The use of the osteoporosis drug denosumab (Prolia) to prevent fractures associated with advanced chronic kidney disease (CKD) in patients on kidney dialysis significantly increases the risk for potentially life-threatening severe hypocalcemia compared with the use of oral bisphosphonates, prompting the US Food and Drug Administration (FDA) to issue a Boxed Warning regarding the risk.
“Based on a completed FDA review of available information, we have concluded that the osteoporosis medicine Prolia (denosumab) increases the risk of severe hypocalcemia, very low blood calcium levels, in patients with advanced chronic kidney disease (CKD), particularly patients on dialysis,” the FDA reported.
“In patients with advanced CKD taking Prolia, severe hypocalcemia resulted in serious harm, including hospitalization, life-threatening events, and death,” they said. “As a result, we are revising the Prolia prescribing information to include a new boxed warning, FDA’s most prominent warning, communicating this increased risk.”
Fracture Risk Exceptionally High in Advanced CKD
Patients who are dependent on kidney dialysis, particularly older patients, have an exceptionally high prevalence of CKD-mineral bone disorder (MBD) and, as a result, have a significantly higher risk for fracture than those without CKD.
With their ability to absorb calcium from the gastrointestinal tract impaired, patients with CKD-MBD must instead heavily rely upon bone as a source of calcium; however, antiresorptive osteoporosis drugs, in inhibiting bone turnover, limit the ability to utilize bone calcium, and denosumab is notably a potent drug in this respect compared with other antiresorptive agents.
As a result, the drug’s labeling already warns that patients with advanced CKD or those undergoing dialysis are at a high risk of developing hypocalcemia. However, with a lack of therapies designed specifically for patients with severe kidney failure, clinicians may nevertheless turn to drugs developed for patients with normal kidney function to prevent fracture.
To further investigate the risk, Steven T. Bird, PhD, PharmD, of the FDA’s Office of Pharmacovigilance and Epidemiology in the Center for Drug Evaluation and Research, and colleagues conducted a cohort study, published this week in JAMA, on 1523 postmenopausal female dialysis-dependent Medicare patients aged 65 and older who initiated treatment with denosumab 60 mg (n = 1523) or oral bisphosphonates (n = 1281) from 2013 to 2020.
The majority of patients who received oral bisphosphates were treated with alendronate (91.8%), most commonly at a dose of 70 mg weekly (75.7%). Nearly all patients had received no antiresorptive treatment in the prior 15 months. Their mean age was 74.5 years in the denosumab group and 73.8 years in the oral bisphosphonate group.
After 12 weeks, the weighted cumulative incidence of severe hypocalcemia, defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis, was 41.1% in the denosumab group vs just 2% in the oral bisphosphonate group, for a weighted risk ratio of 20.7.
The 12-week weighted cumulative incidence of very severe hypocalcemia (defined as serum calcium
Of note, following the initiation of denosumab, patients’ median serum calcium levels dropped sharply within the first month and remained below baseline for 4 months, whereas levels remained unchanged with oral bisphosphonates.
While the majority of cases of severe hypocalcemia with denosumab occurred during weeks 2 through 5, an increased likelihood of severe hypocalcemia continued through approximately week 10, posttreatment.
Of note, those treated with denosumab who had mild to moderate hypocalcemia at treatment initiation, defined as 7.5 mg/dL to 8.5 mg/dL; 38.0%).
Of those developing severe hypocalcemia, 10.7% treated with denosumab and none treated with oral bisphosphonates required hospitalization following the diagnosis, 5.4% had a diagnosis of seizure or ventricular arrhythmia, and 1.3% died within 30 days of the severe hypocalcemia onset.
By contrast, no deaths, seizures, or cardiac arrhythmias occurred in the oral bisphosphonate group.
Nephrologists Rarely Involved in Treatment, Despite Risks
Global studies have also shown a risk for hypocalcemia related to denosumab use ranging from about 15% to 42%, yet, despite the risks, only a small fraction of the dialysis patients in the study received treatment from a specialist in nephrology.
“Although nephrologists may be better positioned to select dialysis patients who are appropriate for treatment, pretreat them to mitigate risk, and monitor for or treat hypocalcemia, nephrologists were responsible for prescribing only 2.3% of denosumab in our study,” the authors reported.
In its Boxed Warning, the FDA further addresses the concern, underscoring that the appropriateness and “treatment with denosumab in patients with advanced CKD, including those on dialysis, and particularly patients with diagnosed CKD-MBD, should involve a healthcare provider with expertise in the diagnosis and management of CKD-MBD.”
Key measures recommended to decrease the risk of developing severe hypocalcemia include supplementation with calcium and activated vitamin D prior to denosumab treatment and close monitoring of blood calcium levels following treatment.
Furthermore, prompt attention to hypocalcemia is important to prevent complications including seizures or arrhythmias, the FDA cautioned.
Therapies Addressing Underpinnings of the Disease ‘Urgently Needed’
Commenting on the issue, Thomas L. Nickolas, MD, of Columbia University Irving Medical Center, New York City, who coauthored an editorial published with the study, said the FDA’s action in issuing the Boxed Warning was not a surprise.
“Given the findings of the study, [the FDA] needed to do something in order to protect the patients,” he told Medscape Medical News.
“The rates of hypocalcemia and mortality are a real concern, and the FDA needed to make prescribers aware of the potential for harm.”
In the editorial, Nickolas, along with coauthor Pascale Khairallah, MD, agreed with the FDA’s stopping short of recommending against denosumab in dialysis patients.
“The high rates of hypocalcemia following denosumab administration should deter clinicians only from its blind prescribing to dialysis patients, rather than its total avoidance,” they wrote.
They point out that “although the 1.3% mortality rate reported [in the study] is unacceptable, mortality rates from hip fracture alone are reported as higher than 1.5 per patient-year in dialysis patients aged 75 years or older.”
Furthermore, the routine use of approaches of cinacalcet and parathyroidectomy to improve skeletal outcomes are also associated with high rates of severe hypocalcemia, at 18.8% and 31%, respectively.
That being said, dialysis patients who may be appropriate candidates for denosumab include patients with severe fracture risk, such as those who have multiple fractures and/or severe osteoporosis, as long as risk mitigation and monitoring are implemented, Nickolas told Medscape Medical News.
“One could also consider using a bisphosphonate in these patients; however, there are concerns regarding the use of those agents that have to do with their long-term effects on bone tissue quality.”
Ultimately, “therapies developed specifically for patients with CKD that address the underlying pathogenic origin of the disease and treat the disorder from a multidimensional and holistic approach are urgently needed,” the authors wrote in the editorial.
“This holistic treatment concept should be promoted by the nephrology community and kidney societies,” they noted.
“Until then, off-label use of FDA-approved osteoporosis therapies will continue in CKD, albeit with known and unknown serious consequences.”
The study was funded by the US FDA through an interagency agreement with the Centers for Medicare & Medicaid Services. Nickolas reported receipt of grants from Amgen and scientific advisory board membership for Pharmacosmos.
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Publish date : 2024-01-22 11:34:33
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