Osteoporosis is a progressive bone disease characterized by decreased bone mass resulting in increased fracture risk. The objective of this investigation was to test whether a recently developed dise...
Ten‐Year Simulation of the Effects of Denosumab on Bone Remodeling in Human Biopsies
ABSTRACT Postmenopausal osteoporosis is a disease manifesting in degradation of bone mass and microarchitecture, leading to weakening and increased risk of fracture. Clinical trials are an essential tool for evaluating new treatments and may provide further mechanistic understanding of their effects in vivo. However, the histomorphometry from clinical trials is limited to 2D images and reflects single time points. Biochemical markers of bone turnover give global insight into a drug's action, but not the local dynamics of the bone remodeling process and the cells involved. Additionally, comparative trials necessitate separate treatment groups, meaning only aggregated measures can be compared. In this study, in silico modeling based on histomorphometry and pharmacokinetic data was used to assess the effects of treatment versus control on μCT scans of the same biopsy samples over time, matching the changes in bone volume fraction observed in biopsies from denosumab and placebo groups through year 10 of the FREEDOM Extension trial. In the simulation, treatment decreased osteoclast number, which led to a modest increase in trabecular thickness and osteocyte stress shielding. Long‐term bone turnover suppression led to increased RANKL production, followed by a small increase in osteoclast number at the end of the 6‐month–dosing interval, especially at the end of the Extension study. Lack of treatment led to a significant loss of bone mass and structure. The study's results show how in silico models can generate predictions of denosumab cellular action over a 10‐year period, matching static and dynamic morphometric measures assessed in clinical biopsies. The use of in silico models with clinical trial data can be a method to gain further insight into fundamental bone biology and how treatments can perturb this. With rigorous validation, such models could be used for informing the design of clinical trials, such that the number of participants could be reduced to a minimum to show efficacy. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Predicting Nonlinear Changes in Bone Mineral Density Over Time Using a Multiscale Systems Pharmacology Model
A mathematical model component that extends an existing physiologically based multiscale systems pharmacology model (MSPM) of calcium and bone homeostasis was developed, enabling prediction of nonlinear changes in lumbar spine bone mineral density (LSBMD). Data for denosumab, a monoclonal antibody osteoporosis treatment, dosed at several levels and regimens, was used for fitting the BMD component. Bone marker and LSBMD data extracted from the literature described on/off‐treatment effects of denosumab over 48 months [Miller, P.D. et al . Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long‐term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43, 222–229 (2008)]. An indirect model linking bone markers to LSBMD was embedded in the existing MSPM, reasonably predicting nonlinear increases in LSBMD during treatment (24 months); LSBMD declines following discontinuation and increases upon treatment reinstitution. This study demonstrates the utility of MSPM extension to describe a phenomena of interest not originally in a model, and the ability of this updated MSPM to predict nonlinear longitudinal changes in the clinically relevant endpoint, LSBMD, with denosumab treatment. CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e14; doi: 10.1038/psp.2012.15 ; advance online publication 14 November 2012
Disease Systems Analysis of Bone Mineral Density and Bone Turnover Markers in Response to Alendronate, Placebo, and Washout in Postmenopausal Women
A previously established mechanism‐based disease systems model for osteoporosis that is based on a mathematically reduced version of a model describing the interactions between osteoclast (bone removing) and osteoblast (bone forming) cells in bone remodeling has been applied to clinical data from women ( n = 1,379) receiving different doses and treatment regimens of alendronate, placebo, and washout. The changes in the biomarkers, plasma bone‐specific alkaline phosphatase activity (BSAP), urinary N‐telopeptide (NTX), lumbar spine bone mineral density (BMD), and total hip BMD, were linked to the underlying mechanistic core of the model. The final model gave an accurate description of all four biomarkers for the different treatments. Simulations were used to visualize the dynamics of the underlying network and the natural disease progression upon alendronate treatment and discontinuation. These results complement the previous applications of this mechanism‐based disease systems model to data from various treatments for osteoporosis.
Application of a mechanism-based disease systems model for osteoporosis to clinical data
A recently proposed mechanism-based disease systems model for osteoporosis (Schmidt et al., J Pharmacokinet Pharmacodyn 38:873–900, 2011) was applied to clinical data from post-menopausal women (n = 767) receiving various doses of the selective estrogen receptor modulator tibolone. Plasma bone-specific alkaline phosphatase activity and urinary N-telopeptide were used as biomarkers reflecting the activity of osteoblasts (bone forming cells) and osteoclasts (bone removing cells), respectively. These data were analyzed in conjunction with data on osteocalcin and on bone mineral density (BMD) (both lumbar spine and total hip), which reflect the activity of both cell types. While the dynamics of bone turnover markers changes rapidly, closely following changes in the activity of bone cells, changes in BMD are slower and have their own dynamics. Application of the mechanism-based disease systems model to the clinical data allowed for an adequate description of the data and yielded parameter estimates that are consistent with physiological values reported in the literature (Lemaire et al., J Theor Biol 229:293–309, 2004). The fitted model enabled characterization of (i) the critical time scales involved in disease progression, (ii) the dynamics of the system during onset and offset of the therapeutic intervention, and (iii) the distinction between responders and low-responders to tibolone treatment.
Estrogen therapy for osteoporosis in the modern era
Menopause predisposes women to osteoporosis due to declining estrogen levels. This results in a decrease in bone mineral density (BMD) and an increase in fractures. Osteoporotic fractures lead to substantial morbidity and mortality, and are considered one of the largest public health priorities by the World Health Organization (WHO). It is therefore essential for menopausal women to receive appropriate guidance for the prevention and management of osteoporosis. The Women’s Health Initiative (WHI) randomized controlled trial first proved hormonal therapy (HT) reduces the incidence of all osteoporosis-related fractures in postmenopausal women. However, the study concluded that the adverse effects outweighed the potential benefits on bone, leading to a significant decrease in HT use for menopausal symptoms. Additionally, HT was not used as first-line therapy for osteoporosis and fractures. Subsequent studies have challenged these initial conclusions and have shown significant efficacy of HT in various doses, durations, regimens, and routes of administration. These studies support that HT improves BMD and reduces fracture risk in women with and without osteoporosis. Furthermore, the studies suggest that low-dose and transdermal HT are less likely associated with the adverse effects of breast cancer, endometrial hyperplasia, coronary artery disease (CAD), and venous thromboembolism (VTE) previously observed in standard-dose oral HT regimens. Given the need for estrogen in menopausal women and evidence supporting the cost effectiveness, safety, and efficacy of HT, we propose that HT should be considered for the primary prevention and treatment of osteoporosis in appropriate candidates. HT should be individualized and the once “lowest dose for shortest period of time” concept should no longer be used. This review will focus on the prior and current studies for various HT formulations used for the prevention and treatment of osteoporosis, exploring the safety profile of low-dose and transdermal HT that have been shown to be safer than oral standard-dose HT.
Postmenopausal osteoporosis
Osteoporosis is a metabolic bone disorder that is characterized by low bone mass and micro-architectural deterioration of bone tissue. Fractures of the proximal femur, the vertebrae and the distal radius are the most frequent osteoporotic fractures, although most fractures in the elderly are probably at least partly related to bone fragility. The incidence of fractures varies greatly by country, but on average up to 50% of women >50 years of age are at risk of fractures. Fractures severely affect the quality of life of an individual and are becoming a major public health problem owing to the ageing population. Postmenopausal osteoporosis, resulting from oestrogen deficiency, is the most common type of osteoporosis. Oestrogen deficiency results in an increase in bone turnover owing to effects on all types of bone cells. The imbalance in bone formation and resorption has effects on trabecular bone (loss of connectivity) and cortical bone (cortical thinning and porosity). Osteoporosis is diagnosed using bone density measurements of the lumbar spine and proximal femur. Preventive strategies to improve bone health include diet, exercise and abstaining from smoking. Fractures may be prevented by reducing falls in high-risk populations. Several drugs are licensed to reduce fracture risk by slowing down bone resorption (such as bisphosphonates and denosumab) or by stimulating bone formation (such as teriparatide). Improved understanding of the cellular basis for osteoporosis has resulted in new drugs targeted to key pathways, which are under development.
Modeling osteoporosis to design and optimize pharmacological 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 analogs, sclerostin inhibitors, and receptor activator of NF-κB ligand 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.
Integrative modeling of drug therapy and the bone turnover
Denosumab has been successfully used for the postmenopausal osteoporosis treatment. This research is focused on the computational analysis of the effect of denosumab on bone remodeling.
Study of the combined effects of PTH treatment and mechanical loading in postmenopausal osteoporosis using a new mechanistic PK-PD model
One of only a few approved and available anabolic treatments for severe osteoporosis is daily injections of PTH (1-34). This drug has a specific dual action which can act either anabolically or catabolically depending on the type of administration, i.e. intermittent or continuous, respectively. In this paper, we present a mechanistic pharmacokinetic–pharmacodynamic model of the action of PTH in postmenopausal osteoporosis. This model accounts for anabolic and catabolic activities in bone remodelling under intermittent and continuous administration of PTH. The model predicts evolution of common bone biomarkers and bone volume fraction (BV/TV) over time. We compared the relative changes in BV/TV resulting from a daily injection of 20 $$\upmu$$g of PTH with experimental data from the literature. Simulation results indicate a site-specific bone gain of 8.66$$\%$$(9.4 ± 1.13$$\%$$) at the lumbar spine and 3.14$$\%$$(2.82 ± 0.72$$\%$$) at the femoral neck. Bone gain depends nonlinearly on the administered dose, being, respectively, 0.68$$\%$$, 3.4$$\%$$and 6.16$$\%$$for a 10, 20 and 40 $$\upmu$$g PTH dose at the FN over 2 years. Simulations were performed also taking into account a bone mechanical disuse to reproduce elderly frail subjects. The results show that mechanical disuse ablates the effects of PTH and leads to a 1.08% reduction of bone gain at the FN over a 2-year treatment period for the 20 $$\upmu$$g of PTH. The developed model can simulate a range of pathological conditions and treatments in bones including different PTH doses, different mechanical loading environments and combinations. Consequently, the model can be used for testing and generating hypotheses related to synergistic action between PTH treatment and physical activity.
Pharmacometrics and systems pharmacology for metabolic bone diseases
Mathematical modelling and simulation (M&S) of drug concentrations, pharmacologic effects and the (patho)physiologic systems within which they interact can be powerful tools for the preclinical, translational and clinical development of drugs. Indeed, the Prescription Drug User Fee Act (PDUFA VI), incorporated as part of the FDA Reauthorization Act of 2017 (FDARA), highlights the goal of advancing model‐informed drug development (MIDD). MIDD can benefit development across many drug classes, including for metabolic bone diseases such as osteoporosis, cancer‐related and numerous rare metabolic bone diseases; conditions characterized by significant morbidity and mortality. A drought looms in terms of the availability of new drugs to better treat these devastating diseases. This review provides an overview of several M&S approaches ranging from simple pharmacokinetic to integrated pharmacometric and systems pharmacology modelling. Examples are included to illustrate the use of these approaches during the development of several drugs for metabolic bone diseases such as bisphosphonates, denosumab, teriparatide and sclerostin inhibitors (romosozumab and blosozumab).
Coping with time scales in disease systems analysis: application to bone remodeling
In this study we demonstrate the added value of mathematical model reduction for characterizing complex dynamic systems using bone remodeling as an example. We show that for the given parameter values, the mechanistic RANK-RANKL-OPG pathway model proposed by Lemaire et al. (J Theor Biol 229:293–309, 2004) can be reduced to a simpler model, which can describe the dynamics of the full Lemaire model to very good approximation. The response of both models to changes in the underlying physiology and therapeutic interventions was evaluated in four physiologically meaningful scenarios: (i) estrogen deficiency/estrogen replacement therapy, (ii) Vitamin D deficiency, (iii) ageing, and (iv) chronic glucocorticoid treatment and its cessation. It was found that on the time scale of disease progression and therapeutic intervention, the models showed negligible differences in their dynamic properties and were both suitable for characterizing the impact of estrogen deficiency and estrogen replacement therapy, Vitamin D deficiency, ageing, and chronic glucocorticoid treatment and its cessation on bone forming (osteoblasts) and bone resorbing (osteoclasts) cells. It was also demonstrated how the simpler model could help in elucidating qualitative properties of the observed dynamics, such as the absence of overshoot and rebound, and the different dynamics of onset and washout.
Toward a Mathematical Modeling of Diseases’ Impact on Bone Remodeling: Technical Review
A wide variety of bone diseases have hitherto been discovered, such as osteoporosis, Patget’s disease, osteopetrosis, and metastatic bone disease, which is not well defined. Some of these diseases are secondary to other pathologies, including cancer, or to some clinical treatments. To better understand bone behavior and prevent its deterioration, bone biomechanics have been the subject of mathematical modeling that exponentially increased over the last years. These models are more and more involving the impact of bone diseases on its quality. The current paper provides a meaningful and critical analysis of previously developed bone remodeling mathematical models, particularly those addressing bone diseases. Besides, mechanistic pharmacokinetic/pharmacodynamic (PK/PD) models, which englobe either bone disease and its treatments’ effect on bone health. Therefore, the review starts by presenting bone remodeling cycle and mathematical models describing this process, followed by introducing some bone diseases and discussing models of pathological mechanisms affecting bone, and ends by exhibiting the available bone treatment procedures and the PK/PD models considering these lasts.
Mathematical modeling of postmenopausal osteoporosis and its treatment by the anti‐catabolic drug denosumab
SUMMARY Denosumab, a fully human monoclonal antibody, has been approved for the treatment of postmenopausal osteoporosis. The therapeutic effect of denosumab rests on its ability to inhibit osteoclast differentiation. Here, we present a computational approach on the basis of coupling a pharmacokinetics model of denosumab with a pharmacodynamics model for quantifying the effect of denosumab on bone remodeling. The pharmacodynamics model comprises an integrated systems biology‐continuum micromechanics approach, including a bone cell population model, considering the governing biochemical factors of bone remodeling (including the action of denosumab), and a multiscale micromechanics‐based bone mechanics model, for implementing the mechanobiology of bone remodeling in our model. Numerical studies of postmenopausal osteoporosis show that denosumab suppresses osteoclast differentiation, thus strongly curtailing bone resorption. Simulation results also suggest that denosumab may trigger a short‐term bone volume gain, which is, however, followed by constant or decreasing bone volume. This evolution is accompanied by a dramatic decrease of the bone turnover rate by more than one order of magnitude. The latter proposes dominant occurrence of secondary mineralization (which is not anymore impeded through cellular activity), leading to higher mineral concentration per bone volume. This explains the overall higher bone mineral density observed in denosumab‐related clinical studies. Copyright © 2013 John Wiley & Sons, Ltd.
Dynamics of Bone Cell Interactions and Differential Responses to PTH and Antibody-Based Therapies
We propose a mathematical model describing the dynamics of osteoblasts and osteoclasts in bone remodeling. The goal of this work is to develop an integrated modeling framework for bone remodeling and bone cell signaling dynamics that could be used to explore qualitatively combination treatments for osteoporosis in humans. The model has been calibrated using 57 checks from the literature. Specific global optimization methods based on qualitative objectives have been developed to perform the model calibration. We also added pharmacokinetics representations of three drugs to the model, which are teriparatide (PTH(1–34)), denosumab (a RANKL antibody) and romosozumab (a sclerostin antibody), achieving excellent goodness-of-fit of human clinical data. The model reproduces the paradoxical effects of PTH on the bone mass, where continuous administration of PTH results in bone loss but intermittent administration of PTH leads to bone gain, thus proposing an explanation of this phenomenon. We used the model to simulate different categories of osteoporosis. The main attributes of each disease are qualitatively well captured by the model, for example changes in bone turnover in the disease states. We explored dosing regimens for each disease based on the combination of denosumab and romosozumab, identifying adequate ratios and doses of both drugs for subpopulations of patients in function of categories of osteoporosis and the degree of severity of the disease.
Integrated model for denosumab and ibandronate pharmacodynamics in postmenopausal women
ABSTRACT This study aims to characterize the pharmacodynamic properties of denosumab, a RANK ligand inhibitor, and ibandronate, a bisphosphonate, using an integrated bone homeostasis model in postmenopausal women. Mean temporal profiles of denosumab, serum and urine N‐telopeptide (sNTX, uNTX), lumbar spine bone mineral density (BMD) following denosumab administration, and urine C‐telopeptide (uCTX) and lumbar spine BMD upon ibandronate administration were extracted from the literature. A mechanistic model was developed that integrates denosumab pharmacokinetics with binding to RANK ligand and ibandronate inhibition of osteoclast precursor differentiation to active osteoclasts (AOC). Biomarker concentrations were linked to the AOC pool. The BMD was characterized by a turnover model with stimulation of bone formation and degradation by AOB (active osteoblasts) and AOC pools. The estimated basal sNTX, uNTX and uCTX concentrations were 7.24 n m , 14.4 nmol/mmolCr and 31 µg/mmolCr. The BMD degradation rate was 0.00161 day ‐1 with stimulation constants associated with AOB and AOC of 1214 and 790 p m ‐1 . The plasma ibandronate concentration producing 50% of maximum inhibition of osteoclast differentiation was 522 ng/l. The integrated model, which incorporates multiple pathways of therapeutic intervention, quantitatively describes changes in clinical biomarkers of bone turnover and BMD after denosumab and ibandronate exposures in postmenopausal women. Copyright © 2011 John Wiley & Sons, Ltd.
Current Status of the Diagnosis and Management of Osteoporosis
Osteoporosis has been defined as the silent disease of the 21st century, becoming a public health risk due to its severity, chronicity and progression and affecting mainly postmenopausal women and older adults. Osteoporosis is characterized by an imbalance between bone resorption and bone production. It is diagnosed through different methods such as bone densitometry and dual X-rays. The treatment of this pathology focuses on different aspects. On the one hand, pharmacological treatments are characterized by the use of anti-resorptive drugs, as well as emerging regenerative medicine treatments such as cell therapies and the use of bioactive hydrogels. On the other hand, non-pharmacological treatments are associated with lifestyle habits that should be incorporated, such as physical activity, diet and the cessation of harmful habits such as a high consumption of alcohol or smoking. This review seeks to provide an overview of the theoretical basis in relation to bone biology, the existing methods for diagnosis and the treatments of osteoporosis, including the development of new strategies.
