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原発性副甲状腺機能亢進症

著者: 山内美香 医療法人社団栄宏会小野病院 骨代謝疾患研究所

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

著者校正済:2021/03/24
現在監修レビュー中
患者向け説明資料

概要・推奨   

  1. 原発性副甲状腺機能亢進症(pHPT)は、副甲状腺に発生した腺腫や過形成あるいは癌から副甲状腺ホルモン(PTH)が自律的かつ過剰に分泌され高Ca血症を来す疾患である。
  1. Ca血症副甲状腺ホルモンが高値場合、リチウム製剤などの投与、および家族性低Ca尿性高Ca血症(FHH)が除外できれば原発性副甲状腺機能亢進症と診断できる。
  1. 原発性副甲状腺機能亢進症患者と家族性低Ca尿性高Ca血症の鑑別には塩酸二分蓄尿下でのCCa/CCrが推奨される(推奨度2)
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  1. 副甲状腺腺腫の局在診断における99mTc-methoxy-isobutyl-isonitrile(MIBI)シンチグラフィの有用性が示されている。特に異所性副甲状腺腺腫を疑った場合は本検査を行うことが推奨される(推奨度2)。
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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:
山内美香 : 特に申告事項無し[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. 定期レビューを行い、加筆修正を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 副甲状腺機能亢進症とは、副甲状腺ホルモン(PTH)の慢性的分泌過剰状態により生じる代謝異常を称する。
  1. このうち、副甲状腺に発生した腺腫や過形成あるいは癌から副甲状腺ホルモンが自律的かつ過剰に分泌され高Ca血症を来したものが、原発性副甲状腺機能亢進症(pHPT)である。
  1. わが国では約2,000~3,000人に1人程度とされているが、診断されていない無症候性例がかなり存在している可能性がある。
  1.  腎結石症・尿管結石症 や 骨粗鬆症 を来すことから、これらをきっかけに本疾患が診断されることも多い。
病歴・診察のポイント  
  1. 本疾患の症状は、高Ca血症による症状が主である。ただし、高Ca血症による症状は非特異的なものが多いうえに、軽度の高Ca血症ではほとんど自覚症状が認められないため、血清Ca値の測定が必須である。

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文献 

著者: Signe Engkjaer Christensen, Peter H Nissen, Peter Vestergaard, Lene Heickendorff, Kim Brixen, Leif Mosekilde
雑誌名: Clin Endocrinol (Oxf). 2008 Nov;69(5):713-20. doi: 10.1111/j.1365-2265.2008.03259.x. Epub 2008 Apr 10.
Abstract/Text BACKGROUND: Familial hypocalciuric hypercalcaemia (FHH) must be differentiated from primary hyperparathyroidism (PHPT) because prognosis and treatment differ. In daily practice this discrimination is often based on the renal calcium excretion or the calcium/creatinine clearance ratio (CCCR). However, the diagnostic performance of these variables is poorly documented.
AIM: To appraise the power of various simple biochemical variables to differentiate between FHH and PHPT using calcium sensing receptor (CASR) gene analysis and histopathological findings as gold standards.
DESIGN: Follow-up approach (direct design).
MATERIALS: We included 54 FHH patients (17 males and 37 females, aged 18-75 years) with clinically significant mutations in the CASR gene and 97 hypercalcaemic patients with histologically verified PHPT (17 males and 80 females, aged 19-86 years). All PHPT patients became normocalcaemic following successful neck exploration.
RESULTS: Based on receiver operating characteristic (ROC) curve analysis, the CCCR was only marginally better, as judged by the area under curve (AUC = 0.923 +/- 0.021 (SE)), than the 24-h calcium/creatinine excretion ratio (AUC = 0.903 +/- 0.027) and the 24-h calcium excretion (AUC = 0.876 +/- 0.029). However, overlap performance analysis disclosed that the CCCR included fewer patients with PHPT together with the FHH patients than the other two variables at different cut-off points. Based on the ROC curve, the optimal cut-off point for diagnosing FHH using CCCR was < 0.0115, which yielded a diagnostic specificity of 0.88 and a sensitivity of 0.80. Overlap analysis revealed that a cut-off point for CCCR at < 0.020 would sample 98% (53/54) of all patients with FHH and include 35% (34/97) of the PHPT patients.
CONCLUSION: Our results support the use of the CCCR as an initial screening test for FHH. We suggest a two-step diagnostic procedure, where the first step is based on the CCCR with a cut-off at < 0.020, and the second step is CASR gene analysis in patients with FHH or PHPT.

PMID 18410554  Clin Endocrinol (Oxf). 2008 Nov;69(5):713-20. doi: 10.1・・・
著者: Richard Eastell, Maria Luisa Brandi, Aline G Costa, Pierre D'Amour, Dolores M Shoback, Rajesh V Thakker
雑誌名: J Clin Endocrinol Metab. 2014 Oct;99(10):3570-9. doi: 10.1210/jc.2014-1414. Epub 2014 Aug 27.
Abstract/Text OBJECTIVE: Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The purpose of this report is to provide an update on the use of diagnostic tests for this condition in clinical practice.
PARTICIPANTS: This subgroup was constituted by the Steering Committee to address key questions related to the diagnosis of PHPT. Consensus was established at a closed meeting of the Expert Panel that followed.
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 by all authors, with comments relating to accuracy from the diagnosis subgroup and by representatives from the participating professional societies.
CONCLUSIONS: We conclude that: 1) reference ranges should be established for serum PTH in vitamin D-replete healthy individuals; 2) second- and third-generation PTH assays are both helpful in the diagnosis of PHPT; 3) normocalcemic PHPT is a variant of the more common presentation of PHPT with hypercalcemia; 4) serum 25-hydroxyvitamin D concentrations should be measured and, if vitamin D insufficiency is present, it should be treated as part of any management course; 5) genetic testing has the potential to be useful in the differential diagnosis of familial hyperparathyroidism or hypercalcemia.

PMID 25162666  J Clin Endocrinol Metab. 2014 Oct;99(10):3570-9. doi: 1・・・
著者: Etienne Cavalier, Adrian F Daly, Daniela Betea, Pamela Nicoleta Pruteanu-Apetrii, Pierre Delanaye, Phil Stubbs, Arthur R Bradwell, Jean-Paul Chapelle, Albert Beckers
雑誌名: J Clin Endocrinol Metab. 2010 Aug;95(8):3745-9. doi: 10.1210/jc.2009-2791. Epub 2010 Jun 2.
Abstract/Text BACKGROUND: Parathyroid carcinoma (PCa) is a rare disease that can be difficult to differentiate initially from severe benign parathyroid adenoma. PCa oversecrete the amino form of PTH, which is recognized by third-generation but not by second-generation PTH immunoassays. In normal individuals, the third-generation to second-generation PTH ratio should be less than 1.
OBJECTIVE: Our objective was to study the utility of the third-generation to second-generation PTH ratio as a means of distinguishing PCa patients (n=24) from control groups with and without disorders of calcium secretion, including patients on renal hemodialysis (n=74), postrenal transplantation (n=60), and primary hyperparathyroidism (PHP; n=30).
SETTING AND DESIGN: We conducted a retrospective, laboratory-based study at tertiary referral academic centers.
RESULTS: The mean third-generation to second-generation ratio was 0.58+/-0.10 in the dialysis patients, 0.54+/-0.10 in the renal transplant group, 0.54+/-0.12 in the elderly healthy patients, and 0.68+/-0.11 in the PHP group. All 245 of these patients presented a PTH third-generation to second-generation ratio of less than 1. In contrast, we observed an inverted third-generation to second-generation PTH ratio of more than one in 20 PCa patients, whereas only four PCa patients had a normal ratio of less than 1.
CONCLUSIONS: An inverted third-generation to second-generation PTH ratio occurred in the majority of patients with advanced PCa and was absent in all 245 relevant controls. A third-generation to second-generation PTH ratio higher than 1 had a sensitivity of 83.3% and a specificity of 100% among PHP patients as a marker for PCa. This ratio may be useful to identify patients with PCa earlier and to detect patients either at risk of developing PCa or those in whom recurrence is taking place.

PMID 20519352  J Clin Endocrinol Metab. 2010 Aug;95(8):3745-9. doi: 10・・・
著者: James M Ruda, Christopher S Hollenbeak, Brendan C Stack
雑誌名: Otolaryngol Head Neck Surg. 2005 Mar;132(3):359-72. doi: 10.1016/j.otohns.2004.10.005.
Abstract/Text OBJECTIVE: To systematically review the current preoperative diagnostic modalities, surgical treatments, and glandular pathologies associated with primary hyperparathyroidism.
STUDY DESIGN: A systematic literature review.
RESULTS: Of the 20,225 cases of primary hyperparathyroidism reported, solitary adenomas (SA), multiple gland hyperplasia disease (MGHD), double adenomas (DA), and parathyroid carcinomas (CAR) occurred in 88.90%, 5.74%, 4.14%, and 0.74% of cases respectively. Tc 99m -sestamibi and ultrasound were 88.44% and 78.55% sensitive, respectively, for SA, 44.46% and 34.86% for MGHD, and 29.95% and 16.20% for DA, respectively. Postoperative normocalcemia was achieved in 96.66%, 95.25%, and 97.69% of patients offered minimally invasive radio-guided parathyroidectomy (MIRP), unilateral, and bilateral neck exploration (BNE). Intraoperative PTH assays (IOPTH) were helpful in approximately 60% of bilateral neck exploration conversion (BNEC) surgeries.
CONCLUSION: The overall prevalence of multiple gland disease (MGD and DA) was lower than often suggested by conventional wisdom. Furthermore, preoperative imaging was less accurate than it is often perceived for accurately imaging MGD. MIRP and UNE were more successful in achieving normocalcemia than is typically quoted. IOPTH was a helpful but not "fool-proof" adjunct in parathyroid exploration surgery.
SIGNIFICANCE: These results support a greater role for the treatment of primary hyperparathyroidism using less invasive approaches. EMB rating: B-3.

PMID 15746845  Otolaryngol Head Neck Surg. 2005 Mar;132(3):359-72. doi・・・
著者: Nathan A Johnson, Sally E Carty, Mitchell E Tublin
雑誌名: Radiol Clin North Am. 2011 May;49(3):489-509, vi. doi: 10.1016/j.rcl.2011.02.009.
Abstract/Text Primary hyperparathyroidism is a common endocrine disorder caused by the overproduction of parathyroid hormone either by a single adenomatous gland or by multiple adenomatous or hyperplastic glands. Surgical resection of the abnormal parathyroid glands is the standard treatment, the goal of initial parathyroidectomy being durable biochemical cure. Surgeons have recently shifted to more minimally invasive and selective techniques for parathyroid exploration. More selective surgical approaches rely on accurate preoperative imaging techniques to localize abnormal parathyroid glands. It is imperative that radiologists are familiar with imaging features of parathyroid glands as well as the role of imaging in patient care.

Copyright © 2011 Elsevier Inc. All rights reserved.
PMID 21569907  Radiol Clin North Am. 2011 May;49(3):489-509, vi. doi: ・・・
著者: John W Kunstman, Jonathan D Kirsch, Amit Mahajan, Robert Udelsman
雑誌名: J Clin Endocrinol Metab. 2013 Mar;98(3):902-12. doi: 10.1210/jc.2012-3168. Epub 2013 Jan 23.
Abstract/Text CLINICAL CONTEXT: The prevalence of hyperparathyroidism, especially primary hyperparathyroidism, has increased in recent decades due to improvements in diagnostic techniques with a corresponding surge in parathyroid surgery, leading to the development of focused, minimally invasive surgical approaches. Focused parathyroidectomy is predicated on preoperative localization of suspected parathyroid pathology. As a result, there has been a proliferation of parathyroid imaging modalities and protocols, resulting in confusion about their indications and applications.
EVIDENCE ACQUISITION: Bibliographies from clinical trials and review articles published since 2000 were reviewed and supplemented with targeted searches using biomedical databases. We also employed our extensive clinical experience.
EVIDENCE SYNTHESIS: The best-studied modalities for parathyroid localization are nuclear scintigraphy and sonography and are widely applied as initial studies. Multiple variations exist, and several additional noninvasive imaging techniques, such as computed tomography and magnetic resonance, are described. The exquisite anatomical detail of 4-dimensional computed tomography must be balanced with significant radiation exposure to the thyroid gland. Invasive venous PTH sampling and parathyroid arteriography have important roles in remedial cases. Due to considerable heterogeneity in imaging, multidisciplinary collaboration between endocrinologists, surgeons, and radiologists is beneficial.
CONCLUSIONS: Parathyroid localization is indicated in surgical candidates. Crucial considerations when selecting an imaging study include availability, cost, radiation exposure, local expertise, and accuracy. Additional factors include the patient's anticipated pathology and whether it is de novo or refractory disease. An approach to imaging for patients with primary hyperparathyroidism is presented.

PMID 23345096  J Clin Endocrinol Metab. 2013 Mar;98(3):902-12. doi: 10・・・
著者: Neil D Gross, Jane L Weissman, Elizabeth Veenker, James I Cohen
雑誌名: Laryngoscope. 2004 Feb;114(2):227-31. doi: 10.1097/00005537-200402000-00010.
Abstract/Text OBJECTIVES/HYPOTHESIS: Successful unilateral or minimal-access parathyroid exploration and reoperative surgery of the parathyroid glands requires accurate preoperative localization of parathyroid disease. Although ultrasound and nuclear imaging techniques have an established role in this regard, the use of computed tomography (CT) for parathyroid exploration is not well understood. The purpose of the present study was to better define the diagnostic utility of CT in preoperative localization of the abnormal gland in surgery for hyperparathyroidism.
STUDY DESIGN: Retrospective cohort study.
METHODS: All parathyroid explorations performed at Oregon Health and Science University (Portland, OR) between 2000 and 2002 were reviewed. The study group was limited to patients with hyperparathyroidism in whom localization failed preoperatively using ultrasound and/or sestamibi scanning and subsequent investigation using CT imaging was performed. Operative, pathological, and imaging reports were then analyzed to assess the accuracy of CT imaging for localizing parathyroid disease.
RESULTS: Twenty-two patients with hyperparathyroidism were investigated preoperatively using CT imaging. Parathyroid exploration was successful in all but one patient, leaving 21 patients in all in the cohort. The majority of cases (67%) were reoperative, and all patients had previously undergone inconclusive ultrasound and/or sestamibi scanning. Computed tomography correctly localized parathyroid disease in 18 (86%) of the 21 patients who underwent successful extirpation of parathyroid disease and was able to identify abnormal glands with equal utility in the neck and the chest.
CONCLUSION: When ultrasound or sestamibi are unsuccessful, CT imaging can provide valuable preoperative localizing information before surgery for hyperparathyroidism, particularly in patients with recurrent or persistent disease.

PMID 14755195  Laryngoscope. 2004 Feb;114(2):227-31. doi: 10.1097/0000・・・
著者: Allison M Grayev, Lindell R Gentry, Michael J Hartman, Herbert Chen, Scott B Perlman, Scott B Reeder
雑誌名: Ann Surg Oncol. 2012 Mar;19(3):981-9. doi: 10.1245/s10434-011-2046-z. Epub 2011 Aug 31.
Abstract/Text PURPOSE: To investigate the use of a chemical shift-based water-fat separation magnetic resonance imaging (MRI) method, and time-resolved contrast-enhanced MRI at 3 T for improved presurgical localization of parathyroid adenomas.
METHODS: Twenty-five patients with primary hyperparathyroidism were prospectively enrolled. Patients underwent MRI, which was reviewed by two experienced neuroradiologists who were blinded to Tc-99m sestamibi imaging and operative results.
RESULTS: Overall, MRI detected 16 adenomas in 25 patients (sensitivity 64%, positive predictive value 67%), while sestamibi detected 18 of 25 adenomas (sensitivity 72%, positive predictive value 90%). Importantly, MRI was able to detect adenomas in four (57%) of the seven patients whose disease was missed by sestamibi analysis. MRI demonstrated excellent image quality and fat suppression by using a chemical shift-based water-fat separation technique. The time-resolved MRI was considered to be less helpful, although in some cases it was indispensable.
CONCLUSIONS: MRI is an excellent adjunct for preoperative parathyroid localization. The advent of improved fat suppression techniques in the neck, including chemical shift-based water-fat separation, is critical to its utility. Although time-resolved MRI was not always helpful, it was crucial in certain cases. It may prove to be more useful with the development of faster scanning techniques.

PMID 21879264  Ann Surg Oncol. 2012 Mar;19(3):981-9. doi: 10.1245/s104・・・
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: D Nakaoka, T Sugimoto, T Kobayashi, T Yamaguchi, A Kobayashi, K Chihara
雑誌名: J Clin Endocrinol Metab. 2000 May;85(5):1901-7. doi: 10.1210/jcem.85.5.6604.
Abstract/Text A major challenge in the management of primary hyperparathyroidism (pHPT) is the decision regarding which patients should undergo parathyroidectomy (PTX), although the Consensus Development Conference of the NIH has proposed guidelines for the indication of surgery. In the present study, changes in bone mineral density (BMD) after PTX were compared between pHPT patients who did and did not meet the NIH criteria, and we further tried to predict the BMD change after PTX from preoperative parameters. The subjects were 44 pHPT patients (30 women and 14 men) who had had successful PTX. Lumbar and radial BMD were measured before and 1 yr after PTX by dual energy x-ray absorptiometry and single photon absorptiometry, respectively. Average annual percent increases in lumbar and radial BMD after PTX were 12.2 +/- 1.4% and 11.6 +/- 1.6% (mean +/- SEM), respectively, and those net increases were 0.0803 +/- 0.0008 and 0.0484 +/- 0.0006 g/cm2, respectively. There were no significant differences in percent or net changes in either radial or lumbar BMD after PTX between the groups divided according to each of the NIH criteria, such as age (> or =50 and <50 yr), serum calcium level (> or =12 and <12 mg/dL) or the existence of urinary stones (presence and absence). On the other hand, when the subjects were divided on the basis of radial BMD (above and below a z-score of -2), the annual percent and net increases in lumbar BMD and percent increase in radial BMD after PTX were significantly higher in the group with the lower z-score. Next, patients were divided into two groups with and without the indication of PTX based on NIH guidelines. Twenty-nine patients had the surgical indication by meeting one or more of these criteria and 15 patients had no indication without meeting any of the criteria. There were no significant differences between the two groups in annual percent or net changes in radial or lumbar BMD after PTX. A stepwise multiple regression analysis revealed that serum alkaline phosphatase level and the severity of cortical bone mass reduction were the best predictors of both percentage and net changes in lumbar BMD, with high determination coefficients (r2 > 0.7). In conclusion, a considerable increase in BMD could be obtained after PTX even in patients without surgical indication from the NIH. Alkaline phosphatase and the severity of cortical bone mass reduction are clinically useful for predicting the changes in lumbar BMD after PTX. The present findings provide a useful clue for the indication of surgery in pHPT.

PMID 10843172  J Clin Endocrinol Metab. 2000 May;85(5):1901-7. doi: 10・・・
著者: H Ejlsmark-Svensson, L Rolighed, T Harsløf, L Rejnmark
雑誌名: Osteoporos Int. 2021 Feb 1;. doi: 10.1007/s00198-021-05822-9. Epub 2021 Feb 1.
Abstract/Text An increased risk of fractures in primary hyperparathyroidism (PHPT) has been reported in a number of relatively small studies. Performing a systematic literature search, we identified available studies and calculated common estimates by pooling results from the individual studies in a meta-analysis. Searching EMBASE and PubMed, we identified published studies reporting the risk of fractures in PHPT compared to a control group. We calculated odds ratio (OR) with 95% confidence interval (CI). A total of 804 studies were identified of which 12 studies were included. Risk of any fracture was increased compared to controls (OR 2.01; 95% CI, 1.61-2.50; I2 46%, 5 studies). Analysis of fracture risk at specific sites showed an increased risk of fracture at the forearm (OR 2.36; 95% CI, 1.64-3.38; I2 0%, 4 studies) and spine (OR 3.00; 95% CI, 1.41, 6.37, I2 88%, 9 studies). Risk estimate for hip fractures was non-significantly increased (OR 1.27; 95% CI, 0.97-1.66; I2 0%, 3 studies). Risk of vertebral fractures (VFx) was also increased if analyses were restricted to only studies with a healthy control group (OR 5.76; 95% CI, 3.86-8.60; I2 29%, 6 studies), studies including patients with mild PHPT (OR 4.22; 95% CI, 2.20-8.12; I2 57%, 4 studies) or studies including postmenopausal women (OR 8.07; 95% CI, 4.79-13.59; I2 0%, 3 studies). PHPT is associated with an increased risk of fractures. Although a number of studies are limited-it seems that the risk is increased across different skeletal sites including patients with mild PHPT and postmenopausal women.

PMID 33527175  Osteoporos Int. 2021 Feb 1;. doi: 10.1007/s00198-021-05・・・
著者: Peter Vestergaard, Leif Mosekilde
雑誌名: World J Surg. 2003 Mar;27(3):343-9. doi: 10.1007/s00268-002-6589-9. Epub 2003 Feb 27.
Abstract/Text Parathyroid hormone (PTH) increases bone turnover and may thus increase fracture risk. As PTH secretion is increased in primary hyperparathyroidism, surgical cure may prevent fractures. We studied fracture risk before and after diagnosis in patients treated surgically and conservatively for primary hyperparathyroidism. All 1201 patients with newly diagnosed primary hyperparathyroidism (PHPT) between 1982 and 1996 in Denmark were identified through the Danish Hospital Discharge Register. Each patient was compared with three age- and gender-matched controls randomly drawn from the background population. Those who were treated surgically ( n = 841; mean age 58.6 +/- 14.6 years) were significantly younger than those who were not ( n = 360; 65.5 +/- 16.8 years; 2 p < 0.01); they had higher plasma ionized calcium (1.58 +/- 0.16 vs. 1.50 +/- 0.10 mmol/L; 2 p = 0.03) and tended to have lower lumbar spine bone mineral Z-scores (-0.72 +/- 1.35 vs. 0.05 +/- 1.05; 2 p = 0.06). Before diagnosis, fracture risk was elevated in both those who subsequently underwent surgery [incidence rate ratio (IRR) 1.45, 95% CI 1.05-1.99] and in those who did not (IRR 1.59, 95% CI 1.10-2.29). After diagnosis, no difference in fracture risk was present between surgically and nonsurgically treated patients. The risk of death was significantly lower in the operated patients than in those who did not have surgery (RR 0.58, 95% CI 0.47-0.73). No differences in fracture risk could be demonstrated between those who had and those who did not have surgery, taking age, gender, and previous fractures into account.

PMID 12607064  World J Surg. 2003 Mar;27(3):343-9. doi: 10.1007/s00268・・・
著者: John P Bilezikian, Maria Luisa Brandi, Richard Eastell, Shonni J Silverberg, Robert Udelsman, Claudio Marcocci, John T Potts
雑誌名: J Clin Endocrinol Metab. 2014 Oct;99(10):3561-9. doi: 10.1210/jc.2014-1413. Epub 2014 Aug 27.
Abstract/Text OBJECTIVE: Asymptomatic primary hyperparathyroidism (PHPT) is routinely encountered in clinical practices of endocrinology throughout the world. This report distills an update of current information about diagnostics, clinical features, and management of this disease into a set of revised guidelines.
PARTICIPANTS: Participants, representing an international constituency, with interest and expertise in various facets of asymptomatic PHPT constituted four Workshop Panels that developed key questions to be addressed. They then convened in an open 3-day conference September 19-21, 2013, in Florence, Italy, when a series of presentations and discussions addressed these questions. A smaller subcommittee, the Expert Panel, then met in closed session to reach an evidence-based consensus on how to address the questions and data that were aired in the open forum.
EVIDENCE: Preceding the conference, each question was addressed by a relevant, extensive literature search. All presentations and deliberations of the Workshop Panels and the Expert Panel were based upon the latest information gleaned from this literature search.
CONSENSUS PROCESS: The expert panel considered all the evidence provided by the individual Workshop Panels and then came to consensus.
CONCLUSION: In view of new findings since the last International Workshop on the Management of Asymptomatic PHPT, guidelines for management have been revised. The revised guidelines include: 1) recommendations for more extensive evaluation of the skeletal and renal systems; 2) skeletal and/or renal involvement as determined by further evaluation to become part of the guidelines for surgery; and 3) more specific guidelines for monitoring those who do not meet guidelines for parathyroid surgery. These guidelines should help endocrinologists and surgeons caring for patients with PHPT. A blueprint for future research is proposed to foster additional investigation into issues that remain uncertain or controversial.

PMID 25162665  J Clin Endocrinol Metab. 2014 Oct;99(10):3561-9. doi: 1・・・
著者: Inga-Lena Nilsson, Li Yin, Ewa Lundgren, Jonas Rastad, Anders Ekbom
雑誌名: J Bone Miner Res. 2002 Nov;17 Suppl 2:N68-74.
Abstract/Text Primary hyperparathyroidism (PHPT) in developing countries is characterized by severe skeletal and renal complications and apparent mortality. This is in contrast with the Western hemisphere where research interests, rather than characteristics of PHPT, seem to differ between regions. In Europe, the "nontraditional" aspects of mild-to-moderate PHPT have attracted particular attention. These symptoms and signs include risk factors for cardiovascular disease such as hypertension, phenotype IV lipoproteinemia, insulin resistance, cardiac and vascular dysfunction, and morbidity in cardiovascular diseases. Mortality in cardiovascular diseases has been found to be increased in studies that include over 6500 European patients; this risk could not be verified in North American patients. By use of the nationwide Cancer Registry and Causes-of-Death Registry, mortality was analyzed in 10,995 Swedish patients (> 20 years of age) subjected to extirpation of single parathyroid adenoma of PHPT during 1958-1997. The Swedish population standardized for age, sex, and calendar year was used as control. The first postoperative year was excluded from the analysis. In total, the study included 102,515 observed person-years in the patients. Results verify an increased risk of dying after operation for PHPT (standard mortality ratio, 1.2; 95% CI, 1.19-1.27). The increased risk persisted far beyond 15 years postoperatively and occurred in both sexes and in all investigated age groups. Principal causes of excess mortality were cardiovascular diseases, diabetes mellitus, and urogenital diseases in all age groups. However, in patients operated on between 1985 and 1997 (n = 6386), overall mortality did not differ from that of the normal population, although there was maintained excess death in stroke, diabetes mellitus, and urogenital diseases. These findings infer that modern paradigms of surgical treatment normalize the risk of dying from PHPT. This improvement may be a late consequence of liberalized calcium screenings that were introduced about 30 years ago and indicate that operation at early disease stages may offer a survival advantage. An association between diabetes mellitus and PHPT is substantiated.

PMID 12412780  J Bone Miner Res. 2002 Nov;17 Suppl 2:N68-74.
著者: E Lundgren, L Lind, M Palmér, S Jakobsson, S Ljunghall, J Rastad
雑誌名: Surgery. 2001 Dec;130(6):978-85. doi: 10.1067/msy.2001.118377.
Abstract/Text BACKGROUND: The natural history of mild hyperparathyroidism is incompletely clarified.
METHODS: Consistent hypercalcemia was found in 172 patients (aged 28-86 years) participating in population-based screenings in both 1969 and 1971. Mortality until 1994 was compared with 344 matched, normocalcemic controls from the study population. Altogether, 55 case-control pairs underwent biochemical analysis in 1992, whereas 86 patients had died, 8 were lost to follow-up, and 23 had undergone parathyroid operation.
RESULTS: Mortality was higher (P = .015) in patients younger than 70 years. Cardiovascular diseases were over-represented causes of death. The hazard ratio for hypercalcemia as an independent cause of cardiovascular mortality was 1.72 (95% CI, 1.24-2.37; P < .001). The initially mild hypercalcemia in patients (2.67 +/- 0.07 mmol/L) decreased over time (P = .0001), whereas the serum calcium value remained constant in the controls. Serum calcium and serum parathyroid hormone values in patients were higher than controls at the follow-up (P < .0001, .01, respectively). All but 17 patients were normocalcemic in 1992, and only 2 (1.4%) developed a serum calcium value higher than 3 mmol/L.
CONCLUSIONS: Mild hypercalcemia in patients followed up for more than 2 decades is accompanied by premature cardiovascular death despite trends to spontaneous resolution. The principal cause of hypercalcemia probably is primary hyperparathyroidism, but mechanisms contributing to its regression over time are speculative.

PMID 11742326  Surgery. 2001 Dec;130(6):978-85. doi: 10.1067/msy.2001.・・・
著者: Ning Yu, Graham P Leese, Peter T Donnan
雑誌名: Clin Endocrinol (Oxf). 2013 Jul;79(1):27-34. doi: 10.1111/cen.12206. Epub 2013 Apr 19.
Abstract/Text OBJECTIVE: This study aims to identify the best biochemical risk factors alongside other factors for predicting adverse outcomes seen in untreated primary hyperparathyroidism (PHPT).
DESIGN: Population-based cohort study, 1997-2006.
SETTING: Tayside, Scotland, UK.
PATIENTS: Patients with untreated diagnosed PHPT. OUTCOME MEASURES AND METHODS: Outcomes considered were all-cause mortality, fatal and nonfatal cardiovascular disease (CVD). Models were derived using survival analysis. Potential biochemical predictors tested were baseline serum calcium, parathyroid hormone (PTH), creatinine and alkaline phosphatase (ALP), and other covariates considered were gender, age at diagnosis, deprivation, previous comorbidities and bisphosphonates usage.
RESULTS: From 1997 to 2006, 2097 patients (mean age, 68·4 years; 69·9% women) with untreated PHPT were identified with a total follow-up of 7338 person years, in the population of Tayside, Scotland. The median baseline calcium was 2·61 mm, and PTH was 7·2 pm. PTH was the only statistically significant risk factor in all outcomes observed adjusting for other covariates. Serum creatinine and ALP predicted mortality outcomes in the short term (≤3 years), but not long term. Calcium was associated with increased risk of all-cause mortality in the short term but had no significant impact on other outcomes.
CONCLUSION: Baseline PTH, rather than calcium, best predicts long-term outcomes in untreated PHPT.

© 2013 John Wiley & Sons Ltd.
PMID 23506565  Clin Endocrinol (Oxf). 2013 Jul;79(1):27-34. doi: 10.11・・・
著者: Shonni J Silverberg, Bart L Clarke, Munro Peacock, Francisco Bandeira, Stephanie Boutroy, Natalie E Cusano, David Dempster, E Michael Lewiecki, Jian-Min Liu, Salvatore Minisola, Lars Rejnmark, Barbara C Silva, Marcella D Walker, John P Bilezikian
雑誌名: J Clin Endocrinol Metab. 2014 Oct;99(10):3580-94. doi: 10.1210/jc.2014-1415. Epub 2014 Aug 27.
Abstract/Text OBJECTIVE: This report summarizes data on traditional and nontraditional manifestations of primary hyperparathyroidism (PHPT) that have been published since the last International Workshop on PHPT.
PARTICIPANTS: This subgroup was constituted by the Steering Committee to address key questions related to the presentation of PHPT. Consensus was established at a closed meeting of the Expert Panel that followed.
EVIDENCE: Data from the 5-year period between 2008 and 2013 were presented and discussed to determine whether they support changes in recommendations for surgery or nonsurgical follow-up.
CONSENSUS PROCESS: Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was undertaken. After extensive review and discussion, the subgroup came to agreement on what changes in the recommendations for surgery or nonsurgical follow-up of asymptomatic PHPT should be made to the Expert Panel.
CONCLUSIONS: 1) There are limited new data available on the natural history of asymptomatic PHPT. Although recognition of normocalcemic PHPT (normal serum calcium with elevated PTH concentrations; no secondary cause for hyperparathyroidism) is increasing, data on the clinical presentation and natural history of this phenotype are limited. 2) Although there are geographic differences in the predominant phenotypes of PHPT (symptomatic, asymptomatic, normocalcemic), they do not justify geography-specific management guidelines. 3) Recent data using newer, higher resolution imaging and analytic methods have revealed that in asymptomatic PHPT, both trabecular bone and cortical bone are affected. 4) Clinically silent nephrolithiasis and nephrocalcinosis can be detected by renal imaging and should be listed as a new criterion for surgery. 5) Current data do not support a cardiovascular evaluation or surgery for the purpose of improving cardiovascular markers, anatomical or functional abnormalities. 6) Some patients with mild PHPT have neuropsychological complaints and cognitive abnormalities, and some of these patients may benefit from surgical intervention. However, it is not possible at this time to predict which patients with neuropsychological complaints or cognitive issues will improve after successful parathyroid surgery.

PMID 25162667  J Clin Endocrinol Metab. 2014 Oct;99(10):3580-94. doi: ・・・
著者: Shyam Sankaran, Greg Gamble, Mark Bolland, Ian R Reid, Andrew Grey
雑誌名: J Clin Endocrinol Metab. 2010 Apr;95(4):1653-62. doi: 10.1210/jc.2009-2384. Epub 2010 Feb 3.
Abstract/Text CONTEXT: Uncertainty exists as to the optimal management and monitoring of the skeletal consequences of mild primary hyperparathyroidism (PHPT).
OBJECTIVE: The aim of this study was to determine the effects of surgical treatment, medical treatment and no treatment on bone mineral density (BMD) in mild PHPT.
DATA SOURCES: Our sources were Medline, EMBASE, and Cochrane CENTRAL prior to January 2009, and abstracts from meetings of international bone and mineral societies from 1987-2008.
STUDY SELECTION: Eligible studies were of at least 1-yr duration and included more than 10 participants with mild PHPT (serum calcium < 12 mg/dl) who had BMD measured by dual-energy x-ray absorptiometry while being observed without intervention, or treated with antiresorptive therapy or surgery. Primary analysis was of studies of up to 2-yr duration. Secondary analysis was of studies with follow-up beyond 2 yr.
DATA EXTRACTION: Data were extracted from the text of the retrieved articles or conference abstracts.
DATA SYNTHESIS: Increases in BMD in response to surgical intervention were comparable to those induced by antiresorptive therapies. Significant bone loss was observed in untreated subjects, but the rates of loss ranged from 0.6-1.0%/yr. Analysis of studies reporting data beyond 2 yr of follow-up demonstrated stable increases in BMD after surgery and stable BMD or slow loss (0.1-0.3%/yr) in untreated PHPT.
CONCLUSIONS: Surgical treatment and antiresorptive therapies increase BMD in mild PHPT to a similar degree, and each represents a reasonable option in a patient with mild PHPT and low BMD. Rapid bone loss does not occur in untreated mild PHPT, such that monitoring of BMD less frequently than every 1-2 yr is reasonable in individuals for whom intervention is not immediately required.

PMID 20130069  J Clin Endocrinol Metab. 2010 Apr;95(4):1653-62. doi: 1・・・
著者: Rikako Nomura, Toshitsugu Sugimoto, Tatsuo Tsukamoto, Mika Yamauchi, Hideaki Sowa, Qingxiang Chen, Toru Yamaguchi, Akira Kobayashi, Kazuo Chihara
雑誌名: Clin Endocrinol (Oxf). 2004 Mar;60(3):335-42.
Abstract/Text OBJECTIVE: Although many reports have demonstrated the sustained increase in bone mineral density (BMD) at trabecular sites in primary hyperparathyroidism (pHPT) after parathyroidectomy (PTX), there have been no data available on BMD changes over the long-term in pHPT patients with and without PTX in Japanese population. The present study was designed to investigate long-term BMD changes at both trabecular and cortical sites in Japanese pHPT patients with or without PTX.
METHODS: The subjects were 97 patients who had been followed up in Kobe University Hospital for at least 1 year up to 6 years with or without PTX. PTX was recommended to all patients whose pathological parathyroid gland(s) could be determined by image diagnosis. BMD was measured at the lumbar spine (L2-L4) and at distal one-third of the radius (R1/3) by dual energy X-ray absorptiometry (QDR2000). Serum levels of calcium, alkaline phosphatase and parathyroid hormone (PTH) were determined at the time of the BMD measurement.
RESULTS: Significant increases in any of the indices of BMD from the baseline values were observed within three months after PTX, followed by sustained increases over 6 years at L2-L4 even in postmenopausal women. Radial BMD also showed a marked increase six years after PTX. L2-L4 eventually reached the normal BMD but R1/3 did not. The percentage changes in L2-L4 were positively and significantly correlated with the preoperative PTH levels over the study period. However, the percentage changes in R1/3 showed a significant correlation with the preoperative PTH levels only 5 and 6 years after PTX. In the patients without PTX, no obvious changes in biochemical indices and BMD were observed over the six years.
CONCLUSION: We demonstrated that PTX led to marked and sustained increases in BMD not only at L2-L4 but also at R1/3 in Japanese pHPT patients, including postmenopausal women. The preoperative PTH level could be a clinically useful index for predicting long-term BMD changes after PTX.

PMID 15008999  Clin Endocrinol (Oxf). 2004 Mar;60(3):335-42.
著者: Lindi H VanderWalde, In-Lu Amy Liu, Philip I Haigh
雑誌名: World J Surg. 2009 Mar;33(3):406-11. doi: 10.1007/s00268-008-9720-8.
Abstract/Text BACKGROUND: Bone mineral density is one parameter used to decide whether patients with primary hyperparathyroidism (PHPT) should undergo parathyroidectomy. However, the influence of bone mineral density and parathyroidectomy on subsequent fracture risk is unclear.
METHODS: The authors conducted a retrospective cohort study of patients with PHPT based on administrative discharge abstract data. The dual energy x-ray absorptiometry (DEXA) scan T-scores at the femur were collected by chart review, and 10-year fracture-free survival (FFS) was the main outcome measured.
RESULTS: A total of 533 patients were identified, most of them > or = 50 years old (89%) and female (87%). Seventeen percent of the patients were black. Mean initial calcium, parathormone, and creatinine levels were 11.1 mg/dl, 116 pg/ml, and 0.9 mg/dl, respectively. Parathyroidectomy was performed in 159 (30%) patients, and 374 (70%) were observed. The 10-year FFS after PHPT diagnosis was 94% in patients treated with parathyroidectomy and 81% in those observed (p = 0.006). Compared to observation, parathyroidectomy improved the 10-year FFS by 9.1% (p = 0.99), 12% (p = 0.92), and 12% (p = 0.02) in patients with normal bones (T-score > or = -1.0), osteopenia (T-score < or = -1.0, > or = -2.5), and osteoporosis (T-score < -2.5), respectively. On multivariate analysis, parathyroidectomy was independently associated with decreased fracture risk (HR = 0.41; 95%CI 0.18, 0.93), whereas non-black race (HR = 2.94; 95%CI 1.04, 8.30) and T-score < -2.5 (HR = 2.29; 95%CI 1.08, 4.88) remained independently associated with increased fracture risk.
CONCLUSIONS: Parathyroidectomy decreases the risk of fracture in patients with normal, osteopenic, and osteoporotic bones. The largest impact from parathyroidectomy is in patients with osteoporosis. The highest risk of fracture is in non-blacks and in patients with osteoporosis.

PMID 18763015  World J Surg. 2009 Mar;33(3):406-11. doi: 10.1007/s0026・・・
著者: Robert Udelsman, Göran Åkerström, Carlo Biagini, Quan-Yang Duh, Paolo Miccoli, Bruno Niederle, Francesco Tonelli
雑誌名: J Clin Endocrinol Metab. 2014 Oct;99(10):3595-606. doi: 10.1210/jc.2014-2000. Epub 2014 Aug 27.
Abstract/Text OBJECTIVE: The surgical management of primary hyperparathyroidism (PHPT) has undergone considerable advances over the past two decades. The purpose of this report is to review these advances.
PARTICIPANTS: This subgroup was constituted by the Steering Committee of the Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism to address key questions related to the surgical management of PHPT.
EVIDENCE: Data since the last International Workshop were presented and discussed in detail. The topics included improvements in preoperative imaging, intraoperative adjuncts, refinements in local and regional anesthesia, and rapid intraoperative PTH assays.
CONSENSUS PROCESS: Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was undertaken. After extensive review and discussion, the subgroup agreed on what recommendations should be made to the Expert Panel regarding surgical approaches to parathyroidectomy.
CONCLUSIONS: 1) All patients with PHPT who meet surgical criteria should be referred to an experienced endocrine surgeon to discuss the risks, benefits, and potential complications of surgery. 2) Patients who do not meet surgical criteria and in whom there are no medical contraindications to surgery may request a visit with an experienced endocrine surgeon. Alternatively, a multidisciplinary endocrine conference with surgeon involvement could be employed to address all relevant issues. 3) Imaging is not a diagnostic procedure; it is a localization procedure to help the surgeon optimize the operative plan. 4) The frequency of hereditary forms of PHPT may be underappreciated and needs to be assessed with increased vigilance. And 5) surgery is likely to benefit patients due to high cure rates, low complication rates, and the likelihood of reversing skeletal manifestations.

PMID 25162669  J Clin Endocrinol Metab. 2014 Oct;99(10):3595-606. doi:・・・
著者: Eugénie Koumakis, Jean-Claude Souberbielle, Emile Sarfati, Marine Meunier, Emilie Maury, Elizabeth Gallimard, Didier Borderie, André Kahan, Catherine Cormier
雑誌名: J Clin Endocrinol Metab. 2013 Aug;98(8):3213-20. doi: 10.1210/jc.2013-1518. Epub 2013 Jun 19.
Abstract/Text CONTEXT: It is unclear whether bone mineral density (BMD) improves in patients with normocalcemic primary hyperparathyroidism (PHPT) after parathyroidectomy (PTX).
OBJECTIVE: The objective of the study was to evaluate and compare the impact of PTX on BMD change at 1 year in normocalcemic vs hypercalcemic PHPT.
DESIGN: This was a longitudinal cohort study.
SETTING: The study took place at a referral center.
PATIENTS: We included 60 PHPT patients (mean age 64.0 ± 10.1 years), successfully treated by PTX by the same surgeon. Two groups were individualized according to baseline serum total (albumin corrected) calcium: 39 patients with normal baseline serum total calcium (normocalcemic group) and 21 patients with hypercalcemia at baseline (hypercalcemic group).
MAIN OUTCOME MEASURE: BMD changes 1 year after PTX were measured.
RESULTS: In the normocalcemic group, BMD increased significantly by +2.3 ± 5.0% at the spine (P = .016) and +1.9 ± 5.7% at the hip (P = .048). In the hypercalcemic group, BMD increased significantly by +4.0 ± 3.8% at the spine (P = .0003) and +3.2 ± 4.2% at the hip (P = .003). There was no difference in these BMD gains between both groups (P > .1). The presence of multiple adenomas or hyperplasia was more frequent in the normocalcemic group than in the hypercalcemic group (P = .04).
CONCLUSION: Our results indicate for the first time that successful PTX in normocalcemic PHPT patients with osteoporosis is followed with mild but significant BMD improvement at the spine and hip at 1 year, comparable with that observed in hypercalcemic PHPT, suggesting that PTX may be beneficial in normocalcemic PHPT.

PMID 23783096  J Clin Endocrinol Metab. 2013 Aug;98(8):3213-20. doi: 1・・・
著者: Munro Peacock, J P Bilezikian, M A Bolognese, Michael Borofsky, Simona Scumpia, L R Sterling, Sunfa Cheng, Dolores Shoback
雑誌名: J Clin Endocrinol Metab. 2011 Jan;96(1):E9-18. doi: 10.1210/jc.2010-1221. Epub 2010 Oct 13.
Abstract/Text CONTEXT: Primary hyperparathyroidism (PHPT) is characterized by elevated serum calcium (Ca) and increased PTH concentrations.
OBJECTIVE: The objective of the investigation was to establish the efficacy of cinacalcet in reducing serum Ca in patients with PHPT across a wide spectrum of disease severity.
DESIGN AND SETTING: The study was a pooled analysis of data from three multicenter clinical trials of cinacalcet in PHPT.
PATIENTS: Patients were grouped into three disease categories for analysis based on the following: 1) history of failed parathyroidectomy (n = 29); 2) meeting one or more criteria for parathyroidectomy but without prior surgery (n = 37); and 3) mild asymptomatic PHPT without meeting criteria for either above category (n = 15).
INTERVENTION: The intervention in this study was treatment with cinacalcet for up to 4.5 yr.
OUTCOMES: Measurements in the study included serum Ca, PTH, phosphate, and bone-specific alkaline phosphatase, and areal bone mineral density (aBMD). Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study period.
RESULTS: The extent of cinacalcet-induced serum Ca reduction, proportion of patients achieving normal serum Ca (≤10.3 mg/dl), reduction in serum PTH, and increase in serum phosphate were similar across all three categories. Except for decreased aBMD at the total femur indicated for parathyroidectomy group at 1 yr, no significant changes in aBMD occurred. The efficacy of cinacalcet was maintained for up to 4.5 yr of follow-up. AEs were mild and similar across the three categories.
CONCLUSIONS: Cinacalcet is equally effective in the medical management of PHPT patients across a broad spectrum of disease severity, and overall cinacalcet is well tolerated.

PMID 20943783  J Clin Endocrinol Metab. 2011 Jan;96(1):E9-18. doi: 10.・・・
著者: M Rossini, D Gatti, G Isaia, L Sartori, V Braga, S Adami
雑誌名: J Bone Miner Res. 2001 Jan;16(1):113-9. doi: 10.1359/jbmr.2001.16.1.113.
Abstract/Text In a large proportion of the patients with primary hyperparathyroidism (PHPT), a variable degree of osteopenia is the only relevant manifestation of the disease. Low bone mineral density (BMD) in patients with PHPT is an indication for surgical intervention because successful parathyroidectomy results in a dramatic increase in BMD. However, low BMD values are almost an invariable finding in elderly women with PHPT, who are often either unwilling or considered unfit for surgery. Bisphosphonates are capable of suppressing parathyroid hormone (PTH)-mediated bone resorption and are useful for the prevention and treatment of postmenopausal osteoporosis. In this pilot-controlled study, we investigated the effects of oral treatment with alendronate on BMD and biochemical markers of calcium and bone metabolism in elderly women presenting osteoporosis and mild PHPT. Twenty-six elderly patients aged 67-81 years were randomized for treatment with either oral 10 mg alendronate on alternate-day treatment or no treatment for 2 years. In the control untreated patients a slight significant decrease was observed for total body and femoral neck BMD, without significant changes in biochemical markers of calcium and bone metabolism during the 2 years of observation. Urine deoxypyridinoline (Dpyr) excretion significantly fell within the first month of treatment with alendronate, while serum markers of bone formation alkaline phosphatase and osteocalcin fell more gradually and the decrease became significant only after 3 months of treatment; thereafter all bone turnover markers remained consistently suppressed during alendronate treatment. After 2 years in this group we observed statistically significant increases in BMD at lumbar spine, total hip, and total body (+8.6 +/- 3.0%, +4.8 +/- 3.9%, and +1.2 +/- 1.4% changes vs. baseline mean +/- SD) versus both baseline and control patients. Serum calcium, serum phosphate, and urinary calcium excretion significantly decreased during the first 3-6 months but rose back to the baseline values afterward. Increase in serum PTH level was statistically significant during the first year of treatment. These preliminary results may make alendronate a candidate as a supportive therapy in patients with mild PHPT who are unwilling or are unsuitable for surgery, and for whom osteoporosis is a reason of concern.

PMID 11149474  J Bone Miner Res. 2001 Jan;16(1):113-9. doi: 10.1359/jb・・・
著者: Aliya A Khan, John P Bilezikian, Annie W C Kung, Mustafa M Ahmed, Sacha J Dubois, Andrew Y Y Ho, Debra Schussheim, Mishaela R Rubin, Atif M Shaikh, Shonni J Silverberg, Timothy I Standish, Zareen Syed, Zeba A Syed
雑誌名: J Clin Endocrinol Metab. 2004 Jul;89(7):3319-25. doi: 10.1210/jc.2003-030908.
Abstract/Text Primary hyperparathyroidism (PHPT) is often associated with reduced bone mineral density (BMD). A randomized, double-blind, placebo-controlled trial was conducted to determine whether alendronate (ALN), 10 mg daily, maintains or improves BMD in patients with PHPT. Eligible patients had asymptomatic PHPT and did not meet surgical guidelines or refused surgery. Forty-four patients randomized to placebo or active treatment arms were stratified for gender. At 12 months, patients taking placebo crossed over to active treatment. All patients were on active treatment in yr 2. The primary outcome index, BMD, at the lumbar spine (LS), femoral neck, total hip, and distal one third radius was measured every 6 months by dual-energy x-ray absorptiometry. Calcium, phosphorous, PTH, bone-specific alkaline phosphatase (BSAP) activity, urinary calcium, and urinary N-telopeptide (NTX) excretion were monitored every 3 months. Treatment with alendronate over 2 yr was associated with a significant (6.85%; micro(d) = 0.052; +/-0.94% se; P < 0.001) increase in LS BMD in comparison with baseline. Total hip BMD increased significantly at 12 months with alendronate by 4.01% (micro(d) = 0.027; +/-0.77% se; P < 0.001) from baseline and remained stable over the next 12 months of therapy. BMD at the one third radius site did not show any statistically significant change in the alendronate-treated group at 12 or 24 months of therapy. At 24 months, the alendronate-treated group showed a 3.67% (micro(d) = 0.022; +/-1.63% se; P = 0.038) gain in bone density at the femoral neck site in comparison with baseline. The placebo group, when crossed over to alendronate at 12 months, showed a significant change of 4.1% (micro(d) = 0.034; +/-1.12% se; P = 0.003) in the LS BMD and 1.7% (micro(d) = 0.012; +/-0.81% se; P = 0.009) at the total hip site in comparison with baseline. There was no statistically significant change seen in the placebo group at 12 months at any BMD site and no significant change at 24 months for the distal one third radius or femoral neck sites. Alendronate was associated with marked reductions in bone turnover markers with rapid decreases in urinary NTX excretion by 66% (micro(d) = -60.27; +/-13.5% se; P < 0.001) at 3 months and decreases in BSAP by 49% at 6 months (micro(d) = -15.98; +/-6.32% se; P < 0.001) and by 53% at 9 and 12 months (micro(d) = -17.11; +/-7.85% se; P < 0.001; micro(d) = -17.36; +/-6.96% se; P < 0.001, respectively) of therapy. In the placebo group, NTX and BSAP levels remained elevated. Serum calcium (total and ionized), PTH, and urine calcium did not change with alendronate therapy. In PHPT, alendronate significantly increases BMD at the LS at 12 and 24 months from baseline values. Significant reductions in bone turnover occur with stable serum calcium and PTH levels. Alendronate may be a useful alternative to parathyroidectomy in asymptomatic PHPT among those with low BMD.

PMID 15240609  J Clin Endocrinol Metab. 2004 Jul;89(7):3319-25. doi: 1・・・
著者: C C Chow, W B Chan, June K Y Li, Norman N Chan, Michael H M Chan, Gary T C Ko, K W Lo, Clive S Cockram
雑誌名: J Clin Endocrinol Metab. 2003 Feb;88(2):581-7. doi: 10.1210/jc.2002-020890.
Abstract/Text The effect of biphosphonate therapy on bone mineral density (BMD) in patients with primary hyperparathyroidism (PHP) is unknown. Forty postmenopausal women (mean age, 70 yr) with PHP were randomized to receive alendronate 10 mg/d or placebo for 48 wk, followed by treatment withdrawal for 24 wk. The mean (+/-SD) changes in BMD at femoral neck (+4.17 +/- 6.01% vs. -0.25 +/- 3.3%; P = 0.011) and lumbar spine (+3.79 +/- 4.04% vs. 0.19 +/- 2.80%; P = 0.016) were significantly higher with alendronate at 48 wk. Serum calcium was reduced with alendronate but not placebo (-0.09 vs. +0.01 mmol/liter; P = 0.018). Serum bone-specific alkaline phosphatase activity was lower with alendronate from 12 wk onward and increased 24 wk after treatment withdrawal (21.1 +/- 12.8 to 7.3 +/- 4.9 IU/liter at 48 wk, and 15.0 +/- 14.8 IU/liter 24 wk after withdrawal; P = 0.002 for trend). Osteocalcin concentration decreased at 48 wk and increased 24 wk after alendronate withdrawal (P = 0.019 for trend of change over time) but not with placebo. Urinary N-telopeptide/creatinine ratio decreased with alendronate at 48 wk and increased 24 wk after treatment withdrawal (P = 0.008 for trend). N-telopeptide/creatinine ratio did not change with placebo. Alendronate improves BMD and reduces bone turnover markers in postmenopausal women with PHP.

PMID 12574184  J Clin Endocrinol Metab. 2003 Feb;88(2):581-7. doi: 10.・・・
著者: Claudio Marcocci, Jens Bollerslev, Aliya Aziz Khan, Dolores Marie Shoback
雑誌名: J Clin Endocrinol Metab. 2014 Oct;99(10):3607-18. doi: 10.1210/jc.2014-1417. Epub 2014 Aug 27.
Abstract/Text OBJECTIVE: Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The only available definitive therapy is parathyroidectomy, which is appropriate to consider in all patients. The purpose of this report is to provide an update on calcium and vitamin D supplementation and medical management for those patients with PHPT who cannot or do not want to undergo surgery.
METHODS: Questions were developed by the International Task Force on PHPT. A comprehensive literature search was undertaken, and relevant articles published between 2008 and 2013 were reviewed in detail. The questions were addressed by the panel of experts, and consensus was established at the time of the workshop.
CONCLUSIONS: The recommended calcium intake in patients with PHPT should follow guidelines established for all individuals. It is not recommended to limit calcium intake in patients with PHPT who do not undergo surgery. Patients with low serum 25-hydroxyvitamin D should be repleted with doses of vitamin D aiming to bring serum 25-hydroxyvitamin D levels to ≥ 50 nmol/L (20 ng/mL) at a minimum, but a goal of ≥75 nmol/L (30 ng/mL) also is reasonable. Pharmacological approaches are available and should be reserved for those patients in whom it is desirable to lower the serum calcium, increase BMD, or both. For the control of hypercalcemia, cinacalcet is the treatment of choice. Cinacalcet reduces serum calcium concentrations to normal in many cases, but has only a modest effect on serum PTH levels. However, bone mineral density (BMD) does not change. To improve BMD, bisphosphonate therapy is recommended. The best evidence is for the use of alendronate, which improves BMD at the lumbar spine without altering the serum calcium concentration. To reduce the serum calcium and improve BMD, combination therapy with both agents is reasonable, but strong evidence for the efficacy of that approach is lacking.

PMID 25162668  J Clin Endocrinol Metab. 2014 Oct;99(10):3607-18. doi: ・・・

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