Article Archive

Fall 2010

Injectable Prolia — Osteoporosis Update
By Juliann Schaeffer
Aging Well
Vol. 3 No. 4 P. 6

Healthcare providers involved in the fight against osteoporosis now have one more weapon in their arsenal, as the FDA recently approved the sale of Prolia (denosumab), a twice-yearly injection indicated for postmenopausal women.

Clinical trials found Prolia just as effective (but really no more effective) than bisphosphonates, which are the current standard for osteoporosis care. Yet the way in which these treatments work their magic differs greatly. “The mechanism of action by which this drug exerts its effects is truly novel,” says Ethel S. Siris, MD, the Madeline C. Stabile professor of clinical medicine in endocrinology and director of the Toni Stabile Osteoporosis Center at Columbia University Medical Center.

Siris explains that in postmenopausal women, the absence of estrogen sets up a deregulation of RANK ligand, “which is a protein that participates in the production and activity of osteoclasts,” she says. “In the postmenopausal state, there is an excessive abundance of RANK ligand floating around because the estrogen is no longer regulating it,” leading to an aggressive resorbing of bone.

Bisphosphonate drugs such as Fosamax (alendronate), Actonel, and Reclast work by layering on the surface of bone and are consumed by the osteoclasts, reducing their activity and remaining in bone for a relatively long time. However, Prolia works by ratcheting down the message that leads to excessive osteoclast-driven bone removal and is active in the body for only six months.

“The way that denosumab (Prolia) works is that it’s a fully human monoclonal antibody to RANK ligand. So when you give somebody a shot in the arm of this drug every six months, they get a six-month period during which the antibody is active, after which it stops working. For the six months that it’s circulating in your system, you have a reduction in RANK ligand levels, which leads to a reduction in the signal to the osteoclasts that makes them overly aggressive, and they behave properly,” says Siris, who was a researcher on the three-year study that served as the basis for the FDA’s approval and a member of Amgen’s steering committee for the study. (Amgen is the company that manufactures Prolia.)

“This drug works by preventing the osteoclasts from maturing or resorbing bone, so it’s a completely different mechanism of action. That said, it appears at the end of the day in terms of reducing fractures and making bones stronger, the end result is about the same as bisphosphonates,” says Nancy E. Lane, MD, director of the Center for Healthy Aging at the University of California, Davis.

Prolia stays in a patient’s system for only a finite period of time, and Siris says this reversibility could be one appeal. “At the end of six months, if you don’t get another dose, it’s gone. So if you felt you didn’t want to use this approach, it’s gone after the six months after the dose is given. It doesn’t linger in the bone for extended periods, which some people have worried about in the past. Bisphosphonates linger in bone long after you stop them, whereas this [drug] is gone in six months,” explains Siris.

Prolia’s dosing could also aid in patient medication adherence. “The twice-yearly dosing [via subcutaneous injection] is a big advantage of Prolia since compliance has been a problem with patients on osteoporosis medications,” says Aurelia Nattiv, MD, director of the UCLA Osteoporosis Center.

Siris agrees on the adherence issue: “Being able to get this shot twice a year could conceivably be a very effective way of assuring adherence because if you’ve personally given the shot, you know it’s in.”

Reclast accomplishes the same goal with a yearly IV infusion dose. However, Siris notes that a high percentage (50% to 60%) of patients on Reclast can experience an acute phase reaction of flulike symptoms the day after the first dose, which can prevent patients from returning for another dose, even though they’re unlikely to experience the symptoms again.

Cost could be seen as an obstacle for patients considering Prolia as a treatment option. While generic Fosamax costs roughly $100 to $200 per year and brand-name bisphosphonates slightly less than $1,000 per year, Prolia will cost about $1,650 per year plus the cost associated with an office visit. Prolia is also more expensive than Reclast, which costs $1,100 for a yearly dose.

But Siris notes that Prolia will be covered under Medicare Part B, so the cost will likely be covered by the healthcare system rather than by many patients receiving this treatment. “Medicare will pay for it the way they would pay for an x-ray or some other office procedure,” says Siris, noting that she expects most commercial payers to cover Prolia for the right patient, most likely those who have already tried bisphosphonates.

As with Reclast, healthcare providers must first buy Prolia themselves to be reimbursed after treating a patient, which makes for more paperwork and initial cost for providers and could make some doctors think twice about offering this new treatment.

Side Effects
Compared with the more commonly used bisphosphonates that can contribute to gastroesophageal reflux and heartburn, Nattiv says Prolia causes “no significant gastrointestinal symptoms in most people.” But Nattiv notes that “there are potentially serious side effects [with Prolia], including skin infections, musculoskeletal pain, urinary tract infections, among other side effects.”

Siris says cellulitis was the main skin infection seen in the Prolia study, affecting roughly 12 women over the course of the three years compared with one woman on placebo. She advises against recommending Prolia for patients highly susceptible to cellulitis, noting that eczema was a more common and less serious skin-related side effect of which patients should be made aware.

Recommending Prolia
The FDA has limited the labeling of Prolia to postmenopausal women who have osteoporosis or those at very high risk. “It’s not for prevention, it’s not for men, and it’s not for premenopausal women,” Lane says.

Nattiv notes that Prolia should be used primarily for patients who are not considered candidates for bisphosphonates, which she says are still the first-line treatment for osteoporosis in most patients.

Since bisphosphonates are cleared by the kidney, patients with low creatinine clearances may also be better off trying Prolia. “In older patients where there’s any concern about renal function (patients with borderline kidney function), I think Prolia has a certain attractiveness in that setting,” says Siris.

While Lane believes bisphosphonates should remain the No. 1 option for osteoporosis treatment “because they’re cost-effective and useful, I think that this is an option if [patients] can’t take bisphosphonates. It’s a good drug and while I don’t think it’s for the masses yet, I think it will add to our armamentarium.”

“I think Prolia offers postmenopausal women another nice option for osteoporosis treatment, especially with the recent possible concerns reported of long-term bisphosphonate use,” says Nattiv.

— Juliann Schaeffer is an editorial assistant at Aging Well.