expected, diabetes was more prevalent in the CS-MET group, and HbA1c was higher. In terms of comorbidities and the degree of hypercortisolism, the two groups were comparable. We did not observe differences in terms of muscle function or body composition. In contrast, bone mineral density in metformin-treated patients was superior to the CS-NOMET group at time of diagnosis (median T-Score -0.8 versus -1.4, p = 0.030). CS-MET patients showed decreased β-CTX levels at baseline (p = 0.041), suggesting reduced bone resorption under metformin treatment during glucocorticoid excess.ConclusionThis retrospective cohort study supports potential protective effects of metformin in patients with endogenous glucocorticoid excess, in particular on bone metabolism.

Associations between Postprandial Gut Hormones and Markers of Bone Remodeling

Gut-derived hormones have been suggested to play a role in bone homeostasis following food intake, although the associations are highly complex and not fully understood. In a randomized, two-day cross-over study on 14 healthy individuals, we performed postprandial time-course studies to examine the associations of the bone remodeling markers carboxyl-terminal collagen type I crosslinks (CTX) and procollagen type 1 N-terminal propeptide (P1NP) with the gut hormones glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) using two different meal types—a standardized mixed meal (498 kcal) or a granola bar (260 kcal). Plasma concentrations of total GIP, total GLP-1, total PYY, CTX, and P1NP were measured up to 240 min after meal intake, and the incremental area under the curve (iAUC) for each marker was calculated. The iAUC of CTX and P1NP were used to assess associations with the iAUC of GIP, GLP-1, and PYY in linear mixed effect models adjusted for meal type. CTX was positively associated with GIP and GLP-1, and it was inversely associated with PYY (all p < 0.001). No associations of P1NP with GIP or GLP-1 and PYY were found. In conclusion, the postprandial responses of the gut hormones GIP, GLP-1, and PYY are associated with the bone resorption marker CTX, supporting a link between gut hormones and bone homeostasis following food intake.

Chrysin alleviates alteration of bone-remodeling markers in ovariectomized rats and exhibits estrogen-like activity in silico

Background Evidences are beginning to accrue that flavonoids, particularly phytoestrogens, could have beneficial effects against several age-related diseases linked to estrogen deficiency including postmenopausal osteoporosis. Methods In this study, the effect of chrysin on selected bone-remodeling markers in ovariectomized rats and its estrogen-like activity in silico were investigated. Results The data indicated that administration of chrysin at 50 mg/kg and 100 mg/kg for 6 weeks to OVX rats significantly ( p < 0.05) prevented body weight gain and partially reverse uterine weight loss. In addition, treatment of OVX rats significantly ( p < 0.01) increased femur dry weight, femur ash weight, bone ash calcium, and phosphorous levels in a dose-dependent manner. However, there was significant ( p < 0.001) decline in serum estradiol level in all OVX rats compared to the sham-operated group. Interestingly, administration of chrysin significantly ( p < 0.05) reversed the reduction of estradiol induced by ovariectomy compared to untreated OVX rats. Moreover, administration of chrysin to OVX rats significantly ( p < 0.05) suppressed excessive elevation of bone-remodeling markers expression compared to untreated OVX rats. Similarly, molecular docking analysis revealed that chrysin interacts with both α and β estrogen receptors with exothermic binding energies of −229.83 kcal/Mol and −252.72 kcal/Mol, respectively, and also fits perfectly into the active site of both α and β estrogen receptors. Conclusion This study demonstrated that chrysin exhibits potential antiosteoporotic effects against bone loss in OVX rats through enhanced bone mineral contents and preventing excessive elevation of bone-remodeling markers and bone-resorbing cytokine.

Bone remodeling markers and their role in oncology

Bone metastases are a common complication of cancer. Patients with bone metastases may have experienced skeletal-related events, such as hypercalcemia, pathological fractures, pain syndrome of varying intensity, spinal cord compression with negative effects on the quality of life. Current diagnostic tools have some limitations, such as high cost and limited availability in the distant areas, as well as falls negative and falls positive results. In this aspect, non-invasive sensitive markers of bone metabolism might give additional valuable information. Bone remodeling markers (N-terminal propeptide of type 1 collagen, osteocalcin, C-terminal telopeptide of type 1 collagen, etc.) have been used for a long time to predict the effectiveness of osteoporosis treatment; as additional risk factors for treatment initiation in patients with osteoporosis, in diagnostic search for secondary forms of osteoporosis; and as predictors of fracture in population studies. This review summarizes the clinically relevant biochemical markers of bone remodeling and the available evidence for their use in the metastatic bone disease in particularly in the diagnosis and prognosis of bone metastases risk and skeletal complications, predicting clinical outcomes, bone disease progression and overall survival. It has been shown that a sufficient suppression of bone remodeling biochemical markers while on treatment with bisphosphonates is associated with an improvement in survival and a decrease in the risk of skeletal complications in patients with bone metastases. New data may become a rational basis for wider use of bone metabolism markers in oncological practice. However, it is necessary to standardize and validate the determination of bone markers and verification of cut-off diagnostic values for their introduction into the routine clinical practice of patients with malignancy.

Effect of Testosterone treatment on bone microarchitecture and bone mineral density in men: a two-year RCT

Context Testosterone treatment increases bone mineral density (BMD) in hypogonadal men. Effects on bone microarchitecture, a determinant of fracture risk, are unknown. Objective Determine the effect of testosterone treatment on bone microarchitecture using high resolution-peripheral quantitative computed tomography (HR-pQCT). Design, Setting, Participants Men&gt;50 years were recruited from six Australian centres. Interventions Injectable testosterone undecanoate or placebo over 2 years on the background of a community-based lifestyle program. Main outcomes Primary endpoint was cortical volumetric BMD (vBMD) at the distal tibia, measured using HR-pQCT in 177 men (one centre). Secondary endpoints included other HR-pQCT parameters and bone remodelling markers. Areal BMD (aBMD) was measured by dual energy X-ray absorptiometry (DXA) in 601 men (five centres). Using a linear mixed model for repeated measures, the mean adjusted differences (MAD) [95% CI] at 12 and 24 months between groups are reported as treatment effect. Results Over 24 months, testosterone treatment, compared to placebo, increased tibial cortical vBMD), 9.33mgHA/cm 3[3.96;14.71],p&lt;0.001 or 3.1%[1.2;5.0], radial cortical vBMD, 8.96mgHA/cm 3[3.30;14.62],p=0.005 or 2.9%[1.0;4.9], total tibial vBMD, 4.16mgHA/cm 3[2.14;6.19],p&lt;0.001 or 1.3%[0.6;1.9] and total radial vBMD, 4.42mgHA/cm 3[1.67;7.16],p=0.002 or 1.8%[0.4;2.0]. Testosterone also significantly increased cortical area and thickness at both sites. Effects on trabecular architecture were minor. Testosterone reduced bone remodeling markers CTX, -48.1ng/L[-81.1;-15.1],p&lt;0.001, and P1NP, -6.8μg/L[-10.9;-2.7], p&lt;0.001. Testosterone significantly increased aBMD at the lumbar spine, 0.04 g/cm 2[0.03;0.05],p&lt;0.001, and the total hip, 0.01g/cm 2[0.01;0.02],p&lt;0.001. Conclusions In men&gt;50 years, testosterone treatment for 2 years increased volumetric bone density, predominantly via effects on cortical bone. Implications for fracture risk reduction require further study.

Bone Remodeling Markers in Assessing of Sternal Reparative Regeneration in Patients With Carbohydrate Metabolism Disorders After Coronary Bypass Surgery

Aim To study time-related changes in bone remodeling markers in patients with ischemic heart disease (IHD) associated with type 2 diabetes mellitus (DM) and disorders of carbohydrate metabolism (CM). Also, a possibility was studied of using these markers for evaluation of breast bone reparative regeneration in early and late postoperative periods following coronary bypass (CB).Materials and methods This study included 28 patients with IHD and functional class II-III exertional angina after CB. Patients were divided into 2 groups based on the presence (group 1) and absence (group 2) of CM disorders. Contents of osteocalcin (OC), C-terminal telopeptide (CTTP) of type 1 collagen, deoxypyridinoline (DPD), and alkaline phosphatase bone isoenzyme (ALPBI) were measured by enzyme immunoassay on admission (Т1) and at early (Т2) and late (Т3) postoperative stages. Sternal scintigraphy with a radiopharmaceutical (RP) was performed at stage 3 following sternotomy.Results The content of OC and CTTP was reduced in group 1 compared to the values in the group without CM disorders (р<0.005) at stages Т1 and Т2. There were no significant intergroup differences in concentrations of ALPBI and DPD throughout the study. Time-related changes in OC, CTTP, and DPD had some intergroup differences: the increase in biomarkers was observed in group 1 considerably later, at stage Т3 (р<0.005), while in group 2, it was observed at stage T2 after sternotomy. Scintigraphy revealed significant intergroup differences in the intensity of RP accumulation in sternal tissue.Conclusion The intergroup differences in the content of biomarkers evidenced a disbalance among processes of formation and resorption of bone tissue and delayed remodeling processes in patients with IHD associated with type 2 DM and CM disorders. The study confirmed significance of comprehensive evaluation of time-related changes in markers for bone tissue metabolism and sternal scintigraphy for diagnosis and evaluation of sternal reparative regeneration following sternotomy in patients with IHD associated with type 2 DM and disorders of CM metabolism.

EFFECT OF BODY VIBRATION ON STRUCTURAL ORGANISATION OF TIBIA NANOCOMPOSITES IN RATS WITH GLUCOCORTICOID-INDUCED OSTEOPOROSIS

The aim of the study was to evaluate the effect of nonphysiological whole body vibration (0,3g) on the bone structure and metabolism in rats treated with methylprednisolone (3 mg/ kg/day every other day, 24 weeks). Amount of crystalline component and collagen in the bones was determined by X-ray diffraction method, and the level of calcium by atomic adsorption spectroscopy. Bone metabolism was assessed by determining the concentration of markers - osteocalcinandtartrate-resistant acid phosphatase 5b. Methylprednisolone reduced the content of the mineral component in the tibia (–16.8%) in I group compared with the control. This significantly accelerated the process of bone metabolism, as evidenced by the increased level of bone remodeling markers. It should be noted that the total nonphysiological whole body vibration did not allow a decrease in the mineral component of the bone until 16 weeks of the experiment compared with I group, although these values were lower than the control group (–28.3%). We suggests that mechanical high-frequency low-intensity whole body vibration can inhibit the negative effects of glucocorticoids on bone structure.