If you’ve recently been diagnosed with osteoporosis or osteopenia, chances are your doctor has mentioned bisphosphonates. Or perhaps you’ve just finished a course of EVENITY or Prolia, and your doctor is recommending a bisphosphonate as your next step.
Either way, you want to understand: is a bisphosphonate the right choice for me?
I’m not philosophically against pharmaceutical intervention, in many cases, it is the appropriate course for individuals at elevated risk of fracture. To help you have an informed conversation with your physician, this post sets out to provide a clear, current understanding of where bisphosphonates fit in your osteoporosis or osteopenia treatment plan.
The treatment landscape has changed significantly in recent years. Guidelines have been updated, new medications have entered the picture, and our understanding of treatment sequencing has evolved. This post reflects the latest evidence, including the 2023 American College of Physicians (ACP) guidelines and the American Association of Clinical Endocrinologists (AACE) recommendations.
Bisphosphonates Osteoporosis Guidelines
I am a Physiotherapist and I treat many patients with osteoporosis. My preferred modality is safe and effective osteoporosis physiotherapy treatment for the individual. However, most of my patients have taken or are prescribed an osteoporosis medication such as a bisphosphonate, Prolia or Forteo.
I am not philosophically against the use of pharmaceutical intervention. In many cases, it is the appropriate course for individuals who are at an elevated risk of fracture. However, I believe that all health care professionals who treat this population be familiar with these medications.
In this post, I will address several questions and topics related to bisphosphonate use:
- What Are Bisphosphonates
- Use of Bisphosphonates
- When to Stop Bisphosphonates • Bisphosphonate Drug Holiday
- Long Term Bisphosphonate Use
- Bisphosphonate Femur Fracture
- Alternatives to Bisphosphonates
What Are Bisphosphonates
Let’s start with a definition of bisphosphonates.
Bisphosphonates arrest the loss of bone density. They bind to the surface of bone and reduce the effects of bone loss caused by osteoclasts (cells that erode bone). Osteoblasts (cells that build bone) can be more effective when it comes to creating bone.
How do they work? An abstract on PubMed explains in more technical detail:
At the tissue level, they decrease the rate of bone resorption and turnover, increase bone mineral density, and maintain or improve structural and material properties of bone and thereby reduce the risk of fractures.
Popular brand name bisphosphonates include: Fosamax, Actonel, Boniva and Reclast and are also referred to as alendronate, risedronate, ibandronate and zoledronate.
Use of Bisphosphonates
The Endocrine Society issued its recommendations about bisphosphonate use in March of 2019. They recommend the following:
- We recommend initial treatment with bisphosphonates for postmenopausal women at high risk of fractures.
- Reassess fracture risk after 3 to 5 years of treatment. This applies to postmenopausal women with osteoporosis who are taking bisphosphonates. Women who remain at high risk of fractures should continue therapy, whereas those who are at low-to-moderate risk of fractures should be considered for a “bisphosphonate holiday.”
A bisphosphonate holiday is a temporary discontinuation of bisphosphonate for up to 5 years. This period may be longer depending on the bone mineral density and clinical circumstances of the individual patient.
These recommendations clearly indicate that individuals at a high risk of fracture start a bisphosphonate treatment program.
FDA Review
The US Federal Drug Administration initiated a review of the long term use of bisphosphonates and raised concerns associated with their use. They noticed an elevated risk of atypical femur fractures and esophageal cancer.
Why are people with low to moderate fracture risk prescribed an osteoporosis medication?
This question has become increasingly confusing and frustrating for people with low bone density. In a recent article in the New York Times on bisphosphonates even the physicians who are quoted disagree on appropriate bisphosphonate use.
FRAX Assessment
The World Health Organization has developed a tool called FRAX to assist individuals in determining their fracture risk. This is a good starting point and you should consult this tool to determine your fracture risk.
Pharmacist Kent MacLeod recommends that patients and their physicians use the online FRAX to determine fracture risk.
- In the US, bisphosphonates should be considered for an individual whose 10 hip year fracture risk is above 3% or their major fracture risk is above 20%.
- In Canada, bisphosphonates should be considered when an individual’s major fracture risk is above 20%. For individuals whose fracture risk is moderate (10 to 20%) pharmaceutical intervention may be considered dependent upon additional risk factors.
The decision has become more complicated now that studies are showing an increased risk of femoral shaft fractures for people who take bisphosphonates for an extended period of time.
In addition, the FDA recently announced an updated warning on kidney impairment associated with the use of Reclast.
Bisphosphonates or Prolia
In a recent interview I had with one of Canada’s leading Osteoporosis Specialists, Dr. Jonathan Adachi, I asked him why many physicians are switching patients from bisphosphonate treatment to Prolia.
He indicated that a physician should make the switch when “patients have side effects to the bisphosphonate, when there are declines in bone mineral density (BMD) or when patients sustain a fracture on bisphosphonates.”
When to Stop Bisphosphonates and Take a Drug Holiday
In 2013 the Journal Therapeutic Advances in Musculoskeletal Disease published a study (1) on bisphosphonate drug holiday. The study was by Diab and Watts, Bisphosphonate Drug Holiday.
The authors state that “it is difficult to find evidence to support the need for a drug holiday or to establish the effectiveness of treatment after restarting therapy.”
However, the authors do believe that “there is logic to support the following clinical scenarios.” The scenarios that Diab and Watts refer to in their bisphosphonate drug holiday study reflect the degree of risk of a fracture. Diab and Watts identify four risk levels and provide guidance for each risk level as it relates to the questions of when to stop bisphosphonates use.
Low Risk Fracture
Bisphosphonate treatment is not needed. Bisphosphonate treatment should be discontinued and not resumed until the patient meets treatment guidelines.
Mild Risk of Fracture
Use bisphosphonates for a 3 to 5 year period and then stop. The bisphosphonate drug holiday can continue until there has been a “significant loss” of bone mineral density.
Moderate Risk of Fracture
Use bisphosphonates for a 5 to 10 year period. At that point “offer a bisphosphonate drug holiday of 3 to 5 years or until there is significant loss of bone mineral density or the patient has a fracture, whichever comes first.”
High Risk of Fracture
Diab and Watts recommend “treat with bisphosphonate for 10 years, offer a ‘drug holiday’ of 1 to 2 years, until there is significant loss of bone mineral density or the patient has a fracture, whichever comes first.”
Long Term Bisphosphonate Use
What about long term bisphosphonate use and what about the possible implications?
On May 9, 2012 the U.S Food and Drug Administration (FDA) published an analysis on bisphosphonates longterm use in post-menopausal women.
According to the FDA, while bisphosphonate therapy has demonstrated “efficacy in preventing fractures in registration trials lasting 3 to 4 years … data on safety have raised concern regarding the optimal duration of use for achieving and maintaining protection against fractures”.
These safety concerns include increased risk of femoral shaft fractures, esophageal cancer and osteonecrosis of the jaw.
Long Term Bisphosphonate Use • Findings and Recommendation
The findings of this analysis were presented to a joint meeting of two FDA committees. The committees jointly decided that the data from the analysis “did not support a regulatory restriction on the duration of drug use”.
However, the joint committees did recommend that the labeling on bisphosphonate drugs be updated. Bisphophonate drugs now contain an “Important Limitation of Use” definition that states:
The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.
What is the FDA Saying?
This recommendation can appear to fall short in terms of specifics. The recommendations probably reflect the fact that the study data reviewed by the FDA was, at times, inconsistent and incomplete.
In addition, the behaviour of bisphosphonate is quite complex and can vary from person to person and from brand to brand. Since bisphosphonates are absorbed into the bone during the treatment phase, they can persist for years – even after cessation of treatment. Further, there have been no long terms studies of the effects of bisphosphonates after cessation.
Basically, the FDA researchers state that more work and study has to be done. Individuals should consult, on a regular basis, with their health provider on what is right for them.
This regular evaluation should include an individual assessment of the risks and benefits of bisphosphonate therapy and patient preference. A good source for your health provider to use in evaluating your fracture risk is the online FRAX tool developed by the World Health Organization and the International Osteoporosis Foundation.
Clearly, the FDA and researchers are grappling with this complex issue.
Bisphosphonates Osteoporosis Guidelines • FDA
The New England Journal of Medicine published another article to accompany the FDA review. This article was written by a group of physicians at a number of medical institutes across the United States.
In the article, the physicians review the data and shed more light on the results. They state the following:
- Vertebral Fractures (i.e., fractures of the spine): Although evidence is limited regarding the risk of fracture with the continuation of bisphosphonate therapy beyond 3 to 5 years, data from randomized controlled trials generally suggest that the risk of vertebral fracture is reduced.
- Nonvertebral Fractures (i.e., fractures of the wrist, ribs, hip, etc): The consistent evidence of a statistically significant reduction in nonvertebral fractures with the continuation of bisphosphonates is lacking.
Further, this team provides guidance regarding continued use of bisphosphonates. The caveat is that these recommendations could change as more research is published.
- Patients with low bone mineral density at the femoral neck (T score below −2.5) after 3 to 5 years of treatment are at the highest risk for vertebral fractures and therefore appear to benefit most from continuation of bisphosphonates.
- Patients with an existing vertebral fracture who have a somewhat higher (although not higher than −2.0) T score for bone mineral density may also benefit from continued therapy.
- Patients with a femoral neck T score above −2.0 have a low risk of vertebral fracture and are unlikely to benefit from continued treatment.
As you can see, these physicians recommend that patients with osteoporosis and a high fracture risk should continue bisphosphonate therapy. Those with low or moderate risk of fracture will probably not see material benefit from continued use of this therapy.
Long Term Bisphosphonate Use • Recommendation
Since each individual’s medical profile is unique, I strongly encourage you to discuss this issue with your physician. Hopefully, articles like this one make you a more informed patient.
As a general rule, if you are at a high risk of fracture, continued use of bisphosphonates is probably the prudent path.
If you are at low or moderate risk of fracture, you need to weigh the risks associated with long term use of this drug (as defined earlier in this article). Research is showing that there is no evidence that bisphoshonates cause a significant reduction in nonvertebral fractures.
A well designed osteoporosis exercise program is something that everyone should be following.
Conclusion
Expect to hear more about this debate in the coming years as researchers spend more resources examining the long term effects of this drug. Clearly, people within the FDA and researchers in the field have concerns with the continued long term use of this drug and its effectiveness when it comes to reducing fracture risk. The problem today is that there is not enough data to provide definitive guidance or change the FDA’s regulatory position with regard to this drug.
Margaret Martin
Further Readings
References
- Diab, Dima and Watts, Nelson, Bisphosphonate Drug Holiday, Therapeutic Advances in Musculoskeletal Disease, 2013 Jun.
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