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Bisphosphonates inhibit surface-mediated osteogenesis.

ABSTRACT: Bisphosphonates (BPs) target osteoclasts, slowing bone resorption thus providing rationale to support osseointegration. However, BPs may negatively affect osteoblasts, impairing peri-implant bone formation. The goal of this study was to assess the effects BPs have on surface-mediated osteogenesis of osteoblasts. MG63 cells were cultured on 15-mm grade 2 titanium disks: smooth, hydrophobic-microrough, or hydrophilic-microrough (Institut Straumann AG, Basel, Switzerland). Tissue culture polystyrene (TCPS) was used as a control. At confluence, cells were treated with 0, 10^-8 , 10^-7 , and 10^-6 M of alendronate, zoledronate, or ibandronate for 24?hr. Sprague Dawley rats were also treated with 1 ?g/kg/day ibandronate or phosphate-buffered saline control for 5?weeks. Calvarial osteoblasts (rat osteoblasts [rOBs]) were isolated, characterized, and cultured on surfaces. Osteogenic markers in the media were quantified using ELISAs. BP treatment reduced osteocalcin, osteoprotegerin, osteopontin, bone morphogenetic protein-2, prostaglandin E₂ , transforming growth factor ?1, interleukin 10, and vascular endothelial growth factor in MG63 cells. The effect was more robust on rough surfaces, and higher concentrations of BPs stunted production to TCPS/PT levels. Ibandronate conditioned rOBs produced less osteogenic markers similar to direct BP treatment. These results suggest that BP exposure jeopardizes the pro-osteogenic response osteoblasts have to microstructured surfaces. Their effects persist in vivo and negatively condition osteoblast response in vitro. Clinically, BPs could compromise osseointegration.

SUBMITTER: Lotz EM

PROVIDER: S-EPMC7771223 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Bisphosphonates inhibit surface-mediated osteogenesis.

Lotz Ethan M EM Lohmann Christoph H CH Boyan Barbara D BD Schwartz Zvi Z

Journal of biomedical materials research. Part A 20200421 8

Bisphosphonates (BPs) target osteoclasts, slowing bone resorption thus providing rationale to support osseointegration. However, BPs may negatively affect osteoblasts, impairing peri-implant bone formation. The goal of this study was to assess the effects BPs have on surface-mediated osteogenesis of osteoblasts. MG63 cells were cultured on 15-mm grade 2 titanium disks: smooth, hydrophobic-microrough, or hydrophilic-microrough (Institut Straumann AG, Basel, Switzerland). Tissue culture polystyren ...[more]

PMID: 32276287

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Project description:BackgroundBisphosphonates are used to prevent the bone loss and fractures associated with osteoporosis, bone metastases, multiple myeloma, and osteogenesis deformans. Distal limb fractures cause regional bone loss with cutaneous inflammation and pain in the injured limb that can develop into complex regional pain syndrome (CRPS). Clinical trials have reported that antiresorptive bisphosphonates can prevent fracture-induced bone loss, inhibit serum inflammatory cytokine levels, and alleviate CRPS pain. Previously, we observed that the inhibition of inflammatory cytokines or adaptive immune responses attenuated the development of pain behavior in a rat fracture model of CRPS, and we hypothesized that bisphosphonates could prevent pain behavior, trabecular bone loss, postfracture cutaneous cytokine upregulation, and adaptive immune responses in this CRPS model.MethodsRats underwent tibia fracture and cast immobilization for 4 weeks and were chronically administered either subcutaneously perfused alendronate or oral zoledronate. Behavioral measurements included hindpaw von Frey allodynia, unweighting, warmth, and edema. Bone microarchitecture was measured by microcomputed tomography, and bone cellular activity was evaluated by static and dynamic histomorphometry. Spinal cord Fos immunostaining was performed, and skin cytokine (tumor necrosis factor, interleukin [IL]-1, IL-6) and nerve growth factor (NGF) levels were determined by enzyme immunoassay. Skin and sciatic nerve immunoglobulin levels were determined by enzyme immunoassay.ResultsRats with tibia fractures developed hindpaw allodynia, unweighting, warmth, and edema, increased spinal Fos expression and trabecular bone loss in the lumbar vertebra and bilateral distal femurs as measured by microcomputed tomography, increased trabecular bone resorption and osteoclast surface with decreased bone formation rates, increased cutaneous inflammatory cytokine and NGF expression, and elevated immunocomplex deposition in skin and nerve. Alendronate (60 μg/kg/d subcutaneously [s.c.]) or zoledronate (3 mg/kg/d orally) treatment for 28 days, started at the time of fracture, completely inhibited the development of hindpaw allodynia and reduced hindpaw unweighting by 44% ± 13% and 58% ± 5%, respectively. Orally administered zoledronate (3 mg/kg/d for 21 days) treatment also completely reversed established allodynia and unweighting when started at 4 weeks postfracture. Histomorphometric and microcomputed tomography analysis demonstrated that both the 3 and 60 μg/kg/d alendronate treatments reversed trabecular bone loss (an 88% ± 25% and 188% ± 39% increase in the ipsilateral distal femur BV/TV, respectively) and blocked the increase in osteoclast numbers and erosion surface observed in bilateral distal femurs and in L5 vertebra of the fracture rats. Alendronate treatment inhibited fracture-induced increases in hindpaw inflammatory mediators, reducing postfracture levels of tumor necrosis factor by 43% ± 9%, IL-1 by 60% ± 9%, IL-6 by 56% ± 14%, and NGF by 37% ± 14%, but had no effect on increased spinal cord Fos expression, or skin and sciatic nerve immunocomplex deposition.ConclusionsCollectively, these results indicate that bisphosphonate therapy inhibits pain, osteoclast activation, trabecular bone loss, and cutaneous inflammation in the rat fracture model of CRPS, data supporting the hypothesis that bisphosphonate therapy can provide effective multimodal treatment for CRPS.

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Bisphosphonates inhibit surface-mediated osteogenesis.

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Bisphosphonates inhibit surface-mediated osteogenesis.

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