Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling

McDonald, Michelle M.; Dulai, Sukhdeep; Godfrey, Craig; Amanat, Negin; Sztynda, Tamara; Little, David

doi:10.1016/j.bone.2008.05.019

Cited by 141 publications

(121 citation statements)

References 52 publications

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“…12,13,36 Similar results were observed in models using dogs and sheep. 37,38 In these studies, mechanical properties of the callus were improved 3,12,13,36 or not significantly changed by treatment with bisphosphonates. 38,39 Woven bone is a prominent feature of clinical stress fractures and provides mechanical protection to a stress fracture line.…”

Section: Discussionmentioning

confidence: 78%

“…1,2 While bisphosphonates reduce the risk of fractures in osteoporosis, fractures still occur during treatment, so it is necessary to understand the effect of these medications on subsequent fracture healing. [2][3][4][5] Stress fractures are an important clinical condition commonly affecting athletes, soldiers, and dancers. 6 They are a form of fatigue injury associated with repetitive loading.…”

mentioning

confidence: 99%

“…In experimental studies of complete fracture in rats, treatment with bisphosphonates consistently increased the hard callus volume, strength and mineral content. 3,12,13 In animal models, stress fractures heal by direct remodeling along the fracture line. 14,15 Treatment with bisphosphonates may therefore have a negative effect on stress fracture healing when compared to complete fractures.…”

mentioning

confidence: 99%

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Bisphosphonate treatment delays stress fracture remodeling in the rat ulna

Kidd

Cowling

et al. 2011

Journal Orthopaedic Research

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Because bisphosphonates (BPs) are potent inhibitors of bone resorption, we hypothesized that they would retard direct remodeling of stress fractures. The aim of this study was to determine the effect of risedronate on direct remodeling and woven bone callus formation following stress fracture formation in the rat ulna. In 135 adult female Wistar rats, cyclic loading of the ulna created stress fractures. Rats were treated daily with oral saline, or risedronate at 0.1 or 1.0 mg/kg. From each bone, histomorphometry was performed on sections stained with toluidine blue at a standard level along the fracture. The high dose of risedronate caused a significant decrease in the percentage of repaired stress fracture and bone resorption along the stress fracture line at 6 and 10 weeks after loading (p < 0.05). At this dose, intracortical resorption was significantly reduced at 10 weeks after loading and intracortical new bone area was significantly reduced at 6 and 10 weeks. Woven bone formation and consolidation phases of stress fracture repair were not affected by low or high doses of risedronate. In conclusion, high dose bisphosphonate treatment impaired healing of a large stress fracture line by reducing the volume of bone resorbed and replaced during remodeling. We also confirmed that periosteal callus formation was not adversely affected by risedronate treatment. ß

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Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Bisphosphonate treatment delays stress fracture remodeling in the rat ulna

Kidd

Cowling

et al. 2011

Journal Orthopaedic Research

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“…However, there were very few TRACP þ multinucleated osteoclasts associated with regions of CT1 þ matrix deposition during the anabolic bone-modeling phase of this model. Other studies in animal models of fracture have inhibited osteoclast number and function either via OPG, (52) denosumab, (53) or bisphosphonate treatment (53,54) and concluded that osteoclasts were not required for normal callus formation but were important during hard callus remodeling. Macrophages are a major source of factors known to promote bone deposition/mineralization, (55)(56)(57)(58) and at least some of these can be induced by CSF-1.…”

Section: Discussionmentioning

confidence: 99%

Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model

Alexander

Chang

Maylin

et al. 2011

Journal of Bone and Mineral Research

417

393

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Bone-lining tissues contain a population of resident macrophages termed osteomacs that interact with osteoblasts in vivo and control mineralization in vitro. The role of osteomacs in bone repair was investigated using a mouse tibial bone injury model that heals primarily through intramembranous ossification and progresses through all major phases of stabilized fracture repair. Immunohistochemical studies revealed that at least two macrophage populations, F4/80matory macrophages, were present within the bone injury site and persisted throughout the healing time course. In vivo depletion of osteomacs/macrophages (either using the Mafia transgenic mouse model or clodronate liposome delivery) or osteoclasts (recombinant osteoprotegerin treatment) established that osteomacs were required for deposition of collagen type 1 þ (CT1 þ ) matrix and bone mineralization in the tibial injury model, as assessed by quantitative immunohistology and micro-computed tomography. Conversely, administration of the macrophage growth factor colony-stimulating factor 1 (CSF-1) increased the number of osteomacs/macrophages at the injury site significantly with a concurrent increase in new CT1 þ matrix deposition and enhanced mineralization. This study establishes osteomacs as participants in intramembranous bone healing and as targets for primary anabolic bone therapies. ß

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“…They promote a bond of hydroxyapatite crystals, thus, inhibiting bone resorption by osteoclasts and decreasing the rate of bone remodeling. Different studies have confirmed that bisphosphonates treatment does not improve fracture healing [57,58]. This happens because bisphosphonate use interferes with the maturation of cartilaginous callus delaying its remodeling to woven bone and, subsequently, to lamellar bone.…”

Section: Antiresorptive Agentsmentioning

confidence: 99%

Updates in biological therapies for knee injuries: bone

Kfuri

Freitas

Batista

et al. 2014

Curr Rev Musculoskelet Med

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Bone is a unique tissue because of its mechanical properties, ability for self-repair, and enrollment in different metabolic processes such as calcium homeostasis and hematopoietic cell production. Bone barely tolerates deformation and tends to fail when overloaded. Fracture healing is a complex process that in particular cases is impaired. Osteoprogenitor cells proliferation, growth factors, and a sound tridimensional scaffold at fracture site are key elements for new bone formation and deposition. Mechanical stability and ample vascularity are also of great importance on providing a proper environment for bone healing. From mesenchymal stem cells delivery to custom-made synthetic scaffolds, many are the biological attempts to enhance bone healing. Impaired fracture healing represents a real burden to contemporary society. Sound basic science knowledge has contributed to newer approaches aimed to accelerate and improve the quality of bone healing.

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Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling

Cited by 141 publications

References 52 publications

Bisphosphonate treatment delays stress fracture remodeling in the rat ulna

Bisphosphonate treatment delays stress fracture remodeling in the rat ulna

Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model

Updates in biological therapies for knee injuries: bone

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