Restoration of Bone Material and Microstructural Properties after Long-Term Remodeling Suppression
Anti-resorptive drugs, principally bisphosphonates (BPs), are the mainstay of osteoporosis treatment. They work by inhibiting bone resorption/remodeling, thus preventing bone loss. However, long-term suppression of bone resorption adversely affects bone tissue mechanical properties, even while conserving bone mass. Lack of remodeling leads to accumulation of fatigue-induced microdamage, altered matrix mineralization and reduction in normal bone tissue heterogeneity, causing impaired strength and fracture toughness. The most severe consequence to patients, while rare, is Atypical Femur Fractures (i.e., complete fatigue fractures of the femoral shaft). To counteract the effects of long-term remodeling suppression, a temporary break in BP treatment (a "drug holiday) has been widely discussed in the clinical literature to allow remodeling to restart and potentially restore material properties. Whether this will work is not known; relevant biomechanical data are scarce. A drug holiday could be tested with an anit-resorptive agent that is cleared from the bone rapidly upon cessation of treatment; however, current clinical BPs have been selected in large part for their high binding affinity for bone mineral, so they can remain in bone for many years after treatment ends. This highlights a practical challenge to an effective drug holiday. The goal of this research is to answer the fundamental question of whether an anti-resorptive drug will work, i.e., whether pre-existing bone microdamage and associated local changes in bone material properties will undergo the targeted bone remodeling needed to restore local bone quality. Our global hypothesis is that the removal of long-term resorption suppression will not result in the spatially appropriate (targeted) bone remodeling needed to repair pre-exising bone. In Aim 1, we identified a novel, non-clinical BP (NE-58025) that prevented bone resorption but reversed rapidly with cessation of treatment due to its low binding affinity to bone mineral. In Aim 2, we examined the effect of long-term antiresorptive treatment with bisphosphonates on remodeling/repair of bone microdamage induced in the ulnar cortex of adult rats using in vivo fatigue loading. Both Alendronate and NE-58025 prevented remodeling/repair of bone microdamage. Moreover, suppression of resorption resulted in an increase in microdamage content, loss of osteocyte integrity and pro-osteoclastogenic signals (i.e., RANKL) and locally increased matrix mineralization. In Aim 3, we tested the extent to which remodeling of pre-existing bone microdamage occurs after long-term BP treatment is stopped. Rats were fatigue-loaded and treated for 4 months with Alendronate or NE-58025 followed by 3 months of no treatment. Remodeling was not activated in microdamaged areas of bone, even with the reversible BP. These data indicate that remodeling reactivated during a bisphosphonate "drug holiday" does not effectively target pre-existing microdamaged bone matrix for resorption and replacement and restoration of bone quality.
Orthopedics, osteoporosis, material properties, osteocytes, resorption, Biomechanics and Biotransport, Musculoskeletal Diseases
City University of New York - City College
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