今日の臨床サポート

高カルシウム血症

著者: 小泉賢洋 東海大学 腎内分泌代謝内科

著者: 深川雅史 東海大学 腎内分泌代謝内科

監修: 花房規男 東京女子医科大学 血液浄化療法科

著者校正済:2021/06/23
現在監修レビュー中
患者向け説明資料

概要・推奨   

  1. 高Ca血症に対する一般的治療行為として、ループ利尿薬を用いるべきではない。
  1. ゾレドロン酸(ゾメタ)は、パミドロン酸よりも強いCa低下作用を有する(推奨度2)。
  1. ビスホスホネート製剤による腎障害は、適切なモニタリングや薬剤の減量および中止により回避することができる(推奨度2)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となりま す。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となり
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:
小泉賢洋 : 特に申告事項無し[2021年]
深川雅史 : 講演料(協和キリン,アストラゼネカ),奨学(奨励)寄付など(中外製薬,小野薬品,鳥居薬品,協和キリン)[2021年]
監修:花房規男 : 講演料(協和キリン,ノーベルファーマ,キッセイ薬品,バイエル薬品株式会社)[2021年]

改訂のポイント:
  1. 定期レビューを行った(変更なし)。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 高カルシウム(Ca)血症は、補正Ca濃度あるいはイオン化Ca濃度が基準値を超過する場合を指し、それぞれの基準値は補正Ca濃度が8.5~10mg/dl程度、イオン化Ca濃度が1.15~1.3mmol/l程度とされている。重篤になると、思考力低下、記銘力障害、意識障害などの症状を来すことがある。
  1. 実臨床において比較的高頻度に遭遇する異常であり、原発性副甲状腺機能亢進症と悪性腫瘍が原因の90%以上を占める[1][2]
  1. 原発性副甲状腺機能亢進症は外来患者における高カルシウム(Ca)血症の最も多い原因であり、一方、悪性腫瘍に伴う高Ca血症は入院患者における高Ca血症の最も多い原因である。
  1. 原発性副甲状腺機能亢進症の発症のピークは40~60歳代であり、以前は骨病変や腎病変を伴う症例がみられたが、最近は軽度の高Ca血症のみを呈する症例が多い。
  1. 高Ca血症が存在する状況下で、intact PTH値がその基準値の上半分(35~65pg/ml)を超えていれば原発性副甲状腺機能亢進症の診断がなされ、超えていなければほかの原因の可能性を検討すべきである[3]
  1. 悪性腫瘍に伴う高Ca血症は、副甲状腺ホルモン関連蛋白質(parathyroid hormone-related protein、PTHrP)やPTHなどの液性因子を介するもの(humoral hypercalcemia of malignancy、HHM)と骨局所での腫瘍による崩壊・融解によるもの(local osteolytic hypercalcemia、LOH)の2つに大別される。
  1. 悪性腫瘍や高齢者における高Ca血症では、脱水とそれに伴う腎障害の存在が大きく影響しており、体液量および腎機能の評価を行うことが重要である。
問診・診察のポイント  
 
問診:
  1. 薬剤歴:ビタミンD(高齢者で骨粗鬆症などに対して活性型製剤が過量に処方されている症例が多くみられ、サプリメントにも含有されていることがある)、サイアザイド系利尿薬、ビタミンA
  1. 家族歴:多発性内分泌腺腫症(MEN I:下垂体+副甲状腺+膵β細胞、MENIIa:副甲状腺、甲状腺、副腎髄質)、家族性低Ca尿症性高Ca血症
  1. 活動性:不動(immobilization)の可能性
  1. 既往歴:悪性腫瘍、慢性肉芽腫性疾患(サルコイドーシス、結核など)、甲状腺機能亢進症
  1. 症状:全身(倦怠感、易疲労感)、消化器(食思不振、吐気・嘔吐、消化性潰瘍、便秘)、心(QT時間短縮、高血圧、血管石灰化)、腎(腎濃縮力障害による口渇・多飲・多尿、尿路結石)、精神(思考力低下、記銘力障害、意識障害) ※特異的な症状に乏しい
 
診察:
  1. 頻脈、血圧低下、起立性低血圧、口腔粘膜の乾燥、頚静脈の虚脱等の脱水を示唆する所見の有無

今なら12か月分の料金で14ヶ月利用できます(個人契約、期間限定キャンペーン)

11月30日(火)までにお申込みいただくと、
通常12ヵ月の使用期間が2ヶ月延長となり、14ヵ月ご利用いただけるようになります。

詳しくはクリック
本サイトの知的財産権は全てエルゼビアまたはコンテンツのライセンサーに帰属します。私的利用及び別途規定されている場合を除き、本サイトの利用はいかなる許諾を与えるものでもありません。 本サイト、そのコンテンツ、製品およびサービスのご利用は、お客様ご自身の責任において行ってください。本サイトの利用に基づくいかなる損害についても、エルゼビアは一切の責任及び賠償義務を負いません。 また、本サイトの利用を以て、本サイト利用者は、本サイトの利用に基づき第三者に生じるいかなる損害についても、エルゼビアを免責することに合意したことになります。  本サイトを利用される医学・医療提供者は、独自の臨床的判断を行使するべきです。本サイト利用者の判断においてリスクを正当なものとして受け入れる用意がない限り、コンテンツにおいて提案されている検査または処置がなされるべきではありません。 医学の急速な進歩に鑑み、エルゼビアは、本サイト利用者が診断方法および投与量について、独自に検証を行うことを推奨いたします。

文献 

著者: F W Lafferty
雑誌名: J Bone Miner Res. 1991 Oct;6 Suppl 2:S51-9; discussion S61. doi: 10.1002/jbmr.5650061413.
Abstract/Text The differential diagnosis of hypercalcemia has expanded to over 25 separate disease states, with primary hyperparathyroidism and malignancy accounting for 80-90% of all hypercalcemic patients. Primary hyperparathyroidism comprises the majority of hypercalcemic patients among the ambulatory population, but malignancy accounts for up to 65% of such patients in the hospital. Factors favoring primary hyperparathyroidism include a family history of hyperparathyroidism or multiple endocrine neoplasia, a history of childhood radiation to the head and neck, the postmenopausal state, a history of renal calculi or peptic ulcer, hypertension, the induction of hypercalcemia by thiazides, or an asymptomatic patient with a prolonged, stable mild hypercalcemia. The usefulness of the serum calcium, parathyroid hormone, chloride, phosphorus, serum 25-OHD, and 1,25-(OH)2D, and urinary calcium in the differential diagnosis of hypercalcemia is discussed. The pitfalls of an excessive reliance on the serum PTH in diagnosing hyperparathyroidism are stressed. The discriminant values of the serum calcium, chloride, phosphorus, and parathyroid hormone are explored, with the serum parathyroid hormone, chloride, and calcium proving most useful in separating primary hyperparathyroidism from other forms of hypercalcemia. Multivariate discriminant analysis using the serum calcium, phosphorus, and chloride and the hematocrit achieves an accuracy of 95-98% and is the most economical method of identifying hyperparathyroidism. The addition of the amino-terminal or intact PTH assay increases the accuracy to 99% and is essential in the presence of renal insufficiency.

PMID 1763670  J Bone Miner Res. 1991 Oct;6 Suppl 2:S51-9; discussion ・・・
著者: W J Burtis, T L Wu, K L Insogna, A F Stewart
雑誌名: Ann Intern Med. 1988 Mar;108(3):454-7.
Abstract/Text
PMID 3277518  Ann Intern Med. 1988 Mar;108(3):454-7.
著者: D B Endres, R Villanueva, C F Sharp, F R Singer
雑誌名: Clin Chem. 1991 Feb;37(2):162-8.
Abstract/Text Parathyrin (parathyroid hormone; PTH) was measured with three immunoassays: a two-site immunochemiluminometric (ICMA) and a two-site immunoradiometric (IRMA) method for intact PTH, and a sensitive radioimmunoassay for mid-region or "total" PTH, measuring both intact hormone and inactive fragments. Single specimens from normal subjects and from individuals with primary hyperparathyroidism, hypercalcemia associated with malignancy, and hypoparathyroidism were analyzed with all three methods. All individuals with primary hyperparathyroidism showed absolutely above-normal concentrations with the mid-region RIA, 28 of 29 did with the ICMA, and 21 of 29 did with the IRMA. PTH concentrations in primary hyperparathyroidism were most increased relative to normal subjects with the mid-region assay (10.4 times), less so with the intact assays (ICMA 5.5 times; IRMA 5.3 times). Concentrations of intact PTH were suppressed below normal in nearly all patients with hypercalcemia associated with malignancy, as measured with the ICMA (26 of 30) and the IRMA (28 of 30) assays. In marked contrast, results for mid-region PTH were normal or slightly above normal, consistent with studies suggesting that the parathyroids secrete both intact hormone and inactive fragments, the former being more sensitive to suppression by hypercalcemia. In hypoparathyroidism PTH concentrations were detectable but below normal in all patients by the intact assays and in all but one patient by the mid-region assay. These low concentrations are probably due to a nonspecific serum effect that could be resolved with selection of a more appropriate standard matrix. Although all three assays are useful in the differential diagnosis of hypercalcemia, two-site intact assays are more convenient and more specific in patients with compromised renal function.

PMID 1993319  Clin Chem. 1991 Feb;37(2):162-8.
著者: S R Nussbaum, R J Zahradnik, J R Lavigne, G L Brennan, K Nozawa-Ung, L Y Kim, H T Keutmann, C A Wang, J T Potts, G V Segre
雑誌名: Clin Chem. 1987 Aug;33(8):1364-7.
Abstract/Text We have developed a highly sensitive, two-site immunoradiometric assay (IRMA) for human parathyrin (PTH) that is specific for the intact, secreted, biologically active 84-amino-acid peptide. This assay has several technical advantages: it does not detect even high concentrations of inactive carboxyl-terminal fragments, results are available within 24 h, and the detection limit for intact hormone is low (1 ng/L). The assay readily measures concentrations of PTH in all healthy subjects and distinguishes these values from low or undetectable PTH values observed in clinical situations in which PTH secretion is expected to be suppressed. We found complete separation of results from 37 patients with surgically proven hyperparathyroidism and those from 23 patients with hypercalcemia associated with malignancy, the latter having PTH values at or below the lower limits of normal for this assay. The sensitivity, specificity, and rapid turnaround time of this two-site IRMA should advance the laboratory evaluation of patients with disorders of calcium metabolism.

PMID 3608153  Clin Chem. 1987 Aug;33(8):1364-7.
著者: L A Austin, H Heath
雑誌名: N Engl J Med. 1981 Jan 29;304(5):269-78. doi: 10.1056/NEJM198101293040505.
Abstract/Text
PMID 7003392  N Engl J Med. 1981 Jan 29;304(5):269-78. doi: 10.1056/N・・・
著者: J P Bilezikian
雑誌名: J Clin Endocrinol Metab. 1993 Dec;77(6):1445-9. doi: 10.1210/jcem.77.6.8263125.
Abstract/Text Hypercalcemia is a very common electrolyte abnormality that is most often seen as a mild elevation in the setting of asymptomatic primary hyperparathyroidism. The hypercalcemia is usually less than 11.2 mg/dL and does not call for specific or vigorous approaches to management. However, more marked elevations in the serum calcium are also seen and call for a more specific approach to management. When the serum calcium is only moderately elevated, the therapeutic approach should be tempered by clinical assessments about the presence of symptoms and the underlying etiology. When the serum calcium is markedly elevated, a more targeted therapeutic approach is called for which now is independent of the presence of symptoms and usually of the underlying etiology. Considerations of hypercalcemia in these three different ranges will tailor the therapeutic approach to the clinical setting.

PMID 8263125  J Clin Endocrinol Metab. 1993 Dec;77(6):1445-9. doi: 10・・・
著者: L J Deftos, B P First
雑誌名: Ann Intern Med. 1981 Aug;95(2):192-7.
Abstract/Text Calcitonin is a peptide hormone produced by the C-cells of the thyroid gland. Its main biological effect is to inhibit the resorption of bone. This effect, in combination with a calciuric action of calcitonin, can produce a lowering of blood calcium. These biological effects of calcitonin have made it useful in the treatment of hypercalcemic and hyperresorptive disorders.

PMID 7258871  Ann Intern Med. 1981 Aug;95(2):192-7.
著者: S Ljunghall
雑誌名: Recent Results Cancer Res. 1989;116:40-5.
Abstract/Text Increased bone resorption and increased renal tubular reabsorption of calcium are involved in the pathogenesis of hypercalcemia of malignancy. Clodronate and calcitonin inhibit bone resorption and have been used as therapy for malignancy-associated hypercalcemia. Both drugs induce significant reductions of serum calcium but the decrease is greater with clodronate, particularly when given intravenously. While the response to calcitonin generally is of short duration, clodronate can maintain normal serum calcium values over several weeks when oral administered. Thus, from the clinical point of view clodronate is a very useful adjunct to the available therapy.

PMID 2527399  Recent Results Cancer Res. 1989;116:40-5.
著者: A Carano, S L Teitelbaum, J D Konsek, P H Schlesinger, H C Blair
雑誌名: J Clin Invest. 1990 Feb;85(2):456-61. doi: 10.1172/JCI114459.
Abstract/Text Bisphosphonates are useful in treatment of disorders with increased osteoclastic activity, but the mechanism by which bisphosphonates act is unknown. We used cultures of chicken osteoclasts to address this issue, and found that 1-hydroxyethylidenediphosphonic acid (EHDP), dichloromethylidenediphosphonic acid (Cl2MDP), or 3-amino-1-hydroxypropylidene-1,1-diphosphonic acid (APD) all cause direct dose-dependent suppression of osteoclastic activity. Effects are mediated by bone-bound drugs, with 50% reduction of bone degradation occurring at 500 nM to 5 microM of the different agents. Osteoclastic bone-binding capacity decreased by 30-40% after 72 h of bisphosphonate treatment, despite maintenance of cell viability. Significant inhibition of bone resorption in each case is seen only after 24-72 h of treatment. Osteoclast activity depends on ATP-dependent proton transport. Using acridine orange as an indicator, we found that EHDP reduces proton accumulation by osteoclasts. However, inside-out plasma membrane vesicles from osteoclasts transport H+ normally in response to ATP in high concentrations of EHDP, Cl2MDP, or APD. This suggests that the bisphosphonates act as metabolic inhibitors. Bisphosphonates reduce osteoclastic protein synthesis, supporting this hypothesis. Furthermore, [3H]leucine incorporation by the fibroblast, which does not resorb bone, is also diminished by EHDP, Cl2MDP and APD except when co-cultured with bisphosphonate-binding bone particles. Thus, the resorption-antagonizing capacities of EHDP, Cl2MDP and APD reflect metabolic inhibition, with selectivity for the osteoclast resulting from high affinity binding to bone mineral.

PMID 2105340  J Clin Invest. 1990 Feb;85(2):456-61. doi: 10.1172/JCI1・・・
著者: P Major, A Lortholary, J Hon, E Abdi, G Mills, H D Menssen, F Yunus, R Bell, J Body, E Quebe-Fehling, J Seaman
雑誌名: J Clin Oncol. 2001 Jan 15;19(2):558-67.
Abstract/Text PURPOSE: Two identical, concurrent, parallel, multicenter, randomized, double-blind, double-dummy trials were conducted to compare the efficacy and safety of zoledronic acid and pamidronate for treating hypercalcemia of malignancy (HCM).
PATIENTS AND METHODS: Patients with moderate to severe HCM (corrected serum calcium [CSC] > or = 3.00 mmol/L [12.0 mg/dL]) were treated with a single dose of zoledronic acid (4 or 8 mg) via 5-minute infusion or pamidronate (90 mg) via 2-hour infusion. A protocol-specified pooled analysis of the two parallel trials was performed. Clinical end points included rate of complete response by day 10, response duration, and time to relapse.
RESULTS: Two hundred eighty-seven patients were randomized and evaluated for safety; 275 were evaluated for efficacy. Both doses of zoledronic acid were superior to pamidronate in the treatment of HCM. The complete response rates by day 10 were 88.4% (P = .002), 86.7% (P = .015), and 69.7% for zoledronic acid 4 mg and 8 mg and pamidronate 90 mg, respectively. Normalization of CSC occurred by day 4 in approximately 50% of patients treated with zoledronic acid and in only 33.3% of the pamidronate-treated patients. The median duration of complete response favored zoledronic acid 4 and 8 mg over pamidronate 90 mg with response durations of 32, 43, and 18 days, respectively.
CONCLUSION: Zoledronic acid is superior to pamidronate; 4 mg is the dose recommended for initial treatment of HCM and 8 mg for relapsed or refractory hypercalcemia.

PMID 11208851  J Clin Oncol. 2001 Jan 15;19(2):558-67.
著者: Susan B LeGrand, Dona Leskuski, Ivan Zama
雑誌名: Ann Intern Med. 2008 Aug 19;149(4):259-63.
Abstract/Text Although primary hyperparathyroidism is the most common cause of hypercalcemia, cancer is the most common cause requiring inpatient intervention. An estimated 10% to 20% of all patients with cancer have hypercalcemia at some point in their disease trajectory, particularly in advanced disease. Aggressive saline hydration and varying doses of furosemide continue to be the standard of care for emergency management. However, a review of the evidence for the use of furosemide in the medical management of hypercalcemia yields only case reports published before the introduction of bisphosphonates, in contrast to multiple randomized, controlled trials supporting the use of bisphosphonates. The use of furosemide in the management of hypercalcemia should no longer be recommended.

PMID 18711156  Ann Intern Med. 2008 Aug 19;149(4):259-63.
著者: Mark A Perazella, Glen S Markowitz
雑誌名: Kidney Int. 2008 Dec;74(11):1385-93. doi: 10.1038/ki.2008.356. Epub 2008 Aug 6.
Abstract/Text Bisphosphonates are valuable agents for the treatment of post-menopausal osteoporosis (PMO), hypercalcemia of malignancy, and osteolytic bone metastases. Oral bisphosphonates are used mainly to treat PMO and are not associated with significant nephrotoxicity. In contrast, nephrotoxicity is a significant potential limiting factor to the use of intravenous (IV) bisphosphonates, and the nephrotoxicity is both dose-dependent and infusion time-dependent. The two main IV bisphosphonates available to treat hypercalcemia of malignancy and osteolytic bone disease in the United States are zoledronate and pamidronate. Patterns of nephrotoxicity described with these agents include toxic acute tubular necrosis and collapsing focal segmental glomerulosclerosis, respectively. With both of these agents, severe nephrotoxicity can be largely avoided by stringent adherence to guidelines for monitoring serum creatinine prior to each treatment, temporarily withholding therapy in the setting of renal insufficiency, and adjusting doses in patients with pre-existing chronic kidney disease. In patients with PMO, zoledronate and pamidronate are associated with significantly less nephrotoxicity, which undoubtedly relates to the lower doses and longer dosing intervals employed for this indication. Ibandronate is approved in the US for treatment of PMO and in Europe for treatment of PMO and malignancy-associated bone disease. Available data suggest that ibandronate has a safe renal profile without evidence of nephrotoxicity, even in patients with abnormal baseline kidney function.

PMID 18685574  Kidney Int. 2008 Dec;74(11):1385-93. doi: 10.1038/ki.20・・・
著者: Matthew H F Wong, Martin R Stockler, Nick Pavlakis
雑誌名: Cochrane Database Syst Rev. 2012 Feb 15;2:CD003474. doi: 10.1002/14651858.CD003474.pub3. Epub 2012 Feb 15.
Abstract/Text BACKGROUND: Bone is the most common site of metastatic disease associated with breast cancer (BC). Bisphosphonates inhibit osteoclast-mediated bone resorption, and novel targeted therapies such as denosumab, inhibit key pathways in the vicious cycle of bone metastases.
OBJECTIVES: To assess the effect of bisphosphonates on skeletal-related events (SREs), bone pain, quality of life (QoL), recurrence and survival in women with breast cancer with bone metastases (BCBM), advanced breast cancer (ABC) without clinical evidence of bone metastases and early breast cancer (EBC).To assess the effect of denosumab on SREs, bone pain and (QoL) in women with (BCBM).
SEARCH METHODS: We searched the Specialised Register maintained by the Cochrane Breast Cancer Group (CBCGSR), MEDLINE, EMBASE and the WHO International Cancer Trials Registry Platform (WHO ICTRP) on 30 April 2011. We conducted additional handsearching of journals and proceedings of key meetings.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing: (a) bisphosphonates and control, or different bisphosphonates in women with BCBM; (b) denosumab and bisphosphonates in women with BCBM; (c) bisphosphonates and control in women with ABC; (d) bisphosphonates and control in women with EBC; and (e) early versus delayed bisphosphonate treatment in women with EBC.
DATA COLLECTION AND ANALYSIS: Two review authors (MW and NP) independently assessed the trials and extracted the data. We collected toxicity information from the trials.
MAIN RESULTS: We included thirty-four RCTs. In nine studies (2806 patients with BCBM), comparing bisphosphonates with placebo or no bisphosphonates, bisphosphonates reduced the SRE risk by 15% (risk ratio (RR) 0.85; 95% confidence interval (CI) 0.77 to 0.94; P = 0.001). This benefit was most certain with intravenous (i.v.) zoledronic acid (4 mg) (RR 0.59; 95% CI 0.42 to 0.82); i.v. pamidronate (90 mg) (RR 0.77; 95% CI 0.69 to 0.87); and i.v. ibandronate (RR 0.80; 95% CI 0.67 to 0.96). A direct comparison of i.v. zoledronic acid and i.v. pamidronate confirmed at least equivalent efficacy in a single large study. In three studies (3405 patients with BCBM), compared with bisphosphonates, subcutaneous (s.c.) denosumab was more effective in reducing the risk of SREs (RR 0.78; 95% CI 0.72 to 0.85; P < 0.00001).Bisphosphonates reduced the SRE rate in 12 studies (median reduction 28%, range 14% to 48%), with statistically significant reductions reported in 10 studies. Women with BCBM treated with bisphosphonates showed significant delays in the median time to SREs. Compared with placebo or no bisphosphonates, treatment with bisphosphonates significantly improved bone pain in six out of eleven studies. Improvements in global QoL with bisphosphonates compared to placebo were reported in two out of five studies (both ibandronate studies). Treatment with bisphosphonates did not appear to affect survival in women with BCBM. Compared to i.v. zoledronic acid, denosumab also significantly reduced the SRE rate, delayed the time to SREs and prolonged the time in developing pain for patients with no or mild pain at baseline; but there was no difference in survival between patients treated with denosumab and zoledronic acid.Bisphosphonates in women with ABC without clinically evident bone metastases did not reduce the incidence of bone metastases, or improve survival in three studies (320 patients).In seven studies (7847 patients with EBC), currently there is no evidence supporting bisphosphonates in reducing the incidence of bone metastases compared to no bisphosphonates (RR 0.94; 95% CI 0.82 to 1.07; P = 0.36). In three studies (2190 patients with EBC), early bisphosphonate treatment also did not significantly reduce the incidence of bone metastases compared to delayed bisphosphonate treatment (RR 0.73; 95% CI 0.40 to 1.33; P = 0.31). Currently, there is insufficient evidence to make a conclusion about the role of adjuvant bisphosphonates in reducing visceral metastases, locoregional recurrence and total recurrence, or improving survival. There was strong heterogeneity in EBC studies examining the outcomes of total recurrence and survival.Reported toxicity was generally mild. Renal toxicity and osteonecrosis of the jaw (ONJ) have been identified as potential problems with bisphosphonate use. ONJ was reported at similar rates for patients on denosumab compared to zoledronic acid. This highlighted a need for maintaining good oral care, prior to and during treatment, for patients who received long-term bone agents.
AUTHORS' CONCLUSIONS: In women with clinically evident BCBM, bisphosphonates (oral and i.v.) and denosumab (s.c.) reduced the risk of developing SREs, as well as delaying the time to SREs. Some bisphosphonates may also reduce bone pain and may improve QoL. The optimal timing and duration of treatment for patients with BCBM remains uncertain. There is currently insufficient evidence to support the routine use of bisphosphonates as adjuvant treatment for patients with EBC. However, a number of large clinical trials investigating bisphosphonates in EBC have completed accrual and are awaiting results.

PMID 22336790  Cochrane Database Syst Rev. 2012 Feb 15;2:CD003474. doi・・・
著者: Brent O'Carrigan, Matthew Hf Wong, Melina L Willson, Martin R Stockler, Nick Pavlakis, Annabel Goodwin
雑誌名: Cochrane Database Syst Rev. 2017 Oct 30;10:CD003474. doi: 10.1002/14651858.CD003474.pub4. Epub 2017 Oct 30.
Abstract/Text BACKGROUND: Bone is the most common site of metastatic disease associated with breast cancer (BC). Bisphosphonates inhibit osteoclast-mediated bone resorption, and novel targeted therapies such as denosumab inhibit other key bone metabolism pathways. We have studied these agents in both early breast cancer and advanced breast cancer settings. This is an update of the review originally published in 2002 and subsequently updated in 2005 and 2012.
OBJECTIVES: To assess the effects of bisphosphonates and other bone agents in addition to anti-cancer treatment: (i) in women with early breast cancer (EBC); (ii) in women with advanced breast cancer without bone metastases (ABC); and (iii) in women with metastatic breast cancer and bone metastases (BCBM).
SEARCH METHODS: In this review update, we searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 19 September 2016.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing: (a) one treatment with a bisphosphonate/bone-acting agent with the same treatment without a bisphosphonate/bone-acting agent; (b) treatment with one bisphosphonate versus treatment with a different bisphosphonate; (c) treatment with a bisphosphonate versus another bone-acting agent of a different mechanism of action (e.g. denosumab); and (d) immediate treatment with a bisphosphonate/bone-acting agent versus delayed treatment of the same bisphosphonate/bone-acting agent.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, and assessed risk of bias and quality of the evidence. The primary outcome measure was bone metastases for EBC and ABC, and a skeletal-related event (SRE) for BCBM. We derived risk ratios (RRs) for dichotomous outcomes and the meta-analyses used random-effects models. Secondary outcomes included overall survival and disease-free survival for EBC; we derived hazard ratios (HRs) for these time-to-event outcomes where possible. We collected toxicity and quality-of-life information. GRADE was used to assess the quality of evidence for the most important outcomes in each treatment setting.
MAIN RESULTS: We included 44 RCTs involving 37,302 women.In women with EBC, bisphosphonates were associated with a reduced risk of bone metastases compared to placebo/no bisphosphonate (RR 0.86, 95% confidence interval (CI) 0.75 to 0.99; P = 0.03, 11 studies; 15,005 women; moderate-quality evidence with no significant heterogeneity). Bisphosphonates provided an overall survival benefit with time-to-event data (HR 0.91, 95% CI 0.83 to 0.99; P = 0.04; 9 studies; 13,949 women; high-quality evidence with evidence of heterogeneity). Subgroup analysis by menopausal status showed a survival benefit from bisphosphonates in postmenopausal women (HR 0.77, 95% CI 0.66 to 0.90; P = 0.001; 4 studies; 6048 women; high-quality evidence with no evidence of heterogeneity) but no survival benefit for premenopausal women (HR 1.03, 95% CI 0.86 to 1.22; P = 0.78; 2 studies; 3501 women; high-quality evidence with no heterogeneity). There was evidence of no effect of bisphosphonates on disease-free survival (HR 0.94, 95% 0.87 to 1.02; P = 0.13; 7 studies; 12,578 women; high-quality evidence with significant heterogeneity present) however subgroup analyses showed a disease-free survival benefit from bisphosphonates in postmenopausal women only (HR 0.82, 95% CI 0.74 to 0.91; P < 0.001; 7 studies; 8314 women; high-quality evidence with no heterogeneity). Bisphosphonates did not significantly reduce the incidence of fractures when compared to placebo/no bisphosphonates (RR 0.77, 95% CI 0.54 to 1.08, P = 0.13, 6 studies, 7602 women; moderate-quality evidence due to wide confidence intervals). We await mature overall survival and disease-free survival results for denosumab trials.In women with ABC without clinically evident bone metastases, there was no evidence of an effect of bisphosphonates on bone metastases (RR 0.96, 95% CI 0.65 to 1.43; P = 0.86; 3 studies; 330 women; moderate-quality evidence with no heterogeneity) or overall survival (RR 0.89, 95% CI 0.73 to 1.09; P = 0.28; 3 studies; 330 women; high-quality evidence with no heterogeneity) compared to placebo/no bisphosphonates however the confidence intervals were wide. One study reported a trend towards an extended period of time without a SRE with bisphosphonate compared to placebo (low-quality evidence). One study reported quality of life and there was no apparent difference in scores between bisphosphonate and placebo (moderate-quality evidence).In women with BCBM, bisphosphonates reduced the SRE risk by 14% (RR 0.86, 95% CI 0.78 to 0.95; P = 0.003; 9 studies; 2810 women; high-quality evidence with evidence of heterogeneity) compared with placebo/no bisphosphonates. This benefit persisted when administering either intravenous or oral bisphosphonates versus placebo. Bisphosphonates delayed the median time to a SRE with a median ratio of 1.43 (95% CI 1.29 to 1.58; P < 0.00001; 9 studies; 2891 women; high-quality evidence with no heterogeneity) and reduced bone pain (in 6 out of 11 studies; moderate-quality evidence) compared to placebo/no bisphosphonate. Treatment with bisphosphonates did not appear to affect overall survival (RR 1.01, 95% CI 0.91 to 1.11; P = 0.85; 7 studies; 1935 women; moderate-quality evidence with significant heterogeneity). Quality-of-life scores were slightly better with bisphosphonates than placebo at comparable time points (in three out of five studies; moderate-quality evidence) however scores decreased during the course of the studies. Denosumab reduced the risk of developing a SRE compared with bisphosphonates by 22% (RR 0.78, 0.72 to 0.85; P < 0.001; 3 studies, 2345 women). One study reported data on overall survival and observed no difference in survival between denosumab and bisphosphonate.Reported toxicities across all settings were generally mild. Osteonecrosis of the jaw was rare, occurring less than 0.5% in the adjuvant setting (high-quality evidence).
AUTHORS' CONCLUSIONS: For women with EBC, bisphosphonates reduce the risk of bone metastases and provide an overall survival benefit compared to placebo or no bisphosphonates. There is preliminary evidence suggestive that bisphosphonates provide an overall survival and disease-free survival benefit in postmenopausal women only when compared to placebo or no bisphosphonate. This was not a planned subgroup for these early trials, and we await the completion of new large clinical trials assessing benefit for postmenopausal women. For women with BCBM, bisphosphonates reduce the risk of developing SREs, delay the median time to an SRE, and appear to reduce bone pain compared to placebo or no bisphosphonate.

PMID 29082518  Cochrane Database Syst Rev. 2017 Oct 30;10:CD003474. do・・・
著者: Karim Fizazi, Michael Carducci, Matthew Smith, Ronaldo Damião, Janet Brown, Lawrence Karsh, Piotr Milecki, Neal Shore, Michael Rader, Huei Wang, Qi Jiang, Sylvia Tadros, Roger Dansey, Carsten Goessl
雑誌名: Lancet. 2011 Mar 5;377(9768):813-22. doi: 10.1016/S0140-6736(10)62344-6. Epub 2011 Feb 25.
Abstract/Text BACKGROUND: Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer.
METHODS: In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed.
FINDINGS: 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9-18·5) for patients on denosumab and 11·2 months (IQR 5·6-17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8-24·9) with denosumab compared with 17·1 months (15·0-19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71-0·95; p = 0·0002 for non-inferiority; p = 0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p = 0·09).
INTERPRETATION: Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer.
FUNDING: Amgen.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21353695  Lancet. 2011 Mar 5;377(9768):813-22. doi: 10.1016/S0140・・・
著者: Pinelopi Kleio Palaska, Vassiliki Cartsos, Athanasios I Zavras
雑誌名: Oncologist. 2009 Nov;14(11):1154-66. doi: 10.1634/theoncologist.2009-0115. Epub 2009 Nov 8.
Abstract/Text Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a complication of long-term bisphosphonate (BP) use. Given the beneficial effects of BP on bone quality in patients with cancer or osteoporosis, it is of great importance to understand the risk as it relates to time to event or cumulative dose until the onset of disease. Because there is no information on the lowest toxic dose from clinical trials, here we report on a review of 71 case series published since 2003. We calculated the weighted mean time to event, as well as the minimum reported time and dose for zoledronate, pamidronate, and oral bisphosphonates. The mean time to BONJ after zoledronate treatment was calculated at 1.8 years and the minimum was 10 months; after pamidronate, the mean time was 2.8 years and the minimum was 1.5 years; and after oral BP therapy, the mean time was 4.6 years and the minimum was 3 years. Zoledronic acid seems to be the most potent among the nitrogen-containing BPs. Factors that seem to affect BONJ and time to event were invasive dental procedures and other comorbid factors such as advanced age, rheumatoid arthritis, diabetes, use of corticosteroids, vitamin D deficiency, and more. Understanding the pathophysiology of the disease requires further research.

PMID 19897878  Oncologist. 2009 Nov;14(11):1154-66. doi: 10.1634/theon・・・
著者: Ana O Hoff, Béla B Toth, Kadri Altundag, Marcella M Johnson, Carla L Warneke, Mimi Hu, Ajay Nooka, Gilbert Sayegh, Valentina Guarneri, Kimberly Desrouleaux, Jeffrey Cui, Andrea Adamus, Robert F Gagel, Gabriel N Hortobagyi
雑誌名: J Bone Miner Res. 2008 Jun;23(6):826-36. doi: 10.1359/jbmr.080205.
Abstract/Text INTRODUCTION: Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates. The incidence and risk factors associated with this disorder have not been clearly defined.
MATERIALS AND METHODS: We conducted a retrospective analysis of 4019 patients treated with intravenous bisphosphonates between 1996 and 2004. Our goals were to estimate the frequency, understand the clinical presentation, and identify risk factors associated with ONJ development.
RESULTS: Sixteen of 1338 patients with breast cancer (1.2%) and 13 of 548 patients with multiple myeloma (2.4%) developed ONJ. The median dose and duration of treatment with pamidronate or zoledronic acid were significantly higher in patients with ONJ (p < 0.0001). Multivariate Cox proportional hazards regression analysis identified treatment with zoledronic acid (hazards ratio [HR], 15.01; 95% CI: 2.41-93.48; p = 0.0037), treatment with pamidronate followed by zoledronic acid (HR, 4.00; 95% CI: 0.86-18.70; p = 0.078), and dental extractions (HR, 53.19; 95% CI: 18.20-155.46; p < 0.0001) as significant risks for ONJ in breast cancer. In multiple myeloma, dental extractions (HR, 9.78; 95% CI: 3.07-31.14; p = 0.0001) and osteoporosis (HR, 6.11; 95% CI: 1.56-23.98; p = 0.0095) were significant risk factors while controlling for bisphosphonate therapy. Thirteen of 29 patients were followed for a median of 17.1 mo (range, 7-67 mo); lesions healed in 3 patients during this period.
CONCLUSIONS: ONJ is an uncommon but long-lasting disorder that occurs mainly in breast cancer and multiple myeloma patients treated with intravenous bisphosphonates. High cumulative doses of bisphosphonates, poor oral health, and dental extractions may be significant risk factors for ONJ development. ONJ resolved in 23% of patients with conservative therapy.

PMID 18558816  J Bone Miner Res. 2008 Jun;23(6):826-36. doi: 10.1359/j・・・
著者: Ashraf Badros, Dianna Weikel, Andrew Salama, Olga Goloubeva, Abraham Schneider, Aaron Rapoport, Robert Fenton, Natalie Gahres, Edward Sausville, Robert Ord, Timothy Meiller
雑誌名: J Clin Oncol. 2006 Feb 20;24(6):945-52. doi: 10.1200/JCO.2005.04.2465.
Abstract/Text PURPOSE: To describe the clinical, radiologic, and pathologic features and risk factors for osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients.
PATIENTS AND METHODS: A retrospective review of 90 MM patients who had dental assessments, including 22 patients with ONJ. There were 62 men; the median age was 61 years in ONJ patients and 58 years among the rest. Prior MM therapy included thalidomide (n = 67) and stem-cell transplantation (n = 72). Bisphosphonate therapy included zoledronate (n = 34) or pamidronate (n = 17) and pamidronate followed by zoledronate (n = 33). Twenty-seven patients had recent dental extraction, including 12 patients in the ONJ group. Median time from MM diagnosis to ONJ was 8.4 years for the whole group.
RESULTS: Patients usually presented with pain. ONJ occurred posterior to the cuspids (n = 20) mostly in the mandible. Debridement and sequestrectomy with primary closure were performed in 14 patients; of these, four patients had major infections and four patients had recurrent ONJ. Bone histology revealed necrosis and osteomyelitis. Microbiology showed actinomycetes (n = 7) and mixed bacteria (n = 9). More than a third of ONJ patients also suffered from long bone fractures (n = 4) and/or avascular necrosis of the hip (n = 4). The variables predictive of developing ONJ were dental extraction (P = .009), treatment with pamidronate/zoledronate (P = .009), longer follow-up time (P = .03), and older age at diagnosis of MM (P = .006).
CONCLUSION: ONJ appears to be time-dependent with higher risk after long-term use of bisphosphonates in older MM patients often after dental extractions. No satisfactory therapy is currently available. Trials addressing the benefits/risks of continuing bisphosphonate therapy are needed.

PMID 16484704  J Clin Oncol. 2006 Feb 20;24(6):945-52. doi: 10.1200/JC・・・
著者: Robert E Marx, Yoh Sawatari, Michel Fortin, Vishtasb Broumand
雑誌名: J Oral Maxillofac Surg. 2005 Nov;63(11):1567-75. doi: 10.1016/j.joms.2005.07.010.
Abstract/Text PURPOSE: Bisphosphonates inhibit bone resorption and thus bone renewal by suppressing the recruitment and activity of osteoclasts thus shortening their life span. Recently three bisphosphonates, Pamidronate (Aredia; Novartis Pharmaceuticals, East Haven, NJ), Zoledronate (Zometa; Novartis Pharmaceuticals), and Alendronate (Fosamax; Merck Co, West Point, VA) have been linked to painful refractory bone exposures in the jaws.
MATERIALS AND METHODS: One hundred-nineteen total cases of bisphosphonate-related bone exposure were reviewed.
RESULTS: Thirty-two of 119 patients (26%) received Aredia, 48 (40.3%) received Zometa, 36 (30.2%) received Aredia later changed to Zometa, and 3 (2.5%) received Fosamax. The mean induction time for clinical bone exposure and symptoms was 14.3 months for those who received Aredia, 12.1 months for those who received both, 9.4 months for those who received Zometa, and 3 years for those who received Fosamax. Sixty-two (52.1%) were treated for multiple myeloma, 50 (42%) for metastatic breast cancer, 4 (3.4%) for metastatic prostate cancer and 3 (2.5%) for osteoporosis. Presenting findings in addition to exposed bone were 37 (31.1%) asymptomatic, 82 (68.9%) with pain, 28 (23.5%) mobile teeth, and 21 (17.6%) with nonhealing fistulas. Eighty-one (68.1%) bone exposures occurred in the mandible alone, 33 (27.7%) in the maxilla, and 5 (4.2%) occurred in both jaws. Medical comorbidities included the malignancy itself 97.5%, previous and/or maintenance chemotherapy 97.5%, Dexamethasone 59.7%. Dental comorbidities included the presence of periodontitis 84%, dental caries 28.6%, abscessed teeth 13.4% root canal treatments 10.9%, and the presence of mandibular tori 9.2%. The precipitating event that produced the bone exposures were spontaneous 25.2%, tooth removals 37.8%, advanced periodontitis 28.6%, periodontal surgery 11.2%, dental implants 3.4% and root canal surgery 0.8%.
CONCLUSIONS: Complete prevention of this complication in not currently possible. However, pre-therapy dental care reduces this incidence, and non-surgical dental procedures can prevent new cases. For those who present with painful exposed bone, effective control to a pain free state without resolution of the exposed bone is 90.1% effective using a regimen of antibiotics along with 0.12% chlorohexidine antiseptic mouth.

PMID 16243172  J Oral Maxillofac Surg. 2005 Nov;63(11):1567-75. doi: 1・・・
著者: M A Dimopoulos, E Kastritis, C Bamia, I Melakopoulos, D Gika, M Roussou, M Migkou, E Eleftherakis-Papaiakovou, D Christoulas, E Terpos, A Bamias
雑誌名: Ann Oncol. 2009 Jan;20(1):117-20. doi: 10.1093/annonc/mdn554. Epub 2008 Aug 9.
Abstract/Text BACKGROUND: Osteonecrosis of the jaw (ONJ) is a well-described complication of bisphosphonates use in patients with multiple myeloma (MM). We investigated whether the occurrence of ONJ decreased after the implementation of preventive measures in 128 patients with MM who received zoledronic acid.
PATIENTS AND METHODS: Patients with MM who received zoledronic acid were included in this analysis. Patients with a previous use of other bisphosphonates were excluded; patients were stratified into group A (n=38) and group B (n=90) if treatment was started before or after the implementation of preventive measures.
RESULTS: One hundred and twenty-eight patients were included in this analysis. Sixteen patients (12.5%) developed ONJ--group A: 8 (26.3%), group B: 2 (6.7%) (P=0.002). The incidence rate (IR) was 0.671/100 person-months for group A and 0.230/100 person-months for group B [IR ratio 2.92, P=0.029, 95% confidence interval 1.06-8.03]. No patient in group B developed stage III ONJ.
CONCLUSION: In conclusion, the risk of developing ONJ after treatment of zoledronic acid is reduced (but not deleted) by the implementation of preventive measures.

PMID 18689864  Ann Oncol. 2009 Jan;20(1):117-20. doi: 10.1093/annonc/m・・・
著者: S J Silverberg, E Shane, T P Jacobs, E Siris, J P Bilezikian
雑誌名: N Engl J Med. 1999 Oct 21;341(17):1249-55. doi: 10.1056/NEJM199910213411701.
Abstract/Text BACKGROUND AND METHODS: In the United States, most patients with primary hyperparathyroidism have few or no symptoms. The need for parathyroidectomy to treat all patients with this disorder has therefore been questioned. We studied the clinical course and development of complications for periods of up to 10 years in 121 patients with primary hyperparathyroidism, 101 (83 percent) of whom were asymptomatic. There were 30 men and 91 women (age range, 20 to 79 years). During the study, 61 patients (50 percent) underwent parathyroidectomy, and 60 patients were followed without surgery.
RESULTS: Parathyroidectomy in patients with or without symptoms led to normalization of serum calcium concentrations and a mean (+/-SE) increase in lumbar-spine bone mineral density of 8+/-2 percent after 1 year (P=0.005) and 12+/-3 percent after 10 years (P=0.03). Bone mineral density of the femoral neck increased 6+/-1 percent after 1 year (P=0.002) and 14+/-4 percent after 10 years (P=0.002). Bone mineral density of the radius did not change significantly. The 52 asymptomatic patients who did not undergo surgery had no change in serum calcium concentration, urinary calcium excretion, or bone mineral density. However, 14 of these 52 patients (27 percent) had progression of disease, defined as the development of at least one new indication for parathyroidectomy. All 20 patients with symptoms had kidney stones. None of the 12 who underwent parathyroidectomy had recurrent kidney stones, whereas 6 of the 8 patients who did not undergo surgery did have a recurrence.
CONCLUSIONS: In patients with primary hyperparathyroidism, parathyroidectomy results in the normalization of biochemical values and increased bone mineral density. Most asymptomatic patients who did not undergo surgery did not have progression of disease, but approximately one quarter of them did have some progression.

PMID 10528034  N Engl J Med. 1999 Oct 21;341(17):1249-55. doi: 10.1056・・・
著者: Mishaela R Rubin, John P Bilezikian, Donald J McMahon, Thomas Jacobs, Elizabeth Shane, Ethel Siris, Julia Udesky, Shonni J Silverberg
雑誌名: J Clin Endocrinol Metab. 2008 Sep;93(9):3462-70. doi: 10.1210/jc.2007-1215. Epub 2008 Jun 10.
Abstract/Text CONTEXT: Primary hyperparathyroidism (PHPT) often presents without classical symptoms such as overt skeletal disease or nephrolithiasis. We previously reported that calciotropic indices and bone mineral density (BMD) are stable in untreated patients for up to a decade, whereas after parathyroidectomy, normalization of biochemistries and increases in BMD ensue.
OBJECTIVE: The objective of the study was to provide additional insights in patients with and without surgery for up to 15 yr.
DESIGN: The study had an observational design.
SETTING: The setting was a referral center.
PATIENTS: Patients included 116 patients (25 men, 91 women); 99 (85%) were asymptomatic.
INTERVENTION: Fifty-nine patients (51%) underwent parathyroidectomy and 57 patients were followed up without surgery.
MAIN OUTCOME MEASURE: BMD was measured.
RESULTS: Lumbar spine BMD remained stable for 15 yr. However, BMD started to fall at cortical sites even before 10 yr, ultimately decreasing by 10 +/- 3% (mean +/- sem; P < 0.05) at the femoral neck, and 35 +/- 5%; P < 0.05 at the distal radius, in the few patients observed for 15 yr. Thirty-seven percent of asymptomatic patients showed disease progression (one or more new guidelines for surgery) at any time point over the 15 yr. Meeting surgical criteria at baseline did not predict who would have progressive disease. BMD increases in patients who underwent surgery were sustained for the entire 15 yr.
CONCLUSIONS: Parathyroidectomy led to normalization of biochemical indices and sustained increases in BMD. Without surgery, PHPT progressed in one third of individuals over 15 yr; meeting surgical criteria at the outset did not predict this progression. Cortical bone density decreased in the majority of subjects with additional observation time points and long-term follow-up. These results raise questions regarding how long patients with PHPT should be followed up without intervention.

PMID 18544625  J Clin Endocrinol Metab. 2008 Sep;93(9):3462-70. doi: 1・・・
著者: John P Bilezikian, Aliya A Khan, John T Potts, Third International Workshop on the Management of Asymptomatic Primary Hyperthyroidism
雑誌名: J Clin Endocrinol Metab. 2009 Feb;94(2):335-9. doi: 10.1210/jc.2008-1763.
Abstract/Text OBJECTIVE: Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The purpose of this report is to guide the use of diagnostics and management for this condition in clinical practice.
PARTICIPANTS: Interested professional societies selected representatives for the consensus committee and provided funding for a one-day meeting. A subgroup of this committee set the program and developed key questions for review. Consensus was established at a closed meeting that followed and at subsequent discussions.
EVIDENCE: Each question was addressed by a relevant literature search (on PubMed), and the data were presented for discussion at the group meeting.
CONSENSUS PROCESS: Consensus was achieved by a group meeting. Statements were prepared and reviewed by all authors who represented the Planning Committee and the participating professional societies.

PMID 19193908  J Clin Endocrinol Metab. 2009 Feb;94(2):335-9. doi: 10.・・・
著者: D P Beall, R H Scofield
雑誌名: Medicine (Baltimore). 1995 Mar;74(2):89-96.
Abstract/Text Milk-alkali syndrome can be caused by ingesting large amounts of calcium carbonate. Coincident with the promotion of calcium carbonate as treatment for both dyspepsia and osteoporosis, milk-alkali syndrome is now a common cause of hypercalcemia severe enough to require admission to the hospital. The syndrome accounted for less than 2% of such admissions before 1990, but from 1990 through 1993, it was the cause of hypercalcemia for over 12% of these patients. Only primary hyperparathyroidism and hypercalcemia of malignancy (excluding multiple myeloma) are more common. The diagnosis of milk-alkali syndrome is made almost entirely based on the patient's history; careful attention to dietary practices and over-the-counter drug use is required, as numerous over-the-counter medications contain calcium carbonate. Modern assays for PTH demonstrate the expected suppression of PTH by hypercalcemia. Nonetheless, measurement of PTH must be performed in a timely manner as treatment with intravenous saline may result in hypocalcemia and elevated PTH soon after admission. Given the pathophysiology of milk-alkali syndrome compared to other causes of hypercalcemia, hypocalcemia with rebound hyperparathyroidism is probably unique to milk-alkali syndrome.

PMID 7891547  Medicine (Baltimore). 1995 Mar;74(2):89-96.
著者: K D Burman, J M Monchik, J M Earll, L Wartofsky
雑誌名: Ann Intern Med. 1976 Jun;84(6):668-71.
Abstract/Text Total and ionized calcium concentrations as well as parathyroid hormone levels were measured in a group of hyperthyroid persons. Ionized and total calcium levels were elevated in 21 of 45 (47%) and in 12 of 45 (27%) thyrotoxic patients, respectively. Mean ionized and total calcium levels were higher in these 45 patients than in normal persons. Using two different radioimmunoassay systems for a total of 44 determinations, mean parathyroid hormone levels were lower in thyrotoxic patients than in subjects with proved hyperparathyroidism. These data suggest that [1] elevations of both ionized and total calcium concentrations occur frequently in thyrotoxic patients; [2] ionized calcium concentrations may be elevated in a higher percentage of hyperthyroid subjects than are total calcium concentrations; and [3] the hypercalcemia associated with thyrotoxicosis is not associated with elevated parathyroid hormone levels.

PMID 937877  Ann Intern Med. 1976 Jun;84(6):668-71.
著者: F Llach, A J Felsenfeld, M R Haussler
雑誌名: N Engl J Med. 1981 Jul 16;305(3):117-23. doi: 10.1056/NEJM198107163050301.
Abstract/Text We studied six oliguric patients with rhabdomyolysis-induced acute renal failure. On admission, all had marked hyperphosphatemia and hypocalcemia associated with low levels of 1,25-dihydroxycholecalciferol [1,25(OH)2D]. During the early polyuric phase, moderate hypercalcemia was accompanied by marked elevations in plasma 1,25(OH)2D and persistent elevations in parathyroid hormone (both amino and carboxy terminals). During the late polyuric phase, the levels of serum calcium and 1,25(OH)2D reverted to normal. Thus, in rhabdomyolysis-induced acute renal failure, the hypocalcemia of the oliguric phase may be secondary to decreased synthesis of 1,25(OH)2D; severe hyperphosphatemia may also have a major role. The hypercalcemia of the polyuric phase may be partly due to increased synthesis of 1,25(OH)2D, resulting from the high parathyroid hormone levels and recovery of renal function.

PMID 6894630  N Engl J Med. 1981 Jul 16;305(3):117-23. doi: 10.1056/N・・・
著者: M J Jamieson
雑誌名: Br Med J (Clin Res Ed). 1985 Feb 2;290(6465):378-82.
Abstract/Text
PMID 3917827  Br Med J (Clin Res Ed). 1985 Feb 2;290(6465):378-82.
著者: Michalis K Picolos, Victor R Lavis, Philip R Orlander
雑誌名: Clin Endocrinol (Oxf). 2005 Nov;63(5):566-76. doi: 10.1111/j.1365-2265.2005.02383.x.
Abstract/Text OBJECTIVE: Milk-alkali syndrome, once a common cause of hypercalcaemia, is now considered rare. Our aim was to estimate the prevalence of milk-alkali syndrome among hypercalcaemic, non-end-stage renal disease (non-ESRD) inpatients of a University Hospital and identify patients' and syndrome characteristics.
DESIGN AND PATIENTS: In this retrospective chart review study, we identified patients hospitalized with possible hypercalcaemia between November 1998 and October 2003 by a computer search of admission, discharge and consultation diagnoses. Patients with renal transplantation, stage 5 chronic kidney disease (CKD-5) and those admitted for parathyroidectomy were excluded. The remaining patients' charts were reviewed for confirmation of hypercalcaemia and identification of the cause. In patients with milk-alkali syndrome, additional historical, clinical, laboratory and imaging data were collected.
RESULTS: We identified 125 patients with hypercalcaemia, 11 (8.8%) of whom had milk-alkali syndrome, 42 (33.6%) had malignancy and 37 (29.6%) hyperparathyroidism. Thirty-five patients had severe hypercalcaemia, defined as corrected serum calcium 3.5 mmol/l. Malignancy accounted for 13 of those patients (37.1%) and milk-alkali for nine (25.7%). Conditions prevalent among the milk-alkali inpatients were female gender, hypertension, chronic kidney disease, osteoporosis, upper gastrointestinal diseases, diuretic treatment and vitamin D derivative supplementation. Five of the patients with milk-alkali syndrome were treated with bisphosphonates and all five developed hypocalcaemia, compared to one of the five who received conventional treatment (P = 0.047).
CONCLUSION: Milk-alkali was the third leading cause of hypercalcaemia of any degree and the second cause of severe hypercalcaemia among inpatients without ESRD. In milk-alkali syndrome, treatment with bisphosphonates contributes to post-treatment hypocalcaemia.

PMID 16268810  Clin Endocrinol (Oxf). 2005 Nov;63(5):566-76. doi: 10.1・・・
著者: Ghada El-Hajj Fuleihan
雑誌名: J Bone Miner Res. 2002 Nov;17 Suppl 2:N51-6.
Abstract/Text Clinical, biochemical, and pathophysiological observations over several decades on familial benign hypocalciuric hypercalcemia (FBHH) ultimately culminated in the 1990s in the unraveling of the genetic basis of this calcium-sensing familial disorder. An intuitive pursuit of the pathophysiology of this "experiment of nature" in a series of elegant molecular biological studies linked FBHH, in the majority of cases, to the short arm of chromosome 3 (FBHH3q), where the calcium-sensing receptor (CaSR) is located. FBHH is a rare autosomal dominant disorder exhibiting benign hypercalcemia, inappropriately normal parathyroid hormone (PTH) levels, and relative hypocalciuria, thus reflecting partial resistance to the normal effects of extracellular calcium on parathyroid glands and kidneys. Patients with FBHH are asymptomatic, and if diagnosed at an early age, seem to have normal longevity and usually do not suffer any of the skeletal (demineralization or fractures) or renal complications of classical primary hyperparathyroidism. Before an adequate recognition of the syndrome, patients with FBHH were misdiagnosed as having primary hyperparathyroidism and may have been subjected to unnecessary and unsuccessful parathyroidectomy. FBHH3q seems to be, in the majority of cases, the clinical manifestation of heterozygous reduction or loss of CaSR function in the parathyroid glands and renal tubules. In general, in view of the benign nature of FBHH, no particular intervention is needed except reassurance and counseling against parathyroidectomy.

PMID 12412778  J Bone Miner Res. 2002 Nov;17 Suppl 2:N51-6.
著者: S J Marx, J L Stock, M F Attie, R W Downs, D G Gardner, E M Brown, A M Spiegel, J L Doppman, M F Brennan
雑誌名: Ann Intern Med. 1980 Mar;92(3):351-6.
Abstract/Text Of 67 patients referred after unsuccessful surgery for presumed primary hyperparathyroidism, six were shown to be members of kindreds with familial hypocalciuric hypercalcemia. This diagnosis had not been recognized in any of the six previosuly. Most of the remaining 61 cases had proven or probable typical primary hyperparathyroidism, and a subgroup of four had hypercalcemia with suppression of the parathyroid glands. Urine calcium excretion expressed as the calcium:creatinine clearance ratio provided an easily measurable and effective index to separate the groups with familial hypocalciuric hypercalcemia, typical primary hyperparathyroidism, and suppressed parathyroids. Thus, at least 9% of patients referred after unsuccessful parathyroidectomy had familial hypocalciuric hypercalcemia. The assessment of urine calcium excretion by indices such as the calcium:creatinine clearance ratio should facilitate recognition of this condition, which responds poorly to standard subtotal parathyroidectomy.

PMID 7356229  Ann Intern Med. 1980 Mar;92(3):351-6.
著者: Peter H Nissen, Signe E Christensen, Lene Heickendorff, Kim Brixen, Leif Mosekilde
雑誌名: J Clin Endocrinol Metab. 2007 Nov;92(11):4373-9. doi: 10.1210/jc.2007-0322. Epub 2007 Aug 14.
Abstract/Text CONTEXT: The autosomal dominantly inherited condition familial hypocalciuric hypercalcemia (FHH) is characterized by elevated plasma calcium levels, relative or absolute hypocalciuria, and normal to moderately elevated plasma PTH. The condition is difficult to distinguish clinically from primary hyperparathyroidism and is caused by inactivating mutations in the calcium sensing receptor (CASR) gene.
OBJECTIVE: We sought to define the mutation spectrum of the CASR gene in a Danish FHH population and to establish genotype-phenotype relationships regarding the different mutations.
DESIGN AND PARTICIPANTS: A total of 213 subjects clinically suspected to have FHH, and 121 subjects enrolled as part of a family-screening program were studied. Genotype-phenotype relationships were established in 66 mutation-positive index patients and family members.
MAIN OUTCOME MEASURES: We determined CASR gene mutations, and correlating levels of plasma calcium (albumin corrected), ionized calcium (pH 7.4), and PTH were measured.
RESULTS: We identified 22 different mutations in 39 FHH families. We evaluated data on circulating calcium and PTH for 11 different mutations, representing a spectrum of clinical phenotypes, ranging from calcium concentrations moderately above the upper reference limit, to calcium levels more than 20% above the upper reference limit. Furthermore, the mean plasma PTH concentration was within the normal range in eight of 11 studied mutations, but mild to moderately elevated in families with the mutations p.C582Y, p.C582F, and p.G553R.
CONCLUSIONS: The present data add 19 novel mutations to the catalog of inactivating CASR mutations and illustrate a variety of biochemical phenotypes in patients with the molecular genetic diagnosis FHH.

PMID 17698911  J Clin Endocrinol Metab. 2007 Nov;92(11):4373-9. doi: 1・・・

ページ上部に戻る

戻る

さらなるご利用にはご登録が必要です。

こちらよりご契約または優待日間無料トライアルお申込みをお願いします。

(※トライアルご登録は1名様につき、一度となります)


ご契約の場合はご招待された方だけのご優待特典があります。

以下の優待コードを入力いただくと、

契約期間が通常12ヵ月のところ、14ヵ月ご利用いただけます。

優待コード: (利用期限:まで)

ご契約はこちらから