Transient Local Bone Remodeling Effects of rhBMP-2 in an Ovine Interbody Spine Fusion Model

Background: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a powerful osteoinductive morphogen capable of stimulating the migration of mesenchymal stem cells (MSCs) to the site of implantation and inducing the proliferation and differentiation of these MSCs into osteoblasts. Vertebral end-plate and vertebral body resorption has been reported after interbody fusion with high doses of rhBMP-2. In this study, we investigated the effects of 2 rhBMP-2 doses on peri-implant bone resorption and bone remodeling at 7 time points in an end-plate-sparing ovine interbody fusion model. Methods: Twenty-one female sheep underwent an end-plate-sparing discectomy followed by interbody fusion at L2-L3 and L4-L5 using a custom polyetheretherketone (PEEK) interbody fusion device. The PEEK interbody device was filled with 1 of 2 different doses of rhBMP-2 on an absorbable collagen sponge (ACS): 0.13 mg (1·) or 0.90 mg (7·). Bone remodeling and interbody fusion were assessed via high-resolution radiography and histological analyses at 1, 2, 3, 4, 8, 12, and 20 weeks postoperatively. Results: Peri-implant bone resorption peaked between 3 and 8 weeks in both the 1· and the 7· rhBMP-2/ACS-dose group. Osteoclastic activity and corresponding peri-implant bone resorption was dose-dependent, with moderate-tomarked resorption at the 7·-dose level and less resorption at the 1·-dose level. Both dose (p \u3c 0.0007) and time (p \u3c 0.0025) affected bone resorption significantly. Transient bone-resorption areas were fully healed by 12 weeks. Osseous bridging was seen at all but 1 spinal level at 12 and at 20 weeks. Conclusions: In the ovine end-plate-sparing interbody fusion model, rhBMP-2 dose-dependent osteoclastic resorption is a transient phenomenon that peaks at 4 weeks postoperatively. Clinical Relevance: Using the U.S. Food and Drug Administration (FDA)-approved rhBMP-2 concentration and matching the volume of rhBMP-2/ACS with the volume of desired bone formation within the interbody construct may limit the occurrence of transient bone resorption

Quantitative analysis of bone reactions to relative motions at implant-bone interfaces

Connective soft tissues at the interface between implants and bone, such as in human joint replacements, can endanger the stability of the implant fixation. The potential of an implant to generate interface bone resorption and form soft tissue depends on many variables, including mechanical ones. These mechanical factors can be expressed in terms of relative motions between bone and implant at the interface or deformation of the interfacial material.\ud \ud The purpose of this investigation was to determine if interface debonding and subsequent relative interface motions can be responsible for interface degradation and soft tissue interposition as seen in experiments and clinical results. A finite element computer program was augmented with a mathematical description of interface debonding, dependent on interface stress criteria, and soft tissue interface interposition, dependent on relative interface motions. Three simplified models of orthopaedic implants were constructed: a cortical bone screw for fracture fixation plates, a femoral resurfacing prosthesis and a straight stem model, cemented in a bone. The predicted computer configurations were compared with clinical observations. The computer results showed how interface disruption and fibrous tissue interposition interrelate and possibly enhance each other, whereby a progressive development of the soft tissue layer can occur.\ud \ud Around the cortical bone screw, the predicted resorption patterns were relatively large directly under the screw head and showed a pivot point in the opposite cortex. The resurfacing cup model predicted some fibrous tissue formation under the medial and lateral cup rim, whereby the medial layer developed first because of higher initial interface stresses. The straight stem model predicted initial interface failure at the proximal parts. After proximal resorption and fibrous tissue interposition, the medial interface was completely disrupted and developed an interface layer. The distal and mid lateral side maintained within the strength criterion.\ud \ud Although the applied models were relatively simple, the results showed reasonable qualitative agreement with resorption patterns found in clinical studies concerning bone screws and the resurfacing cup. The hypothesis that interface debonding and subsequent relative (micro)motions could be responsible for bone resorption and fibrous tissue propagation is thereby sustained by the results

Short-term Osteoclastic Activity Induced by Locally High Concentrations of Recombinant Human Bone Morphogenetic Protein–2 in a Cancellous Bone Environment

Study Design. An experimental study investigating osteoclastic activity induced by rhBMP-2 in sheep. Objective. To examine the effects of increasing local rhBMP-2 concentration on osteoclastic response and peri-implant bone resorption. Summary of Background Data. Level I clinical studies have established the safe and effective volume and concentration of rhBMP-2 delivered on an absorbable collagen sponge. However, peri-implant bone resorption appearing as decreased mineral density has been observed radiographically in rare instances after implantation of rhBMP-2 on an absorbable collagen sponge (rhBMP-2/ACS). Methods. Bilateral corticocancellous defects were created in the distal femora of 30 adult sheep. Combinations of rhBMP-2/ACS implant volume (V) (1V = normal fill or 2V = overfilled) and rhBMP-2 solution concentration (⤫) (1 ⤫ normal concentration or 3.5 ⤫ = hyperconcentrated) resulted in local rhBMP-2 concentrations of 0⤫, 1⤫, 2⤫, 3.5⤫, and 7⤫ the estimated effective concentration for this model. Faxitron radiography, quantitative CT, histology, and quantitative histomorphometry were conducted in a blinded fashion to analyze the effect of the treatments. Results. At 1 week, the normal fill-normal concentration implants (1⤫) produced the least transient osteoclastic activity resulting in limited peri-implant resorption. Overfilledhyperconcentrated implants (2⤫, 3.5⤫) demonstrated moderate resorption zones. Overfilled-hyperconcentrated implants (7⤫) demonstrated extensive osteoclastic activity and marked resorption. Results at 4 and 8 weeks revealed dense osteoid and bone in the voids with progressive bony healing. Control defects showed no osteoclastic activity with little to no bony healing. Conclusion. Increasing the local rhBMP-2 concentration by overfilling the defect with rhBMP-2/ACS or hyper-concentrating the rhBMP-2 solution on the absorbable collagen sponge led to a concentration-dependent osteoclastic resorption of peri-implant bone. The osteoclastic effect was transient, and progressive healing took place over the 8-week survival period

Bone matrix components activate the NLRP3 inflammasome and promote osteoclast differentiation

AbstractThe NLRP3 inflammasome senses a variety of signals referred to as danger associated molecular patterns (DAMPs), including those triggered by crystalline particulates or degradation products of extracellular matrix. Since some DAMPs confer tissue-specific activation of the inflammasomes, we tested the hypothesis that bone matrix components function as DAMPs for the NLRP3 inflammasome and regulate osteoclast differentiation. Indeed, bone particles cause exuberant osteoclastogenesis in the presence of RANKL, a response that correlates with NLRP3 abundance and the state of inflammasome activation. To determine the relevance of these findings to bone homeostasis, we studied the impact of Nlrp3 deficiency on bone using pre-clinical mouse models of high bone turnover, including estrogen deficiency and sustained exposure to parathyroid hormone or RANKL. Despite comparable baseline indices of bone mass, bone loss caused by hormonal or RANKL perturbations is significantly reduced in Nlrp3 deficient than in wild type mice. Consistent with the notion that osteolysis releases DAMPs from bone matrix, pharmacologic inhibition of bone resorption by zoledronate attenuates inflammasome activation in mice. Thus, signals originating from bone matrix activate the NLRP3 inflammasome in the osteoclast lineage, and may represent a bone-restricted positive feedback mechanism that amplifies bone resorption in pathologic conditions of accelerated bone turnover.</jats:p

Strontium ranelate: A novel mode of action leading to renewed bone quality

Various bone resorption inhibitors and bone stimulators have been shown to decrease the risk of osteoporotic fractures. However, there is still a need for agents promoting bone formation by inducing positive uncoupling between bone formation and bone resorption. In vitro studies have suggested that strontium ranelate enhances osteoblast cell replication and activity. Simultaneously, strontium ranelate dose-dependently inhibits osteoclast activity. In vivo studies indicate that strontium ranelate stimulates bone formation and inhibits bone resorption and prevents bone loss and/or promotes bone gain. This positive uncoupling between bone formation and bone resorption results in bone gain and improvement in bone geometry and microarchitecture, without affecting the intrinsic bone tissue quality. Thus, all the determinants of bone strength are positively influenced. In conclusion, strontium ranelate, a new treatment of postmenopausal osteoporosis, acts through an innovative mode of action, both stimulating bone formation and inhibiting bone resorption, resulting in the rebalancing of bone turnover in favor of bone formation. Strontium ranelate increases bone mass while preserving the bone mineralization process, resulting in improvement in bone strength and bone qualit

Resorption controls bone anabolism driven by PTH receptor signaling in osteocytes

The contribution of remodeling-based bone formation coupled to osteoclast activity versus modeling-based bone formation that occurs independently of resorption, to the anabolic effect of PTH remains unclear. We addressed this question using transgenic mice with activated PTH receptor signaling in osteocytes that exhibit increased bone mass and remodeling, recognized skeletal effects of PTH elevation. Direct inhibition of bone formation was accomplished genetically by overexpressing the Wnt antagonist Sost/sclerostin; and resorption-dependent bone formation was inhibited pharmacologically with the bisphosphonate alendronate. We found that bone formation induced by osteocytic PTH receptor signaling on the periosteal surface depends on Wnt signaling but not on resorption. In contrast, bone formation on the endocortical surface results from a combination of Wnt-driven increased osteoblast number and resorption-dependent osteoblast activity. Moreover, elevated osteoclasts and intracortical/calvarial porosity is exacerbated by overexpressing Sost and reversed by blocking resorption. Furthermore, increased cancellous bone is abolished by Wnt inhibition but further increased by blocking resorption. Thus, resorption induced by PTH receptor signaling in osteocytes is critical for full anabolism in cortical bone, but tempers bone gain in cancellous bone. Dissecting underlying mechanisms of PTH receptor signaling would allow targeting actions in different bone compartments, enhancing the therapeutic potential of the pathway

Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts

Despite recent progress in its treatment, Multiple Myeloma (MM) remains incurable and its associated bone disease persists even after complete remission. Thus, identification of new therapeutic agents that simultaneously suppress MM growth and protect bone is an unmet need. Herein, we examined the effects of Aplidin, a novel anti-cancer marine-derived compound, on MM and bone cells. In vitro, Aplidin potently inhibited MM cell growth and induced apoptosis, effects that were enhanced by dexamethasone (Dex) and bortezomib (Btz). Aplidin modestly reduced osteocyte/osteoblast viability and decreased osteoblast mineralization, effects that were enhanced by Dex and partially prevented by Btz. Further, Aplidin markedly decreased osteoclast precursor numbers and differentiation, and reduced mature osteoclast number and resorption activity. Moreover, Aplidin reduced Dex-induced osteoclast differentiation and further decreased osteoclast number when combined with Btz. Lastly, Aplidin alone, or suboptimal doses of Aplidin combined with Dex or Btz, decreased tumor growth and bone resorption in ex vivo bone organ cultures that reproduce the 3D-organization and the cellular diversity of the MM/bone marrow niche. These results demonstrate that Aplidin has potent anti-myeloma and anti-resorptive properties, and enhances proteasome inhibitors blockade of MM growth and bone destruction

Tiludronate and clodronate do not affect bone structure or remodeling kinetics over a 60 day randomized trial

Background Tiludronate and clodronate are FDA-approved bisphosphonate drug therapies for navicular disease in horses. Although clinical studies have determined their ability to reduce lameness associated with skeletal disorders in horses, data regarding the effect on bone structure and remodeling is lacking. Additionally, due to off-label use of these drugs in young performance horses, effects on bone in young horses need to be investigated. Therefore, the purpose of this randomized, experimental pilot study was to determine the effect of tiludronate and clodronate on normal bone cells, structure and remodeling after 60 days in clinically normal, young horses. Additionally, the effect of clodronate on bone healing 60 days after an induced defect was investigated. Results All horses tolerated surgery well, with no post-surgery lameness and all acquired biopsies being adequate for analyses. Overall, tiludronate and clodronate did not significantly alter any bone structure or remodeling parameters, as evaluated by microCT and dynamic histomorphometry. Tiludronate did not extensively impact bone formation or resorption parameters as evaluated by static histomorphometry. Similarly, clodronate did not affect bone formation or resorption after 60 days. Sixty days post-defect, healing was minimally affected by clodronate. Conclusions Tiludronate and clodronate do not appear to significantly impact bone tissue on a structural or cellular level using standard dose and administration schedules