Bone Mineral Density and Bone Turnover 10 Years After a Single 5 mg Dose or Two 5-Yearly Lower Doses of Zoledronate in Osteopenic Older Women: An Open-Label Extension of a Randomized Controlled Trial

Abstract

Intravenous zoledronate reduces fracture risk (5 mg at 18-month intervals) and prevents bone loss (doses of 1 to 5 mg for 3 to >5 years), but the duration of action of a single 5 mg dose and the effects of lower doses beyond 5 years are unknown. We report the second open-label extension (years 5 to 10) of a 2-year randomized, multidose, placebo-controlled, double-blinded trial. A total of 116 older women who completed 5 years of participation either continued observation without further treatment (zoledronate 5 mg and placebo at baseline) or received repeat doses of 1 or 2.5 mg zoledronate (zoledronate 1 mg and zoledronate 2.5 mg at baseline, respectively). Outcomes were spine, hip, and total body bone mineral density (BMD) and serum markers of bone turnover. After a single 5 mg dose of zoledronate, mean BMD at the lumbar spine and total hip was maintained at or above baseline levels for 9 and 10 years, respectively. The mean level of the bone resorption marker β-C-terminal telopeptide of type I collagen (β-CTX) was at least 25% lower than that in the placebo group for 9 years. In women administered 5-yearly doses of 2.5 mg zoledronate, mean BMD at the total hip and lumbar spine was maintained at or above baseline levels for 9 and 10 years, respectively. Redosing with 1 or 2.5 mg zoledronate at 5 years reduced bone turnover markers for 3 to 4 years. BMD increased for 3 to 4 years after redosing with 1 mg zoledronate. In the group given 5-yearly 2.5 mg zoledronate, β-CTX was at least 20% lower than that in the placebo group for 10 years. Both a single baseline 5 mg dose of zoledronate and 5-yearly doses of 1 and 2.5 mg zoledronate prevented bone loss at hip and spine for 8 to 10 years in older postmenopausal women. Clinical trials to evaluate the effects on fracture risk of these very infrequent and lower doses of zoledronate are justified.

EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: Osteoporosis management

“…This suggestion of prolonged activity of zoledronate was mirrored in in vitro data documenting its high potency and its very high affinity for bone mineral (50). As a result, Andrew Grey undertook trials to determine the duration of effect of a single infusion of zoledronate 5 mg on BMD and bone turnover, finding residual beneficial effects even a decade later (51). Lower doses of zoledronate (1 and 2.5 mg) were found to have similar BMD effects initially, but the longevity of effects was dose-related (52).…”

“…However, we now know that at least comparable anti-fracture efficacy can be achieved with dosing every 18 months over 6 years (31), so it seems more sensible to adopt this cheaper and more convenient regime with proven efficacy beyond year 3. After year 6, even less frequent dosing is reasonable, since this can maintain suppression of resorption markers and the increases in BMD (51,85).…”

Bisphosphonates Preserve Bone Mineral Density and Suppress Bone Turnover Markers in Early Menopausal Women: A Systematic Review and Meta‐Analysis of Randomized Trials

“…(12)(13)(14)(15) This management paradigm is reactive and not always aligned with patient preferences: many women wish to take a proactive approach, initiating pharmacologic therapy before experiencing a fracture or reaching a high-risk status. (16) Given the long skeletal half-life of nitrogen-containing bisphosphonates, (17)(18)(19) there has been recent interest in preventative treatment with either intermittent short courses of oral bisphosphonates or infrequently dosed intravenous zoledronate, (20) beginning at the time of menopause. Modeling analyses indicate that a preventative strategy in which zoledronate is administered every 5 years, starting at age 50 years, could substantially reduce the future burden of osteoporosis and fragility fracture, but empirical data are lacking.…”

Bisphosphonate Drug Holidays: Evidence From Clinical Trials and Real‐World Studies

“…( 7 , 12 ) The skeletal halflife of BP may be prolonged, in some cases beyond a decade, and relates to baseline degrees of bone turnover, BP‐specific binding affinity, and duration of use. ( 13 , 14 ) On the other hand, denosumab, a fully human monoclonal antibody, exerts reversible effects on receptor activator of NF‐κB ligand (RANKL) inhibition with transient inhibition of osteoclast‐mediated bone resorption and risk of vertebral fractures with discontinuation. ( 15 , 16 , 17 ) Reversible effects are also seen with osteoanabolic agents, including the sclerostin inhibitor romosozumab and parathyroid hormone analogues such as teriparatide, which promote the transient recruitment of osteoblasts with new bone matrix formation.…”