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Biomedical subjects

A M Parfitt

Publications and source records attributed to A M Parfitt.

At least 199 records · Page 11Linked to original sources
PubMed1976

The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease. Part IV of IV parts: The state of the bones in uremic hyperaparathyroidism--the mechanisms of skeletal resistance to PTH in renal failure and pseudohypoparathyroidism and the role of PTH in osteoporosis, osteopetrosis, and osteofluorosis.

In early chronic renal failure, the state of the bones resembles that of type II primary hyperparathyroidism. Cortical bone becomes thinner and more porous, and there is increased extent of surface remodeling. These changes are followed in turn by osteomalacia and osteitis fibrosa, although sometimes these may be alternate rather than successive stages. Bone turnover is less than would be expected for the elevation of PTH level, probably because of 1,25 (OH)2D3 deficiency. The resorption velocity and lamellar bone appositional rates are depressed, but woven bone appositional rate may be increased, possibly because of hyperphosphatemia. Bone mass reflects the summation of three independent processes: loss of lamellar bone due to hyperparathyroidism (depending on the extent of insulation by osteoid); accumulation of partly mineralized osteoid because of osteomalacia; accumulation of woven bone because of osteitis fibrosa. Osteosclerosis may be growth-related metaphyseal, subchondral or diffuse axial, and periosteal neostosis may also occur. Some patients on hemodialysis lose bone because of planing rather than lacunar or dissecting resorption, combined with depression of both lamellar and woven bone formation. Hyperparathyroid bone disease tends to improve slowly after renal transplantation. Persistent hypocalcemia reflects a defect in the calcium homeostatic system and cannot be explained solely by the known stimuli to secondary hyperparathyroidism. The increment in plasma calcium in response to PTH infusion is subnormal, both in early chronic and in acute renal failure, probably because of 1,25(OH)2D3 deficiency. This is also the most likely explanation for the depressed level of blood-bone equilibrium. The activity of all three of the PTH responsive cell systems in bone is depressed in renal failure, probably because all three require 1,25(OH)2D3 in order to function normally. In pseudohypoparathyroidism, as in chronic renal failure, hypocalcemia results from a defect in the regulation of the blood-bone equilibrium. The bone-remodeling system shows all gradations of response, from slight depression of bone turnover to overt osteitis fibrosa, but bone turnover is never as low as in PTH deficiency. These differences may reflect the presence or absence of resistance to PTH of the osteoprogenitor cell as well as of the calcium homeostatic system, or may be due to varying degrees of 1,25(OH)2D3 deficiency, as in chronic renal failure. An increase in plasma calcium in response to PTH can occur either in the untreated state or after treatment with vitamin D because either the error-correcting or remodeling system remains responsive to PTH. Pseudohypoparathyroidism may be subdivided into three types, depending on whether the urinary cyclic-AMP response to PTH remains defective despite treatment with vitamin D, improves with treatment, or is normal before treatment. Only the former is associated with the genetic syndrome of Albright's hereditary osteodystrophy...

Bone Diseases↗
PubMed1976

The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone diseases. II. PTH and bone cells: bone turnover and plasma calcium regulation.

Kinetic and morphologic studies in patients with parathyroid disease, and a wide variety of studies in experimental animals indicate that one major effect of PTH is to increase the proliferation of osteoprogenitor cells into osteoclasts and so to increase bone turnover. PTH stimulates bone cells by increasing cell membrane permeability to calcium and consequently increasing calcium influx and by activating membrane-bound adenyl-cyclase. It is likely that the former event precedes the latter and that calcium is the second messenger and cyclic AMP the third messenger. PTH increases the production by bone cells of lactate, citric and carbonic acids, lysosomal enzymes, collagenase, and hyaluronic acid, some or all of which are concerned in the mechanism of bone resorption. With the exception of lactate which probably comes mainly from osteocytes, the increase in metabolic activity is largely due to the increase in the number of osteoclasts. There is also ultrastructural, biochemical, and biophysical evidence that PTH stimulates existing osteoclasts, but this most likely represents the transformation of inactive cells into an active state, and is a transient and nonsustainable effect. As yet, there is no evidence that either increased osteoprogenitor cell proliferation or increased osteoclast activity is mediated by adenyl-cyclase activation. PTH also acts on the deep osteocyte to cause rapid mobilization of calcium from the zone of hypomineralized metabolically active perilacunar bone. This effect is mediated by adenyl-cyclase activation and is preceded by a slight fall in plasma calcium probably due to the movement of calcium into bone cells. The function of this rapid hypercalcemic response to PTH is correct errors in the prevailing steady-state level of plasma calcium...

Animals↗
PubMed1976

The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease. Part I of IV parts: mechanisms of calcium transfer between blood and bone and their cellular basis: morphological and kinetic approaches to bone turnover.

The supracellular organization of living bone enables the study of isolated cellular and subcellular systems to be related to the study of the whole organism. Bone is formed by osteoblasts in successive stages, separated in both time and space, of matrix formation and primary mineralization. Osteoblasts are joined by tight junctions and largely cover the osteoid seam which separates them from mineralized bone. Secondary mineralization is not completed for several months and is not regulated by the osteoblast. Bone is resorbed by osteoclasts which simultaneously accomplish mineral dissolution and matrix digestion. Active osteoblasts occupy about 5% of the free bone surface, osteoid seams with less active osteoblasts about 10%, active osteoclasts about 0.5%, and Howship's lacunae at which bone remodeling is either quiescent or arrested about 5%. The remaining 80% of the free bone surface is covered by a leaky envelope of thin flattened cells, termed surface osteocytes. Some osteoblasts become permanently buried in the bone as deep osteocytes, around which a specialized and metabolically active perilacunar bone is formed. This bone is less highly mineralized and can temporarily lose or gain calcium in accordance with homeostatic needs. Deep osteocytes maintain contact with each other and with the surface osteocytes, their cell processes within canaliculi being joined by gap junctions. Remodeling of cortical bone proceeds with the excavation by osteoclasts of a longitudinal tunnel which is refilled by osteoblasts to form a new osteon. The anatomically discrete longitudinally oriented structure consisting of a cutting cone of osteoclasts in front and a closing cone of osteoblasts behind is termed a cortical remodeling unit. The events of centrifugal resorption and centripetal formation which occur in a single cross section is termed a cortical remodeling cycle. Normally each new cycle is slightly out of phase with its predecessor. The quantities which characterize cortical remodeling are the birth rate of new remodeling cycles or activation frequency (mu), and the durations of the resorptive period (sigma r), the quiescent interval (sigma q) and the formation period (sigma f). The average distances traveled by the osteoclast and osteoblast are indicated respectively by the mean cement line diameter and mean wall thickness of completed osteons. These quantities show little interindividual variation. Because of this constancy the magnitude of bone turnover (the bone formation rate) is almost entirely a function of mu, the activation frequency of new remodeling cycles. Variations in the velocity of advance of osteoclasts (the linear resorption rate) or of osteoblasts (the appositional rate) alter inversely both the extent of surface engaged in resorption or formation and the time taken to replace a particular moiety of bone, but in a steady state do not influence the rate of turnover of the skeleton as a whole...

Animals↗
PubMed1976

The effect of cellulose phosphate on plasma and urinary magnesium at different levels of parathyroid function in man.

1. Previously published data obtained by magnesium infusion in man were found to conform to a Tm/glomerular filtration rate (GFR) model on the assumption of 80% diffusibility of plasma magnesium. The lower limit of Tm,Mg/GFR was 625 mumol/l. 2. Previously published data concerning the effect of cellulose phosphate on magnesium metabolism in normal subjects, patients with latent hypoparathyroidism and patients with primary hyperparathyroidism were found to conform to the same model, with the same limit for Tm,Mg/GFR for all three levels of parathyroid function. 3. The threshold for magnesium excretion is sharper with less 'splay' than for phosphate, but as for phosophate it is close to the normal blood concentration. 4. Because of the geometrical relationship between different methods of presentation of data, at a constant value for Tm,Mg/GFR changes in magnesium load or in GFR automatically produce changes in fractional magnesium clearance. This is the explanation for the increase in fractional magnesium clearance which occurs which with diminishing renal function. 5. Renal conservation of magnesium is a passive consequence of the fall in plasma magnesium. There was no evidence of augmented tubular reabsorption of magnesium in response to magnesium deprivation in any of the three groups of subjects. 6. The tubular reabsorption of magnesium was not altered detectably by a moderate deficiency or excess of parathyroid hormore. Changes in parathyroid hormone secretion are probably not concerned in normal magnesium homeostasis.

Biological Transport, Active↗
PubMed1975

Effect of cellulose phosphate on calcium and magnesium homeostasis: studies in normal subjects and patients with latent hypoparathyroidism.

1. The bivalent cation-binding agent, cellulose phosphate, was given for 6 days to four normal subjects and six patients with latent hypoparathyroidism (diagnosed by impaired response to EDTA infusion), all of whom were on a moderately low calcium diet. 2. In normal subjects, there was a prompt and sustained fall in urinary calcium with no change in plasma calcium, indicating increased tubular reabsorption. Plasma and urinary magnesium fell, without increase in tubular reabsorption. The urinary total hydroxyproline increased and Tm,P/glomerular filtration rate fell after 2 days; these changes were transient and were consistent with a transient increase in parathyroid hormone secretion. 3. In the hypoparathyroid patients, urinary calcium fell more slowly and a fall in plasma calcium occurred in several subjects, the extent and duration of which corresponded with parathyroid status determined by EDTA infusion. Urinary conservation of calcium was impaired but plasma and urinary magnesium fell as in normal subjects. Urinary total hydroxyproline did not change and Tm,P/glomerular filtration rate fell more slowly than in the normal subjects. 4. The relative contributions of increased tubular reabsorption and reduced filtered load to calcium conservation in response to calcium depletion depend on the prevailing level of parathyroid function; the former is more important when parathyroid function is normal, the latter when parathyroid function is impaired. 5. In the detection of reduced parathyroid reserve, the assessment based on the plasma calcium response to cellulose phosphate agrees closely with the assessment based on the degree of recovery from EDTA-induced hypocalcaemia.

Adult↗
PubMed1975

Effect of cellulose phosphate and dietary calcium restriction in primary hyperparathyroidism.

1. The bivalent cation-binding agent, cellulose phosphate, together with a low calcium diet was given for 6 days to nine patients with primary hyperparathyroidism subsequently verified at surgery. 2. Urinary calcium fell promptly by 8-4 mmol/24 h, and by 70% and reached amounts below 4-0 mmol/24 h in five of the nine patients. The magnitude of fall may have been related to increased synthesis of vitamin D by the skin in a sub-tropical environment. Plasma magnesium fell steadily and urinary magnesium fell by 80%. 3. The plasma calcium showed two types of response. In five patients there was no significant change because a reduction in calcium load was offset by a further increase in the already high tubular reabsorption of calcium. In the remaining four patients, the tubular reabsorption of calcium was at a higher level initially and failed to increase further on the experimental regime, with a corresponding fall in plasma calcium. 4. The hypercalcaemia of primary hyperparathyroidism can be explained by increased renal tubular reabsorption of calcium; net bone resorption makes only a small contribution but an additional factor dependent on the blood-bone equilibrium is not ruled out. 5. Comparison with other published data suggests that the fall in urinary calcium in response to a calcium-depleting regimen is prevented by concurrent depletion of inorganic phosphate and may be enhanced by concurrent depletion of magnesium. 6. Persistence of hypercalcaemia combined with an increase in tubular reabsorption of calcium in response to cellulose phosphate may be of diagnostic value in suspected primary hyperparathyroidism. 7. Cellulose phosphate may be of value in stone prevention in patients with primary hyperparathyroidism who are unsuitable for surgical treatment.

Adult↗
PubMed1972

The interactions of thiazide diuretics with parathyroid hormone and vitamin D. Studies in patients with hypoparathyroidism.

In order to clarify the mechanisms of thiazide diuretic-induced hypocalciuria, the effect of a thiazide was studied for 7 days in seven patients with hypoparathyroidism on Vitamin D and one on calcium infusion, and seven euparathyroid patients with hypercalciuria. In the control group, calcium excretion (mg/24 hr) fell by 44% from 415 to 232 within 4 days and remained at this level. Plasma total calcium corrected for total protein did not change. In the hypoparathyroid group, calcium excretion fell by 11% from 351 to 311 and then returned to the base line level. Plasma total calcium (mg/100 ml) increased from 10.09 to 10.88, 11.29 and 10.77 at the end of the 2nd, 4th, and 7th day of thiazide administration. In the patient having i.v. calcium and no Vitamin D, neither plasma nor urinary calcium changed significantly. In both groups sodium excretion increased on the first 2 days and fell to or below base line level thereafter. Urinary phosphate, magnesium, and potassium increased, plasma phosphate rose, and magnesium and potassium fell. It is concluded that: (a) The hypocalciuric effect of thiazides requires the presence of parathyroid hormone and is not solely a result of sodium depletion. (b) The hypercalcemic effect of thiazides in hypoparathyroidism is due to increased release of calcium from bone and requires the presence of a pharmacologic dose of Vitamin D. (c) Thiazides enhane the action of parathyroid hormone on bone and kidney; Vitamin D can replace parathyroid hormone in this interaction in bone but not in kidney.

Adult↗