News from NAMS 2017: “Bisphosphonate drug holiday” not mandatory

A presentation at the North American Menopause Society (NAMS) Annual Meeting in Philadelphia October 11-14, will  present new evidence regarding long term safety and effectiveness of Bisphosphonates and denosumab in treating postmenopausal osteoporosis.

According to International Osteoporosis Foundation, Osteoporosis is estimated to affect 200 million women worldwide - approximately one-tenth of women aged 60, one-fifth of women aged 70, two-fifths of women aged 80 and two-thirds of women aged 90.

Bisphosphonates and denosumab are the most commonly prescribed treatments for osteoporosis. There is no cure for osteoporosis and the effects of these drugs wear-off as treatment ceases, hence prevention is the best bet.

As Bisphosphonates therapy is started, protection from osteoporosis is gained in first few months and persists as long as treatment is continued.

If Bisphosphonate treatment is continued beyond 3 years, increasing risk of unusual or “atypical” fractures of the femur (thigh bone) is observed. The risk increases gradually as patient continue to take the drug beyond 3 years: the risk is 20/100,000 patients at 5 years and 1/1,000 patients at 8-10 years.

If the drug is stopped, protection from fractures is lost gradually in 3-5 years.

This combination of increased risk of atypical fractures on continued treatment and decline in protection from fractures as treatment is stopped led to the confusing concept of a “bisphosphonate holiday.”

The American Society for Bone and Mineral Research (ASBMR) has recently provided clear recommendations about “bisphosphonate holidays.”

ASBMR recommends that, after 3-5 years of treatment with bisphosphonates, a patient risk of fracture should be evaluated. If the patient remains at ‘high risk’ for fracture because of low BMD, previous history of hip, spine, or multiple other fractures, the treatment should not be stopped.

Patient can continue the same treatment or change to some other drugs like denosumab.

Those patients who are at ‘low risk’ for fracture, the treatment can be stopped for 3-4 years, but it is not mandatory.

The concept of ‘drug holiday’ only holds good for Bisphosphonates only, and not for other drugs like raloxifene, teriparatide, and denosumab because beneficial effects of these drugs are lost as soon as they are stopped.

Dr. Michael McClung of the Oregon Osteoporosis Center in Portland, Oregon, who will be presenting his recommendations on long-term osteoporosis therapy at the NAMS Annual Meeting said, “Because protection from fractures disappears quickly if denosumab treatment is stopped, and since there are no currently known safety issues that limit the duration of denosumab therapy, there is no justification for a drug holiday with this treatment.”

“Just as we do not recommend stopping treatment for high blood pressure or diabetes, it is necessary to have a long-term treatment plan for postmenopausal women with osteoporosis if the benefits of our therapies are to be realized,” he further added.

Dr. JoAnn Pinkerton, NAMS executive director said, “Prevention of osteoporosis should be a goal for those treating menopausal women, as up to 20% of bone loss occurs within the first five years of menopause. Once diagnosed with osteoporosis, the goal becomes lowering the risk of fractures as fractures can be life changing or life limiting. This presentation will offer valuable insights about the need for long-term treatment and will change the way health care providers approach long-term osteoporosis management.”

ACP updates guideline for treating Osteoporosis.

American College of Physicians (ACP) recently updated it’s 2008 treatment guideline for treatment of low bone density and osteoporosis in men and women. This update is also endorsed by American Academy of Family Physicians.

The guidelines were published online May 8 in the Annals of Internal Medicine along with an Editorial by Eric S. Orwoll.

According to International Osteoporotic Foundation (IOF), 1 in 3 women over age 50 will experience osteoporotic fractures and nearly 200 million women suffer from osteoporosis worldwide.

The reviewers searched databases for observational studies, RCTs, meta-analysis and systematic review from 2 January 2005 to 3 June 2011 and added a machine learning method from 2014 to 2016 to gather and grade the necessary evidence in formulating the guidelines.

The target audience for this update is all physicians and target population is all adult men and women with low bone density or osteoporosis.

Recommendations:

1) ACP recommends that pharmacologic treatment with 3 bisphosphonates; alendronate, risedronate, zoledronic acid, or newer biologic agent denosumab is beneficial for women who have osteoporosis (T scores ≤ –2.5 or those who have experienced fragility fractures) (Grade: strong recommendation; high-quality evidence)

Raloxifene, ibandronate and teriparatide are not advocated as a first-line pharmacologic treatment. Calcitonin which is widely used in osteoporosis was not included in this guideline.

The role played by Calcium and Vitamin D supplementation is also not clear. They can be given with careful dosing strategies to avoid hypercalcemia.

2) The duration of treatment recommended for women with osteoporosis is 5 years, most studies included in the analysis continued treatment for 5 years. (Grade: weak recommendation; low-quality evidence).

Treatment beyond that period should be based on individual case evaluation.

3) Monitoring the women for bone density during the duration of treatment is not recommended as no additional treatment benefit is derived from it.

The guidelines also advise against the frequent monitoring of women with normal BMD for development of osteoporosis. Most women who have normal DXA scores are unlikely to develop osteoporosis in next 15 years.

4) The guideline also does not support the use of hormone-replacement therapy (HRT), either estrogen alone or in combination with progesterone as a treatment option in postmenopausal women with established osteoporosis.

The serious side effects such as cerebrovascular accidents and venous thromboembolism outweighs any potential benefits derived from it. Use of selective estrogen-receptor modulator (SERM) raloxifene is also not advised because of the harmful side effects.

Eric Orwoll, MD, Oregon Health and Science University, Portland, Oregon, does not agree with the ACP on issues regarding the role of HRT in osteoporosis.

He writes in an accompanying editorial "Estrogen replacement reduces fractures in postmenopausal women overall, and it is likely to do the same in osteoporotic women."

"Therefore, although estrogen should not be the first choice for osteoporosis therapy, if a woman is using estrogen for other reasons (such as menopausal symptoms), skeletal benefits can be expected without the addition of a second osteoporosis drug," Dr Orwoll further added.

5) The ACP advises the physicians to take their own decision when it comes to treatment of osteopenic women who are 65 years or older based on patients risk for fractures and her individual treatment preferences.

6) The guidelines also urged physician to prescribe generic drugs in an effort to keep the cost down, as cost is an important aspect of adherence to treatment.

Dr Orwoll further discussed the exclusion of teriparatide, an anabolic agent from the treatment guidelines. He opines that it may be a good option in case of sequential therapy.

FDA recently approved abaloparatide (Tymlos, Radius Health) similar to teriparatide for treating osteoporosis patients at high risk of fracture.

Dr Orwoll cautioned about starting the treatment based only on BMD “Clinicians should take into account more than BMD in judging risk and in guiding therapeutic decisions………….[That] is absolutely critical."

"Further, these guidelines are but one of several that exist, [and] clinicians must carefully examine the considerable differences among them," he added.

Full Text of the article in Annals of Internal Medicine can be accessed here.