Accepted Manuscript Statins and alveolar bone resorption: a narrative review of preclinical and clinical studies Erwan de Monès, MD Silke Schlaubitz, PhD Sylvain Catros, DDS, PhD JeanChristophe Fricain, DDS, PhD PII:
S2212-4403(14)01303-0
DOI:
10.1016/j.oooo.2014.09.030
Reference:
OOOO 1034
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 29 May 2014 Revised Date:
14 August 2014
Accepted Date: 10 September 2014
Please cite this article as: de Monès E, Schlaubitz S, Catros S, Fricain J-C, Statins and alveolar bone resorption: a narrative review of preclinical and clinical studies, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2014), doi: 10.1016/j.oooo.2014.09.030. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Statins and alveolar bone resorption: a narrative review of preclinical and clinical studies. Erwan de Monès Fricain
a,b,e
a,b, c
MD, Silke Schlaubitz
b,d
PhD, Sylvain Catros
a,b,e
DDS, PhD, Jean-Christophe
DDS, PhD
a
INSERM U1026, Tissue Bioengineering,146 rue Léo-Saignat, F-33000 Bordeaux, France Univ. Bordeaux, 146 rue Léo-Saignat, F-33000 Bordeaux, France c Department of Otolaryngology - Head and Neck Surgery, Univ. Bordeaux, Place Amélie Raba Léon, F-33000 Bordeaux, France d Bordeaux University Hospital, CIC 1401, PTIB, Xavier Arnozan Hospital, F-33600 Pessac, France e Department of Dentistry, Univ. Bordeaux, Place Amélie Raba Léon, F-33000 Bordeaux, France
RI PT
b
Erwan de Monès: [email protected]
Sylvain Catros: [email protected]
SC
Silke Schlaubitz: [email protected]
M AN U
Jean-Christophe Fricain: [email protected]
Corresponding author:
TE D
Dr. Erwan de Monès Service d’otorhinolaryngologie Hôpital Pellegrin Place Amélie Raba Léon 33076 Bordeaux cedex France Email : [email protected] Business telephone: + 33 5 56 79 59 71 Fax number: + 33 5 56 79 87 68
Disclosures: This work was not supported by any funding source. The authors have no conflict of interest.
EP
Word count for the abstract: 131
Complete manuscript word count: 5202 (including abstract, 3 tables and references) Number of figures/tables: 3 tables
AC C
Number of references: 39
ACCEPTED MANUSCRIPT
Abstract Context: Tooth extraction and periodontal disease are both common clinical situations associated with alveolar bone loss.
RI PT
Purpose: The objective was to analyze the reported results of in vivo studies investigating the effectiveness of statins to reduce alveolar bone resorption.
Material and methods: Systematic electronic search of the MEDLINE-Pubmed database.
Results: A total of 21 studies satisfied the inclusion criteria. This review showed that the use of statins
SC
reduced significantly alveolar bone resorption observed during periodontal disease and after tooth extraction. Oral administration was effective using high statin concentrations although local
M AN U
administration using a biodegradable carrier was effective with lower concentrations. It was recently reported that statins were effective to reduce alveolar bone loss as an adjunct to SRP in several clinical trials. Further studies are needed to confirm these promising results.
AC C
EP
TE D
Key words: statin; alveolar bone resorption; tooth extraction; periodontitis
ACCEPTED MANUSCRIPT
Introduction Tooth extraction and periodontal disease are both common clinical situations associated with alveolar bone loss. Following tooth extraction, human studies showed horizontal bone loss of 29-63% and 1
vertical bone loss of 11-22% after 6 months . This alveolar bone resorption may compromise
RI PT
prosthetic and dental implant rehabilitations. Various techniques have been investigated to preserve 2
alveolar ridge (early implantation, bone substitutes, primary flap closure) .. Considering periodontal diseases, up to 50% of the adult population suffer from chronic periodontitis 3. If left untreated, the 4
SC
destruction of the tooth-supporting tissue may lead to teeth loss .
Statins are molecules that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the proximal and rate-limiting enzyme in the mevalonate pathway. They are widely prescribed for their
M AN U
lipid-lowering activity thanks to the decreased hepatic synthesis of cholesterol. Statin therapy is 5
essential in the primary and secondary prevention of coronary artery disease . Recent experimental and clinical evidence suggests that the beneficial effects of statins may extend beyond their cholesterol-lowering effects, to include so-called pleiotropic effects
6,7
. Since first reports by Mundy et
al. in 1999, it has been reported that several statins have anabolic effects on bone metabolism
8,9
. It
TE D
has been clarified that statins stimulate osteoblastic differentiation by increasing the gene expression of BMP-2 10. Statins may also increase bone formation by inhibiting osteoblast apoptosis 9. Since bone is constantly remodeling, which includes formation and resorption, inhibition of osteoclast activity contributes to bone preservation. It has been reported that statins decrease osteoclastic activity 11,12
.
EP
through the RANK-ROS pathway
The primary objectives of this narrative review were to evaluate recent pre-clinical and clinical studies
AC C
that investigated the effectiveness of statins to decrease alveolar bone resorption after tooth extraction and as a therapeutic adjuvant in the management of periodontal disease. Secondary objectives were to report the drug delivery strategies and drug concentrations used to deliver statins. Material and methods : Search strategy: A systematic electronic search of the MEDLINE-Pubmed database was conducted, for articles published in English between January 1990 and March 2014. The following key words were used: (“HMGCoA reductase” OR “statin” OR “simvastatin” OR “atorvastatin” OR “fluvastatin” OR
ACCEPTED MANUSCRIPT
“rosuvastatin”) AND (“bone regeneration” OR “bone healing” OR “alveolar bone” OR “periodontol desease”, “periodontology” OR “mandibule” OR “tooth extraction” OR “periodontitis”). Furthermore, the bibliographies of all publications selected for inclusion in this review were also scanned for potentially relevant articles.
RI PT
Selection criteria:
Studies were included if they were conducted on animal or human subjects, with a tooth extraction or an inflammatory alveolar bone defect, with systemic or local statin administration, and if the outcome
SC
was assessed in the form of changes in the clinical, radiological or histological alveolar bone characteristics.
M AN U
Selection of studies:
The initial electronic search resulted in the identification of 845 titles from the MEDLINE-Pubmed database. After careful independent screening of the titles, a total of 166 titles were considered for possible inclusion. Retrieval of the 166 abstracts led to 28 full-text articles being selected. From these 28 studies, 7 clinical studies were excluded because they were cross sectional observational studies and not randomized clinical trials. Collectively, a total of 21 studies (14 animal studies and 7
TE D
randomized clinical trials) were included in this review (tables 1, 2, and 3). Reported methods used to analyze the effectiveness of statins against alveolar bone loss are presented in the tables for each
Results :
EP
study. Only results that reached statistical significance have been reported (p value < 0.05).
AC C
Statins effects for alveolar socket preservation: animal studies (table 1) The effectiveness of statin on residual ridge resorption following tooth extraction has been reported in 3 studies with local simvastatin application PLGA (poly-lactic-co-glycolic acid)
13–15
. For 2 studies, simvastatin was locally applied with
13,14
.. The relative height of the residual alveolar ridge in the
experimental group (simvastatin-PLGA) was significantly larger compared to the control group (PLGA alone) (after 12 weeks: 96% versus 92 %; p=0.014). Histological examination revealed more newly formed bone in the experimental group after 2 weeks and less infiltration of inflammatory cells, but no histomorphometric analysis has been performed. Bone mineral density increased 4 weeks after
ACCEPTED MANUSCRIPT
implantation onset, measured by dual-energy X-ray absorptiometry (p=0.014). Scaffolds were completely replaced by newly formed woven bone in the tooth socket in both groups at 12 weeks, but the bone deposition line was remarkably obvious in the experimental group. In-situ hybridization revealed significant increased expression of different growth factors involved in bone regeneration
RI PT
(TGF-β1, VEGF and BMP-2) in the experimental group compared to control group (p
S2212-4403(14)01303-0
DOI:
10.1016/j.oooo.2014.09.030
Reference:
OOOO 1034
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 29 May 2014 Revised Date:
14 August 2014
Accepted Date: 10 September 2014
Please cite this article as: de Monès E, Schlaubitz S, Catros S, Fricain J-C, Statins and alveolar bone resorption: a narrative review of preclinical and clinical studies, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2014), doi: 10.1016/j.oooo.2014.09.030. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Statins and alveolar bone resorption: a narrative review of preclinical and clinical studies. Erwan de Monès Fricain
a,b,e
a,b, c
MD, Silke Schlaubitz
b,d
PhD, Sylvain Catros
a,b,e
DDS, PhD, Jean-Christophe
DDS, PhD
a
INSERM U1026, Tissue Bioengineering,146 rue Léo-Saignat, F-33000 Bordeaux, France Univ. Bordeaux, 146 rue Léo-Saignat, F-33000 Bordeaux, France c Department of Otolaryngology - Head and Neck Surgery, Univ. Bordeaux, Place Amélie Raba Léon, F-33000 Bordeaux, France d Bordeaux University Hospital, CIC 1401, PTIB, Xavier Arnozan Hospital, F-33600 Pessac, France e Department of Dentistry, Univ. Bordeaux, Place Amélie Raba Léon, F-33000 Bordeaux, France
RI PT
b
Erwan de Monès: [email protected]
Sylvain Catros: [email protected]
SC
Silke Schlaubitz: [email protected]
M AN U
Jean-Christophe Fricain: [email protected]
Corresponding author:
TE D
Dr. Erwan de Monès Service d’otorhinolaryngologie Hôpital Pellegrin Place Amélie Raba Léon 33076 Bordeaux cedex France Email : [email protected] Business telephone: + 33 5 56 79 59 71 Fax number: + 33 5 56 79 87 68
Disclosures: This work was not supported by any funding source. The authors have no conflict of interest.
EP
Word count for the abstract: 131
Complete manuscript word count: 5202 (including abstract, 3 tables and references) Number of figures/tables: 3 tables
AC C
Number of references: 39
ACCEPTED MANUSCRIPT
Abstract Context: Tooth extraction and periodontal disease are both common clinical situations associated with alveolar bone loss.
RI PT
Purpose: The objective was to analyze the reported results of in vivo studies investigating the effectiveness of statins to reduce alveolar bone resorption.
Material and methods: Systematic electronic search of the MEDLINE-Pubmed database.
Results: A total of 21 studies satisfied the inclusion criteria. This review showed that the use of statins
SC
reduced significantly alveolar bone resorption observed during periodontal disease and after tooth extraction. Oral administration was effective using high statin concentrations although local
M AN U
administration using a biodegradable carrier was effective with lower concentrations. It was recently reported that statins were effective to reduce alveolar bone loss as an adjunct to SRP in several clinical trials. Further studies are needed to confirm these promising results.
AC C
EP
TE D
Key words: statin; alveolar bone resorption; tooth extraction; periodontitis
ACCEPTED MANUSCRIPT
Introduction Tooth extraction and periodontal disease are both common clinical situations associated with alveolar bone loss. Following tooth extraction, human studies showed horizontal bone loss of 29-63% and 1
vertical bone loss of 11-22% after 6 months . This alveolar bone resorption may compromise
RI PT
prosthetic and dental implant rehabilitations. Various techniques have been investigated to preserve 2
alveolar ridge (early implantation, bone substitutes, primary flap closure) .. Considering periodontal diseases, up to 50% of the adult population suffer from chronic periodontitis 3. If left untreated, the 4
SC
destruction of the tooth-supporting tissue may lead to teeth loss .
Statins are molecules that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the proximal and rate-limiting enzyme in the mevalonate pathway. They are widely prescribed for their
M AN U
lipid-lowering activity thanks to the decreased hepatic synthesis of cholesterol. Statin therapy is 5
essential in the primary and secondary prevention of coronary artery disease . Recent experimental and clinical evidence suggests that the beneficial effects of statins may extend beyond their cholesterol-lowering effects, to include so-called pleiotropic effects
6,7
. Since first reports by Mundy et
al. in 1999, it has been reported that several statins have anabolic effects on bone metabolism
8,9
. It
TE D
has been clarified that statins stimulate osteoblastic differentiation by increasing the gene expression of BMP-2 10. Statins may also increase bone formation by inhibiting osteoblast apoptosis 9. Since bone is constantly remodeling, which includes formation and resorption, inhibition of osteoclast activity contributes to bone preservation. It has been reported that statins decrease osteoclastic activity 11,12
.
EP
through the RANK-ROS pathway
The primary objectives of this narrative review were to evaluate recent pre-clinical and clinical studies
AC C
that investigated the effectiveness of statins to decrease alveolar bone resorption after tooth extraction and as a therapeutic adjuvant in the management of periodontal disease. Secondary objectives were to report the drug delivery strategies and drug concentrations used to deliver statins. Material and methods : Search strategy: A systematic electronic search of the MEDLINE-Pubmed database was conducted, for articles published in English between January 1990 and March 2014. The following key words were used: (“HMGCoA reductase” OR “statin” OR “simvastatin” OR “atorvastatin” OR “fluvastatin” OR
ACCEPTED MANUSCRIPT
“rosuvastatin”) AND (“bone regeneration” OR “bone healing” OR “alveolar bone” OR “periodontol desease”, “periodontology” OR “mandibule” OR “tooth extraction” OR “periodontitis”). Furthermore, the bibliographies of all publications selected for inclusion in this review were also scanned for potentially relevant articles.
RI PT
Selection criteria:
Studies were included if they were conducted on animal or human subjects, with a tooth extraction or an inflammatory alveolar bone defect, with systemic or local statin administration, and if the outcome
SC
was assessed in the form of changes in the clinical, radiological or histological alveolar bone characteristics.
M AN U
Selection of studies:
The initial electronic search resulted in the identification of 845 titles from the MEDLINE-Pubmed database. After careful independent screening of the titles, a total of 166 titles were considered for possible inclusion. Retrieval of the 166 abstracts led to 28 full-text articles being selected. From these 28 studies, 7 clinical studies were excluded because they were cross sectional observational studies and not randomized clinical trials. Collectively, a total of 21 studies (14 animal studies and 7
TE D
randomized clinical trials) were included in this review (tables 1, 2, and 3). Reported methods used to analyze the effectiveness of statins against alveolar bone loss are presented in the tables for each
Results :
EP
study. Only results that reached statistical significance have been reported (p value < 0.05).
AC C
Statins effects for alveolar socket preservation: animal studies (table 1) The effectiveness of statin on residual ridge resorption following tooth extraction has been reported in 3 studies with local simvastatin application PLGA (poly-lactic-co-glycolic acid)
13–15
. For 2 studies, simvastatin was locally applied with
13,14
.. The relative height of the residual alveolar ridge in the
experimental group (simvastatin-PLGA) was significantly larger compared to the control group (PLGA alone) (after 12 weeks: 96% versus 92 %; p=0.014). Histological examination revealed more newly formed bone in the experimental group after 2 weeks and less infiltration of inflammatory cells, but no histomorphometric analysis has been performed. Bone mineral density increased 4 weeks after
ACCEPTED MANUSCRIPT
implantation onset, measured by dual-energy X-ray absorptiometry (p=0.014). Scaffolds were completely replaced by newly formed woven bone in the tooth socket in both groups at 12 weeks, but the bone deposition line was remarkably obvious in the experimental group. In-situ hybridization revealed significant increased expression of different growth factors involved in bone regeneration
RI PT
(TGF-β1, VEGF and BMP-2) in the experimental group compared to control group (p
