Bisphosphonate treatment delays stress fracture remodeling in the rat ulna

Kidd, Lisa; Cowling, Nicholas; Wu, Andy C.K.; Kelly, Walton R.; Forwood, Mark R.

doi:10.1002/jor.21464

Cited by 55 publications

(49 citation statements)

References 43 publications

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“…Loading sessions were conducted by placing the flexed carpus and elbow in cups and applying axial cyclic loading on the ulnae of rats using methods we described previously. 16,17 Briefly, displacement in the limb during loading was monitored using a LVDT connected to the loading device, and recorded using Maclab (AD Instruments, Colorado Springs, CO). Under isoflourane and oxygen anesthesia, loading was applied as cyclic compressive loading at 17-24 N load and 2 Hz cycle frequency.…”

Section: Loading Modelmentioning

confidence: 99%

“…15,16 In addition, the model is sensitive to pharmaceutical treatments that may influence resorption or formation phases of SFx healing. 9,17 Because of their wide availability and use, it is important to examine the effects non-selective NSAIDs on the healing of SFx. In animal models, the non-selective NSAIDs cause a greater negative effect on fracture healing.…”

mentioning

confidence: 99%

“…In addition, SFx repair does not rely on endochondral ossification for fracture healing. 9,16,17 COX-2 inhibition may, therefore, have different effects to that seen in complete fracture healing.…”

mentioning

confidence: 99%

“…As previously described, 17 histomorphometry was performed on one toluidine blue-stained section from each bone at a standard level along the fracture. This section was the point where the fracture line was half-way between the medial cortical margin and the medullary cavity of the bone in transverse section.…”

mentioning

confidence: 99%

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Selective and non‐selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna

Kidd

Cowling

et al. 2012

Journal Orthopaedic Research

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Anti-inflammatory drugs are widely used to manage pain associated with stress fractures (SFxs), but little is known about their effects on healing of those injuries. We hypothesized that selective and non-selective anti-inflammatory treatments would retard the healing of SFx in the rat ulna. SFxs were created by cyclic loading of the ulna in Wistar rats. Ulnae were harvested 2, 4 or 6 weeks following loading. Rats were treated with non-selective NSAID, ibuprofen (30 mg/kg/day); selective COX-2 inhibition, [5,5-dimethyl-3-3 (3 fluorophenyl)-4-(4 methylsulfonal) phenyl-2 (5H)-furanone] (DFU) (2.0 mg/kg/day); or the novel c5a anatagonist PMX53 (10 mg/kg/ day, 4 and 6 weeks only); with appropriate vehicle as control. Quantitative histomorphometric measurements of SFx healing were undertaken. Treatment with the selective COX-2 inhibitor, DFU, reduced the area of resorption along the fracture line at 2 weeks, without affecting bone formation at later stages. Treatment with the non-selective, NSAID, ibuprofen decreased both bone resorption and bone formation so that there was significantly reduced length and area of remodeling and lamellar bone formation within the remodeling unit at 6 weeks after fracture. The C5a receptor antagonist PMX53 had no effect on SFx healing at 4 or 6 weeks after loading, suggesting that PMX53 would not delay SFx healing. Both selective COX-2 inhibitors and non-selective NSAIDs have the potential to compromise SFx healing, and should be used with caution when SFx is diagnosed or suspected. ß

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Section: Loading Modelmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Selective and non‐selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna

Kidd

Cowling

et al. 2012

Journal Orthopaedic Research

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“…(4,5) These fractures affect a subset of patients on longterm BPs, and although the incidence is low, these fractures are recalcitrant to treatment. (6) In an attempt to reduce the risk of atypical fractures, BP "holidays" have been recommended by some, whereby medication is intentionally discontinued to allow for a washout period. The risk of atypical fractures has been reported to be reduced with 1 year off BPs; (7) however, this washout period may be prolonged in individuals with years of treatment and/or low bone turnover.…”

Section: Introductionmentioning

confidence: 99%

PTH(1-34) Treatment Increases Bisphosphonate Turnover in Fracture Repair in Rats

Murphy

Schindeler

Cantrill

et al. 2014

Journal of Bone and Mineral Research

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Bisphosphonates (BP) are antiresorptive drugs with a high affinity for bone. Despite the therapeutic success in treating osteoporosis and metabolic bone diseases, chronic BP usage has been associated with reduced repair of microdamage and atypical femoral fracture (AFF). The latter has a poor prognosis, and although anabolic interventions such as teriparatide ) have been suggested as treatment options, there is a limited evidence base in support of their efficacy. Because PTH acts to increase bone turnover, we hypothesized that it may be able to increase BP in turnover in the skeleton, which, in turn, may improve bone healing. To test this, we employed a mixture of fluorescent Alexa647-labelled pamidronate (Pam) and radiolabeled 14 C-ZA (zoledronic acid). These traceable BPs were dosed to Wistar rats in models of normal growth and closed fracture repair. Rats were cotreated with saline or 25 mg/kg/d PTH , and the effects on BP liberation and bone healing were examined by X-ray, micro-CT, autoradiography, and fluorescent confocal microscopy. Consistent with increased BP remobilization with PTH , there was a significant decrease in fluorescence in both the long bones and in the fracture callus in treated animals compared with controls. This was further confirmed by autoradiography for 14 C-ZA. In this model of acute BP treatment, callus bone volume (BV) was significantly increased in fractured limbs, and although we noted significant decreases in callus-bound BP with PTH (1-34) , these were not sufficient to alter this BV. However, increased intracellular BP was noted in resorbing osteoclasts, confirming that, in principle, PTH increases bone turnover as well as BP turnover.

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Bone Healing

Kawcak

2022

Fractures in the Horse

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Bisphosphonate treatment delays stress fracture remodeling in the rat ulna

Cited by 55 publications

References 43 publications

Selective and non‐selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna

Selective and non‐selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna

PTH(1-34) Treatment Increases Bisphosphonate Turnover in Fracture Repair in Rats

Bone Healing

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