Advances in mechanobiological pharmacokinetic-pharmacodynamic models of osteoporosis treatment - Pathways to optimise and exploit existing therapies.

Osteoporosis (OP) is a chronic progressive bone disease which is characterized by reduction of bone matrix volume and changes in the bone matrix properties which can ultimately lead to bone fracture. The two major forms of OP are related to aging and/or menopause. With the worldwide increase of the elderly population, particularly age-related OP poses a serious health issue which puts large pressure on health care systems. A major challenge for development of new drug treatments for OP and comparison of drug efficacy with existing treatments is due to current regulatory requirements which demand testing of drugs based on bone mineral density (BMD) in phase 2 trials and fracture risk in phase 3 trials. This requires large clinical trials to be conducted and to be run for long time periods, which is very costly. This, together with the fact that there are already many drugs available for treatment of OP, makes the development of new drugs inhibitive. Furthermore, an increased trend of the use of different sequential drug therapies has been observed in OP management, such as sequential anabolic-anticatabolic drug treatment or switching from one anticatabolic drug to another. Running clinical trials for concurrent and sequential therapies is neither feasible nor practical due to large number of combinatorial possibilities. In silico mechanobiological pharmacokinetic-pharmacodynamic (PK-PD) models of OP treatments allow predictions beyond BMD, i.e. bone microdamage and degree of mineralisation can also be monitored. This will help to inform clinical drug usage and development by identifying the most promising scenarios to be tested clinically (confirmatory trials rather than exploratory only trials), optimise trial design and identify subgroups of the population that show benefit-risk profiles (both good and bad) that are different from the average patient. In this review, we provide examples of the predictive capabilities of mechanobiological PK-PD models. These include simulation results of PMO treatment with denosumab, implications of denosumab drug holidays and coupling of bone remodelling models with calcium and phosphate systems models that allows to investigate the effects of co-morbidities such as hyperparathyroidism and chronic kidney disease together with calcium and vitamin D status on drug efficacy.

An in silico approach to elucidate the pathways leading to primary osteoporosis: age-related vs. postmenopausal.

Numerical models of bone remodelling have traditionally been used to perform in silico tests of bone loss in postmenopausal women and also to simulate the response to different drug treatments. These models simulate the menopausal oestrogen decline by altering certain signalling pathways. However, they do not consider the simultaneous effect that ageing can have on cell function and bone remodelling, and thus on bone loss. Considering ageing and oestrogen decline together is important for designing osteoporosis treatments that can selectively counteract one or the other disease mechanism. A previously developed bone cell population model was adapted to consider the effect of ageing through: (1) the decrease of TGF- ß contained in the bone matrix and (2) an increased production of sclerostin by non-skeletal cells. Oestrogen deficiency is simulated in three different ways: (a) an increase in RANKL expression, (b) a decrease in OPG production, and (c) an increase in the responsiveness of osteoclasts to RANKL. The effect of ageing was validated using the cross-sectional study of (Riggs et al. in J Bone Miner Res 19: 1945-1954, 2004) on BMD of trabecular bone of the vertebral body of men. The joint effect of ageing and oestrogen deficiency was validated using these same clinical results but in women. In ageing, the effect of the increasing production of sclerostin is more important than the decrease of TGF- ß , while the three mechanisms used to simulate the effect of oestrogen deficiency produce almost identical responses. The results show that an early menopause leads to a lower average density in the fifth decade, but after the sixth decade the average density is independent of the age at menopause. Treatment of osteoporosis with denosumab was also simulated to conclude that the drug is not very effective if started before 10 years after menopause or before age 60.

Spatio-temporal simulations of bone remodelling using a bone cell population model based on cell availability.

Here we developed a spatio-temporal bone remodeling model to simulate the action of Basic Multicelluar Units (BMUs). This model is based on two major extensions of a temporal-only bone cell population model (BCPM). First, the differentiation into mature resorbing osteoclasts and mature forming osteoblasts from their respective precursor cells was modelled as an intermittent process based on precursor cells availability. Second, the interaction between neighbouring BMUs was considered based on a "metabolic cost" argument which warrants that no new BMU will be activated in the neighbourhood of an existing BMU. With the proposed model we have simulated the phases of the remodelling process obtaining average periods similar to those found in the literature: resorption ( ∼ 22 days)-reversal (∼8 days)-formation (∼65 days)-quiescence (560-600 days) and an average BMU activation frequency of ∼1.6 BMUs/year/mm3. We further show here that the resorption and formation phases of the BMU become coordinated only by the presence of TGF-ß (transforming growth factor ß), i.e., a major coupling factor stored in the bone matrix. TGF-ß is released through resorption so upregulating osteoclast apoptosis and accumulation of osteoblast precursors, i.e., facilitating the transition from the resorption to the formation phase at a given remodelling site. Finally, we demonstrate that this model can explain targeted bone remodelling as the BMUs are steered towards damaged bone areas in order to commence bone matrix repair.

Assessment of Strategies for Safe Drug Discontinuation and Transition of Denosumab Treatment in PMO-Insights From a Mechanistic PK/PD Model of Bone Turnover.

Denosumab (Dmab) treatment against postmenopausal osteoporosis (PMO) has proven very efficient in increasing bone mineral density (BMD) and reducing the risk of bone fractures. However, concerns have been recently raised regarding safety when drug treatment is discontinued. Mechanistic pharmacokinetic-pharmacodynamic (PK-PD) models are the most sophisticated tools to develop patient specific drug treatments of PMO to restore bone mass. However, only a few PK-PD models have addressed the effect of Dmab drug holidays on changes in BMD. We showed that using a standard bone cell population model (BCPM) of bone remodelling it is not possible to account for the spike in osteoclast numbers observed after Dmab discontinuation. We show that inclusion of a variable osteoclast precursor pool in BCPMs is essential to predict the experimentally observed rapid rise in osteoclast numbers and the associated increases in bone resorption. This new model also showed that Dmab withdrawal leads to a rapid increase of damage in the bone matrix, which in turn decreases the local safety factor for fatigue failure. Our simulation results show that changes in BMD strongly depend on Dmab concentration in the central compartment. Consequently, bone weight (BW) might play an important factor in calculating effective Dmab doses. The currently clinically prescribed constant Dmab dose of 60 mg injected every 6 months is less effective in increasing BMD for patients with high BW (2.5% for 80 kg in contrast to 8% for 60 kg after 6 years of treatment). However, bone loss observed 24 months after Dmab withdrawal is less pronounced in patients with high BW (3.5% for 80kg and 8.5% for 60 kg). Finally, we studied how to safely discontinue Dmab treatment by exploring several transitional and combined drug treatment strategies. Our simulation results indicate that using transitional reduced Dmab doses are not effective in reducing rapid bone loss. However, we identify that use of a bisphosphonate (BP) is highly effective in avoiding rapid bone loss and increase in bone tissue damage compared to abrupt withdrawal of Dmab. Furthermore, the final values of BMD and damage were not sensitive to the time of administration of the BP.

A novel algorithm to resolve lack of convergence and checkerboard instability in bone adaptation simulations using non-local averaging.

Checkerboard is a typical instability in finite element (FE) simulations of bone adaptation and topology optimization in general. It consists in a patchwork pattern with elements of alternating stiffness, producing lack of convergence and instabilities in the predicted bone density. Averaging techniques have been proposed to solve this problem. One of the most acknowledged techniques (node based formulation) has severe drawbacks such as: high sensitivity to mesh density and type of element integration (full vs reduced) and, more importantly, oscillatory solutions also leading to lack of convergence. We propose a new solution consisting in a non-local smoothing technique. It defines, as the mechanical stimulus governing bone adaptation in a certain integration point of the mesh, the average of the stimuli obtained in the neighbour integration points. That average is weighted with a decay function of the distance to the centre of the neighbourhood. The new technique has been shown to overcome all the referred problems and perform in a robust way. It was tested on a hollow cylinder, resembling the diaphysis of a long bone, subjected to bending or torsion. Checkerboard instability was eliminated and local convergence of bone adaptation was achieved rapidly, in contrast to the other averaging technique and to the model without control of checkerboard instability. The new algorithm was also tested with good results on the same geometry but in a model containing a void, which produces a stress concentration that usually leads to checkerboard instability, like in other applications such as simulations of bone-implant interfaces.

Are drug holidays a safe option in treatment of osteoporosis? - Insights from an in silico mechanistic PK-PD model of denosumab treatment of postmenopausal osteoporosis.

Recent reviews by the clinical bone research community suggest caution with prescription of drug holidays for patients with postmenopausal osteoporosis (PMO) treated with denosumab for an extended period of time. Main reasons for this suggestion are based on the fact that discontinuation of denosumab treatment leads to a relapse of osteoclastic bone resorption and a loss of bone mineral density (BMD) to pre-treatment levels at only 12-28 months. The question remains what is the best treatment option for cases where it is required to discontinue and/or reduce the drug dose and what are the consequences on BMD and bone turnover markers (BTMs). The latter questions are difficult to be addressed using clinical trials alone given the large number of parameter combinations involved to answer this problem. In this paper, we apply a recently developed in silico mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model of the effect of denosumab on bone remodelling in PMO. To address the above clinical relevant questions, we design a wide range of current and virtual treatment regimens to study the effect of drug holiday duration and therapy resumption on the evolution of BTMs, BMD and mineral content. Our numerical simulation results indicate the symptomatic effect of denosumab, which is lost once treatment is stopped. This effect is most clearly seen on rapid loss of BMD to pre-treatment levels 12 months after the last injection (8% and 3.6% per year in the lumbar spine and femoral neck, respectively). Also, we identify that independently of the duration of drug holiday (i.e. 12, 16 or 18 months) resuming treatment can restore BMD quite effectively. However, the latter result does not consider the possibility of potential fractures that can occur during the drug holiday. Finally, we identify a treatment case most promising for achieving maintenance of BMD and mineral content, while moderately increasing BTMs. The latter case uses no drug holiday, but reduces the most commonly prescribed denosumab dose (60 mg every 6 months) by half at same interval.

Diferencias entre pacientes institucionalizados y pacientes en atención domiciliaria en la provincia de Sevilla / Differences between institutionalized patients and those included in a home care program in Seville

OBJETIVO: Conocer las características y las diferencias clínicas entre pacientes institucionalizados y los de programas de atención domiciliaria. DISEÑO: Estudio observacional descriptivo transversal multicéntrico. EMPLAZAMIENTO; Sevilla, 2016. PARTICIPANTES: Un total de 1.857 pacientes ancianos (1.441 institucionalizados y 416 en domicilio). MEDICIONES: Las variables estudiadas fueron: sexo, edad, estado civil, apoyo familiar, patologías, criterios de pluripatología y fármacos. Se valoraron el estado funcional y el cognitivo mediante las escalas de Barthel, Lawton-Brody y Pfeiffer. RESULTADOS: Un 71,40% fueron mujeres. Estadísticamente el hecho de estar institucionalizados o vivir en el domicilio se relaciona con las siguientes patologías y categorías: esquizofrenia (p < 0,001), HTA (p = 0,012), DM (p = 0,001), FA (p < 0,001) y neoplasias (p = 0, 012), A1 (p = 0,012), A2 (p < 0,001), B1 (p < 0,001), B2 (p = 0,002), C (p < 0,001), E1 (p < 0,001), E3 (p = 0,01), F2 (p < 0,01), G2 (p = 0,024) y H (p = 0,005). El promedio del índice de Barthel de la muestra fue de 49,1 ± 34,45 (IC 95%: 47,49-50,7), el de Lawton-Brody en domicilio fue de 2,33 ± 2,49 y en institucionalizados, de 1,59 ± 2,12. La media de la escala de Pfeiffer fue de 4,93 ± 3,53. CONCLUSIONES: Se asocia con la institucionalización el deterioro cognitivo, consecuencia de posibles patologías neurológicas (categoría E3) y psiquiátricas. Por el contrario, no se asocia con la comorbilidad del paciente, puesto que es muy elevada en pacientes en situación de atención domiciliaria con mejores estados de independencia funcional y cognitivo

OBJECTIVES: To describe the characteristics and clinical differences between institutionalised patients and those included in a home care program. DESIGN: A descriptive, observational, cross-sectional, and multicentre study. Site Seville, 2016. STUDY SUBJECTS: A total 1857 elderly patients of similar characteristics (1441 institutionalised and 416 at home) in Seville in 2016. MEASUREMENTS: The variables studied included gender, age, civil status, family support, pathologies, multiple pathology criteria, and medication prescriptions. Functional and cognitive status was evaluated using the Barthel index, and the Lawton-Brody and Pfeiffer scales. RESULTS: The majority of patients (71.40%) were women. The fact of being institutionalised or being included in a home care program were statistically related to the following pathologies and categories: schizophrenia (p < .001), arterial hypertension (p = .012), diabetes mellitus (p = .001), atrial fibrillation (p < .001), and neoplasia (p = .012), A1 (p = .012), A2 (p < .001), B1 (p < .001), B2 (p = .002), C (p < .001), E1 (p < .001), E3 (p = .01), F2 (p < .01), G2 (p = .024), and H (p = .005). The mean Barthel index of the sample was 49.1 ± 34.45 (95% confidence interval: 47.49-50.7). The mean Lawton-Brody scale in the case of patients included the home care program was 2.33 ± 2.49 and in those institutionalised 1.59 ± 2.12. The mean Pfeiffer scale was 4.93 ± 3.53. CONCLUSIONS: Cognitive impairment was related to institutionalisation, being a result of possible neurological (E3 category) and psychiatric diseases. On the other hand, patient comorbidity was not related to it, because it is very high in patients included in a home care program, in whom functional and cognitive independency status is better

[Differences between institutionalized patients and those included in a home care program in Seville]. / Diferencias entre pacientes institucionalizados y pacientes en atención domiciliaria en la provincia de Sevilla.

OBJECTIVES: To describe the characteristics and clinical differences between institutionalised patients and those included in a home care program. DESIGN: A descriptive, observational, cross-sectional, and multicentre study. Site Seville, 2016. STUDY SUBJECTS: A total 1857 elderly patients of similar characteristics (1441 institutionalised and 416 at home) in Seville in 2016. MEASUREMENTS: The variables studied included gender, age, civil status, family support, pathologies, multiple pathology criteria, and medication prescriptions. Functional and cognitive status was evaluated using the Barthel index, and the Lawton-Brody and Pfeiffer scales. RESULTS: The majority of patients (71.40%) were women. The fact of being institutionalised or being included in a home care program were statistically related to the following pathologies and categories: schizophrenia (p<.001), arterial hypertension (p=.012), diabetes mellitus (p=.001), atrial fibrillation (p<.001), and neoplasia (p=.012), A1 (p=.012), A2 (p<.001), B1 (p<.001), B2 (p=.002), C (p<.001), E1 (p<.001), E3 (p=.01), F2 (p<.01), G2 (p=.024), and H (p=.005). The mean Barthel index of the sample was 49.1±34.45 (95% confidence interval: 47.49-50.7). The mean Lawton-Brody scale in the case of patients included the home care program was 2.33±2.49 and in those institutionalised 1.59±2.12. The mean Pfeiffer scale was 4.93±3.53. CONCLUSIONS: Cognitive impairment was related to institutionalisation, being a result of possible neurological (E3 category) and psychiatric diseases. On the other hand, patient comorbidity was not related to it, because it is very high in patients included in a home care program, in whom functional and cognitive independency status is better.