Long-term disuse osteoporosis seems less sensitive to bisphosphonate treatment than other osteoporosis.
We sought to determine whether risedronate can preserve cortical bone mass and mechanical properties during long-term disuse in dogs, assessed by histomorphometry and biomechanics on metacarpal diaphyses. Risedronate slowed cortical thinning and partially preserved mechanical properties, but it was unable to suppress bone loss to the degree seen in other osteoporoses.


BACKGROUND
Disuse induces dramatic bone loss resulting from greatly elevated osteoclastic resorption. Targeting osteoclasts with antiresorptive agents, such as bisphosphonates, should be an effective countermeasure for preventing disuse osteoporosis.


METHODS
Single forelimbs from beagles (5-7 years old, n = 28) were immobilized (IM) for 12 months. Age-matched, non-IM dogs served as controls. One-half the animals received either risedronate (RIS, 1 mg/kg) or vehicle daily. Histomorphometry was performed on second metacarpal mid-diaphyses. Cortical mechanical properties were determined by testing third metacarpal diaphyses in four-point bending.


RESULTS
IM caused marked reduction in cortical area (-42%) and cortical thinning (-40%) through endocortical resorption, extensive intracortical tunneling, and periosteal resorption; both bone resorption and formation were significantly elevated over control levels on all envelopes. IM also decreased maximum load and stiffness by approximately 80% compared with controls. RIS reduced both periosteal bone loss and marrow cavity expansion; however, cortical area remained significantly lower in RIS-treated IM animals than in untreated non-IM controls (-16%). RIS also increased resorption indices in all envelopes compared with nontreated IM, indicating that RIS suppressed osteoclast activity but not osteoclast recruitment. RIS did not affect bone formation. RIS treatment conserved some whole bone mechanical properties, but they were still significantly lower than in controls. There were no significant differences in tissue level material properties among the groups.


CONCLUSIONS
RIS treatment reduces cortical bone loss at periosteal and endocortical surfaces caused by long-term immobilization, thus partially conserving tissue mechanical properties. This modest effect contrasts with more dramatic actions of the bisphosphonate in other osteoporoses. Our results suggest that risedronate impairs osteoclastic function but cannot completely overcome the intense stimulus for osteoclast recruitment during prolonged disuse.
Li
Chao Yang
CY
Leni and Peter W. May Department of Orthopaedics, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
Price
Christopher
C
Delisser
Kemesha
K
Nasser
Philip
P
Laudier
Damien
D
Clement
Mariza
M
Jepsen
Karl J
KJ
Schaffler
Mitchell B
MB
D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D004164:Diphosphonates / Q000627:therapeutic use*; D004285:Dogs; D004351:Drug Resistance; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005552:Forelimb / Q000473:pathology; D007103:Immobilization; D010024:Osteoporosis / Q000188:drug therapy*; D000068296:Risedronic Acid
D002121:Calcium Channel Blockers; D004164:Diphosphonates; D000068296:Risedronic Acid; D012968:Etidronic Acid