Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair

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 acid locally. Incorporating one fifth of the recommended systemic dose of zoledronate with different apatite matrices and types of bone defects has been shown to enhance bone regeneration significantly in vivo. We expect the local delivery of zoledronate to overcome the limitations and side effects associated with systemic usage; however, we need to know more about the bioavailability and the biological effects. The local use of BMP-2 and zoledronate as a combination has a proven additional effect on bone regeneration. This review focuses primarily on the local use of zoledronate alone, or in combination with bone anabolic factors, in various preclinical models mimicking different orthopaedic conditions.Cite this article: I. Qayoom, D. B. Raina, A. Širka, Š. Tarasevičius, M. Tägil, A. Kumar, L. Lidgren. Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair: A review. Bone Joint Res 2018;7:548–560. DOI: 10.1302/2046-3758.710.BJR-2018-0015.R2.

Augmentation of implant surfaces with BMP-2 in a revision setting

“…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.…”

“…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 …”

“…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.…”

Inflammatory response in postmenopausal osteoporotic fracture healing

“…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.…”

Bone mineral as a drug-seeking moiety and a waste dump

“…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 …”