Phosphorus, regulation of plasma calcium, and secondary hyperparathyroidism: a hypothesis to integrate a historical and modern perspective.

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 (1 HPT) and hypoparathyroidism (2–5). 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 (2–7), 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 1 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 1 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 Received July 20, 1998. Accepted November 8, 1998. Correspondence to Dr. Arnold J. Felsenfeld, Nephrology Section (111L), West Los Angeles VA Medical Center, 11301 Wilshire Boulevard, Los Angeles, CA 90073. Phone: 310-268-4381; Fax: 310-268-4653; E-mail: [email protected]