Efficacy and safety of human parathyroid hormone-(1-84) in increasing bone mineral density in postmenopausal osteoporosis

Daily sc injections of N-terminal analogs of PTH increase bone mass and decrease fractures in osteoporotic women. We investigated the efficacy and safety of human PTH-(1-84) (full-length PTH) in the treatment of postmenopausal osteoporosis in a double-blind, placebo-controlled study. The women (n = 50-53/group) self-administered PTH (50, 75, or 100 microg) or placebo by daily sc injection for 12 months. PTH treatment induced time- and dose-related increases in lumbar spine bone mineral density (BMD). The 100-microg dose increased BMD significantly at 3 months (+2.0%) and 12 months (+7.8%). BMD underestimated the anabolic effect of PTH in lumbar spine (bone mineral content, +10.0%) because bone area increased significantly (+2.0%). A nonsignificant decrease (-0.9%) in total hip BMD occurred during the first 6 months with the 100-microg dose, but this trend reversed (+1.6%) during the second 6 months. Bone turnover markers increased during the first half of the study and were maintained at elevated levels during the second 6 months. Protocol compliance was excellent (95-98%), and treatment was generally safe and well tolerated. Dose-related incidences of transient hypercalcemia occurred, but only one patient (100-microg group) was withdrawn because of repeated hypercalcemia. Thus, full-length PTH was efficacious and safe over 12 months.     

Plasma levels of parathyroid hormone (1-84) whole molecule and parathyroid hormone (7-84)-like fragments in pseudohypoparathyroidism type I

PTH (7-84) has antagonistic effects on the calcemic and phosphaturic actions of PTH (1-84) whole molecule (bioPTH). Human plasma contains bioPTH and PTH (7-84)-like fragments. Using bioPTH-specific and nonspecific assays, we found that the patients with pseudohypoparathyroidism (PHP) type I with PTH-resistant hypocalcemia and hyperphosphatemia had the increased plasma levels of bioPTH and PTH (7-84)-like fragments than normal subjects (26.8 +/- 13.2 vs. 2.37 +/- 0.75 pmol/liter, P < 0.01 and 16.2 +/- 8.8 vs. 0.82 +/- 0.47 pmol/liter, P < 0.01, respectively). Calcitriol treatment increased phosphaturic response to PTH (1-34) (P < 0.05), and there was a negative correlation between phosphaturic response and the PTH levels (P < 0.05). These results suggested that the increased bioPTH and PTH (7-84)-like fragment levels may be related to the impaired phosphaturic response to PTH (1-34) in PHP type I. We also examined bioPTH-calcium dynamics in PHP type Ib patients and found that set-point calcium was 0.928 +/- 0.045 mmol/liter and the baseline to maximal ratio of bioPTH was 0.96 +/- 0.04. Calcitriol treatment increased set-point calcium to 1.129 +/- 0.028 mmol/liter (P < 0.01) and suppressed baseline to maximal ratio of bioPTH to 0.35 +/- 0.21 (P < 0.01). These bio-PTH calcium dynamics studies revealed the maximally stimulated baseline PTH secretion in PHP type Ib and demonstrated the effects of calcitriol on PTH-calcium curve shift and the degree of relative stimulation of baseline secretion.     

人甲状旁腺激素相关蛋白片段对骨质疏松大鼠股骨和腰椎骨密度的影响

目的观察人甲状旁腺激素相关蛋白（PTHrP1-34）对去卵巢的骨质疏松大鼠股骨、腰椎骨密度（BMD）的影响。方法80只4月龄Wistar健康雌性大鼠。其中60只行双侧卵巢摘除术，20只做假手术，6w后各处死10只证实骨质疏松造模成功。剩余50只骨质疏松模型鼠随机分为5个治疗组，每组10只，其他10只假手术组作对照。PTHrP治疗组（PTHrP20组，PTHrP40组，PTHrP80组）分别用20、40、80μg／kg剂量，每日皮下注射1次PTHrP1-04；雌二醇治疗组（E2组）用苯甲酸雌二醇40μg/kg，每3天注射1次；安慰荆组及假手术对照组分别用生理盐水，每3d注射1次。治疗3个月后，测定并比较股骨、腰椎不同部位BMD及血清钙、磷、碱性磷酸酶（ALP）水平。结果双侧卵巢摘除6W后，大鼠腰椎BMD明显低于假手术组（P〈0．05）。3个月治疗后，PTHrP40组和PTHrP80组大鼠股骨、腰椎BMD明显高于安慰剂组，与E2组无显著差异，腰椎BMD较PTHrP20组明显升商（P〈0．05）；PTHrP40组与PTHrP80组无明显差异。结论每日每公斤体重皮下注射40和80μg PTHrP1-34对左卵巢骨质疏松大鼠股骨、腰椎BMD均有增高作用。对腰椎作用更为明显。     

The effects of recombinant human parathyroid hormone, rhPTH(1-84), on bone mass in undernourished rats

Energy intake restriction reduces bone formation both in protein-energy malnourished children and in undernourished rats, and such conditions might cause partial or irreversible bone loss. Because the use of anti-resorptive agents in this situation is seemingly limited, we examined the effect of the anabolic agent, recombinant human parathyroid hormone (rhPTH(1-84)), on bones in undernourished conditions. First, the osteopenic changes of rat bones with 40% restricted diet for 4 weeks were confirmed. Subsequently, another set of the rats were randomized into four groups and studied for 8 weeks: the freely fed group (control group); the restricted diet, then freely fed group (restriction-ad libitum group); the restricted diet-vehicle-treated group (restriction-vehicle group); and the restricted diet-PTH-treated group (restriction-PTH group). In the restriction-vehicle group, total femoral bone mineral density (BMD) was lower and femoral length was shorter than the control group by 15.4% and 8.1% respectively (P<0.05). In the restriction-ad libitum group, these parameters recovered fully to those of the control group. In the case of intermittent PTH treatment in the persistent undernourished state, the BMD of total femur caught up with those of the control or the restriction-ad libitum group. However, the femoral length remained shorter than those of the other groups. Serum osteocalcin was significantly reduced in continuously undernourished rats, whereas it was elevated in the restriction-PTH group. In conclusion, BMD of total femur was low in undernourished rats. However, it increased after re-feeding ad libitum or intermittent PTH treatment. We suggest that rhPTH(1-84) may be a possible therapeutic agent for ongoing bone loss, especially in patients in a chronically undernourished condition.     

Atorvastatin enhances bone density in ovariectomized rats given 17beta-estradiol or human parathyroid hormone(1-34)

We investigated the in vivo effect of atorvastatin on bone mineral density (BMD) in ovariectomized (OVX) rats. Eight-week-old female rats underwent either a sham operation or ovariectomy, and treatments with vehicle, atorvastatin, 17β-estradiol (E₂) and human parathyroid hormone(1–34) [hPTH(1–34)] were initiated 6 wk after the surgery. E₂ (10 μg/kg) treatment for 12 wk significantly increased lumbar BMD (L2–L4), whereas atorvastatin did not affect lumbar BMD. The combination of atorvastatin (2 mg/kg) and E₂ significantly enhanced the BMD of lumbar vertebrae (L2–L4) and femoral metaphyseal area (2/10–4/10 segments from the most proximal point) compared to that of either E₂ or atorvastatin alone. A low dose 1 μg/kg of hPTH (1–34) did not alter lumbar or femoral BMD, whereas a high dose 17.5 μg/kg of the peptide significantly increased BMD. Concomitant injections of atorvastatin (2 mg/kg) with hPTH(1–34) (1 μg/kg) for 8 wk significantly enhanced the BMD of lumbar vertebrae and the metaphyseal area of the femur in OVX rats. These findings demonstrate that chronic administration of atorvastatin appears to modestly enhance the BMD of the lumbar vertebrae and femoral metaphysis of OVX rats treated with submaximal doses of E₂ and hPTH(1–34).     

Clinical utility of an immunoradiometric assay for parathyroid hormone (1-84) in primary hyperparathyroidism

The reliable diagnosis of primary hyperparathyroidism depends on the measurement of PTH. The PTH assays in widespread use measure not only the hormone but also hormone fragments, thus limiting the clinical utility of the assays. A new immunoradiometric assay (IRMA) using an antigenic determinant at the extreme amino-terminal of the PTH molecule detects only full-length PTH (1-84). We compared three PTH assays and determined the presence of PTH (1-84) and PTH fragments in serum and parathyroid adenomas of patients with primary hyperparathyroidism. We studied 56 patients with primary hyperparathyroidism. PTH levels were increased in 63% using the midmolecule RIA; in 73% in the "intact" IRMA; and in 96% in the PTH (1-84)-IRMA. The PTH (1-84)-IRMA correlated with the other assays (midmolecule RIA R = +0.736; P < 0.0001; "intact"-IRMA R = +0.951; P < 0.0001) and indices of disease activity (serum calcium R = +0.511, P < 0.0001; alkaline phosphatase R = +0.489, P = 0.001; and radius bone density R = -0.366, P < 0.01). In 21 consecutive patients undergoing parathyroidectomy, 18 had parathyroid adenomas. Intact PTH was higher than PTH (1-84)-IRMA in both serum and glandular homogenates from these patients. Similar proportions of PTH (1-84) and hormone fragments were found in both adenomas [66 +/- 3% of "intact" PTH-reflected PTH (1-84) and sera (73 +/- 2% of "intact" PTH reflected PTH (1-84)]. We conclude that the PTH (1-84)-IRMA offers improved diagnostic sensitivity in patients with primary hyperparathyroidism than other currently available assays. This study also provides evidence that both PTH (1-84) and PTH fragments are produced in parathyroid adenomas and that peripheral metabolism of hormone and fragment does not alter the proportion of bioactive hormone.     

Effects of growth hormone replacement on parathyroid hormone sensitivity and bone mineral metabolism

Adult GH deficiency (AGHD) is associated with reduced bone mineral density, and decreased end-organ sensitivity to the effects of PTH has been suggested as a possible underlying mechanism. We investigated the effects of GH replacement (GHR) on PTH circulating activity and its association with phosphocalcium metabolism and bone turnover in 16 (8 men and 8 women) AGHD patients. Half-hourly blood and 3 hourly urine sampling was performed on each patient over a 24-h period before GHR and then after 1, 3, 6, and 12 months of GHR. GH was commenced at a dose of 0.5 IU/d and was titrated to achieve and maintain an IGF-I SD score within 2 SD of the age-related reference range. The target IGF-I SD score was achieved within 3 months and was maintained at 12 months after GHR in all patients. Our results demonstrated a significant decrease in serum PTH at all visits after GHR compared with baseline values (P < 0.001), with a concomitant increase in nephrogenous cAMP excretion at 1 (P < 0.001) and 3 (P < 0.05) months and increases in serum calcium (P < 0.001), serum phosphate (P < 0.001), 1,25-dihydroxyvitamin D(3) (P < 0.001), type I collagen C-telopeptide (a bone resorption marker; P < 0.001), and procollagen type I amino-terminal propeptide (a bone formation marker; P < 0.001). Simultaneously, we observed a significant decrease in urinary calcium excretion (P < 0.001) and an increase in maximum tubular phosphate reabsorption (P < 0.001). Together these results suggest increased end-organ responsiveness to the effects of circulating PTH resulting in increased bone turnover and reduced calcium excretion. Significant circadian rhythms were observed for serum PTH, phosphate, type I collagen C-telopeptide, and procollagen type I amino-terminal propeptide before and after GHR. However, sustained PTH secretion was observed between 1400-2200 h, with a reduced nocturnal rise in untreated AGHD patients, whereas PTH secretion decreased significantly between 1400-2200 h (P < 0.001), with a significant increase in nocturnal PTH secretion (P < 0.001) after 12 months of GHR. Our results demonstrate that GH may have a regulatory role in bone mineral metabolism, and our data provide a possible underlying mechanism for the development of osteoporosis in AGHD patients. The changes observed after GHR may further explain the beneficial effects of GHR on bone mineral density that have consistently been reported.     

Relationships between vitamin D, parathyroid hormone and bone mineral density in inflammatory bowel disease

Objectives. To explore the relationships between vitamin D intake, serum parathyroid hormone (PTH) and 25-hydroxyvitamin D (250HD) concentrations, and bone mineral density (BMD) in inflammatory bowel disease (IBD).
Setting. A university hospital clinic in Finland.
Subjects. One hundred and fifty randomly selected patients with IBD from the hospital register and 73 healthy controls.
Measurements. BMD of the lumbar spine and the proximal femur was measured with dual energy X-ray absorptiometry. Vitamin D intake and serum levels of 250HD and PTH were determined.
Results. The IBD patients had a lower serum 250HD concentration (28.4 [SD 12.0] nmol L^-1) than the controls (36.1 [16.7] nmol L^-1; P =0.001), whereas no differences in the vitamin D intake or the serum PTH levels were found. The serum 250HD concentrations and the vitamin D intake of the patients with ulcerative colitis ( n =67) were similar to those of the Crohn's disease patients ( n =76). The patients with Crohn's disease of the small bowel had slightly, but not significantly, lower serum 250HD concentrations (25.6 [11.0] nmol L^-1) than the other Crohn's disease patients (31.4 [14.3] nmol L^-1; P =0.061). In the IBD patients, the vitamin D intake and the serum 250HD and PTH concentrations were not associated with BMD.
Conclusions. Patients with IBD have lower serum levels of 250HD than healthy controls, but similar serum PTH concentrations and vitamin D intake. Vitamin D intake, and the serum levels of 250HD and PTH are not associated with BMD, and malabsorption is unlikely to be a major factor in the aetiology of bone loss in unselected IBD patients.     

Repeated in vivo determinations of bone mineral density during parathyroid hormone treatment in ovariectomized mice

The recent development of different genetically modified mice with potentially interesting bone phenotypes has increased the demand for effective non-invasive methods to evaluate effects on bone of mice during growth and development, and for drug evaluation. In the present study, the skeleton was analyzed by repeated in vivo scans using dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Ovariectomized (ovx) mice treated with parathyroid hormone (PTH) were used as an animal model to evaluate these two techniques at different times after the onset of treatment. Female mice (6 weeks of age) were allocated randomly to four groups: (1) sham-operated+vehicle; (2) ovx+vehicle; (3) sham-operated+PTH(1-84) 150 microg/kg per day; (4) ovx+PTH. Six weeks after ovariectomy the drug treatment began and was continued for 8 weeks. The total body bone mineral content (BMC) and total body areal bone mineral density (BMD) were measured by DXA. Ovariectomy reduced total body BMC and total body areal BMD by 6.2+/-1.7% and 2.6+/-0.9% respectively. No effect of PTH on total body BMC was seen during the treatment period. The trabecular volumetric BMD was measured by pQCT. Ovariectomy reduced the trabecular volumetric BMD by 52+/-6.7%. The pQCT technique detected a clear effect on trabecular volumetric BMD after 2 weeks of PTH treatment (ovx 94+/-29% and sham-operated 46+/-10% more than vehicle-treated). The cortical bone was measured in a mid-diaphyseal pQCT scan of the tibia. Ovariectomy reduced the cortical BMC by 9+/-2%. PTH treatment for 8 weeks increased cortical BMC in ovx mice. In conclusion, the pQCT technique is more sensitive than the DXA technique in the detection of bone loss after ovariectomy and increased bone mass after PTH treatment in mice. Notably, the pQCT, but not the DXA, technique detected a dramatic effect as early as after 2 weeks of PTH treatment. Dynamic pQCT measurements will be useful for monitoring skeletal changes during growth and development, and for drug evaluation in mice.     

Elevations in serum and urinary calcium with parathyroid hormone (1-84) with and without alendronate for osteoporosis

CONTEXT: The effect of PTH therapy on serum and urinary calcium levels and the risk of hypercalcemia or hypercalciuria has not been formally evaluated. OBJECTIVE: The objective was to examine changes in serum and urinary calcium associated with PTH(1-84) therapy in the PaTH trial and the extent to which a defined algorithm resolved the elevated values. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: A total of 178 postmenopausal women were randomized to PTH(1-84) either alone or in combination with alendronate during the first year of the PaTH study. MAIN OUTCOME MEASURE(S): The main outcome measures were fasting serum calcium at baseline and 1, 3, and 12 months and 24-h urinary calcium at baseline and 3 months. RESULTS: In 14% of participants, serum calcium more than 10.5 mg/dl (>2.6 mmol/liter) developed. Following the defined algorithm, 58% of elevated measurements were normal on repeat testing; 38% required discontinuation of calcium and vitamin D supplementation, and one necessitated a decrease in PTH injection frequency to normalize serum calcium. One participant developed transient hypercalcemia between study visits and required hospitalization; the episode resolved with iv hydration and PTH discontinuation. Baseline characteristics associated with the development of hypercalcemia were serum calcium [relative hazards = 1.9 per 0.5 mg/dl (0.12 mmol/liter); 95% confidence interval = 1.1-3.2] and serum 1,25-dihydroxyvitamin D [relative hazard = 1.9 per 10 pg/ml (26 pmol/liter); 95% confidence interval = 1.2-3.1]. Fifteen women (8%) developed hypercalciuria [urinary calcium > 400 mg (100 mmol)/24 h or calcium/creatinine ratio > 0.4]; 80% of cases resolved after discontinuing calcium and vitamin D, 13% without intervention, and one after PTH injection frequency was decreased. Higher baseline urinary calcium excretion was associated with development of hypercalciuria [relative hazard = 1.5 per 50 mg/d (12.5 mmol/d); 95% confidence interval = 1.2-4.0]. Proportions of patients with elevated serum and urinary calcium were similar on single and combination therapy. CONCLUSIONS: The frequency of episodic hypercalcemia or hypercalciuria in the PaTH trial was 21%. Episodes were generally mild, and nearly all cases resolved spontaneously or with discontinuation of calcium and vitamin D. The algorithms used to address hypercalcemia and hypercalciuria in the PaTH trial proved effective in safely resolving clinical episodes of increased urinary or serum calcium and might therefore be helpful to clinicians caring for patients on PTH.     

The circadian rhythm of intact parathyroid hormone (1-84) and nephrogenous cyclic adenosine monophosphate in normal men

A pronounced circadian rhythm has been demonstrated for intact parathyroid hormone (1-84) in the serum of normal male adults. The broad nocturnal rise of parathyroid hormone (1-84) secretion appears to be of physiological significance, for it is accompanied by a significant rise in nephrogenous cyclic adenosine monophosphate. The rate of return of parathyroid hormone (1-84) to baseline concentrations varies between individuals, an observation which has implications for the optimal time of sampling for the investigation of possible mild hyperparathyroidism.     

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.