Pharmacodynamic Actions of a Long‐Acting PTH Analog (LA‐PTH) in Thyroparathyroidectomized (TPTX) Rats and Normal Monkeys

Hypoparathyroidism is a disease of chronic hypocalcemia and hyperphosphatemia due to a deficiency of parathyroid hormone (PTH). PTH and analogs of the hormone are of interest as potential therapies. Accordingly, we examined the pharmacological properties of a long‐acting PTH analog, [Ala^1,3,12,18,22, Gln¹⁰,Arg¹¹,Trp¹⁴,Lys²⁶]‐PTH(1‐14)/PTHrP(15‐36) (LA–PTH) in thyroparathyroidectomized (TPTX) rats, a model of HP, as well as in normal monkeys. In TPTX rats, a single intravenous administration of LA‐PTH at a dose of 0.9 nmol/kg increased serum calcium (sCa) and decreased serum phosphate (sPi) to near‐normal levels for longer than 48 hours, whereas PTH(1‐34) and PTH(1‐84), each injected at a dose 80‐fold higher than that used for LA‐PTH, increased sCa and decreased sPi only modestly and transiently (<6 hours). LA‐PTH also exhibited enhanced and prolonged efficacy versus PTH(1‐34) and PTH(1‐84) for elevating sCa when administered subcutaneously (s.c.) into monkeys. Daily s.c. administration of LA‐PTH (1.8 nmol/kg) into TPTX rats for 28 days elevated sCa to near normal levels without causing hypercalciuria or increasing bone resorption markers, a desirable goal in the treatment of hypoparathyroidism. The results are supportive of further study of long‐acting PTH analogs as potential therapies for patients with hypoparathyroidism. © 2016 American Society for Bone and Mineral Research.     

烟酰胺联合司维拉姆治疗血液透析高磷血症的临床研究

目的 探讨烟酰胺片联合碳酸司维拉姆片治疗血液透析高磷血症的临床疗效。方法 选取2016年3月—2017年3月在云阳县人民医院肾内科维持血液透析的高磷血症患者100例作为研究对象,所有患者随机分为对照组和治疗组,每组各50例。对照组患者餐中口服碳酸司维拉姆片,用量根据具体血磷水平进行调整（当血磷≥2.41 mmol/L,口服剂量为1 600 mg/次;当血磷<2.41 mmol/L,口服剂量为800 mg/次）,3次/d;治疗组患者在对照组治疗的基础上口服烟酰胺片,500 mg/次,1次/d。两组患者均连续治疗2个月。观察两组患者的临床疗效,比较治疗前后的血清学指标、冠状动脉钙化积分（CACS）、白细胞介素-6（IL-6）和甲状旁腺激素（PTH）水平。结果 治疗后,对照组和治疗组的临床总有效率分别为78.00%、94.00%,两组比较差异具有统计学意义（P<0.05）。治疗后,两组患者的血磷、钙磷乘积水平均显著降低,血钙水平显著升高,同组治疗前后比较差异具有统计学意义（P<0.05）;且治疗后治疗组血清学指标显著优于对照组,两组比较差异具有统计学意义（P<0.05）。治疗后,两组患者的CACS、IL-6、PTH水平均显著降低,同组治疗前后比较差异具有统计学意义（P<0.05）;且治疗后治疗组患者CACS、IL-6、PTH水平显著低于对照组,两组比较差异具有统计学意义（P<0.05）。结论 烟酰胺片联合碳酸司维拉姆片治疗血液透析高磷血症患者疗效显著,可显著降低血磷水平,减轻炎性反应,安全性较高,具有一定的临床推广应用价值。     

药用炭片联合碳酸镧治疗血液透析高磷血症的临床研究

目的探讨药用炭片联合碳酸镧治疗血液透析高磷血症的临床疗效。方法选取2014年5月—2016年5月在驻马店市中心医院治疗的血液透析高磷血症患者160例,随机分为对照组(80例)和治疗组(80例)。对照组口服碳酸镧咀嚼片,1 g/次,3次/d;治疗组在对照组基础上口服药用炭片,1.5 g/次,3次/d。两组患者均经过12周。观察比较治疗前后两组患者临床疗效和血清学指标。结果治疗后,对照组和治疗组临床总有效率分别为81.25%、93.75%,两组比较差异具有统计学意义(P0.05)。治疗后,两组血磷、血钙、血甲状旁腺激素(PTH)、超敏C反应蛋白(hs-CRP)、成纤维生长因子23(FGF-23)和钙磷乘积水平均明显降低,同组治疗前后比较差异具有统计学意义(P0.05);且治疗组血清学指标低于对照组,两组比较差异具有统计学意义(P0.05)。结论药用炭片联合碳酸镧治疗血液透析高磷血症可有效改善患者生存质量,具有一定的临床推广应用价值。     

Propranolol Promotes Bone Formation and Limits Resorption Through Novel Mechanisms During Anabolic Parathyroid Hormone Treatment in Female C57BL/6J Mice

Although the nonselective β-blocker, propranolol, improves bone density with parathyroid hormone (PTH) treatment in mice, the mechanism of this effect is unclear. To address this, we used a combination of in vitro and in vivo approaches to address how propranolol influences bone remodeling in the context of PTH treatment. In female C57BL/6J mice, intermittent PTH and propranolol administration had complementary effects in the trabecular bone of the distal femur and fifth lumbar vertebra (L₅), with combination treatment achieving microarchitectural parameters beyond that of PTH alone. Combined treatment improved the serum bone formation marker, procollagen type 1 N propeptide (P1NP), but did not impact other histomorphometric parameters relating to osteoblast function at the L₅. In vitro, propranolol amplified the acute, PTH-induced, intracellular calcium signal in osteoblast-like cells. The most striking finding, however, was suppression of PTH-induced bone resorption. Despite this, PTH-induced receptor activator of nuclear factor κ-B ligand (RANKL) mRNA and protein levels were unaltered by propranolol, which led us to hypothesize that propranolol could act directly on osteoclasts. Using in situ methods, we found Adrb2 expression in osteoclasts in vivo, suggesting β-blockers may directly impact osteoclasts. Consistent with this, we found propranolol directly suppresses osteoclast differentiation in vitro. Taken together, this work suggests a strong anti-osteoclastic effect of nonselective β-blockers in vivo, indicating that combining propranolol with PTH could be beneficial to patients with extremely low bone density. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Potentielle application de l’axe fibroblast growth factor 23-Klotho dans la maladie rénale chronique

Membrane Alpha Klotho (α-klotho) is expressed in the kidney and functions as a co-receptor of FGF receptors (FGFRs) to activate specific fibroblast growth factor 23 (FGF23) signal pathway. FGF23 is produced in bones and participates in mineral homeostasis. The extracellular domain of transmembrane αklotho can be cleaved by proteases and released into the circulation as soluble α-klotho. Klotho deficiency is a pathogenic factor for chronic kidney disease progression and cardiovascular diseases. The FGF23 excess may also contribute to cardiovascular diseases where its pathogenic effect acts via the FGFR4 and independently of α-klotho. The decline in serum α-klotho followed by a rise in serum FGF23 at an early stage of chronic kidney disease can serve as a robust predictor for risk of cardiovascular diseases and mortality in both CKD patients and the general population. The first randomized trials suggest the possibility to reduce FGF23 excess in chronic kidney disease by controlling the phosphate serum using phosphate binders and reducing PTH levels with calcimimetic drug. New strategies emerge, including the administration of α-klotho recombinant and the use of epidrugs in order to correct the klotho deficiency. The FGR4 inhibitors are promising to limit the development of left ventricular hypertrophy linked to FGF23 excess. Finally, a better understanding of the molecular mechanisms of FGF23/α-klotho axis will allow us to find new strategic approaches and improve the CKD patient's management and their outcomes.     

In Healthy Adults,Biological Activity of Vitamin D,as Assessed by Serum PTH,Is Largely Independent of DBP Concentrations

Vitamin D insufficiency, as measured by 25‐hydroxyvitamin D (25[OH]D) levels, has been associated with important health outcomes. The majority of vitamin D in circulation is bound to vitamin D–binding protein (DBP) and albumin, and recent genetic studies have demonstrated that serum DBP is a major determinant of 25(OH)D concentrations in adults. The impact of circulating DBP levels on vitamin D's biologic action, is unclear, but is of particular relevance to vitamin D epidemiology, because a lack of control for DBP levels could strongly influence the association of vitamin D with disease. Serum parathyroid hormone (PTH) levels can act as a biological readout of 25(OH)D activity. We therefore assessed the relationship between serum total and free 25(OH)D and PTH with and without adjusting for DBP, in 2073 subjects of European descent. Total 25(OH)D levels correlated positively (r = 0.19, p = 1.8 × 10^?17) with DBP, whereas the free 25(OH)D correlated negatively (r = ?0.14, p = 5.0 × 10^?12). Total and free 25(OH)D levels correlated negatively with PTH (r = ?0.29, p = 1.3 × 10^?39; r = ?0.26, p = 1.9 × 10^?33, respectively). Including age, body mass index (BMI), sex, estimated glomerular filtration rate, calcium, and season of blood draw as covariates, total 25(OH)D levels were significantly associated with log‐transformed PTH (lnPTH) levels (linear term: β = ?0.010, p < 0.0001, squared term: β = 0.00004, p < 0.0001) and this association was not changed by adjusting for DBP. These findings provide evidence that in a largely vitamin D–sufficient cohort, the biological effect of vitamin D on PTH levels is mainly independent of DBP concentration. Accordingly, this study may provide useful information for studies investigating the relationship between vitamin D, DBP, and disease. © 2014 American Society for Bone and Mineral Research.