What are the expected benefits and potential harms of bisphosphonates for the treatment of osteoporosis?

This summary is based on the article published in the Canadian Family Physician journal: Bisphosphonates for treatment of osteoporosis. Expected benefits, potential harms, and drug holidays. A Clinical review. (April 2014)

Jacques P. Brown MD; Suzanne Morin MD MSc; William Leslie MD; Alexandra Papaioannou MD; Angela M. Cheung MD PhD; Kenneth S. Davison PhD; David Goltzman MD; David Arthur Hanley MD; Anthony Hodsman MD; Robert Josse MD; Algis Jovaisas MD; Angela Juby MD; Stephanie Kaiser MD; Andrew Karaplis MD; David Kendler MD; Aliya Khan MD; Daniel Ngui MD; Wojciech Olszynski MD PhD; Louis-Georges Ste-Marie MD; and Jonathan Adachi MD

Context 

• Osteoporotic fractures decrease personal independence, ² increase morbidity, ^3-5 and shorten life ^6,7; thus, their prevention is paramount.
• Aminobisphosphonates (alendronate, risedronate, and zoledronic acid) are first-line therapies for the prevention of fracture in high-risk individuals.⁸
• Aminobisphosphonates might also increase survival in ways at least partially independent of their contribution to decrease in fracture incidence. ^9-11
• While the antifracture efficacy and relative safety of the aminobisphosphonates have been well established in clinical trials, ^12-16 there have been concerns that prolonged use of these drugs might increase the risk of rare, but serious, adverse events. ^17-21

Purpose of the Review

To outline the efficacy and risks of bisphosphonate therapy for the management of osteoporosis and describe which patients might be eligible for bisphosphonate “drug holiday.”

Key Findings

• When bisphosphonates are prescribed to patients at high risk of fracture, their antifracture benefits considerably outweigh their potential for harm. For patients taking bisphosphonates for 3 to 5 years, there is a need to reassess the necessity of ongoing therapy.

Unique characteristics of aminobisphosphonates

• Bisphosphonates, potent inhibitors of osteoclast-mediated bone remodeling, bind to bone and have prolonged residence in the skeleton. Bisphosphonates can remain bound to bone for many years. Consequently, after bisphosphonate discontinuation, bound bisphosphonate provides residual pharmacologic action for many years. ^23,24

Safety of long-term bisphosphonate use

• As osteoporosis is a chronic disease, antifracture therapy could conceivably continue for the rest of a patient’s life. Unfortunately, there are few data to guide use of any osteoporosis therapy for more than 3 to 5 years.

Osteonecrosis of the jaw

• At the present time, evidence suggests that there is a dose-response relationship between bisphosphonate use and the development of ONJ. ³¹
• While the current consensus accepts a causal relationship between bisphosphonate exposure and ONJ, the pathologic mechanism or mechanisms have yet to be elucidated.
• It is suggested that patients should complete any invasive dental procedures before initiating bisphosphonates […]; however, those taking bisphosphonates should not delay emergency dental procedures or dental implants.
• Factors associated with the development of ONJ include poor oral hygiene and administration of high-dose antiresorptive treatment in oncology patients.

Atypical subtrochanteric and diaphyseal femur fracture

• Little is known about the factors associated with the development of atypical femur fractures (AFFs). Concern has arisen that long-term bisphosphonate use might increase the risk of these fractures through a number of putative mechanisms. ^31,36,51
• Long-term clinical trial data (10 years for alendronate, ^52-54 7 years for risedronate, ⁵⁵ 6 years for zoledronic acid ⁵⁶) have not demonstrated an increase in AFF incidence with prolonged bisphosphonate exposure, but such studies are too small to detect rare events.
• For high- and moderate-risk individuals, the risk of an AFF is greatly overshadowed by the antifracture benefit gained from bisphosphonate therapy; the lifetime risk of hip fracture is 1 fracture in 8 Canadian women, ⁷⁴ and aminobisphosphonate therapy in high-risk individuals decreases this risk by 20% to 50% over 3 years of therapy. ⁷⁵

Atrial fibrillation

• The first trial to suggest an association between AF and bisphosphonate use was the pivotal 3-year phase 3 trial for zoledronic acid in which there was an increased risk of AF requiring hospitalization in patients provided zoledronic acid compared with placebo recipients (1.3% vs 0.5%, P < .001).¹⁴
• However, recent large database analyses79-81 and a meta-analysis82 have concluded that there is no association between the use of bisphosphonates and the incidence of AF, with 1 study even suggesting a protective effect. ⁸³
• Therefore, at this time, the weight of the evidence would suggest no association between bisphosphonate use and AF. ⁸⁴

Esophageal cancer

• At this time, there is no consistent indication of elevated risk of esophageal cancer with oral bisphosphonate use, but more data are needed.

Renal function and bisphosphonates

• In patients with poor renal function (estimated glomerular filtration rate of less than 35 mL/min), bisphosphonates are contraindicated.

Bisphosphonate drug holiday

• With increased safety concerns surrounding the long-term use of bisphosphonates, ^30,36,85 questions have arisen regarding the applicability of “drug holidays” to minimize long-term bisphosphonate exposure and avoid potential adverse events while maintaining some degree of antifracture efficacy through the residual antiresorptive activity of retained bisphosphonate.
• The 2010 Osteoporosis Canada guidelines state that “Individuals at high risk for fracture should continue osteoporosis therapy without a drug holiday [grade D].”⁸
• However, since these guidelines were published, additional data have become available to further guide our decision making. The US Food and Drug Administration has recently published guidance in this regard. ⁹⁰

References

List of references (PDF)