Study Finds PTH Needs Another Hormone to Help Lower Phosphate Levels

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by Margarida Maia PhD |

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Replacement therapy with parathyroid hormone (PTH) — the hormone found at low levels in patients with hypoparathyroidism — requires the presence of another hormone called fibroblast growth factor 23 (FGF23) to help the kidneys expel excess phosphate, a small study has found.

The study, “PTH and FGF23 exert interdependent effects on renal phosphate handling: evidence from patients with hypoparathyroidism and hyperphosphatemic familial tumoral calcinosis treated with synthetic human PTH 1–34,” was published in the Journal of Bone and Mineral Research.

Hypoparathyroidism is characterized by a deficiency of PTH, a hormone that helps the body control the levels of calcium, phosphorus, and vitamin D in the blood. People with hypoparathyroidism have hypocalcemia (low blood levels of calcium) and hyperphosphatemia or high blood levels of phosphate, a molecule that contains phosphorus.

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To keep the right levels of phosphate, the body needs the kidneys, the parathyroid glands, and the bones to share information with one another. This is done through so-called feedback loops.

When phosphate levels are high, PTH — produced in the parathyroid glands — decreases the absorption of phosphate before it is expelled by the kidneys. When phosphate levels are low, PTH breaks down bone to release phosphate. FGF23 — mainly produced in bone cells — helps the kidneys handle an excess of phosphate by getting rid of it.

However, PTH and FGF23 have opposing actions on vitamin D, with PTH stimulating and FGF23 suppressing its production. Vitamin D also has a role in phosphate regulation.

“Clinical data suggest that adequate renal [kidney] phosphate handling requires the presence of both FGF23 and PTH, but robust evidence is lacking,” the researchers wrote.

To look for more evidence, they measured the blood levels of phosphate, FGF23, and other molecules in a group of patients before and after PTH replacement therapy.

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The study included 11 patients (10 female and one male) with hypoparathyroidism who had high FGF23 levels. All were part of a Phase 3 clinical trial (NCT00395538) at the National Institutes of Health, whose goal was to see how well a lab-made PTH, called PTH 1–34, works as a replacement therapy for hypoparathyroidism. The patients ranged in age from 20 to 59 years, with a median average age of 42.

The study also included a male patient, 29, who had hyperphosphatemic familial tumoral calcinosis (HFTC), a genetic condition characterized by a functional deficiency of FGF23 and by hyperphosphatemia.

All hypoparathyroidism patients were given an under-the-skin injection of 0.2 micrograms (mcg) of PTH 1–34 per kilogram of body weight twice daily. For the participant with HFTC, he was treated initially with a single dose of 40 mcg of PTH 1–34, and one month later with 20 mcg twice daily for six days.

In patients with hypoparathyroidism, PTH 1–34 increased the levels of kidney-derived cAMP — a measure of parathyroid function. The amount of phosphate moving from the kidneys into the bloodstream decreased at four to eight hours after an injection of PTH 1–34. This resulted in a sustained decrease in blood phosphate that was followed by a drop in FGF23 to normal levels.

“PTH administration overcame FGF23 resistance, suggesting the full phosphaturic [phosphate clearance] effect of FGF23 is PTH-dependent and demonstrating the interdependence of PTH and FGF23,” the researchers wrote.

In the patient with HFTC, injection of PTH 1–34 also increased the levels of kidney-derived cAMP, but this was “insufficient to bring about a phosphaturic effect in the absence of sufficient FGF23.”

Although the number of patients was small, the findings suggest that the effects of PTH and FGF23 may depend on one another, the investigators said. “Both are required to adequately regulate renal phosphate handling,” they wrote.