Burosumab for the Treatment of Tumor-Induced Osteomalacia

Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..     

Immunoheterogeneity of parathyroid hormone pre- and postoperatively in primary hyperparathyroidism

Zusammenfassung Bei primärem Hyperparathyreoidismus (pHPT) kann, wie man weiß, eine Freisetzung eher von intaktem PTH (i-PTH) als von Fragmenten mit end-ständigen Carboxylgruppen erfolgen. Wir untersuchten, ob die Freisetzung von PTH-Fragmenten mit terminalen Aminogruppen (N-PTH) sich ebenfalls ändert. Es wurden die Serumspiegel von i-PTH und N-PTH unter folgenden Bedingungen bestimmt: (1) bei 6 pHPT-Patienten (a) ohne Kalziumgabe, (b) nach oraler Kalziumgabe vor und unmittelbar nach Operation und (2) bei 7 gesunden Personen. Bei ersteren waren präoperativ beide Spiegel — i-PTH und N-PTH — erhöht, die i-PTH-Spiegel etwas stärker. Daher war das Verhältnis N-PTH/i-PTH im Vergleich zu gesunden Personen vermindert (p<0,05). Postoperativ war am 1. Tag das Serum-i-PTH stärker vermindert als das N-PTH, wodurch das N-PTH/i-PTH-Verhältnis gegenüber Gesunden zunahm (p<0,05); am 5. Tag normalisierte sich dieses Verhältnis. Präoperativ verbesserte sich die Supprimierung von i-PTH-Kalzium bei den Patienten, während die Supprimierung von N-PTH-Kalzium normal blieb, was seinen Ausdruck fand in einem unveränderten N-PTH/i-PTH-Verhältnis während der oralen Kalziumeinnahme. Im Gegensatz dazu vergrößerte sich das N-PTH/i-PTH-Verhältnis in normaler Weise während der Kalziumeinnahme am 5. Tag postoperativ (p<0,05). Schlußfolgerungen: (1) Bei pHPT ändert sich die zirkulierende PTH-Immunheterogenität mit einer vorzugsweisen Freisetzung von i-PTH im Vergleich zu N-PTH, und diese Veränderung normalisiert sich nach Operation. (2) Die Sekretion von i-PTH und N-PTH zeigt unterschiedliche Sensitivität gegenüber einer Inhibierung durch Kalzium.

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Immunoheterogeneity of parathyroid hormone pre- and postoperatively in primary hyperparathyroidism

In primary hyperparathyroidism (pHPT), a preferential release of intact PTH (i-PTH) versus carboxyl-terminal PTH fragments is known to occur. We studied whether the release of amino-terminal PTH fragments (N-PTH) is also changed. Serum levels of i-PTH and N-PTH were determined under basal conditions and following oral intake of calcium in six patients with pHPT before and immediately after surgery and in seven healthy subjects. In the patients, baseline levels of both i-PTH and N-PTH were increased preoperatively. The increase was larger in i-PTH compared to N-PTH. Therefore, the N/i ratio was reduced compared to healthy subjects (P<0.05). On the first postoperative day, serum i-PTH decreased to a larger extent than N-PTH, which increased the N/i ratio above that in healthy subjects (P< 0.05). On the 5th postoperative day, the N/i ratio was normalized. Preoperatively, the suppressibility of i-PTH calcium was impaired in the patients (P<0.05), whereas the suppressibility of N-PTH was normal, resulting in unchanged N/i ratio during the oral calcium load. In contrast, the N/i ratio increased normally during the calcium load at day 5 postoperatively (P<0.05). We therefore conclude that: (1) in pHPT, circulating PTH immunoheterogeneity is altered with a preferential release of intact PTH compared to N-terminal PTH fragments and this alteration is normalized after surgery, (2) the secretion of intact PTH and N-terminal PTH shows different sensitivity to inhibition by calcium.

     

尿毒症患者甲状旁腺素水平与营养关系的探讨

目的探讨尿毒症患者甲状旁腺素与营养状况的关系,为延缓慢性肾功能不全进展而改善患者营养状况提供临床依据。方法测定患者血清甲状旁腺素(PTH)、ALB、Hb;使用改良定量主观评估表 MQSGA 评估患者营养状况。结果 PTH 与 MQSGA、ALB,存在相关关系(P<0.05),与 Hb 存在显著相关关系( P<0.001);PTH 与 MQSGA、Hb 之间 Logistic 回归分析(P<0.05)。结论 PTH 是影响尿毒症患者营养状况的重要尿毒素。清除血清 PTH 能改善患者营养状况。     

Bioactive N‐terminal undecapeptides derived from parathyroid hormone: the role of α‐helicity*

Abstract: The N‐terminal 1–34 segment of parathyroid hormone (PTH) is fully active in vitro and in vivo and it can reproduce all biological responses in bone characteristic of the native intact PTH. Recent studies have demonstrated that N‐terminal fragments presenting the principal activating domain such as PTH(1–11) and PTH(1–14) with helicity‐enhancing substitutions yield potent analogues with PTH(1–34)‐like activity. To further investigate the role of α‐helicity on biological potency, we designed and synthesized by solid‐phase methodology the following hPTH(1–11) analogues substituted at positions 1 and/or 3 by the sterically hindered and helix‐promoting C^α‐tetrasubstituted α‐amino acids α‐amino isobutyric acid (Aib), 1‐aminocyclopentane‐1‐carboxylic acid (Ac₅c) and 1‐aminocyclohexane‐1‐carboxylic acid (Ac₆c): Ac₅c‐V‐Aib‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( I ); Aib‐V‐Ac₅c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( II ); Ac₆c‐V‐Aib‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( III ); Aib‐V‐Ac₆c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( IV ); Aib‐V‐Aib‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( V ); S‐V‐Aib‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( VI ), S‐V‐Ac₅c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( VII ); Ac₅c‐V‐S‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( VIII ); Ac₆c‐V‐S‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( IX ); Ac₅c‐V‐Ac₅c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( X ); Ac₆c‐V‐Ac₆c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( XI ). All analogues were biologically evaluated and conformationally characterized in 2,2,2‐trifluoroethanol (TFE) solution by circular dichroism (CD). Analogues I – V , which cover the full range of biological activity observed in the present study, were further conformationally characterized in detail by nuclear magnetic resonance (NMR) and computer simulations studies. The results of ligand‐stimulated cAMP accumulation experiments indicated that analogues I and II are active, analogues III , VI and VII are very weakly active and analogues IV , V , VIII–XI are inactive. The most potent analogue, I exhibits biological activity 3500‐fold higher than that of the native PTH(1–11) and only 15‐fold weaker than that of the native sequence hPTH(1–34). Remarkably, the two most potent analogues, I and II , and the very weakly active analogues, VI and VII , exhibit similar helix contents. These results indicate that the presence of a stable N‐terminal helical sequence is an important but not sufficient condition for biological activity.     

重组人甲状旁腺激素效价测定方法的研究

采用酶标法、放免法、化学发光法对 rh PTH效价进行测定,并进行了比较性研究。结果表明,三种方法间无显著性差异。酶标法简单快捷、安全,更适合作为常规重组人甲状旁腺激素生物学活性的测定。     

更年乐水丸对去卵巢大鼠骨质疏松症的早期干预作用

目的:探讨更年乐水丸治疗摘除卵巢所致雌性大鼠骨质疏松的作用机理。方法:选用55只3月龄SD雌性大鼠随机分为假手术组、模型对照组、阳性对照组、更年乐水丸低剂量组、更年乐水丸高剂量组。后4组摘除双侧卵巢,于造模后第2天开始中药灌胃,连续45 d,处死动物后,取动物左侧股骨,测定骨密度;测定血清E2、PTH、IL-6、Alp、Acp的水平。结果:更年乐水丸能增加大鼠骨密度及提高血清E2水平,降低Alp、Acp、PTH、IL-6含量。结论:更年乐水丸可改变绝经后早期骨代谢高转换状态。     

复方α-酮酸对慢性肾脏病钙磷代谢的影响

目的通过极低蛋白饮食联合复方α-酮酸(开同)和常规低蛋白饮食在慢性肾脏病(chronic kidney disease,CKD)IV期中的作用,评估其对钙磷代谢和PTH的影响。方法采用前瞻、随机、对照临床研究,对24例CKD患者,肌酐清除率低于30ml/min,随机分为两组,极低蛋白饮食+开同组(VLPD+Ket组)和低蛋白饮食组(LPD组),每组12例患者,观察4个月。结果所有患者营养状态均得到充分维持,游离钙在VLPD+Ket组无明显变化,LPD组趋于下降;血磷在VLPD+Ket组下降[(1.48±0.16)mmol/L和(1.29±0.36)mmol/L,P<0.05],LPD组无变化。LPD组甲状旁腺激素明显升高[(241±138)pg/ml和(494±390)pg/ml,P<0.01],该参数与钙呈负相关(r=-0.75,P=0.02),而与磷呈正相关(r=0.71,P=0.03)。结论 VLPD+Ket能维持CKD IV期患者正常的营养状况,同时还具有改善钙磷代谢、降低尿素氮和稳定PTH的作用,进一步预防和降低肾性骨病的发生,有明显底预防和降低肾性骨病发生的作用。     

糖尿病大鼠骨代谢的变化

目的研究糖尿病早期骨代谢改变。方法测定６周实验性糖尿病（ＳＴＺ－ＤＭ）大鼠空腹血糖、ＨｂＡ１ｃ、胰岛素、钙离子浓度、骨钙素、降钙素、ＰＴＨ和维生素Ｄ３。收集２４ｈ尿，测定白蛋白、肌酐、吡啶酚。结果糖尿病大鼠与正常对照组相比，血清钙浓度显著升高［（１３５．８５±１１．２８）对（１１７．２１±６．５２）ｍｇ／Ｌ，Ｐ＜０．０１］，骨钙素水平升高［（０．０７±０．０４）对（０．０５±０．０１）ｎｇ／ｍｌ，Ｐ＜０．０５］，维生素Ｄ３水平显著降低［（７．６３±１．８８）对（１１．５５±４．１１）ｎｇ／ｍｌ，Ｐ＜０．０５］，尿吡啶酚／肌酐显著降低［（４．７９±０．７５）对（７５．８４±６０．６７）ｎｍｏｌ／ｍｍｏｌ，Ｐ＜０．０１］；而血清降钙素和甲状旁腺素水平改变无统计学意义。结论糖尿病状态下存在骨代谢异常，主要表现为维生素Ｄ３降低、骨钙素升高及尿吡啶酚水平降低。糖尿病性骨质疏松可能与维生素Ｄ３水平降低及由于胰岛素缺乏所致的骨胶原合成障碍有关     

前列腺癌患者血清甲状旁腺相关蛋白测定的意义

目的观察前列腺癌患者血清甲状旁腺相关蛋白（ＰＴＨｒＰ）与病情及前列腺特异抗原（ＰＳＡ）的关系。方法采用免疫放射法（ＩＲＭＡ）和放射免疫法（ＲＩＡ）测定３１例前列腺癌患者血清ＰＴＨｒＰ、ＰＳＡ和钙离子，并以５０例前列腺增生症（ＢＰＨ）、５５例健康人和５７例其它恶性肿瘤患者作对照。结果前列腺癌组血清ＰＴＨｒＰ（４．６±４．４ｐｍｏｌ／Ｌ）和ＰＳＡ（８０．０±５２．６μｇ／Ｌ）明显高于ＢＰＨ和健康组（均为Ｐ＜０．０１）。３１例前列腺癌患者中１３例（４１．６％）血清ＰＴＨｒＰ增高，这１３例均属Ｄ期，其血清ＰＴＨｒＰ水平明显高于Ａ期（Ｐ＜０．０１）。２１例前列腺癌伴发高钙血症（ＨＨＭ）者血清ＰＴＨｒＰ与ＰＳＡ呈正相关关系（ｒ＝０．８２３，Ｐ＜０．００１）。ＢＰＨ组无１例血清ＰＴＨｒＰ增高。结论血清ＰＴＨｒＰ与前列腺癌的病程进展有关，其含量增高表明肿瘤已属晚期