FDA Approves Denosumab Biosimilars and Issues Hypocalcemia Safety Guidance

The FDA approved Boncresa (denosumab-mobz) and Oziltus (denosumab-mobz) on December 22, 2025, as biosimilars referencing Prolia and Xgeva, respectively. The agency has also issued safety updates under the Risk Evaluation and Mitigation Strategy (REMS) program for the biosimilars denosumab-qbde (Enoby) and denosumab-dssb (Ospomyv), which both reference denosumab (Prolia).

The REMS updates for both biosimilars emphasize the increased risk for severe hypocalcemia following administration in patients with advanced chronic kidney disease, defined as those with estimated glomerular filtration rate levels below 30 mL/min/1.73 m2, including patients dependent on dialysis. The updates note that cases of severe hypocalcemia resulting in life-threatening events, hospitalization, and death have been reported.

Denosumab is a monoclonal antibody that inhibits bone resorption and is widely used across oncology and osteoporosis-related conditions. Enoby and Ospomyv are both indicated for use in all indications of their reference product, which include the increase of bone mass in women receiving adjuvant aromatase inhibitor therapy for breast cancer who are at high risk for fracture; the increase of bone mass in men receiving androgen deprivation therapy for nonmetastatic prostate cancer who are at high risk for fracture; the management of osteoporosis in postmenopausal women at high risk for fracture; the increase of bone mass in men with osteoporosis at high risk for fracture; and the management of glucocorticoid-induced osteoporosis in patients at high risk for fracture.

The safety updates indicate that health care providers should assess patients for the presence of chronic kidney disease mineral and bone disorder, including those with intact parathyroid hormone, serum calcium, 25(OH) vitamin D, and 1,25 (OH)2 vitamin D levels, before deciding whether to treat with either of these biosimilars. Providers should also consider evaluating bone turnover status via bone biopsy or serum markers of bone turnover to identify the possible presence of underlying bone disease.

After the administration of Enoby or Ospomyv to patients who are fit to receive this therapy, providers should monitor serum calcium levels on a weekly basis during the first month after administration, as well as every month thereafter. If treating patients with advanced chronic kidney disease, providers should also coordinate patient care with input from providers who have expertise in managing chronic kidney disease mineral and bone disorder.

The safety updates highlight that health care providers should give each patient a copy of the patient guide for the agent they are receiving; review the information in the guides with each patient, including the serious risks associated with the agents and the symptoms of severe hypocalcemia; and recommend that each patient seek immediate medical attention if they develop symptoms or signs of severe hypocalcemia.

Enoby was approved by the FDA on September 30, 2025, in conjunction with a simultaneous approval for denosumab-qbde (Xtrenbo), a biosimilar referencing denosumab (Xgeva). This regulatory decision was supported by a comprehensive collection of nonclinical, clinical, and analytical data that were submitted to the FDA. Ospomyv was approved by the FDA on February 17, 2025, in conjunction with a simultaneous approval for denosumab-dssb (Xbryk), a biosimilar referencing denosumab (Xgeva). This regulatory decision was backed by findings from a phase 1 trial (NCT06095427) that investigated the use of the denosumab biosimilar LY06006 compared with US- and EU-sourced denosumab in healthy male patients.

Under the partnership between Amneal Pharmaceuticals and mAbxience, mAbxience is responsible for development and manufacturing, while Amneal holds exclusive U.S. commercialization rights. With the addition of two denosumab biosimilars, Amneal now has five commercial biosimilars.

Both drugs should be administered by a healthcare provider. Patients should be advised to maintain serum calcium levels and to seek medical attention for an allergic reaction. Prolia has a Boxed Warning for severe hypocalcemia in patients with advanced chronic kidney disease, which can be life-threatening. Pregnancy must be ruled out prior to administration. In postmenopausal women, reported adverse drug events included back pain, musculoskeletal pain, hypercholesterolemia, and cystitis. Back pain, joint pain, and nasopharyngitis were frequently reported by men.

The most serious reported adverse drug reaction for Xgeva was dyspnea, with other reactions including fatigue, nausea, and hypophosphatemia. For patients been treated for bone metastases, common side effects were fatigue and nausea, while those with multiple myeloma frequently experienced gastrointestinal issues and anemia. Cases of giant cell tumor and hypercalcemia of malignancy showed frequent pain, nausea, and headache. Discontinuation occurred in some patients due to osteonecrosis or hypocalcemia. The drug can cause fetal harm and females of reproductive potential should use effective contraception.

According to IQVIA, U.S. annual sales for Prolia and Xgeva for the 12 months ended October 2025 were approximately $5.3 billion.