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.
