Prevalence of Pseudohypoparathyroidism and Nonsurgical Hypoparathyroidism in Japan in 2017: A Nationwide Survey.

BACKGROUND: Pseudohypoparathyroidism (PHP) and nonsurgical hypoparathyroidism (NS-HypoPT) are rare diseases with hypocalcemia, hyperphosphatemia, and high and low parathyroid hormone levels, respectively. In Japan, over 20 years have passed since the last survey on these diseases. We carried out a nationwide cross-sectional survey to estimate the prevalence of these diseases in 2018. METHODS: We conducted a nationwide mail-based survey targeting hospitals in 2018. From a total of 13,156 departments throughout Japan, including internal medicine, pediatrics, neurology, and psychiatry, 3,501 (27%) departments were selected using a stratified random sampling method. We asked each included department to report the number of patients with PHP and NS-HypoPT in 2017. RESULTS: The overall survey response rate was 52.0% (1,807 departments). The estimated number of patients with PHP and NS-HypoPT was 1,484 (95% confidence interval [CI], 1,143-1,825) and 2,304 (95% CI, 1,189-3,419), respectively; the prevalence per 100,000 population was 1.2 and 1.8, respectively. CONCLUSION: In this study, we generated estimates of the national prevalence of PHP and NS-HypoPT in Japan during 2017, which were found to be higher than those previously reported.

Clinical performance of a novel chemiluminescent enzyme immunoassay for FGF23.

INTRODUCTION: Measurement of fibroblast growth factor 23 (FGF23) has been reported to be clinically useful for the differential diagnosis of chronic hypophosphatemia. However, assays for research use only are available in Japan. Thus, the objective of this study was to examine the clinical utility of a novel and automated chemiluminescent enzyme immunoassay for the measurement of FGF23. MATERIALS AND METHODS: Participants were recruited from July 2015 to January 2017 at six facilities in Japan. Thirty-eight patients with X-linked hypophosphatemic rickets (XLH 15 males, 23 females, age 0-66 years), five patients with tumour-induced osteomalacia (TIO 3 males, 2 females, age 60-73 years), and twenty-two patients with hypophosphatemia (11 males, 11 females, age 1-75 years) caused due to other factors participated in this study. RESULTS: With the clinical cut-off value of FGF23 at 30.0 pg/mL indicated in the Diagnostic Guideline of Rickets/Osteomalacia in Japan, the sensitivity and specificity of FGF23-related hypophosphatemic rickets/osteomalacia without vitamin D deficiency (disease group-1) were 100% and 81.8%, respectively, which distinguished it from non-FGF23-related hypophosphatemia (disease group-2). Furthermore, the diagnostic sensitivity of FGF23-related hypophosphatemia with vitamin D deficiency remained at 100%. Among the four patients with FGF23 levels ≥ 30.0 pg/mL in disease group-2, two patients with relatively higher FGF23 values were suspected to have genuine FGF23-related hypophosphatemia, due to the ectopic production of FGF23 in pulmonary and prostate small cell carcinomas. CONCLUSION: The novel FGF23 assay tested in this study is useful for the differential diagnosis of hypophosphatemic rickets/osteomalacia in a clinical setting.

Factors predicting endocrine late effects in childhood cancer survivors from a Japanese hospital.

We retrospectively analyzed endocrine late effects in 81 childhood cancer survivor (CCS) patients who had been referred to our endocrinology department in Chiba Children's Hospital between January 1, 2008 and December 31, 2016. Among 69 eligible patients (33 male, 36 female), endocrine late effects were identified in 56 patients (81.1%). The median age at the last visit to our endocrinology department was 17.4 years (range: 7.1-35.3 years). The most common primary cancer was acute lymphoblastic leukemia (22 patients, 31.8%). Forty-four patients (64%) were treated using radiation therapy. A primary brain tumor and high doses (≥6 g/m2) of cyclophosphamide were significantly associated with growth hormone deficiency (GHD). Our present study suggests that high doses of cyclophosphamide is a risk factor for GHD. Adult heights and pubertal growth spurts of patients treated with radiation therapy were significantly lower than patients not treated with radiation therapy. Our retrospective study reconfirmed that hematopoietic stem cell transplantation and chronic graft versus host disease (GVHD) were associated with elevated risks of primary hypothyroidism. However, it is unclear whether GVHD induces thyroid dysfunction. Gonadal radiation and busulfan were associated with primary hypogonadism as reported in previous studies. We found high doses of cyclophosphamide to be involved in pituitary disorders. We suggest that pediatric endocrinologists should discuss the potential effects of radiation therapy on adult height and pubertal growth spurt in CCS patients. Moreover, patients who have been treated with high doses of cyclophosphamide or have chronic GVHD require long-term follow-up for endocrine late effects.

Assessment criteria for vitamin D deficiency/insufficiency in Japan: proposal by an expert panel supported by the Research Program of Intractable Diseases, Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research and the Japan Endocrine Society [Opinion].

Vitamin D is indispensable for the maintenance of bone and mineral health. Inadequate vitamin D action increases the risk for various musculoskeletal/mineral events including fracture, fall, secondary hyperparathyroidism, diminished response to antiresorptives, rickets/osteomalacia, and hypocalcemia. Its most common cause in recent years is vitamin D deficiency/insufficiency, clinically defined by a low serum 25-hydroxyvitamin D [25(OH)D] level. Guidelines for vitamin D insufficiency/deficiency defined by serum 25(OH)D concentrations have been published all over the world. In Japan, however, the information on the associations between serum 25(OH)D and bone and mineral disorders has not been widely shared among healthcare providers, partly because its measurement had not been reimbursed with national medical insurance policy until August 2016. We have set out to collect and analyze Japanese data on the relationship between serum 25(OH)D concentration and bone and mineral events. Integrating these domestic data and published guidelines worldwide, here, we present the following assessment criteria for vitamin D sufficiency/insufficiency/deficiency using serum 25(OH)D level in Japan. (1) Serum 25(OH)D level equal to or above 30 ng/ml is considered to be vitamin D sufficient. (2) Serum 25(OH)D level less than 30 ng/ml but not less than 20 ng/ml is considered to be vitamin D insufficient. (3) Serum 25(OH)D level less than 20 ng/ml is considered to be vitamin D deficient. We believe that these criteria will be clinically helpful in the assessment of serum 25(OH)D concentrations and further expect that they will form a basis for the future development of guidelines for the management of vitamin D deficiency/insufficiency.

Assessment criteria for vitamin D deficiency/insufficiency in Japan - proposal by an expert panel supported by Research Program of Intractable Diseases, Ministry of Health, Labour and Welfare, Japan, The Japanese Society for Bone and Mineral Research and The Japan Endocrine Society [Opinion].

Vitamin D is indispensable for the maintenance of bone and mineral health. Inadequate vitamin D action increases the risk for various musculoskeletal/mineral events including fracture, fall, secondary hyperparathyroidism, diminished response to antiresorptives, rickets/osteomalacia, and hypocalcemia. Its most common cause in recent years is vitamin D deficiency/insufficiency, clinically defined by low serum 25-hydroxyvitamin D [25(OH)D] level. Guidelines for vitamin D insufficiency/deficiency defined by serum 25(OH)D concentrations have been published all over the world. In Japan, however, the information on the associations between serum 25(OH)D and bone and mineral disorders has not been widely shared among healthcare providers, partly because its measurement had not been reimbursed with national medical insurance policy until August 2016. We have set out to collect and analyze Japanese data on the relationship between serum 25(OH)D concentration and bone and mineral events. Integrating these domestic data and published guidelines worldwide, here we present the following assessment criteria for vitamin D sufficiency/insufficiency/deficiency using serum 25(OH)D level in Japan. 1) Serum 25(OH)D level equal to or above 30 ng/mL is considered to be vitamin D sufficient. 2) Serum 25(OH)D level less than 30 ng/mL but not less than 20 ng/mL is considered to be vitamin D insufficient. 3) Serum 25(OH)D level less than 20 ng/mL is considered to be vitamin D deficient. We believe that these criteria will be clinically helpful in the assessment of serum 25(OH)D concentrations and further expect that they will form a basis for the future development of guidelines for the management of vitamin D deficiency/insufficiency.

[Update on recent progress in vitamin D research. Vitamin D treatment for hypoparathyroidism.]

The patients with hypoparathyroidism have been treated with active vitamin D(ie, alfacalcidol and calcitriol). Parathyroid hormone(PTH)increases extracellular calcium concentration partly through the activation of vitamin D, and active vitamin D corrects hypocalcemia mainly by increasing intestinal calcium abosorption. PTH coordinately increases blood calcium level with vitamin D in bone and kidney, however, renal tubular reabsorption of calcium is regulated by PTH-dependent mechanism. Hypercalciuria is an complication of long-term vitamin D treatment for PTH-deficient hypoparathyroidism.

Pathogenesis and diagnostic criteria for rickets and osteomalacia--proposal by an expert panel supported by the Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research, and the Japan Endocrine Society.

Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations have revealed that the causes of rickets and osteomalacia are quite variable. Although these diseases can severely impair the quality of life of affected patients, rickets and osteomalacia can be completely cured or at least respond to treatment when properly diagnosed and treated according to the specific causes. On the other hand, there are no standard criteria to diagnose rickets or osteomalacia nationally and internationally. Therefore, we summarize the definition and pathogenesis of rickets and osteomalacia, and propose diagnostic criteria and a flowchart for the differential diagnosis of various causes of these diseases. We hope that these criteria and the flowchart are clinically useful for the proper diagnosis and management of these diseases.

Pathogenesis and diagnostic criteria for rickets and osteomalacia - proposal by an expert panel supported by Ministry of Health, Labour and Welfare, Japan, The Japanese Society for Bone and Mineral Research and The Japan Endocrine Society.

Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations revealed that the causes for rickets and osteomalacia are quite variable. While these diseases can severely impair the quality of life of the affected patients, rickets and osteomalacia can be completely cured or at least respond to treatment when properly diagnosed and treated according to the specific causes. On the other hand, there are no standard criteria to diagnose rickets or osteomalacia nationally and internationally. Therefore, we summarize the definition and pathogenesis of rickets and osteomalacia, and propose the diagnostic criteria and a flowchart for the differential diagnosis of various causes for these diseases. We hope that these criteria and flowchart are clinically useful for the proper diagnosis and management of patients with these diseases.

Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment.

A nationwide epidemiologic survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases was conducted in 2010 to clarify the prevalence and the clinical presentations of the disorders. A questionnaire inquiring the experience of patients with these diseases was sent to randomly selected hospitals throughout Japan. The estimated annual incidence of the diseases was 117 cases (95% CI 75 - 160), 55 males (95% CI 30 - 81) and 62 females (95% CI 40 - 84). Tumor-induced osteomalacia (TIO) and X-linked hypophosphatemic rickets (XLH) were the most prevalent causes of acquired and genetic FGF23-related hypophosphatemic diseases, respectively. The estimated incidence of XLH was about 1 in 20,000. We have also collected clinical data of the patients by a secondary survey. These patients showed FGF23 levels of above 30 pg/mL by intact assay in the presence of hypophosphatemia. While complete resection of responsible tumors improved biochemical abnormalities in patients with TIO, treatment with phosphate and/or active vitamin D3 did not normalize serum phosphate and tubular maximum transport of phosphate in patients with XLH. Our results suggest that there is no racial difference in the incidence of XLH. While FGF23 measurement is useful for the diagnosis of FGF23-related hypophosphatemic diseases, the better management is necessary especially for patients with genetic hypophosphatemic rickets caused by excessive actions of FGF23.

Higher dose of methimazole causes frequent adverse effects in the management of Graves' disease in children and adolescents.

OBJECTIVE: Methimazole (MMI) is used as a first-line antithyroid drug in children and adolescents with Graves' disease (GD). The aim of this study was to evaluate the correlation between the initial dose of MMI and the clinical course of GD after treatment. DESIGN: Retrospective and collaborative study. SETTING: Nine facilities in Chiba prefecture, Japan. PATIENTS: Sixty-four children and adolescents with GD were analyzed. The subjects were divided into three groups by the initial daily dose of MMI: group A, 0.4±0.1 mg/kg (mean±SD, n=11); group B, 0.7±0.2 (n=37); group C, 0.9±0.2 (n=16). MAIN OUTCOME MEASURES: The duration of time required for normalization of serum free T4 on initial treatment and the incidence of adverse effects for 1 year after the start of MMI were compared. Outcomes were compared among patients who were followed more than 3 years (group A, n=7; group B, n=24; group C, n=12). RESULTS: Mean duration of times for normalization of T4 was 1.9±1.5 months in group A, 1.6±0.9 in group B and 1.9±1.5 in group C (NS). No major adverse reactions were observed. Minor adverse effects occurred in 9.1% of cases in group A, 13.5% in group B and 62.0% in group C (p<0.01). Remission rates did not differ among the three groups. CONCLUSIONS: Higher doses of MMI are harmful for initial use in children and adolescents with GD.

Autoimmune thyroid disease following hematopoietic stem cell transplantation in childhood cancer survivors.

Thyroid dysfunction has been observed in childhood cancer survivors (CCSs) who have undergone hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed the thyroid function of 54 CCSs who underwent HSCT and were referred to our endocrinology department at Chiba Children's Hospital between January 1, 2008, and December 31, 2019. Three patients developed autoimmune thyroid disease (AITD) after HSCT. Two of these patients had Graves' disease (GD), and the third had autoimmune thyroiditis. The association between HSCT and AITD remains unclear. All three patients had chronic graft versus host disease (GVHD). AITD was reported to be induced by the transmission of abnormal T or B lymphocyte clones from the donor to the recipient. One patient with GD was treated with a high dose of anti-thymocyte globulin (ATG). Some studies have reported that ATG is associated with a risk of severe T cell depletion and GD onset. In conclusion, CCSs who received HSCT rarely developed AITD. We suggest that CCSs treated with ATG and/or experiencing an onset of chronic GVHD should be carefully monitored for thyroid function because it might reveal AITD.

Elevation of serum fibroblast growth factor 23 level in a pediatric patient with lupus nephritis.

Fibroblast growth factor 23 (FGF-23), a hormone mainly secreted by osteocytes and osteoblasts, regulates phosphate and vitamin D levels. However, the in vivo significance of FGF-23 is not fully elucidated. This case report describes a 12-year-old girl with systemic lupus erythematosus (SLE), lupus nephritis, and an elevated serum FGF-23 level. The patient was treated with active vitamin D and oral sodium phosphate medications to manage low serum phosphate levels (2.2 mg/dL). Magnetic resonance imaging (MRI) revealed a high-intensity area in the left femur, but somatostatin receptor scintigraphy images did not indicate tumor-induced osteomalacia. SLE treatment using mycophenolate mofetil (1500 mg/day) was initiated, and serum complements levels increased as FGF-23 level increased. Serum FGF-23 level gradually decreased as urinary protein levels decreased after treatment with steroids; however, there was no change in the high-intensity area on MRI. Recent studies have reported that serum FGF-23 level is associated with iron deficiency and inflammation; yet, the mechanism related to these associations is not fully elucidated. The findings from this case suggest that elevated serum FGF-23 levels noted in our patient were related to silent lupus nephritis and lupus nephritis activity.

Establishment of diagnosis by bisulfite-treated methylation-specific PCR method and analysis of clinical characteristics of pseudohypoparathyroidism type 1b.

Pathogenesis of pseudohypoparathyroidism type 1b (PHP-1b) is related to the loss of methylation at the GNAS exon A/B region, which is combined with epigenetic defects at other differentially methylated GNAS regions in most sporadic cases. In this study, we established a method for evaluating the methylation status of a CpG island in exon A/B using a methylation-specific polymerase chain reaction (MSPCR). We designed two primer pairs specific for the methylated and unmethylated alleles and evaluated the methylation status of GNAS exon A/B in samples from PHP-1b patients and normal controls. We examined 20 Japanese patients and 20 normal controls, and one primer set was found to be appropriate for diagnosis. Furthermore, we evaluated the clinical data of patients. Weight and height of patients were not significantly different from the normal population. Short stature (adult height ≤ 2SD) was observed in one patient and short metacarpals in two. Obesity was observed in six patients, and no patient showed ectopic subcutaneous calcification. Seven patients showed subclinical hypothyroidism because of resistance to thyroid stimulating hormone, but no patient had an abnormally low free thyroxine level, and none received oral thyroid hormone replacement. For diagnosis of PHP-1b, only clinical data is not sufficient because a few PHP-1b patients show clinical features similar to PHP-1a, and hence, molecular biology techniques are required for correct diagnosis. We concluded that MSPCR is applicable for rapid molecular diagnosis of PHP-1b.

Comparison of methimazole and propylthiouracil in the management of children and adolescents with Graves' disease: efficacy and adverse reactions during initial treatment and long-term outcome.

OBJECTIVE: The aim of this study was to compare the efficacy and adverse reactions during initial treatment and long-term outcome between children and adolescents with Graves' disease (GD) treated with propylthiouracil (PTU) and those treated with methimazole (MMI). DESIGN, SETTING AND PARTICIPANTS: Retrospective and collaborative study. Children and adolescents with GD were divided into group M (MMI: n=64) and group P (PTU: n=69) and into four subgroups by initial dose: group M1 (<0.75 mg/kg of MMI, n=34), group M2 (> or = 0.75 mg/kg, n=30), group P1 (<7.5 mg/kg of PTU, n=24) and group P2 (> or = 7.5 mg/kg, n=45). MAIN OUTCOME MEASURES: The duration for normalization of serum T4 on initial treatment, the incidence of adverse effects for one year and outcomes at 10 years after were compared. RESULTS: Mean durations for normalization of T4 (+/- SD) were 1.7 +/- 1.0 months in group M and 2.3 +/- 2.4 in group P [not significant (NS)], while the mean duration in group P1 (3.1 +/- 3.3) was significantly longer than those in the other subgroups (M1: 1.9 +/- 1.2; M2: 1.4 +/- 0.7; P2; 1.7 +/- 1.3). No major adverse reaction was observed. Minor adverse effects occurred in 25.0% of cases in group M and 31.9% in group P (NS). The incidence in group P2 (44.4%) was significantly higher than those in group M1 (20.6%) and group P1 (8.3%). Remission rates did not differ between the MMI-treated group (35.0%, n=20) and PTU-treated group (50.0%, n=40). CONCLUSIONS: PTU may not be suitable for initial use in children and adolescents with GD, even with the risk of major adverse reactions such as liver failure excluded.

Acute kidney injury caused by ammonium acid urate crystals in diabetic ketoacidosis at the onset of type 1 diabetes mellitus.

SUMMARY: Ammonium acid urate (AAU) crystals are rare in industrialized countries. Furthermore, the number of children with diabetic ketoacidosis (DKA) who develop severe acute kidney injury (AKI) after hospitalization is small. We encountered two patients with AKI caused by AAU crystals during the recovery phase of DKA upon admission. They were diagnosed with severe DKA and hyperuricemia. Their urine volume decreased and AKI developed several days after hospitalization; however, acidosis improved in both patients. Urine sediment analysis revealed AAU crystals. They were treated with urine alkalization and diuretics. Excretion of ammonia in the urine and urine pH levels increased after treatment of DKA, which resulted in the formation of AAU crystals. In patients with severe DKA, the urine and urine sediment should be carefully examined as AAU can form in the recovery phase of DKA. LEARNING POINTS: Ammonium acid urate crystals could be formed in the recovery phase of diabetic ketoacidosis. Diabetic ketoacidosis patients may develop acute kidney injury caused by ammonium acid urate crystals. Urine and urine sediment should be carefully checked in patients with severe DKA who present with hyperuricemia and volume depletion.

A novel missense mutation in the AVPR2 gene of a Japanese infant with nephrogenic diabetes insipidus.

We describe an infant with nephrogenic diabetes insipidus (NDI) with a novel mutation in the arginine vasopressin receptor 2 (AVPR2) gene. A 1-month-old infant showed failure to thrive and hypernatremia. The water deprivation test revealed elevated serum osmolality and low urine osmolality. The patient showed a slight but not significant response to intramuscular injection of arginine vasopressin (AVP). DNA analysis revealed a novel missense mutation involving substitution of proline for leucine at position 173 (P173L), which was reported to be important for stabilizing the hydrogen bond between tyrosine at position 205 and leucine at position 169. This mutation was not detected in 116 ethnic-matched controls. This case, with clinical data including the water deprivation test and P173L mutation, will facilitate understanding the structure and function of the A VPR2.

[Clinical aspect of recent progress in phosphate metabolism. Treatment of hypophophatemia].

Most hypophosphatemic patients will not require immediate replacement therapy with phosphate. In only the patients with acute severe hypophosphatemia (<1 mg/dL) or symptoms, intravenous phosphate replacement therapy is indicated. On the other hand, the patients with chronic hypophosphatemia require the medical treatment with oral administration of calcitriol and neutral phosphate since this condition causes hypophosphatemic rickets/osteomalacia. However, the treatment regimen has not been standardized, and nephrocalcinosis and tertially hyperparathyroidism are the complication of the long-term treatment. Adjuvant therapy with calcimimetics or suppression therapy for FGF23 action may improve long-term outcome.

Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients: proposal of diagnostic criteria using FGF23 measurement.

Fibroblast growth factor 23 (FGF23) plays important roles in the development of hypophosphatemic diseases such as tumor-induced osteomalacia (TIO) and X-linked hypophosphatemic rickets/osteomalacia (XLH). However, clinical usefulness of measurement of FGF23 has not been established. The objective of this study is to examine the importance of FGF23 measurement in the diagnosis of hypophosphatemic diseases. Biochemical parameters concerning phosphate metabolism were analyzed in a cross-sectional study. 32 patients with TIO, 28 patients with XLH and 16 hypophosphatemic patients with other causes including vitamin D deficiency, Fanconi's syndrome and Cushing's syndrome were studied. In patients with TIO and XLH, FGF23 was above the upper limit of the reference range in most patients irrespective of medical treatment. The lowest FGF23 in these patients was 38.0 pg/ml. FGF23 in hypophosphatemic patients with other causes was undetectable (less than 3 pg/ml) in 12 patients and the highest FGF23 in this group was 23.9 pg/ml. Relationship between phosphate and FGF23 indicated that TIO and XLH are diseases with high FGF23 and hypophosphatemia judged by age-dependent reference ranges for serum phosphate. FGF23 measurement is useful for differential diagnosis of hypophosphatemic diseases caused by excess actions of FGF23 and other etiologies. High FGF23 with low phosphate judged by age-dependent reference ranges for phosphate establishes the diagnosis of diseases caused by excess actions of FGF23.

Causes and differential diagnosis of hypocalcemia--recommendation proposed by expert panel supported by ministry of health, labour and welfare, Japan.

Serum calcium (Ca) level is maintained within a narrow range mainly by actions of parathyroid hormone (PTH) and 1,25-dihydroxyvitmain D [1,25(OH)(2)D]. While it is not rare to encounter hypocalcemia in clinical practice, there is currently no practical guideline for the differential diagnosis of hypocalcemia. We therefore propose flowcharts for the differential diagnosis of hypocalcemia and hypoparathyroidism, especially PTH-deficient hypoparathyroidism in which many genetic or other causes have been identified recently. Hypocalcemia can be divided into two categories, hypocalcemia with low serum phosphate level, and one with normal to elevated serum phosphate level. Deficient actions of 1,25(OH)(2)D, loss of Ca into urine, and deposition of Ca in bone or soft tissues are main causes of hypocalcemia with low to low normal serum phosphate level. Hypocalcemia with high normal to high serum phosphate level includes chronic renal failure and hypoparathyroidism. Hypoparathyroidism is subdivided into PTH-deficient hypoparathyroidism and pseudohypoparathyroidism. Recent investigations identified several causes of PTH-deficient hypoparathyroidism, including genetic abnormalities and parathyroid autoantibodies, which should be differentiated from idiopathic hypoparathyroidism. Physical and laboratory findings, the time of the onset of diseases and accompanying illness can be clues for identifying causes of PTH-deficient hypoparathyroidism.

Efficacy of intravenous alendronate for the treatment of glucocorticoid-induced osteoporosis in children with autoimmune diseases.

Our objective was to investigate the efficacy of intravenous alendronate for the treatment of glucocorticoid-induced osteoporosis (GIOP) in children with autoimmune diseases. Five children with autoimmune disease and GIOP were treated with 5 mg intravenous alendronate once every 3 months. After 1 and 2 years, we evaluated the changes in the Z score of the femoral neck bone mineral density (BMD), serum bone alkaline phosphatase, and urinary deoxypyridinoline. Six patients with GIOP, whose BMD could be observed over a 1-year period without alendronate treatment, were defined as controls. After 1 and 2 years of treatment, intravenous treatment significantly inhibited bone loss. The efficacy of alendronate demonstrated a significant correlation with a high level of bone turnover markers before alendronate treatment. Intravenous alendronate is considered to be a good choice for the treatment of GIOP because of its excellent efficacy. In addition, our study suggests that the efficacy of alendronate depends on the bone turnover of patients before treatment. Intervention with bisphosphonates during periods of high bone turnover may be recommended.