Parathyroid gland function and the set point for PTH release: understanding the available data.
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Humans↗
Biomedical subjects
W G Goodman
Publications and source records attributed to W G Goodman.
In vivo studies of parathyroid gland function in secondary hyperparathyroidism.
In contrast to studies in vitro, in vivo tests of parathyroid gland function in human subjects with secondary hyperparathyroidism present a number of technical and theoretical difficulties. The four-parameter model was originally developed to characterize the secretion of PTH in vitro by a defined number of parathyroid cells in tissue culture, whereas comparisons among in vivo studies in patients with varying degrees of parathyroid gland hyperplasia may not be feasible with this model. Maximum serum PTH levels during hypocalcemic stimuli in vivo reflect not only the amount of PTH released by each parathyroid cell but also the total number of cells available for hormone secretion. Parathyroid gland size varies markedly in patients with secondary hyperparathyroidism, and there is currently no reliable technique for accurately measuring the amount of parathyroid tissue present. Accordingly, in vivo comparisons of calcium-regulated PTH release among subjects with parathyroid glands of substantially different sizes may not be valid with the four-parameter model. Kwan et al. have suggested that parathyroid gland function be assessed over a wide range of different calcium concentrations. In this model, the set point for calcium-regulated PTH secretion is not calculated, but the relationship between serum ionized calcium and PTH levels is examined by linear regression after semilog transformation of the data. Linearizing the calcium-PTH curve eliminates the need for more complex curve-fitting analyses. Differences in parathyroid gland function have been reported before and after calcitriol therapy when this approach is used, but the severity of secondary hyperparathyroidism varied widely in the patients evaluated. Alternatively, the Cica-clamp technique to quantify PTH secretion has been developed by Schwarz et al. By employing sequential standardized hypocalcemia and hypercalcemia, set point values obtained with this method closely agree with in vitro data obtained by Brown in normal parathyroid tissues. Advantages of the Cica-clamp technique include a shorter duration of study, reproducibility of the method, and absence of adverse effects; its utility in evaluating patients with either primary or secondary hyperparathyroidism remains to be determined. Based on data currently available, separate assessments of the pattern of change in serum PTH levels during hypocalcemia and hypercalcemia, expressed as the percent change from baseline values (see Fig 4), may provide more useful information about disturbances in the regulation of PTH release by calcium in patients with secondary hyperparathyroidism. Nevertheless, alterations in the set point for calcium-mediated PTH secretion do not adequately explain the excess PTH secretion of patients with secondary hyperparathyroidism, nor do they account for the reduction in serum PTH levels after treatment with calcitriol.
Animals↗
The set point revisited, again.
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Calcium↗
Recent advances in radioimmunoassay technology for the juvenile hormones.
Recent refinements in juvenile hormone radioimmunoassay technology now make this method significantly more sensitive and easier to use. Rabbit polyclonal antisera against (10R) JH III and racemic JH II have been developed to determine hemolymph hormone titers in the low picogram range. The antisera display minimal cross-reactivity with JH metabolites, JH analogs, and hemolymph lipids. One antiserum recognizes racemic JH I, II, and (10R) III almost equivalently, exhibiting 50% displacement between 100 and 130 pg per tube. Another antiserum is JH II-specific and exhibits 50% displacement at 35 pg per tube. Assay sensitivity has been enhanced by using (10R,11S) [methyl-3H]-JH II of very high specific activity (> 80 Ci/mmol) generated with Hyalophora cecropia accessory gland S-adenosylmethionine transferase and S-[methyl-3H]-adenosyl-L-methionine. Preparation of biological samples has been simplified with overall recoveries of JH from hemolymph ranging between 60 and 75%.
Animals↗
Skeletal response to recombinant human growth hormone (rhGH) in children treated with long-term corticosteroids.
Corticosteroid therapy causes osteopenia and growth retardation in children; such changes are associated with diminished rates of bone formation and turnover. Since growth hormone activates bone remodeling, the biochemical and skeletal responses to rhGH were evaluated in four pediatric patients, aged 12.8 +/- 3 years, with long-term corticosteroid use (5 +/- 2 years). Recombinant human growth hormone (rhGH), 0.125 mg/kg, was given 3 times/week by subcutaneous injection for 12 months. Iliac crest bone biopsies were obtained after double tetracycline labeling before and at the end of rhGH therapy; serum levels of calcium, phosphorus, alkaline phosphatase, parathyroid hormone (intact), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D3, osteocalcin (BGP), and insulin-like growth factor-1 (IGF-1) were measured every 3 months during the treatment period. The average dose of prednisone was 0.24 +/- 0.05 mg/kg/day initially, and this did not change during the study. Serum calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D3, and BGP were unchanged during the rhGH therapy, but the serum IGF-1 level increased by 71%, p < 0.01. Eroded bone perimeter and cancellous bone area did not change significantly during rhGH therapy. Bone formation rates rose from 423 +/- 475 to 781 +/- 407 microns2/mm2/day, p < 0.05, and the length of double tetracycline-labeled bone perimeter increased by 85%, p < 0.05. The bone formation rate in the growth hormone group exceeded the values of an age-matched reference group (14.3 +/- 3 years), 780 +/- 407 microns2/mm2/day versus 411 +/- 479 microns2/mm2/day, p < 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)
25-Hydroxyvitamin D 2↗
Histomorphometric and biochemical characterization of bone following acute severe burns in children.
Severe burns in adults is associated with an uncoupling of normal remodeling, low bone formation without reduced resorption. The risk of osteopenia that may occur under such circumstances is heightened by our detection in a cross-sectional study of low bone mass in severely burned children. We report here the acute histomorphometric and biochemical response of bone to severe burn injury, as well as bone mass in severely burned children. We enrolled 24 patients ages 5.8 to 17.5 years following burns of 63 +/- 16% (SD) body surface area. Serum and urine were collected weekly until iliac crest bone biopsy was obtained 26 +/- 10 days postburn. Seventeen of 18 patients, including 5 patients receiving growth hormone treatment to accelerate wound healing, failed to take up doxycycline in trabecular bone, and had no detectable osteoblasts at the osteoid seam, while eroded surface was normal and osteoblasts were documented by staining. Thus, bone formation was virtually absent. There was an eightfold elevation in urinary free cortisol excretion and high serum levels of acute phase reactants and interleukin-1 beta and -6. Biochemical markers of bone formation, osteocalcin, and type I procollagen propeptide were low, as were resorptive markers urinary pyridinoline and deoxypyridinoline. However, there was no correlation with resorptive surface. Mean age-related z-score for bone mass was -1.06 +/- 1.05, 40 days postburn. Immobilization and endogenous corticosteroid production may be the main factors responsible for acutely reduced bone formation while inflammatory cytokines may mediate resorption.
Absorptiometry, Photon↗
Growth hormone and calcitriol as modifiers of bone formation in renal osteodystrophy.
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Animals↗
Calcium-regulated parathyroid hormone secretion in adynamic renal osteodystrophy.
Hypercalcemia and low serum parathyroid hormone (PTH) levels are features of the adynamic lesion (AD) of renal osteodystrophy, but there is little information about parathyroid gland function in this disorder. Therefore, the four parameter model was used to evaluate calcium-regulated PTH release in patients with either adynamic bone or secondary hyperparathyroidism (OF) as documented by bone biopsy and in normal volunteers (NL). Patients had undergone CCPD for 20 +/- 4.2 months, and all received calcium carbonate as the sole phosphate-binding agent. During two hours infusions of sodium citrate, the rate of decline in serum ionized calcium levels did not differ among groups; serum PTH levels rose from 136 +/- 38 to 342 +/- 140 pg/ml in AD and from 691 +/- 99 to 869 +/- 121 pg/ml in OF. Maximum PTH levels were 322 +/- 42% of baseline values in AD but only 146 +/- 9.7% of baseline in OF (P < 0.001), and the increase above baseline levels in AD did not differ from that in NL (300 +/- 25%, NS). During calcium infusions, serum PTH levels fell from 164 +/- 75 to 39 +/- 11 pg/ml in AD and from 622 +/- 76 to 171 +/- 29 pg/ml in OF; minimum serum PTH levels, expressed as a percentage of pre-infusion values, were 25 +/- 2% in AD and 26 +/- 5% in OF (NS).(ABSTRACT TRUNCATED AT 250 WORDS)
Calcium↗
Calcium-regulated parathyroid hormone release in patients with mild or advanced secondary hyperparathyroidism.
Differences in the regulation of parathyroid hormone (PTH) release by calcium are thought to account for excess PTH secretion in patients with secondary hyperparathyroidism (2 degrees HPTH). To determine whether calcium-regulated PTH release varies with the severity of 2 degrees HPTH in patients with end-stage renal disease, dynamic tests of parathyroid gland function were done using the four-parameter model in 26 patients with 2 degrees HPTH documented by bone biopsy. Estimates of the set point did not differ among patients categorized as mild (basal serum PTH < 400 pg/ml), moderate (basal PTH 400 to 600 pg/ml) or severe (basal PTH > 600 pg/ml) 2 degrees HPTH; values were 1.23 +/- 0.06 mmol/liter, 1.24 +/- 0.06 mmol/liter and 1.23 +/- 0.05 mmol/liter, respectively, and none of these set point estimates differed from results obtained in normal volunteers, 1.21 +/- 0.02 mmol/liter (NS). The slope of the sigmoidal ionized calcium-PTH curve also did not differ among groups. Set point values did not correspond to basal serum PTH levels, to the maximum serum PTH level observed during hypocalcemia or to the minimum serum PTH level seen during hypercalcemia in patients with 2 degrees HPTH. In contrast, basal serum PTH values were positively correlated with both the maximum serum PTH level observed during hypocalcemia (r = 0.76, P < 0.01), and the minimum serum PTH level attained during calcium infusions (r = 0.78, P < 0.01). Calcium-regulated PTH release does not differ with the degree of 2 degrees HPTH, and set point abnormalities do not account for excess PTH secretion in patients with chronic renal failure as judged by in vivo dynamic tests of parathyroid gland function. The results suggest that variations in parathyroid gland size are the major contributor to excessive PTH secretion in patients with chronic renal failure.
Adolescent↗
Use of the low-dose desferrioxamine test to diagnose and differentiate between patients with aluminium-related bone disease, increased risk for aluminium toxicity, or aluminium overload.
BACKGROUND: Aiming at a safe method in the diagnosis of aluminium-related bone disease (ARBD)/aluminium overload the low-dose desferrioxamine (DFO) test was developed. In a multicentre study histological and histochemical data and aluminium bulk analysis of bone biopsies of 77 dialysis patients were correlated with the results of both the 5 mg/kg and 10 mg/kg DFO tests. METHODS: ARBD was considered to be present when > 15% of the bone surface was positively stained for aluminium and the bone formation rate was below 220 microns 2/mm2/day. Patients in which the Aluminon staining was positive (> 0%) were considered at an increased risk for aluminium toxicity independent of the type of renal osteodystrophy. Patients were considered aluminium overloaded when the bone aluminium content was > 15 micrograms/g wet weight and/or the Aluminon staining was positive (> 0%). RESULTS: Using the proposed criteria 15 patients were found to have ARBD; 13 of them presenting with a serum iPTH below 150 ng/l. In conjunction with an iPTH measurement the DFO test had a more than acceptable sensitivity and specificity in the diagnosis of ARBD. The test was considered positive when a post-DFO serum aluminium increment (delta sA1) above 50 micrograms/l (5 mg/kg) or 70 micrograms/l (10 mg/kg) together with a serum iPTH below 150 ng/l was found. Using these cut-off levels the 5 and 10 mg/kg tests in the diagnosis of ARBD had a sensitivity of 87% and a specificity of 95% and 92% respectively whereas the predictive value for a positive test for the population under study was 80% (5 mg/kg). Not a single patient with a serum iPTH > 650 ng/l had a positive staining (> 0%) even when the bone aluminium level was elevated (> 15 micrograms/g wet weight). In the detection of patients at risk for aluminium toxicity delta sA1 thresholds of 50 micrograms/l (5 mg/kg) and 70 micrograms/l (10 mg/kg) in combination with a serum iPTH < 650 ng/l had a sensitivity of 92% and specificity of 86% and 84% respectively. In the clinical setting of aluminium overload, threshold delta sA1 levels of 50 micrograms/l (5 mg/kg) and 70 micrograms/l (10 mg/kg) had a sensitivity of 91% and a specificity of 95% and 90% respectively. CONCLUSIONS: The low-dose DFO test is a reliable test for the detection of aluminium overload; however, it is not specific enough to differentiate between ARBD, increased risk of aluminium toxicity, and aluminium overload unless it is used in combination with a serum iPTH measurement. In conjunction with a serum iPTH measurement it is an important tool in the differential diagnosis and may avoid the necessity of a bone biopsy in the majority of patients. Data obtained in the present study have allowed us to update the strategies for monitoring, diagnosis and patient follow-up proposed at the Consensus Conference on Diagnosis and Treatment of Aluminium Overload in End-Stage Renal Failure; Paris, 1992.
Adult↗
A nuclear juvenile hormone-binding protein from larvae of Manduca sexta: a putative receptor for the metamorphic action of juvenile hormone.
A 29-kDa nuclear juvenile hormone (JH)-binding protein from the epidermis of Manduca sexta larvae was purified by using the photoaffinity analog for JH II ([3H]epoxyhomofarnesyldiazoacetate) and partially sequenced. A 1.1-kb cDNA was isolated by using degenerate oligonucleotide primers for PCR based on these sequences. The cDNA encoded a 262-amino acid protein that showed no similarity with other known proteins, except for short stretches of the interphotoreceptor retinoid-binding protein, rhodopsin, and human nuclear protein p68. Recombinant baculovirus containing this cDNA made a 29-kDa protein that was covalently modified by [3H]epoxyhomofarnesyldiazoacetate and specifically bound the natural enantiomer of JH I (Kd = 10.7 nM). This binding was inhibited by the natural JHs but not by methoprene. Immunocytochemical analysis showed localization of this 29-kDa protein to epidermal nuclei. Both mRNA and protein are present during the intermolt periods; during the larval molt, the mRNA disappears but the protein persists. Later when cells become pupally committed, both the mRNA and protein disappear with a transient reappearance near pupal ecdysis. The properties of this protein are consistent with its being the receptor necessary for the antimetamorphic effects of JH.
Amino Acid Sequence↗
Biochemical markers of renal osteodystrophy in pediatric patients undergoing CAPD/CCPD.
Serum intact PTH [1-84] levels were evaluated as a potential non-invasive method for the diagnosis of renal osteodystrophy in children treated with CAPD/CCPD. Sixty-eight bone biopsy samples were obtained from 55 patients, aged 13 +/- 5 (X +/- SD) years, undergoing CAPD/CCPD for 29 +/- 13 months; osteitis fibrosa was present in 34 cases, mild lesions of secondary hyperparathyroidism in six, 15 had adynamic lesions, and 13 were classified as normal histology. Serum calcium levels were higher in patients with adynamic bone or normal bone histology than in those with secondary hyperparathyroidism, whereas serum phosphorus, alkaline phosphatase and PTH levels were greater in patients with osteitis fibrosa. The combination of a serum PTH level > 200 pg/ml and a serum calcium value < 10 mg/dl was 85% sensitive and 100% specific for identifying patients with high-turnover lesions of bone. Serum PTH values < 200 pg/ml were 100% sensitive but only 79% specific for patients with adynamic bone; specificity increased to 92%, however, using the combined criteria of a PTH level < 150 pg/ml and a serum calcium level > 10 mg/dl. Higher serum calcium levels and serum PTH values within or below the normal range characterize patients with the adynamic lesion of renal osteodystrophy. Serum PTH levels of approximately 200 pg/ml are useful for distinguishing patients with low-turnover lesions of renal osteodystrophy from those with secondary hyperparathyroidism.
Adolescent↗
Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy.
Intermittent calcitriol therapy is commonly used to treat secondary hyperparathyroidism in patients undergoing regular dialysis, but there is little available information about the histologic response of bone to this form of therapy. Accordingly, 14 children and adolescents with biopsy-proven secondary hyperparathyroidism were treated with intermittent oral or intraperitoneal doses of calcitriol for 12 months. Biochemical indices of mineral metabolism including serum intact PTH levels were measured monthly throughout the study, and bone biopsies were repeated at the end of treatment. Before treatment, 11 patients had osteitis fibrosa and three had mild lesions of secondary hyperparathyroidism. Histologic improvement was seen in 12 of 14 patients, and osteitis fibrosa resolved in 10 of 11 cases. Bone formation decreased in all patients during intermittent calcitriol therapy, falling from 861 +/- 380 to 150 +/- 170 microns2/mm2/day, P < 0.001. Bone formation decreased to normal in six patients, but six patients developed adynamic lesions of bone with subnormal bone formation rates. Serum PTH and alkaline phosphatase levels declined in those who developed adynamic bone, but values remained elevated in patients with normal rates of bone formation at follow-up evaluation. Neither the mean dose of calcitriol nor the average dose per kilogram body weight differed in patients with adynamic lesions. Thus, adynamic renal osteodystrophy develops in a substantial number of patients during intermittent calcitriol therapy. Although declining serum PTH and alkaline phosphatase levels suggest the development of the adynamic lesion, bone formation decreases in some patients despite persistently high serum PTH levels. Calcitriol may directly suppress osteoblastic activity in patients with secondary hyperparathyroidism when given in large doses to patients undergoing peritoneal dialysis.
Adolescent↗
Gender differences in vertebral body sizes in children and adolescents.
PURPOSE: To determine whether differences in vertebral bone densities or sizes account for gender differences in skeletal mass during growth. MATERIALS AND METHODS: Quantitative computed tomography (CT) was used to measure the densities of cortical and cancellous bone and dimensions of the lumbar vertebral bodies in 196 healthy children and adolescents, ages 4-20 years. RESULTS: Neither cancellous nor cortical bone densities differed between boys and girls with age or level of sexual development. In contrast, the cross-sectional areas of the vertebral bodies were greater in boys than girls throughout childhood and adolescence. Even when prepubertal children were matched for chronologic age, bone age, height, and weight, the size of the vertebral bodies was 17% greater in boys. This disparity in vertebral body size increased with level of sexual development and was greatest at sexual maturity. CONCLUSION: Lower vertebral bone mass of women as compared with men may result from early gender differences in the sizes of bones rather than differences in bone densities.
Adolescent↗
Gender differences in vertebral sizes in adults: biomechanical implications.
PURPOSE: To determine if vertebral bone densities or vertebral body sizes contribute to gender differences in vertebral bone mass in adults. MATERIALS AND METHODS: Cancellous and cortical bone densities and dimensions of three lumbar vertebrae in 25 women and 18 men were measured with quantitative computed tomography (CT) and statistically analyzed. RESULTS: Neither cancellous nor cortical vertebral bone densities differed in healthy adults. Vertebral bodies in women had lower cross-sectional areas (8.22 cm2 +/- 1.09 [standard deviation] versus 10.98 cm2 +/- 1.25, P < .001) and volumes (22.42 cm3 +/- 2.40 versus 30.86 cm3 +/- 2.6, P < .001). These differences also were evident in men and women matched for age, weight, vertebral bone density, and vertebral body height. Overall cross-sectional areas of vertebral bodies are 25% smaller in women than men. Vertebral bone densities do not differ between sexes. Estimates of mechanical stress within vertebral bodies are 30%-40% higher in women than men for equivalent applied loads. CONCLUSION: Smaller vertebral bodies in women confer biomechanical disadvantages that may contribute to more vertebral fractures in elderly women.
Adult↗
Calcitriol therapy and calcium-regulated PTH secretion in patients with secondary hyperparathyroidism.
Calcitriol lowers serum parathyroid hormone (PTH) levels in patients with secondary hyperparathyroidism, but its effect on calcium-regulated PTH release remains controversial. Thus 11 patients with secondary hyperparathyroidism underwent dynamic tests of parathyroid function before and after 4 mo of intermittent calcitriol therapy. Serum calcitriol levels rose from 8 +/- 1 to 55 +/- 9 (SE) pg/ml, P < 0.01, serum total and ionized calcium levels increased, and serum PTH levels decreased from 584 +/- 154 to 154 +/- 31 pg/ml, P < 0.05. The maximum increase in serum PTH during hypocalcemia did not differ before (248 +/- 78 pg/ml) or after (280 +/- 100 pg/ml) treatment, but the increase in PTH, expressed as a percentage of preinfusion values, was greater after treatment (329 +/- 73 vs. 132 +/- 10%, P < 0.05). The decreases in serum PTH during calcium infusions did not differ before (70 +/- 5%) or after (73 +/- 5%) therapy, and the set point for PTH release did not change (1.20 +/- 0.03 vs. 1.23 +/- 0.01 mmol/l, not significant). Calcitriol modifies PTH secretion during hypocalcemia in secondary hyperparathyroidism without affecting the set point for PTH release; although calcitriol lowers serum PTH levels, it may also restore the secretory reserve of hyperplastic parathyroid tissues during hypocalcemia.
Adolescent↗
Age-related changes in cortical and cancellous vertebral bone density in girls: assessment with quantitative CT.
OBJECTIVE: Bone mass increases during growth, but little information is available about the changes in cortical and cancellous bone densities during skeletal development or their relative contributions to age-related increases in bone mass. Accordingly, separate measurements of cancellous and cortical bone density were done at each stage of sexual development in white girls during childhood and adolescence. SUBJECTS AND METHODS: Quantitative CT was used to measure the densities of cortical and cancellous bone of the lumbar spine in 96 healthy white girls 4-20 years old. The relationships among various anthropometric indexes, pubertal status, and corresponding densities of cortical and cancellous bone were then examined. RESULTS: Cortical bone density increased with age, and values were significantly correlated with the anthropometric indexes of height (r = .61), weight (r = .62), body mass index (r = .61), and muscle volume (r = .58). In contrast, cancellous vertebral bone density increased only during the later stages of puberty. Moreover, cancellous bone density in prepubertal girls was inversely related to age (r = -.27) as well as to both the volume (r = -.20) and the height (r = -.15) of the vertebral body. CONCLUSION: The results suggest that weight bearing and/or mechanical stresses are important determinants of cortical bone density in the lumbar spine throughout growth, whereas cancellous vertebral bone density is more strongly influenced by hormonal and/or metabolic factors associated with sexual development during late adolescence.
Adolescent↗
Affinity purification and binding analysis of the hemolymph juvenile hormone binding protein from Manduca sexta.
A high-affinity juvenile hormone binding protein was purified from the hemolymph of the tobacco hornworm, Manduca sexta, employing ammonium sulfate precipitation and affinity and size-separation chromatography. The naturally occurring enantiomer of juvenile hormone III (10R) was converted to juvenile hormone III acid and then covalently attached to aminohexyl-Sepharose 4B. Hemolymph from early fifth stadium (60 h postecdysis) larvae was used as the source of hJHBP. The yield of hJHBP was approximately 25% of the starting material, with 3.5 mg of highly purified, biologically active hJHBP recovered from 100 mL of hemolymph. Binding parameters were examined using equilibrium dialysis and highly purified, enantiomerically correct juvenile hormone I and II and racemic JH III. The equilibrium dissociation constants for juvenile hormone I and II were approximately 6 x 10(-10) M at 4 degrees C, while racemic juvenile hormone III displayed an equilibrium dissociation constant of 1.9 x 10(-9) M. At 25 degrees C the equilibrium dissociation constant for juvenile hormone I was 1.6 x 10(-9) M. Half-times of dissociation were also determined for the three homologs. The half-time of dissociation was 30 s for juvenile hormone I, 20 s for juvenile hormone II, and 13 s for juvenile hormone III at either 4 or 25 degrees C. Using the new equilibrium dissociation constants, we calculate that better than 99% of the circulating juvenile hormone titer may be bound to this hemolymph protein.
Animals↗