Effect of short‐term treatment with alendronate on ulnar bone adaptation to cyclic fatigue loading in rats

Abstract

Targeted remodeling of fatigue-injured bone involves activation of osteoclastic resorption followed by local bone formation by osteoblasts. We studied the effect of parenteral alendronate (ALN) on bone adaptation to cyclic fatigue. The ulnae of 140 rats were cyclically loaded unilaterally until 40% loss of stiffness developed. We used eight treatment groups: (1) baseline control; (2) vehicle (sterile saline) and (3) alendronate before fatigue, no adaptation (Pre-VEH, Pre-ALN, respectively); (4) vehicle and (5) alendronate during adaptation to fatigue (Post-VEH, Post-ALN, respectively); (6) vehicle before fatigue and during adaptation (Pre-VEH/Post-VEH); (7) alendronate before fatigue and vehicle during adaptation (Pre-ALN/Post-VEH); (8) alendronate before fatigue and during adaptation (Pre-ALN/Post-ALN). Bones from half the rats/group were tested mechanically; remaining bones were examined histologically. The following variables were quantified: volumetric bone mineral density (vBMD); ultimate force (F u ); stiffness (S); work-tofailure (U); cortical area (Ct.Ar); new woven bone tissue area (Ne.Wo.B.T.Ar); resorption space density (Rs.N/T.Ar). Microcracking was only seen in fatigue-loaded ulnae. A significant effect of alendronate on vBMD was not found. Preemptive treatment with alendronate did not protect the ulna from structural degradation during fatigue. After fatigue, recovery of mechanical properties by adaptation occurred; here a significant alendronate effect was not found. An alendronate-specific effect on adaptive Ne.Wo.B.T.Ar was not found. In the fatigue-loaded ulna, Rs.N/T.Ar was increased in vehicle-treated adapted groups, but not alendronate-treated adapted groups, when compared with baseline control. These data suggest that short-term alendronate treatment does not protect bone from fatigue in this model. Inhibition of remodeling may reduce microcrack repair over time.

Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the american society for bone and mineral Research

“…(65) Animal studies using repetitive ulnar loading in combination with BP treatment also show that prior alendronate treatment does not protect against a fatigue-related reduction in mechanical properties. (66) However, prior alendronate treatment did eliminate the adaptive remodeling response, suggesting that BP treatment could impair the healing response to a stress fracture. Therefore, it is possible that in the case of a developing stress fracture, reduction of bone remodeling would prevent or delay the repair of the stress reaction without suppressing the appearance of a periosteal callus and that this may result eventually in consolidation of the damage and a complete fracture of the stressed site.…”

“…Several different animal models have been used to study the pathogenesis of stress fractures. Existing rodent models (3,4,66) may not be appropriate because of their lack of haversian remodeling, but attempts should be made to adapt fatigueloading techniques that have been developed in rodents to larger animals. Nonhuman primates would be acceptable but are expensive.…”

Bisphosphonate treatment delays stress fracture remodeling in the rat ulna

“…The use of bisphosphonates has been proposed as a preventive measure against stress fractures. 8,9 However a trial in army recruits failed to show any preventive efficacy of risedronate therapy. 8 Treatment with pamidronate was reported to produce a beneficial effect in clinical stress fractures in young athletes, 10 but this study only had small numbers of cases.…”

“…The woven bone response was not affected by alendronate treatment initiated before or after loading. 9 These effects were, however, only examined at a maximum of 2 weeks following loading. Another study using the rat ulna loading model demonstrated that treatment with aledronate did not affect resorption space area, repaired crack length or woven bone area at 2 and 4 weeks after stress fracture creation but that mineral apposition rate and bone formation rate were decreased at 4 weeks after loading.…”

“…19 Previous studies have used thick sections of plastic embedded bone to examine the histomorphometry of stress fracture healing in the rat ulnar loading model. 9,14 This provides a method for measuring flourochrome labels and bone formation indices, but does not allow for detailed examination of resorption and formation indices of healing along the fracture line. We used thin sections of paraffin embedded bone in this study to allow a detailed analysis of the cellular resorption and formation activity within the BMUs, and thus provide valuable information on the effect of bisphosphonates on the progression and activity of cells within a BMU.…”