Raimann, J. G. | Search bioRxiv

bioRxiv2021

Modeling osteoporosis to design and optimize pharmacologic therapies comprising multiple drug types

For the treatment of postmenopausal osteoporosis, several drug classes with different mechanisms of action are available. Since only a limited set of dosing regimens and drug combinations can be tested in clinical trials, it is currently unclear whether common medication strategies achieve optimal bone mineral density gains or are outperformed by alternative dosing schemes and combination therapies that have not been explored so far. Here we develop a mathematical framework of drug interventions for postmenopausal osteoporosis that unifies fundamental mechanisms of bone remodeling and the mechanisms of action of four drug classes: bisphosphonates, parathyroid hormone (PTH) analogs, sclerostin inhibitors and receptor activator of NF-{kappa}B ligand (RANKL) inhibitors. Using data from several clinical trials, we calibrate and validate the model, demonstrating its predictive capacity for complex medication scenarios including sequential and parallel drug combinations. Via simulations, we reveal that there is a large potential to improve gains in bone mineral density by exploiting synergistic interactions between different drug classes, without increasing the total amount of drug administered.

pharmacology and toxicology↗

bioRxiv2017

Meta-analysis and Commentary: Preemptive Correction of Arteriovenous Access Stenosis

BackgroundA recent meta-analysis by Ravani and colleagues (Ravani, P., et al., Am J Kidney Dis, 2016. 67(3): p. 446-60.) studied the effect of pre-emptive correction of arterio-venous dialysis vascular access versus deferred care, based on data from 11 trials. The authors reported a non-significant protective treatment effect of pre-emptive correction on access loss, while showing a significant protective effect on thrombosis rates conferred by pre-emptive correction. We revisit this analysis, including data extraction and effects of a heterogenous study population.\n\nMethodsWe repeated data extraction from all referenced publications in the meta-analysis by Ravani et al. and corrected event counts where applicable. We repeated the meta-analyses with access loss as the outcome for studies that recruited patients with arterio-venous fistulae (AVF) and grafts (AVG), respectively, using a random effects model with relative risk (RR) and risk difference (RD) of access loss as the outcomes of interest. We repeated data extraction from all referenced publications, and corrected event counts where applicable.\n\nResultsOur conclusions differ from the original findings in two ways. First, after some amendment of the event counts extracted from Mayer et al. (Vascular and Endovascular Surgery 1993), we find a significant overall positive effect of pre-emptive correction on arterio-venous access loss in the overall study population [RR 0.80 (95% CI 0.64 to 0.99), RD -0.07 (95% CI -0.12 to -0.02); Figure 1]. Secondly, we highlight the impact of heterogeneous study populations on the meta-analysis. Whereas the data do not conclusively show a benefit of pre-emptive correction for arteriovenous grafts (AVG; RR = 0.87, 95% CI: 0.69 - 1.11), they show a strong protective effect for arteriovenous fistulae (AVF; RR = 0.5, 95% CI: 0.29 to 0.86).\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC=\"FIGDIR/small/179580_fig1.gif\" ALT=\"Figure 1\">\nView larger version (41K):\norg.highwire.dtl.DTLVardef@af3c13org.highwire.dtl.DTLVardef@911a50org.highwire.dtl.DTLVardef@568cf1org.highwire.dtl.DTLVardef@3f3c08_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:C_FLOATNO Meta-analysis of access loss, overall and by access type using risk ratio (RR) as the measure of association.\n\nC_FIG\n\nDiscussion and ConclusionThese findings corroborate clinical arguments such as superior long-term patency of AVF and the nature of AVG failure that often involve infectious causes. The available data indicate mild or no benefit of pre-emptive correction for AVG, but strongly support tight monitoring of dialysis accesses and preemptive intervention and correction upon the slightest suspicion of access stenosis for AVF.

epidemiology↗