Effect of Calcium and the Calcimimetic AMG 641 on Matrix-Gla Protein in Vascular Smooth Muscle Cells

Vascular calcification (VC) is frequently observed in patients with chronic renal failure and appears to be an active process involving transdifferentiation of vascular smooth muscle cells (VSMCs) to osteoblast-like cells. Reports of VC prevention in uremic rodents by calcimimetics coupled with identification of the calcium-sensing receptor (CaSR) in VSMCs led us to hypothesize that CaSR activation in arterial cells and VSMCs may elicit expression of an endogenous inhibitor of VC. Toward this end, we determined the effects of calcium and the calcimimetic AMG 641 on arterial wall and isolated VSMC expression of matrix-Gla protein (MGP). Bovine VSMCs were incubated with increasing calcium chloride or AMG 641 concentrations, while in vivo experiments were carried out on healthy and uremic rats. Both AMG 641 and hypercalcemia induced MGP expression in the arterial wall in healthy and uremic rats. The results obtained in vitro supported those from in vivo experiments. In conclusion, selective CaSR activation, either by extracellular calcium or AMG 641, increased MGP expression in vivo in the arterial wall and in vitro in bovine VSMCs. This local upregulation of MGP expression provides one potential mechanism by which calcimimetics prevent VC.     

The effect of calcitriol, paricalcitol, and a calcimimetic on extraosseous calcifications in uremic rats

Vitamin D derivatives and calcimimetics are used to treat secondary hyperparathyroidism in patients with chronic renal failure. We investigated the effect of calcitriol, paricalcitol, and the calcimimetic AMG 641 on soft-tissue calcification in uremic rats with secondary hyperparathyroidism. Control and uremic rats were treated with vehicle, calcitriol, paricalcitol, AMG 641, or a combination of AMG 641 plus calcitriol or paricalcitol. Parathyroid hormone levels were reduced by all treatments but were better controlled by the combination of paricalcitol and AMG 641. The calcimimetic alone did not induce extraosseous calcification but co-administration of AMG 641 reduced soft-tissue calcification and aortic mineralization in both calcitriol- and paricalcitol-treated rats. Survival was significantly reduced in rats treated with calcitriol and this mortality was attenuated by co-treatment with AMG 641. Our study shows that extraskeletal calcification was present in animals treated with calcitriol and paricalcitol but not with AMG 641. When used in combination with paricalcitol, AMG 641 provided excellent control of secondary hyperparathyroidism and prevented mortality associated with the use of vitamin D derivatives without causing tissue calcification.     

Activity of testis angiotensin converting enzyme (ACE) in ejaculated human spermatozoa

Testicular angiotensin converting enzyme (ACE) isozyme is likely to play important functional roles in male reproduction. Several studies have shown that ACE is released from human spermatozoa during capacitation and that ACE is associated with reduced sperm motility. Recently, we established an assay to detect testicular ACE activity in human spermatozoa. The purpose of this study was to determine if testicular ACE activity is related to sperm motility in human ejaculates. Semen samples were collected from 80 infertile patients. According to the semen characteristics, they were divided into four (WHO) categories. Enzyme activities of ACE in spermatozoa (testicular ACE) and seminal plasma (somatic ACE) were spectrophotometrically determined. Total testicular ACE activity in spermatozoa was measured by solubilization of spermatozoa with Triton X-100. Membrane testicular ACE activity was measured in a sperm : PBS suspension. Sperm concentration and sperm motility were 136.6 +/- 154.1 x 10(6)/mL and 58.6 +/- 23.4%, respectively (mean +/- SD). Enzyme activities of membrane testicular ACE, total testicular ACE and somatic ACE were 0.273 +/- 1.219 microU/10(6) spermatozoa, 0.35 +/- 1.34 microU/10(6) spermatozoa and 684.7 +/- 226.6 mU/mL, respectively. A negative correlation was observed between sperm motility and membrane testicular ACE activity (p < 0.05). Membrane testicular ACE activity in 44 normal semen samples was 0.04 +/- 0.02 microU/10(6) spermatozoa, whilst that in 36 abnormal semen samples was 0.24 +/- 0.42 microU/10(6) spermatozoa. There was a significant difference between these two groups (p < 0.01). Membrane testicular ACE in sperm samples from normozoospermic men was significantly lower than that from oligoasthenozoospermic men (p < 0.05). These findings suggest that testicular ACE is released from normal functional spermatozoa for them to have fertilizing ability.     

Protective effect of alpha glucosyl hesperidin (G‐hesperidin) on chronic vanadium induced testicular toxicity and sperm nuclear DNA damage in male Sprague Dawley rats

The study was conducted to evaluate the vanadium‐induced testicular toxicity and its effect on sperm parameters, sperm nuclear DNA damage and histological alterations in Sprague Dawley rats and to assess the protective effect of G‐hesperidin against this damage. Treatment of rats with vanadium at a dose of 1 mg kg bw^?1 for 90 days resulted in significant reduction in serum testosterone levels, sperm count and motility. Further, a parallel increase in abnormal sperm morphology and adverse histopathological changes in testis was also associated with vanadium administration when compared to normal control. Moreover, sperm chromatin dispersion assay revealed that vanadium induces sperm nuclear DNA fragmentation. A marked increase in testicular malondialdehyde levels and decreased activity of antioxidant enzymes such as superoxide dismutase and catalase indicates vanadium‐induced oxidative stress. Co‐administration of G‐hesperidin at a dose of 25 and 50 mg kg bw^?1 significantly attenuated the sperm parameters and histological changes by restoring the antioxidant levels in rat testis. These results suggested that vanadium exposure caused reduced bioavailability of androgens to the tissue and increased free radical formation, thereby causing structural and functional changes in spermatozoa. G‐hesperidin exhibited antioxidant effect by protecting the rat testis against vanadium‐induced oxidative damage, further ensures antioxidant potential of bioflavonoids.     

Effect of relaxin on human sperm functions

Relaxin is a circulating hormone with functions in pregnancy, parturition, and other aspects of female reproduction. It is also secreted from the prostate gland into the seminal fluid; however, the role of relaxin in male reproduction is debated. Studies conducted in the past have suggested possible actions on human spermatozoa, but the data were contrasting. Here, we show that the relaxin receptor RXFP1 (Relaxin Family Peptide Receptor 1) is expressed in human spermatozoa, and it mainly localizes in the astrodome. In vitro studies on human sperm demonstrated that this hormone attenuates the natural decline in sperm motility and maintains higher mitochondrial activity and lower apoptosis level. Furthermore, relaxin induced an increase in sperm hyperactivation, intracellular calcium and cAMP, and acrosome reaction. These effects were abolished by the use of the specific anti-RXFP1 antibody. Relaxin concentrations were low in the blood (x ± SD, 0.16 ± 0.03 nM) and very high in the seminal plasma (x ± SD, 10.3 ± 4.0 nM), confirming its secretion mainly by the prostate. Taken together, these data demonstrate that relaxin influences positively many sperm functions linked to fertilizing ability, and it preserves sperm functionality, with possible practical value in assisted reproduction techniques.     

The Use of Calcimimetics for the Treatment of Secondary Hyperparathyroidism: A 10 Year Evidence Review

Until the discovery of calcimimetics, the management of secondary hyperparathyroidism (SHPT) relied exclusively on treatment with phosphate binders, vitamin D derivatives or surgical parathyroidectomy with limited success. The therapeutic use of calcimimetic agents, together with a better understanding of the pivotal role of the calcium‐sensing receptor (CaSR) in the physiological regulation of parathyroid gland function, substantially advanced the management of hyperparathyroidism in dialysis practice. Calcimimetics bind selectively to the CaSR receptor in parathyroid tissue and enhance the inhibitory effect of extracellular calcium ions on parathyroid hormone (PTH) secretion, thereby reducing PTH levels even when serum calcium concentrations are normal or low. The availability of calcimimetic agents for clinical use has opened a new era in the management of patients with SHPT. Indeed, calcimimetic compounds have been shown to reduce PTH levels and to lower serum calcium concentrations in all forms of hyperparathyroidism, including primary hyperparathyroidism (PHPT) and parathyroid carcinoma. Such findings underscore the critical importance of the CaSR as a therapeutic target in this family of clinical disorders. New calcimimetic agents are being developed that have the potential to offer improved efficacy and safety compared with currently available calcimimetic compounds.     

Effects of α-Interferon on Sperm Production, Concentration, and Motility in the Rat

Background :
We evaluated possible effects of α-interferon (α-IFN) on testicular spermatogenesis and epididymal sperm quality in the nude rat.
Methods :
Nude male rats were administered subcutaneous injections of human α-IFN daily for 3 months. The luminal content of the cauda epididymidis was collected by micropuncture. Daily sperm production was determined by Amann's method and sperm concentrations were determined by microassay. Progressive motility was judged by evaluating the linear distance traveled by the sperm in a diluent. Serum levels of testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) were also measured at the end of the experiment.
Results :
Daily sperm production and epididymal sperm concentrations were significantly increased after administration of α-IFN, while progressive motility of the spermatozoa was not altered. α-IFN significantly increased serum testosterone levels, while it decreased serum LH levels and left serum FSH levels unchanged.
Conclusion :
α-IFN may improve testicular spermatogenesis and increase the epididymal sperm concentration in the rat. These promising results with α-IFN may pave the way for a new approach to treating male infertility.     

Sperm dysfunction in subfertile patients with varicocele and marginal semen analysis

A comparative analysis of potentially functional spermatozoa per ejaculate, progressive motility, hypo-osmotic swelling test, acrosome integrity and sperm viability (24 and 48 h) was carried out in a group of 40 subfertile patients with varicocele and marginal semen analysis and 40 fertile subjects, in order to identify subclinical abnormalities that may explain subfertility. Patients with varicocele had lower numbers of potentially functional spermatozoa per ejaculate, progressive motility, acrosome and membrane integrity and sperm viability. These abnormalities were not related to the grade of varicocele, testicular volume or serum FSH concentration. A positive correlation between the hypo-osmotic swelling test and progressive motility (r = 0.71) and between potentially functional spermatozoa and the hypo-osmotic swelling test (r = 0.69) was found in patients with varicocele. These data suggest that some of the deleterious effects produced by the varicocele might be related to sperm migration and viability in the female genital tract and others to sperm-zona interaction and/or sperm-egg fusion.     

Morphology and fertility of guinea pig spermatozoa aged in vivo

The morphology and fertility of spermatozoa from vasa deferentia of guinea pigs were observed following hemicastration or castration for approximately 40 days. The morphology of these aged sperm was studied from living and fixed preparations. Fertilizing ability was assayed by artificial insemination of estrous females and subsequent counting of embryos. Spermatozoa underwent morphological changes including dissociation of rouleaux, curving of tails, and loss of acrosomes; physiological changes included a decline in the number of sperm with progressive motility and increased numbers of immotile spermatozoa with time after the operations. The fertilizing capacity of spermatozoa was maintained for approximately 30 days in both groups. However, sperm from one of the hemicastrated males resulted in conception 36 days postoperation. The data suggest that the loss of motility and decline in fertilizing ability were the result of spermatozoa senescence rather than testicular androgen deficiency.     

Gonadotropins,testosterone and prolactin in men with abnormal semen findings and an evaluation of the hormone profile

Over a 4-year period, 259 men were investigated regarding primary (86.5%) or secondary (13.5%) infertility. Men with azoospermia had significantly higher concentrations of FSH and LH and lower concentrations of testosterone than those with spermatozoa. High concentrations of FSH and LH in serum were found in case of low sperm density. Men with low testicular voluem had high concentrations of FSH and LH and low concentrations of testosterone. FSH was closely correlated with LH and also with total testicular volume. A negative correlation was found between both gonadotropins and testosterone. The correlation between LH and testosterone was stronger in azoospermic men than in those with spermatozoa in semen. Serum concentrations of prolactin were higher in men with high sperm motility than among men with low motility of spermatozoa. Otherwise, prolactin concentrations were not correlated either with sperm density or with the morphology of spermatozoa or total testicular volume. A ‘hormone profile’ of FSH, LH and testosterone concentrations is suggested useful in the routine investigation of the infertile man, as more information is given by this profile than by FSH concentrations alone.     

Influence of fibronectin on the motility of human spermatozoa

The objective of the present study was to scrutinize the concentration of seminal fibronectin and the potential effects of exogenous fibronectin on human sperm motility. In addition, variability in the localization of fibronectin on human spermatozoa from andrological patients was studied, at both the light and electron microscopic levels. A total of 58 freshly ejaculated semen samples from patients attending for infertility treatment were submitted to sperm motility analysis and ELISA quantification of seminal plasma and cell-bound fibronectin. Immunofluorescence and immunoelectron microscopy revealed a relatively broad distribution pattern of fibronectin immunoreactivity on sperm heads and testicular spermatids. Addition of a fibronectin antiserum to vital spermatozoa in vitro at a moderate dilution (1:50) resulted in a significant increase in sperm motility. Purified plasma fibronectin, added at various concentrations to a preparation of live spermatozoa, was found to inhibit sperm motility in a dose-dependent manner. At concentrations from 0.18 to 0.5 mg fibronectin per ml ejaculate, no motile spermatozoa were recorded. Seminal plasma fibronectin ranged between 0.8 and 1000 μg/ml in infertility patients. There was a significant inverse correlation between sperm motility and seminal fibronectin in patients with oligo-astheno-teratozoospermia. In a preliminary study in patients with varicocele or hypogonadism, no such correlation was found.     

Teratospermic and normospermic domestic cats: ejaculate traits, pituitary-gonadal hormones, and improvement of spermatozoal motility and morphology after swim-up processing

Electroejaculate traits, testicular volume, and circulating FSH, LH, and testosterone concentrations were compared between two populations of domestic cats consistently producing either a high (greater than 60%, normospermic) or low (less than 40%, teratospermic) incidence of structurally normal spermatozoa/ejaculate. The effects of semen dilution in Biggers, Whitten and Whittingham (BWW) or modified Krebs Ringer bicarbonate (mKRB) medium and swim-up processing on sperm viability and duration of motility in vitro also were assessed. Ejaculate volume, percent sperm motility, sperm progressive motility, motile spermatozoa/ejaculate, testes volume, and mean serum FSH and LH concentrations were similar (P greater than 0.05) between normospermic and teratospermic cats. However, sperm concentration/ml of ejaculate was greater and circulating testosterone levels were lower in teratospermic males. Swim-up processing increased (P less than 0.05) percent sperm motility, progressive motility, and the number of structurally normal sperm cells recovered and also prolonged the duration of sperm motility in both cat populations. In teratospermic ejaculates, swim-up separation increased the proportion of morphologically normal spermatozoa recovered by more than two-fold. Diluting cat semen with either BWW or mKRB increased flagellar bending in both normospermic and teratospermic cats. The sperm motility characteristics of only the teratospermic ejaculates were influenced by medium type; mKRB increased percent sperm motility and progressive motility whereas BWW had no effect. Compared with undiluted raw ejaculates, the duration of sperm motility was improved 18- to 24-fold by diluting semen in either BWW or mKRB medium followed by swim-up processing. This study demonstrates that the electroejaculate characteristics of domestic cats vary markedly and that some males consistently produce high proportions of morphologically abnormal spermatozoa. Diminished serum testosterone concentrations and normal pituitary secretion of FSH and LH in teratospermic males suggest that there is an inverse relationship between gonadal androgen production and pleiomorphic spermatozoa in the domestic cat. The swim-up procedure is effective for recovering motile, structurally normal spermatozoa from teratospermic cats.     

Possible effects of the kallikrein-kinin system on male reproductive functions

All four components of the kallikrein-kinin system--kininogens, tissue kallikreins, kinins, and kininases--have been found in human male genital secretions. Kinins are continuously released from seminal plasma kininogens through limited proteolysis by kininogenases like tissue kallikrein from prostate and sperm acrosin. Kinins are the terminal effectors of the kallikrein-kinin system and increase sperm motility and sperm metabolism at nanomolar concentrations. Recent investigations indicate that these effects are possibly mediated by a specific sperm membrane integrated bradykinin receptor, subtype B2. The two major kininase that are present in seminal plasma are kininase II and neutral metallo-endopeptidase. Kininase II, which is identical with angiotensin-converting enzyme, is also involved in the renin-angiotensin system as it converts angiotensin I into angiotensin II and thus is the connecting enzyme of both systems. Apart from the observed effects of kinins on sperm motility, the kallikrein-kinin system is thought to be involved in the regulation of spermatogenic functions of the testis: in the rat, kallikrein activates Sertoli cell function, increases the relative number of spermatocytes and the [3H] thymidine incorporation of testicular tissue, enhances glucose-intake, and increases testicular blood flow. Clinical trials showed that systemic administration of kallikrein may be particularly useful for treatment of infertile men suffering from asthenozoospermia and/or oligozoospermia. During kallikrein therapy, the number of spermatozoa and both quantitative and qualitative sperm motility increased, and a significant improvement of the conception rate was achieved. An increased sperm number was also observed after application of the specific kininase II inhibitor captopril.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo study of LDH isoenzyme activities in heart, liver and testis cytosols of gossypol-treated rats

LDH isoenzyme activities of heart, liver and testis homogenates were measured in rats treated for 15 or 30 days with 30 mg gossypol acetic acid/kg body weight daily, a dose which severely suppressed sperm motility. No differences in LDH activities of the examined organs were found in comparison with control animals. LDH-X, the main LDH isoenzyme in spermatozoa and testicular germ cells from primary spermatocytes onwards was also unaffected. These results contrast with in vitro experiments on human, rabbit, and boar spermatozoa, purified bovine LDH-X and rat testis homogenate which show dose-dependent inhibition of LDH-X after incubation with gossypol. Our results therefore suggest that inhibition of LDH by gossypol is not the primary cause of sperm immotility.     

Freezing of testicular tissue as a minced suspension preserves sperm quality better than whole-biopsy freezing when glycerol is used as cryoprotectant

Frozen-thawed testicular spermatozoa have been used successfully for ICSI, especially in cases of obstructive azoospermia with normal spermatogenesis. Fewer attempts, however, have been made to check whether these rather immature spermatozoa, in a different environment with several other cell types present, have cryobiological requirements other than those of ejaculated spermatozoa. This is the reason why the freezing protocols and cryoprotectants (glycerol) used for freezing testicular tissue are based on experience with semen freezing. This study aimed to assess whether cryosurvival and/or motility was influenced by freezing of testicular tissue either as an intact biopsy or as a shredded tissue suspension, when glycerol was used as cryoprotectant. Freezing of testicular tissue as a suspension preserved motility (type B + C) significantly better than freezing of whole biopsies (9.2% vs. 4.0%). Similar observations have been made for vitality (39.3% vs. 25.4%). Centrifugation on 50% Percoll in order to remove the cryoprotectant resulted in a huge loss of spermatozoa (or late spermatids) and should therefore be especially avoided in cases of testicular failure. On the basis of these observations, mincing of the testicular biopsies before freezing may be advocated. Testicular spermatozoa seem to be better preserved when frozen in suspension, at least when slowly permeating glycerol is used as a cryoprotectant.     

Assay of testicular angiotensin-converting enzyme activity in human spermatozoa

The testicular isozyme of angiotensin-converting enzyme (ACE) is associated with male fertility. Spermatozoa from mice lacking ACE showed defects in transport within the oviducts and in binding to zonae pellucidae although the animals had normal sperm count, morphology and motility. In fact, unexplained infertility is difficult to be predicted by conventional parameters such as sperm count. We measured membrane testicular ACE activity in a sperm suspension in PBS and total testis ACE activity in spermatozoa by solubilization with Triton X-100. Total testis ACE activity and membrane testis ACE activity of the same subject were compared in 12 control subjects. We demonstrated that testicular ACE is stable in spermatozoa and the assay of testicular ACE activity is possible. Total testicular ACE activity was approximately twice the membrane testicular ACE activity in all of the subjects tested. The assay of testicular ACE activity in human spermatozoa could be a new method for the assessment of sperm function.     

IVF outcome with cryopreserved testicular sperm

The introduction of intracytoplasmic sperm injection and the use of spermatozoa extracted from the testicles have changed the option for conception for azoospermic patients. The purpose of the present study was to evaluate the IVF outcome after using cryopreserved testicular sperm samples in comparison with fresh ones. A total of 667 in vitro fertilisation cycles with fresh or cryopreserved testicular sperm obtained by an open biopsy and testicular needle aspiration were evaluated. Sperm motility was present in 70.9% of the cycles in Group-I, 77.8% cycles in Group-II and in 83.3% In Group-III (NS). The fertilisation rates were similar in the three study groups (50%, 48.6% and 54.8% respectively). The pregnancy rates were 26.7%, 22.2% and 16.3% respectively (NS). The delivery rate, however, was significantly lower in Group-III (4.1%) than in Group-I and -II (18.4% and 15.9%, respectively, P < 0.05). The IVF results after use of cryopreserved testicular sperm are comparable with those obtained with the fresh specimens. Lack of sperm motility before cryopreservation does not exclude favourable outcome and therefore testicular sperm freezing is feasible whenever there are enough sperm cells in the extracted testicular tissue.     

Efficiency of percutaneous testicular sperm aspiration as a mode of sperm collection for intracytoplasmic sperm injection in nonobstructive azoospermia

PURPOSE: We determined the feasibility of obtaining mature spermatozoa for intracytoplasmic sperm injection (ICSI) by percutaneous testicular sperm aspiration in men with nonobstructive azoospermia. We also compared the results of ICSI using spermatozoa recovered by open excisional biopsy versus percutaneous testicular sperm aspiration. MATERIALS AND METHODS: A total of 84 men with nonobstructive azoospermia underwent percutaneous testicular sperm aspiration to recover testicular spermatozoa for ICSI on the day of ova retrieval from the wife. Percutaneous testicular sperm aspiration was performed with the patient under general anesthesia in the upper and lower poles of each testis. It was followed by immediate microscopic search of the aspirate to confirm the presence of spermatozoa. In the absence of spermatozoa open excisional biopsy was performed in the same setting. RESULTS: Percutaneous testicular sperm aspiration resulted in the recovery of mature spermatozoa in 45 men (53.6%). Of the remaining 39 men (46.4%) requiring open biopsy adequate spermatozoa were recovered in 28 (71.8%). Although the fertilization rate was significantly higher in the sperm aspiration group, the cleavage and pregnancy rates were similar in the 2 groups. CONCLUSIONS: Percutaneous testicular sperm aspiration was a successful initial approach to collect mature spermatozoa in a high proportion of men with nonobstructive azoospermia. It is safe, minimally invasive and well tolerated by all patients.     

The role of expression of extracellular matrix proteins and epidermal growth factor receptor activity on fertilization capacity of testicular harvested spermatozoa

It has been suggested that multiple growth factors are crucial for spermatogenesis. We analyzed whether alterations on epidermal growth factor receptor activity and different expression pattern of extracellular matrix proteins had an impact on the fertilization capacity of spermatozoa and pregnancy rate after testicular sperm extraction and intracytoplasmic injection. Extracellular matrix proteins and epidermal growth factor receptor were immunohistochemically evaluated in testis of 88 patients with nonobstructive azoospermia. Testicular sperm extraction and intracytoplasmic injection procedure was also performed in 32 of the patients for whom mature sperm could be harvested from the testicular tissue. While collagen Type-IV and laminin activity percentages were 33.1% and 86.4% in motile sperm harvested testicular tissue, these activities were 23.3% and 89.3% in immotile sperm harvested testicular tissue, respectively. In addition, the mean epidermal growth factor receptor expression was higher in immotile than motile sperm obtained tissue (56.4% vs. 51.1%, P=0.4928). There was no statistically significant relationship between the extracellular matrix protein and epidermal growth factor receptor expression patterns and sperm motility, fertilization and pregnancy rates in testicular sperm extraction and intracytoplasmic injection. However, further studies are required to investigate the relationship between other growth factors and sperm fertilization capacity.     

The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism

BACKGROUND: A need exists for a therapy that lowers parathyroid hormone (PTH) without increasing calcium x phosphorus in patients with secondary hyperparathyroidism. The calcimimetic AMG 073 increases the sensitivity of the parathyroid calcium-sensing receptor to extracellular calcium, thereby reducing PTH secretion. Consequently, AMG 073 may provide a novel therapy for secondary hyperparathyroidism. METHODS: Seventy-eight hemodialysis patients with secondary hyperparathyroidism were enrolled into this 18-week, double-blind, randomized, placebo-controlled, dose titration study. Daily oral AMG 073 doses were administered to determine the effect on PTH, serum calcium, phosphorus, and calcium x phosphorus. RESULTS: The mean baseline PTH was similar in patients administered AMG 073 or placebo (632 +/- 280.1 pg/mL vs. 637 +/- 455.9 pg/mL, respectively). PTH decreased by 26.0% in the AMG 073-treated group, compared with an increase of 22.0% in the placebo group (P < 0.001). A greater proportion in the AMG 073 group (38%) had a decrease in PTH >or=30%, compared with the placebo group (8%) (P = 0.001). Decreases in PTH were independent of baseline vitamin D usage. Patients receiving AMG 073 had an 11.9% decrease in calcium x phosphorus compared with a 10.9% increase in the placebo group (P < 0.001). Use of vitamin D sterols, as well as both calcium and noncalcium-containing phosphate binders. were similar between treatment groups. Administration of AMG 073 was safe and well tolerated in this 18-week study. CONCLUSIONS: The calcimimetic AMG 073 decreases both PTH and calcium x phosphorus levels in hemodialysis patients with secondary hyperparathyroidism.