Phosphorus, Regulation of Plasma Calcium, and Secondary Hyperparathyroidism

Fifty years ago, Fuller Albright in his classic book, Parathyroid Glands and Metabolic Bone Disease, advanced the concept that phosphorus was critical for the modulation of calcium mobilization from bone and the regulation of plasma calcium (1). The basis for his conclusions were elegantly summarized in his book and were derived from his meticulously performed clinical studies during the previous 20 years in which prolonged calcium and phosphorus balance studies were obtained in patients with parathyroid disorders. In these studies, parathyroid extract was infused in healthy volunteers and in patients with primary hyperparathyroidism (10 HPT) and hypoparathyroidism (2,3,4,5). Albright observed that the increase in serum calcium always followed the phosphaturic response. In a separate series of studies, the administration of vitamin D and AT10 (dihydrotachysterol) and the infusion of calcium were evaluated in patients with hypoparathyroidism (6,7). In these studies, Albright observed that even in the absence of parathyroid hormone (PTH), an increase in serum calcium was associated with a decrease in serum phosphorus and increased urinary phosphorus excretion. As a result of these studies (2,3,4,5,6,7), Albright concluded that the primary action of PTH was on renal phosphorus excretion and that the resulting changes in serum calcium were not due to a direct effect of PTH on bone but rather were secondary to PTH-induced changes in serum phosphorus. Thus, according to Albright, the increased calcium mobilization from bone was an indirect effect of PTH due to its lowering of serum phosphorus (1). Although we do not believe or even suggest that PTH does not have a direct effect on bone, we do believe that Albright's observations about the central role of phosphorus on calcium mobilization from bone and plasma calcium regulation deserve much greater emphasis. In this article, we use available data from previous clinical and experimental studies to develop our hypothesis that phosphorus plays a critical role in the regulation of plasma calcium and PTH-mediated calcium mobilization from bone. In his 1948 book (1), Albright concluded that PTH-enhanced renal excretion of phosphorus was the primary mechanism for increased calcium mobilization from bone for the following reasons. (1) The first consequence of PTH administration was to increase phosphorus excretion and all else followed subsequently. In more recent studies, it has been shown that after a PTH infusion, a rapid decrease in serum phosphorus and increase in urinary phosphorus are observed before any change in serum calcium (8). (2) Forced feeding of phosphorus to patients with 10 HPT lowered serum calcium and urinary calcium excretion; perhaps it should be added that today we also know that such an approach increases PTH levels, and still serum calcium decreases (9). (3) In patients with renal insufficiency and phosphorus retention, it was not possible to increase serum calcium with parathyroid extract. (4) Many patients with 10 HPT never develop bone disease. This suggested to Albright that the bone disease was a secondary complication (1). These observations clearly show that Albright had thought in considerable depth about the mechanism of PTH action. In 1942, Collip, the first investigator to prepare biologically active parathyroid extract in 1925 (10) and who advanced the concept that PTH had a direct effect on bone, performed a study that strengthened Albright's belief in the primacy of phosphorus. A bilateral nephrectomy or ureteral ligation was performed in dogs to prevent the urinary excretion of phosphorus and any reduction in serum phosphorus. The study showed that the infusion of parathyroid extract failed to increase the serum calcium (11). Although Albright believed that PTH-induced phosphorus excretion was responsible for calcium mobilization from bone, he also acknowledged in his book (1) that considerable evidence available from previous studies, including his own (12), suggested that PTH had a direct effect on bone. We believe that the concept advanced by Albright that phosphorus directly modifies calcium mobilization from bone has failed to receive sufficient attention. As so often happens, when the primacy of one concept gains ascendancy (direct effect of PTH on bone), other observations that were correct (effect on phosphorus on calcium mobilization from bone) are left to languish and fail to be adequately integrated into the framework of the accepted dogma. Although our emphasis will be on clinical and animal studies, it should also be noted that several excellent in vitro studies, one of which is shown in Figure 1, have convincingly demonstrated that an increase in the medium concentration of phosphorus profoundly reduced calcium efflux from bone and dramatically reduced the calcemic action of PTH on bone (13,14). In these studies, a distinct effect of phosphorus was shown between a 1 mM and 2 mM phosphorus concentration, a range observed in humans and many animal species.Figure 1.: Results of an in vitro study demonstrating that parathyroid hormone (PTH) enhances calcium efflux from bone and that phosphate markedly reduces calcium efflux from bone both in the presence and absence of PTH. ○, PTH-live; □, control-live; Symbol, PTH-killed; ▪, control-killed. From Raisz et al., (13) and reprinted with permission from Endocrinology.SymbolConcept of the Equilibrium Operating Point (Set Point) To show that phosphorus is a critical factor in the modulation of calcium mobilization from bone, we have used an approach to the PTH—calcium relationship that has been advocated to Parfitt (15,16). In this approach, the relationship between serum calcium and PTH is expressed as a function of each other and has been described as reciprocal causality in which the dependent and independent status are interchanged. Parfitt states that these functions can be of mathematical form, provided that they are monotonic and have slopes of opposite sign so that they intersect at only one point, referred to as the equilibrium operating point (15,16,17). As shown in Figure 2, the equilibrium operating point or the point to be with the point of the is the of the function when PTH modifies the serum calcium and the serum calcium modifies PTH. The is obtained when of PTH are infused and serum calcium is in clinical studies, the to such studies has this The function is obtained when PTH is by changes in the serum this is the that has been performed in many animal and clinical studies The approach advocated by Parfitt and that the for calcium between the parathyroid bone, and should be as an that is by several including and renal and bone These calcium as a function of PTH is to show that on previous studies performed in both and humans and phosphorus has a critical role in the of the relationship between PTH and from Parfitt The is that of reciprocal causality between calcium and PTH. In 1, calcium is a function of and in 2, PTH is a function of The of the function the equilibrium operating point or point for the PTH is in but we have the by Parfitt so that the PTH the in studies in healthy humans in which the and PTH are and et al., with permission from and as a of PTH In our recent of PTH were infused in As shown in Figure we that the of PTH to a serum calcium and phosphorus in on a was this PTH also a Thus, this PTH should be to a PTH of which was in on the As in previous studies, we were not to infused PTH in the serum the infused PTH of which is greater the should be to an PTH of This it is the PTH that we have used in previous studies to the calcemic to PTH in and As we will show this infused of PTH on the calcemic of PTH in experimental during which other such as and renal were study also showed that a reciprocal relationship between serum calcium and phosphorus a range of at each PTH for the the was at the PTH the was greater the increase in serum calcium was not by a in serum phosphorus. These observations were to years by Fuller Albright The of this reciprocal relationship between serum calcium and phosphorus for in which the to decrease serum phosphorus to increases in serum suggested to Albright that a PTH-induced reduction in phosphorus was critical for the increase in serum The serum calcium are shown for each of PTH that was infused for with a The the PTH is on the for which the are a and 2 and The serum phosphorus are shown for each of PTH that was infused for with a The the PTH is on the for which the are a and 2 and The serum calcium and phosphorus obtained after a infusion of PTH are shown for each The the relationship between serum calcium and phosphorus is on the a 2, for which the are a and 2 and From et al., and reprinted with permission from Operating Point (Set Point) as by and As a result of our PTH infusion studies in we were to develop the shown in Figure 2 in which calcium is a function of PTH This function was in by on a the serum calcium for of infused PTH. in this function should be as a that changes with the PTH and the bone to PTH. the in which PTH is a function of the serum calcium we have used the in on a provided by and in these the PTH was The of these the equilibrium operating point or the point of the As shown in Figure we to that both phosphorus often by and an increase in serum the point operating to the left so that PTH is to the serum calcium an increase in phosphorus as by an increase in serum a decrease in serum and renal the point to the so that more PTH is to the serum calcium In the it should be that the serum calcium is as a function of PTH. is available on PTH changes as a function of serum but a phosphorus concentration and change the PTH to function one in which calcium is a function of PTH and in which PTH is a function of The first as a function of was in in which of PTH were infused for The as a function of was obtained in as a result of an infusion to serum calcium and a calcium infusion to increase serum The of the function the equilibrium operating point or point for the shown are that can the equilibrium operating point to the left of and to the of The for the that PTH were by or during the PTH infusion studies the of PTH to the serum calcium and phosphorus in was a PTH of in on the the PTH was Thus, when the infused PTH was greater the PTH was a of previous studies, we have evaluated the of phosphorus and in and in with renal In Figure the serum calcium and phosphorus are shown for with renal function renal to and advanced renal These a phosphorus or a phosphorus for before a PTH infusion As shown in Figure this infused of PTH is to an PTH of as a in Figure A and is the relationship for with renal function which were on a and of PTH that from to of the PTH increased as the of renal increased and were markedly for serum calcium Thus, the operating were the PTH only increased with renal and were only for serum calcium Thus, the in renal the operating were the PTH infusion, the calcemic to PTH or perhaps more as the serum calcium for a PTH concentration was much greater at of renal function in on the on the and should also be noted that in that were on the the serum calcium for a PTH infusion of was greater the in the and the in the Thus, these studies show that in phosphorus clearly the point and the of PTH to a serum calcium in renal when calcium was a function of PTH during the PTH infusion, phosphorus the calcemic action of PTH in both and The effect that a phosphorus has on the equilibrium operating point in and in with and advanced renal The use of a phosphorus in renal in a of the equilibrium operating The use of a phosphorus in not have much effect on the equilibrium operating point with on a phosphorus the calcemic to a infused of to was reduced in on a a phosphorus In renal was a decrease in the calcemic to a PTH The for PTH as a function of serum calcium performed in is as a The effect that a phosphorus has on the equilibrium operating point in and in with and advanced renal The use of a phosphorus in renal in a but of the equilibrium operating The use of a phosphorus in to the equilibrium operating point to the left with on a phosphorus and the calcemic to a infused of PTH to was greater in on a a phosphorus In renal was a decrease in the calcemic to a PTH infusion, but the calcemic to PTH was the in on a phosphorus as in with renal on a phosphorus The for PTH as a function of serum calcium performed in is as a the of Figure for an of and of data in Figure from our previous studies show in changes in phosphorus the of the calcemic to PTH in of renal The of the study the of renal and the and phosphorus were the as in the previous In the serum and phosphorus were not between on a or a serum the serum calcium was after the PTH infusion in the on the on a were to a during the PTH infusion, the serum calcium was not in the on the Thus, this study that the serum phosphorus concentration not always the phosphorus in and the phosphorus is responsible for calcium from bone. on a were to a for during the PTH infusion, the bone to PTH was to the of a and renal function the excretion of any phosphorus that had before the PTH calcium and phosphorus for renal function renal and advanced renal for on and phosphorus are A of on a phosphorus was to a phosphorus before the PTH infusion, which has been shown to be the PTH PTH as a function of serum calcium is shown as a this was only performed in with renal function and is shown as a point of the of Figure for an of and of of the relationship between PTH and calcium in renal are shown in Figure the of the study the point was between the and Thus, a greater PTH in the was to a serum and the serum phosphorus was also greater the much greater PTH the PTH infusion, serum phosphorus increased with the as a serum calcium was much for a PTH on a were to a during the PTH infusion, the serum phosphorus was not from that of the on a the infusion serum calcium for PTH was between the and This result was in with renal which a and were to a during the PTH Thus, it is that the presence of renal not the excretion of the phosphorus These the concept that phosphorus the calcemic of and the serum phosphorus often the phosphorus develop in which the serum phosphorus not the phosphorus renal excretion of phosphorus be more bone should be noted that a has been shown to develop during in which the rapid in serum phosphorus during is not an of the phosphorus a rapid during which serum phosphorus increase The in advanced renal show that phosphorus markedly the calcemic of PTH the study in the equilibrium operating point, and phosphorus were observed between the and Thus, with the a greater PTH with the was not to a serum a greater the serum phosphorus was much greater in the were on a during the PTH infusion, serum calcium serum phosphorus the to which the infusion of PTH PTH in these is not the was to a during the PTH infusion, the serum calcium was between the and even the infusion serum phosphorus was not from the These show that with renal more is to an equilibrium and the phosphorus should also be that of the to phosphorus during advanced renal the phosphorus that during the study was also greater in the In during phosphorus more PTH was to a serum calcium and when PTH was the serum calcium was for PTH of and the of We have provided a of our experimental studies we believe that an of the approach in which the equilibrium operating point is evaluated into the of many previous clinical and animal Although in studies it not be possible to calcium as a function of PTH by a series of PTH the of calcium on the and PTH on the the direct of the PTH for a serum calcium and clearly the point operating for the integrated for calcium As we will we believe that several the calcemic of PTH. The of these are the serum phosphorus more the phosphorus serum and renal As we have shown in our experimental studies in which it was possible to the serum calcium as a function of changes in serum phosphorus an role in the calcemic of PTH. as will be we to that in renal a serum phosphorus with an PTH should be as an serum in the presence of a the serum phosphorus should be We believe that this decrease in phosphorus the bone more to the calcemic action of PTH. In the we will to the that in all in which PTH is a reduction in serum phosphorus enhances the calcemic action of PTH. In renal when an increased PTH is to the serum the calcemic to PTH is reduced even by a serum phosphorus. In our of secondary hyperparathyroidism we will the of phosphorus is in renal vitamin D of 20 we suggest that be a of 20 HPT and will the of phosphorus in the from a should be that in the of 20 HPT that will be is calcium for PTH to As to 10 in which the calcemic action of PTH is operating in an the serum calcium is or even in the 20 HPT of vitamin D renal and for renal the decreases an increased PTH reduces serum phosphorus. Thus, this with a serum calcium and a result in a more for calcium efflux from bone. This is by the in vitro study of and in which a calcium concentration reduced PTH-induced calcium efflux from bone. as has been shown in by et the relationship between PTH and calcium is but has a between serum calcium from to 10 for greater 10 This a greater of PTH in the range of serum calcium for on phosphate in the of 20 it to show the healthy to a phosphate In an excellent study by et in phosphate was infused for As shown in 1, on 1 of the phosphate infusion, PTH increased by serum phosphorus increased by and calcium the increase in PTH. to of the infusion, PTH at a increased greater but calcium was to serum phosphorus had to during the urinary phosphorus excretion had increased by from Thus, for a PTH the calcium was when the serum phosphorus was and when the serum phosphorus was to on the first after the phosphate infusion was serum PTH had to serum phosphorus and calcium to be greater This study that the healthy can to a phosphate by markedly urinary phosphorus excretion. Thus, the to a phosphate calcium was by a increase in PTH and a decrease in serum phosphorus of phosphorus on serum and urinary calcium and phosphorus and PTH in of and of studies of parathyroid function and in healthy and As shown in 2, serum PTH were greater and serum phosphorus by in the serum were not In previous studies, the increase in PTH observed with has been shown to be associated with a decrease in serum phosphorus in but not is to renal phosphorus excretion and decrease the efflux of phosphorus from bone the decrease in during be for this and data of in healthy and shown in Figure we have the of the study by et in the of the relationship between PTH and calcium with serum calcium on the and PTH on the Thus, as is to the serum calcium more PTH is in the it is our belief that the serum phosphorus in the functions to the calcemic action of PTH. We also believe that the serum phosphorus were the as in the to PTH have been increased in result in a to that observed in renal in which a PTH serum phosphorus does not decrease or the decrease is were between the Thus, we believe that to PTH during perhaps due to a but it also be a result of in bone the be due to with bone and calcium available for calcium efflux from bone The increased PTH in a lowering of the serum which functions to the calcemic action of The is from the studies of et and et in which a was performed in and As observed in A for the serum calcium at the PTH was greater in the The PTH which are for each were obtained before the and calcium In a PTH infusion was performed at a shown in a previous study to increase PTH by in volunteers et al., ○, Symbol, with permission from The of provided by the study shown in Figure is when with study by the performed in the of in which the calcemic to infused PTH was between the healthy and To the of both studies and show a of to that in our animal studies in which PTH and calcium were shown as a relationship a mathematical The of infused PTH used for the infusion was This PTH was used in an study and increased PTH in healthy Thus, in Figure we the infused PTH to be greater in the As was shown in Figure serum calcium for a PTH in the was also observed during the PTH infusion both the of increase and the serum calcium for a PTH was in the the This result was observed even the serum phosphorus in the the PTH infusion This result be to the calcemic action of PTH on bone. These suggest to as perhaps they have to Fuller Albright, that the serum phosphorus was not a consequence of the hyperparathyroidism as was suggested by the but rather it also functions as an mechanism to the bone to PTH. in D of In an study of vitamin D et and the at in dogs on a vitamin and for in Figure are the for and during the first of the and of the vitamin and PTH increased to 2, and serum calcium not and was a for serum to increase a decrease in phosphorus from mM at to of and mM at and these changes decreases of and calcium as PTH to to at as to The serum phosphorus at was which a decrease from Thus, the to increases in PTH from to of the vitamin and were associated with decreases in serum phosphorus from at to at We suggest that as shown in our experimental studies and this decrease in serum phosphorus to the calcemic action of PTH and a serum The of this be that serum phosphorus not decrease or the decrease was both of which in renal to PTH resulting in greater increases in PTH and changes in PTH are the and PTH and and during the first of a study in which dogs were on a and vitamin for the increase in serum PTH and the decrease in serum the serum calcium to In during the first increase even are from et al., and reprinted with permission from The of Bone and in of We to renal it is perhaps the and to the such as and are all and each is and directly by renal are which suggest to that in renal a reduction in serum phosphorus and which are at by PTH result in a to that in the and to a of 20 should also be that a series of studies performed in the by and to the which that in renal a increase in serum phosphorus a PTH to the serum phosphorus and a serum calcium in studies this hypothesis was an increase in serum phosphorus was not observed in renal studies of phosphate showed that phosphorus excretion was even in renal We believe that the hypothesis by and and the observations are both The is that the of phosphorus excretion and the lowering of the serum phosphorus are not for the of hyperparathyroidism in renal In studies of phosphate the serum phosphorus was not or only in patients with renal even PTH were more for a serum phosphorus in the healthy and in the vitamin and the of for a increased PTH was greater observed in renal Thus, we believe that as renal the of phosphorus excretion for a increase in PTH is the serum phosphorus be in renal the serum phosphorus is for the of and this serum phosphorus with renal to to PTH. was the in our study in on a for after of renal were all of renal serum and were not from in with renal to these a increase in PTH was at the serum a greater increase in PTH was We believe that the to the serum phosphorus as PTH increased reduced the calcemic action of PTH and to the of the 20 as renal to a in which and a reduction in serum are even greater to PTH In renal PTH increase and serum phosphorus but it is our that due to the renal the decrease in serum phosphorus is not for the of PTH. that the to the serum phosphorus to the to PTH. To our we have the data in recent studies in which of patients with of renal was In the study by et of and in to the of of parathyroid function are shown in These studies were performed in and patients with and advanced renal were and In the renal with a that was not from the all of the were to in the is to that the calcium were not in the In the with a reduction in the a increase in PTH was to a serum serum phosphorus to be but were not from As to the study in the vitamin dogs in which a increase in PTH was associated with a decrease in serum phosphorus or in the study healthy and in which a increase in PTH was associated with a reduction in serum the decrease in serum phosphorus was only in the in the study by et in patients with renal PTH greater were to a serum the increase in the decrease in serum phosphorus was only We believe that even in renal the decrease in serum phosphorus is for the PTH and the to serum phosphorus increases and in a for even PTH as shown in the as renal an even of PTH is to a serum and the increase in the serum phosphorus is Thus, it is our that the serum phosphorus is the to and to the of 20 in patients with of renal Fifty years in his classic book, Fuller Albright summarized he believed that serum phosphorus was critical for calcium Although Albright was in his belief that the calcemic action of PTH on bone was an indirect effect by PTH-induced changes in serum many have shown that phosphorus directly the calcemic action of PTH on bone. to a these observations have failed to be adequately integrated into the of PTH regulation of the use of a of regulation first suggested by and by Parfitt to to calcium we have to (1) phosphorus the of calcium regulation by PTH and (2) phosphorus the of 20 HPT in renal We have advanced the concept that during the of 20 a reduction in serum phosphorus in to an in PTH enhances the calcemic to PTH. we have also evidence to show that as to of 20 the decrease in serum phosphorus in the 20 HPT of renal does not to be for the of PTH we have that in renal a serum phosphorus with an PTH should not be and the to decrease serum phosphorus reduces the calcemic to PTH and enhances the of 20 Thus, studies are to the of renal at which it be to phosphorus phosphorus to for the of PTH to the renal excretion of phosphorus and to the serum phosphorus The for his many during the of this