Tara Haelle

October 17, 2017

PHILADELPHIA — For women with osteoporosis, drug holidays from denosumab (Prolia, Amgen) are unnecessary and potentially risky, according to an expert who spoke here at the North American Menopause Society 2017 Annual Meeting.

Even for women taking bisphosphonates who are at low risk for fracture, a drug holiday should be considered "an opportunity, not a necessity and not mandatory," said Michael McClung, MD, director of the Oregon Osteoporosis Center in Portland.

"There is no rule that therapy must be stopped after any interval of time," he added.

The whole idea of a drug holiday from bisphosphonates has been talked about so much that the concept has been applied to all the other osteoporosis drugs.

"Bisphosphonates are by far the most common drugs used to treat osteoporosis," but the mechanism of their action is different than that of other osteoporosis therapies, Dr McClung told Medscape Medical News. "The whole idea of a drug holiday from bisphosphonates has been talked about so much that the concept has been applied to all the other osteoporosis drugs."

In 1995, the bisphosphonate alendronate (Fosamax) became the first nonhormonal drug approved for the long-term treatment of osteoporosis. In 2010, the monoclonal antibody denosumab became the first nonhormonal biologic and the second type of drug approved for the long-term treatment of osteoporosis.

The protective effects of bisphosphonates and of denosumab become evident in the months after the start of therapy and continue as long as women take the drugs. They reduce vertebral fracture by 60% to 70%, hip fracture by 40% to 50%, and nonvertebral fracture by 20% to 35%, Dr McClung reported.

However, the risk for atypical fracture of the femur increases from two per 10,000 patients after 3 years of bisphosphonate treatment to 10 per 10,000 patients after 8 to 10 years of treatment. And protection against fractures and increases in bone density begin in the first year or two of bisphosphonate treatment, but then plateau.

These factors led to the idea of a temporary drug holiday after 3 to 5 years of bisphosphonate therapy. A holiday can make sense for women at low to moderate risk for fracture because protection from fracture lasts 1 to 2 years after bisphosphonate therapy is discontinued, Dr McClung pointed out.

Drug Holiday

Evidence suggests that bisphosphonate holidays should be 2 to 3 years for alendronate and zoledronic acid but, because the "off effect" of risedronate is faster, that therapy should be reassessed after 1 year.

For women who are still at high risk for fracture after 3 to 5 years of treatment, such as those with low bone mineral density or a previous vertebral fracture, remaining on bisphosphonates won't help, he told Medscape Medical News.

In such cases, evidence suggests that a switch to denosumab "is the most appealing strategy," he said. "When patients have been on bisphosphonates for several years and then are switched to denosumab, progressive increases in bone density occur."

Women can continue to receive treatment with denosumab for up to 10 years, with reassessments every 2 to 3 years, he added.

Ten-year data from the FREEDOM study of denosumab showed progressive increases in bone density over the full 10 years, stability in the risk for spine fracture over those years, and a progressive decrease in fractures at other sites the longer treatment is given, as reported by Medscape Medical News. FREEDOM was the first study to demonstrate those outcomes after long-term osteoporosis therapy, Dr McClung noted.

In addition, there was no increase in the risk for adverse events over 10 years.

However, studies have shown an immediate and sharp decline in bone mineral density when women stop taking denosumab, Dr McClung explained.

Both bisphosphonates and denosumab are appropriate long-term therapies, but there is no need for a denosumab holiday because its protective effects wane immediately after the drug is discontinued, he told Medscape Medical News.

In fact, Dr McClung described a study in which 24 patients experienced vertebral fractures 3 to 18 months after the discontinuation of denosumab therapy, prompting concern about a rebound risk for fracture, similar to that seen after the discontinuation of estrogen therapy (J Bone Miner Res. 2017;32:1291-1296).

The idea that we could treat women for a short time and then not need to treat them anymore really is wishful thinking.

"Patients and general physicians need to appreciate that osteoporosis, like hypertension and other chronic diseases, requires a long-term management plan," he explained. "The idea that we could treat women for a short time and then not need to treat them anymore really is wishful thinking."

If a woman reaches a treatment target or cannot tolerate an adverse effect of denosumab, the physician should consider another therapy to reduce fracture risk and prevent rapid bone loss after a year.

"At present, the most appealing strategy would be to treat with a bisphosphonate for 2 years and to then re-evaluate the patient," Dr McClung said.

"People in general don't really appreciate the importance of osteoporosis," said Mary Jane Minkin, MD, clinical professor of obstetrics and gynecology at the Yale Medical School in New Haven, Connecticut.

"That's basically the problem," she told Medscape Medical News. "Patients don't understand that fracture is a very bad thing."

She reported a key statistic cited by several speakers during a premeeting symposium on musculoskeletal health: "If you look at the mortality within a year of a hip fracture, you've got 20% people dying, or they go into a nursing home. In an older person, a hip fracture is devastating."

Muscular Health Is Also Important

"Having crummy bones is one of the issues, but falling is another," said Dr Minkin. "If you can keep people strong and keep their muscles in good shape so they're not falling, that will set them up a lot less for a fracture."

Physicians need to overcome any uneasiness they have about long-term osteoporosis therapies, said Dr McClung. Uncertainty about drug holidays and concern about rare adverse effects that only occur after long-term exposure have led to some reluctance to treat women.

But "the benefit–risk ratio is so favorable if we treat the right patients — those at high risk — that physicians should not be anxious about beginning therapy," he told Medscape Medical News.

"We've got very strong evidence that these drugs are quite effective in protecting patients from hip and spine fractures — the two most devastating fractures patients have," he said.

Dr McClung reports receiving honoraria for speaking and serving on the scientific advisory boards for both Amgen and Radius. Dr Minkin is a consultant for Shionogi, Pfizer, Novo Nordisk, and Enzymatic Therapies.

North American Menopause Society (NAMS) 2017 Annual Meeting. Presented October 11, 2017.

Follow Medscape Ob/Gyn on Twitter @MedscapeObGyn and Tara Haelle @tarahaelle

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