Abstract:During the last decades, several research groups have used bisphosphonates for local application to counteract secondary bone resorption after bone grafting, to improve implant fixation or to control bone resorption caused by bone morphogenetic proteins (BMPs). We focused on zoledronate (a bisphosphonate) due to its greater antiresorptive potential over other bisphosphonates. Recently, it has become obvious that the carrier is of importance to modulate the concentration and elution profile of the zoledronic ac… Show more
“…Bisphosphonates are viewed as capable of enhancing the intrinsic anabolic potential of bone, 22 and our intention to protect newly formed bone was reached with systemic zoledronate, despite low values of retained allograft, normally viewed as a lattice for new bone formation. 23 No significant anabolic effect of rhBMP-2 irrespective of zoledronate administration route was seen.…”
Section: Discussionmentioning
confidence: 99%
“…The larger surface area of new bone with local zoledronate compared to systemic zoledronate may stem from a peripheral effect by zoledronate eluting from allograft, as seen with bisphosphonate-augmented implants. 22 With systemic zoledronate, bone mineralization may not have been extensive enough at zoledronate administration points, or zoledronate, a high affinity bisphosphonate, was bound peripherally in the grafted gap leaving the surface unprotected. 26 …”
Section: Discussionmentioning
confidence: 99%
“…Osteoclasts are perceived as the only cell able to internalize N-bisphosphonates in amounts sufficient to induce apoptosis to interfere with farnesyl pyrophosphate synthase (FPPS), an enzyme path ubiquitous in all cell lines. 22 However, angiogenesis and osteoblasts have in vitro been inhibited in a non-FPPS dependent manner by bone-bound N-bisphosphonates. 27 , 28 While systemic zoledronate seemingly has the advantage of lower toxicity, the poor protection of allograft observed here allowed osteoclast-mediated resorption.…”
Aims We wanted to evaluate the effects of a bone anabolic agent (bone morphogenetic protein 2 (BMP-2)) on an anti-catabolic background (systemic or local zoledronate) on fixation of allografted revision implants. Methods An established allografted revision protocol was implemented bilaterally into the stifle joints of 24 canines. At revision surgery, each animal received one BMP-2 (5 µg) functionalized implant, and one raw implant. One group (12 animals) received bone graft impregnated with zoledronate (0.005 mg/ml) before impaction. The other group (12 animals) received untreated bone graft and systemic zoledronate (0.1 mg/kg) ten and 20 days after revision surgery. Animals were observed for an additional four weeks before euthanasia. Results No difference was detected on mechanical implant fixation (load to failure, stiffness, energy) between local or systemic zoledronate. Addition of BMP-2 had no effect on implant fixation. In the histomorphometric evaluation, implants with local zoledronate had more area of new bone on the implant surface (53%, p = 0.025) and higher volume of allograft (65%, p = 0.007), whereas implants in animals with systemic zoledronate had the highest volume of new bone (34%, p = 0.003). Systemic zoledronate with BMP-2 decreased volume of allograft by 47% (p = 0.017). Conclusion Local and systemic zoledronate treatment protects bone at different stages of maturity; local zoledronate protects the allograft from resorption and systemic zoledronate protects newly formed bone from resorption. BMP-2 in the dose evaluated with experimental revision implants was not beneficial, since it significantly increased allograft resorption without a significant compensating anabolic effect. Cite this article: Bone Joint Res 2021;10(8):488–497.
“…Bisphosphonates are viewed as capable of enhancing the intrinsic anabolic potential of bone, 22 and our intention to protect newly formed bone was reached with systemic zoledronate, despite low values of retained allograft, normally viewed as a lattice for new bone formation. 23 No significant anabolic effect of rhBMP-2 irrespective of zoledronate administration route was seen.…”
Section: Discussionmentioning
confidence: 99%
“…The larger surface area of new bone with local zoledronate compared to systemic zoledronate may stem from a peripheral effect by zoledronate eluting from allograft, as seen with bisphosphonate-augmented implants. 22 With systemic zoledronate, bone mineralization may not have been extensive enough at zoledronate administration points, or zoledronate, a high affinity bisphosphonate, was bound peripherally in the grafted gap leaving the surface unprotected. 26 …”
Section: Discussionmentioning
confidence: 99%
“…Osteoclasts are perceived as the only cell able to internalize N-bisphosphonates in amounts sufficient to induce apoptosis to interfere with farnesyl pyrophosphate synthase (FPPS), an enzyme path ubiquitous in all cell lines. 22 However, angiogenesis and osteoblasts have in vitro been inhibited in a non-FPPS dependent manner by bone-bound N-bisphosphonates. 27 , 28 While systemic zoledronate seemingly has the advantage of lower toxicity, the poor protection of allograft observed here allowed osteoclast-mediated resorption.…”
Aims We wanted to evaluate the effects of a bone anabolic agent (bone morphogenetic protein 2 (BMP-2)) on an anti-catabolic background (systemic or local zoledronate) on fixation of allografted revision implants. Methods An established allografted revision protocol was implemented bilaterally into the stifle joints of 24 canines. At revision surgery, each animal received one BMP-2 (5 µg) functionalized implant, and one raw implant. One group (12 animals) received bone graft impregnated with zoledronate (0.005 mg/ml) before impaction. The other group (12 animals) received untreated bone graft and systemic zoledronate (0.1 mg/kg) ten and 20 days after revision surgery. Animals were observed for an additional four weeks before euthanasia. Results No difference was detected on mechanical implant fixation (load to failure, stiffness, energy) between local or systemic zoledronate. Addition of BMP-2 had no effect on implant fixation. In the histomorphometric evaluation, implants with local zoledronate had more area of new bone on the implant surface (53%, p = 0.025) and higher volume of allograft (65%, p = 0.007), whereas implants in animals with systemic zoledronate had the highest volume of new bone (34%, p = 0.003). Systemic zoledronate with BMP-2 decreased volume of allograft by 47% (p = 0.017). Conclusion Local and systemic zoledronate treatment protects bone at different stages of maturity; local zoledronate protects the allograft from resorption and systemic zoledronate protects newly formed bone from resorption. BMP-2 in the dose evaluated with experimental revision implants was not beneficial, since it significantly increased allograft resorption without a significant compensating anabolic effect. Cite this article: Bone Joint Res 2021;10(8):488–497.
“…So far, there have been different studies targeting bone formation-related pathways such as the BMP signalling pathway. 84 , 85 The tight interaction between the immune system and the skeletal system has been recognized in the emerging research field of osteoimmunology. 86 Thus, the inflammatory response could also be one potential target for immune-modulatory approaches to enhance fracture healing, as a previous study demonstrated that modulation of inflammatory reaction could enhance osteogenesis.…”
A balanced inflammatory response is important for successful fracture healing. The response of osteoporotic fracture healing is deranged and an altered inflammatory response can be one underlying cause. The objectives of this review were to compare the inflammatory responses between normal and osteoporotic fractures and to examine the potential effects on different healing outcomes. A systematic literature search was conducted with relevant keywords in PubMed, Embase, and Web of Science independently. Original preclinical studies and clinical studies involving the investigation of inflammatory response in fracture healing in ovariectomized (OVX) animals or osteoporotic/elderly patients with available full text and written in English were included. In total, 14 articles were selected. Various inflammatory factors were reported; of those tumour necrosis factor-α (TNF-α) and interleukin (IL)-6 are two commonly studied markers. Preclinical studies showed that OVX animals generally demonstrated higher systemic inflammatory response and poorer healing outcomes compared to normal controls (SHAM). However, it is inconclusive if the local inflammatory response is higher or lower in OVX animals. As for clinical studies, they mainly examine the temporal changes of the inflammatory stage or perform comparison between osteoporotic/fragility fracture patients and normal subjects without fracture. Our review of these studies emphasizes the lack of understanding that inflammation plays in the altered fracture healing response of osteoporotic/elderly patients. Taken together, it is clear that additional studies, preclinical and clinical, are required to dissect the regulatory role of inflammatory response in osteoporotic fracture healing. Cite this article: Bone Joint Res 2020;9(7):368–385.
“…Of the antiresorptive bisphosphonates available today, those containing nitrogen in the heterocyclic ring, for example zoledronic acid, are 10,000 times more potent than non-nitrogen-containing bisphosphonates. 25 , 26 Bisphosphonates are today widely used for retarding osteoporosis by acting on osteoclasts and slowing bone resorption. 25 , 27 …”
Section: Hydroxyapatite As a Drug-seeking Moietymentioning
Bone is a dynamic tissue with a quarter of the trabecular and a fifth of the cortical bone being replaced continuously each year in a complex process that continues throughout an individual’s lifetime. Bone has an important role in homeostasis of minerals with non-stoichiometric hydroxyapatite bone mineral forming the inorganic phase of bone. Due to its crystal structure and chemistry, hydroxyapatite (HA) and related apatites have a remarkable ability to bind molecules. This review article describes the accretion of trace elements in bone mineral giving a historical perspective. Implanted HA particles of synthetic origin have proved to be an efficient recruiting moiety for systemically circulating drugs which can locally biomodulate the material and lead to a therapeutic effect. Bone mineral and apatite however also act as a waste dump for trace elements and drugs, which significantly affects the environment and human health. Cite this article: Bone Joint Res 2020;9(10):709–718.
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