Denosumab for Bone Density Loss: Benefits vs. Risks

By Elesa Swirgsdin
Friday, July 30, 2021

For some patients with degenerative bone disorders, the human monoclonal antibody denosumab can reduce BMD loss and the risk for fractures. Ongoing research is revealing the advantages and risks.

In 2010, denosumab became the first RANK ligand inhibitor to be approved by the FDA. At the time, the drug was authorized only for the treatment of osteoporosis in postmenopausal women with an increased risk for bone fractures, including those with a history of fracture or who were unable to take other drugs for osteoporosis.

As continued trials and research revealed the benefits of denosumab over other drugs for certain conditions that cause bone degeneration, the FDA expanded the scope of its use. Over the following decade, denosumab was approved as a therapy for steroid-induced osteoporosis, bone loss resulting from cancer treatments and men with osteoporosis.

While denosumab offers advantages for some patients, it is not without risk. Recent studies have shown that discontinuation of the drug can result in a rebound phenomenon, in which the increased bone mineral density (BMD) achieved during treatment is reversed and rapid bone loss occurs, leaving some patients at even higher risk of multiple vertebral fractures.

Many researchers still agree that denosumab can be a safe and effective treatment for bone density loss in many patients, but more studies are needed to determine the scope of its use, as well as its risks, compared with other therapies.

Lowering Osteoporosis Fracture Risk

Denosumab is now among the most common drugs prescribed for bone resorption suppression in postmenopausal women with osteoporosis, as it prevents high bone turnover and lessens the risk of osteoporotic fracture, particularly vertebral fracture. It has also been proven more effective at boosting BMD than bisphosphonates.

Yet in 2018, medical researcher Emma Deeks noted in the journal Drugs & Aging that it remains unclear whether these differences lead to greater anti-fracture efficacy.

“Denosumab is a key treatment option for postmenopausal women with osteoporosis who have an increased/high risk of fracture or failure/intolerance of other osteoporosis therapies, although the potential for multiple vertebral fractures to occur after discontinuation of the drug requires consideration of subsequent management options,” she concludes.

Later studies found denosumab to be an effective treatment for men with osteoporosis, raising BMD in the lumbar spine, neck, hip and one-third radius sites. While other therapies have proven effective in clinical studies, challenges with administering the treatments make them underutilized and other options are needed.

Exciting Findings

The status of denosumab as an imperfect solution to age-associated bone loss continues to evolve. One result that has emerged from denosumab studies is the possibility for reduced need for hip revision surgery following total hip arthroplasty. The only available treatment for wear-induced osteolysis after joint replacement surgery to date is revision surgery. This procedure comes with an increased risk of complications and has a higher mortality rate than joint replacement alone. But a proof-of-concept clinical trial by the University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, appearing in Lancet Rheumatology in January 2021, found that denosumab can prevent osteolysis and the need for another surgery.

“It is very clear from our bone biopsies and bone imaging that the [denosumab] injection stops the bone absorbing the microplastic particles from the replacement joint and therefore could prevent the bone from being eaten away and the need for revision surgery,” writes senior author Mark Wilkinson, MBChB, PhD, professor of orthopedics at the University of Sheffield’s Department of Oncology and Metabolism, noting that the need for as many as half of all revision surgeries could be eliminated based on this finding.

“These results justify the need for future trials that target earlier-stage disease to test for clinical efficacy in reducing the need for revision surgery,” the authors conclude.

BMD Loss from Steroids and Cancer Treatments

Recent research also reveals that denosumab is a promising treatment for bone loss related to certain cancer treatments, which over time can lead to skeletal issues such as osteoporosis, loss of BMD and a high risk for bone fractures. In the journal Expert Opinion on Biological Therapy, November 2020, the authors conclude that denosumab is highly effective at preventing these problems in patients with breast and prostate cancer, as well as nonmetastatic prostate cancer. Denosumab has now outpaced all other therapies, making up 50% of prescriptions by March 2020.

Likewise, another recent study found that denosumab offers superior spine BMD increases in patients with bone loss as a result of long-term glucocorticoid treatments. The small study focused on patients receiving long-term prednisolone therapy, revealing that denosumab suppressed bone-turnover markers more effectively than alendronate did after 12 months. The authors have determined that while the results are encouraging, larger randomized controlled trials are necessary.

Limitations and Risks

While denosumab has been proven effective at increasing BMD and preventing vertebral fractures, no major difference has been found between denosumab and bisphosphonates in the risk of hip fractures. More research is needed to determine the efficacy of both drugs for this issue.

The biggest hurdle the research has uncovered during trials is the bone loss that occurs after the discontinuation of denosumab, greatly increasing the risk for multiple vertebral fractures. Some studies found that the rate and amount of bone loss correlates with the length of treatment. “The discontinuation of Dmab [denosumab] leads to significant and abrupt changes in bone remodeling,” report the authors of a study published in the Journal of Clinical Medicine in January 2021. “Enhanced osteoclastogenesis and osteoblastogenesis is evident at tissue level leading to seriously compromised bone structure.”

However, preliminary research suggests that bisphosphonates can decrease this bone loss when given after denosumab treatment has stopped. More research is being done to determine the best course of treatment with bisphosphonates and whether administering them prior to starting denosumab also decreases bone loss risk.