New Parathyroid Hormone Disease Guidelines Make Their Debut

A pair of clinical guidelines on hypo- and hyperparathyroidism, respectively, had a coming-out party at the American Society for Bone and Mineral Research‘s (ASBMR) annual meeting on Sunday, allowing attendees to get an advance preview before they are officially published.

For hypoparathyroidism, panel members “suggested” — i.e., issued a weak recommendation based on low-quality evidence — that most patients receive the longstanding mainstays of treatment, calcium-based supplements and vitamin D, along with diuretics, instead of parathyroid hormone (PTH) replacement.

And in primary hyperparathyroidism, surgical treatment was recommended as first-line for most patients irrespective of phenotype.

Both guidelines were updates of previous ASBMR guidelines on these conditions — 2011 for hypoparathyroidism (although the Endocrine Society issued one in 2016) and 2013 for hyperparathyroidism — and emerged from an international workshop on parathyroid diseases. They are now in preparation for publication, spread across a total of 17 papers summarizing the evidence review and the final recommendations.

Hypoparathyroidism

Workshop co-chair Aliya Khan, MD, of McMaster University in Hamilton, Ontario, outlined the main findings on underactive parathyroid. Although the overarching conclusion about conventional treatment versus PTH replacement only reached “suggestion” status, panel members did make some firmer recommendations.

For example, the effort identified some benefits for PTH replacement: moderate evidence indicates that it “probably” improves quality of life somewhat and almost certainly allows patients to reduce calcium and vitamin D supplement doses by at least 50%.

Another important clinical concern was identifying those patients at risk for permanent hypoparathyroidism following total thyroidectomy. Workshop participants determined that measuring PTH in the hours immediately after surgery deserved a “strong” recommendation, based on moderate quality evidence that few patients with PTH levels above 10 pg/mL 12-24 hours later will develop permanent hypoparathyroidism. And even for those with lower levels, the risk remains below 50%.

But most of the guidance ended up being founded on expert opinion, reflecting the many unknowns about hypoparathyroidism. The development process included a survey of practicing endocrinologists. Management approaches for particular aspects of hypoparathyroidism, for which at least 70% of respondents said they used it in at least 70% of their patients, earned an “ungraded” recommendation.

Genetic testing was among those aspects receiving such opinion-backed endorsement. In particular, patients with certain clinical and lab features, including young age and other endocrine or metabolic abnormalities, may benefit from genomic analyses, the guideline indicated.

Other suggestions in hypoparathyroidism included maintaining calcium in a normal range (preferably the lower half), especially during pregnancy, and to seek to normalize phosphate, magnesium, and 25-(OH)D levels. PTH replacement should be considered when conventional therapy fails to achieve these goals.

The particulars of which diagnostic and monitoring tests to run were also covered by these recommendations: serum creatinine, calcium, magnesium, phosphate, and 25(OH)D should be checked both initially and at follow-up.

Khan concluded her presentation with a slide outlining new drug therapies still in the development pipeline. These included long-acting PTH analogues, PTH receptor agonists, so-called calcilytics, and several others. She didn’t elaborate, citing her time limitation, but told attendees “the future is very bright.”

Primary Hyperparathyroidism

The workshop’s other co-chair, John Bilezikian, MD, of Columbia University in New York City, took on the guideline for primary hyperparathyroidism.

Treatment and outcomes are most patients’ primary concerns, and on that note, the guideline should be very reassuring, his presentation suggested.

“In the hands of experienced surgeons, surgery achieves a biochemical cure in 97.8% [of patients] and is a safe procedure,” Bilezikian said, noting that this conclusion was backed by high-quality evidence. Patients undergoing parathyroid removal also can expect a “significant reduction” in 10-year vertebral fracture risk, he said.

“This is a curable disease,” he declared.

Bilezikian noted that, over the years, hyperparathyroidism has gone from a disease of “bones, stones, and groans” to one defined by biochemistry and imaging, such that asymptomatic cases can now be diagnosed and treated.

Indeed, surgery can be recommended for many of the latter cases (albeit based on the clinician survey, not hard evidence): any patient younger than 50 or with elevated serum calcium, occult fractures or low bone mineral density, renal deficiency, or kidney stones revealed by imaging.

But most of Bilezikian’s talk, presumably mirroring the final guideline, went to issues besides treatment — diagnosis, epidemiology, etiology, and subgroup management — that are just as important for clinicians.

The condition primarily affects women, at rates of 23 per 10,000 versus 8.5 per 10,000 men, he said, citing the most recent U.S. data. Such figures are intimately associated with the degree to which people undergo biochemical screening, as this “leads to an increase in incidence whenever screening is introduced.” Many of these incidentally-discovered cases are initially classed as asymptomatic, although subsequent examination may show previously unrecognized symptoms.

Hyperparathyroidism’s most common subtype is marked by excessive serum calcium, which can occur with elevated PTH or with “inappropriately normal intact PTH,” Bilezikian noted. For diagnostic purposes, the hypercalcemia should be confirmed by second- or third-generation tests performed at least 2 weeks apart.

About 10% of primary hyperparathyroidism cases are genetic in origin, but genomic testing is not required or recommended to diagnose the condition.

Primary hyperparathyroidism doesn’t have to involve hypercalcemia, however. It is, of course, defined by elevated PTH (as confirmed with a second test at least 2 weeks later) and can be diagnosed when causes that would make it secondary hyperparathyroidism, such as vitamin D deficiency or medication side-effects, have been ruled out. Surgery is effective for this subtype, and other glandular systems may be involved, more so than with the hypercalcemic version.

Once a diagnosis has been made, it’s necessary to check for its complications, most notably bone and kidney abnormalities. The guideline will recommend that dual energy X-ray absorptiometry testing for bone mineral density at lumbar spine, hip, and radius, as well as vertebral imaging should be performed. Similarly, kidney function should be evaluated and imaging for stones conducted.

Although numerous other complications can occur — gastrointestinal, neuropsychiatric, cardiovascular, and metabolic — they are “nonclassical” and don’t have to be evaluated routinely or taken into account when considering surgical treatment, Bilezikian said.

For patients refusing or contraindicated for surgery, there are medical options. These include bisphosphonates to reduce fractures, as well as vitamin D supplementation and cinacalcet (Sensipar).

As with hypoparathyroidism, pregnancy is a special case. In these cases, bisphosphonates as well as denosumab (Prolia) should be avoided, and not much is known about cinacalcet. Surgery is best performed in the second trimester, when serum calcium exceeds 11 mg/dL. If waiting until after delivery is chosen, newborns should be monitored closely for hypocalcemia, and the surgery should be performed before the patient becomes pregnant again, Bilezikian said.

Finally, he presented an extensive research agenda, as the new hyperparathyroid guideline, too, depended heavily on the clinician survey for its particulars.

  • John Gever was Managing Editor from 2014 to 2021; he is now a regular contributor.

Disclosures

The guideline development was supported by grants from Amolyt, Ascendis, Calcilytix, and Takeda.

Khan reported relationships with numerous pharmaceutical companies. Bilezikian declared he had no relevant financial interests.

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