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Long-term PTH Linked to Bone Improvements in Hypoparathyroidism

DENVER — Long-term treatment with recombinant human parathyroid hormone (rhPTH[1-84]) is associated with significant improvements in bone abnormalities that can occur with hypoparathyroidism, while showing safety in various biochemical parameters.

"This analysis includes the longest reported experience with rhPTH(1-84) for the treatment of hypoparathyroidism," said first author Mishaela Rubin, MD, an assistant professor of clinical medicine at Columbia University, New York, in presenting the findings here at the American Society for Bone and Mineral Research (ASBMR) 2017 Annual Meeting.

"To our knowledge, these are the first histomorphometric data reflecting a long exposure of rhPTH(1-84) or of any PTH for any disease."

Hypoparathyroidism, a rare disorder characterized by low parathyroid hormone levels and hypocalcemia, has been shown in previous research from Dr Rubin and her colleagues to be associated with multiple abnormalities in bone properties, including increased cancellous bone volume, increased cortical thickness, and substantial reductions in bone remodeling.

Whereas previous research from the team showed improvements in those measures with 2 years of rhPTH(1-84) treatment, evidence on the longer-term effects is lacking.

"Given the chronic nature of hypoparathyroidism, along with the lack of a restriction on duration of rhPTH(1-84) use, longer-term data on the skeletal effects of the drug are needed," she explained.

Study Findings

For the analysis of longer-term effects, the authors evaluated skeletal measures on 13 patients who had been treated with rhPTH for a mean of 8.2 (range, 6–10) years and compared them with 45 age-and sex-matched controls with normal parathyroid function. Of the hypothyroid patients, the average age was 45 and 10 were female. All had received bone biopsies at baseline and following their long-term rhPTH treatment.

In comparison with baseline levels and with the control group, those in the long-term treatment group had improvements in trabecular bone structure, including levels of cancellous bone volume, which increased by 1.5-fold compared with controls (= .006); however, there were no differences in trabecular width.

The long-term treatment group showed a 1.4-fold increase in trabecular number, with a reciprocal 1.3-fold decline in trabecular separation compared with the control group (= .002).

Cortical width and porosity were only slightly changed after long-term treatment (P = .04 and .05, respectively).

In terms of bone remodeling, measures of mineralizing surface — which were dramatically lower in the hypoparathyroid patients compared with controls at baseline — increased with long-term treatment (P = .01), and the rate of bone formation — which was also substantially lower at baseline — increased significantly with long-term treatment.

Measures of osteoid width and surface each increased in the long-term treatment group — from being significantly lower than control levels at baseline to approaching or slightly exceeding the control levels. And measures of eroded bone surface increased from being similar to controls to 1.8-fold times greater (P < .001).

Long-Term rhPTH Therapy Associated With Big Improvements

"The findings show long-term rhPTH(1-84) treatment is associated with improvements in structural bone parameters, including increases in cancellous bone volume and intratrabecular tunneling, as well as cortical porosity," Dr Rubin said.

"In terms of remodeling parameters, there were increases in bone formation, osteoid surface, and eroded surface, and most changes overall exceeded euparathyroid levels."

The findings that some of the changes exceeded measures seen in controls was particularly notable, Dr Rubin said.

"Most of these changes exceed euthyroid levels, suggesting that a new steady state is achieved with long-term rhPTH treatment that is different from the steady state seen not only in baseline hypoparathyroid patients but also different from that in control patients," she said.

The findings prompted questions from the audience on whether some of the findings could truly be viewed as improvements, particularly with cortical porosity.

"I think it's a different paradigm with this disease compared, for instance, with osteoporosis, where we don't want the bone to be thinner — we want it to be thicker," Dr Rubin responded.

"With this disease, we don't know, and it could be that the bone becoming thinner could in fact lead to a healthier bone."

In a separate poster presentation, Dr Rubin and colleagues presented findings on long-term biochemical parameters observed in 33 patients treated with rhPTH(1-84) for a mean of 7.5 years.

Those showed stable levels of measures including albumin-corrected serum calcium, urinary calcium, serum phosphate, and serum creatinine at all time points in the treatment, as well as stable estimated glomerular filtration rates and levels of calcium-phosphate product.

"The results document that rhPTH(1-84) treatment is characterized by maintenance of biochemical parameters, including stable renal function, within normal or target ranges for this disease," they concluded.

Quality of Life Improved, Too

In a third poster, researchers in Italy further described efficacy and, for the first time, improvements in quality-of-life measures in surgical hypoparathyroidism patients treated for 2 years with PTH(1-34).

Mean serum levels of calcium increased significantly at 3 months (P < .001) and remained stable at 12 and 24 months, and mean calcium supplementation decreased over the same period (< .001). There were also significant improvements over the 2 years in quality of life, seen in all eight domains of physical and mental health on the Rand 36-Item Short Form Health Survey(SF-36).

The findings are important because such improvements are typically not expected with standard treatment.

"Unfortunately, serum calcium control obtained with the standard therapy of calcium and vitamin D supplementation is rarely accompanied by improved functioning or sense of well-being," first author Andrea Palermo, MD, of the department of endocrinology and diabetes, University Campus Bio-Medico, Italy, told Medscape Medical News.

She noted that physical and mental functioning improvements have previously been shown with rhPTH(1-84) regardless of serum calcium level.

"We have confirmed that also PTH(1-34) may increase the quality of life in subjects with chronic postsurgical hypoparathyroidism," Dr Palermo said.

"Probably, the PTH itself (1-34 or 1-84) can play an important direct role. Indeed, it has been hypothesized that PTH analogues might interact with the PTH2 receptor that is located in the brain, leading to a good cognitive effect."

While the current study did not measure bone-density changes, Dr Palermo noted that previous research has shown maintained bone-mineral density in hypoparathyroidism treated with PTH(1-34) and maintenance of mean bone-mineral density Z-scores at the anterior-posterior lumbar spine, femoral neck, distal radius, and whole body within the normal range.


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