Possible Role Of Parathyroid Hormone Research Articles

Association between High Levels of Parathyroid Hormone and Frailty: The Nepean Osteoporosis and Frailty (NOF) Study.

Frailty is associated with poor outcomes hence identification of risks factors is pivotal. Since the independent role of parathyroid hormone (PTH) in frailty remains unexplored, we aimed to determine this in a population of older individuals with a history of falling. Cross-sectional study. Falls and Fracture Clinic, Nepean Hospital (Penrith, Australia). 692 subjects (mean age=79, 65% women) assessed between 2009-2015. Assessment included clinical examination, mood, nutrition, grip strength, gait velocity, bone densitometry and posturography. Chemistry included serum PTH, calcium, vitamin D (25(OH)D3), creatinine and albumin. Normocalcemic subjects were divided into 4 groups: (1) Normal: 25(OH)D3 >50nmol/L and PTH between 1.6-6.8pmol/L; (2) PTH responsive: low 25(OH)D3 (<50nmol/L) and high PTH (>6.8pmol/L); (3) PTH unresponsive: low 25(OH)D3 and normal PTH; (4) Hyper PTH (>6.8pmol/L) with normal 25(OH)D3. Frailty was defined using Fried's criteria. Difference between the groups was assessed using one-way ANOVA and X2 analysis. Multinomial logistic regression evaluated the association between the groups and the number of Fried's criteria adjusted for age, BMI, renal function, 25(OH)D3 levels, and albumin. 22.6% subjects had high PTH levels (>6.8pmol/L). All subjects in the high PTH groups had significantly lower grip strength, gait velocity, limits of stability, and higher BMI. The PTH responsive group had a higher risk of pre-frailty (β=3.8, 95% CI = 3.42 - 5.22, p≷ 0.01) and frailty (β=8.26, 95% CI = 2.8-16.1, p<0.01). The risk of frailty was also higher in the Hyper PTH group (β=2.3, 95% CI = 1.74-4.32, p<0.01). We have reported an independent association of high PTH levels with high number of falls and with the clinical components of physical frailty in community dwelling older persons. Our results suggest a possible role of PTH in frailty that deserves further exploration.

ASSOCIATION BETWEEN HIGH LEVELS OF PARATHYROID HORMONE AND FRAILTY: THE NEPEAN OSTEOPOROSIS AND FRAILTY (NOF) STUDY

Background: Frailty is associated with poor outcomes hence identification of risks factors is pivotal. Since the independent role of parathyroid hormone (PTH) in frailty remains unexplored, we aimed to determine this in a population of older individuals with a history of falling. Design: Cross-sectional study. Setting: Falls and Fracture Clinic, Nepean Hospital (Penrith, Australia). Participants: 692 subjects (mean age=79, 65% women) assessed between 2009-2015. Measurements: Assessment included clinical examination, mood, nutrition, grip strength, gait velocity, bone densitometry and posturography. Chemistry included serum PTH, calcium, vitamin D (25(OH)D3), creatinine and albumin. Normocalcemic subjects were divided into 4 groups: (1) Normal: 25(OH)D3 &gt;50nmol/L and PTH between 1.6-6.8pmol/L; (2) PTH responsive: low 25(OH)D3 (&lt;50nmol/L) and high PTH (&gt;6.8pmol/L); (3) PTH unresponsive: low 25(OH)D3 and normal PTH; (4) Hyper PTH (&gt;6.8pmol/L) with normal 25(OH)D3. Frailty was defined using Fried’s criteria. Difference between the groups was assessed using one-way ANOVA and X2 analysis. Multinomial logistic regression evaluated the association between the groups and the number of Fried’s criteria adjusted for age, BMI, renal function, 25(OH)D3 levels, and albumin. Results: 22.6% subjects had high PTH levels (&gt;6.8pmol/L). All subjects in the high PTH groups had significantly lower grip strength, gait velocity, limits of stability, and higher BMI. The PTH responsive group had a higher risk of pre-frailty (β=3.8, 95% CI = 3.42 – 5.22, p&lt; 0.01) and frailty (β=8.26, 95% CI = 2.8-16.1, p&lt;0.01). The risk of frailty was also higher in the Hyper PTH group (β=2.3, 95% CI = 1.74-4.32, p&lt;0.01). Conclusion: We have reported an independent association of high PTH levels with high number of falls and with the clinical components of physical frailty in community dwelling older persons. Our results suggest a possible role of PTH in frailty that deserves further exploration.

Uremic pruritus

Uremic pruritus

Effects of Parathyroid Hormone on Immune Function

Parathyroid hormone (PTH) function as immunologic mediator has become interesting with the recent usage of PTH analogue (teriparatide) in the management of osteoporosis. Since the early 1980s, PTH receptors were found on most immunologic cells (neutrophils, B and T cells). The in vitro evaluations for a possible role of PTH as immunomodulator have shown inconsistent results mainly due to methodological heterogeneity of these studies: it used different PTH formulations (rat, bovine, and human), at different dosages and different incubating periods. In some of these studies, the lymphocytes were collected from uremic patients or animals, which renders the interpretation of the results problematic due to the effect of uremic toxins. Parathyroidectomy has been found to reverse the immunologic defect in patients with high PTH levels. Nonetheless, the clinical significance of these findings is unclear. Further studies are needed to define if PTH does have immunomodulatory effects.

Neutral phosphate-induced renal tubular metabolic alkalosis

A severely burned patient receiving neutral phosphate supplement developed renal tubular alkalosis. This phenomenon is compared with the results of experimental observations on animals, reported in the literature. The physiologic mechanism, including the possible role of parathyroid hormone, is illustrated.

CRITICAL ROLE OF PARATHYROID HORMONE IN FUROSEMIDE-INDUCED NEPHROCALCINOSIS IN THE YOUNG RAT. † 2127

The pathophysiologic mechanism of furosemide (F)-induced nephrocalcinosis(NC) is yet unknown. A few neonates treated with F were reported to developed hyperparathyroidism. To clarify the possible role of parathyroid hormone (PTH) in F-induced NC we studied 26 male 4-wk old Sprague-Dawley rats. They were divided into 4 groups: (a) intact, controls (n=7) (b) intact, treated with F 40 mg/kg I.P., QD (n=7) (c) parathyroidectomized (PTX), controls (n=6) (d) PTX, treated with F as in (b) (n=6). PTX animals were supplemented with 5% Ca gluconate in the drinking water. The study lasted 2 weeks during which animals had free access to water and food. In the last week rats were placed in metabolic cages for urine collection and recording of water and food intake. At the end, rats were anesthetized and exsanguinated. One kidney was studied histologically and the other ashed for Ca determination. Results: There were no differences among the groups with regard to food intake/100 gm animal. Animals in groups (b) and (d) had higher urine output and H2O intake, but less weight gain than groups (a) and (c) respectively, demonstrating the diuretic effect of F. Rats in (b) developed NC with kidney Ca content(μgm/gm dry tissue) 2446±1417 (mean ± SD) compared with (a) 199±39 (p<0.01). Kidney Ca in (c) 249±127 and (d) 178±38 were similar, and they were both significantly lower than (b)(p<0.01) and not different from (a). Similar observations were made on the histologic NC score in which only (b) animals developed NC. Daily Ca excretion in (d) 2361.7±995.4 μgm/100gmBW exceeded that in (b) 818.8±512.1 (p<0.02). Similarly, fractional Ca excretion in (d) 6.63±2.34 was higher than in (b) 1.86±0.84 (p<0.01). Conclusions: (1) PTX protects against F-induced NC, indicating that PTH has as least an important permissive role in the pathophysiology of the phenomenon.(2) Urine Ca per se is not the cause of F-induced NC in this model.

PTH receptor coupling to phospholipase C is an alternate pathway of signal transduction in bone and kidney

The parathyroid hormone (PTH) receptor is coupled via a guanine nucleotide-binding regulatory protein (G protein) to phospholipase C (PLC). Binding of PTH to its receptor leads to activation of PLC with the subsequent hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 generation leads to the release of intracellular calcium stores, which produces an increase in the intracellular calcium concentration. DAG activates protein kinase C (PKC). Both IP3 metabolites and PKC may play a role in returning the intracellular calcium concentration back to base line, by stimulating the movement of calcium from the intracellular to the extracellular compartment, as well as by sequestering calcium within intracellular organelles. PKC appears to be important in the development of desensitization and downregulation of the PTH receptor to PTH. Activation of PLC may be important in modulating the well-known effects of PTH on bone and kidney and also may be relevant to recently described actions, such as the possible role of PTH as a growth factor in skeletal tissue. Important issues that need to be addressed in this field include 1) characterization of the PTH receptor, 2) the possible role of low-molecular-weight G proteins in PTH signal transduction, and 3) further description of the role of alternate pathway signal transduction in producing the effects of PTH.

Experimental and immunohistochemical studies on the possible role of parathyroid hormone in uraemic pruritus.

Secondary hyperparathyroidism has been suggested as a cause of itching in chronic renal failure. The aim of the present study was to evaluate the possible role of parathyroid hormone (PTH) in pruritus affecting patients undergoing maintenance haemodialysis. In agreement with our previous findings, patients with pruritus had significantly (P less than 0.01) higher serum levels of PTH fragment 53-68 (m-PTH53-68) than patients without pruritus, 47.7 +/- 40.0 and 23.4 +/- 17.1 micrograms l-1 respectively. Serum concentrations of other substances including calcium, phosphate and magnesium did not differ between the two groups of patients. Intradermal injections of human PTH1-34 and PTH44-68 failed to evoke any acute or delayed cutaneous reactions in either patients or controls. Immunohistochemical investigations of skin biopsies from uraemic patients using several different antibodies against PTH were negative. Thus, the present results do not support PTH as a peripheral mediator of uraemic itching.

Parathyroid hormone mediates changes in calcium transport in uremic rat brain synaptosomes.

In previous studies, we showed that Ca2+ transport by both Na+ gradient-stimulated Ca2+ uptake and ATP-stimulated Ca2+ uptake was increased in synaptosomes from uremic rat brain. The possible role of parathyroid hormone (PTH) in this observation was investigated by performing Ca2+ transport studies in synaptosomes by these two mechanisms. Studies were performed in vesicles from rats that were either normal, uremic, uremic parathyroidectomized (PTX-U), or uremic parathyroidectomized but treated with PTH. In uremic rats, transport by both Na+ gradient-stimulated Ca2+ uptake and ATP-stimulated Ca2+ uptake was increased by 30 and 47%, respectively, whereas uptake was returned to base line in synaptosomes from PTX-U rats. Additionally, the administration of PTH to PTX-U rats resulted in a significant increase (P less than 0.001) of 36 and 41%, respectively, above the values observed in PTX-U rats. To determine whether the increased accumulation of Ca2+ in synaptosomes in uremia was a result of PTH alone and/or to the uremic environment, we next performed uptake studies in synaptosomes that were isolated from nonuremic rats that were either normal, parathyroidectomized (PTX) or PTX but treated with 2.8-100 micrograms PTH. By both transport mechanisms, uptake was significantly (P less than 0.01) decreased from normal by 27% in the PTX group, and either 2.8 or 110 micrograms PTH resulted in a significant increase in transport to base line by Na+-gradient stimulated Ca2+ uptake. However, Ca2+ accumulation by ATP-stimulated Ca2+ uptake was significantly increased to base line only with 100 micrograms PTH.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypercalciuria of mineralocorticoid escape: clearance and micropuncture studies in the rat.

Chronic mineralocorticoid excess results in the predicted retention of salt and water followed by a period of escape from sodium retention and hypercalciuria. We studied a rat model during mineralocorticoid escape (ME) with clearance and micropuncture studies to ascertain the nephron site and possible role of parathyroid hormone. Rats during ME were hypercalciuric compared with a matched saline group. Clearance studies revealed a marked difference in the calcium-to-sodium fractional excretion ratio (FECa/FENa) between saline-expanded and mineralocorticoid (desoxycorticosterone acetate, DOCA)-escaped animals (saline-expanded, 0.40 +/- 0.09 vs. DOCA, 1.02 +/- 0.14; P less than 0.01). The addition of either hydrochlorothiazide (HCTZ) or amiloride (AMIL) to the ME animals significantly lowered this ratio from that seen in the intact ME group (DOCA-HCTZ, 0.47 +/- 0.07; DOCA-AMIL, 0.83 +/- 0.14). Neither parathyroidectomy (PTX) nor parathyroid hormone infusions (PTH) in ME animals altered the FECa/FENa from that seen in the intact ME group (DOCA-PTX, 1.15 +/- 0.20; DOCA-PTH, 1.25 +/- 0.18). Segmental micropuncture along the length of superficial nephrons demonstrated no differences in calcium delivery to late proximal, early distal, and late distal sites. However, FECa was markedly increased in ME animals compared with saline controls (saline, 0.48 +/- 0.13% vs. DOCA, 1.62 +/- 0.24%; P less than 0.05). We conclude that the hypercalciuria of ME is independent of PTH and can be significantly reduced by HCTZ or AMIL. Micropuncture and clearance data suggest that the hypercalciuria of ME is mediated in the terminal nephron. The differences in the results when superimposing various factors that influence distal nephron calcium reabsorption on ME may be related to differences in their site(s) of activity on calcium transport.

Clinical and biochemical effects of EHDP in Paget's disease of bone: Patterns of response to initial treatment and to long-term therapy

Studies regarding the efficacy of EHDP in the treatment of Paget's disease of bone conducted at our institution are described. An initial placebo-controlled clinical trial established that doses of 5 mg/kg/day for 6 months produced symptomatic improvement and a 50% lowering of serum alkaline phosphatase and urinary hydroxyproline. A subsequent study Indicated that the biochemical suppression was maintained during the ensuing 6 months without therapy. Current results of long-term Intermittent EHDP treatment in 40 patients studied for 5–8 years demonstrate that a small minority of Individuals experience a sustained remission after a single six-month course of therapy, while a majority require repeated courses of 5 mg/kg/day for 6 of every 12 months to maintain their Initial Improvement. Data are also presented describing the successful use of EHDP at a dose of 20 mg/kg/day for 1 of every 4 months in patients reractory to conventional low doses of therapy. The possible role of parathyroid hormone In the expression of Paget's disease Is also discussed, and recommendations regarding the pharmacologic management of patients with this disorder are provided.

Radiocalcium metabolism in disuse osteoporosis in man

Combined calcium balance and radioactive calcium turnover studies have been performed in a series of normal and paralyzed adults. The purpose of this investigation was to evaluate the kinetic factors responsible for disuse osteoporosis. Patients with acutely developing disuse osteoporosis were found to have bone formation rates from normal to twice normal and bone resorption rates from two to three times normal. The increased bone resorption rates more than accounted for the negative calcium balances of these subjects. Patients with chronic, stable (but severe) disuse osteoporosis were found to be in calcium equilibrium, with bone formation and resorption rates either normal or slightly low. These observations indicate clearly that the absence of mechanical stresses did not, of itself, reduce bone forming activity, and that a primary increase in bone resorption was responsible for the development of disuse osteoporosis. In vivo uptake measurements of Sr 85 in one subject confirmed the kinetic observations, to the effect that a more severely paralyzed extremity took up more isotope than did its less severely involved mate. Treatment of five of the paralyzed subjects with anabolic steroids produced the expected improvement in calcium balance, but kinetic analysis indicated that in the acute group the effect was entirely anticatabolic: i.e., there was no increase in bone forming activity, but a considerable decrease in bone resorption. Measurement of gastrointestinal calcium absorption in all subjects studied revealed gross depression of absorption efficiency in the acute stage of osteoporosis. This change, together with elevations in both serum calcium and serum phosphorus, are interpreted as indications of suppression of endogenous parathyroid function. As such, this evidence precludes any possible role of parathyroid hormone in the genesis of disuse osteoporosis.