Review of the Osteoporosis Drug Denosumab (PROLIA)

Osteoporosis is a decline in bone mass and density, which, if extensive enough, makes bones more fragile and susceptible to fracture. Drug treatment can prevent broken bones in some osteoporosis patients. But drugs are not always necessary and can cause harmful adverse effects.

Denosumab (PROLIA) was approved by the Food and Drug Administration (FDA) in 2010 for the treatment of postmenopausal women with osteoporosis who are at high risk of fracture.[1] The FDA subsequently approved the drug for several other uses, including to increase bone mass in men with osteoporosis who are at high risk of fracture.[2] Public Citizen's Health Research Group has designated Prolia as Do Not Use because it has serious unique risks that outweigh its benefits.

Osteoporosis overview

Bone is a living tissue that is constantly being broken down and reformed. Osteoporosis occurs when the rate of bone breakdown exceeds the rate of new bone formation.[3] Risk factors for osteoporosis include female sex; increasing age; early menopause; white and Asian race; family history of osteoporosis; inactive lifestyle; lifetime diet low in calcium and vitamin D; excessive alcohol use; and glucocorticoid use.[4]

Doctors diagnose osteoporosis by measuring bone mineral density with a simple X-ray test.[5] If a postmenopausal woman (or a man over age 50) has a bone density that is much lower than that of an average young, healthy adult, he or she is diagnosed with osteoporosis.[6],[7]

According to the U.S. Preventive Services Task Force, an independent panel of experts in evidence-based disease prevention, the following individuals should be screened for osteoporosis:

• Women aged 65 years or older
• Women younger than 65 who are at increased risk of osteoporosis based on a standard risk assessment tool that takes into account the major osteoporosis risk factors[8]

Effectiveness of denosumab

Denosumab is the first drug in its class and works through a different mechanism than other osteoporosis drugs currently on the market. It is a synthetic antibody that blocks the cells in the bone responsible for bone breakdown.[9] The drug is administered by an injection under the skin once every six months.

The FDA's initial approval of denosumab for treatment of postmenopausal women with osteoporosis was based on a single randomized clinical trial involving more than 7,800 subjects.[10] The postmenopausal women with osteoporosis received injections of denosumab or a placebo every six months. The women were followed for up to three years and underwent yearly spinal x-rays to look for vertebral fractures. At least one new vertebral fracture was documented by x-ray in 2 percent of women in the denosumab group and 7 percent of women in the placebo group, a difference that was statistically significant. Of note, vertebral fractures often occur without symptoms. Hip fractures — the most serious type of fracture in osteoporosis patients — occurred in 0.7 percent of women in the denosumab group and 1.2 percent of women in the placebo group. Finally, denosumab clearly increased bone mineral density.

The FDA's subsequent approval of denosumab to increase bone mass in men with osteoporosis was based on a single randomized trial involving only 242 subjects.[11] The men received denosumab injections or placebo injections every six months for one year. The trial showed that the denosumab resulted in significantly greater increases in bone density than placebo.

Importantly, denosumab has not been shown to be more effective for preventing clinically important bone fractures in women or men with osteoporosis than other, older osteoporosis drugs, such as the bisphosphonates (for example, alendronate [BINOSTO, FOSAMAX], ibandronate [BONIVA] and risedronate [ACTONEL, ATELVIA], which we have designated as Limited Use).

Although denosumab does enhance bone mineral density, the drug can cause many serious, sometimes life-threatening adverse effects, in part because it also affects many normal bodily functions, particularly the immune system.

Adverse effects

According to the independent French drug journal Prescrire International, there have been several thousand reports worldwide of immune-related adverse events linked to denosumab use from 2010 to 2018.[12] For example, hypersensitivity reactions, including anaphylaxis — a type of allergic reaction characterized by throat tightness, drop in blood pressure, swelling of the upper airways, and hives — have been reported.[13] These reactions can be life-threatening because they can cause the airways to close, impeding breathing. As of April 2018, a European database containing reports of adverse drug events included 201 reports of hypersensitivity reactions linked to denosumab, including one death, 58 anaphylactic reactions and 16 cases of anaphylactic shock.[14]

Denosumab's effects on the immune system also raised concerns about an increased risk of serious infections. In the large clinical trial that involved more than 7,800 women, serious infections leading to hospitalization were reported more frequently in denosumab-group subjects than in placebo-group subjects. Serious skin infections, as well as infections of the abdomen, urinary tract, ear and heart valves, were more frequent in subjects given denosumab.[15]

Denosumab also causes adverse skin reactions, such as dermatitis (inflammation), eczema and rashes, which again occurred at a significantly higher rate in the denosumab group than in the placebo group.[16] Most of the reported skin-related adverse effects were not at the injection site, indicating a systemic — not just local — immune-related adverse effect.

Denosumab's effects on bone can result in markedly decreased blood calcium levels. It also can cause atypical fractures of the hip bone that occur with minimal or no trauma and osteonecrosis (bone death) of the jaw, as well as severe musculoskeletal, bone and joint pain.[17]

Importantly, unlike bisphosphonates, which become embedded into the bone and have prolonged effects on bone density after discontinuation, denosumab leaves the body relatively quickly. This means that denosumab's effects wane quickly after cessation of the drug, leading to rapid loss of bone density.[18]

Because of this, cessation of denosumab can lead to a risk of developing multiple vertebral fractures, known as rebound-associated vertebral fractures.[19] Several case series have reported on the enhanced susceptibility to vertebral fractures upon denosumab treatment cessation.[20],[21],[22],[23] These fractures often occur within a year of the final denosumab dose, and in one case after only eight months.[24] Current French guidelines therefore recommend that patients switch to bisphosphonate therapy six to twelve months after denosumab cessation.[25]

What You Can Do

You should avoid starting denosumab for treatment of osteoporosis if you are not currently taking it. If you are already taking it, consult with your doctor about switching to a bisphosphonate. Do not stop denosumab treatment without talking to your doctor.
 

References

[1] Food and Drug Administration. Application Number: 125320 Approval Letter. June 1, 2010. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125320s000Approv.pdf. Accessed February 18, 2019.

[2] Amgen. Label: denosumab (PROLIA). May 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125320s186lbl.pdf. Accessed February 18, 2019.

[3] Rodan G.A., Martin T.J. Therapeutic approaches to bone diseases. Science. 2000;289(5484):1508-1514.

[4] National Institutes of Health. Osteoporosis overview. October 2018. https://www.bones.nih.gov/health-info/bone/osteoporosis/overview. Accessed February 18, 2019.

[5] Bernabei R, Martone A, Ortolani E, et al. Screening, diagnosis and treatment of osteoporosis: A brief review. Clinical Cases in Mineral and Bone Metabolism. 2014;11(3):201-207.

[6] Dilemmas in the management of osteoporosis. Drug and Therapeutics Bulletin. 2015;53:18-21.

[7] Willson T, Nelson SD, Newbold J, et al. The clinical epidemiology of male osteoporosis: A review of the recent literature. Clin Epidemiol. 2015;7:65-76.

[8] U.S. Preventive Services Task Force. Osteoporosis to prevent fracture: Screening. June 2018. https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/osteoporosis-screening1. Accessed February 18, 2019.

[9] Amgen. Label: denosumab (PROLIA). May 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125320s186lbl.pdf. Accessed February 18, 2019.

[10] Food and Drug Administration. Application number 125320: Summary review. May 28, 2010. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125320s000SumR.pdf. Accessed February 18, 2019. 

[11] Amgen. Label: denosumab (PROLIA). May 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125320s186lbl.pdf. Accessed February 18, 2019.

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

[13] Amgen. Label: denosumab (PROLIA). May 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125320s186lbl.pdf. Accessed February 18, 2019.

[14] Denosumab: immune dysfunction. Prescrire Int. 2018. 38(418): 591-592.

[15] Amgen. Label: denosumab (PROLIA). May 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125320s186lbl.pdf. Accessed February 18, 2019.

[16] Ibid.

[17] Ibid.

[18] Bone HG, Bolognese MA, Kin Yuen C, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96(4):972–980.

[19] Lamy O, Gonzalez-Rodriguez E, Stoll D, et al. Severe rebound-associated vertebral fractures after denosumab discontinuation: 9 clinical cases report. Clin Endocrinol Metab. 2017;102(2):354–358.

[20] Anastaskilakis AD, Polyzos SA, Makras P, et al. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Miner Res. 2017:32(6):1291-1296.

[21] Tripto-Shkolnik L, Rouach V, Marcus Y, et al. Vertebral fractures following denosumab discontinuation in patients with prolonged exposure to bisphosphonates. Calcif Tissue Int. 2018;103(1):44-49.

[22] Aubry-Rozier B, Gonzalez-Rodriguez E, Stoll D, Lamy O. Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports. Osteoporos Int. 2016;27(5):1923-1925.

[23] Polyzos SA, Terpos E. Clinical vertebral fractures following denosumab discontinuation. Endocrine. 2016;54(1):271–272.

[24] Anastaskilakis AD, Polyzos SA, Makras P, et al. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Miner Res. 2017:32(6):1291-1296. 

[25] Denosumab: multiple vertebral fractures after discontinuation. Prescrire Int. 2018;27(198):269.