Manipulating the anabolic and catabolic response in bone graft remodeling: Synergism by a combination of local BMP‐7 and a single systemic dosis of zoledronate

Abstract

Remodeling of a bone graft can be influenced both by anabolic substances, such as a bone morphogenic protein (BMP) and by anticatabolic substances, such as the bisphosphonates. BMPs are potent bone anabolic substances, but also boost catabolism and cause resorption. Bisphosphonates inhibit osteoclast function and can be used to postpone resorption. In the present study a combination of both drugs was explored in a rat bone chamber model. Cancellous bone grafts were treated with either BMP-7 or saline and placed in a bone chamber implanted in the proximal tibia. After 2 weeks, an injection of either zoledronate 0.1 mg/kg or saline was given subcutaneously. The rats were killed after 6 weeks, and bone ingrowth distance into the graft and graft resorption were measured by histomorphometry. BMP-7 significantly (p ¼ 0.007) increased new bone ingrowth distance into the graft from 2.0 mm (SD ¼ 0.98 mm) in the controls to 3.1 mm (SD ¼ 0.93 mm). If bisphosphonate was not given, most of the newly formed and old graft bone was resorbed. A single injection of zoledronate significantly (p < 0.001) increased the trabecular volume/total volume to 40% (SD ¼ 9%) compared to 14% (SD ¼ 10%) in the nonbisphosphonate treated. In total, the net amount of bone increased by 400% when BMP-7 and zoledronate combined was compared to saline. A bone graft can be treated with BMP-7 to increase new bone formation and at the same time be protected against premature catabolism by a single dose of a bisphosphonate. This combination might be useful in various conditions in orthopedic reconstruction. Healing and normal physiological skeletal repair involve a complex set of regulated signaling pathways that control the formation of new bone matrix and the resorption of damaged bone at the disease or injury site. These pathways are mediated by a number of effector cells, primarily the catabolic bone-resorbing osteoclasts and the anabolic bone-forming osteoblasts, which produce new bone tissue to restore skeletal integrity. A balance between them is required for normal fracture repair and bone graft remodeling. Delayed healing or non-union can be a failure of the anabolic response, an increased or premature catabolic response, or sometimes both. 1 The anabolic and catabolic responses can be manipulated with pharmaceuticals, and in the bone conduction chamber, 2 we can study how drugs, separately or in combinations, influence bone formation and resorption.Bisphosphonates reduce osteoclastic catabolic activity in experimental studies. Circulating bisphosphonates bind to bone mineral, and, when the bone is resorbed by osteoclasts, bisphosphonates are internalized and interfere with cell metabolism leading to osteoclast apoptosis. 3 Systemic bisphosphonate treatment can postpone resorption of a bone graft. 4 In fractures, postponing the catabolic response and in consequence the resorption of the new-forming callus, leads to a stronger callus. 5 Bone morphogenic proteins (BMPs) bind to specific cell receptors, starting a signaling cascade that l...

In vivo local co-delivery of recombinant human bone morphogenetic protein-7 and pamidronate via poly-D, L-lactic acid

“…Again, a combination of local rhBMP-7 and bolus systemic ZA (0.1 mg/kg) increased bone ingrowth and net bone formation, compared to controls. In the context of an unloaded chamber, intrinsic catabolic pressures were high and the bisphosphonate-free controls showed tremendous resorption within the same time period (Tägil et al, 2006;Harding et al, 2008). Similar findings …”

“…A number of prior studies have examined the interactions between BMPs and systemic bisphosphonates in animal models Little et al, 2005;Tägil et al, 2006;Harding et al, 2008). In the earliest of these studies, rhBMP-7/carboxymethylcellulose (OP-1) was used in combination with the bisphosphonate ZoledronicAcid (ZA) to stimulate healing in a rat criticalsized femoral defect.…”

“…Bone resorption may be additionally problematic in the context of bone tissue engineering, where the new bone is often mechanically unloaded (Cooley et al, 2005;Seeherman et al, 2010). Consequently, one approach to maximize the effects of BMPs is to systemically administer an antiresorptive (such as a bisphosphonate), and this has been effective in small animal critical-size bone defect repair (Seeherman et al, 1998;Seeherman et al, 2000;Bouxsein et al, 2001;Little et al, 2005), and bone remodelling in bone graft chambers (Harding et al, 2008;Tägil et al, 2006), as well as non-human primate bone defects . Bisphosphonates accumulate at sites of bone mineral deposition, and in particular in regions of high bone turnover.…”

A collagen–hydroxyapatite scaffold allows for binding and co-delivery of recombinant bone morphogenetic proteins and bisphosphonates

“…An emerging paradigm in orthopedics is the concept of synergistically harnessing anabolic and anticatabolic drug treatments for improved bone healing [44][45][46][47] . BPs alone inhibit bone resorption and do not promote bone formation.…”

Modulation of anabolic and catabolic responses via a porous polymer scaffold manufactured using thermally induced phase separation

“…This led to increased union rates and mechanical strength at 6 weeks. Other studies have illustrated advantages of this systemic bisphosphonates dosing in a rat ectopic bone formation model (Gong et al, 2003), an unloaded rat bone chamber model (Tägil et al, 2006;Harding et al, 2008), and non-human primate models Seeherman et al, 2001). For bisphosphonates, local delivery has emerged as an appealing alternative to systemic delivery for two reasons.…”