The Osteoporosis Drug Denosumab (PROLIA): an Update

In January 2024, the Food and Drug Administration (FDA) added a boxed warning — the agency’s most prominent warning — to the prescribing information for the osteoporosis drug denosumab (PROLIA) because of an increased risk of severe hypocalcemia (decreased blood calcium levels) in patients with advanced chronic kidney disease, which can lead to hospitalization and death.[1] Patients on dialysis and those with mineral and bone disorders related to chronic kidney disease are especially at risk.

This warning reinforces Public Citizen’s Health Research Group’s designation of denosumab as a Do Not Use drug. Unlike other osteoporosis treatments, one dose of denosumab works for six months. However, the benefits of denosumab do not outweigh the serious risks, as described in more detail below.[2]

In 2010, the FDA approved denosumab to treat postmenopausal women with osteoporosis who are at high risk of fracture.[3] Subsequently, the agency approved the drug for additional uses in people at high risk of fracture: to increase bone mass in men with osteoporosis, to increase bone mass in men receiving androgen deprivation therapy for nonmetastatic prostate cancer, to increase bone mass in women receiving aromatase inhibitor therapy for breast cancer and to treat men and women with osteoporosis related to the use of glucocorticoids.

Denosumab is a monoclonal antibody that is administered by subcutaneous (under the skin) injection every six months. It is more expensive than several other osteoporosis drugs;[4] the cost per injection is about $1,730. In March 2024, an interchangeable biosimilar drug (JUBBONTI) became available.[5],[6]

Osteoporosis overview

Bone is a living tissue in which cells called osteoclasts continuously break down and remove damaged bone, which is then repaired by cells called osteoblasts that form new bone.[7] Osteoporosis occurs when the bone breakdown exceeds the rate of new bone formation.[8],[9] The resulting decline in bone mass and density can increase the risk of fractures. Risk factors for osteoporosis include female sex, increasing age, family history of osteoporosis and glucocorticoid use. Postmenopausal women are at particular risk.[10]

Because available medications to prevent fractures in some osteoporosis patients have serious adverse effects, initial approaches are lifestyle strategies, such as weight-bearing and balance-maintaining exercise; adequate calcium and vitamin D intake; low or no alcohol consumption; and smoking cessation. When drug treatment is needed, bisphosphonates such as alendronate (BINOSTO, FOSAMAX), ibandronate (generic only) and risedronate (ACTONEL, ATELVIA) are recommended initial treatments.[11],[12] Bisphosphonates, however, are associated with certain adverse events, such as atypical femur fractures. Public Citizen’s Health Research Group has designated bisphosphonates as Limited Use drugs and recommends that their use be limited to patients with high fracture risk. To minimize the risk of adverse events, we recommend against the continuous use of bisphosphonates for more than five years.[13]

The effectiveness of denosumab

Although denosumab increases bone mineral density, it has not been shown to be more effective than bisphosphonates for preventing clinically important bone fractures in women or men with osteoporosis.[14] For instance, a systematic review and network meta-analysis of 12 randomized, controlled trials published in 2023 found that denosumab was not associated with significant improvements in vertebral or nonvertebral fractures compared with several other treatments for postmenopausal osteoporosis, including bisphosphonates and placebo.[15] Bisphosphonates, however, were associated with significant improvements in femoral-neck and lumbar-spine bone mineral density compared with denosumab. Another meta-analysis (also published in 2023) of seven randomized, controlled, industry-funded trials on postmenopausal osteoporosis did not find that treatment with denosumab led to fewer fractures than treatment with bisphosphonates. Importantly, although denosumab increased bone mineral density in the hip and spine, this increase was not associated with fracture reduction.[16]

Denosumab’s serious adverse effects

Denosumab interferes with bodily processes such as immune function and bone metabolism and is associated with many serious, sometimes life-threatening, adverse effects, several of which may make it necessary to discontinue treatment with this drug.[17],[18]

Bone-related adverse effects

Denosumab suppresses osteoclasts, the cells responsible for breaking down damaged bone. Discontinuing denosumab, or even skipping or delaying a dose, can cause rapid bone loss, which increases the risk of multiple vertebral fractures. This risk has not been observed with other osteoporosis drugs. If treatment with denosumab needs to be discontinued, other medications (such as bisphosphonates) should be initiated to prevent bone loss.

Like other osteoporosis drugs, denosumab in rare instances may lead to osteonecrosis (death of bone) of the jaw that can occur after tooth extractions and to atypical fractures in the femoral shaft. Atypical femoral fractures can occur with little or no trauma and can cause pain in the thigh or groin. Moreover, severe bone, joint and/or muscle pain is one of the most common adverse events associated with denosumab.

Hypocalcemia

Denosumab now includes a boxed warning in the prescribing information after an FDA investigation found that patients with advanced chronic kidney disease have an increased risk of severe, life-threatening hypocalcemia.[19]

A retrospective cohort study of about 2,800 female, dialysis-dependent Medicare beneficiaries, published at the time that the boxed warning was added, found that after 12 weeks of treatment, patients in the denosumab group had a higher incidence of severe hypocalcemia (41.1%) and very severe hypocalcemia (10.9%) than did those who had received oral bisphosphonates (2.0% and 0.4%, respectively).[20] None of the patients in the bisphosphonates group required hospitalization, whereas 10.7% of denosumab-treated patients with severe hypocalcemia were hospitalized, 5.4% developed arrhythmias or seizures and 1.3% died. In another study including about 1.6 million female Medicare beneficiaries with chronic kidney disease, denosumab-treated subjects were also more likely to require treatment for severe hypocalcemia, especially if they had mineral and bone disorders related to chronic kidney disease, than were those who had received bisphosphonates.[21]

Immune system disorders

Because denosumab can affect the body’s ability to fight infections, patients are at an increased risk of infections that may require hospitalization, including serious infections of the abdomen, ear and urinary tract, compared with those treated with placebo.[22],[23] Moreover, postmenopausal women who took denosumab for the treatment of osteoporosis were significantly more likely than those treated with placebo to have serious skin infections, such as dermatitis (inflammation of the skin), eczema and rashes.

Denosumab also can cause serious allergic reactions (known as hypersensitivity reactions), including anaphylactic reactions and anaphylactic shock, which can be fatal.[24]

What You Can Do

Although denosumab has the advantage of requiring treatment only once every six months, Public Citizen’s Health Research Group recommends that you do not use the drug for the treatment of osteoporosis. If you already are taking denosumab, especially if you have advanced chronic kidney disease or chronic kidney disease-mineral bone disorder, consult with your clinician about switching to a bisphosphonate to reduce the fracture risk related to postmenopausal osteoporosis.

Do not stop taking denosumab without consulting your clinician, because a sudden discontinuation of the drug can lead to serious adverse effects, such as increasing the risk of bone fracture.
 

References

[1] Food and Drug Administration. FDA adds boxed warning for increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking osteoporosis medicine prolia (denosumab). January 19, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease?utm_medium=email&utm_source=govdelivery. Accessed March 29, 2024.

[2] New warnings for bone drug denosumab (PROLIA). Worst Pills, Worst Pills News. November 2014. https://www.worstpills.org/newsletters/view/931. Accessed April 4, 2024.

[3] Amgen Inc. Label denosumab (PROLIA). March 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125320s213lbl.pdf. Accessed March 29, 2024.

[4] Thal KA, Nudy M, Moser EM, et al. Denosumab versus bisphosphonates for reducing fractures in postmenopausal women with osteoporosis: a meta-analysis. J Am Board Fam Med. 2023;36(1):175-185.

[5] Food and Drug Administration. FDA approves first interchangeable biosimilars to Prolia and Xgeva to treat certain types of osteoporosis and prevent bone events in cancer. March 5, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-interchangeable-biosimilars-prolia-and-xgeva-treat-certain-types-osteoporosis-and. Accessed April 4, 2024.

[6] Sandoz Inc. Label denosumab-bbdz (JUBBONTI). March 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761362s000lbl.pdf. Accessed March 29, 2024.

[7] Cleveland Clinic. Osteoblasts and Osteoclasts. Reviewed March 27, 2023. https://my.clevelandclinic.org/health/body/24871-osteoblasts-and-osteoclasts. Accessed April 4, 2024.

[8] National Institutes of Health. Overview of Osteoporosis. Reviewed December 2022. https://www.niams.nih.gov/health-topics/osteoporosis. Accessed April 4, 2024.

[9] Manolagas, SC. Pathogenesis of osteoporosis. UpToDate. Updated January 29, 2024.

[10] Centers for Disease Control and Prevention. Osteoporosis or low bone mass in older adults: United States, 2017–2018. March 31, 2021. https://www.cdc.gov/nchs/products/databriefs/db405.htm. Accessed March 29, 2024.

[11] Rosen HN. Denosumab for osteoporosis. UpToDate. Updated February 5, 2024.

[12] Drug profile. Worst Pills, Best Pills News. Last reviewed July 31, 2023. https://www.worstpills.org/monographs/view/67. Accessed April 4, 2024.

[13] Review of romosozumab (EVENITY) for severe postmenopausal osteoporosis. Worst Pills, Worst Pills News. December 2023. https://www.worstpills.org/newsletters/view/1570. Accessed April 9, 2024.

[14] Review of the osteoporosis drug denosumab (PROLIA). Worst Pills, Worst Pills News. April 2019. https://www.worstpills.org/newsletters/view/1256. Accessed April 4, 2024.

[15] Moshi MR, Nicolopoulos K, Stringer D, et al. The clinical effectiveness of denosumab (Prolia®) for the treatment of osteoporosis in postmenopausal women, compared to bisphosphonates, selective estrogen receptor modulators (SERM), and placebo: a systematic review and network meta-analysis. Calcif Tissue Int. 2023;112(6):631-646.

[16] Thal KA, Nudy M, Moser EM, et al. Denosumab versus bisphosphonates for reducing fractures in postmenopausal women with osteoporosis: a meta-analysis. J Am Board Fam Med. 2023;36(1):175-185.

[17] Amgen Inc. Label denosumab (PROLIA). March 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125320s013lbl.pdf. Accessed March 29, 2024.

[18] Rosen HN. Denosumab for osteoporosis. UpToDate. Updated February 5, 2024.

[19] Food and Drug Administration. FDA adds boxed warning for increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking osteoporosis medicine prolia (denosumab). January 19, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease?utm_medium=email&utm_source=govdelivery. Accessed March 29, 2024.

[20] Bird ST, Smith ER, Gelperin K, et al. Severe hypocalcemia with denosumab among older female dialysis-dependent patients. JAMA. 2024;331(6):491-499.

[21] Food and Drug Administration. FDA adds boxed warning for increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking osteoporosis medicine prolia (denosumab). January 19, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease?utm_medium=email&utm_source=govdelivery. Accessed March 29, 2024.

[22] Amgen Inc. Label denosumab (PROLIA). March 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125320s213lbl.pdf. Accessed March 29, 2024.

[23] Rosen HN. Denosumab for osteoporosis. UpToDate. Updated February 5, 2024.

[24] Denosumab: immune dysfunction. Prescrire Int. November 2018;27(198):268-269.