共查询到20条相似文献,搜索用时 109 毫秒
1.
Tanja Sikjaer Lars Rejnmark Lars Rolighed Lene Heickendorff Leif Mosekilde the Hypoparathyroid Study Group 《Journal of bone and mineral research》2011,26(10):2358-2370
In hypoparathyroidism, plasma parathyroid hormone (PTH) levels are inadequate to maintain plasma calcium concentration within the reference range. On conventional treatment with calcium supplements and active vitamin D analogues, bone turnover is abnormally low, and BMD is markedly increased. We aimed to study the effects of PTH‐replacement therapy (PTH‐RT) on calcium‐phosphate homeostasis and BMD. In a double‐blind design, we randomized 62 patients with hypoparathyroidism to daily treatment with PTH(1–84) 100 µg or similar placebo for 24 weeks as add‐on therapy to conventional treatment. Compared with placebo, patients on PTH(1–84) reduced their daily dose of calcium and active vitamin D significantly by 75% and 73%, respectively, without developing hypocalcemia. However, hypercalcemia occurred frequently during the downtitration of calcium and active vitamin D. Plasma phosphate and renal calcium and phosphate excretion did not change. Compared with placebo, PTH(1–84) treatment significantly increased plasma levels of bone‐specific alkaline phosphatase (+226% ± 36%), osteocalcin (+807% ± 186%), N‐terminal propeptide of procollagen 1 (P1NP; +1315% ± 330%), cross‐linked C‐telopeptide of type 1 collagen (CTX; +1209% ± 459%), and urinary cross‐linked N‐telopeptide of type 1 collagen (NTX; (+830% ± 165%), whereas BMD decreased at the hip (?1.59% ± 0.57%), lumbar spine (?1.76% ± 1.03%), and whole body (?1.26% ± 0.49%) but not at the forearm. In conclusion, the need for calcium and active vitamin D is reduced significantly during PTH‐RT, whereas plasma calcium and phosphate levels are maintained within the physiologic range. In contrast to the effect of PTH(1–84) treatment in patients with osteoporosis, PTH‐RT in hypoparathyroidism causes a decrease in BMD. This is most likely due to the marked increased bone turnover. Accordingly, PTH‐RT counteracts the state of overmineralized bone and, during long‐term treatment, may cause a more physiologic bone metabolism. © 2011 American Society for Bone and Mineral Research 相似文献
2.
Sofia Ish-Shalom Yoseph Caraco Nariman Saba Khazen Michal Gershinsky Auryan Szalat Phillip Schwartz Ehud Arbit Hillel Galitzer Jonathan CY Tang Gregory Burshtein Ariel Rothner Arthur Raskin Miriam Blum William D Fraser 《Journal of bone and mineral research》2021,36(6):1060-1068
The standard treatment of primary hypoparathyroidism (hypoPT) with oral calcium supplementation and calcitriol (or an analog), intended to control hypocalcemia and hyperphosphatemia and avoid hypercalciuria, remains challenging for both patients and clinicians. In 2015, human parathyroid hormone (hPTH) (1-84) administered as a daily subcutaneous injection was approved as an adjunctive treatment in patients who cannot be well controlled on the standard treatments alone. This open-label study aimed to assess the safety and efficacy of an oral hPTH(1-34) formulation as an adjunct to standard treatment in adult subjects with hypoparathyroidism. Oral hPTH(1-34) tablets (0.75 mg human hPTH(1-34) acetate) were administered four times daily for 16 consecutive weeks, and changes in calcium supplementation and alfacalcidol use, albumin-adjusted serum calcium (ACa), serum phosphate, urinary calcium excretion, and quality of life throughout the study were monitored. Of the 19 enrolled subjects, 15 completed the trial per protocol. A median 42% reduction from baseline in exogenous calcium dose was recorded (p = .001), whereas median serum ACa levels remained above the lower target ACa levels for hypoPT patients (>7.5 mg/dL) throughout the study. Median serum phosphate levels rapidly decreased (23%, p = .0003) 2 hours after the first dose and were maintained within the normal range for the duration of the study. A notable, but not statistically significant, median decrease (21%, p = .07) in 24-hour urine calcium excretion was observed between the first and last treatment days. Only four possible drug-related, non-serious adverse events were reported over the 16-week study, all by the same patient. A small but statistically significant increase from baseline quality of life (5%, p = .03) was reported by the end of the treatment period. Oral hPTH(1-34) treatment was generally safe and well tolerated and allowed for a reduction in exogenous calcium supplementation, while maintaining normocalcemia in adult patients with hypoparathyroidism. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). 相似文献
3.
Mara J Horwitz Mary Beth Tedesco Susan M Sereika Linda Prebehala Caren M Gundberg Bruce W Hollis Alessandro Bisello Adolfo Garcia‐Ocaña Raquel M Carneiro Andrew F Stewart 《Journal of bone and mineral research》2011,26(9):2287-2297
Human in vivo models of primary hyperparathyroidism (HPT), humoral hypercalcemia of malignancy (HHM), or lactational bone mobilization for more than 48 hours have not been described previously. We therefore developed 7‐day continuous‐infusion models using human parathyroid hormone(1–34) [hPTH(1–34)] and human parathyroid hormone–related protein(1–36) [hPTHrP(1–36)] in healthy human adult volunteers. Study subjects developed sustained mild increases in serum calcium (10.0 mg/dL), with marked suppression of endogenous PTH(1–84). The maximal tolerated infused doses over a 7‐day period (2 and 4 pmol/kg/h for PTH and PTHrP, respectively) were far lower than in prior, briefer human studies (8 to 28 pmol/kg/h). In contrast to prior reports using higher PTH and PTHrP doses, both 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3] and tubular maximum for phosphorus (TmP/GFR) remained unaltered with these low doses despite achievement of hypercalcemia and hypercalciuria. As expected, bone resorption increased rapidly and reversed promptly with cessation of the infusion. However, in contrast to events in primary HPT, bone formation was suppressed by 30% to 40% for the 7 days of the infusions. With cessation of PTH and PTHrP infusion, bone‐formation markers abruptly rebounded upward, confirming that bone formation is suppressed by continuous PTH or PTHrP infusion. These studies demonstrate that continuous exposure of the human skeleton to PTH or PTHrP in vivo recruits and activates the bone‐resorption program but causes sustained arrest in the osteoblast maturation program. These events would most closely mimic and model events in HHM. Although not a perfect model for lactation, the increase in resorption and the rebound increase in formation with cessation of the infusions are reminiscent of the maternal skeletal calcium mobilization and reversal that occur following lactation. The findings also highlight similarities and differences between the model and HPT. © 2011 American Society for Bone and Mineral Research 相似文献
4.
David B Karpf Susanne Pihl Sanchita Mourya Eva Mortensen Eshwari Kovoor Denka Markova Jonathan A Leff 《Journal of bone and mineral research》2020,35(8):1430-1440
TransCon PTH is a sustained-release, essentially inactive prodrug transiently bound to an inert carrier, designed to release PTH(1-34), and in development for hypoparathyroidism (HP). This phase 1, randomized, placebo-controlled, single and multiple ascending dose (SAD and MAD, respectively) trial evaluated safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of TransCon PTH in healthy adults. SAD and MAD cohorts consisted of 10 subjects (eight active, two placebo) who received up to seven single or six multiple ascending doses of TransCon PTH, respectively. TransCon PTH doses ranged from 3.5 to 124 μg PTH(1-34) for the SAD cohorts and 3.5 to 24 μg PTH(1-34)/day for the MAD cohorts. The primary PK endpoint was Free PTH. The PD endpoints included albumin adjusted serum calcium (sCa), fractional excretion of calcium (FECa), intact endogenous PTH(1-84), bone turnover markers, renal tubular maximum reabsorption of phosphate/glomerular filtration rate (TMP/GFR), serum phosphate (sP) and magnesium, and 1,25 dihydroxyvitamin D. TransCon PTH was generally well tolerated; there were no drug-related serious adverse events (SAEs), and all AEs were transient in nature. Free PTH demonstrated an effective half-life of approximately 60 hours and a dose-dependent, sustained exposure with an infusion-like profile within the calculated physiologic range for active PTH at steady-state. Albumin-adjusted sCa demonstrated a dose-dependent, sustained response with complete control of FECa despite modest hypercalcemia at higher doses. Renal tubular maximum reabsorption of phosphate/glomerular filtration rate (TMP/GFR) showed a dose-dependent decrease, resulting in a dose-dependent decrease in sP. TransCon PTH administered daily for 10 days showed no increase in the osteoblastic bone formation markers, serum bone-specific alkaline phosphatase (BSAP) or P1NP, or the osteoclastic bone resorption marker, urine NTx, but modestly and transiently increased the osteoclast marker, serum CTx. These phase 1 data support TransCon PTH as a daily replacement therapy for HP providing physiological levels of PTH 24 hours per day and advancement into phase 2 clinical development. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research. 相似文献
5.
Sikjaer T Rejnmark L Thomsen JS Tietze A Brüel A Andersen G Mosekilde L 《Journal of bone and mineral research》2012,27(4):781-788
Hypoparathyroidism (hypoPT) is characterized by a state of low bone turnover and high bone mineral density (BMD) despite conventional treatment with calcium supplements and active vitamin D analogues. To assess effects of PTH substitution therapy on 3‐dimensional bone structure, we randomized 62 patients with hypoPT into 24 weeks of treatment with either PTH(1‐84) 100 µg/day subcutaneously or similar placebo as an add‐on therapy. Micro‐computed tomography was performed on 44 iliac crest bone biopsies (23 on PTH treatment) obtained after 24 weeks of treatment. Compared with placebo, PTH caused a 27% lower trabecular thickness (p < 0.01) and 4% lower trabecular bone tissue density (p < 0.01), whereas connectivity density was 34% higher (p < 0.05). Trabecular tunneling was evident in 11 (48%) of the biopsies from the PTH group. Patients with tunneling had significantly higher levels of biochemical markers of bone resorption and formation. At cortical bone, number of Haversian canals per area was 139% higher (p = 0.01) in the PTH group, causing a tendency toward an increased cortical porosity (p = 0.09). At different subregions of the hip, areal BMD (aBMD) and volumetric BMD (vBMD), as assessed by dual‐energy X‐ray absorptiometry (DXA) and quantitative computed tomography (QCT), decreased significantly by 1% to 4% in the PTH group. However, at the lumbar spine, aBMD decreased by 1.8% (p < 0.05), whereas vBMD increased by 12.8% (p = 0.02) in the PTH compared with the placebo group. © 2012 American Society for Bone and Mineral Research. 相似文献
6.
The 'oral 1,25-dihydroxyvitamin D3 pulse therapy' in hemodialysis patients with severe secondary hyperparathyroidism 总被引:3,自引:0,他引:3
Y Tsukamoto M Nomura Y Takahashi Y Takagi A Yoshida T Nagaoka K Togashi R Kikawada F Marumo 《Nephron》1991,57(1):23-28
Many hemodialysis patients are still suffering from secondary hyperparathyroidism although 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has been used to treat renal osteodystrophy for the last two decades. The main reason for its failure to correct the secondary hyperparathyroidism is that in patients, hypercalcemia occurs before adequate parathyroid hormone (PTH) suppression is obtained when a large daily dose of 1,25(OH)2D3 is started. In this study, the oral dose of 1,25(OH)2D3 (4.0 micrograms) was administered only twice a week at the end of hemodialysis ('oral 1,25(OH)2D3 pulse therapy'), in 19 patients with severe secondary hyperparathyroidism. Serum immunoreactive PTH started to decrease after 6 weeks of therapy, and the original level of 41.2 +/- 7.24 was reduced to 24.4 +/- 6.12 ng/ml by the end of the 6-month therapy (p less than 0.001). Serum alkaline phosphatase also was reduced by 64.4%. Three out of 19 patients suffered from hypercalcemia during the 4th month of therapy. Calcium supplement given to 6 other patients with severe secondary hyperparathyroidism did not lower serum PTH levels significantly after 6 weeks of therapy, although serum calcium levels increased and were sustained above 10 mg/dl for the last 5 weeks. These findings strongly suggest that the suppressive effect of the oral 1,25(OH)2D3 pulse therapy was attained by a direct action of 1,25(OH)2D3 on the parathyroid gland rather than by its ability to elevate serum calcium levels. In conclusion, the oral 1,25(OH)2D3 pulse therapy effectively lowered PTH levels in hemodialysis patients who cannot tolerate large daily doses of 1,25(OH)2D3. 相似文献
7.
The objective of this study was to assess the effect on calcium homeostasis of changing PTH replacement therapy (PTH-RT) from intact PTH (PTH1–84) to teriparatide (PTH1–34). This study is a consecutive case series. All patients with postoperative hypoparathyroidism who changed medication from PTH1–84 (100 µg) to PTH1–34 (20 µg) were included. Plasma ionized calcium, daily dose of 1α-hydroxylated-vitamin D metabolites alfacalcidol, calcium, TSH and PTH was collected. Eight patients (women = 88 %) with a mean age of 54 ± 12 years and a duration of hypoPT of 13 ± 6 years were included. Before initiation of PTH1–84, the mean daily dose of alfacalcidol was 1.9 ± 1.1 µg/d and calcium supplements were 1,550 ± 705 mg. Alfacalcidol dose was reduced with 88 ± 29 % (p < 0.01) after 6 months of PTH1–84 treatment and terminated in six patients. Calcium levels were reduced with 78 ± 36 % (p = 0.02) to 273 ± 353 mg/d and stopped in five patients. Six patients received 100 µg PTH1–84 daily, the seventh 2 out of 3 days and the last every second day. When changing from PTH1–84 to PTH1–34, plasma ionized calcium initially dropped and the demand for supplements increased. Alfacalcidol was resumed in five patients; mean daily dose increased to 1.50 ± 1.56 µg/d, (p = 0.02) and calcium increased to 329 ± 368 mg/d, (p = 0.72). Five patients received 20 µg PTH1–34 a day, two patients twice-a-day and one 20/40 µg/d alternately. Compared with PTH1–34, PTH1–84 has a longer plasma half-life and a higher calcemic response. We have shown a need for higher doses of alfacalcidol and calcium supplements to maintain normal serum calcium when treated with PTH1–34 compared to PTH1–84 and in some a need for more than one daily PTH1–34 dose. 相似文献
8.
Finch JL Brown AJ Slatopolsky E 《Journal of the American Society of Nephrology : JASN》1999,10(5):980-985
1,25-Dihydroxy-vitamin D3 [1,25-(OH)2D3] suppresses the secretion and synthesis of parathyroid hormone (PTH) and has been used in the treatment of secondary hyperparathyroidism. However, 1,25-(OH)2D3 can induce hypercalcemia, which often precludes its use. Therefore, an analog of 1,25-(OH)2D3 that would retain its therapeutic effects but produce minor effects on calcium and phosphorus metabolism could be an ideal tool for the treatment of secondary hyperparathyroidism. It has been shown that 19-nor-1,25-dihydroxy-vitamin D2 [19-nor-1,25-(OH)2D2], an analog of 1,25-(OH)2D3, can suppress PTH levels in uremic rats at doses that do not affect plasma ionized calcium levels. The experiments presented here, using parathyroidectomized rats fed diets deficient in either calcium (0.02%) or phosphorus (0.02%), were performed to compare the effects of 1,25-(OH)2D3 and 19-nor-1,25-(OH)2D2 on calcium and phosphorus resorption in bone. Parathyroidectomized rats received daily intraperitoneal injections of vehicle, 1,25-(OH)2D3 (100 ng), or 19-nor-1,25-(OH)2D2 (100 or 1000 ng) for 9 d. Plasma calcium and phosphorus levels were monitored during the study, and ionized calcium levels were determined at the end of the study. By 9 d, 1,25-(OH)2D3 (100 ng/d) increased total calcium levels to 12.4+/-0.26 mg/dl, compared with 6.32+/-0.25 mg/dl (P<0.001) in control animals. The same dose of 19-nor-1,25-(OH)2D2 (100 ng/d) was much less potent (9.45+/-0.28 mg/dl, P<0.001). Similar results were seen with ionized calcium levels [19-nor-1,25-(OH)2D2, 3.61+/-0.12 mg/dl; 1,25-(OH)2D3, 5.03+/-0.16 mg/dl; P<0.001]. Ionized calcium levels were also lower in rats receiving the higher dose (1000 ng) of 19-nor-1,25-(OH)2D2 (4.59+/-0.09 mg/dl, P<0.05). Similar results were seen in rats fed the phosphorus-deficient diet. 1,25-(OH)2D3 (100 ng) increased plasma phosphorus levels from 4.30+/-0.39 mg/dl in vehicle-treated rats to 7.43+/-0.26 mg/dl (P<0.001). The same dose of 19-nor-1,25-(OH)2D2 had no effect (5.19+/-0.32 mg/dl), whereas the high dose (1000 ng) increased plasma phosphorus levels (7.31+/-0.24 mg/dl) in a manner similar to that of 1,25-(OH)2D3 (100 ng). Therefore, 19-nor-1,25-(OH)2D2 is approximately 10 times less effective in mobilizing calcium and phosphorus from the skeleton, compared with 1,25-(OH)2D3. With its ability to suppress PTH at noncalcemic doses, 19-nor-1,25-(OH)2D2 is a potential therapeutic tool for the treatment of secondary hyperparathyroidism in chronic renal failure. 相似文献
9.
Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2 vitamin D. 总被引:1,自引:0,他引:1
Mara J Horwitz Mary Beth Tedesco Susan M Sereika Mushtaq A Syed Adolfo Garcia-Oca?a Alessandro Bisello Bruce W Hollis Clifford J Rosen John J Wysolmerski Pamela Dann Caren Gundberg Andrew F Stewart 《Journal of bone and mineral research》2005,20(10):1792-1803
Osteoblast activity and plasma 1,25(OH)2 vitamin D are increased in HPT but suppressed in HHM. To model HPT and HHM, we directly compared multiday continuous infusions of PTH versus PTHrP in humans. Continuous infusion of both PTH and PTHrP results in marked and prolonged suppression of bone formation; renal 1,25(OH)2D synthesis was stimulated effectively by PTH but poorly by PTHrP. INTRODUCTION: PTH and PTH-related protein (PTHrP) cause primary hyperparathyroidism (HPT) and humoral hypercalcemia of malignancy (HHM), respectively. Whereas HHM and HPT resemble one another in many respects, osteoblastic bone formation and plasma 1,25(OH)2 vitamin D are increased in HPT but reduced in HHM. MATERIALS AND METHODS: We performed 2- to 4-day continuous infusions of escalating doses of PTH and PTHrP in 61 healthy young adults, comparing the effects on serum calcium and phosphorus, renal calcium and phosphorus handling, 1,25(OH)2 vitamin D, endogenous PTH(1-84) concentrations, and plasma IGF-1 and markers of bone turnover. RESULTS: PTH and PTHrP induced comparable effects on renal calcium and phosphorus handling, and both stimulated IGF-1 and bone resorption similarly. Surprisingly, PTH was consistently more calcemic, reflecting a selectively greater increase in renal 1,25(OH)2 vitamin D production by PTH. Equally surprisingly, continuous infusion of both peptides markedly, continuously, and equivalently suppressed bone formation. CONCLUSIONS: PTHrP and PTH produce markedly different effects on 1,25(OH)2 vitamin D homeostasis in humans, leading to different calcemic responses. Moreover, both peptides produce profound suppression of bone formation over multiple days, contrasting with events in HPT, but mimicking HHM. These findings underscore the facts that the mechanisms underlying the anabolic skeletal response to PTH and PTHrP in humans is poorly understood, as are the signal transduction mechanisms that link the renal PTH receptor to 1,25(OH)2 vitamin D synthesis. These studies emphasize that much remains to be learned regarding the normal regulation of vitamin D metabolism and bone formation in response to PTH and PTHrP in humans. 相似文献
10.
Diphtheria Toxin‐ and GFP‐Based Mouse Models of Acquired Hypoparathyroidism and Treatment With a Long‐Acting Parathyroid Hormone Analog
下载免费PDF全文
![点击此处可从《Journal of bone and mineral research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Ruiye Bi Yi Fan Kelly Lauter Jing Hu Tomoyuki Watanabe Jim Cradock Quan Yuan Thomas Gardella Michael Mannstadt 《Journal of bone and mineral research》2016,31(5):975-984
Hypoparathyroidism (HP) arises most commonly from parathyroid (PT) gland damage associated with neck surgery, and is typically treated with oral calcium and active vitamin D. Such treatment effectively increases levels of serum calcium (sCa), but also brings risk of hypercalciuria and renal damage. There is thus considerable interest in using PTH or PTH analogs to treat HP. To facilitate study of this disease and the assessment of new treatment options, we developed two mouse models of acquired HP, and used them to assess efficacy of PTH(1–34) as well as a long‐acting PTH analog (LA‐PTH) in regulating blood calcium levels. In one model, we used PTHcre‐iDTR mice in which the diphtheria toxin (DT) receptor (DTR) is selectively expressed in PT glands, such that systemic DT administration selectively ablates parathyroid cells. For the second model, we generated GFP‐PT mice in which green fluorescent protein (GFP) is selectively expressed in PT cells, such that parathyroidectomy (PTX) is facilitated by green fluorescence of the PT glands. In the PTHcre‐iDTR mice, DT injection (2 × 5 μg/kg, i.p.) resulted in moderate yet consistent reductions in serum PTH and sCa levels. The more severe hypoparathyroid phenotype was observed in GFP‐PT mice following GFP‐guided PTX surgery. In each model, a single subcutaneous injection of LA‐PTH increased sCa levels more effectively and for a longer duration (>24 hours) than did a 10‐fold higher dose of PTH(1–34), without causing excessive urinary calcium excretion. These new mouse models thus faithfully replicate two degrees of acquired HP, moderate and severe, and may be useful for assessing potential new modes of therapy. © 2015 American Society for Bone and Mineral Research. 相似文献
11.
Diana Ovejero Iris R Hartley Luis Fernandez de Castro Diaz Elizabeth Theng Xiaobai Li Rachel I Gafni Michael T Collins 《Journal of bone and mineral research》2022,37(2):179-184
Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) both influence blood phosphate levels by regulating urinary phosphate reabsorption. Clinical data suggest that adequate renal phosphate handling requires the presence of both FGF23 and PTH, but robust evidence is lacking. To investigate whether the phosphaturic effects of PTH and FGF23 are interdependent, 11 patients with hypoparathyroidism, which features high blood phosphate in spite of concomitant FGF23 elevation, and 1 patient with hyperphosphatemic familial tumoral calcinosis (HFTC), characterized by deficient intact FGF23 action and resulting hyperphosphatemia, were treated with synthetic human PTH 1–34 (hPTH 1–34). Biochemical parameters, including blood phosphate, calcium, intact FGF23 (iFGF23), nephrogenic cAMP, 1,25(OH)2 vitamin D (1,25D), and tubular reabsorption of phosphate (TRP), were measured at baseline and after hPTH 1–34 treatment. In patients with hypoparathyroidism, administration of hPTH 1–34 increased nephrogenic cAMP, which resulted in serum phosphate normalization followed by a significant decrease in iFGF23. TRP initially decreased and returned to baseline. In the patient with HFTC, hPTH 1–34 administration also increased nephrogenic cAMP, but this did not produce changes in phosphate or TRP. No changes in calcium were observed in any of the studied patients, although prolonged hPTH 1–34 treatment did induce supraphysiologic 1,25D levels in the patient with HFTC. Our results indicate that PTH and FGF23 effects on phosphate regulation are interdependent and both are required to adequately regulate renal phosphate handling. Published 2021. This article is a U.S. Government work and is in the public domain in the USA. 相似文献
12.
Lieke S Kamphuis Femke Bonte‐Mineur Jan A van Laar P Martin van Hagen Paul L van Daele 《Journal of bone and mineral research》2014,29(11):2498-2503
Granulomas in sarcoidosis express high levels of 1α‐hydroxylase, an enzyme that catalyzes the hydroxylation of 25‐OH vitamin D to its active form, 1,25(OH)2 vitamin D. Overproduction of 1α‐hydroxylase is held responsible for the development of hypercalcemia in sarcoidosis patients. Corticosteroids are used as first‐line treatment in organ‐threatening sarcoidosis. In this light, osteoporosis prevention with calcium and vitamin D (CAD) supplementation is often warranted. However, sarcoidosis patients are at risk for hypercalcemia, and CAD supplementation affects the calcium metabolism. We studied calcium and vitamin D disorders in a large cohort of sarcoidosis patients and investigated if CAD supplementation is safe. Retrospectively, data of 301 sarcoidosis patients from July 1986 to June 2009 were analyzed for serum calcium, 25‐hydroxy vitamin D (25‐(OH)D), 1,25‐dihydroxy vitamin D (1,25(OH)2D), and use of CAD supplementation. Disease activity of sarcoidosis was compared with serum levels of vitamin D. Hypercalcemia occurred in 8%. A significant negative correlation was found between 25‐(OH)D and disease activity of sarcoidosis measured by somatostatin receptor scintigraphy. In our study, 5 of the 104 CAD‐supplemented patients developed hypercalcemia, but CAD supplementation was not the cause of hypercalcemia. Patients without CAD supplementation were at higher risk for developing hypercalcemia. During CAD supplementation, no hypercalcemia developed as a result of supplementation. Hypovitaminosis D seems to be related with more disease activity of sarcoidosis and, therefore, could be a potential risk factor for disease activity of sarcoidosis. Thus, vitamin D–deficient sarcoidosis patients should be supplemented. © 2014 American Society for Bone and Mineral Research. 相似文献
13.
Mara J Horwitz Marilyn Augustine Leila Kahn Emily Martin Christine C Oakley Raquel M Carneiro Mary Beth Tedesco Angela Laslavic Susan M Sereika Alessandro Bisello Adolfo Garcia‐Ocaña Caren M Gundberg Jane A Cauley Andrew F Stewart 《Journal of bone and mineral research》2013,28(11):2266-2276
Parathyroid hormone‐related protein (PTHrP)(1‐36) increases lumbar spine (LS) bone mineral density (BMD), acting as an anabolic agent when injected intermittently, but it has not been directly compared with parathyroid hormone (PTH)(1‐34). We performed a 3‐month randomized, prospective study in 105 postmenopausal women with low bone density or osteoporosis, comparing daily subcutaneous injections of PTHrP(1‐36) to PTH(1‐34). Thirty‐five women were randomized to each of three groups: PTHrP(1‐36) 400 µg/day; PTHrP(1‐36) 600 µg/day; and PTH(1‐34) 20 µg/day. The primary outcome measures were changes in amino‐terminal telopeptides of procollagen 1 (PINP) and carboxy‐terminal telopeptides of collagen 1 (CTX). Secondary measures included safety parameters, 1,25(OH)2 vitamin D, and BMD. The increase in bone resorption (CTX) by PTH(1‐34) (92%) (p < 0.005) was greater than for PTHrP(1‐36) (30%) (p < 0.05). PTH(1‐34) also increased bone formation (PINP) (171%) (p < 0.0005) more than either dose of PTHrP(1‐36) (46% and 87%). The increase in PINP was earlier (day 15) and greater than the increase in CTX for all three groups. LS BMD increased equivalently in each group (p < 0.05 for all). Total hip (TH) and femoral neck (FN) BMD increased equivalently in each group but were only significant for the two doses of PTHrP(1‐36) (p < 0.05) at the TH and for PTHrP(1‐36) 400 (p < 0.05) at the FN. PTHrP(1‐36) 400 induced mild, transient (day 15) hypercalcemia. PTHrP(1‐36) 600 required a dose reduction for hypercalcemia in three subjects. PTH(1‐34) was not associated with hypercalcemia. Each peptide induced a marked biphasic increase in 1,25(OH)2D. Adverse events (AE) were similar among the three groups. This study demonstrates that PTHrP(1‐36) and PTH(1‐34) cause similar increases in LS BMD. PTHrP(1‐36) also increased hip BMD. PTH(1‐34) induced greater changes in bone turnover than PTHrP(1‐36). PTHrP(1‐36) was associated with mild transient hypercalcemia. Longer‐term studies using lower doses of PTHrP(1‐36) are needed to define both the optimal dose and full clinical benefits of PTHrP. © 2013 American Society for Bone and Mineral Research. © 2013 American Society for Bone and Mineral Research. 相似文献
14.
Vivian Y Pao Sandra Chang Dolores M Shoback Daniel D Bikle 《Journal of bone and mineral research》2009,24(6):1135-1139
Nephrogenic systemic fibrosis (NSF) is a disease of thickened, hard, hyperpigmented skin lesions with or without systemic fibrosis occurring in patients with renal insufficiency and associated with the administration of gadolinium‐containing contrast. The pathogenesis of this disease is unclear, and there is no definitive treatment. We describe a 71‐yr‐old patient with stable chronic lymphocytic leukemia (CLL), end‐stage renal disease (ESRD), and NSF who presented with hypercalcemia in 2006. Before onset of renal insufficiency in 2002, serum calcium, phosphorus, and PTH levels were normal. In 2004, the patient began hemodialysis, and he was diagnosed with NSF in 2005, shortly after undergoing an MRI with gadolinium contrast administration. Over the next 6 mo, albumin‐corrected serum total calcium levels rose from 9.9 to 13.1 mg/dl (normal range, 8.5–10.5 mg/dl) with normal serum phosphorus levels. On admission in September 2006, 1,25‐dihydroxyvitamin D [1,25(OH)2D] levels were elevated at 130.7 pg/ml (normal range, 25.1–66.1 pg/ml). Biopsy of an NSF lesion showed increased 25‐hydroxyvitamin D3–1‐α hydroxylase (CYP27B1) immunostaining compared with the biopsy from a normal control. This is the first reported association of NSF with hypercalcemia caused by elevated 1,25(OH)2D levels. This metabolic disturbance should be sought in future cases to determine a connection between NSF, 1,25(OH)2D metabolism, and CYP27B1 activation in the skin, which may shed light on the pathogenesis of this unusual local and systemic fibrosing disorder. 相似文献
15.
Sara Piemonte Elisabetta Romagnoli Cristiana Cipriani Valeria Fassino Romano Del Fiacco Vincenzo Carnevale Alfredo Scillitani Emilio D’Erasmo Andrea Tancredi Salvatore Minisola 《Calcified tissue international》2009,85(4):287-292
We investigated the frequency of hypercalcemia and/or hypercalciuria following parathyroid hormone (PTH) 1–34 and 1–84 administration
in a crossover trial. Ten postmenopausal osteoporotic women previously treated with bisphosphonates were subdivided into two
groups of five patients each. A 24-h urine collection to determine baseline calcium (Ca) and creatinine (Cr) the day before
administration of PTH was followed by determination of serum ionized Ca (Ca2+), Cr, 25(OH)D, and 1,25(OH)2D at baseline. Thereafter, 100 mcg of PTH(1–84) or 20 mcg of PTH(1–34) was administered. A 24-h urinary collection and blood
samples 2, 4, and 24-h after each PTH administration were again taken. One week after the first PTH administration patients
were rechallenged with the second PTH. The PTH peptides did not differ with respect to changes in Ca2+ at 2, 4, and 24 h postinjection; at the last time point the values were virtually identical to the initial values. There
was no difference in urinary Ca on the day following PTH injection compared to baseline, in terms both of Ca/Cr and of Ca
excretion. The two PTH peptides did not differ with respect to changes in 1,25(OH)2D at 2, 4, and 24 h considering both the absolute values and the percent changes with respect to baseline (24-h 1–84 = 125.6 ± 58.6 pg/ml,
153% increase; 1–34 = 124.1 ± 64.7, 130%). Our results indicate no difference in postinjection serum Ca2+, 1,25(OH)2D, or urinary Ca excretion after a single dose of either PTH(1–84) or PTH(1–34) in patients previously treated with bisphosphonates. 相似文献
16.
Rana Samadfam Qingwen Xia Dengshun Miao Geoffrey N Hendy David Goltzman 《Journal of bone and mineral research》2008,23(8):1257-1266
PTH and 1,25(OH)2D each exert dual anabolic and catabolic skeletal effects. We assessed the potential interaction of PTH and 1,25(OH)2D in promoting skeletal anabolism by comparing the capacity of exogenous, intermittently injected PTH(1‐34) to produce bone accrual in mice homozygous for the 1α(OH)ase‐null allele [1α(OH)ase?/? mice] and in wildtype mice. In initial studies, 3‐mo‐old wildtype mice were either injected once daily (40 μg/kg) or infused continuously (120 μg/kg/d) with PTH(1–34) for up to 1 mo. Infused PTH reduced BMD, increased the bone resorption marker TRACP‐5b, and raised serum calcium but did not increase serum 1,25(OH)2D. Injected PTH increased serum 1,25(OH)2D and BMD, raised the bone formation marker osteocalcin more than did infused PTH, and did not produce sustained hypercalcemia as did PTH infusion. In subsequent studies, 3‐mo‐old 1α(OH)ase?/? mice, raised on a rescue diet, and wildtype littermates were injected with PTH(1–34) (40 μg/kg) either once daily or three times daily for 1 mo. In 1α(OH)ase?/? mice, baseline bone volume (BV/TV) and bone formation (BFR/BS) were lower than in wildtype mice. PTH administered intermittently increased BV/TV and BFR/BS in a dose‐dependent manner, but the increases were always less than in wildtype mice. These studies show that exogenous PTH administered continuously resorbs bone without raising endogenous 1,25(OH)2D. Intermittently administered PTH can increase bone accrual in the absence of 1,25(OH)2D, but 1,25(OH)2D complements this PTH action. An increase in endogenous 1,25(OH)2D may therefore facilitate an optimal skeletal anabolic response to PTH and may be relevant to the development of improved therapeutics for enhancing skeletal anabolism. 相似文献
17.
M. Kurajoh M. Inaba S. Yamada Y. Imanishi T. Tsuchida E. Ishimura Y. Nishizawa 《Osteoporosis international》2008,19(5):709-716
Summary As the serum calcium and glomerular filtration rate decreased, the proportion of active PTH(1–84) molecules in PTH immunoreactivity
increased in serum from predialysis uremic patients, particularly those with vitamin D insufficiency.
Introduction The PTH(1–84) fraction was altered in predialysis patients with chronic renal failure (CRF).
Methods Serum PTH in predialysis CRF patients without any medication was measured by PTH(1–84)-specific whole PTH assay and intact
PTH assay cross-reacting with N-truncated PTH.
Results In CRF patients, the glomerular filtration rate (GFR) correlated positively with serum Ca and 1,25-dihydroxyvitamin D (1,25(OH)2D), and inversely with serum Pi, log intact PTH, and log whole PTH. In multiple regression analysis, including age, gender,
body mass index, GFR, Ca, and Pi and 1,25(OH)2D as independent variables, serum Ca and GFR associated significantly with serum log whole PTH and intact PTH. Serum log whole
PTH/intact PTH ratio, which increased as serum Ca and GFR decreased, retained a negative correlation in those with serum 25-hydroxyvitamin
D levels below 20 ng/ml, but not in those above 20 ng/ml. The ratio also correlated positively with serum log tartrate-resistant
acid-phosphatase-5b, log cross-linked N-telopeptide of type-I collagen, and log bone alkaline-phosphatase.
Conclusion As GFR declined with suppression of serum Ca, the proportion of active PTH molecules increased in predialysis CRF patients,
particularly those with vitamin D insufficiency. 相似文献
18.
M. R. Rubin J. Sliney Jr. D. J. McMahon S. J. Silverberg J. P. Bilezikian 《Osteoporosis international》2010,21(11):1927-1934
Summary
Hypoparathyroidism, a disorder characterized by low parathyroid hormone (PTH), is generally treated with oral calcium and vitamin D supplementation. We investigated the effects of PTH(1–84) treatment in 30 hypoparathyroid subjects for 24 months. PTH(1–84) treatment in hypoparathyroidism significantly reduced supplemental calcium and 1,25-dihydroxyvitamin D requirements without generally altering serum and urinary calcium levels. 相似文献19.
Chronic kidney disease (CKD) disturbs mineral homeostasis, leading to mineral and bone disorders (MBD). CKD-MBD is a significant problem and currently available treatment options have important limitations. Phosphate retention is thought to be the initial cause of CKD-MBD but serum phosphate remains normal until the late stages of CKD, due to elevated levels of the phosphaturic hormone fibroblast growth factor-23 (FGF-23), and parathyroid hormone (PTH). Reduction of 1,25-dihydroxy-vitamin D (1,25[OH]2D) concentration is the next event in the adaptive response of the homeostatic system. We argue, and provide the rationale, that calcium retention which takes place concurrently with phosphate retention, could be the reason behind the hysteresis in the response of PTH. If indeed this is the case, intermittent administration of PTH in early CKD could prevent the hysteresis, which arguably leads to the development of secondary hyperparathyroidism, and provide the platform for an effective management of CKD-MBD. © 2020 American Society for Bone and Mineral Research (ASBMR). 相似文献
20.
Lars Holten-Andersen Susanne Pihl Caroline E Rasmussen Joachim Zettler Guillaume Maitro Julia Baron Stefan Heinig Eric Hoffmann Thomas Wegge Mathias Krusch Frank Faltinger Steffen Killian Kennett Sprogoe David B Karpf Vibeke Miller Breinholt Felix Cleemann 《Journal of bone and mineral research》2019,34(11):2075-2086
Hypoparathyroidism (HP) is a condition of parathyroid hormone (PTH) deficiency leading to abnormal calcium and phosphate metabolism. The mainstay of therapy consists of vitamin D and calcium supplements, as well as adjunct Natpara (PTH(1-84)). However, neither therapy optimally controls urinary calcium (uCa) or significantly reduces the incidence of hypercalcemia and hypocalcemia. TransCon PTH, a sustained-release prodrug of PTH(1-34) in development for the treatment of HP, was designed to overcome these limitations. To determine the pharmacokinetics and pharmacodynamics of TransCon PTH, single and repeat s.c. dose studies were performed in rats and monkeys. TransCon PTH demonstrated a half-life of 28 and 34 hours in rats and monkeys, respectively. After repeated dosing, an infusion-like profile of the released PTH, characterized by low peak-to-trough levels, was obtained in both species. In intact rats and monkeys, daily subcutaneous administration of TransCon PTH was associated with increases in serum calcium (sCa) levels and decreases in serum phosphate levels (sP). In monkeys, at a single dose of TransCon PTH that increased sCa levels within the normal range, a concurrent decrease in uCa excretion was observed. In 4-week repeat-dose studies in intact rats and monkeys, uCa excretion was comparable to controls across all dose levels despite increases in sCa levels. Further, in a rat model of HP, TransCon PTH normalized sCa and sP levels 24 hours per day. This was in contrast to only transient trends toward normalization of sCa and sP levels with an up to 6-fold higher molar dose of PTH(1-84). After repeated dosing to HP rats, uCa excretion transiently increased, corresponding to increases in sCa above normal range, but at the end of the treatment period, uCa excretion was generally comparable to sham controls. TransCon PTH was well tolerated and the observed pharmacokinetics and pharmacodynamics were in line with the expected action of physiological replacement of PTH. © 2019 American Society for Bone and Mineral Research. 相似文献