C A S E R E P O R T
The treatment of diffuse sclerosing osteomyelitis with oral bisphosphonates
H. Taylor , V. Patel, J. Matharu & J. Kwok
Oral Surgery Department, Guy’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
Key words:
alendronic acid, bisphosphonate, diffuse sclerosing osteomyelitis
Corresponding to:
H. Taylor
Oral Surgery Department Guy’s Hospital
Great Maze Pond London SE1 9RT UK
Tel.: 0207 188 3885 Fax: 0207 188 4360
email: hazel.taylor@gstt.nhs.net Accepted: 15 August 2017 doi:10.1111/ors.12302
Abstract
Diffuse sclerosing osteomyelitis (DSO) is a rare inflammatory disease of bone. The underlying cause is poorly understood and traditional management techniques have struggled to provide patients with adequate relief. A number of reports in the literature have described the use of bisphosphonates to manage DSO; however, these have predominantly been associated with the intravenous formulation.
Understandably, there is an element of angst due to its underlying and well-recognised risk of osteonecrosis of the jaw. In this article, we review the literature for the management of DSO including the novel approach of using bisphosphonates. As an example, we present a case of a 56-year-old female with DSO where conventional therapies failed to manage her symptoms; however, treatment with oral alendronic acid led to complete and sustained resolution. This case in conjunction with additional reported cases provides further evidence of the value of bisphosphonates in DSO and highlights that the use of oral bisphosphonates can be successful and could be a viable consideration prior to the use of intravenous versions.
Introduction
Diffuse sclerosing osteomyelitis (DSO) is a rare inflammatory disease of bone, which affects the mandible and other long bones. Reported symptoms include intermittent pain, swelling, trismus, paraes- thesia and occasionally lymphadenopathy1,2. Its occurrence can burden patients for many years with the condition recognised for its refractory nature.
Recent evidence has shown bisphosphonates can be useful in the long-term management of this debili- tating disease. Two small studies and multiple case reports and mini-series have suggested that the use of intravenous (IV) bisphosphonates can help improve patient symptoms, and decrease disease activity3–5. In addition to these few cases, we present a patient with DSO who has had symptom resolu- tion following the commencement of oral alendronic acid.
Case report
A 56-year-old female was referred to Guys Dental Hospital in 1997 regarding persistent jaw pain and swelling. On attendance, she reported having pain and swelling on the left side of her jaw which had been present for 14 months. She had presented having previously had root canal treatment of her lower left canine, 1st premolar and 1st molar and extraction of her lower left 2nd premolar and 2nd molar. In addition, the lower left canine and 1st molar has undergone re-root canal treatment by the endodontic department. All of the proposed and completed treatment had failed to resolve her symptoms and she continued to experience pain, swelling and infection that required continuing antibiotic therapy. At this stage, she was referred to the oral surgery department for assessment and management.
On examination, extra oral palpation revealed bowing of the left lower border of the mandible.
Intraoral examination showed buccal expansion in the left body of the mandible extending to the mid- line. There was no lingual expansion or draining sinuses. A dental panoramic tomograph showed the lower left canine, 1st premolar and 1st molar were root filled and had periapical radiolucencies; how- ever, clinically, they were not tender to percussion (Fig. 1). A lower standard occlusal radiograph showed the soft tissue outline to be pronounced in a buccal position. A diagnosis of osteomyelitis was made and the patient was commenced on antimicro- bial therapy. Over the course of 2 years, she required repeat prescriptions for cyclic infections of differing intensity.
Due to recurring symptomatic episodes, treatment with salmon calcitonin was commenced in January 2000. A varying dose based on symptoms (25–100 units weekly via subcutaneous injection) was pre- scribed and treatment lasted for 5 years. In 2005, she was changed to the nasal spray version for ease of administration. She remained on calcitonin nasal spray for a further 8 years reporting sporadic symp- tomatic events treated with either antimicrobials alone (erythromycin and metronidazole) or in com- bination with diclofenac. Between 1997 until 2013, radiographic evidence confirmed further progression of DSO extending across to the right body of the mandible (Fig 2). It was at this juncture, alendronic acid (70 mg, once weekly) was started.
Following the commencement of alendronic acid, the patient reported symptom improvement in com- parison to the previous treatments attempts. At 5 months, the patient’s symptoms had completely resolved. She was maintained on alendronic acid and the overall duration of the medication was 20 months with no acute episodes of pain, swelling or infection. She reported no side effects from alen- dronic acid and at the 2-year review from com- mencement radiographically the mandibular lesions were seen to have almost fully resolved, there was
no evidence of further expansion or periosteal reac- tion (Fig. 3).
Discussion
The basic definition for osteomyelitis is well recog- nised as infection of the medullary cavity of bone and the disease is seen in various bones of the skele- ton. In the jaws, various sub-categories of osteomyelitis have been proposed; however, no internationally agreed classification has been agreed which has led to some confusion in the literature as to which terminology to use. The Zurich classifica- tion6 has gained popularity and sub-divides osteomyelitis into three areas: acute osteomyelitis, secondary chronic osteomyelitis (supperative) and primary chronic osteomyelitis (non-supperative) 7. Figure 4 shows the flow diagram outlining the vari- ous sub-categories of osteomyelitis.
Acute osteomyelitis of the jaws is rarely seen these days due to the availability of antibiotics. Infection tends to be odontogenic in origin and often results in intense pain, swelling, lymphadenopathy and pyr- exia lasting less than 4 weeks. Non-resolution or progression beyond this time frame leads to sec- ondary chronic osteomyelitis, which is also often referred to as ‘chronic supperative osteomyelitis’ as
Figure 1 DPT Dec 1998. Arrow A shows loss of cortical bone. Arrow B shows generalised diffuse sclerosis throughout the mandible.
Figure 2 DPT Jan 2010. During management phase of calcitonin, anti-inflammatories and antibiotics. Arrow A shows an osteolytic area of the cortex at the lower border of left mandible. Arrow B shows generalised sclerotic areas throughout the body of the mandible.
Figure 3 DPT Jan 2017. After treatment with alendronic acid. Arrow A shows bony healing, the lower border of the mandible has well- defined cortex. Arrow B shows the bony pattern throughout the mandible appears near normal.
an interchangeable term. In this type of osteomyeli- tis pus, sinuses and sequestrate are seen clinically.
Pain tends to be dull in character and with firm swelling due to the periosteal reaction. Radiographi- cally, it can vary from osteolytic to osteosclerotic in appearance. Primary chronic osteomyelitis (PCO) or
‘chronic non-supperative osteomyelitis’ describes a group of osteomyelitis conditions where there is no pus or fistulae. Unlike the acute or secondary chronic forms of osteomyelitis where a bacterial source is the aetiological factor, in PCO the aetiology is unknown. The lack of pus, sequestra or fistulae clearly distinguishes PCO from acute or secondary chronic osteomyelitis. The symptoms tend to be insidious in onset, be long lasting and fluctuate in intensity7. The terminology used to describe PCO and its various forms has changed over the years with DSO being the most commonly used alternative term. Garre’s osteomyelitis is a term that has been used to describe PCO where predominantly perios- teal reaction is seen both radiographically and histo- logically. It is characterised by periosteal sclerosis and peripheral deposition of bone, rather than the diffuse endosteal reaction seen in DSO2.
Sapho
SAPHO (skin, acne, pustulosis, hyperostosis, osteitis) syndrome was first reported by Chamot et al. in 1987 and describes a condition where patients suffer with synovitis, acne, pustulosis, hyperostosis and/or osteitis8. A recognised link between SAPHO and PCO
exists. Hayem et al. reported 13/120 (11%) patients with SAPHO had clinical and radiological manifesta- tions resembling DSO of the mandible while Khan et al. showed the incidence at 8% (7/85 patients)9,10. Many authors have also described DSO as the mandibular presentation of SAPHO8–11.
Diffuse sclerosing osteomyelitis
The pathogenesis of DSO is poorly understood and no aetiological factor has been confirmed; however, various causes have been suggested, including infec- tive, autoimmune and genetic. Clinically, there is pain and swelling without suppuration.
Most commonly, the mandible is affected, usually unilaterally, although it is acknowledged that other long bones can be affected with reports of DSO in the femur, tibia and humerus12,13. This involvement of other long bones of the skeleton supports an aeti- ological factor beyond dental infection alone12,13.
Diagnosis of DSO is made from clinical and radio- graphic findings. In addition, histopathology and Technetium (Tc) scintigraphy are also used to inves- tigate and aid diagnosis. Radiographically, sclerosing radio-opaque and radio-dense mixed areas can be seen. Overtime, these become increasingly sclerotic.
Destruction of the cortical bone is seen in later stages of the disease and in older patients14. In the past decade, cone beam CT has become a valuable inves- tigatory and monitoring adjunct with its ability to provide high-resolution images of the jaws where these changes can be seen in much better detail.
SAPHO Osteomyelitis
Chronic
Primary chronic
Diffuse sclerosing osteomyelitis Garre's
Secondary chronic Acute
Figure 4 Summary diagram of osteomyelitis.
These changes histopathologically are seen as non- specific inflammation and sclerotic changes within the bone1,15.
Traditional therapies
The management of DSO has always been challeng- ing and this is seen in the various strategies employed, all of which have had limited success.
Treatments include the use of analgesics, long-term antimicrobials, calcitonin, corticosteroids, hyperbaric oxygen or surgical interventions, including decortica-
tion1,4,16. As evident in the current case, often
patients will have tried a number of these treatments with some approaches simultaneously.
The use of long-term antibiotics has been the pri- mary and most popular form of treatment for patients with DSO. No antibiotic has been found to cure DSO, but most patients find that without con- tinual antibiotics their symptoms recur or worsen.
This is less than ideal, as sustained antibiotic therapy risks resistance. In addition, most patients also require regular NSAIDs for pain relief, often taken daily for several years which has its own side effects and complications. The use of long-term corticos- teroids is also non-ideal due to the long-term side effects and well-recognised consequences on general health. The introduction of calcitonin was promising due to the positive effect it had on osteoclast activity as well as the analgesic benefits; however, in 2012, evidence arose which found that patients on long- term use were at increased risk of cancer17. It uses essentially discontinued understandably for DSO.
Hyperbaric oxygen therapy has been suggested as a potential therapy; however, the evidence and out- comes behind its use are poor. The treatment is both costly and time-consuming with no proven benefits.
Surgery has been reserved for refractive DSO and has shown variable results and in some cases exacer- bated the condition. The lack of success and confi- dence in these proposed treatments over the past 50 years has led to other therapies being investi- gated, including bisphosphonates.
Bisphosphonates
Bisphosphonates are pyrophosphate analogues that share a common phosphorous–carbon–phosphorous chemical core, and inhibit the resorption of bone18. They aim to reduce bone turnover through a decrease in osteoclast activity, leading to increased bone density and are well established for the man- agement of various bone diseases.
Bisphosphonates bind to bone mineral and build up in high concentrations particularly in areas of high bone turnover. They are then taken in by the surrounding osteoclasts, and disrupt their function in multiple ways; by reducing the lifespan of each osteoclast, reducing the recruitment of new osteo- clasts, and reducing the effectiveness of osteoclast activity on the bone19,20. Several studies have shown bisphosphonates to be effective at reducing pain as well as increasing the density of bone although the exact mechanism for this is not known21,22.
Bisphosphonates are often categorised by the absence or presence of the nitrogen side arm, which also relates to their potency with the latter group being more potent. The first-generation non-nitro- gen-containing bisphosphonates (e.g. etidronate, clo- dronate and tiludronate) are metabolised within the osteoclast resulting in a build-up of adenosine triphosphate (ATP) analogues, which becomes cyto- toxic and causes apoptosis of the osteoclast. The sec- ond and third generation are nitrogen-containing bisphosphonates (e.g. alendronate, risedronate, iban- dronate, pamidronate, zoledronate) which work by inhibiting farnesyl pyrophosphate synthase which is a key enzyme in cholesterol production, ultimately leading to cell apoptosis.
Bisphosphonates are well recognised for their potential to cause medication related osteonecrosis of the jaw (MRONJ) which has no guaranteed cure and is of concern for the dental and surgical commu- nity. This risk is heightened with the intravenous formulations of these drugs compared to the oral type. The American Association of Oral & Maxillofa- cial Surgery (AAOMS) 2014 guidance23 advises that the risk of developing MRONJ for patients taking long-term oral bisphosphonates can be estimated at
~0.5% after a single tooth extraction. This is signifi- cantly lower than the estimate for cancer patients who had received IV bisphosphonates, which was estimated to be between 1.6% and 14.8%. Impor- tantly, it is recognised that the oral bisphosphonate risk for MRONJ still remains very low even with continuous use after 4 years which is seen as the threshold for when true risk occurs23.
Bisphosphates in the management of DSO The use of bisphosphonates in DSO is a novel approach. In light of this and the rarity of DSO, a limited number of cases are present in the literature.
Two studies, two cases series and nine case reports totalling 36 patients discuss the use of bisphospho- nates in managing DSO (Table 1). Of these 36
Table1Managementofdiffusesclerosingosteomyelitiswithbisphosphonates CitationAuthor&year publishedNo.patientsDiagnosticcriteriaPrevioustreat- mentMethodofbispho- sphonateadminis- tration Lengthof clinical follow-up
ClinicaloutcomeRadiographicoutcome IVbisphosphonatesinDSOmandible–Studies Ibandronate treatmentof diffusesclerosing osteomyelitisof themandible:Pain reliefandinsight into pathogenesis.5
Otto201511(9F,2M)1Patienthistory 2Clinical 3Radiographic 4Histopathology
1Analgesics 2Antibiotics 3Corticosteroids 4Hyperbaric oxygen 5Surgery, including corticotomies IVIbandronate singleinfusion 6mg
17–39months10outof11patients haddistinct improvementin painscores
1Lesspronouncedsclerosis 2clearervisibilityofthe inferioralveolarchannel Disodium clodronateinthe treatmentof diffusesclerosing osteomyelitis (DSO)ofthe mandible.3
Montonen 20016(6F)1Clinical 2Radiographic 3Histopathology Disodium clodronate(a non-nitrogen- containing bisphosphonate
12monthsMedianVASscores lessforbisphos. group.At6months painislessfor bisphos.group.At 12months-fewer exacerbationsof pain,inbisphos. group,butnot statistically significant.
At12months–nodifference betweenplaceboand bisphosphonategroup IVbisphosphonatesinDSOmandible–CaseSeries/CaseReports Initialresultsofthe treatmentof diffusesclerosing osteomyelitisof themandiblewith bisphosphonates.4
Kuijpers20117(6F,1M12– 78years)1History 2Clinical 3Radiographic 4Histopathology 5Tcscans 1Analgesics 2Antibiotics 3Physiotherapy 4Corticosteroids 5Surgery IVPamidronate 15mg/day 3–5days(total 45–75mg) Repeatedevery 3months dependenton ptresponse 30months7outof7patients hadadecreasein pain
Tcscansofallpatients showedadecreasein uptakeinDSOareaat 1year Diffusesclerosing osteomyelitisof themandible successfully treatedwith pamidronate:a long-term follow-upreport.25
Urade20121(61yoF)1Clinical 2Radiographic 3Histopathology 499mTcscintig raphy 1Anti-inflamma- toryagents 2Antibiotics 3Curettage 4Decorticationof themandible IVpamidronate singleinfusion 45mg
6yearsPainresolved3days afterinfusion. Trismusimproved. Symptomfreeat 6yearfollow-up Nearnormalappearanceof bonetrabeculaeat 3years.99mTcscintigraphy showeddecreased accumulationat2months, almostdisappearedat 3years
Table1(Continued) CitationAuthor&year publishedNo.patientsDiagnosticcriteriaPrevioustreat- mentMethodofbispho- sphonateadminis- tration Lengthof clinical follow-up
ClinicaloutcomeRadiographicoutcome Remarkable responseof juvenilediffuse sclerosing osteomyelitisof mandibleto pamidronate.26
Yamazaki20071(9yoM)1Clinical 2Radiological– CT 3Tcscintigram 4Histological
1Extractionof tooth 2Antibiotics 3Curettage 4Decorticationof themandible 5Hyperbaricoxy- gen 6NSAIDs IVPamidronate 30mg+30mgat 3months+30mg at10months(for humeruslesion)
ReductioninpainReappearanceoflaminadura andalveolarbonewith normaldensity.Scintigraphy at5monthsshowed reductioninuptakeinthe mandible. Responseofdiffuse sclerosing osteomyelitisof themandibleto alendronate: follow-upstudyby 99mTc scintigraphy27
Hino20051(44yo)1History 2Clinical 3Radiographic+ CT 499mTCScintig- raphy 5Histology 1Extractionof tooth 2Antibiotics 3Curettage 4Decorticationof themandible
IVAlendronate 10mg12monthsPainresolvedwithin 24hoursTcuptakeconsiderably reducedat3months Successful managementof severefacialpain inpatientswith diffusesclerosing osteomyelitis (DSO)ofthe mandibleusing disodium clodronate.28
Sugata,20031(60yoF)1History 2Clinical 3Radiographic 4CT 599mTCScintig- raphy 1Antibiotics 2Decorticationof themandible (98) 3NSAIDs
IVPamidronate 30mg6monthsPainresolvedwithin 72hours Pamidronateinthe treatmentof diffusesclerosing osteomyelitisof themandible.29
Soubrier20011(67yoF)1Clinical 299mTCScintig- raphy 3Histology 4Radiographic+ CT 1Antibiotics 2NSAIDs
IVPamidronate 2960mgPainresolvedwithin 72hours
Table1(Continued) CitationAuthor&year publishedNo.patientsDiagnosticcriteriaPrevioustreat- mentMethodofbispho- sphonateadminis- tration Lengthof clinical follow-up
ClinicaloutcomeRadiographicoutcome Implicationof bisphosphonate useinthe treatmentof SAPHOsyndrome: Casereportand discussionof currentliterature24
Gorecki20151(39yoF)1History 2Clinical 3Radiographic 4Histology 5PainandTher- malSensitivity Test 6Scintigraphy 7MRI 1Antibiotics 2NSAIDs 3Apicectomy 4Splinttherapy 5Corticosteriods
IVZoledronate 5mg1monthInitialfever+pain (sideeffect)Reliefof pain,norelapseat 1month
NochangestoMRI3weeks postbisphosphonate AcaseofSAPHO syndromeinitially diagnosedas diffuse sclerosing osteomyelitisof themandible and effectively treatedby bisphosphonate.30
Suzuki20151(32yoM)1Antibiotics 2NSAIDs 3Hyperbaricoxy- gen
IVPamidronate10yearsPaindisappearedCTimprovementat 5months. OralBisphosphonatesDSOmandible–CaseReports AcaseofSAPHO syndromewith diffusesclerosing osteomyelitisof themandible treatedsuccessfully withprednisolone and bisphosphonate.31
Hatano 20121(61yoM)1History 2Clinicalfindings 3Radiographic findings 499mTc scintigram 5MRI 1Antibiotics 2Decorticationof themandible 3Hyperbaricoxy- gen 4Corticosteroids OralRisendronate 17.5mg/day+ prednisolone (60mg-2mg/ day)for 12months 12monthsResolutionofpain/ swelling.Nosignof recurrence
TcScanshoweddecreasein levelandrangeofuptake inmandibleafter 12months Thetreatmentof diffusesclerosing osteomyelitis withoral bisphosphonates.
Taylor20171(56yoF)1History 2Clinicalfindings 3Radiographic findings 1Analgesics 2Antibiotics 3Calcitonin OralAlendronic Acid70mg/ week 20months 24monthsResolutionofpain/ swellingat5month review.Nosignof recurrenceafter 2years Radiographicallyresolutionof mandibularlesionseenat 2yearreview
Table1(Continued) CitationAuthor&year publishedNo.patientsDiagnosticcriteriaPrevioustreat- mentMethodofbispho- sphonateadminis- tration Lengthof clinical follow-up
ClinicaloutcomeRadiographicoutcome IVbisphosphonatesforDSOinotherbones Bonemarker responsein chronicdiffuse sclerosing osteomyelitis treatedwith intravenous ibandronate.12
Armstrong 20053(27yoF femur,38yo Ftibia+ femur,21yo Ftibia+ femur) 1History 2Clinical 3Radiographic 4MRI 5Scintigraphy 6Histology 1Excision 2Bonegrafting 3Externalfixation oftibia
1Oral Risendronate 2months,IV Ibandronate 392mg over 3months 2IVPamidronate 6infusions+ oralrisendro nate+IV Ibandronate 2mg,3mg, 3mg 3IVpamidronate IVIbandronate 492mg 1Risendronate= rapidbuttemporary improvement, Ibandronate= Immediate symptomaticrelief 2Pamidronate+ risendronate= temporary improvementin symptoms. Ibadronate=rapid +persistent improvementin symptoms
2decreaseinactivityon TcScan 3Nochangeswith Pamidronate. Chronicdiffuse sclerosing osteomyelitis treatedwith risedronate.13
WrightSA, MillarAM1(21yo FFemur)1History 2Radiology 3Histopathology 1AnalgesiaRisendronateDramatic improvementin symptoms+ biochemicalmarkers ofboneturnover
patients, 33 had mandibular lesions and four had lesions affecting the femur or tibia. They had all pre- viously undergone various treatments outlined ear- lier unsuccessfully. In all the cases reported, bisphosphonate treatment had a beneficial effect on the patients’ pain, often within a few days of com- mencing treatment. One case reported fever lasting 2 days related to IV zoledronate, which is a recog- nised side effect of the drug24. The follow-up periods ranged from 1 month to 10 years. Radiographically, the bony appearance improved, and Tc scintigraphy showed a reduction in uptake in all cases that were scanned. Twenty out of 36 patients required repeat bisphosphonate infusion. To date, there appears to be no reported MRONJ in patients who have had treatment with bisphosphonates for DSO.
Almost all published reports on bisphosphonates for the management of DSO have used IV formula- tions. In the case presented, we found that the same benefits and resolution of symptoms can be achieved with oral alendronic acid. There are a number of benefits of using oral alendronic acid over the IV infusions. Firstly, the risk of developing MRONJ is extremely unlikely with oral bisphosphonates. Sec- ondly, the annual cost of treatment with oral bispho- sphonate in the United Kingdom is a fraction of that for IV infusions with oral alendronic acid costing approximately £13/annum compared to £215/infu- sion of zoledronic acid. Finally, oral alendronic acid can be taken at home while IV bisphosphonates require hospital attendance.
Conclusion
The exact mechanism of DSO is not understood, but the fact that bisphosphonates have been successful in managing the disease has led authors to believe that osteoclasts could play an important role in the patho- genesis. This could be due to a discrepancy in balance between the osteoblast–osteoclast activity or through the effect they have on the local tissue environment possibly causing a change in pH or through the release of pain causing factors5. In the current case, the use of oral alendronic acid at a dose of 70 mg weekly for 20 months provided the patient with complete resolu- tion of symptoms. Furthermore, at this dose for this length of time, the risk of MRONJ remains extremely low23. It is therefore worth considering the use of alendronic acid as a first-line treatment for the man- agement of DSO. Failure to achieve adequate symp- tom control with this method would still allow prescription of more potent intravenous bisphospho- nate versions if necessary.
Ultimately, more research is required regarding the regime and dose of bisphosphonates in the man- agement of DSO ideally through a randomised con- trol trial; however, due to the rarity of this disease, sufficiently populating such a study is likely to be difficult. Until then, we are reliant on case reports such as this to build evidence.
Declaration
No ethical approval required.
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