Zoledronic Acid Is Not Equally Potent on Osteoclasts Generated From Different Individuals

Abstract

Zoledronic acid is a bisphosphonate commonly used to treat bone diseases such as osteoporosis and cancer-induced bone disease. Patients exhibit a variable sensitivity to zoledronic acid; the underlying explanation for this remains unclear. The objective of this study was to obtain more knowledge in this regard. We hypothesized that osteoclasts generated from different individuals would show a variable sensitivity to zoledronic acid in vitro. Osteoclasts were generated using monocytes from 46 healthy female blood donors (40 to 66 years). Matured osteoclasts were reseeded onto bone slices precoated with different concentrations of zoledronic acid. IC50 values were determined based on total eroded bone surface after 3 days of resorption. The IC50 for inhibition of osteoclastic bone resorption varied from 0.06 to 12.57μM zoledronic acid; thus, a more than 200-fold difference in sensitivity to zoledronic acid among osteoclasts from different individuals was observed. Multiple linear regression analyses showed that the determined IC50 correlated with smoking status, and the average number of nuclei per osteoclast in vitro. Further analyses showed that: (i) increasing protein levels of mature cathepsin K in osteoclast cultures rendered the osteoclasts less sensitive to zoledronic acid; (ii) surprisingly, neither the gene nor the protein expression of farnesyl diphosphate synthase was found to correlate with the IC50; and (iii) trench-forming osteoclasts were found to be more sensitive to zoledronic acid than pit-forming osteoclasts within the same cell culture. Thus, we conclude that there indeed is a high degree of variation in the potency of zoledronic acid on osteoclasts when generated from different individuals. We propose that our findings can explain some of the varying clinical efficacy of zoledronic acid therapy observed in patients, and may therefore be of clinical importance, which should be investigated in a clinical trial combining in vitro and in vivo investigations.

Alendronate Use and Risk of Type 2 Diabetes: A Nationwide Danish Nested Case-Control Study

“…Smoking is a risk factor for type 2 diabetes but as are obesity, alcohol and pancreatitis of which the ORs did not change after sensitivity analyses. It may be that smoking impacts on alendronates mechanism of action, as has been addressed recently (39), although this warrants further research.…”

Zoledronic Acid for Periprosthetic Bone Mineral Density Changes in Patients With Osteoporosis After Hip Arthroplasty—An Updated Meta-Analysis of Six Randomized Controlled Trials

“…Nevertheless, it needed to be noted that ZA may not be effective in all patients with osteoporosis. Moller et al ( 32 ) have reported that patients exhibit a variable sensitivity to ZA. Therefore, the alternative bisphosphonates and sequential therapy should be considered when necessary ( 33 ).…”

The Mechanism Switching the Osteoclast From Short to Long Duration Bone Resorption

“…Common experience is that osteoclasts seeded on bone slices (obtained by sawing and therefore exposing mineralized bone Søe et al, 2013;Merrild et al, 2015;Panwar et al, 2016Panwar et al, , 2017Borggaard et al, 2020 • Decreased by bisphosphonates Møller et al, 2020a • Appears to favor coupling with bone formation Delaisse et al, 2020 See section 1 for the definition of pit and trench modes. *Note that in a typical in vitro experiment, (performed with osteoclasts generated from CD14-positive monocytes from blood donors) 90% of the trench formation events start as a pit which is thereafter enlarged laterally, whereas half of the resorption events do not go beyond the formation of a pit (Søe and Delaissé, 2017).…”

“…More trenches were also produced by osteoclasts generated from males compared to females ( Merrild et al, 2015 ). In contrast, pharmacological agents like bisphosphonates decrease the prevalence of trenches ( Møller et al, 2020a ) and cathepsin K inhibitors completely abrogate them ( Søe et al, 2013 ; Merrild et al, 2015 ; Panwar et al, 2016 , 2017 ; Borggaard et al, 2020 ). Furthermore, pit and trenches appear to differently affect bone strength ( Vanderoost et al, 2013 ).…”

“…Glucocorticoids were reported to increase both cathepsin K levels ( Swanson et al, 2006 ) and trench formation ( Søe and Delaissé, 2010 ). Interestingly, the number of nuclei per osteoclast (supporting protein-synthesis power) is another characteristic that shows variability amongst donors ( Møller et al, 2020b ) and that positively correlates with cathepsin K levels ( Møller et al, 2020a ) and prevalence of trenches ( Møller et al, 2020c ). Overall, one may conclude that the differences in active cathepsin K levels amongst individuals will affect the duration of the resorption events and the size of the resorption cavities.…”