Quantitative prediction of bone mineral density by using bone turnover markers in response to antiresorptive agents in postmenopausal osteoporosis: A model‐based meta‐analysis

Abstract

Aims This study aimed to predict time course of bone mineral density (BMD) by using corresponding response of bone turnover markers (BTMs) in women with postmenopausal osteoporosis under antiresorptive treatments. Methods Data were extracted from literature searches in accessible public database. Time courses of percent change from baseline in serum C‐telopeptide of type 1 collagen (sCTX) and N‐telopeptide of type 1 collagen were described by complex exponential onset models. The relationship between BTM changes and BMD changes at lumbar spine and total hip was described using a multiscale indirect response model. Results The dataset included 41 eligible published trials of 5 US‐approved antiresorptive agents (alendronate, ibandronate, risedronate, zoledronic acid and denosumab), containing over 28 800 women with postmenopausal osteoporosis. The time courses of BTM changes for different drugs were differentiated by maximal effect and onset rate in developed model, while sCTX responses to zoledronic acid and denosumab were captured by another model formation. Furthermore, asynchronous relationship between BTMs and BMD was described by a bone remodelling‐based semimechanistic model, including zero‐order production and first‐order elimination induced by N‐telopeptide of type 1 collagen and sCTX, separately. After external and informative validations, the developed models were able to predict BMD increase using 1‐year data. Conclusion This exploratory analysis built a quantitative framework linking BTMs and BMD among antiresorptive agents, as well as a modelling approach to enhance comprehension of dynamic relationship between early and later endpoints among agents in a certain mechanism of action. Moreover, the developed models can offer predictions of BMD from BTMs supporting early drug development.

Resveratrol‐Induced Suppression of C‐type Natriuretic Peptide Associates With Increased Vertebral Bone Density in Postmenopausal Women

“…( 19 ) The reduction in plasma NTproCNP (median 1.4 pmol/L), expressed as percentage of values at 12 months (18 pmol/L, 8%), is not trivial, bearing in mind the multiple tissues potentially contributing to levels in plasma. ( 1 ) Notably, the increase in lumbar spine BMD (mean 4.7%) after resveratrol is similar to that found in meta‐analyses (4% to 5%) of the impact of 1 year of treatment with bisphosphonates, ( 23 ) which was associated with 50% to 70% fall in markers of both bone resorption (CTX) and formation (PINP). In the current randomized controlled trial (RCT) using within‐subject changes over 2 years, there was an associated 7% to 8% decrease in NTproCNP, no change in CTX, and a 4.8% increase in ALP.…”

TC and LDL-C are negatively correlated with bone mineral density in patients with osteoporosis

“…In contrast, bone turnover markers (BTMs) exhibit rapid responsiveness to physiological changes of bone and offer superior accuracy in reflecting alterations in bone cell metabolism. They serve as reliable predictors of bone loss and fracture risk, and contribute significantly to the diagnosis of osteoporosis [25,26]. Therefore, combining BMD and BTMs [27] to evaluate bone status by integrating the advantages of both is a promising method for predicting the risk of osteoporosis and fractures.…”

Optimization of the dosage regimen of zoledronic acid with a kinetic-pharmacodynamic model and exposure-response analysis

“…Therefore, quantitative pharmacological methods for dose optimization have become the most ideal and efficient methods. Although a dose-bone turnover markers (BTMs) - bone mineral density (BMD) model has been established after a single dose ( Pillai et al, 2004 ; Mori et al, 2018 ; Wu et al, 2021 ), the tolerance model has not been integrated, there is an error in predicting multiple doses, and dose optimization has not been performed in combination with APR. In addition, the existing models all use one or two BTMs to drive BMD to evaluate the change in BMD.…”