A theoretical analysis of long-term bisphosphonate effects on trabecular bone volume and microdamage

Abstract

Bisphosphonates increase bone mass and reduce fracture risk, but their anti-resorptive action may lead to increases in fatigue microdamage. To investigate how bisphosphonate effects influence changes in bone volume and microdamage in the long term, a strain-adaptive model of bone remodeling and microdamage balance was developed for a continuum-level volume of postmenopausal trabecular bone by invoking Frost's mechanostat hypothesis. Both disuse and fatigue microdamage were assumed to stimulate the activation frequency of basic multicellular units (BMUs) such that bone remodeling served to remove excess bone mass and microdamage. Bisphosphonate effects were simulated as follows: low, intermediate, high, or complete suppression of BMU activation frequency either without a change in resorption by the BMU or with an independent decrease in resorption while the bone formation process was unaffected (i.e., formation initially exceeded resorption). Of the bisphosphonate effects, a reduction in resorption relative to formation dictated the long-term gain in bone volume while the potency of activation frequency suppression controlled the rate of gain. A plateau in the bone mass gain that typically occurs in clinical studies of bisphosphonate treatment was predicted by the model because the resultant reduction in strain forced bone formation by the BMU to decrease over time until it matched the reduction in BMU resorption. A greater suppression of activation frequency proportionally increased microdamage, but the accumulation was limited over the long term as long as remodeling was incompletely suppressed. The results of the model suggest creating bisphosphonates that provide minimal suppression of remodeling and a large decrease in BMU resorption because this would minimize damage accumulation and increase bone mass, respectively.

Computational Model of Alendronate Effects on Canine Rib Remodeling and Microdamage

“…Because resorption and formation are coupled, by decreasing bone turnover rate, the newly formed bone and older bone will have more time to complete mineralization therefore increasing the mineral content of bone [16]. Bisphosphonates increase bone mass by reducing remodeling space which reduces porous areas and creates a positive bone balance where resorption does not exceed formation [10].…”

“…Osteoclasts bind to the bone surface as usual, but when bisphosphonates are taken up by the osteoclasts, the cytoskeleton of the cell is disrupted, causing the ruffled border to disappear. Bone resorption declines due to the lack of a ruffled border which plays an integral role in the osteoclasts ability to resorb bone [10].…”

“…Bisphosphonates are used to manage the rate of bone remodeling in order to reduce the risk of fractures; however, when bone remodeling is reduced, microdamage removal is also reduced, making the bone weaker which in the long run, may increase fracture risk and cause bone to be more brittle [10]. Although bisphosphonates suppress bone remodeling and the resorption of bone in order to increase tissue mineralization and bone volume [17], they have also been associated with the impairment of microdamage removal in canines which has been shown to lead to weaker bones [10].…”

“…Although bisphosphonates suppress bone remodeling and the resorption of bone in order to increase tissue mineralization and bone volume [17], they have also been associated with the impairment of microdamage removal in canines which has been shown to lead to weaker bones [10]. An increase in mineralization along with the increase in microdamage make bone less resistant to crack propagation and more susceptible to fractures [10].…”

“…Although bisphosphonates suppress bone remodeling and the resorption of bone in order to increase tissue mineralization and bone volume [17], they have also been associated with the impairment of microdamage removal in canines which has been shown to lead to weaker bones [10]. An increase in mineralization along with the increase in microdamage make bone less resistant to crack propagation and more susceptible to fractures [10]. Although several studies have confirmed the increase in microdamage accumulation following bisphosphonate treatment [9,10,17,18] , three year results have shown similar levels of microdamage as one year treatment results which suggests that microdamage accumulation is limited beyond the initial increase after one year of treatment [18].…”