Long-term treatment of hypoparathyroidism: a randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium

Hypoparathyroidism is one of the few remaining hormonal insufficiency states for which replacement therapy is unavailable. Previous short-term controlled trials have shown PTH to be a safe and effective treatment of hypoparathyroidism. In this randomized, parallel group, open-label trial, we compared synthetic human PTH-(1-34) (PTH) with conventional therapy, calcitriol and calcium, over a 3-yr period. Twenty-seven patients with confirmed hypoparathyroidism, aged 18-70 yr, were randomized to either twice daily sc PTH or oral calcitriol and calcium. The primary end points were calcium levels in serum and urine. Secondary end points were creatinine clearance, markers of bone turnover, and bone mineral density. Throughout the 3-yr study period, serum calcium levels were similar in both treatment groups within or just below the normal range. Mean urinary calcium excretion was within the normal range from 1-3 yr in PTH-treated patients, but remained above normal in the calcitriol group. Bone mineral content and bone mineral density showed no significant between-group differences over the 3-yr study period. We conclude that treatment with twice daily sc PTH provides a safe and effective alternative to calcitriol therapy and is able to maintain normal serum calcium levels without hypercalciuria for at least 3 yr in patients with hypoparathyroidism.     

Effects of once versus twice-daily parathyroid hormone 1-34 therapy in children with hypoparathyroidism

Context: Hypoparathyroidism is among the few hormonal insufficiency states not treated with replacement of the missing hormone. Long-term conventional therapy with vitamin D and analogs may lead to nephrocalcinosis and renal insufficiency. Objective: Our objective was to compare the response of once-daily vs. twice-daily PTH 1-34 treatment in children with hypoparathyroidism. Setting: The study was conducted at a clinical research center. Subjects: Fourteen children ages 4-17 yr with chronic hypoparathyroidism were studied. Study Design: This was a randomized cross-over trial, lasting 28 wk, which compared two dose regimens, once-daily vs. twice-daily PTH1-34. Each 14-wk study arm was divided into a 2-wk inpatient dose-adjustment phase and a 12-wk outpatient phase. Results: Mean predose serum calcium was maintained at levels just below the normal range. Repeated serum measures over a 24-h period showed that twice-daily PTH 1-34 increased serum calcium and magnesium levels more effectively than a once-daily dose. This was especially evident during the second half of the day (12-24 h). PTH 1-34 normalized mean 24-h urine calcium excretion on both treatment schedules. This was achieved with half the PTH 1-34 dose during the twice-daily regimen compared with the once-daily regimen (twice-daily, 25 +/-15 mug/d vs. once-daily, 58 +/- 28 mug/d; P < 0.001). Conclusions: We conclude that a twice-daily PTH 1-34 regimen provides a more effective treatment of hypoparathyroidism compared with once-daily treatment because it reduces the variation in serum calcium levels and accomplishes this at a lower total daily PTH 1-34 dose. The results showed, as in the previous study of adult patients with hypoparathyroidism, that a twice-daily regimen produced significantly improved metabolic control compared with once-daily PTH 1-34.     

Synthetic human parathyroid hormone 1-34 fragment for diagnostic testing

Since bovine parathyroid extract became unavailable for stimulatory testing, the differentiation between hypoparathyroidism and pseudohypoparathyroidism has been made from the measurement of serum parathyroid hormone (PTH) values alone. Responsiveness to PTH can once again be tested with teriparatide acetate, the newly available, biologically active 1-34 fragment of human PTH. The PTH infusion test can be used to confirm a preliminary diagnosis based on serum immunoreactive PTH values, to differentiate between type 1 and type 2 pseudohypoparathyroidism, or to detect a subtle abnormality of calcium metabolism in normocalcemic patients with features suggesting pseudohypoparathyroidism. Of several variables used to express changes in renal metabolism of cyclic adenosine 3',5'-monophosphate (cAMP) or phosphate, the 30-minute change in cAMP excretion per unit of glomerular filtration and the 60-minute percentage fall in the tubular maximum for phosphate reabsorption provide the best discrimination. Teriparatide has a low incidence of adverse reactions and provides an effective diagnostic tool.     

Transient hypoparathyroidism induced by synthetic human parathyroid hormone-(1-34) treatment

Daily injections of low doses of a synthetic fragment of human PTH [hPTH-(1-34) have increased iliac trabecular bone volume when used in the treatment of osteoporosis. In approximately 50 patients no major side-effects had occurred. However, during daily sc 100-micrograms injections of the peptide, one patient repeatedly developed parathyroid hypofunction which resolved each time treatment was stopped. Specific immunoglobulin G (IgG) antibodies binding [125I]hPTH-(1-34) were identified in the patient's serum, and positive immunohistochemical reactions were obtained when bovine parathyroid sections were exposed to the patient's IgG. After adsorption with PTH, the patient's IgG, free of anti-PTH antibodies, reacted with renal cell membranes, as demonstrated by indirect immunofluorescence and blocked renal PTH-dependent adenylate-cyclase activation in vitro. These results support the hypothesis that anti-PTH receptor as well as anti-PTH antibodies were generated during hPTH-(1-34) treatment, which led to the development of hypoparathyroidism when their titers were high.     

Growth hormone (GH) replacement in GH-deficient adults: a crossover trial comparing the effect on metabolic control, well-being and compliance of three injections per week versus daily injections

Growth hormone (GH) replacement therapy regimens in adults using daily subcutaneous (sc) injections may not be optimal with respect to carbohydrate and lipid metabolism. The aim of this study was to compare the efficacy of three times weekly injections with daily sc GH injections in terms of serum IGF-I, IGFBPs, lipoprotein levels, serum bone markers, glucose metabolism, body composition, compliance and well-being.Twenty hypopituitary men, 46–76 years, on a course of stable conventional GH replacement therapy for more than 12 months, were included in a 16-week crossover trial. During the first 8 weeks GH was administered three times per week followed by 8 weeks with daily sc injections with the same weekly dose of GH. Fasting serum samples were collected at baseline and on two consecutive days at the end of each 8-week period.Serum IGF-I and IGFBP-3 concentrations were lower both the first and second morning after the last injection during the period with three injections per week. The second morning after the last GH injection in this period the IGF-I/BP-3 ratio, plasma insulin and FFA were lower whereas IGFBP-1 was increased as compared with values obtained during the period with daily injections. Serum Lp(a) levels, body composition, fat distribution, well-being and compliance were not differently affected by the two treatment regimens.These results suggest that the same weekly dose of GH given as three injections per week reduces serum IGF-I and IGFBP-3 levels without affecting Lp(a) levels. The day-to-day variation in glucose metabolism and FFA serum levels differs considerably between the two modes of GH administration.     

Prospective randomized crossover trial comparing fibre with lactulose in the treatment of idiopathic chronic constipation

Background Fibre is often recommended as the first-choice treatment but its effects can be uneven. The aim of the study was to compare the clinical efficacy and tolerability of fibre versus lactulose in outpatients with chronic constipation. Methods In a prospective randomized crossover trial, patients were randomized to receive fibre or lactulose for four weeks. Between treatments, patients had at least one week free of laxatives. Results 50 patients, of median age 50 years (range, 18–85) were recruited and 39 patients completed the trial. Compared to fibre, lactulose resulted in significantly higher mean bowel frequency (7.3, 95% CI 5.7 to 8.9 vs. 5.5, 95% CI 4.4 to 6.5; p=0.001) and stool consistency score (3.4, 95% CI 3.1 to 3.7 vs. 2.9, 95% CI 2.5 to 3.3; p=0.018). Scores for ease of evacuation were similar. The frequencies of adverse effects were not significantly different, but greater in the lactulose group. Mean patients’ recorded improvement score was significantly higher after taking lactulose than fibre (6.2, 95% CI 5.5 to 7.0 vs. 4.8, 95% CI 4.0 to 5.9; p=0.017). Of the 39 patients who completed the trial, 24 (61.5%) preferred lactulose and 14 (35.9%) preferred fibre. Conclusions Lactulose had better efficacy than fibre for chronic constipation in ambulant patients, although both treatments were equally well tolerated in terms of adverse effects.     

Synthetic human parathyroid hormone-(1-34) for the study of pseudohypoparathyroidism

The synthetic amino-terminal fragment of PTH, PTH-(1-34), was recently released for clinical testing of PTH responsiveness. We measured the urinary cAMP and phosphaturic responses to infusion of PTH-(1-34) [3U/kg BW (200 U maximum), iv in 10 min] in patients with pseudohypoparathyroidism and idiopathic hypoparathyroidism, as well as normal subjects. The protocol used data from 5 30-min urine collections and 4 blood samples. Based on the results in 7 patients with pseudohypoparathyroidism (hypocalcemia with increased serum immunoreactive PTH concentrations), 2 patients with suspected pseudohypoparathyroidism, 9 patients with surgical hypoparathyroidism, and 10 normal subjects, this testing protocol differentiated well among these conditions. The patients with pseudohypoparathyroidism had blunted cAMP and phosphaturic responses to PTH-(1-34) administration compared to those of either normal or hypoparathyroid subjects. Induced hypercalcemia failed to restore a normal cAMP response to PTH-(1-34) infusion in 2 patients with pseudohypoparathyroidism. Calculation of the cAMP response to PTH-(1-34) as nanomoles per dL glomerular filtrate during the first 30 min after infusion provided better differentiation among groups than other parameters of cAMP metabolism. Calculating the phosphaturic response as the percent fall in tubular maximum for phosphate reabsorption during the first hour after infusion gave the best degree of statistical separation among groups. We conclude that this new diagnostic agent is effective for the study of renal responsiveness to PTH, and that the protocol described here reliably differentiates patients with pseudohypoparathyroidism from those with hypocalcemia due to other causes.     

甲状旁腺素1-34对骨质疏松大鼠治疗作用的实验研究

目的探讨甲状旁腺素134(hPTH134)对骨质疏松的治疗作用以及与血钙、磷、维生素D代谢和生长因子的关系。方法用摘除大鼠双侧卵巢的方式制备骨质疏松模型(OVX),实验动物分为4个组:模型对照组(OVX组,摘除大鼠双侧卵巢不作任何处理);hPTH134治疗组(PTH组,摘除大鼠双侧卵巢12w后用hPTH134治疗8w);盐酸雷洛昔芬治疗组(摘除大鼠双侧卵巢12w后用雷洛昔芬治疗8w);假手术组(Sham组,仅切除卵巢周围的脂肪组织约3g,术后12w纳入实验)。应用HOLOGIC第4代双能X线4500W骨密度仪测大鼠腰椎、股骨上段骨密度值(BMD);以骨形态计量学测股骨骨小梁面积、矿化沉积率;用ELISA法测定血清IGF1水平和血清25OHVitD浓度以及血淋巴细胞VitD受体(VDR)含量。结果hPTH134治疗组、盐酸雷洛昔芬治疗组均较OVX组腰椎、股骨上段骨密度增高,组间比较差异有显著性(P<0.01)。hPTH134治疗组较盐酸雷洛昔芬治疗组股骨上段骨密度增高,两组之间差异有显著性(P<0.01)。hPTH134治疗组骨小梁面积明显增加、矿化沉积率增高。hPTH134治疗组、盐酸雷洛昔芬治疗组血清IGF1浓度值、血清25OHVitD浓度值升高,与OVX组比较差异有显著性(P<0.01)。各组血淋巴细胞VDR含量无明显变化,与OVX组比较差异无显著性(P>0.05)。结论hPTH134能够预防腰椎、股骨上段骨密度丢失,使骨小梁面积明显增加、矿化沉积率增高并且血清IGF1及血清25OHVitD浓度值升高,但对VDR含量无明显作用。     

Propafenone versus disopyramide: a double-blind randomized crossover trial in patients presenting chronic ventricular arrhythmias

In vitro and in vivo electrophysiological studies have shown that propafenone could be classified as a class I antiarrhythmic agent. The aim of this study was to investigate the short-term antiarrhythmic efficacy and safety of propafenone in 10 patients compared to disopyramide in a double-blind randomized protocol. Included patients suffered from ventricular arrhythmias with at least 60 ventricular premature beats (VPB) per hour refractory to at least two other antiarrhythmic agents. At the end of the control period and of the two treatment periods during which patients received either propafenone (300 mg three times a day) or disopyramide (200 mg three times a day), clinical examination, Holter recordings, electrocardiogram, and clinical laboratory tests were performed. The PR interval and the QRS interval were significantly increased with propafenone, but not with disopyramide. The cQT interval was not significantly changed by either propafenone or disopyramide. Heart rate was decreased with propafenone (p less than 0.05) with no change in the diurnal/nocturnal circadian ratio variation. Heart rate was significantly decreased with disopyramide only during the day. Five of nine patients in the propafenone group and two of nine patients in the disopyramide group showed a reduction in ventricular premature beats greater than 80%. Total resolution of severe arrhythmias (repetitive events) was seen in 5 of 8 patients with propafenone; 2 of 8 with disopyramide. Adverse events, when they occurred, were mild (visual disturbances, epigastric discomfort, changes in taste perception, transient atrioventricular block with propafenone, and photophobia with disopyramide), and did not require reduction or discontinuation of study drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

国产rhPTH1-34治疗绝经后骨质疏松症的有效性和安全性:随机对照、多中心临床研究

目的 以原研特立帕肽和鲑鱼降钙素为阳性对照,观察国产基因重组人甲状旁腺素氨基端1-34片段(recombinant human parathyroid hormone N-terminal 1-34 fragment, rhPTH1-34)治疗绝经后骨质疏松症的有效性和安全性。方法 纳入绝经后骨质疏松症女性214例,按照1∶1∶1∶0.5比例,随机分为4组：rhPTH1-34 20μg组(n=59)及40μg组(n=62)分别每天注射国产rhPTH1-34 20及40μg;降钙素组(n=61)给予鼻喷鲑鱼降钙素200 IU;特立帕肽组(n=32)给予原研特立帕肽注射20μg/d;疗程均为24周。观察治疗前后腰椎(L1-4)和髋部骨密度(bone mineral density, BMD)的变化率,骨转换生化指标的变化率,包括血清Ⅰ型前胶原N-端肽(procollagen typeⅠN-terminal propeptide, P1NP)和Ⅰ型胶原交联C-末端肽(β-cross linked C-telopeptide of typeⅠcollagen,β-CTX),以及药物治疗的安全性。结果 治疗24周后,rhPTH1-34 20μg及40μg组L1-4 BMD较基线分别增加3.42%和4.82%,特立帕肽组L1-4 BMD增加3.66%(均P<0.05),rhPTH1-34治疗组间骨密度变化率无明显差异;降钙素组腰椎骨密度变化率为-0.01%,骨密度无明显增加(P>0.05)。国产及原研特立帕肽的疗效均优于鼻喷降钙素组。国产与原研rhPTH1-34 20μg组治疗24周使血清P1NP分别升高534.22%和277.86%,使β-CTX水平分别升高247.88%和202.25%(均P<0.001),P1NP增幅大于β-CTX。国产与原研rhPTH1-34组的安全性较好。结论 每天皮下注射20μg国产rhPTH1-34治疗24周能够显著提升腰椎BMD,促进骨形成,疗效及安全性与原研特立帕肽相当,且优于降钙素鼻喷剂。     

Comparisons of avian renal responses to bovine parathyroid extract, synthetic bovine (1-34) parathyroid hormone, and synthetic human (1-34) parathyroid hormone

The structure of avian parathyroid hormone (PTH) is only partially known, therefore studies of the avian renal responses to PTH have been conducted using bovine parathyroid extract (bPTE), synthetic human PTH (h(1-34)PTH), and synthetic bovine PTH (b(1-34)PTH). In vitro studies indicate that these peptides may have quite different chick kidney receptor binding affinities and adenylate cyclase activation potencies. In the present study, the in vivo renal responses to bPTE, b(1-34)PTH, and h(1-34)PTH have been compared in immature domestic fowl. The following parameters were evaluated: glomerular filtration rates; renal plasma flow rates; urine pH; and fractional excretion of sodium, potassium, chloride, calcium, magnesium, and inorganic phosphate. Overall, the different hormonal peptides elicited qualitatively similar responses: they all were phosphaturic, natriuretic, diuretic, hypomagnesiuric, hypocalciuric, and kaliuretic. This is the first study to show an effect of PTH on renal magnesium transport in avian species. Quantitative comparisons make it clear that bPTE is more natriuretic and diuretic, but less phosphaturic than either b(1-34)PTH or h(1-34)PTH. A temporal dissociation of the phosphaturic response from the other mineral and electrolyte responses suggests that the phosphaturic response is mediated by a separate mechanism.     

A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis

Teriparatide (rDNA origin) injection [recombinant human PTH (1-34)] stimulates bone formation, increases bone mineral density (BMD), and restores bone architecture and integrity. In contrast, bisphosphonates reduce bone resorption and increase BMD. We compared the effects of teriparatide and alendronate sodium on BMD, nonvertebral fracture incidence, and bone turnover in 146 postmenopausal women with osteoporosis. Women were randomized to either once-daily sc injections of teriparatide 40 micro g plus oral placebo (n = 73) or oral alendronate 10 mg plus placebo injection (n = 73). Median duration of treatment was 14 months. At 3 months, teriparatide increased lumbar spine BMD significantly more than did alendronate (P < 0.001). Lumbar spine-BMD increased by 12.2% in the teriparatide group and 5.6% in the alendronate group (P < 0.001 teriparatide vs. alendronate). Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one third distal radius decreased, compared with alendronate (P < or = 0.05). Nonvertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group (P < 0.05). Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. In conclusion, teriparatide, a bone formation agent, increased BMD at most sites and decreased nonvertebral fractures more than alendronate.     

Comparison between recombinant human parathyroid hormone(1-34) and elcatonin in treatment of primary osteoporosis

Objective:To evaluate the efficacy and safety of rhPTH(1-34) vs.elcatonin.Methods:Sixty palients with primary OP were randomly divided into two groups according to the ratio of 3:1.rhPTH(1-34) group(PTH group) was treated with subcutaneous injection of rhPTH(1-34) 20 μg daily for 18 months,and the elcalonin group(CT group) was treated with intramuscular injection of elcatonin 20 U weekly for 12 months.Bone mineral density(BMD) of the lumbar spine 2-4(L_(2-4))and femoral neck,serum calcium and phosphorus,urinary calcium,serum hone specific alkaline phosphatase(BSAP).and urinary c-terminal telopeptides of type Ⅰ collagen/creatinine(uCTX-Ⅰ /Cn were tested at baseline,and 6.12.and 18 months after treatment.Results:In PTH group.HMD of L_(2-4),at 6,12.and 18 months,BDM of Femoral neck at 18 month,BSAP at 6 and 12 months and uCTX- Ⅰ /Cr at 6.12 and 18 months were all significantly raised.In CT group.HMD of L_(2-4) at12 month and that of femoral neck at 12 and 18 months were significantly elevated,while HSAP was significantly decreased at 12 and 18 months,and no significant difference on CTX- Ⅰ /Cr was observed.When BMD growth and growth rate between two groups were compared.PTH group had better improvement in L_(2-4) BMD and growth rate than CT group at 6.12.and 18 months.BMD growth and growth rale of femoral neck al 12 month and its growth at 18 month in CT group were higher than in PTH group,hut there was no significant difference between two groups regarding the growth rates at 18 month.Besides,there were no significant differences regarding the rales ol adverse reactions between two groups.Conclusions:rhPTH(1—34),is safe and effective in the treatment of primary OP.It is superior to elcatonin in improving vertebral HMD at onset time,growth rate and growth range,but inferior to elcatonin at HMD of femoral neck.     

Osteopenia in young hypogonadal women with systemic lupus erythematosus receiving chronic steroid therapy: a randomized controlled trial comparing calcitriol and hormonal replacement therapy

OBJECTIVE: To evaluate the efficacy of calcitriol and hormonal replacement therapy (HRT) in the treatment of steroid-induced osteoporosis in hypogonadal women. METHODS: We studied 28 young patients (aged 37 +/- 6 yr) with systemic lupus erythematosus (SLE) on chronic steroid therapy for 130 +/- 22 months and requiring more than 10 mg/day prednisone. They were amenorrhoeic for more than 2 yr with proven ovarian failure. All had osteopenia with a T score at L2-4 of less than -1. They were randomized to receive HRT (conjugated oestrogen 0.625 mg daily from day 1 to day 21 plus medroxyprogesterone acetate 5 mg daily days 10-21) or calcitriol 0.5 microg daily. All received calcium carbonate 1 g/day. RESULTS: There were no differences in the baseline demographic, bone mineral density (BMD) and biochemical data between the two groups. Lumbar spine BMD increased by 2.0 +/- 0.4% after 2 yr with HRT (P<0.05), but reduced by 1.74 +/- 0.4% (P<0.05) with calcitriol treatment. No change was seen at the distal one-third radius with HRT treatment but significant bone loss (2.3 +/- 1.4%, P<0.02) was observed with calcitriol therapy. BMD at the hip did not change in both groups. Comparing both treatment groups, significant differences in the BMD at the spine (P<0.03) and radius (P<0.05) were seen at the end of 2 yr. The changes in urinary n-telopeptide excretion but not serum osteocalcin at 6 months and 12 months were inversely correlated with the changes in lumbar spine BMD at 24 months. HRT did not cause an adverse effect on SLE disease activity. CONCLUSION: HRT but not calcitriol could prevent bone loss in young hypogonadal women on chronic steroid therapy.     

Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized, controlled clinical trial.

Alendronate and estrogen are effective therapies for postmenopausal osteoporosis, but their efficacy and safety as combined therapy are unknown. The objective of this study was to evaluate the addition of alendronate to ongoing hormone replacement therapy (HRT) in the treatment of postmenopausal women with osteoporosis. A total of 428 postmenopausal women with osteoporosis, who had been receiving HRT for at least 1 yr, were randomized to receive either alendronate (10 mg/day) or placebo. HRT was continued in both groups. Changes in bone mineral density (BMD) and biochemical markers of bone turnover were assessed. Compared with HRT alone, at 12 months, alendronate plus HRT produced significantly greater increases in BMD of the lumbar spine (3.6% vs. 1.0%, P < 0.001) and hip trochanter (2.7% vs. 0.5%, P < 0.001); however, the between-group difference in BMD at the femoral neck was not significant (1.7% vs. 0.8%, P = 0.072). Biochemical markers of bone turnover (serum bone-specific alkaline phosphatase and urine N-telopeptide) decreased significantly at 6 and 12 months with alendronate plus HRT, and they remained within premenopausal levels. Addition of alendronate to ongoing HRT was generally well tolerated, with no significant between-group differences in upper gastrointestinal adverse events or fractures. This study demonstrated that, in postmenopausal women with low bone density despite ongoing treatment with estrogen, alendronate added to HRT significantly increased bone mass at both spine and hip trochanter and was generally well tolerated.     

Post-cholecystectomy alkaline reactive gastritis: a randomized trial comparing sucralfate versus rabeprazole or no treatment

OBJECTIVE: At present there are no well-established pharmacological approaches in the management of post-cholecystectomy alkaline reactive gastritis. The aim of this study was to assess the effect of sucralfate versus rabeprazole or no treatment on dyspeptic symptoms and endoscopic/histological signs in a population of patients with a history of cholecystectomy and evidence of alkaline reactive gastritis. METHODS: Sixty dyspeptic patients fulfilling the following criteria of inclusion took part in this study: (1) a history of cholecystectomy; (2) no use of anti-inflammatory steroidal and non-steroidal drugs, or abuse of alcohol; (3) evidence of abundant gastric bile reflux at endoscopy; (4) endoscopic signs of chronic gastritis; (5) histological signs of chronic gastritis; and (6) absence of Helicobacter pylori infection. Dyspeptic symptoms were evaluated by means of a self-administered validated questionnaire. Patients included in the study were randomly assigned to one of three treatment groups for 3 months: sucralfate, rabeprazole, observation. Patients were re-evaluated at the end of the treatment. RESULTS: Sucralfate and rabeprazole therapies were both able to significantly reduce epigastric pain, heartburn, bloating and halitosis. Endoscopic/histological signs were lower in both treatment groups compared to the observation group. CONCLUSION: Both sucralfate and rabeprazole therapies are effective treatment options in the patients with alkaline gastritis when compared with observation.