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The Fracture Risk Assessment Tool (FRAX) showed efficacy in predicting which patients with primary hyperparathyroidism may benefit when treated with parathyroidectomy, suggesting the surgery may reduce fracture risk in a broader range of patients than indicated under current guidelines, according to the results of a new study.

“There is a growing body of evidence that current guidelines may be too restrictive and fail to capture patients with primary hyperparathyroidism who could still derive meaningful benefit from parathyroidectomy,” Vivek R. Sant, MD, Section of Endocrine Surgery, Department of Surgery, UT Southwestern Medical Center, Dallas, told Medscape Medical News.

“Our study contributes to this evolving understanding by identifying fracture risk thresholds where surgery appears beneficial, even among patients who do not meet traditional criteria,” said Sant, first author of the study recently published in JAMA Network Open.

Primary hyperparathyroidism affects nearly 3 million individuals in the US, predominantly postmenopausal women, causing progressive bone loss and contributing to the increased risk for osteoporosis and fracture that already exists in that age group.

While surgical parathyroidectomy effectively reduces the fracture risk — and is indeed considered the only reliable cure — only about 25%-33% of patients who meet guideline criteria undergo the procedure, Sant explained.

Consequently, primary hyperparathyroidism “remains substantially undertreated,” he said.

Using the FRAX to Predict Fracture Risk

Guideline criteria recommend parathyroidectomy for asymptomatic patients with primary hyperparathyroidism who have osteoporosis; however, studies have shown that parathyroidectomy can reduce fracture risk even in some asymptomatic patients with normal bone mineral density (BMD).

The FRAX, commonly used to assess fracture risk in various other populations, gauges risk based on clinical risk factors including femoral neck (hip) BMD, age, sex, fracture history, steroid use, secondary osteoporosis, and other measures.

To determine if the FRAX can help in surgical decision-making in primary hyperparathyroidism, Sant and colleagues conducted the current retrospective cohort study, identifying 59,194 patients with primary hyperparathyroidism, ranging in age from 40 to 90, in the US-based TriNetX health record database between January 2000 and January 2024.

Clinical factors considered in the FRAX 10-year fracture estimation, obtained at the time of cohort inclusion, included age, sex, race and ethnicity, weight, parental and personal fracture history, glucocorticoid use, and other factors. BMD was not available for individuals and was therefore not used in the risk calculation.

The patients had a mean age of 65.9 years, 75.2% were female, and 25% were treated with parathyroidectomy.

For a balanced comparison of those who did and did not receive parathyroidectomy, a propensity score analysis matched patients based on factors including age, sex, race and ethnicity, BMI, osteoporosis, fracture history, and a variety of other factors.

With a median follow-up of 2.7 years, the results showed that the FRAX predictions slightly underestimated the actual rates of major osteoporotic fracture, which was a composite of the hip, spine, distal forearm, and proximal humerus sites, and hip fractures over the study period at all deciles of risk.

Overall, those receiving parathyroidectomy showed a 12% reduced incidence of major osteoporotic fracture (hazard ratio [HR], 0.88) and a 13% reduced incidence of hip fracture (HR, 0.87) compared with those who did not receive the surgery.

The reduced fracture risk that was associated with parathyroidectomy was observed in terms of major osteoporotic fracture when the FRAX-assessed risk exceeded 1.2%; when the hip fracture risk exceeded 2.7%; and for all fractures, when the risk exceeded 3.2%. 

Risk in Patients Who Don’t Meet Criteria for Surgery

Overall, 44% of patients in the cohort did not meet standard international guideline criteria for treatment with parathyroidectomy, which specifically includes being asymptomatic but younger than 50 years, exhibiting osteoporosis on a DEXA scan, and nephrolithiasis or chronic kidney disease of stage 3 or higher.

However, as many as 25% of these patients had FRAX thresholds of risk higher than the 2.7% risk that corresponded with a hip fracture reduction associated with parathyroidectomy, and nearly all, 99.2%, had a risk higher than the 1.2% associated with a reduction in major osteoporotic fracture. For a corresponding reduction in all fractures associated with parathyroidectomy, 100% of these patients had a hip score > 0, and 83.9% had a major osteoporotic fracture score > 3.2%.

The authors noted that the development of the FRAX involved calibration across broad diverse populations, and the FRAX has performed well in other subpopulations with higher anticipated baseline fracture risks, such as in patients with cancer.

“If confirmed in other cohorts, our findings may allow clinicians to expand consideration of fracture benefit in patients with primary hyperparathyroidism beyond the traditional recommendation of osteoporosis on BMD testing,” they wrote.

Surgery the ‘Preferred Option’

Commenting on the study, Robert D. Blank, MD, PhD, who authored an editorial published concurrently with the study, told Medscape Medical News that in his opinion, “surgery is the preferred option for most patients with non-syndromic primary hyperparathyroidism.”

“It is curative and safe when performed by an experienced surgeon,” said Blank, of the Bone Biology Program at the Garvan Institute of Medical Research in Darlinghurst, Australia.

He added that the paper importantly shows that “in patients opting for nonsurgical management, the fracture risk is higher than previously believed. So the impact of the paper should be to increase the fraction of patients being treated surgically.”

A “major limitation” of the FRAX is that it only considers major osteoporotic fractures, while ignoring fractures at other sites, he noted.

“These other sites collectively account for more fractures than major osteoporotic fractures,” he explained. “They also are associated with elevated mortality and refracture risks. So FRAX estimates [in the study] are low, by definition, because of the fracture site restriction.”

DEXA and FRAX

DEXA can meanwhile be helpful in improving the predictive performance of the FRAX, Blank added.

“I personally endorse use of [DEXA] at diagnosis of primary hyperparathyroidism regardless of whether immediate parathyroidectomy is the plan,” he said, noting the exception of cases in which DEXA was performed within a year prior to diagnosis. Also, “[DEXA] monitoring is useful for gauging response (or not) to therapy.”

In his editorial, Blank noted that the study findings are consistent with previous research from the Danish Primary Hyperparathyroidism Study Group, showing an important predictive role of the FRAX beyond DEXA scans in subpopulations, such as those with type 2 diabetes, and in relation to other factors such as number and recency of prior fractures.

“Each of these scenarios highlights the existence of bone fragility factors that are not captured by densitometry or other current assessment methods,” he wrote.

Such findings should “support [FRAX] for more informed decision-making, more precisely tailored to each patient’s fracture risk,” he said.

Ultimately, however, “the decision between surgical and nonsurgical management remains challenging. Patient preference, surgical expertise, and the burdens imposed by expectant care, possibly for decades, are all important factors to consider,” said Blank.

The study was supported in part by the Paul LoGerfo Research Award from The American Association of Endocrine Surgeons and the National Center for Advancing Translational Sciences of the National Institutes of Health. Sant had no disclosures to report. Blank reported receiving personal fees from Elsevier, Wolters Kluwer, GLG, Guidepoint, Atheneum, and Feiger & Feiger.