Long‐term Natpara Treatment Improves Bone Remodeling, Study Shows

Long-term treatment with Takeda’s parathyroid hormone therapy Natpara normalizes bone remodeling and bone density in people with hypoparathyrodism, according to a four-year study.

This is the longest study of Natpara’s effects on bone structure in this patient population, as assessed with a non-invasive method called high resolution peripheral quantitative computed tomography (HRpQCT).

The study, “Changes in Skeletal Microstructure Through Four Continuous Years of rhPTH(1–84) Therapy in Hypoparathyroidism,” was published in the Journal of Bone and Mineral Research.

Hypoparathyroidism is caused by abnormally low levels of the parathyroid hormone (PTH), either associated with an unknown cause or with a surgery in the neck region — where the parathyroid glands, responsible for PTH production, are located.

PTH regulates calcium balance in blood and bones, which is essential for bone remodeling. In this lifelong process, old and defective bone tissue is broken down and new bone tissue is formed, maintaining bone strength.

People with hypoparathyroidism usually show impaired bone remodeling and an increase in bone density, or mass. However, this bone mass increase does not translate into stronger bones, as several studies have shown that these patients have lower bone strength and subsequently a higher risk of fractures.

Natpara is a synthetic (recombinant) form of human PTH or rhPTH(1-84) developed by Shire — now part of Takeda’s group — and sold as Natpar in Europe. It is approved as an add-on therapy to calcium and vitamin D supplementation for people with hypoparathyroidism. Delivered daily as an under-the-skin injection, Natpara is intended to mimic the effects of the natural hormone.

A previous study showed that eight years of Natpara treatment led to sustained improvements in bone remodeling and bone structure in people with hypoparathyroidism. Notably, bone parameters were assessed using bone biopsies, or small samples of patients’ bone tissues.

Now, the same team evaluated bone health in hypoparathyroidism patients after four years on Natpara, using HRpQCT.

Compared with dual-energy X-ray absorptiometry (DXA) — the standard non-invasive method of bone density assessment — HRpQCT measures the bone density volume (rather than area), is less affected by overlying soft tissue, and can distinguish cortical (harder) from trabecular (spongy) bone compartments.

The study involved 33 people with chronic hypoparathyroidism (24 women and nine men), with an average age of 47 (range 26–72), and who had received no prior PTH-treatment. The disease developed post-surgery in 19 patients, while it had no known cause in 14.

Most patients (62%) were treated with 100 μg of Natpara every other day. Median duration of treatment was 33 months (almost three years). At four years, the median daily dose was 50 μg.

HRpQCT was used to assess bone density, structure, and remodeling in the lower arm and leg, while DXA was used to measure bone density in the spine, hip, upper leg, and lower arm.

Results showed that long-term Natpara treatment normalized bone remodeling and bone density in lower arm and leg bones, as detected by HRpQCT. In fact, after four years of treatment, values of treated people with hypoparathyroidism surpassed those of healthy controls.

Notably, these declines in bone density were detected only in the cortical compartment of bones.

“The distinction between trabecular and cortical bone by HRpQCT helps to identify the cortical compartment as the one that is more prone to show declines with PTH therapy,” the researchers wrote.

While DXA also detected significantly lower bone density in the lower arm bone and in the hip, it showed increased bone mass in the spine and higher leg bone after four years of treatment. The team said these differences may be associated with the distinct proportions of cortical and trabecular compartments among the different bones evaluated.

Also, long-term Natpara treatment significantly reduced doses of calcium supplements (by 36%) and vitamin D (calcitriol, by 64%), which was consistent with previous reports.

The scientists also emphasized that the every-other-day regimen of Natpara likely does not reflect the natural dynamics of PTH production and levels in the body and its potential benefits in bone health.

“It remains to be seen whether more physiologic dosage regimens will show different results,” the researchers wrote.

This work was funded partly by Shire. In September 2019, Takeda issued a U.S. recall of Natpara following concerns of potential contamination. The therapy will not be available in the U.S. until March 2021 at the earliest.