今日の臨床サポート

骨軟化症

著者: 福本誠二 徳島大学先端酵素学研究所藤井節郎記念医科学センター

監修: 平田結喜緒 公益財団法人 兵庫県予防医学協会 健康ライフプラザ

著者校正/監修レビュー済:2020/06/19
参考ガイドライン:
  1. 日本内分泌学会日本骨代謝学会、厚生労働省難治性疾患克服研究事業 ホルモン受容機構異常に関する調査研究班:くる病・骨軟化症の診断マニュアル(2015)
  1. 日本内分泌学会日本骨代謝学会、厚生労働省難治性疾患克服研究事業 ホルモン受容機構異常に関する調査研究班:ビタミンD不足・欠乏の判定指針(2017)
患者向け説明資料

概要・推奨   

  1. ビタミンD欠乏性骨軟化症には、天然型ビタミンDに加え、活性型ビタミンD3製剤も有効である(推奨度1)
  1. 低リン血症性ビタミンD抵抗性くる病に対しては、リンと活性型ビタミンD3製剤の併用が有効である(推奨度1)
  1. 症状を有する成人X染色体顕性低リン血症性くる病・骨軟化症に対して、リンと活性型ビタミンD3の併用は有効である(推奨度1)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
福本誠二 : 講演料(協和キリン),企業などが提供する寄付講座(協和キリン)[2021年]
監修:平田結喜緒 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 新規検査項目、薬剤の保険適用に際し、加筆修正を行った。

病態・疫学・診察

疾患情報  
  1. 骨軟化症とは、成長軟骨帯閉鎖以降に発症する、骨石灰化障害を特徴とする疾患である。このため骨軟化症では、骨中のカルシウム(Ca)量が減少する。
  1. 二重エネルギーX線吸収測定法などによる骨量測定法は、骨中のCa含量を測定する。したがって骨軟化症は、骨粗鬆症とともに、骨量が減少する疾患である。
  1. 骨軟化症の原因は多岐にわたる。各病因の診断、治療は、それぞれ異なる。
  1. 慢性低リン血症が、骨軟化症の病因であることが多い。
  1. くる病と骨軟化症は、同一の病因によって惹起される。成長軟骨帯閉鎖以前に発症したものを、特にくる病と呼んでいる。
  1. 骨軟化症患者は骨痛や筋力低下を訴え、神経・筋疾患などと混同されることがある。このため、特に低リン血症や高ALP血症を認める患者では、骨軟化症の存在を考慮に入れることが重要である。
  1. ビタミンD欠乏性くる病/骨軟化症は、天然型ビタミンDにより治癒し得る。天然型ビタミンDの効果が乏しい疾患が、ビタミンD抵抗性くる病/骨軟化症と呼ばれている。
  1. ビタミンD抵抗性くる病/骨軟化症は、FGF23関連低リン血症性疾患、Fanconi症候群、高Ca尿症を伴う遺伝性低リン血症性くる病(hereditary hypophosphatemic rickets with hypercalciuria:HHRH)などを含む疾患群である。
  1. FGF23は、骨によって産生され、血中リン濃度を低下させるように作用するホルモンである。FGF23は、腎臓でKlotho-FGF受容体複合体に結合することにより、作用を発揮する。FGF23は、近位尿細管刷子縁膜上に発現する2a型、および2c型ナトリウム-リン共輸送体の発現を低下させることにより、リン再吸収を抑制する。FGF23はまた、ビタミンD代謝酵素発現調節を介し、血中1,25-水酸化ビタミンD[1,25(OH)2D]濃度を低下させ、腸管リン吸収を抑制する。
  1. 過剰なFGF23作用により惹起される低リン血症性くる病・骨軟化症を、FGF23関連低リン血症性くる病・骨軟化症と呼んでいる。
  1. ビタミンD抵抗性くる病/骨軟化症、およびビタミンD依存性くる病/骨軟化症は、指定難病であり、中等症以上の場合などでは、申請し認定されると保険料の自己負担分の一部が公費負担として助成される。(ビタミンD抵抗性くる病/骨軟化症ビタミンD依存性くる病/骨軟化症 平成27年7月施行)
  1. 難病法に基づく医療費助成制度
問診・診察のポイント  
  1. 発症時期の確定のため、小児期の成長、症状の発現時期を確認する。

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文献 

著者: S E Papapoulos, T L Clemens, L J Fraher, J Gleed, J L O'Riordan
雑誌名: Lancet. 1980 Sep 20;2(8195 pt 1):612-5.
Abstract/Text Circulating concentrations of hydroxylated metabolites of vitamin D were measured in seven Asian patients with histologically proven osteomalacia before and during treatment with either cholecalciferol (vitamin D3) or 1,25-dihydroxycholecalciferol. All patients showed an excellent clinical and biochemical response to treatment irrespective of type of vitamin D administered. Circulating concentrations of 25-hydroxycholecalciferol and 24,25, 25,26, and 1,25 dihydroxycholecalciferols were abnormally low in the untreated patients. In five patients treated with small doses of cholecalciferol (3000 units, 75 micrograms daily) the concentration of 1,25-dihydroxycholecalciferol rose rapidly to normal and reached supra-normal levels within 72 h. Raised concentrations (up to 200 pg/ml) were sustained for several months and then started falling to normal. Serum 24,25 and 25,26 dihydroxycholecalciferols rose only gradually, after circulating 25-hydroxycholecalciferol concentration had increased to normal. In contrast, in the two patients who received 1,25-dihydroxycholecalciferol (1 microgram daily) serum concentrations of this metabolite rose to normal and only occasionally exceeded the upper limit of normal. The highest concentration observed was 80 pg/ml. Healing of osteomalacia occurred, however, in these two patients in the absence of any measurable increases in 25-hydroxycholecalciferol and 24,25 or 25,26 dihydroxycholecalciferols which all remained abnormally low. Thus, it seems that 1,25-dihydroxycholecalciferol is the most important factor for the healing of vitamin D-deficient osteomalacia and that other hydroxy metabolites are unimportant.

PMID 6107407  Lancet. 1980 Sep 20;2(8195 pt 1):612-5.
著者: W Sullivan, T Carpenter, F Glorieux, R Travers, K Insogna
雑誌名: J Clin Endocrinol Metab. 1992 Sep;75(3):879-85. doi: 10.1210/jcem.75.3.1517380.
Abstract/Text Current treatment of X-linked hypophosphatemia (XLH) employs the combined administration of oral phosphate and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Although this drug regimen significantly improves the clinical course of the disease in children, the value of medical treatment in symptomatic adults with XLH has not been established. We, therefore, investigated the clinical, biochemical, and histological responses to phosphate and 1,25-(OH)2D3 in 16 symptomatic adult patients with XLH followed for a mean of 4.2 yr. Eighty-seven percent of the patients had an improvement in bone or joint pain with therapy. There was a significant increase in mean serum phosphate (from 0.61 +/- 0.03 to 0.77 +/- 0.03 mmol/L) and urinary calcium excretion (from 2.45 +/- 0.38 to 4.39 +/- 0.44 mmol/day) with treatment. Pretreatment bone biopsies demonstrated findings characteristic of osteomalacia, including abnormally increased osteoid volume and decreased mineral apposition rates. Treatment was accompanied by a significant decrease in osteoid thickness as well as a reduction in mean osteoid volume. However, therapy did not completely normalize these parameters. Disease severity, as assessed by histomorphometric parameters, did not correlate with any pretreatment serum or urinary biochemical measurement, but did seem to correlate with symptom score. Although most patients tolerated therapy without difficulty, 1 patient developed tertiary hyperparathyroidism during treatment and renal insufficiency that progressed despite cessation of therapy. This study provides evidence that therapy with oral phosphate and 1,25-(OH)2D3 in symptomatic adults with XLH can result in significant clinical and histomorphometric improvement.

PMID 1517380  J Clin Endocrinol Metab. 1992 Sep;75(3):879-85. doi: 10・・・
著者: F H Glorieux, P J Marie, J M Pettifor, E E Delvin
雑誌名: N Engl J Med. 1980 Oct 30;303(18):1023-31. doi: 10.1056/NEJM198010303031802.
Abstract/Text We treated 11 children with vitamin D-resistant rickets with a phosphate mixture either alone (1.2 to 3.6 g per day) or combined with ergocalciferol (vitamin D2, to 50 x 103 IU per day) or with calcitriol (1,25-dihydroxyvitamin D3, 0.25 to 1 microgram per day). Serum calcitriol concentrations were normal in all patients. Calcitriol therapy circulating levels of the hormone to values above normal and increased intestinal phosphate absorption. In some patients this regimen decreased the need for phosphate supplements. None of the treatment regimens corrected the renal phosphate leak. Radiologic studies and bone histomorphometric analyses showed that phosphate (alone or with ergocalciferol) induced the mineralization of the growth plate but not of the endosteal bone surface. Combined calcitriol and phosphate therapy for a total of 2850 patient-days greatly improved the mineralization of trabecular bone. Short-term episodes of hypercalcemia were easily controlled by changes in calcitriol dosage. The data indicate that the combined calcitriol and phosphate regimen is useful in the treatment of vitamin D-resistent rickets.

PMID 6252463  N Engl J Med. 1980 Oct 30;303(18):1023-31. doi: 10.1056・・・
著者: Karl L Insogna, Karine Briot, Erik A Imel, Peter Kamenický, Mary D Ruppe, Anthony A Portale, Thomas Weber, Pisit Pitukcheewanont, Hae Il Cheong, Suzanne Jan de Beur, Yasuo Imanishi, Nobuaki Ito, Robin H Lachmann, Hiroyuki Tanaka, Farzana Perwad, Lin Zhang, Chao-Yin Chen, Christina Theodore-Oklota, Matt Mealiffe, Javier San Martin, Thomas O Carpenter, AXLES 1 Investigators
雑誌名: J Bone Miner Res. 2018 Aug;33(8):1383-1393. doi: 10.1002/jbmr.3475. Epub 2018 Jun 26.
Abstract/Text In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n = 68) or placebo (n = 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean ± standard error [SE] difference, -8.1 ± 3.24; p = 0.012). Reductions in WOMAC physical function subscale (-4.9 ± 2.48; p = 0.048) and Brief Pain Inventory worst pain (-0.5 ± 0.28; p = 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
PMID 29947083  J Bone Miner Res. 2018 Aug;33(8):1383-1393. doi: 10.100・・・
著者: Erik A Imel, Francis H Glorieux, Michael P Whyte, Craig F Munns, Leanne M Ward, Ola Nilsson, Jill H Simmons, Raja Padidela, Noriyuki Namba, Hae Il Cheong, Pisit Pitukcheewanont, Etienne Sochett, Wolfgang Högler, Koji Muroya, Hiroyuki Tanaka, Gary S Gottesman, Andrew Biggin, Farzana Perwad, Meng Mao, Chao-Yin Chen, Alison Skrinar, Javier San Martin, Anthony A Portale
雑誌名: Lancet. 2019 Jun 15;393(10189):2416-2427. doi: 10.1016/S0140-6736(19)30654-3. Epub 2019 May 16.
Abstract/Text BACKGROUND: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.
METHODS: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.
FINDINGS: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.
INTERPRETATION: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy.
FUNDING: Ultragenyx Pharmaceutical and Kyowa Kirin International.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 31104833  Lancet. 2019 Jun 15;393(10189):2416-2427. doi: 10.1016/・・・

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