The 2023 Guidelines for the management and treatment of glucocorticoid-induced osteoporosis.

INTRODUCTION: Although synthetic glucocorticoids (GCs) are commonly used to treat autoimmune and other diseases, GC induced osteoporosis (GIOP) which accounts for 25% of the adverse reactions, causes fractures in 30-50% of patients, and markedly decreases their quality of life. In 2014, the Japanese Society for Bone and Mineral Research (JSBMR) published the revised guidelines for the management and treatment of steroid-induced osteoporosis, providing the treatment criteria based on scores of risk factors, including previous fractures, age, GC doses, and bone mineral density, for patients aged ≥18 years who are receiving GC therapy or scheduled to receive GC therapy for ≥3 months. MATERIALS AND METHODS: The Committee on the revision of the guidelines for the management and treatment of GIOP of the JSBMR prepared 17 clinical questions (CQs) according to the GRADE approach and revised the guidelines for the management and treatment of GIOP through systematic reviews and consensus conferences using the Delphi method. RESULTS: Bisphosphonates (oral and injectable formulations), anti-RANKL antibody teriparatide, eldecalcitol, or selective estrogen receptor modulators are recommended for patients who has received or scheduled for GC therapy with risk factor scores of ≥3. It is recommended that osteoporosis medication is started concomitantly with the GC therapy for the prevention of fragility fractures in elderly patients. CONCLUSION: The 2023 guidelines for the management and treatment of GIOP was developed through systematic reviews and consensus conferences using the Delphi method.

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.

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.

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.

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.

Prevalent vertebral fracture is dominantly associated with spinal microstructural deterioration rather than bone mineral density in patients with type 2 diabetes mellitus.

BACKGROUND: An assessment of bone strength based on bone mineral density (BMD) underestimates the risk of fracture in patients with diabetes mellitus (T2DM). However, using the trabecular bone score (TBS) for estimating bone microarchitecture, previous studies showed that bone fragility is associated with deterioration of the microstructure concomitantly with decreased BMD. This study was conducted to clarify which of these skeletal-related factors had a more prominent relationship with bone fragility. RESEARCH DESIGN AND METHODS: A retrospective cross-sectional study was performed at Shimane University Hospital. A total of 548 Japanese patients with T2DM [257 postmenopausal women and 291 men aged over 50 years] were included. TBS of the spine was computed from dual-energy X-ray absorptiometry images obtained from BMD measurements. RESULTS: Vertebral fractures (VFs) were identified in 74 (28.8%) women and 115 (39.5%) men. A relationship between BMD and VFs was observed in the limited subgroup of women with a BMD T-score ≤-1.0. According to multivariate logistic regression analysis, low TBS was significantly correlated with prevalent VFs, independent of BMD in both genders, except for men with a BMD T-score > -1.0. The decision tree showed that the priority factor for determining VFs was TBS, not BMD. CONCLUSION: Spinal microarchitecture represented by TBS was a more dominant skeletal factor for bone fragility than the decrease in bone mass, independent of BMD, in patients with T2DM. This observation suggests that loss of structural bone quality was crucial underlying pathogenesis for bone brittleness in these populations, regardless of gender. An integrated assessment of bone strength by BMD and TBS would help diagnose diabetic osteoporosis.

[Wnt signaling and bone metabolic diseases.]

Wnt signaling is known to be involved in metabolic bone disorders. Serum levels of sclerostin, a bone-specific protein that inhibits Wnt signaling, have been investigated in a variety of metabolic bone disorders. Serum sclerostin levels are positively correlated with bone mineral density in patients with osteoporosis. Elderly women with high serum sclerostin levels, however, are at increased risk of bone fractures. Since serum sclerostin levels are low in primary hyperparathyroidism and high in hypoparathyroidism, parathyroid hormone could be classified as a factor that regulates sclerostin levels. Serum sclerostin levels are high in glucocorticoid-induced osteoporosis and diabetes mellitus, which feature reduced bone formation. Finally, serum sclerostin levels increase with decreasing renal function. These findings highlight the potential of serum sclerostin levels as a new index for bone assessments which are different in nature from bone mineral density and bone metabolic markers.

Identification of IgG1 Aggregation Initiation Region by Hydrogen Deuterium Mass Spectrometry.

Antibody aggregates are a potential risk for immunogenicity; therefore, rational approaches to improve associated aggregation properties need to be developed. Here, we report the amino acid region responsible for aggregation initiation. Two types of therapeutic IgG1 antibody monomer samples were prepared: IgG1 mAb40-3M stored at 40°C for 3 months, which existed in monodisperse state, and the monomer mAb65-5m, which was dissociated from small soluble aggregates by heating at 65°C for 5 min. Hydrogen deuterium exchange mass spectrometry of mAb40-3M identified 2 sites in the Fc region (site 1, F239-M256; site 2, S428-G450) with increased exchange rates. Site 1 includes a region reported as being susceptible to structural change induced by stress. Exposure of site 1 was undetected after 2 months of storage at 40°C but was subsequently detectable after 3 months. As site 2 is spatially close to site 1, the structural change of site 1 could propagate site 2. Besides these 2 regions, hydrogen deuterium exchange mass spectrometry of mAb65-5m identified an exposure of I257-W281 in Fc (site 3), within which a peptide sequence with high aggregation tendency was discovered. We thus concluded that exposure of site 3 is a trigger for the association of a partially denatured antibody.

Late-onset isolated adrenocorticotropic hormone deficiency caused by nivolumab: a case report.

BACKGROUND: Immune checkpoint inhibitors including nivolumab, an anti-programmed cell death protein 1 antibody, are recently developed cancer immunotherapy agents. Immune checkpoint inhibitors are known to cause autoimmune-related side effects including endocrine dysfunctions. However, there are few reports on late-onset isolated adrenocorticotropic hormone (ACTH) deficiency caused by nivolumab. CASE PRESENTATION: The patient was a 72-year-old female. When she was 64 years old, she was diagnosed with malignant melanoma of the left thigh accompanied by left inguinal lymph node metastases, and she received several courses of chemotherapy for malignant melanoma followed by the resection of these lesions. At 71 years of age, multiple metastases were found and treatment with nivolumab 2 mg/kg every 3 weeks was initiated. Six months later, replacement with levothyroxine was started because of hypothyroidism following mild transient thyrotoxicosis. Eleven months after the beginning of nivolumab, the treatment was discontinued because of tumor expansion. Four months after the discontinuation of nivolumab, general malaise and appetite loss worsened, and 2 months later, hyponatremia (Na; 120-127 mEq/L) and hypoglycemia (fasting plasma glucose; 62 mg/dL) appeared. Her ACTH and cortisol levels were extremely low (ACTH; 9.6 pg/mL, cortisol; undetectable). Challenge tests for anterior pituitary hormones showed that responses of ACTH and cortisol secretion to corticotropin-releasing hormone were disappeared, although responses of other anterior pituitary hormones were preserved. Thus, she was diagnosed with isolated ACTH deficiency. Her symptoms were improved after treatment with hydrocortisone. CONCLUSIONS: The present report showed a case of late-onset isolated ACTH deficiency accompanied by hyponatremia, which was diagnosed 6 months after the discontinuation of nivolumab. The effects of nivolumab last for a long time and the side effects of nivolumab can also appear several months after discontinuation of the drug. Repeated monitoring of serum sodium levels may be a beneficial strategy to find the unexpected development of adrenal insufficiency even after discontinuation of nivolumab.

[Secondary osteoporosis. Glucocorticoid excess-related osteoporosis.]

Glucocorticoid(GC)excess is one of the most common causes of secondary osteoporosis, which can be associated with a disease(GC excess due to Cushing's syndrome)or with a treatment(GC medications). In addition to Cushing's syndrome, subclinical Cushing's syndrome, which occurs more frequently, can also increase the risk of fractures. Thus, it is important to consider these diseases when making the diagnosis for osteoporosis. GC-induced osteoporosis leads to reduction of bone mineral density and increased risk of fracture from the early stage after initiation of GC treatment, and thus requires management from the time of initiation. The 2014 revised Guidelines on the Management and Treatment of GC-induced Osteoporosis should be used routinely in the clinical settings as they introduce a scoring system that is easily adoptable.

[Rickets/Osteomalacia. Non-skeletal effects of vitamin D.]

A variety of epidemiological studies and meta-analyses have shown that vitamin D insufficiency or deficiency not only affects bone and mineral metabolism, but is also linked to sarcopenia, metabolic diseases such as diabetes, obesity, and metabolic syndrome, cancer, autoimmune disease, and other diseases. There has been accumulating evidence that vitamin D deficiency, defined as a serum 25(OH)D value below 20 ng/mL, is a significant risk factor for each of these diseases. However, vitamin D supplementation has not shown a therapeutic effect in any of these diseases, and a detailed cause-and-effect relationship remains elusive. Future studies should consider non-skeletal effects when investigating cutoff levels of serum 25(OH)D for therapeutic intervention in vitamin D insufficiency and deficiency, the required supplement dose, and the length of supplementation.

Acute suppurative thyroiditis caused by thyroid papillary carcinoma in the right thyroid lobe of a healthy woman.

BACKGROUND: The thyroid gland is resistant to microbial infection, because of its organ characteristics such as encapsulation, iodine content, and rich blood supply. Therefore, acute suppurative thyroiditis (AST), as a bacterial infection of the thyroid gland, is rarely seen. AST typically takes places on the left side the neck region in children, because of the coincidence of the left piriform sinus fistula, as a most common route of infection. AST is also usually seen in immunocompromised hosts. Herein, we report a rare case of AST in the right thyroid lobe of adult woman without any immunocompromised condition. CASE PRESENTATION: A 59-year-old woman was introduced to our hospital for the further examination with fever, sore throat, and right anterior neck swelling. The patient appeared not to be immunodeficient. Neck ultrasonography showed a 47-mm, hypoechoic, heterogeneous nodule with ill-defined margins and irregular form, suggesting a right thyroid malignant nodule. Fine needle aspiration (FNA) biopsy specimen revealed numerous number of neutrophils in the background without nuclear atypia. Based on the clinical course and cytology, AST was confirmed to be diagnosed. Complete response was obtained by an intravenous administration of antimicrobial agents within a week. Image findings such as CT scan did not show any piriform sinus fistula. Four months later, neck ultrasonography showed a significant decrease in size of the nodule in the right thyroid gland to 27 mm, but the lesion still resembled a malignant nodule. So, FNA was repeated again and cytological examination confirmed papillary thyroid carcinoma (PTC). The patient subsequently underwent total thyroidectomy and bilateral level D1 lymph node dissection. Histological findings revealed a 20-mm PTC in the right lobe with sternothyroid muscle invasion of the tumor. CONCLUSIONS: This report represents a rare case of AST associated with PTC on the right side of thyroid gland, found in a healthy adult woman. The reason why AST coincided with malignant thyroid tumor is unclear. We have to take it into our account that malignant tumor may exist in the background when AST is identified on the right side of thyroid gland with a healthy subject.

[Update on recent progress in vitamin D research. Vitamin D and metabolic disease.]

Numerous epidemiological studies and meta-analyses have indicated that there is a link between Vitamin D insufficiency/deficiency and metabolic disorders such as type 1 and type 2 diabetes mellitus as well as metabolic syndrome. However, vitamin D supplementation has not demonstrated improvement effects in obesity, disorders of glucose and lipid metabolism in any of these illnesses;therefore, the details of the causal relationship remain unclear. Improvement in glucose metabolism was observed in a study in which only vitamin D deficient patients with 25-hydroxyvitamin D[25(OH)D]levels of less than 20 ng/mL were given native vitamin D supplementation. Further studies are needed to determine the 25(OH)D level at which intervention is needed along with the required amount and duration of such supplementation.

[New methods for the evaluation of bone quality. The importance of assessing bone quality.]

Fracture risk in patients with secondary osteoporosis, which includes glucocorticoid-induced osteoporosis, was found to be higher than the fracture risk predicted by decreased bone mineral density. Moreover, a large scale randomized clinical study also found that an increased bone mineral density was not a strong predictor of the effectiveness of anti-resorptive agents in preventing fractures. The accumulation of such evidence has led us to conclude that an explanatory factor of bone strength other than bone mineral density must be bone quality. The development of a new method for assessment of bone quality is imperative to more efficiently i)identify patients at high risk of fracture, ii)determine drug selection and assess drug effectiveness, and iii)decide on drug continuation, discontinuation, or changes.

[Etiology and pathogenesis of primary hyperparathyroidism.]

Primary hyperparathyroidism(pHPT)is a frequent endocrine disease in which abnormal calcium(Ca)regulation leads to hypercalcemia. The most frequent cause of pHPT in more than 80% of patients is an adenoma, followed by hyperplasia in about 15%, and cancer in 1~5%. Although most cases of pHPT are sporadic, a few are familial(hereditary), and this is known as familial hyperparathyroidism(FHPT). Gene abnormalities that affect cyclin D1 signaling(CCND1, CDC73, CDKN1B), Wnt/ß-catenin signaling(MEN1), and calcium-sensing receptor signaling(CaSR, GNA11, AP2S1)play a role in the etiology and pathogenesis of pHPT. Vitamin D insufficiency/deficiency and CaSR dysfunction also play a role in pHPT severity. Continued elucidation of the etiology and pathogenesis of pHPT may lead to development of new treatments for pHPT as well as further understanding of Ca regulation.