dental implants are now a reliable solution for the functional and esthetic rehabilitation of partially and completely edentulous patients ; this has been demonstrated by long - term clinical trials , with survival rates of greater than 95% [ 13 ] . in order to achieve long - term survival , osseointegration of the dental implant
needs to occur ; that is , a direct connection must be established between the bone and the implant surface , without the interposition of fibrous tissue ; once established , this close bond must be maintained over time , resulting in a clinically asymptomatic fixation of the implant under functional load .
osseointegration is a complex phenomenon and depends on many factors ; some are related to the implant ( material , macroscopic design , and implant surface ) , others to the surgical - prosthetic protocol ( surgical technique , loading conditions , and time ) , and others to the patient ( quantity / quality of bone at the receiving site and the host response ) [ 4 , 5 ] . although survival rates of dental implants are now high , there still remains a seemingly unavoidable number of failures : either cases in which correctly placed implants do not integrate with the bone or cases of peri - implant tissue infection [ 6 , 7 ] . to be specific , failure to osseointegrate and peri - implantitis are the most frequent causes of early implant failure [ 3 , 6 , 7 ] .
such events occur during the early stages of healing ( within 2 - 3 months of implantation ) and therefore before the implant is functionally loaded with the prosthetic restoration ; these failures are unevenly distributed within the general population and tend to occur in some subjects in particular . in these individuals
early failures occur even when optimal materials are used , surgical protocols are strictly followed , and the quantity / quality of bone at the recipient site is sufficient [ 68 ] .
all these observations would suggest the existence of specific patient - related risk factors ; this prompts an investigation into the regulatory mechanisms controlling bone metabolism , bone remodelling , and bone turnover [ 9 , 10 ] .
it is a fat - soluble vitamin which promotes the absorption of calcium in the intestine and regulates calcium and phosphate homoeostasis in the tissues and it is a fundamental element in the mineralization of bones and teeth [ 1113 ] .
it also acts as a hormone and is vital for the health of the blood vessels and the brain [ 14 , 15 ] .
it has been demonstrated that vitamin d plays a crucial role in the health of the cardiovascular tract , the immune system , and the respiratory tract [ 18 , 19 ] .
vitamin d in an inactive form ( cholecalciferol or vitamin d3 ) is ingested or produced in the skin on exposure to sunlight [ 11 , 12 ] .
this inactive form undergoes double hydroxylation in the liver and the kidneys and is thereby transformed into its active form , known as either calcitriol or 1,25-dihydroxyvitamin d3 [ 11 , 12 ] .
this active form exerts its action on various tissues by binding to the vitamin d receptors and regulating the transcription of specific target genes [ 1223 ] .
serum levels of vitamin d in the 25(oh)d form are the most accurate way of determining vitamin d status : a subject with < 10  ng / ml is considered to be vitamin d deficient ; one with 1030  ng / ml is considered to have low levels of vitamin d. the optimal blood level of vitamin d is a value > 30  ng / ml [ 12 , 13 ] .
vitamin d deficiency is high in the general population : in italy , for example , it is estimated that about 80% of people can be deficient , particularly in the northern regions where exposure to the sun is lower .
this deficiency increases with age and encompasses the majority of the elderly population of italy who are not taking vitamin d supplements . until a few years ago , the guidelines estimated that the daily intake of vitamin d required to maintain adequate blood levels was 200  iu ( 5  mcg ) in adults aged between 19 and 50 , 400  iu ( 10  mcg ) in adults aged between 51 and 69 , and at least 600  iu ( 15  mcg ) in those over 70 [ 12 , 13 ] .
these guidelines have now been revised upwards and it is currently believed that the amount of vitamin d which should be taken daily is 2000  iu ( 50  mcg ) and up to 4000 ( 100  mcg ) in the case of , for example , pregnant women [ 12 , 13 ]
. there is now substantial literature on the negative effects of low levels of vitamin d , especially in severely compromised patients : vitamin d deficiency seems to be associated with increased mortality , cardiovascular events , and reduced functioning of the immune and musculoskeletal systems [ 1519 , 2123 ] . on the other hand , normalizing levels of vitamin d can lead to substantial benefits for critically ill patients , with effects on the muscles , the respiratory system , the heart , and the immune system [ 18 , 21 , 23 ] . despite the importance of vitamin d and its effects on bone metabolism [ 11 , 12 ] few studies have , to date , investigated the effects of its depletion on the osseointegration of dental implants [ 9 , 2435 ] : almost all these studies have been done on animal models [ 2432 ] and very few on humans [ 3335 ] .
the purpose of this retrospective study was therefore to investigate any possible correlation between low blood levels of vitamin d and early implant failure ( failure occurring in the four months prior to the full restoration of the implant , because of a lack of osseointegration or because of infection ) .
all patients who had been treated with morse - taper connection dental implants ( leone implant system , florence , italy ) [ 3 , 8 ] inserted to support fixed prosthetic restorations in one single dental centre ( gravedona , como , italy ) , in the period between january 2003 and december 2015 , were evaluated for possible enrollment into this retrospective study .
patients were enrolled into the study if they were over 18 years of age , had good oral and general health , and had not undergone bone regenerative therapy prior to implant placement .
the exclusion criteria were incomplete medical records , the presence of specific systemic diseases ( uncontrolled diabetes mellitus , immunodeficient states , and bleeding disorders ) , and the abuse of alcohol and drugs ; patients undergoing radiotherapy and chemotherapy and those who were pregnant were also excluded .
all the data used for the study were obtained from the medical records of the patients enrolled .
the patient data was evaluated ; this included gender ( male or female ) , age at time of surgery , history of chronic periodontal disease , smoking habits , and serum vitamin d levels .
vitamin d levels were taken from blood tests , which had been requested two weeks prior to surgery .
the medical records also contained a range of information as regards the implant or implants , that is , their site ( maxilla or mandible ) , location ( incisor , canine , premolar , and molar ) , the length and diameter of the implant , the type of prosthetic restoration , and the loading conditions .
these included their cause ( lack of osseointegration in the absence of infection , infection of the peri - implant tissues or peri - implantitis , or implant failure due to progressive bone loss caused by to prosthetic overload ) .
it also included their classification : early failure , occurring in the early healing period , that is , the four months after implant placement , prior to the placement of restoration and loading , or late failure , occurring after loading .
there were also details of any possible biological complications ( peri - implant mucositis and peri - implantitis ) and/or prosthetic complications ( mechanical and/or technical ) .
all implants were inserted under the same strict protocol by the same specialist ( c. m. ) who had 25 years ' experience in implant dentistry , in the period between january 2003 and december 2015 .
the implants were inserted after raising a full thickness mucoperiosteal flap ; the implant site preparation and implant placement were performed in compliance with modern surgical protocols and in accordance with the manufacturer 's instructions .
after placement , cover screw was positioned and the implants were submerged . immediately after positioning , patients were prescribed antibiotic coverage with 2  g of amoxicillin ( or 600  mg of clindamycin in patients allergic to penicillins ) for 6 days .
patients were given detailed instructions on oral hygiene and were prescribed chlorhexidine 0.12% mouth rinse twice a day for 6 days .
the implants were left to heal submerged for a total period of 4 months , to allow undisturbed healing and achieve osseointegration .
after 4 months of undisturbed healing , the patient was recalled for the implant to be uncovered .
two weeks later , the sutures were removed and an impression was taken for the manufacture of the temporary restoration .
the temporary restoration was maintained in situ for 3 months , in order to monitor the response of the implant , as well as the peri - implant tissues , to masticatory load ; at the end of this period , the temporary restoration was replaced with the final restoration .
the final restorations were metal porcelain , cemented with a zinc oxide - eugenol cement . a periapical radiograph was taken to check on the sealing of the restoration .
all patients were included in a follow - up protocol with an annual check - up at one of the scheduled professional oral hygiene sessions .
early implant failure , occurring within 4 months after implant placement and therefore prior to placement of the prosthetic restoration and the functional load of the implant , was the primary outcome studied .
early implant failures were divided into two different categories : ( a ) early failures due to lack of osseointegration and subsequent implant mobility , in the absence of clinical signs of infection ; ( b ) early failures due to infection of the bone tissue around the implant , with inflammation ( peri - implantitis ) of peri - implant tissues and the presence of fistula , pain , swelling , pus and/or exudate , pocket depth > 6  mm with bleeding , and marginal bone resorption > 2.5  mm .
all the data retrieved from the individual medical records were recorded on a generic spreadsheet ( excel , microsoft office , redmond , ma , usa ) which was used for the descriptive , qualitative , and quantitative analyses .
the mean , standard deviation , median , and confidence intervals were calculated for the quantitative variables ( e.g. , patients ' age and vitamin d levels in serum ) .
a patient - based technique was used to calculate implant survival . in this analysis ,
the  event  was implant failure : thus in patients receiving more than one implant , the occurrence of even a single implant failure led to the patient being classified as a  failure . 
the influence of different variables on implant survival was taken into consideration : gender ( male or female ) , age at time of surgery ( three age groups were examined : < 40 , 4060 years , and > 60 years ) , smoking habits ( regardless of the actual number of cigarettes smoked ) , a history of chronic periodontitis , and serum levels of vitamin d. in the analysis of serum levels of vitamin d , three classes of patients were considered : severely deficient patients ( serum vitamin d < 10  ng / ml ) , patients with low levels ( serum vitamin d between 10 and 30  ng / ml ) , and patients with adequate levels ( serum vitamin d > 30  ng / ml ) .
the influence of each of these variables on implant survival was calculated using the chi square test .
the overall implant survival , the survival within the different groups , and the analysis of the influence of the different variables on survival were all made using dedicated statistical analysis software ( spss 17.0 , spss inc . ,
of the 915 patients originally evaluated for enrollment in this study , 93 presented with conditions corresponding to the exclusion criteria and were therefore excluded from the assessment . by contrast , 822 patients ( mean age 57.3  14.2 years ; median age 58 ; range 1890 ; and 95% ci , 56.358.2 ) , receiving 1625 implants , did not have any of the conditions contained in the exclusion criteria and were therefore enrolled into this retrospective study .
the distribution of patients by groups , with relative incidence of failures , was reported in table 1 . in total , 27 early failures were recorded ( 19 due to failure of osseointegration and 8 due to peri - implant tissue infection ) , with an overall incidence of 3.2% .
no differences were observed in the incidence of early failures between males and females ( p = 0.97 ) nor according to age at time of surgery ( p = 0.98 ) .
although the percentage of early failures in smokers was slightly higher than that detected in nonsmokers , there was no statistically significant difference ( p = 0.56 ) between these two groups of patients . the same was true for patients with a history of periodontal disease ; they displayed a slightly higher incidence of early failures than patients who had not been affected by periodontitis , but this difference was not significant ( p = 0.73 ) .
the average serum level of vitamin d in the general population was 29.9  ng / ml ( 12.1 ; median 29 ; range 573 ; and 95% ci , 29.130.7 ) . in patients in whom early implant failure occurred ,
the average serum level of vitamin d was 25.5 ( 13.2 ; median 24 ; range 855 ; and 95% ci , 20.630.4 ) .
statistical analysis reported a rather low incidence of early failures ( 2.2% ) in patients with blood vitamin d levels > 30  ng / ml . the incidence of early failure was almost double in patients with insufficient serum levels of vitamin d ( 1030  ng / ml ) and became even higher ( 9.0% ) in patients with serious vitamin d deficiency . although the statistical analysis revealed a trend toward an increased incidence of failure in patients with severe vitamin d deficiency , the analysis did not reveal a statistically significant difference ( p = 0.15 ) in the incidence of early implant failure in these three groups of patients .
similar results ( p = 0.14 ) were obtained comparing the incidence of failures in the group of severely deficient patients ( 2/22 : 9.0% ) with the incidence of failures in all other patients ( 25/800 : 3.1% ) . finally , the statistical analysis did not reveal a significant difference ( p = 0.13 ) when comparing the incidence of failures in the group of patients with serum vitamin d levels > 30  ng / ml ( 9/394 : 2.2% ) with the incidence of failures in all other patients ( 18/428 : 4.2% ) .
a relatively small number of experimental studies has attempted to investigate the effects of vitamin d on the osseointegration of dental implants [ 2432 ] .
the majority of these studies would appear to indicate a positive effect of vitamin d on osseointegration , but it is not yet entirely clear whether supplementation would promote the healing of peri - implant bone tissue clinically [ 24 , 3335 ] .
a recent review of the literature on animal studies has shown that vitamin d supplementation can stimulate new bone formation and increase the contact between the bone and the surface of titanium implants .
specifically , kelly et al . demonstrated that vitamin d deficiency could significantly compromise the establishment of osseointegration of ti6al4v implants in rats .
in an experimental study on ovariectomized rats , the authors demonstrated that vitamin d deficiency could impair the formation of peri - implant bone ; the normalization of blood levels via supplementation of vitamin d stimulated new bone formation .
similar results were reported by zhou et al . , who found an increase in osseointegration in osteoporotic rats given vitamin d supplements , and wu et al . , who demonstrated an increase in the percentage of contact between bone and implant in diabetic rats given vitamin d supplements .
finally , liu et al . reported that the administration of vitamin d could increase the fixation of dental implants in mice suffering from chronic kidney disease . a further possibility for study , in order to understand the effects of the administration of vitamin d on bone healing of the peri - implant tissues , is that of coating the implant surface with vitamin d [ 3032 ] .
evaluated the effect of the topical application of vitamin d to the surface of implants inserted in postextraction sockets in dogs , with histological and histomorphometric analyses of tissues removed at 12 weeks .
topical application of vitamin d increased the percentage of bone to implant contact of 10% .
similarly promising results were reported by cho et al . in a histological and histomorphometric study on rabbits , where the coating of anodized implant surfaces with a solution of poly(d , l - lactide - co - glycolide ) plga and 1,25-dihydroxyvitamin d3 ( 1,25-(oh)2d3 ) stimulated the apposition of new bone on fixtures . finally ,
in a further experimental work in rabbits , implants with a surface coated in 1,25-(oh)2d3 have shown an improved tendency to osseointegrate compared to noncoated implants ; however , this difference was not statistically significant .
unfortunately , very few clinical studies have so far investigated the effects of vitamin d deficiency on osseointegration and on bone regeneration in dentistry [ 3335 ] .
this is probably due to the fact that there are many factors which can determine the success or failure of dental implants ; the attention of clinicians has been mostly focused on drawing up surgical and prosthetic protocols and identifying new materials and implant surfaces to improve osseointegration , rather than on the analysis of patient - related risk factors [ 69 ] . in a recent clinical work , alvim - pereira et al
. found no relationship between polymorphism of the vitamin d receptor and implant failure . in a randomized ,
investigated the effects of supplementation with a combination of vitamin d3 ( 5000  iu ) and calcium ( 600  mg ) on the formation of new bone following maxillary sinus lift .
ten patients were assigned to the test group and given vitamin d and calcium ; ten other patients were assigned to the control group and received only calcium .
six to eight months after surgery for bone regeneration , bone samples were taken for histological analysis during implant placement .
although supplementation with vitamin d3 would have increased the serum levels of vitamin d with potentially positive effects on bone remodelling at the cellular level , no statistically significant difference was demonstrated between the two groups at the histological level .
the results of our study would appear to suggest that a severe deficiency of vitamin d in the blood might be related to an increase in the incidence of early implant failure .
in fact , the incidence of early implant failure was rather low ( 2.2% ) in patients with normalized levels of vitamin d in the blood ( > 30  ng / ml ) , rose to almost double ( 3.9% ) in patients with insufficient serum levels ( 1030  ng / ml ) , and were rather high ( 9.0% ) in patients characterized by severe deficiency states .
however , despite the tendency to an increased incidence of early failure in patients characterized by deficiency states , the differences between the three groups of patients were not statistically significant ( p = 0.15 ) .
our study also confirms that the serum values of vitamin d in the local population are rather low : we found that the proportion of patients with insufficient levels was 49.4% and that the percentage with a severe deficiency was 2.7% .
this is not surprising , as most of the patients treated came from northern italy and southern switzerland , regions where exposure to sunlight is somewhat reduced for long periods of the year .
in the light of this , the administration of vitamin d in the weeks prior to placement of a dental implant could be useful , particularly in patients with severe deficiency states ; in these patients , vitamin d supplementation should be maintained for the whole life , in order to guarantee a good remodelling of the bone around the implant .
this study has the distinction of being one of the first clinical studies carried out on a large number of patients to investigate the possibility of an association between low blood levels of vitamin d and the incidence of early failure in implantology . by restricting the analysis to early failures , occurring in the first period of healing and therefore prior to placement of the prosthetic restoration
, we were able to focus our research and avoid a range of factors ( linked to the restoration itself and the prosthetic load ) which could have confused the issue in the study .
it is , in fact , well known that implant survival and thus osseointegration depend on a large number of factors ( related to the surgical and prosthetic protocol , the materials used , and lastly the patient ) [ 4 , 5 ] and it can be difficult to identify which of them might be determining the success or failure of the treatment . in order to avoid this and to limit the confounding factors , the same materials were used for all the patients in this study ( the same implant system for all the patients ) [ 1 , 3 , 8 ] . in addition , the same surgical protocol was used , involving submerged healing in the absence of prosthetic loading . thus the only possible confounding factors were the different quantity and quality of bone at the implant receiving sites and the patients ' responses : these are unavoidable factors .
however , some of those categories of patients most at risk of implant failure ( patients undergoing bone regeneration to create the conditions for the positioning of the implant fixtures or those with particular medical conditions which might increase the risk of treatment failure ) were excluded in the present study .
it is a retrospective work , in which the number of patients having a severe deficiency of vitamin d in the blood was low ( only 22 ) ; thus the presence of even just one less failure in this group would have led to quite different results .
it is possible that some residual confounding may have biased the association between vitamin d and implant failures that we observed .
for instance , this study did not investigate the influence of other patient - related factors ( e.g. , the bone quality ) which can affect implant survival in the period immediately following implant placement .
in addition , if subjects with low levels of vitamin d were also likely to receive more than 1 implant , their risk of being classified as  failures  may increase .
however , no patient in this study experienced more than 1 failure , and the probability of implant failure was not higher ( 1.5% versus 2.1% ) in presence of another implant .
therefore , randomized , controlled clinical trials are needed to confirm the presence of an association between low serum levels of vitamin d and an increase in the incidence of early failure in implantology .
it would be appropriate to assess whether supplementation of vitamin d in the weeks before the operation could lead to a reduction in early failures , whether due to lack of osseointegration or implant infection .
further scientific studies with an appropriate design and a more rigorous statistical analysis will therefore be required in order to thoroughly investigate this issue .
until now , very few studies , and those mainly on animal models , have involved assessing the influence of blood levels of vitamin d levels on the osseointegration of dental implants .
although most of these studies have shown that the administration of vitamin d can improve the healing of the peri - implant bone tissue , it is not yet clear whether vitamin d supplements can promote the osseointegration of dental implants .
our retrospective clinical study aimed to investigate if there is a link between low levels of vitamin d in the blood and an increased risk of early implant failures . although the incidence of early implant failures was higher in patients with low serum levels of vitamin d , our study failed in proving an effective link between low levels of vitamin d in the blood and an increased risk of early implant failure .
further higher level studies ( prospective controlled trials or , even better , randomized controlled clinical trials ) with a more rigorous statistical analysis are therefore needed to investigate this issue .
if an association between low serum levels of vitamin d and higher risk of early implant failure could be demonstrated , the clinician could give a set dose of vitamin d in the weeks before surgery , in order to normalize serum levels and obtain a positive effect on the healing process .
 
 aim . to investigate whether there is a correlation between early dental implant failure and low serum levels of vitamin d. methods . 
 all patients treated with dental implants in a single centre , in the period 20032015 , were considered for enrollment in this study . 
 the main outcome was early implant failure . 
 the influence of patient - related variables on implant survival was calculated using the chi - square test . 
 results . 
 822 patients treated with 1625 implants were selected for this study ; 27 early failures ( 3.2% ) were recorded . 
 there was no link between gender , age , smoking , history of periodontitis , and an increased incidence of early failures . 
 statistical analysis reported 9 early failures ( 2.2% ) in patients with serum levels of vitamin d > 30  ng / ml , 16 early failures ( 3.9% ) in patients with levels between 10 and 30  ng / ml , and 2 early failures ( 9.0% ) in patients with levels < 10  ng / ml . although there was an increasing trend in the incidence of early implant failures with the worsening of vitamin d deficiency , the difference between these 3 groups was not statistically significant ( p = 0.15 ) . conclusions . 
 this study failed in proving an effective link between low serum levels of vitamin d and an increased risk of early implant failure . 
 further studies are needed to investigate this topic . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusions