Renewed bone remodeling after pausing long-term bisphosphonate use: Does it replace regions of impaired bone quality and restore mechanical integrity?

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SUMMARY Bisphosphonates (BPs) are the mainstay for treatment of postmenopausal osteoporosis. They are highly effective at preventing bone resorption and loss. However, long-term use of BPs and other antiresorptives is also known to negatively impact bone quality, with long-term sequelae including bone microdamage accumulation, altered matrix composition and heterogeneity, leading in some case to Atypical Femur Fractures. These sequelae have led to the idea of a “drug holiday,” i.e., pausing anti-resorptive treatment to allow renewed bone remodeling to resorb and replace bone areas with accumulated microdamage or associated material defects. However, it is not known if it is possible for renewed remodeling to target long-standing compromised bone tissue. The proposed research will address this critical knowledge gap. In Aim 1, we will first establish consequences of long-term BP use on evolution of controlled bone microdamage introduced in vivo by ulnar bending fatigue in rats and determine associated effects on osteocyte loss, local bone composition, material properties and diaphyseal fracture resistance. RNA in-situ hybridization will be used to investigate remaining viable osteocytes, focusing on major genes that regulate bone remodeling, mineral and matrix mineralization. In a companion study, we will determine bone quality, fracture resistance and osteocyte changes in mouse long bones with long-term BP use after ovariectomy – a combination of challenges that leads to osteocyte loss, that is not related to bone microdamage. In Aim 2, we will perform the first direct test of whether renewed remodeling during a drug holiday replaces long-standing microdamaged- or osteocyte-deficient bone tissue to restore bone quality. In a second series of studies, we will expand upon exciting preliminary data which suggests that a BP drug holiday can trigger other mechanically beneficial bone adaptations in diaphyseal shape that can potentially improve fracture resistance in a manner which is independent of tissue turnover and bone quality. In all studies, animals will be treated long-term with either Alendronate (ALN, high bone mineral binding = long-reversal time), Risedronate (RIS, moderate bone mineral binding = intermediate reversal time) or a rapidly reversible BP NE58025 (low bone mineral binding = short reversal time) in order to compare their effects on bone and osteocytes (Aim 1), and then we examine the efficacy of each BP in restoring diaphyseal biomechanical integrity during a drug holiday (Aim 2). Once completed, the results of these studies will provide the first robust mechanistic insights into the essential clinical-biomechanical question of whether a “drug holiday” can be effective in repairing the bone quality defects that accumulate with long-term bisphosphonate use and improving bone fracture resistance.