Long-Term Drug Therapy and Drug Holidays for Osteoporosis Fracture Prevention: A Systematic Review

Abstract

Purpose of ReviewTo summarize the effects of long-term osteoporosis drug treatment and of osteoporosis drug treatment discontinuation and holidays. Key Messages• Evidence on the effects of long-term osteoporosis drug treatment and drug continuation versus discontinuation is mostly limited to white, healthy, postmenopausal women. • Long-term alendronate reduces radiographic vertebral and nonvertebral fractures in women with osteoporosis; long-term zoledronate reduces vertebral and nonvertebral fractures in women with osteopenia or osteoporosis. • Long-term bisphosphonates may increase atypical femoral fractures and osteonecrosis of the jaw, although both are rare. • In women with osteoporosis, long-term raloxifene reduces vertebral fractures, but not hip or nonvertebral fractures, and increases venous thromboembolism. • Long-term oral hormone therapies reduce hip and clinical fractures but increase multiple serious harms. • Evidence is insufficient about the effects of long-term denosumab, risedronate, ibandronate, teriparatide, and abaloparatide on fractures and harms. • Continuing bisphosphonates after 3-5 years versus discontinuation reduces some measures of vertebral fractures, but not nonvertebral fractures.

Duration of Bisphosphonate Drug Holidays in Osteoporosis Patients: A Narrative Review of the Evidence and Considerations for Decision-Making

“…Despite these real-world studies, knowledge gaps remain, as more nuanced depictions of drug holiday effects in diverse populations are critical. Specifically, no studies have examined the fracture effects of different lengths of a drug holiday by drug or patient characteristics, according to recent systematic reviews by Fink and Marchand [ 7 , 41 ]. Yet fracture risk over time during a drug holiday will likely change based on patient and therapy factors that affect duration of protective effects and baseline fracture risk [ 7 , 41 ].…”

“…Oral bisphosphonates are considered first-line therapy for the treatment of osteoporosis in many jurisdictions. Alendronate and risedronate are the most commonly used oral bisphosphonates, with robust evidence demonstrating their benefits on vertebral and nonvertebral fracture prevention in women and men with primary and glucocorticoid-induced osteoporosis (GIOP) [ 5 , 6 , 7 , 8 , 9 ]. Ibandronate is used less frequently as most meta-analyses show therapy has limited effects on hip fracture risk [ 10 , 11 ].…”

“…Another important consideration related to drug holidays is that very rare but serious adverse effects have been linked to prolonged bisphosphonate use [ 7 , 17 , 18 , 25 ]. Osteonecrosis of the jaw has mainly been documented after high bisphosphonate dosages (i.e., cancer indications), but atypical femoral fractures (AFF) have been linked to bisphosphonate treatment for osteoporosis [ 7 , 17 ].…”

“…Another important consideration related to drug holidays is that very rare but serious adverse effects have been linked to prolonged bisphosphonate use [ 7 , 17 , 18 , 25 ]. Osteonecrosis of the jaw has mainly been documented after high bisphosphonate dosages (i.e., cancer indications), but atypical femoral fractures (AFF) have been linked to bisphosphonate treatment for osteoporosis [ 7 , 17 ]. Rates of AFF appear to increase after three to five years of bisphosphonate therapy, with estimates ranging from an odds ratio of 2.7 for an AFF among those with more than five years of therapy compared to those with less than five years [ 25 ] to a relative risk of AFF 63.5 when comparing those with eight to ten years of therapy to those with less than one year [ 26 ].…”

“…Rates of AFF appear to increase after three to five years of bisphosphonate therapy, with estimates ranging from an odds ratio of 2.7 for an AFF among those with more than five years of therapy compared to those with less than five years [ 25 ] to a relative risk of AFF 63.5 when comparing those with eight to ten years of therapy to those with less than one year [ 26 ]. The variation in estimates is likely due to heterogenous study populations and outcome measurement [ 7 ]; true incidence of AFF in patients with and without bisphosphonate exposure is unclear. Other potential risk factors for AFF include Asian ethnicity, diabetes mellitus, rheumatoid arthritis, use of glucocorticoids and proton pump inhibitors, and osteopenia (versus osteoporosis) [ 17 , 27 , 28 ].…”