Accepted Manuscript

Vitamin D (25-OHD) deficiency may increase the prevalence of medication-relatedosteonecrosis of the jaw

Nils Heim, MD, DMD, Felix Benjamin Warwas, MD, Christian Tim Wilms, MD, DMD,Rudolph Reich, MD, DMD, PhD, Head of department, Markus Martini, MD, DMD,Chief resident

PII: S1010-5182(17)30324-4

DOI: 10.1016/j.jcms.2017.09.015

Reference: YJCMS 2788

To appear in: Journal of Cranio-Maxillo-Facial Surgery

Received Date: 9 March 2017

Revised Date: 28 July 2017

Accepted Date: 15 September 2017

Please cite this article as: Heim N, Warwas FB, Wilms CT, Reich R, Martini M, Vitamin D (25-OHD)deficiency may increase the prevalence of medication-related osteonecrosis of the jaw, Journal ofCranio-Maxillofacial Surgery (2017), doi: 10.1016/j.jcms.2017.09.015.

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https://doi.org/10.1016/j.jcms.2017.09.015

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ACCEPTED MANUSCRIPTVitamin D (25-OHD) deficiency may increase the prevalence of medication-related

osteonecrosis of the jaw

Nils Heim (MD, DMD)1 – Corresponding author – nils.heim@web.de

Felix Benjamin Warwas (MD)1 – felix.warwas@ukb.uni-bonn.de

Christian Tim Wilms (MD, DMD)1 – christian.wilms@ukb.uni-bonn.de

Rudolph Reich (MD, DMD, PhD - Head of department)1 – rudolf.reich@ukb.uni-bonn.de

Markus Martini, Markus (MD, DMD – Chief resident)1 – markus.martini@ukb.uni-bonn.de

1 Department for Oral & Cranio-Maxillo and Facial Plastic Surgery, University of Bonn,

Bonn, Germany

Full name of department:

Department for Oral and Cranio-Maxillo and Facial Plastic Surgery

(Head: Prof. Dr. Dr. Rudolf H. Reich)

University of Bonn, Germany

Corresponding author:

Dr. Nils Heim

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Abteilung für Mund-, Kiefer- und

Plastische Gesichtschirurgie - Universitätsklinikum Bonn

Sigmund-Freud-Strasse 25, Haus 11, 2. OG

D- 53127 Bonn

Germany

Contact:

phone

0049 (0) 228 287 16867

fax

0049 (0) 228 287 22604

e-mail

nils.heim@ukb.ubi-bonn.de

Financial disclosure

There are no financial disclosures or commercial interests from any authors.

Conflict of interest

There were no conflicts of interest.

Acknowledgments

None

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Vitamin D Deficiency (25-OHD) May Increase the Prevalence of Medication

Related Osteonecrosis of the Jaw

Abstract

Introduction: Osteonecrosis of the jaw (ONJ) is a severe complication of antiresorptive

medication (AM) in the treatment of bone-affecting cancer-related conditions and osteoporosis.

Aim of this study was to reveal whether patients treated with AM and show Medication Related

OsteoNecrosis of the Jaw (MRONJ) are vitamin D defficient or not.

Materials and methods: A 2 year retrospective study evaluated hospital records of 63 patients

who received AM. Patients were devided into two groups. One group (n=45) consisted of

patients who presented a stage 2 ONJ (eb+ = exposed bone). Second group patients (n=18) (eb-

= no exposed bone) presented for extraction of teeth. Serum levels of vitamin D (25-OHD) were

analyzed. P values ≤ 0.05 in t-test were regarded as statistically significant. Results: Serum levels of 25-OHD were significantly higher in the eb(-) group (29.5 ng/ml), than

in the eb(+) group (20.49 ng/ml). Blood levels of calcium were also significantly higher in eb(-)

group (2.25 mmol/L; 0.11 SD) than in eb(+) group (2.175 mmol/L; 0.16 SD).

Conclusion:Prevalence of MRONJ in AM treated patients seems to be increased by low serum

25-OHD. A measurable tendency in the role of 25-OHD for the development of MRONJ was

recorded and leads to the recommendation for a sufficient vitamin D substitution in patients

treated with AM.

1. Introduction

Osteonecrosis of the jaw (ONJ) is a severe complication of antiresorptive therapy in the

treatment of bone-affecting cancer-related conditions, such as bone metastasis of prostate,

breast and lung cancer, multiple myeloma and osteoporosis (Hellstein, 2014).

In 2014, the American Association of Oral and Maxillofacial Surgeons (AAOMS) recommended

the change in the nomenclature from bisphosphonate-related osteonecrosis of the jaw (BRONJ)

to medication-related osteonecrosis of the jaw (MRONJ), due to the use of new classes of

antiresorptive medications, such as denosumab, which cause similar complications (Otte et al.,

2013; Ruggiero et al. 2014). Moreover, MRONJ is defined by the appearance of three

characteristics: (1) current or previous treatment with antiresorptive or antiangiogenic agents,

(2) exposed necrotic bone or bone that can be probed through an intraoral or extraoral fistula in

the maxillofacial region that has persisted for longer than 8 weeks and (3) no history of

radiation therapy to the jaws, or obvious metastatic localization to the jaws (Ruggiero et al.,

2014). Bisphosphonates (BPs) are nonmetabolized analogues of pyrophosphate, potent

inhibitors of osteoclast activation and subsequently prevent bone resorption (Ficarra et al.,

2005). In the past BPs represented the agents of choice for the treatment of pathologies that

affect bone metabolism (Nancollas et al., 2006). In the recent past similar clinical conditions are

also encountered in patients treated with denosumab, a monoclonal antibody against the

receptor activator of nuclear factor-κB ligand (RANKL), which inhibits osteoclast functions and

associated bone resorption.

In general vitamin D is part of a group of fat-soluble secosteroids. Secosteroids are derived from

cholesterol and are characterized by a broken bond in one of the steroid rings. Of the more than

50 different vitamin D metabolites known, all with biological activity, two major forms are D3

(cholecalciferol) and D2 (ergocalciferol) (Zerwekh, 2008).

The metabolisms of vitamin D are complex and difficult processes, involving UVB radiation,

which is the predominant source for vitamin D in humans and hydroxilating enzymes for

synthesis and catabolism (Elias et al., 2014). UVB radiation with a wavelength between 290 and

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ACCEPTED MANUSCRIPT315nm initiates the synthesis of vitamin D in the skin. Additionaly vitamin D can be obtained

directly from the diet, which usually represents only 10-20% from the total intake (Willet,

2005). In order to convert vitamin D into a biologically active form, two hydroxilation reactions

are required. The first hydroxilation is primarily performed by the cytochrome P450 enzyme

CYP2R1 and leads to 25-OHD. 25-OHD undergos a second hydroxilation by another P450

enzyme (CYP27B1), producing 1,25-(OH)2D (Fig.1).

Guidlines recommend measuring the circulating serum 25-OHD level to evaluate patients’

vitamin D status. It is highly evidential that serum 25-OHD can be associated with clinical

outcomes in terms of fracture risk, bone mineralization and all-cause mortality events (Priemel

et al., 2010; Herrmann et al., 2015).

Vitamin D serum levels (25-OHD) 30 ng/ml are constituting a normal range of 25-OHD serum levels.

Vitamin D deficiency is a widely spread problem in many populations worldwide (Lips, 2010).

Nomerous studies proved, that vitamin D plays a role in inflammatory, vascular, neoplastic and

neurodegenerative diseases (Holick, 2007). The vitamin D status of ONJ patients has not been

established yet (Lehrer et al., 2008). Thus, the group of patients showing multiple risk-factors

for devloping ONJ, in many cases appear to be the same group with low levels of vitamin D. It is

well known, that low levels of the major circulating vitamin D metabolite (25-OHD) leads to a

reduced intestinal calcium absorption (Lips, 2010). Further vitamin D plays an important role in

the regulation of various immune reactions (White, 2008). Beside the immune system, the

majority of cells and tissues have vitamin D receptors (VDRs) and 25-OHD activating enzymes

(Jilka, 2007). Badros et al. (2008) showed that 40% of multiple myeloma patients had a vitamin

D deficiency and 35% had a vitamin D insufficiency (Badros et al., 2008). Further a vitamin D

insufficiency was revealed for 30.2% of breast cancer patients (Lowe et al., 2005).

The implication of a role for vitamin D in ONJ is further seen in a prospective study that

developed a rat model with vitamin D defecient and vitamin D sufficient rats. Both groups

received intravenous bisphosphonate injection in combination with tooth extraction. It was

found that ONJ lesions developed significantly higher in vitamin D defficient rats than in

sufficient rats (Hokugo et al., 2010).

The exact pathologic mechanisms of the development of ONJ in humans, either treated with

nitrogen-containing bisphosphonates or denosumab, is still uknown. The aim of this study is to

reveal whether patients treated with these drugs and show the clinical signs of MRONJ are

vitamin D defficient or not. Further a control group of patients, also treated with antiresorptive

medications, but without exposed bone (eb) as a clinical sign for MRONJ were examined for

vitamin D deficiency in order to point out differences between the two groups.

2. Materials and methods

2.1 Patients

A 2 year retrospective study evaluated hospital records of 63 patients who received

antiresorptive medications. The patients were devided into two groups. One of the groups

(n=45) consisted of patients who presented a stage 2 osteonecrosis. Patients of the second

group (n=18) presented for extraction of one or more teeth in our department of Oral and

Craniomaxillofacial Plastic Surgery. Those patients received IV antibiotics before and after

surgery to lower the risk of developing a MRONJ. In both groups, patients’ clinical data were

reviewed, including sex, age, diagnosis that lead to the need of administerd antiresorptive

medications, localisation of exposed bone, causing event of exposed bone and vitamin D

substitution. Further, levels of serum vitamin D (25-OHD) and calcium were investigated (Tab.1

& 2).

2.2 Methods

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ACCEPTED MANUSCRIPTThe serum levels of vitamin D (25-OHD) and calcium were analyzed from the blood that was

routinely taken from each patient of both groups on the first day of inpatient treatment. All

additional data was investigated from routinely received patient data.

2.3 Statistical analysis

Measurements were described by the means and corresponding standard deviations (SD).

Unpaired t-tests were used for comparisons between the two groups and the subgroups. P

values ≤ 0.05 were regarded as statistically significant.

3. Results

A total of 63 subjects (27 male, 42.85%, and 36 female, 57,15%) from 40 to 91 years of age were

enrolled in the study. The mean age was 72.1 (±10.73 standard deviation [SD]). The patients were devided into two groups, whether presenting exposed bone under

antiresorptive medication (eb+) or not (eb-) (Fig. 2). The serum level of vitamin D (25-OHD) was

significantly higher (p=0.0224) in the eb(-) group (29.5 ng/ml), than in the eb(+) group (20.49

ng/ml). Blood levels of calcium were higher in eb(-) group (2.25 mmol/L; 0.11 SD) than in eb(+)

group (2.175 mmol/L; 0.16 SD). Calcium levels less than 2.1 mmol/L are defiened as

hypocalcemia (Minisola et al., 2015). Both groups present a low normal level of calcium. Thus,

comparing the two groups shows a significant difference of the calcium levels (p=0.032).

Further we investigated the diagnosis of each patient which substantiated the administered

antiresorptive medication (Fig. 3). The distribution of diagnosis in each group were different. In

eb(+) group 9 patients (20%) were diagnosed with osteoporosis. Further 12 patients were

diagnosed with osseous metastasis from breast cancer (26.6%) and 17 with osseous metastasis

from prostate cancer (37.7%). Three patients (6.6%) presented a multiple myeloma and 2

patients (4.4%) with kidney cancer. One patient (2.2%) was diagnosed with lung cancer and 1

with a plasmocytoma (2.2%).

In eb(-) group, most of the patients presented with osteoporosis (n=10; 55.5%). Another 4

patients were diagnosed with breast cancer (22.2%). Further, one patient suffered from prostate

cancer (5.5%) and one from lung cancer (5.5%).

Groups were additionaly sorted by the administered substances (Fig. 4). In eb(+) group

denosumab (Ds) was the predominant prescribed medication (n=24; 53.3%). The second

leading substance was zoledronic acid (Za) (n=16; 35.5%). Alendronic acid (Aa) was

administered in 3 patients (6.6%) and ibandronic acid (Ia) and risedronic acid (Ra) was

prescribed each in one case (2.2%). The distribution of the administered medication in eb(-)

group was more balanced. In each case 4 patients (22.2%) received Ds, Za or Ia. Aa was

administerd in 27.7% of the cases (n=5). One patient (5.5%) received pamidronic acid (Pi).

In eb(+) group vitamin D serum levels were compared between Ds (n=24) and Za (n=21). The

Ds-eb (+) group showed a vitamin D (25-OHD) serum level of 19.845 ng/ml (± 9.75 SD). Za-eb (+) showed a level of 21.23 ng/ml (±14.67 SD). Differences in those two groups were not significant (p=0.71) (Fig. 5).

Additionally we examined the rate of vitamin D substitution in both groups (eb+ vs. eb-). In

eb(+) group 5 patients received vitamin D substitution (11.1%). In eb(-) group half of the

subjects (50%) received vitamin D substitution (n=9). Within eb(-) group, patients with

substitution (29.1 ng/ml ± 14.3 SD) showed no significantly higher (p=0.906) vitamin D serum levels than patients with no substitution (29.9 ng/ml ± 13.52) (Fig. 6). Clinical reasons for exposed bone and stage 2 osteonecrosis in eb(+) group were extraction of

teeth in 39 cases (86.6%) and dental pressure points in 6 cases (13.4%). The mandible alone

was affected in 33 cases (73.3%). The maxilla alone was affected in 8 cases (17.7%). In 4 cases

(8.9%) mandible and maxilla were affected at the same time in one patient (Tab.1).

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ACCEPTED MANUSCRIPTEach of the patients of eb(-) group presented for tooth-extraction under inpatient condition and

IV antibiotics (Tab. 2).

Overall 67% (n=30) of the eb(+) group were heald after the first surgical intervention. In 33%

(n=15) of the cases, patients had to undergo a second surgical treatment after developing

exposed bone in the same anatomical region (Fig. 7).

In eb(-) group, only one patient (6%) presented exposed bone in follow-up after tooth extraction

(Fig. 8).

4. Discussion

So far, very few studies measured all parameters, including serum vitamin D level (25-OHD),

calcium, intake of bisphosphonates or denosumab and osteonecrosis of the jaw. To the best of

our knowledge, this is the first study comparing two groups of patients, both containing of

people receiving antiresorptive medication but only one group with clinical signs of a stage 2

osteonecrosis. In this retrospective study we systematically reviewed the hospital records and

blood levels of patients receiving antiresorptive medication, to prove the role of vitamin D and

calcium serum levels on the developement of osteonecrosis of the jaw. One article proved the

endangerment of a vitamin D defeciancy in the development of BRONJ in rats with

bisphosphonate treatment in combination with dental surgery (Hokugo et al., 2010). In all cases

of this study, vitamin D defeciancy also produced disorders in calcium levels, likewise our study.

For ethical reasons it is unjustifiable to design a similar study with human subjects. Therefore

we decided to compare the two given groups of patients receiving antiresorptive medications

and either presenting ONJ or not.

We documented a significantly higher serum level of 25-OHD (p=0.0244) and calcium (p=0.032)

in eb(-) group (fig. 2). These results accentuate the findings of other studies in which 77% of bp-

treated patients with osteonecrosis suffered osteomalacia in comparison with 5% of control

subjects without ostenecrosis (Bedogni et al., 2012).

The two groups in this study show great differences regarding the diagnosis (Fig. 3) leading to

the indication for administering antiresorptive medications, as well as the different substances

(Fig. 4) that the patients received. Bisphosphonates and denosumab have a completely different

effect mechanism, thus far presenting similar side effects and complications regarding ONJ

(Henry et al., 2011). Due to the differences in the effect mechanism of denosumab versus

bisphosphonates we took heed of this issue by comparing the vitamin D serum levels of patients

receiving either denosumab or bisphosphonates in eb(+) group (Fig. 5). Both groups presented a

vitmanin D defeciancy, but without significant differences between them (p=0.71).

Another great issue in comparing the vitamin D levels of eb(+) and eb(-) group is the extend of

vitamin D substitution. It is evident, that sufficient vitamin D substitution leads to higher serum

vitamin D levels (Zitt et al., 2015). Taking into consideration, that in eb(+) group only 11.1%

were substituted with vitamin D, while at the same time 50% of the patients of eb(-) were

treated with vitamin D leads to the assumption that the measured vitamin D levels are distorted

by the substitution. Hence, we statistically compared the patients of eb(-) group who received

substitution to those who did not of the same group. The difference of vitamin D serum levels

were not significant (p=0.906) (Fig. 6). Thus, both groups were small (n=9 each) and therefore

not impeccable for undisputed statistical results.

We documented a mandible dominance regarding ONJ in eb(+) group, as reported in other

studies (Ruggiero et al., 2009). The occurence of ONJ was predisposed by two of the major local

factors: tooth extraction and ill fitting dentures, as also reported in literature (Walter et al.,

2008; Kyrgidis et al., 2008).

Complete healing after the first surgical intervention was observed in 30 (67%) of the 45 sites

included in eb(+) group (Fig. 7). Other studies report higher numbers of healing ranging

between 85-95% after surgical treatment in combination with pre- and postoperative antibiotic

treatment (Carlson & Basile 2009; Wilde et al., 2011). Higher numbers of recurrence in our

study may be due to very extended lesions in some cases, leading to a higher risk of developing

bone exposure by performing wide surgical debridement (Khosla et al., 2007). Further we

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ACCEPTED MANUSCRIPTexcluded stage 0 and stage 1 osteonecrosis which show lower recurrence rates after surgical

management in general (Nisi et al., 2015).

Patients with a history of antiresorptive medication and the need to receive tooth extraction

benefit most from a biphasic treatment, pre- and postoperative antibiotic prophylaxis and

avoidance of invasive dental procedures in combination with sufficient covering of the bone

with well blood supplied tissue (Montefusco et al., 2008). Adhering to these treatment

procedures led to a very low rate of bone exposure in only one case (6%) of the eb(-) group.

Against the backdrop of a limited number of patients in both groups, patients in eb(+) group

presented a significantly lower serum vitamin D level than subjects in eb(-) group. Issues

regarding the effect mechanism of different antiresorptive substances and the role of vitamin D

substitution could not be confirmed in terms of a possible distorsion of the given data.

Nevertheless, similar to the multifactorial causes of MRONJ, the role of vitamin D in the

developement of ONJ seems to be very complex and multifactorial as well.

Since the role of vitamin D in developing a significant inflammation at the post-tooth extraction

bone was already reported in human ONJ cases (Raje et al., 2008), inflammation could endorse

the occurence of necrotic bone. Further microbial-activated toll-like receptors are able to

increase the regulation of vitamin D receptors (VDRs) and CYP27b1-hydroxylase in

macrophages (Liu et al., 2006). Antimicrobial peptide genes (as cathelicidin) are shown to be

transcriptional targets of VDR-1,25(OH)2D interaction in macrophages (Gombart et al., 2005).

On this account, low 25-OHD levels may result in extended bacterial infection of the mouth.

5. Conclusion

This study presents the results of a retrospective investigation of medical records and serum

vitamin D and calcium blood levels of patients treated with antiresorptive drugs. We

documented a significantly lower serum vitamin D level (25-OHD) in subjects with stage 2

osteonecrosis than in patients without exposed bone. Thus, a different effect mechanism is

given, denosumab and bisphosphonates did not present significant differences in serum vitamin

D levels when osteonecrosis was shown.

The prevalence of MRONJ in patients treated with antiresorptive medication seems to be

increased by low serum vitamin D levels.

Although the number of patients in both groups (eb+ and eb-) are too minor for explicit

statistical statements, a measurable tendency in the role of vitamin D for the development of

MRONJ was recorded and leads us to the recommendation for a sufficient vitamin D substitution

in patients treated with antiresorptive medication.

No conflict of interest

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No ethical approvement needed

Table 1 – Patient characterstics in eb(+) group

diag = diagnosis; local = localisation of exposed bone; vit-D subst = vitamin D substitution; med =

administered medication; PC = prostate cancer; BC = breast cancer; KC = kidney cancer; LC =

lung cancer; MM = multiple myeloma; OP = osteoporosis; Pl = Plasmocytoma; LJ = lower jaw; UJ

= upper jaw; ex = tooth extraction; dpp = denture pressure points; ds = denosumab; ia =

ibandronic acid; za = zoledronic acid; aa = alendronic acid; ra = risedronic acid

Table 2 – Patient characteristics in eb(-) group

diag = diagnosis; local = localisation of jaw in which extraction was planned; planed proc =

planned procedure; vit-D subst = vitamin D substitution; med = administered medication; PC =

prostate cancer; BC = breast cancer; KC = kidney cancer; LC = lung cancer MM = multiple

myeloma; OP = osteoporosis; LJ = lower jaw; UJ = upper jaw; ex = tooth extraction; dpp =

denture pressure points; ds = denosumab; ia = ibandronic acid; za = zoledronic acid; aa =

alendronic acid; pa = paledronic acid

Figure 1 – Vitamin D metabolisation

Figure 2 – Vitamin D (25-OHD) levels in eb(+) and eb(-) group

Figure 3 – Distribution of diagnosis in eb(+) and eb(-) group

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myeloma; OP = osteoporosis; Pl = Plasmocytoma

Figure 4 – Distribution of antiresorptive substances in % in eb(+) and eb(-) group

Ds = denosumab; Ia = ibandronic acid; Za = zoledronic acid; Aa = alendronic acid; Ra = risedronic

acid; Pa = paledronic acid

Figure 5 – Vitamin D (25-OHD) levels in eb(+) group receiving zoledronic acid (za) or

denosumab (ds)

Figure 6 – Vitamin D (25-OHD) levels in eb(-) group with vitamin substitution (sub+) or without

vitamin D substitution (sub-).

Figure 7 – Number of patients in eb(+) group healed after surgery vs. patients showing

recurrence after surgery

Figure 8 – Number of patients in eb(-) group healed after extraction vs. patients showing

exposed bone after extraction

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2015

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Table 1

No. sex age diag local causing event vit-D subst med Calcium mmol/L 25-OHD ng/ml

1 m 84 PC LJ UJ ex no ds 2,03 10,4

2 m 72 PC LJ ex no ds 2,26 34

3 w 80 BC LJ ex no ia 2,28 16,6

4 m 71 PC LJ ex no ds 2,15 14,9

5 m 70 KC UJ ex no za 2,37 45,7

6 m 81 PC UJ ex no ds 2,06 22,5

7 m 77 PC UJ ex yes ds 2,06 31,5

8 m 71 MM LJ ex no za 2,29 25,5

9 w 76 BC LJ ex no ds 2,17 16,7

10 w 41 BC LJ ex no ds 2,19 6,1

11 m 80 PC LJ ex yes ds 2,23 15,3

12 m 76 PC LJ ex no ds 1,66 22,7

13 w 68 BC LJ dpp no za 2,42 11,5

14 w 91 OP LJ dpp no aa 2,07 35,8

15 w 50 BC LJ ex yes ds 2,09 3,5

16 m 65 PC LJ ex no za 2,26 26,4

17 m 70 OP LJ ex no ds 2,15 20

18 w 76 OP UJ ex no aa 2,01 7,5

19 w 80 BC LJ ex no ds 2,14 4,3

20 w 52 BC LJ ex no za 2,16 17

21 w 74 OP LJ ex no za 2,24 50,4

22 m 85 PC LJ ex no ds 1,75 5,8

23 w 74 OP LJ dpp no ds 2,31 17,2

24 m 80 PC LJ UJ ex no ds 2,17 9,3

25 w 80 OP LJ ex no ds 2,17 26,9

26 m 76 LC LJ ex yes ds 2,08 19

27 w 76 OP LJ ex no aa 2,19 7,4

28 m 79 MM UJ ex no za 2,05 12,6

29 m 82 PC LJ ex no ds 2,13 35,2

30 m 69 PC LJ UJ ex no ds 2,24 27

31 w 55 BC LJ UJ ex no ds 2,29 29,3

32 m 87 PC LJ UJ ex no za 2,22 15,2

33 w 77 OP LJ ex no ra 2,29 33,4

34 m 76 PC LJ dpp no ds 2,47 22,2

35 m 79 Plas LJ ex no za 2,02 5,9

36 w 70 BC UJ ex no za 2,54 9

37 w 85 OP LJ ex no za 2,38 52

38 m 74 MM LJ ex yes za 2,29 18

39 m 53 KC UJ ex no ds 2,28 29,5

40 w 77 BC UJ dpp no za 2,14 27

41 m 78 PC LJ dpp no za 2,07 9,4

42 w 60 BC LJ ex no ds 2,01 32,2

43 w 40 BC LJ ex no ds 2,06 20,8

44 m 80 PC LJ ex no za 2,07 5

45 m 78 PC LJ ex no za 2,26 14,5

2,175 20,49

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Table 2

No. sex age diag local planed proc vit-D subst med Calcium mmol/L 25-OHD ng/ml

1 w 62 OP LJ UJ ex yes aa 2,13 10,4

2 w 69 OP LJ ex no aa 2,21 34

3 w 73 BC LJ ex yes za 2,21 16,6

4 w 83 LC LJ ex yes aa 2,19 14,9

5 w 72 OP UJ ex no ia 2,09 45,7

6 w 69 BC UJ ex yes ds 2,41 22,5

7 w 56 OP UJ ex no za 2,42 31,5

8 w 53 BC LJ ex no za 2,34 25,5

9 w 76 OP LJ ex yes za 2,18 16,7

10 w 77 OP LJ ex yes ds 2,14 6,1

11 w 56 BC LJ ex no ia 2,17 15,3

12 w 68 OP LJ ex no ia 2,25 22,7

13 m 75 OP LJ ex yes ia 2,49 11,5

14 w 79 BC LJ ex yes aa 2,18 35,8

15 m 79 PC LJ ex no ds 2,22 3,5

16 w 67 BC LJ ex no ds 2,27 26,4

17 w 72 OP LJ ex no pa 2,14 20

18 w 82 OP UJ ex yes aa 2,28 7,5

2,25 29,5

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Vitamin D (25-OHD) deficiency may increase the prevalence of medication-related osteonecrosis of the jaw.学霸图书馆link:学霸图书馆