New Hypoparathyroidism Guidelines Stress Long-term Well-being

Becky McCall

July 14, 2015

(updated July 15, 2015) How best to monitor and treat chronic hypoparathyroidism, with emphasis on patient well-being and long-term outcomes, is the focus of a new guideline produced by the European Society of Endocrinology (ESE).

Dr Jens Bollerslev (Oslo University Hospital, Norway) led the committee that developed the guideline, which is published online in the August issue of the European Journal of Endocrinology. Hypoparathyroidism is a rare (orphan) endocrine disease with low calcium and inappropriately low (insufficient) circulating parathyroid hormone levels, most often occurring in adults secondary to thyroid surgery.

"Patients are often young and of fertile age, and therefore the long-term perspective is important to ensure quality of life and protect the patient [from] complications," Dr Bollerslev told Medscape Medical News. "Special attention is also needed during pregnancy and lactation, for the mother but also for the child."

Of note, he remarked that the process of developing the guideline revealed how little clinical evidence was available. "Clinical data have emerged over recent years, primarily based on case-control studies. What is really needed is prospective and randomized controlled trials initiated and performed by independent clinical researchers."

Parathyroid Hormone Replacement Newly Available, but Only in US

Commenting on the motivation for developing the guideline, Dr Bollerslev said that an overall review of guidelines for endocrine diseases by the ESE in 2013 revealed that chronic hypoparathyroidism was an area lacking an evidence-based clinical guideline that met European standards.

He also explained that hypoparathyroidism presents challenges different from many hormone-deficiency syndromes because parathyroid hormone (PTH) replacement is not the standard of care.

"We do not have a product that covers the patient around the clock," he explained. "Standard care is an indirect treatment with activated vitamin D, calcium, and magnesium substitution and ensuring an optimal level of vitamin D in the circulation.

"It should be emphasized that most patients do very well on this regime, but still there is room for improvement," he continued. "On top of this, parathyroid hormone might come in as an add-on for the very special cases, but it remains that parathyroid hormone is very costly, and unless given by an insulin pump, treatment is not physiological."

Asked to comment on the new guideline, Dr Mack R Harrell (Memorial Healthcare System, Hollywood, Florida), immediate past president of the American Association of Clinical Endocrinologists (AACE), echoed Dr Bollerslev's remarks in stressing the need for more research in this area.

"Because the ESE's new guideline highlights the need for randomized controlled trials to assess the clinical efficacy of various hypoparathyroidism treatment alternatives, it will be welcomed in the United States and throughout the world," he observed.

"It is essential that physicians have [such] trials on which to base decisions for optimizing therapy in this controversial area, particularly in light of the recent introduction of expensive parathyroid-hormone-replacement options into the pharmacopeia," he added.

A once-daily subcutaneous injectable recombinant parathyroid hormone (rPTH) product (Natpara, NPS Pharmaceuticals) has recently been approved in the United States, but this is given as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism. The product is still awaiting approval in Europe.

And Dr Bart Clarke (Mayo Clinic, Minnesota) told Medscape Medical News that management of hypoparathyroidism has been challenging due to lack of recommendations in the past. "This is the first clinical guideline to address management of this rare but serious bone disorder."

However, he agrees that "firm conclusions are difficult. There are no studies that relate target calcium levels with clinically relevant end points. The European guideline acknowledges these limitations and indicates that [the advice] is mainly based on how patients are managed clinically, as reported in small case series and on the authors' experiences."

US guidelines are under development "based on outcomes of the recent First International Congress on Hypoparathyroidism held in Florence, Italy, in May 2015" and should be available within a few months, he added.

Special Attention Paid to Pregnancy and Breastfeeding

In developing the new European guideline, Dr Bollerslev and Dr Olaf Dekkers (Leiden University Medical Center, the Netherlands) led a working group of endocrinologists, an endocrine surgeon, and a nephrologist.

A systematic literature search was carried out, and data were eventually drawn from 32 full-text articles that discussed the best treatment for chronic hypoparathyroidism.

The findings were made available for consultation by ESE members and then presented at this year's European Congress of Endocrinology in May, prior to publication.

Dr Bollerslev added that in order to guide patients, "we have further developed patient leaflets, adding input from patient organizations."

Importantly, the guideline highlights the need for special attention during pregnancy and lactation for the mother and the child.

"Pregnancy and the breastfeeding period are a challenge because of a calcium-regulating hormone, called parathyroid hormone-related protein (PTHrP), which controls calcium production in the placenta and in breast tissue," Dr Bollerslev explained. In the case of hypoparathyroidism, PTHrP "needs to be closely controlled in order not to over/undershoot treatment," he added.

The recommendation for pregnant and breastfeeding women is treatment with activated vitamin D analogs and calcium supplements, as in nonpregnant women, as well as monitoring serum ionized calcium regularly with levels to be kept at the lower end of the normal range.

The guideline also recommends that the pediatrician and/or neonatologist be informed of maternal hypoparathyroidism and be involved in the immediate care and monitoring of the infant for possible consequences of the treatment of the mother and the underlying maternal disorder.

No Routine Treatment with PTH Analogs

The new guideline recommends "against the routine use of replacement therapy with PTH or PTH analogs," Dr Bollerslev noted.

This is because parathyroid hormone is normally secreted in a pulsatile way, regulating the calcium level within seconds to minutes, and this effect cannot be mimicked by one or two daily injections of recombinant hormone, he explained.

"The US recommendation for the use of [recombinant] parathyroid hormone is on the top of conventional treatment with activated vitamin D and calcium supplements, the dosages of which then should be lowered," he noted.

"This regime might lead to a more stable daily calcium level compared with conventional treatment alone, but of importance, the regime has not been shown to lower the daily excretion of calcium, to improve quality of life, or to protect against long-term complications."

He added that the same is true for parathyroid-hormone infusion therapy, where evidence so far is based on studies with a restricted number of patients.

The guideline focuses on patient well-being in daily life and stresses that clinicians should consider the risk of complications when assessing this.

"This aims to ensure individualization of treatment," said Dr Bollerslev, adding that "most patients are well managed with their calcium level falling within the defined target zone, but if it is slightly below, we suggest a trial to raise the level to target." But if this results in little benefit, there is likely no point in raising the calcium level, he explained.

In any one individual patient who prefers high calcium levels that are still within the "normal" range, close attention should be paid to monitor for complications, he concluded.

Dr Bollerslev has declared no relevant financial relationships. Disclosures for the coauthors are listed in the article. Dr Harrell has reported no relevant financial relationships.

Eur J Endocrinol. 2015;173:G1-G20. Article

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