Could an Osteoporosis Drug Reduce Need for Hip Revision Surgery?

A single injection of denosumab (Prolia, Amgen), frequently used to treat osteoporosis, may reduce the need for revision surgery in patients with symptomatic osteolysis following total hip arthroplasty, a new proof-of-concept study suggests.

Aseptic loosening is the result of wear-induced osteolysis caused by the prosthetic hip and is a major contributor to the need for revision surgery in many parts of the world.

"The only established treatment for prosthesis-related osteolysis after joint replacement is revision surgery, which carries substantially greater morbidity and mortality than primary joint replacement," say Mohit M. Mahatma, MRes, of the University of Sheffield, UK, and colleagues in their article published online January 11 in Lancet Rheumatology.

As well as an increased risk of infection and other complications, revision surgery is much more costly than a first-time operation, they add.

"The results of this proof-of-concept clinical trial indicate that denosumab is effective at reducing bone resorption activity within osteolytic lesion tissue and is well tolerated within the limitations of the single dose used here," they conclude.

Commenting on the findings, Antonia Chen, MD, associate professor of orthopedic surgery, Harvard Medical School, Boston, Massachusetts, emphasized that further studies are needed to assess the effectiveness of this strategy to reduce the need for hip revision surgery.

Nevertheless, "osteolysis is still unfortunately a problem we do have to deal with and we do not have any other way to prevent it," she told Medscape Medical News. "So it's a good start...although further studies are definitely needed," Chen added.

In an accompanying editorial, Hannu Aro, MD, Turku University Hospital in Finland, agrees: "Without a doubt, the trial is a breakthrough, but it represents only the first step in the development of pharmacological therapy aiming to slow, prevent, or even reverse the process of wear-induced periprosthetic osteolysis."

Small Single-Center Study

The phase 2, single-center, randomized, controlled trial involved 22 patients who had previously undergone hip replacement surgery at Sheffield Teaching Hospitals and were scheduled for revision surgery due to symptomatic osteolysis. They were randomized to a single subcutaneous injection of denosumab at a dose of 60 mg or placebo on their second hospital visit.

"The primary outcome was the between-group difference in the number of osteoclasts per mm of osteolytic membrane at the osteolytic membrane-bone interface at week 8," the authors note.

At this timepoint, there were 83% fewer osteoclasts at the interface in the denosumab group compared with placebo, at a median of 0.05 per mm in the treatment group compared with 0.30 per mm in the placebo group (P = .011).

Secondary histological outcomes were also significantly improved in favor of the denosumab group compared with placebo (Table 1).

Table 1. Secondary Outcomes With Denosumab vs Placebo After 8 Weeks

Histological Endpoint	Denosumab	Placebo	Difference vs placebo	P
Length of osteoclast surface	0.14%	1.04%	87% shorter	.0089
Length of eroded surface	0.22%	0.78%	72% shorter	.015
Length of osteoblast surface	0.05%	0.53%	91% shorter	.015
Osteoblast number	0.04 per mm	0.41 per mm	90% fewer	.017

Potential to Prevent Half of All Hip Revision Surgeries?

Patients who received denosumab also demonstrated an acute fall in serum and urinary markers of bone resorption following administration of the drug, reaching a nadir at week 4, which was maintained until revision surgery at week 8.

In contrast, "no change in these markers was observed in the placebo group [P < .0003 for all biomarkers]," the investigators note. Rates of adverse events were comparable in both treatment groups.

As the authors explain, osteolysis occurs following joint replacement surgery when particles of plastic wear off from the prosthesis, triggering an immune reaction that attacks the bone around the implant, causing the joint to loosen.

"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," said senior author Mark Wilkinson, MBChB, PhD honorary consultant orthopedic surgeon, Sheffield Teaching Hospitals, in a press release from his institution.

"This study is a significant breakthrough as we've demonstrated that there is a drug, already available and successful in the treatment of osteoporosis, that has the potential to prevent up to half of all revised replacement surgeries which are caused by osteolysis," he added.

Wilkinson and coauthors say their results justify the need for future trials targeting earlier-stage disease to further test the use of denosumab to prevent or reduce the need for revision surgery.

In 2018, aseptic loosening accounted for over half of all revision procedures as reported to the National Joint Registry in England and Wales.

Older Polyethylene Prostheses Are the Main Culprit

Commenting further on the study, Chen noted that osteolysis still plagues orthopedic surgeons because the original polyethylene prostheses were not very good. A better prosthesis developed at the Massachusetts General Hospital is made up of highly crossed-link polyethylene and still wears over time but to a much lesser extent than the older polyethylene prostheses.

Metal and ceramic prostheses can also induce osteolysis, but again to a much lesser extent than the older polyethylene implants.

"Any particle can technically cause osteolysis but plastic produces the most particles," Chen explained. Although hip revision rates in the United States are low to begin with, aseptic loosening is still one of the main reasons that patients need to undergo revision surgery there, she observed.

"A lot of patients are still living with the old plastic [implants] so there is still a need for something like this," she stressed.

However, many questions about this potential new strategy remain to be answered, including when best to initiate treatment and how to manage patients at risk for osteolysis 20 to 30 years after they have received their original implant.

In his editorial, Aro says that serious adverse consequences often become evident 10 to 20 years after a patient has undergone their original hip replacement, when they are potentially less physically fit than they were at the time of the operation and thus less able to withstand the rigors of a difficult revision surgery.

"In this context, the concept of nonsurgical pharmacological treatment of periprosthetic osteolysis...brings a new hope for the ever-increasing population of patients with total hip arthroplasty to avoid revision surgery," Aro suggests.

However, Aro cautions that reduction of bone turnover by antiresorptive agents such as denosumab has been associated with the development of atypical femoral fractures.

The study was funded by Amgen. Wilkinson has reported receiving a grant from Amgen. Chen has reported serving as a consultant for Striker and b-One Ortho. Aro has reported receiving a grant to his institution from Amgen Finland and the Academy of Finland. He has also served as a member of an advisory scientific board for Amgen Finland.

Lancet Rheum. Published online January 11, 2021. Abstract, Editorial

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