Progressive Thymic Hyperplasia With Graves' Disease: A Case Report.

We treated a 36-year-old man with thymic hyperplasia complicated with Graves' disease. Thymic hyperplasia was observed on thoracic computed tomography (CT) three months after the onset of thyrotoxicosis symptoms. One month after thiamazole initiation, he displayed drug-induced liver injury and underwent a total thyroidectomy. Seven months after surgery, we observed a dramatic reduction of thymic size associated with normalizing the soluble interleukin-2 receptor (sIL-2R) levels. The rapid development of hyperplasia after the onset of thyrotoxicosis and the restoration in thymus volume after total thyroidectomy associated with suppression of sIL-2R, in this case, suggests the complexity of the pathogenesis of thymic hyperplasia in the thyrotoxicosis.

Graves' disease after exposure to the SARS-CoV-2 vaccine: a case report and review of the literature.

BACKGROUND: Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is characterized by immune system dysregulation after exposure to adjuvants, such as aluminum. Although cases of autoimmune thyroid diseases caused by ASIA have been reported, Graves' disease is one of the rarer diseases. There are some reports that vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause ASIA. Here, we describe a case of Graves' disease following SARS-CoV-2 vaccination and a review of the literature. CASE PRESENTATION: A 41-year-old woman was admitted to our hospital because of palpitations and fatigue. Two weeks after receiving the second SARS-CoV-2 vaccine (BNT162b2, Coronavirus Modified Uridine messenger RNA (mRNA) Vaccine, Pfizer), she developed fatigue and gradually worsened. On admission, she exhibited thyrotoxicosis (thyroid-stimulating hormone (TSH) < 0.01 mIU/L (0.08-0.54), free triiodothyronine (FT3) 33.2 pmol/L (3.8-6.3), and free thyroxine (FT4) 72.1 pmol/L (11.6-19.3)) and palpitations associated with atrial fibrillation. TSH receptor antibody (TRAb) was positive (TRAb 5.0 IU/L (< 2.0)), and 99mTc scintigraphy showed diffuse uptake in the thyroid gland, suggesting that the thyrotoxicosis in this case was caused by Graves' disease. Thiamazole was prescribed to correct her condition, and soon after this treatment was initiated, her symptoms and thyroid hormone levels were significantly reduced. CONCLUSIONS: This case report reinforces the potential correlation between ASIA affecting the thyroid and SARS-CoV-2 mRNA vaccines. The clinical course suggests that it is essential to consider the possibility of developing ASIA, such as Graves' disease, after exposure to the SARS-CoV-2 vaccine.

Association Between Papillary Thyroid Carcinoma and Vertebral Fracture.

Suppression of TSH levels associated with levothyroxine treatment is a known risk factor for fracture. However, it is unclear whether patients with papillary thyroid carcinoma (PTC) have a higher risk of vertebral fracture (VF) before TSH suppression. The aim of the study was to examine whether the risk of VF is higher in PTC than in healthy subjects. A hospital-based, matched case-control study was conducted comparing PTC and healthy individuals. We enrolled 43 postoperative patients with PTC scheduled for radioiodine therapy and 43 age- and sex-matched healthy controls. Serum and urinary biological parameters, bone mineral density (BMD), and presence of VFs were evaluated in both groups. We compared these indices using χ2 and Mann-Whitney U-test and analyzed the association between PTC and VF by logistic regression analysis. The PTC group had higher BMI, HbA1c and phosphorus, and lower intact PTH than the control group. Lumbar and femoral neck BMD did not differ between the two groups. Prevalence of VFs was significantly higher in the PTC group (44.1%) than in the control group (16.3%). Multivariate logistic regression analyses adjusted for age, sex, and BMI identified PTC as being associated with the presence of VFs (odds ratio, 5.63; 95% confidence interval: 1.82 to 17.5). This relationship remained significant after additional adjustment for HbA1c and BMD. There is an association between PTC and a risk of VF independent of sex, BMI, glucose metabolism, and BMD, suggesting the importance of fracture risk assessment before TSH suppression.

Successful Control of Hypercalcemia with Sorafenib, Evocalcet, and Denosumab Combination Therapy for Recurrent Parathyroid Carcinoma.

Parathyroid carcinoma (PC) is a rare type of endocrine cancer. Recurrence and metastasis are common after surgery, and refractory hypercalcemia often leads to a poor prognosis. However, there are currently no specific strategies for PC recurrence. We herein report a 61-year-old Japanese man with metastatic PC who was treated with sorafenib, a multikinase inhibitor. In this case, the serum calcium level was under control for 10 months after the initiation of sorafenib. This case suggests that combination therapy with sorafenib, evocalcet, and denosumab may be an alternative, stronger management option for refractory hypercalcemia in recurrent PC.

Thyroid crisis caused by metastatic thyroid cancer: an autopsy case report.

BACKGROUND: Thyroid crisis is a life-threatening condition in thyrotoxic patients. Although differentiated thyroid cancer is one of the causes of hyperthyroidism, reports on thyroid crisis caused by thyroid cancer are quite limited. Here, we describe a case of thyroid crisis caused by metastatic thyroid cancer. CASE PRESENTATION: A 91-year-old woman was admitted to our hospital because of loss of appetite. Two years prior to this hospitalization, she presented with subclinical thyrotoxicosis and was diagnosed with histologically unidentified thyroid cancer with multiple metastases, and she refused aggressive medical interventions. On admission, she exhibited extreme thyrotoxicosis, and the presence of fever, severe tachycardia, impaired consciousness, and heart failure revealed the presence of thyroid crisis. All thyroid autoantibodies were negative. Multidisciplinary conservative treatment was initiated; however, she died on the fifth day after admission. Autopsy revealed the presence of primary anaplastic thyroid carcinoma and multiple metastatic foci arising from follicular thyroid carcinoma. Both primary and metastatic follicular thyroid carcinoma likely induced thyrotoxicosis, which could have been exacerbated by anaplastic thyroid carcinoma. CONCLUSIONS: Even though the trigger of thyroid crisis in this patient is not clear, the aggravated progression of her clinical course suggests that careful monitoring of thyroid hormones and appropriate intervention are essential for patients with thyroid cancer.

High glucose promotes mineralization via bone morphogenetic protein 4-Smad signals in early stage of osteoblast differentiation.

Diabetes mellitus is associated with bone fragility. Although osteoblast maturation is disturbed in patients with diabetes mellitus, the involvement of high glucose (HG) in different stages of osteoblast maturation is unclear. We used MC3T3-E1 cells, a murine osteoblastic cell line. The cells were incubated in high glucose medium (16.5 and 27.5 mM) with three different time courses: throughout 21 days, only first 7 days (early stage) and only last 7 days (late stage). Mineralization assay showed that HG throughout 21 days increased mineralization compared with control (5.5 mM). In the time course experiment, HG increased mRNA expression of Alp, osteocalcin (Ocn), runt-related transcription factor 2 and osterix on days 3 and 5. By contrast, long-term treatment with HG (14 and 21 days) decreased expression of these osteoblastic markers. HG only during early stage enhanced mineralization, while HG only during late stage had no effects. HG increased the expression of bone morphogenetic protein (BMP) 4 and enhanced phosphorylation of Smad1/5/8. Treatment with a BMP receptor antagonist LDN193189 prevented the HG-induced mineralization during early stage of osteoblast differentiation, indicating that HG in the early stage promotes mineralization by BMP4. In conclusion, the study demonstrates that continuous HG treatment might enhance early osteoblast differentiation but disturbs osteoblast maturation, and that BMP-4-Smad signal might be involved in the HG-induced differentiation and mineralization of osteoblasts.

Osteomalacia caused by atypical renal tubular acidosis with vitamin D deficiency: a case report.

Osteomalacia is a systemic metabolic bone disease. Hypophosphatemia is one of the most important causes of impaired mineralization. Here, we describe a case of osteomalacia associated with atypical renal tubular acidosis. A 43-year-old woman was admitted to our hospital due to sustained unrelieved bilateral flank pain. She had a history of fragile fracture with vitamin D deficiency and had been treated with active vitamin D. On admission, she presented with hypophosphatemia, hypocalcemia, high bone-specific alkaline phosphatase level, bone pain, and low bone mineral density. Multiple areas of uptake were also confirmed by bone scintigraphy, and she was diagnosed with osteomalacia. An increased dose of alfacalcidol was initiated for her vitamin D deficiency; her symptoms remained unstable and unrelieved. Her blood gas examination revealed metabolic acidosis without an increase in the anion gap (HCO3- 11.8 mEq/L, anion gap 3.2 mEq/L). Tubular dysfunction, tubular damage, kidney stones, and inadequate urinary acidification were all observed, suggesting the presence of renal tubular acidosis from a combination of both distal and proximal origin. She also had overt proteinuria, decreased renal function, and hypothalamic hypogonadism. In addition to alfacalcidol, sodium bicarbonate and oral phosphorus supplementation were initiated. After this prescription, her pain dramatically improved in association with the restoration of acid-base balance and electrolytes; renal dysfunction and proteinuria were unaltered. This case indicated that careful assessments of tubular function and acid-base balance are essential for the management of osteomalacia in addition to the evaluation of the calcium/phosphate balance and vitamin D status.

Higher Serum Uric Acid is a Risk Factor of Reduced Muscle Mass in Men with Type 2 Diabetes Mellitus.

OBJECTIVE: Sarcopenia has been recognized as a diabetic complication, and hyperuricemia is often accompanied by type 2 diabetes mellitus (T2DM). However, it is unknown whether serum uric acid (UA) levels are associated with reduced muscle mass in T2DM. METHODS: We conducted a cross-sectional study to investigate the association of serum UA with muscle mass in 401 subjects with T2DM (209 men and 192 postmenopausal women). The relative skeletal muscle mass index (RSMI) was evaluated using whole-body dual-energy x-ray absorptiometry. RESULTS: Multiple regression analyses adjusted for body weight, age, serum creatinine, hemoglobin A1c (HbA1c), and duration of T2DM showed that serum UA was negatively associated with RSMI in all subjects and men with T2DM (ß=-0.13, p=0.001 and ß=-0.17, p=0.003, respectively). Moreover, logistic regression analyses adjusted for these confounding factors showed that a higher serum UA level was significantly associated with low RSMI in men with T2DM [odds ratio (OR)=1.94, 95% confidence interval (CI)=1.10-3.45 per SD increase, p=0.023]. In addition, higher serum UA levels were significantly associated with low RSMI after additional adjustment for age, duration of T2DM, HbA1c level, serum creatinine level, and sex in all subjects with T2DM [OR=1.80, 95% CI=1.20-2.72 per SD increase, p=0.005]. CONCLUSIONS: The present study showed for the first time that higher serum UA is an independent risk factor of reduced muscle mass in men with T2DM.

A pregnant woman with an autonomously functioning thyroid nodule: a case report.

BACKGROUND: The epidemiology and natural history of autonomously functioning thyroid nodules (AFTNs) have not been elucidated. Here we report the pregnant Japanese woman with an AFTN. CASE PRESENTATION: The patient was a 31-year-old woman who was hospitalized due to the placenta previa associated with threatened abortion at the 16 weeks of her third pregnancy. At her second pregnancy, she was euthyroid but had a single, 2.3 cm nodule on her right thyroid lobe. Her thyroid hormone level was trended increased with her pregnancy progression, and the thyrotoxic state was remained after delivery. Before her third pregnancy, her hyper-vascular nodule enlarged to 3.4 cm at regular monitoring. When she visited our hospital, she was at 16 weeks of pregnancy and had thyrotoxicosis with negative TSH-receptor antibody. She delivered a baby weighing 2615 g without hypothyroidism at 39 weeks of pregnancy by natural delivery. After delivery, a 99mTc scintigram showed a hot spot in her right thyroid lobe. She was diagnosed with AFTN and treated with methimazole while nursing. CONCLUSIONS: This case showed that hCG stimulation during pregnancy caused thyroid nodule enlargement and enhanced thyroid hormone production. The pregnancy could be the pathological stimulus and provides chance to diagnosis for AFTNs.

A case of insulin-like growth factor 2-producing gastrointestinal stromal tumor with severe hypoglycemia.

BACKGROUND: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome that secretes incompletely processed high molecular weight insulin growth factor 2 (big-IGF2), which results in stimulation of the insulin receptor and subsequently induces hypoglycemia. Gastrointestinal stromal tumor (GIST) is a common intestinal mesenchymal neoplasm of the gastrointestinal tract. The most frequent site of GIST is the stomach; NICTH induced by IGF2-producing stomach GISTs is rare. CASE PRESENTATION: An 84-year-old man was admitted to the hospital due to impaired consciousness (JCS II-10) in the morning. At the time of admission, his serum glucose was 44 mg/dL; his consciousness was restored with 20 ml of 50% glucose. To avoid hypoglycemia, a continuous intravenous infusion of glucose as well as dietary intervention was required. At the time of hypoglycemia, the levels of insulin and C-peptide were suppressed. Additionally, IGF1 levels were below the normal range. Abdominal computed tomography revealed that he had a large lobulated mass (116 × 70 × 72 mm) around the gastric corpus. Pathological analysis of biopsy specimens identified disarray of spindle cells and positivity for c-kit as well as strong positivity for DOG-1. Further analysis revealed high levels of Ki-67 (Mib-1 index: 15.5%) and mitotic index (7/50HPF); the tumor was diagnosed as high-risk GIST, and complete surgical resection was performed. Hypoglycemia resolved immediately after tumor resection. The resected tumor specimen was positive for IGF2 staining, and big-IGF2 (11-18 kDa) was detected in preoperative serum and tumor samples; the patient was diagnosed with NICTH due to an IGF2-producing tumor. CONCLUSIONS: NICTH is rare in GIST of the stomach; however, the large GIST could produce big-IGF2 and subsequently cause severe hypoglycemia, requiring prompt evaluation and complete tumor resection.

Graves' disease and vertebral fracture: Possible pathogenic link in postmenopausal women.

BACKGROUND AND OBJECTIVE: Thyrotoxicosis is associated with accelerated bone turnover and increases the risk of fractures and osteoporosis. Graves' disease is the most common cause of hyperthyroidism. However, studies that examined risk factors associated with fragility fractures only in patients with Graves' disease are limited. Here, we investigated whether the risk of vertebral fracture (VF) of postmenopausal Graves' disease patients is high and tried to identify the risk factors for VF in that population. DESIGN AND METHODS: Forty-three postmenopausal women with Graves' disease were enrolled. Physical and biochemical indices, thyroid indices and bone mineral density (BMD) were measured, and lateral X-rays were obtained to evaluate VFs. Age- and sex-matched healthy individuals were enrolled as the control group (n = 86). RESULTS: The prevalence of VFs (35% vs 17%, P < .05), osteoporosis (63% vs 33%, P < .01) and severe osteoporosis (40% vs 17%, P < .01) was significantly higher in the Graves' disease group. Although there was no significant difference in either thyroid hormone levels or the positive ratio of thyroid antibodies, the prevalence of thyroid-stimulating antibody (TSAb) was significantly higher in Graves' disease patients with VF compared to without (100% vs 68%, P < .05). Multivariate logistic regression analyses adjusted for age identified Graves' disease as being associated with the presence of VFs (OR 2.72, 95% CI: 1.13-6.54, P < .05) in postmenopausal women. CONCLUSIONS: Postmenopausal Graves' disease patients had high risks of VF and severe osteoporosis. TSAb could be involved as a risk factor for VF in postmenopausal Graves' disease.

Higher Serum Uric Acid is a Risk Factor of Vertebral Fractures in Postmenopausal Women with Type 2 Diabetes Mellitus.

PURPOSE: Serum uric acid (UA) level may affect bone metabolism because it has an anti-oxidative effect. However, whether serum UA level is associated with a fracture risk in type 2 diabetes mellitus (T2DM) is unclear. We thus aimed to clarify the association between serum UA and bone parameters in T2DM. METHODS: We conducted a cross-sectional study to investigate the association of serum UA with bone mineral density (BMD) at lumbar spine (LS) and femoral neck (FN), bone turnover markers such as osteocalcin and urine type I collagen cross-linked N-telopeptide (uNTX), and the prevalence of vertebral fractures (VF) in 356 postmenopausal women and 512 men with T2DM. RESULTS: Multiple regression analyses adjusted for age, duration of diabetes, hemoglobin A1c, body mass index and log (serum creatinine) showed that serum UA level was significantly and negatively associated with uNTX in postmenopausal women with T2DM, whereas it was not associated with osteocalcin or BMD at each site. In men, serum UA was not associated with BMD or bone turnover markers. Because postmenopausal women with VF were significantly older and had longer duration of diabetes, higher serum creatinine level and lower BMD than those without it, logistic regression analyses adjusted for these confounding factors were performed. Higher serum UA level was significantly associated with the presence of VF. CONCLUSIONS: The present study showed that higher serum UA is a risk factor for VF independently of BMD in postmenopausal women with T2DM.

Papillary thyroid carcinoma is a risk factor for severe osteoporosis.

INTRODUCTION: Thyroid-stimulating hormone (TSH)-suppressive therapy is recommended after surgical treatment in high-risk papillary thyroid carcinoma (PTC) patients. TSH-suppressive therapy is a known risk factor for osteoporosis and fractures. However, whether patients with PTC themselves are at a higher risk of osteoporosis than healthy individuals remains unclear. This study aimed to clarify whether PTC is a risk factor for osteoporosis. MATERIALS AND METHODS: Serum and urinary biochemical parameters, bone mineral density (BMD), and presence of vertebral fractures (VFs) and non-VFs were evaluated in 35 PTC patients and 35 age- and sex-matched healthy individuals. We compared the parameters between PTC and control subjects and performed multiple logistic regression analyses after adjustments for variables. RESULTS: Patients with PTC had higher body mass index (BMI) and hemoglobin (Hb)A1c, as well as lower eGFR and intact PTH than controls (p < 0.05, each). There were no significant differences in the prevalence of osteoporosis and VFs and non-VFs between patients with PTC and controls. However, the prevalence of severe osteoporosis diagnosed according to WHO criteria was significantly higher in PTC subjects (34.3%) than in controls (11.4%, p < 0.05). Multivariate logistic regression analyses adjusted for age, BMI, eGFR and HbA1c identified PTC as being associated with the presence of severe osteoporosis (odds ratio, 4.20; 95% confidence interval, 1.05-16.8; p < 0.05). CONCLUSIONS: We identified PTC as a risk factor for severe osteoporosis, independent of BMI, renal function and glucose profile.

Bazedoxifene Ameliorates Homocysteine-Induced Apoptosis via NADPH Oxidase-Interleukin 1ß and 6 Pathway in Osteocyte-like Cells.

Homocysteine (Hcy) increases oxidation and inflammation; however, the mechanism of Hcy-induced bone fragility remains unclear. Because selective estrogen modulators (SERMs) have an anti-oxidative effect, SERMs may rescue the Hcy-induced bone fragility. We aimed to examine whether oxidative stress and pro-inflammatory cytokines such as interleukin (IL)-1ß and IL-6 are involved in the Hcy-induced apoptosis of osteocytes and whether bazedoxifene (BZA) inhibits the detrimental effects of Hcy. We used mouse osteocyte-like cell lines MLO-Y4-A2 and Ocy454. Apoptosis was examined by DNA fragmentation ELISA and TUNEL staining, and gene expression was evaluated by real-time PCR. Hcy 5 mM significantly increased expressions of NADPH oxidase (Nox)1, Nox2, IL-1ß, and IL-6 as well as apoptosis in MLO-Y4-A2 cells. Nox inhibitors, diphenyleneiodonium chloride and apocynin, significantly suppressed Hcy-induced IL-1ß and IL-6 expressions. In contrast, an IL-1ß receptor antagonist and an IL-6 receptor monoclonal antibody had no effects on Hcy-induced Nox1 and Nox2 expressions, but significantly rescued Hcy-induced apoptosis. BZA (1 nM-1 µM) and 17ß estradiol 100 nM significantly rescued Hcy-induced apoptosis, while an estrogen receptor blocker ICI 182,780 reversed the effects of BZA and 17ß estradiol. BZA also rescued Hcy-induced apoptosis of Ocy454 cell, and ICI canceled the effect of BZD. Moreover, BZA significantly ameliorated Hcy-induced expressions of Nox1, Nox2, IL-1ß, and IL-6, and ICI canceled the effects of BZA on their expressions. Hcy increases apoptosis through stimulating Nox 1 and Nox 2-IL-1ß and IL-6 expressions in osteocyte-like cells. BZA inhibits the detrimental effects of Hcy on osteocytes via estrogen receptor.

Phloretin Suppresses Bone Morphogenetic Protein-2-Induced Osteoblastogenesis and Mineralization via Inhibition of Phosphatidylinositol 3-kinases/Akt Pathway.

Phloretin has pleiotropic effects, including glucose transporter (GLUT) inhibition. We previously showed that phloretin promoted adipogenesis of bone marrow stromal cell (BMSC) line ST2 independently of GLUT1 inhibition. This study investigated the effect of phloretin on osteoblastogenesis of ST2 cells and osteoblastic MC3T3-E1 cells. Treatment with 10 to 100 µM phloretin suppressed mineralization and expression of osteoblast differentiation markers, such as alkaline phosphatase (ALP), osteocalcin (OCN), type 1 collagen, runt-related transcription factor 2 (Runx2), and osterix (Osx), while increased adipogenic markers, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), fatty acid-binding protein 4, and adiponectin. Phloretin also inhibited mineralization and decreased osteoblast differentiation markers of MC3T3-E1 cells. Phloretin suppressed phosphorylation of Akt in ST2 cells. In addition, treatment with a phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor, LY294002, suppressed the mineralization and the expression of osteoblast differentiation markers other than ALP. GLUT1 silencing by siRNA did not affect mineralization, although it decreased the expression of OCN and increased the expression of ALP, Runx2, and Osx. The effects of GLUT1 silencing on osteoblast differentiation markers and mineralization were inconsistent with those of phloretin. Taken together, these findings suggest that phloretin suppressed osteoblastogenesis of ST2 and MC3T3-E1 cells by inhibiting the PI3K/Akt pathway, suggesting that the effects of phloretin may not be associated with glucose uptake inhibition.

Insulin-Like Growth Factor-I Protects Against the Detrimental Effects of Advanced Glycation End Products and High Glucose in Myoblastic C2C12 Cells.

Previous studies suggested that advanced glycation end products (AGEs) and insulin-like growth factor-I (IGF-I) are involved in the mechanism of diabetes-induced sarcopenia. In this study, we examined effects of treatments with AGEs and/or IGF-I for 24 h on myogenic differentiation and apoptosis in mouse myoblastic C2C12 cells. Real-time PCR and Western blot were performed to investigate mRNA and protein expressions, and apoptosis was examined by using a DNA fragment detection ELISA kit. AGE3 significantly decreased mRNA and protein expressions of MyoD and Myogenin, whereas IGF-I significantly increased them and attenuated the effects of AGE3. AGEs significantly decreased endogenous IGF-I mRNA expression and suppressed IGF-I-induced Akt activation. High glucose (22 mM) significantly increased mRNA expression of Rage, a receptor for AGEs, while IGF-I significantly decreased it. DNA fragment ELISA showed that AGE2 and AGE3 significantly increased apoptosis of C2C12 cells, whereas IGF-I significantly suppressed the AGE2- and AGE3-induced apoptosis. In contrast, high glucose enhanced AGE3-induced apoptosis. IGF-I significantly attenuated the effects of high glucose plus AGE3 on the mRNA and protein expressions of MyoD and Myogenin as well as the apoptosis. These findings indicate that AGEs inhibit myogenic differentiation and increase apoptosis in C2C12 cells, and that high glucose increases RAGE and enhances the AGE3-induced apoptosis, suggesting that AGEs and high glucose might contribute to the reduction of muscle mass and function. Moreover, IGF-I attenuated the detrimental effects of AGEs and high glucose in myoblastic cells; thus, IGF-I-Akt signal could be a therapeutic target of DM-induced sarcopenia.

A scoring assessment tool for the risk of vertebral fractures in patients with type 2 diabetes mellitus.

BACKGROUND: Development of assessment tool for fracture risk is an urgent task, because bone mineral density (BMD) is less useful for evaluating fracture risk in type 2 diabetes mellitus (T2DM). SUBJECTS AND METHODS: In total, 808 T2DM patients were enrolled in this cross-sectional study. To develop a scoring assessment tool using clinical risks for vertebral fracture (VF), we evaluated which variables were associated with VF by logistic regression analysis, and categorized these variables based on cut-off values obtained by using receiver operating characteristic (ROC) curves. For calculation of the score, the relative weight of the factors was determined, and a tentative score was assigned. Then, cut-off point of the score was examined to predict VF. RESULTS: Logistic regression analyses showed that age, diabetes duration, body mass index (BMI), serum albumin, and T score at femoral neck (FN-T score) were associated with VF risk. Parameter estimates for each risk factor obtained by logistic analyses were converted to risk scores (maximum score 23). ROC analysis showed that 8.5 was the cut-off value for detecting VF. Multiple logistic regression analysis adjusted for confounding factors showed that score ≥9 was significantly associated with an increased risk of prevalent VF (odds ratio 1.99, 95% confidence interval 1.22-3.24, p = 0.006). CONCLUSIONS: This is the first study to show that a scoring assessment tool using age, duration of diabetes, BMI, serum albumin, and FN-T score is useful to estimate VF risk in patients with T2DM, being more sensitive than BMD alone in detecting bone fragility.

Overweight and underweight are risk factors for vertebral fractures in patients with type 2 diabetes mellitus.

The aim of this cross-sectional study was to examine the association between body mass index (BMI) and the prevalence of vertebral fracture (VF) in Japanese patients with type 2 diabetes (T2DM). A total of 798 patients with T2DM were enrolled. VF was determined semi-quantitatively using lateral X-ray films. The association between BMI quartiles (Q1: ≤ 21.2 kg/m2, Q2: 21.3-23.4 kg/m2, Q3: 23.5-25.8 kg/m2, Q4: 25.9≤ kg/m2) and the presence of VF was examined. Multiple logistic regression analyses adjusted for age, sex, diabetes duration, hemoglobin A1c (HbA1c), estimated glomerular filtration rate, and albumin showed that Q1, Q3, and Q4 were significantly associated with an increased VF risk compared to Q2, which served as a reference [Q1; odds ratio (OR) = 1.91, 95% confidence interval (CI) 1.24-2.95, p = 0.004, Q3; OR = 1.65, 95% CI 1.07-2.55, p = 0.023, and Q4; OR = 2.18, 95% CI 1.39-3.41, p < 0.001]. Moreover, these associations remained significant after additional adjustment for femoral neck T-score, a bone resorption marker, urinary N-terminal cross-linked telopeptide of type-I collagen, and use of insulin and thiazolidinedione. Our study shows for the first time that both overweight and underweight were associated with the bone mineral density (BMD)-independent risk of VF in patients with T2DM. Therefore, body weight control should be considered as a protective measure against diabetes-related bone fragility.

Osteoblast AMP-activated protein kinase regulates glucose metabolism and bone mass in adult mice.

Previous studies have shown that AMP-activated protein kinase (AMPK), a crucial regulator of energy homeostasis, plays important roles in osteoblast differentiation and mineralization. However, little is known about in vivo roles of osteoblastic AMPK in glucose metabolism and bone mass regulation in adult mice. Here, we used the inducible Cre system to control the onset of Ampk disruption after birth by removing doxycycline supplementation. We conditionally inactivated Ampk in osterix (Osx)-expressing cells in 3-week-old Ampk-/- mice. After 6 months of Ampk inactivation, the Ampk-/- mice displayed lower serum osteocalcin levels as well as glucose intolerance and insulin resistance, as indicated by glucose tolerance and insulin tolerance tests, respectively, when compared with wild-type mice. After 18 months of Ampk inactivation, micro computed tomography showed significant reductions in trabecular bone volume and cortical bone thickness in the femur of Ampk-/- mice when compared with wild-type mice. Moreover, bone stiffness was significantly lower in Ampk-/- mice than in wild-type mice. This is the first study to show that osteoblast AMPK plays an important roles in glucose metabolism and in maintaining trabecular bone volume, cortical thickness, and bone strength in adult mice.