Most XLH Patients Develop Hard-to-treat Hyperparathyroidism as Side Effect of Standard Therapy, Study Reports

More than 80% of people with X-linked hypophosphatemia (XLH) develop hyperparathyroidism as a side effect of treatment with oral phosphate and active vitamin D, a study reports.

Tertiary hyperparathyroidism, which results from prolonged hyperparathyroidism, is hard to treat. Surgical removal of the parathyroid glands is not usually effective, as the condition often persists or comes back after surgery, research shows.

The study, “Hyperparathyroidism and parathyroidectomy in X-linked hypophosphatemia patients,” was published in the journal Bone.

XLH is an inherited disorder marked by low levels of phosphate and vitamin D that lead to skeletal problems such as rickets in children and osteomalacia in adults, which refer to abnormal softening and weakening of bones.

Standard treatment consists of phosphate salts combined with active forms of vitamin D, such as calcitriol (which helps the body take in phosphate), given in multiple oral doses per day.

However, this combined treatment may result in several side effects, including nephrocalcinosis — calcium deposits in the kidneys — excess levels of calcium in the blood (hypercalcemia) and urine (hypercalciuria), high blood pressure, and hyperparathyroidism.

Hyperparathyroidism occurs when there is too much production of parathyroid hormone (PTH) from the parathyroid glands, causing hypercalcemia.

When phosphate levels build up as a consequence of treatment with phosphate salts and vitamin D, blood calcium levels fall. If they get too low, the parathyroid glands secrete more PTH to stimulate the release of calcium from bones into the bloodstream, reduce urinary excretion of calcium, and promote production of vitamin D in the kidneys.

People with XLH risk developing secondary hypoparathyroidism — caused by kidney disease or vitamin D deficiency — or progress to tertiary hypoparathyroidism as a result of chronic excessive PTH production which makes the parathyroid glands become permanently overactive. This leads to chronically high calcium levels in the blood.

Studies on hypoparathyroidism in XLH patients are scarce so researchers in the study sought to assess the prevalence of the condition and its associated treatment outcomes in people with XLH.

The researchers reviewed the medical charts of 104 adults and children with XLH, all attending endocrinology practices at Indiana University School of Medicine from 2000 to 2017.

Results showed that, among 84 patients with available data on their calcium and PTH levels (40 adults and 44 children), 70 (83.3%, 36 children and 34 adults) had secondary or tertiary hyperparathyroidism at some point during follow-up.

Most patients with secondary hyperparathyroidism, especially children — 34 of 36 (94.4%) children and 22 of 34 (64.7%) adults — did not progress to the tertiary condition.

Yet, secondary hyperparathyroidism persisted in 62.2% of the patients over a median follow-up of five years.

The overall prevalence of tertiary hyperparathyroidism was 16.7% (14 of 84 patients). To treat the condition, eight of these patients underwent surgery to remove the parathyroid glands (parathyroidectomy). However, the surgery was not successful long-term in six patients, as hyperparathyroidism persisted or returned after a median of six years after surgery (up to 29 years after the procedure).

One patient developed chronic hypoparathyroidism and another achieved normal PTH and calcium levels, which lasted up to four  years after surgery.

Treatment with cinacalcet, an oral medication used to treat high levels of calcium in the blood, was attempted in 5 of 14 (35.7%) patients with tertiary hyperparathyroidism. However, patient responses to this therapy were variable.

Those with tertiary hyperparathyroidism more often had nephrocalcinosis (60% vs. 18.6% of people without tertiary hyperparathyroidism) and chronic kidney disease (35.7% vs. 1.5%).

“The majority of patients with XLH develop secondary hyperparathyroidism during treatment with phosphate and active vitamin D. A significant proportion develops tertiary hyperparathyroidism and most have recurrence or persistence of hypercalcemia after surgery,” the researchers wrote.

“Further studies are needed to determine the best approach to preventing hyperparathyroidism, and the effect of novel therapies on its development,” they added.