In vivo effects of geranylgeraniol on the development of bisphosphonate-related osteonecrosis of the jaws

Koneski, Filip; Popovic-Monevska, Danica; Gjorgoski, Icko; Krajoska, Jovanka; Поповска, Мирјана; Muratovska, Ilijana; Velickovski, Boris; Petrushevska, Gordana; Popovski, V.

doi:10.1016/j.jcms.2017.11.007

Cited by 28 publications

(37 citation statements)

References 39 publications

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“…Other investigators have also shown that GGOH when delivered as a liquid in vivo directly to the extracted tooth socket "locally" and daily for 35 days resulted in improved socket healing in a rat model of MRONJ. [7] This delivery method would be impractical for human patients. It has been also shown that GGOH delivered systemically in the rat model can reverse the effects of MRONJ.…”

Section: Discussionmentioning

confidence: 99%

“…It has been also shown that GGOH delivered systemically in the rat model can reverse the effects of MRONJ. [7] Aside from the issue of GGOH toxicity, systemic administration might negate the anti-metatastic effect of nitrogen containing bisphosphonates in patients receiving chemotherapy for breast, lung and other cancers. The aim in this study is to develop a biocompatible, resorbable and tunable carrier that could be used as a vehicle to deliver GGOH locally to avoid these systemic effects.…”

Section: Discussionmentioning

confidence: 99%

“…Daily local administration of high concentrations of GGOH as shown by Koneski in the form of a spray would be impractical for the patient and an ine cient way of delivering this drug. [7] Currently, there is no method to deliver clinically effective doses of GGOH in a controllable manner to cells of the oral cavity.…”

Section: Introductionmentioning

confidence: 99%

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Geranylgeraniol in Bone Cement Rescues Osteoclasts from the Toxic Effects of Pamidronate and Restores Function

Feldman¹,

Yagnik²,

Taub³

et al. 2020

Preprint

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BackgroundExposed intraoral bone in medically related osteonecrosis of the jaw (MRONJ) is a devastatingly side effect of treatment with nitrogen containing bisphosphonates(NBPs) The pathogenesis of the condition is thought to be caused by NBP inhibition of farnesyl diphosphate synthase (FDPS), a critical enzyme in the mevalonate pathway. This block suppresses the prenylation of factors necessary for the maintenance and survival of osteoclasts. Geranylgeraniol (GGOH), a metabolite in the mevalonate pathway downstream of FDPS, reverses the block NBPs impose on osteoclasts. However, no effective method currently exists to deliver GGOH locally to NBP-induced lesions in the mouth. The purpose of this study is to develop a biocompatible, resorbable and tunable carrier to deliver GGOH intraorally and thereby reverse the damaging effects of MRONJ.MethodsPrimary human oral fibroblasts and RAW264.7 osteoclasts were exposed to pamidronate in vitro and GGOH contained within a bone cement pellet and survival of the cells was measured. The kinetics of release of 3HGGOH from the bone cement was measured.. The resorptive function of osteoclasts exposed to pamidronate with or without GGOH was quantitated by measuring the release of bound fluorescent dye from a CaPO4 coated plate. Resorption areas on this plate were photographed.ResultsHuman gingival fibroblasts exposed to pamidronate (100uM) alone decreased survival by 49% (p<0.001) over 72 hours, 2mM GGOH incorporated into bone cement rescued these cells from the toxic effect of NBP (p=0.0024).Exposure of osteoclasts to 400 and 800uM pamidronate over 72 hours showed a 49% and 69% loss of viability respectively. (p<0.0001 for each concentration). 2mM GGOH incorporated into bone cement increased survival by 247% (p=0.0001) for the cells treated with 800uM pamidronate and 4mM GGOH by 450% (p<0.0001). Pamidronate at both concentrations reduced osteoclast function and 4mM GGOH completely restored resorbtive function. At a powder to liquid ration of 2.5:1 92% of the loaded metabolite was released into medium after in 96 hours.ConclusionsGGOH contained in a bone cement carrier can rescue osteoclast function from the toxic effects of pamidronate. This carrier may be the first step in local delivery of this metabolite in the oral cavity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Geranylgeraniol in Bone Cement Rescues Osteoclasts from the Toxic Effects of Pamidronate and Restores Function

Feldman¹,

Yagnik²,

Taub³

et al. 2020

Preprint

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“…Despite their positive effectiveness on bone disorders, most of these drugs carry concerning side effects [ 24 ]. For example, bisphosphonates have been widely used to manage bone disease, but they are reported to induce severe side effects such as BRONJ (bisphosphonate-related osteonecrosis of the jaw) and esophageal irritation [ 25 – 27 ]. Estrogen and raloxifene therapy for osteoporosis is associated with thromboembolism [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

Cordycepin Accelerates Osteoblast Mineralization and Attenuates Osteoclast Differentiation In Vitro

Kim

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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Bone homeostasis destruction is triggered by the uncontrolled activity of osteoblasts and osteoclasts. Targeting both the regulation of bone formation and resorption is a promising strategy for treating bone disorders. Cordycepin is a major component of Chinese caterpillar fungus Cordyceps militaris. It exerts a variety of biological actions in various cells and animal models. However, its function on bone metabolism remains unclear. In the present study, we discovered a dual-action function of cordycepin in murine MC3T3-E1 and RAW264.7 cells. MC3T3-E1 cells were cultured in an osteogenic medium in the presence of 1 μM cordycepin for up two weeks. Cordycepin was used for effects of osteoblast and osteoclast differentiation. Cell viability was measured using the MTT assay. Osteoblast differentiation was confirmed by alizarin red staining, ALP activity, western blot, and real-time PCR. Osteoclast differentiation and autophagic activity were confirmed via TRAP staining, pit formation assay, confocal microscopy, western blot, and real-time PCR. Cordycepin promoted osteoblast differentiation, matrix mineralization, and induction of osteoblast markers via BMP2/Runx2/Osterix pathway. On the other hand, RAW264.7 cells were differentiated into osteoclast by RANKL treatment for 72 h. 1 μM cordycepin significantly inhibited RANKL-induced osteoclast formation and resorption activity through disturbing the actin ring-formatted sealing zone and activating cathepsin K and MMP9. These findings indicate that cordycepin might be an innovative dual-action therapeutic agent for bone disease caused by an imbalance of osteoblasts and osteoclasts.

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“…Various methods, materials, and drugs have been investigated to prevent this complication and some have proven somewhat effective, but none have been approved as a standard method of prevention. Among these methods are the use of triparatide (adjunctive parathyroid hormone) [12][13][14] , autologous platelet concentrate 15 , human mesenchymal stem cells 3,16 , antibiotics (penicillin) 17 , vitamin D 18 , and geranylgeraniol 19 . (Table 1) Melatonin is a hormone secreted by numerous organs, including the pineal gland, the retina, bone marrow, digestive tract, and immune system.…”

Section: Introductionmentioning

confidence: 99%

The effect of melatonin on prevention of bisphosphonate-related osteonecrosis of the jaw: an animal study in rats

Yadegari

Aminzadeh

Seyyedkhamesi

et al. 2020

JKAOMS

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Objectives: Melatonin induces human stem cells, converts pre-osteoblasts to mature osteoblasts, and reduces the duration of this transition. However, melatonin itself prevents activation of osteoclasts. Here, we evaluate the role of melatonin in prevention of bisphosphonate-related osteonecrosis of the jaw. Materials and Methods: In this experimental-interventional study, 30 rats were evaluated in 3 groups. The first and second groups received saline and zoledronic acid, respectively, for 4 weeks and the third group received 4 weeks of zoledronic acid and 3 weeks of melatonin simultaneously. Firstright-maxillary-molar extraction was performed for all animals, which were sacrificed after 4 weeks of recovery. The extraction sockets were examined histologically for the presence of osteonecrosis, number of osteoclasts and fibroblasts, severity of inflammation, and vascularization. Data were analyzed by chi-square, one-way ANOVA, Tukey, Kruskal-Wallis and Fisher's exact statistical tests (α=0.05). Results: Osteonecrosis was observed in 20%, 90%, and 70% of the first, second and third groups, respectively (P=0.008). The lowest number of osteoclasts and fibroblasts was seen in the third group. Conclusion: Melatonin may effectively prevent some undesirable side effects of bisphosphonates. However, further studies are required to confirm the results of this study.

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In vivo effects of geranylgeraniol on the development of bisphosphonate-related osteonecrosis of the jaws

Cited by 28 publications

References 39 publications

Geranylgeraniol in Bone Cement Rescues Osteoclasts from the Toxic Effects of Pamidronate and Restores Function

Geranylgeraniol in Bone Cement Rescues Osteoclasts from the Toxic Effects of Pamidronate and Restores Function

Cordycepin Accelerates Osteoblast Mineralization and Attenuates Osteoclast Differentiation In Vitro

The effect of melatonin on prevention of bisphosphonate-related osteonecrosis of the jaw: an animal study in rats

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