Combined Effects of Exercise and Denosumab Treatment on Local Failure in Post-menopausal Osteoporosis–Insights from Bone Remodelling Simulations Accounting for Mineralisation and Damage

Abstract

Denosumab has been shown to increase bone mineral density (BMD) and reduce the fracture risk in patients with post-menopausal osteoporosis (PMO). Increase in BMD is linked with an increase in bone matrix mineralisation due to suppression of bone remodelling. However, denosumab anti-resorptive action also leads to an increase in fatigue microdamage, which may ultimately lead to an increased fracture risk. A novel mechanobiological model of bone remodelling was developed to investigate how these counter-acting mechanisms are affected both by exercise and long-term denosumab treatment. This model incorporates Frost's mechanostat feedback, a bone mineralisation algorithm and an evolution law for microdamage accumulation. Mechanical disuse and microdamage were assumed to stimulate RANKL production, which modulates activation frequency of basic multicellular units in bone remodelling. This mechanical feedback mechanism controls removal of excess bone mass and microdamage. Furthermore, a novel measure of bone local failure due to instantaneous overloading was developed. Numerical simulations indicate that trabecular bone volume fraction and bone matrix damage are determined by the respective bone turnover and homeostatic loading conditions. PMO patients treated with the currently WHO-approved dose of denosumab (60 mg administrated every 6 months) exhibit increased BMD, increased bone ash fraction and damage. In untreated patients, BMD will significantly decrease, as will ash fraction; while damage will increase. The model predicted that, depending on the time elapsed between the onset of PMO and the beginning of treatment, BMD slowly converges to the same steady-state value, while damage is low in patients treated soon after the onset of the disease and high in patients having PMO for a longer period. The simulations show that late treatment PMO patients have a significantly higher risk of local failure compared to patients that are treated soon after the onset of the disease. Furthermore, overloading resulted in an increase of BMD, but also in a faster increase of damage, which may consequently promote the risk of fracture, specially in late treatment scenarios. In case of mechanical disuse, the model predicted reduced BMD gains due to denosumab, while no significant change in damage occurred, thus leading to an increased risk of local failure compared to habitual loading.

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

“…The latter stress state would approximate the area of the femoral neck subjected to tensile stresses due to bending. The value of the stresses were adjusted to produce a homeostasis state for the corresponding value of f bm , as done in Figure 4 of ( Martínez-Reina et al, 2021b ). The following error was computed from the comparison: where the superscripts model and clin refer to the in-silico and clinical results, respectively; the subscript i stands for lumbar spine and hip and the subscript j refers to the time points for which the results by Bone et al ( Bone et al, 2011 ) were available and could be compared (see Figure 2 ).…”

“…To evaluate P RANKL , the RANKL production rate of Eq. 9 , we have assumed that RANKL is expressed by osteocytes and osteoblasts precursors, following experimental evidence ( Nakashima et al, 2011 ; Xiong et al, 2015 ) and then: where is the RANKL production due to PMO; β RANKL,Ot and are the RANKL production rate of osteocytes and osteoblast precursors, respectively; is a co-regulatory function that takes into account the up-regulation of RANKL transcription by the parathyroid hormone (PTH) and its inhibition by nitric oxide (NO) ( Martin et al, 2019 ) and is an activator function accounting for the upregulation of RANKL expression by osteocytes due to microstructural damage ( Martínez-Reina et al, 2021b ) (see the details of both regulatory functions in the Supplementary Material). Finally, [RANKL] max is the saturation concentration of RANKL above which no further expression takes place and [RANKL] tot is the total concentration of RANKL (bound and free) and is defined as follows: …”

“…Following ( Martínez-Reina et al, 2021b ), the RANKL production due to PMO, is modelled as a sigmoidal function of time: where is the maximum (long-term) RANKL production due to PMO, t onset is the time of onset of the disease, δ PMO is a time constant establishing when the 50% of is reached and γ is the sigmoidicity factor.…”

“…3 , 4 have the same structure: and different constants: and . In previous works ( Martínez-Reina and Pivonka, 2019 ; Martínez-Reina et al, 2021a ; Martínez-Reina et al, 2021b ) both constants were chosen equal in Eq. 3 , so resulting in a constant pool of Oc p in the steady state.…”

“…The majority of these models are based on mechanistic PK-PD models of drug treatments in osteoporosis ( Lemaire et al, 2004 ; Pivonka et al, 2008 ; Scheiner et al, 2013 ; Martínez-Reina and Pivonka, 2019 ). A major finding of these models was that in order to be able to accurately model the effects of anti-resorptive drugs on BMD it is essential to take into account bone mineralisation as a physiological process ( Scheiner et al, 2014 ; Martínez-Reina and Pivonka, 2019 ) together with accumulation of microcracks due to increased brittleness of the bone matrix ( Martínez-Reina et al, 2021a ; Martínez-Reina et al, 2021b ).…”