Ischemic osteonecrosis under fixed partial denture pontics: Radiographic and microscopic features in 38 patients with chronic pain

Ischemic osteonecrosis under fixed partial denture pontics: Radiographic and microscopic features in 38 patients with chronic pain Jerry E. Bouquot, DDS, MSD,a and Michael G. LaMarche, DDSb The Maxillofacial Center for Diagnostics and Research, Morgantown, W. Va. Statement of problem. Previous studies have identified focal areas of alveolar tenderness, elevated mucosal temperature, radiographic abnormality, and increased radioisotope uptake or “hot spots” within the quadrant of pain in most patients with chronic, idiopathic facial pain (phantom pain, atypical facial neuralgia, and atypical facial pain). Purpose. This retrospective investigation radiographically and microscopically evaluated intramedullary bone in a certain subset of patients with histories of endodontics, extraction, and fixed partial denture placement in an area of “idiopathic” pain. Material and methods. Patients from 12 of the United States were identified through tissue samples, histories, and radiographs submitted to a national biopsy service. Imaging tests, coagulation tests, and microscopic features were reviewed. Of 38 consecutive idiopathic facial pain patients, 32 were women. Results. Approximately 90% of subpontic bone demonstrated either ischemic osteonecrosis (68%), chronic osteomyelitis (21%), or a combination (11%). More than 84% of the patients had abnormal radiographic changes in subpontic bone, and 5 of 9 (56%) patients who underwent radioisotope bone scan revealed hot spots in the region. Of the 14 patients who had laboratory testing for coagulation disorders, 71% were positive for thrombophilia, hypofibrinolysis, or both (normal: 2% to 7%). Ten pain-free patients with abnormal subpontic bone on radiographs were also reviewed. Conclusions. Intraosseous ischemia and chronic inflammation were suggested as a pathoetiologic mechanism for at least some patients with atypical facial pain. These conditions were also offered as an explanation for poor healing of extraction sockets and positive radioisotope scans. (J Prosthet Dent 1999;81:148-58.)

CLINICAL IMPLICATIONS This study has shown that painful and radiographically abnormal bone under fixed partial denture pontics typically demonstrates diseased cancellous bone and marrow. Usually diagnosed microscopically as ischemic osteonecrosis or chronic osteomyelitis, this diseased bone is capable of producing varied, often severe, pain, and is also capable of interfering with proper alveolus healing and remodeling after extraction. Most affected patients have a previously undiagnosed, underlying clotting defect.

W

hen a dentist cannot identify a dental or temporomandibular origin for chronic facial or jaw pain, the most frequent assumption for the cause of discomfort has been a disorder of the trigeminal nerve. Diagnostic terms such as neuralgia, causalgia, phantom pain, deafferentation, hyperalgesia, and anesthesia dolorosa are applied, depending on the patient’s symptoms.1-3 This is typically the termination of the diagnostic workup, except for CT or MRI scans, to exclude tumors or vascular abnormalities of the brain. Many patients then drift from 1 health professional to another in an understandable attempt to eliminate pain. Additional health care professionals reconfirm the initial neuralgic diagaDirector

of Research; Former Chair, Department of Oral and Maxillofacial Pathology, West Virginia University School of Dentistry. bClinical Investigator; and Private practice, Lake Stevens, Wash. 148 THE JOURNAL OF PROSTHETIC DENTISTRY

nosis and concentrate on administration of an effective medication or other pain-control therapy, or discovering the psychological origin for the patient’s “selfinflicted” pain. However, there is another class of pain-producing conditions that require no nerve damage to explain chronic “idiopathic” pain. These conditions are related to compromised blood flow through bone marrow or low-grade inflammatory changes of medullary tissues (Table I). Many of these diseases create no swelling or erythema of overlying skin or mucosa, no alteration in routine laboratory values, and minimal or no aberrant radiographic images of an affected area. This article examined one of these maladies, ischemic osteonecrosis, a relatively common disease of the human skeleton, responsible for approximately 20% of all hip replacements in the United States.4-11 The disease is also VOLUME 81 NUMBER 2

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Table I. Causes of “idiopathic” chronic jawbone pain, excluding temporomandibular disorders and dental infection1-11,15

Table II. Radiographic staging for ischemic osteonecrosis (applies predominantly to hip lesions and ends of long bones); patients at all stages may or may not have pain7,8,10

Nerve damage/degeneration • Traumatic/inflammatory neuritis • Traumatic neuroma • Trigeminal neuralgia • Atypical facial neuralgia/pain • Phantom toothache/odontalgia/causalgia • Deafferentation • Demyelination (multiple sclerosis, etc) Blood flow alterations • Intramedullary hypertension • Intramedullary ischemia/claudication (from either poor inflow or poor outflow) • Distention of marrow veins/capillaries • Intravascular marrow thrombi • Intramedullary microinfarction Inflammation • Cytokines from intraosseous inflammation • Bacterial toxins from intraosseous infections • Neuropathic inflammation

Stage

known by a variety of other names: aseptic osteomyelitis, avascular necrosis, transient ischemic osteoporosis, transient ischemic arthritis, medullary engorgement-pain syndrome, bone marrow edema syndrome, and bone compartment disease.4-11 Almost every human bone can be affected by ischemic osteonecrosis. This includes such strange locations as the bony wall of the ear canal, where it has been called necrotizing (malignant) otitis externa. It seems remarkable that a disease that has been known for generations has only recently been recognized as occurring within the marrow spaces of the jaws.12-17 Perhaps this has occurred because jawbone examples are usually among the less severe cases (relative to marrow damage, not to pain). This disease is also notorious for its lack of obvious radiographic changes until extensive destruction.8,18,19 Radiographic and other imaging changes are commonly so subtle that radiologists have created a unique stage 0 classification for those cases that are completely negative to all known forms of imaging technology (Table II).7,8,10 The current investigators have been unable to find another radiographic entity for which a stage 0 classification was included as part of a routine diagnostic protocol. This disease, once called “coronary disease of bone” because of its ischemic and infarctive phenomena, usually affects the long bones, especially the head of the femur.8 Trauma and infection are well-established “causes” or triggering events for osteonecrosis. It seems ironic that the jawbones, the most traumatized bones of the skeleton and the bones most likely to become infected, have until recently never been reportFEBRUARY 1999

0

1

2

3 4 5 6

Findings

Techniques to use

All techniques normal or nondiagnostic; necrosis on biopsy X-rays and CT scan normal; positive results from at least 1 of test to right

Biopsy and histology

X-ray abnormalities (osteopenia; cysts; sclerosis) without collapse of cortex Subcortical radiolucencies; “crescent sign” in hip Flattening or collapse of cortex As for stage 4, with narrowing of the joint space As for stage 5, with destruction and degeneration of the joint/bone

Radionuclide scan MRI Functional bone investigation Biopsy and histology

Radiographs CT scan initially Radiographs only

ed with osteonecrosis except in patients irradiated for cancer (osteoradionecrosis).15,20,21 Friedman22 recently reported that 15 of 18 patients with chronic idiopathic facial pain (atypical facial pain) had localized areas of alveolar tenderness in the painful quadrant. Seventeen of the 18 also had areas of elevated mucosal temperature in the painful quadrant. Denucci et al.23 expanded the research by evaluation of a similar group of patients with single proton emission computed tomography (SPECT) scans designed to identify medullary inflammation or osteonecrosis. A remarkable 75% of the patients had localized “hot spots” of increased isotope uptake within the quadrant of pain. Areas of reactive periodontitis and periapical pathoses were excluded by study design. These results suggested that intraosseous inflammation or osteonecrosis were associated with chronic idiopathic facial pain, but neither study included bone biopsies in its protocol. This investigation was designed to proceed with the next logical step. The purpose of this study was to evaluate microscopic features of the alveolar bone of patients with idiopathic facial pain and areas of tenderness/pain, abnormal radioisotope uptake, or abnormal radiographic appearance in the quadrant of pain. Because of certain documented histories or scenarios, it was elected to examine specifically areas of previous extraction and prosthetic replacement in the same quadrant as the facial or jaw pain. Subpontic marrow biopsy samples were specifically assessed for various 149

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Table III. Coagulation disorders found in patients with ischemic osteonecrosis of the hips, knees, and jaws. These are compared with the proportions found in patients with deep vein thrombosis of soft tissues and with the normal population.30-35 Resulting proportions do not total 100% because some patients had multiple disorders. Thrombophilia = increased tendency to develop thrombi; hypofibrinolysis = reduced ability to lyse thrombi Normal population

Deep vein thrombosis

Osteonecrosis

2%-5% 3%-7%

5%-9% 20%-50%

50%-70% 33%

<1% <1%

5%-15% 20%-25%

18%-22% 50%

2%-7%

20%-50%

65%-87%

Thrombophilia Hereditary types* Acquired types Hypofibrinolysis Hereditary types* Acquired types Total (includes multiple coagulopathies) *Usually autosomal dominant.

patterns of osteomyelitis and osteonecrosis. Because a large proportion of patients with osteonecrosis are pain free, a certain number of patients without histories of pain were also evaluated. These had routine fixed partial dentures (FPDs) but demonstrated radiographic evidence of poor healing of a subpontic extraction site.

A COMMON EXAMPLE A common scenario in the practice of general or prosthetic dentistry involves the patient who describes a chronic, localized “toothache” without an obvious cause. After some empirical dental procedures, such as occlusal adjustment, replacement of restorations and then endodontic treatment with apicoectomy, the offending tooth is usually extracted. Two problems may then result. First, (case 1 scenario) the pain may remain, at which point neurologic diagnoses are typically applied.24 Second (case 2 scenario), the pain may disappear for months or years, only to reemerge when the adjacent teeth are prepared for a FPD and the dentist is accused of causing the pain. A frustrating subset of this group has no pain before dental treatment, and the litigious nature of this predicament is obvious.25 All pain-affected patients in this study followed one of these scenarios.

MATERIAL AND METHODS Consecutive intramedullary biopsy samples were submitted to the national biopsy service of Head and Neck Diagnostics of America in Morgantown, W.Va. Biopsy samples included radiographs that allowed identification of the sample as subpontic alveolar bone. For ethical reasons, blind biopsy samples of subpontic bone were not performed prospectively during this study. The analysis included only retrospective cases and 150

undoubtedly suffered from sample collection biases of all clinicopathologic reports that use databases from surgical pathology services.26 In other words, the sample did not represent a particular population, only biopsy samples of patients who had idiopathic jaw pain or radiographic abnormalities, according to attending surgeons who submitted specimens. Forty-nine patients (41 women, 8 men) were identified in the archives of Head and Neck Diagnostics, and represented biopsy submissions from 21 dentists or oral surgeons in 12 of the United States. When appropriate information was unavailable on the surgical pathology request form received with each tissue sample, the professional was called to confirm the presence or absence of pain at the biopsy site and that there was no surgery at the site for at least 1 year before the biopsy. No patient demonstrated periodontitis or mucosal erythema at the site at the time the biopsy sample was taken. All patients with pain had experienced temporary but complete or almost complete pain reduction with local anesthesia, with the anesthesia/hyperesthesia test of Ratner-McMahon,27-29 or the Wrobleski periosteal microanesthesia test. The Wrobleski test consisted of the injection of a small amount of local anesthetic, without vasoconstrictor, in the periosteum of the facial surface of alveolar bone directly over the area of suspected pain induction. Technitium MDP bone scans or SPECT scans are radioisotope imaging tests widely used for osteonecrosis.4-10,15 Pre-operative scans were available for 9 of the identified pain cases. Recent research has also identified a variety of hypofibrinolysis and thrombophilia factors in a great majority of patients with osteonecrosis of the hip, knee, and jaws (Table III).30-35 Laboratory results relating to coagulation function were available for 14 patients in the pain cohort. None of the patients had been formally evaluated for elevated mucosal temperature, with the technique of Friedman.22 In addition, 11 consecutive biopsy samples were identified in patients without histories of pain in the area, but with radiographic abnormalities of alveolar bone beneath a pontic. This patient cohort excluded patients who had extractions or other surgical procedures in the subpontic area during the previous year. Histopathologic criteria for osteonecrosis and osteomyelitis in this study were selected from standard orthopedic and rheumatologic texts and contemporary reports.4-12,15,36,37 All diagnoses were confirmed by an oral and maxillofacial pathologist who had extensive experience in inflammatory bone diseases and a Bone Pathology Fellowship at the Mayo Clinic in Rochester, Minn.

RESULTS Thirty-eight pain patients were identified and consisted of 32 women and 6 men. Of these, 31 patients VOLUME 81 NUMBER 2

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Table IV. Demographic, radiographic, and histopathologic features of 49 patients with subpontic pain or radiographic abnormality. Resulting proportions do not total 100% because of overlapping of the various radiographic and microscopic features

Patient characteristics Percent females Average age (age range) Coagulation disorder* Radiographic characteristics No radiographic changes Residual socket Laminar rain Socket sclerosis Irregular radiolucency Irregular radiopacity Subpontic osseous hyperplasia Radioisotope “hot spot”** Microscopic characteristics Normal bone and marrow Ischemic osteonecrosis Acute osteomyelitis Chronic osteomyelitis Sclerosing osteomyelitis Fibrin/platelet aggregates Hematopoietic marrow defect

Patients with jaw pain (n = 38)

Patients without jaw pain (n = 11)

All patients (n = 49)

84.2% 44.0 y (24-76) 71.4%

81.8% 50.3 y (38-66) NA

83.7% 48.1 y (24-76) NA

15.8% 39.5% 42.1% 2.6% 55.3% 2.6% 2.6% 57.1%

0.0% 18.2% 36.4% 9.1% 27.7% 18.2% 0.0% NA

12.2% 34.7% 40.8% 4.1% 59.2% 6.1% 2.0% NA

10.5% 79.0% 0.0% 31.6% 0.0% 7.9% 0.0%

9.1% 36.4% 0.0% 63.6% 9.1% 0.0% 9.1%

10.2% 69.4% 0.0% 38.8% 2.1% 6.1% 2.1%

Fig. 1. Residual socket with relatively well-defined lamina dura (large arrows) is still present 12 years after fixed partial denture placement and 15 years after onset of chronic pain. Area of increased radiolucency just under alveolar crest (white arrows) was completely hollow cavitation at surgery. Trabecular pattern superimposed over socket site is probably from interface of trabecular remnants with cortex, as suggested by Schwartz and Foster.46

*Based on 14 patients with available laboratory values: 6 with thrombophilia, 4 with hyperfibrinolysis, 4 with normal values. **Based on 9 patients who had undergone scintiscans.

had histories of spontaneous, continuous, worsening pain not obviously associated with, or alleviated by, dental treatment. They followed the case 1 scenario. The additional 7 patients included those with pain initiated or recurring in the affected site within days or weeks of abutment preparation or FPD placement, namely, they followed the case 2 scenario. Of the 11 patients without pain histories, 9 were women and 2 were men. All had innocuous tooth preparations and placement of FPDs, but exhibited radiographic abnormalities in subpontic bone. The average age of patients when the biopsy was taken was 48 years (range: 24-76 years), but was slightly less for the group of patients with pain than without facial pain (Table IV). Of the 38 pain patients, investigated subpontic bone included 23 cases from molar sites, 9 from premolar sites, and 6 from lateral incisor areas, with even distribution between the maxilla and mandible, except incisor areas, which were all in the maxillary arch. Patients without pain involved mainly molar regions, with the exception of 2 cases from the maxillary incisor region. FEBRUARY 1999

Fig. 2. Preoperative radiograph shows shadow outline of premolar socket (black arrows) in long-edentulous area. Area was pain-free until adjacent teeth were prepared for full crown coverage (case 2 scenario, as described in text). Generalized, poorly demarcated radiolucency extends beyond confines of residual socket, and areas of cortical destruction on crest of ridge and small area of increased radiolucency (white arrow) are seen.

Radiographic features Approximately 75% of the patients, including those without pain, demonstrated radiographically visible vertical remnants of lamina dura within subpontic bone (Table IV). More than a third of patients displayed a relatively complete, albeit sometimes faint, outline of the former tooth socket, whereas an additional 151

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Fig. 3. Shadow outline of molar socket (arrows) is seen 18 years after extraction. Poorly demarcated, diffuse radiolucency extends several millimeters beyond residual socket in this preoperative radiograph. This pain patient demonstrated combination of osteonecrosis and osteomyelitis when biopsy was taken. Second socket outline is just mesial to that outlined by arrows.

Fig. 5. Vertical, poorly defined radiolucency, with small remnants of lamina dura (arrows) is still present 2 years after extraction of hemisected mesial root. Failing endodontic treatment of distal root presumably contributed to patient’s pain, but pain persisted for more than 6 months after distal root extraction.

Fig. 4. Vertical remnants of lamina dura, laminar rain (arrows), show less definition of apical dura; even Jacob’s ladder interradicular horizontal trabeculae (curved arrow) remain unremodeled. Both root sockets remain many years after extraction. This patient was diagnosed with atypical facial neuralgia/atypical facial pain 4 years earlier.

Fig. 6. Rounded outline of unremodeled maxillary first molar region encases area of increased radiodensity, namely, socket sclerosis (arrows), in patient with no history of facial pain. This was microscopically diagnosed as chronic sclerosing osteomyelitis and radiograph represents area before prosthetic replacement of edentulous space.

41% showed only ragged, often zigzagged vertical remnants of the dura (laminar rain, laminar lightning), with apparent remodeling or healing of the apical portion of the socket (Figs. 1 through 5). Two residual sockets were more sclerotic than surrounding bone (socket sclerosis38) (Fig. 6), but the others were slightly radiolucent compared with normal bone. In addition, almost 60% of patients demonstrated irregular, ill-defined radiolucencies within subpontic bone, often with a triangular shape with the base of the triangle parallel to the crest of the ridge (Fig. 7). These

varied from 3 to 10 mm in size and were often identified in radiographs lacking a substantial residual lamina dura. Some radiolucencies had scalloped borders, but without sclerosis of the border. The radiolucency typically extended outside the lamina dura when a residual socket was present. Three patients demonstrated well-demarcated radiolucencies of the affected areas with scalloped borders and small, irregular areas of radiopacity in the subpontic bone (Fig. 8). These were similar to chronic sclerosing osteomyelitis. One patient exhibited subpontic

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Fig. 7. Poorly defined inverted-triangle radiolucency extends from alveolar crest to apical area (arrows) in facial pain patient with extensive marrow necrosis from retromolar area to first molar area, extending below alveolar neurovascular bundle, which was partially exposed. Widened apical periodontal ligament in both remaining molars, which were viable by electric pulp testing. Fig. 9. Area of increased radioisotope uptake, “hot spot” (large arrow), is seen on this technetium-MDP scan in area of partial denture and focal pain in patient diagnosed with atypical facial neuralgia. Hot spot extends beyond area of diseased bone and areas of lesser involvement are noted in anterior maxilla and sphenoid bone (small arrows).

70% to 80% previously reported for maxillofacial osteonecrosis/osteomyelitis patients, but the sample was rather small and was not representative. 15,23,39 Two of the 5 positive cases were among those that revealed no abnormalities on the routine radiographs.

Coagulation profiles

Fig. 8. Mixed radiolucent/radiopaque area with scalloped borders is seen beneath pontic along with area of subpontic osseous hyperplasia (arrows) in patient who developed facial pain within days of partial denture placement. Large arrow points to second area of necrotic marrow, which proved to be completely hollow space measuring 2.0 × 0.8 × 0.7 cm and extended into ramus. Subpontic bone was diagnosed as chronic sclerosing osteomyelitis.

Of the 14 pain patients for whom laboratory values were recorded, 10 (71%) demonstrated hereditary or acquired coagulopathies; all in patients with microscopic evidence of ischemia or infarction of marrow (Table IV). This was similar to the proportion found in previous, larger cohorts of patients with osteonecrosis of various bones (65% to 87%), was more than the 20% to 50% found in patients with deep venous thrombosis of soft tissues, and was considerably more than the 2% to 7% found in the normal population (Table III).30-35

Microscopic features osseous hyperplasia of the crest of the ridge (Fig. 8), and 6 patients demonstrated no radiographic abnormalities whatsoever in the area of localized pain.

Bone scan features Of the 9 pain patients who had technitium MDP bone scans (n = 6) or SPECT scans (n = 3), 5 showed areas of increased radioisotope uptake or “hot spots” in the subpontic bone (Fig. 9). This was less than the FEBRUARY 1999

Approximately 90% of subpontic bone demonstrated ischemic osteonecrosis, chronic osteomyelitis, or both (Table IV). Representative tissue is illustrated in Figures 10 through 12, and normal fatty marrow is illustrated in Figure 13 for comparison. Pain patients were more likely (79%) to suffer from marrow ischemia and infarction, whereas nonpain patients were more likely (73%) to have osteomyelitis. Of the 34 pain patients with osteonecrosis, 4 also showed evidence of 153

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Fig. 10. Area of fat necrosis with serious ooze (plasmostasis) between residual fat globules. Loose fibrosis at left margin is characteristic of chronic ischemic change, whereas necrotic fatty marrow is presumably secondary to focal infarction. Adjacent bone (on left) is less involved, with most osteocytes intact.

Fig. 11. Photomicrograph of necrosis of fatty marrow is characterized by loss of adipocyte cell walls with release of numerous fat globules (clear spaces) of varying sizes, as seen in lower left area. Smudged appearance of degenerated/ necrosed tissues between fat globules is also characteristic. Small area of normal fatty/hematopoietic marrow, with mild fibrosis, is seen in upper right-hand corner.

chronic osteomyelitis. Conversely, of the 12 pain patients with osteomyelitis, 4 were combined osteomyelitis and osteonecrosis. Acute infection was not demonstrated in any specimen and all tissue from patients with positive radioisotope scans was positive for bone disease: 6 osteonecrosis, 1 chronic osteomyelitis, and 2 with a combination of both entities. This lack of false-positives is in agreement with literature on bone scanning of osteonecrosis.40 One tissue sample from a patient with known hypofibrinolysis, and 2 samples from patients without 154

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Fig. 12. Loose fibrous replacement of normal fatty marrow is called reticular fatty degeneration and is characteristic response to chronic ischemia. Almost all osteocytes are missing or pyknotic, leaving small empty spaces in bone. Excessive numbers of dark cement lines are present, with occasional microcracks along them (arrows). There is virtually no osteoblastic activity in this bone, presumably because ischemia has prevented new bone formation or remodeling.

laboratory data available also demonstrated fibrin/ platelet aggregates in marrow tissues; 1 sample revealed these aggregates within dilated veins (Fig. 14). Almost 11% of all patients demonstrated microscopically normal bone and bone marrow. These patients may have truly had normal marrow, or this may have represented tissue sampling errors or tissue from less involved patients with relatively complete healing of the bone by the time the biopsy sample was taken. These 5 cases demonstrated radiographic abnormalities, but only 3 were tender to palpation; 2 were discovered in patients without histories of pain; and 1 fit criteria for hematopoietic marrow defect.

DISCUSSION The purpose of this study was to evaluate subpontic bone in sites of FPD placement that also were associated with pain or radiographic abnormality. Osteonecrosis or nonsuppurative osteomyelitis was discovered in alveolar bone of almost 90% of patients with chronic idiopathic facial pain, which offered an explanation for localized alveolar tenderness, elevated mucosal temperatures, and positive bone scans reported by Friedman22 and Denucci et al.23 in idiopathic facial pain patients. It served as a clear warning that bone-related pain may explain idiopathic pain that begins as toothache-like pain and evolved into phantom pain or facial neuralgia.24,39 Persistent remnants of lamina dura after extraction may be more than a simple variation of normal radiographic anatomy. This study suggests that it is more VOLUME 81 NUMBER 2

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Fig. 13. Normal bone marrow has almost no fibers visible between fat cells, as seen here. Fat cells are seen as uniform, rounded clear spaces with thin, barely visible cell membranes. Fat has been dissolved by tissue processing, but some cells show artifactual haziness in cytoplasm because of collapsed membranes. Marrow blood vessels are abundant but are small and readily apparent only when slightly dilated (arrows). Bone in lower left corner shows no missing osteocytes.

reasonable to consider laminar rain as a sign of underlying inflammatory or physiologic processes that were preventing proper remodeling of bone. Bone is a dynamic tissue in constant flux and there is no physiologic reason for postextraction alveolar bone not to remodel to accommodate the new lack of tooth-related stresses.41,42 Under ischemic conditions, intraosseous fibrous “scar” tissue (marrow fibrosis, reticular fatty degeneration, myelofibrosis) is created rather than new bone, because osteoblasts and osteoclasts require abundant nutrition and oxygen to perform physiologic functions, whereas fibroblasts do not.43 Fibrosis of marrow is a profound alteration. Fibers in bone marrow are usually small in size and numbers, and almost invisible on stained microscopic slides. Presumably, laminar rain may represent this fibroplasia phenomenon, with the extraction socket becoming permanently filled with fibers rather than with new bone. Laminar rain did not allow a formal diagnosis, it served merely as a “red flag” that something may be wrong with the local bone. Cancellous bone does not usually exhibit obvious radiolucent destruction until disease is in late stages (stages 3 and 4 in long bones), so radiographic signs of poor healing in earlier stages is significant.40 A lesson can also be derived from what is not observed. Dramatic damage to cancellous bone is possible without radiographic evidence of change. This occurs especially in the ends of long bones and particularly with lesions, such as osteonecrosis and osteomyelitis, which do not have a sharp demarcation from surrounding bone.44 Similar evidence has been FEBRUARY 1999

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Fig. 14. Some patients with subpontic osteonecrosis demonstrated large aggregates of fibrin/platelets within dilated marrow sinusoids or veins (arrows), which is unusual for inflammatory disease and is suggestive of, but not diagnostic for, coagulation disorder.

available for alveolar bone of the jaws,45-47 but most dentists tend to forget this. A lack of radiographic changes does not necessarily indicate that bone contains no disease. False-negatives can occur, as they do in other tests.

What is osteonecrosis? Ischemic osteonecrosis is not a disease in the usual sense but is the result of a wide variety of local and systemic disorders that eventually lead to ischemia and infarction of the marrow and bone (Table V). For example, when a jawbone is irradiated the blood vessels are damaged, become entombed by fibrous tissue and lead to a chronically poor blood flow (after initial hyperemia) with the often painful condition previously mentioned as osteoradionecrosis. Medullary blood flow is similarly compromised in corticosteroidinduced osteonecrosis, not by fibrosis but by endothelial injury and outflow veins partially collapsed by enlarged adipocytes.7,10,36 A more common mechanism of compromised marrow blood flow has been blockage of the vessels by thrombi. For example, multiple bone infarctions have been a major medical problem for patients with sickle cell anemia.11,15 Rigid erythrocytes become blocked within the smaller vessels of the marrow and the resulting localized infarction is often extremely painful. Other causes of intramedullary infarction have been less obvious. However, a substantial breakthrough was achieved by Glueck et al.30-35 who reported that a majority (65% to 87%) of osteonecrosis patients, including those with jawbone involvement, had major hereditary or acquired clotting disorders that had not been previously diagnosed or even suspected (Table III). 155

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Table V. Localized and systemic diseases and problems associated with ischemic osteonecrosis4-12,15 Local factors Trauma (mild or severe) Radiation therapy for cancer Intraosseous inflammation/infection Arthritis Corticosteroid injection of joint Intraosseous malignancy (especially lymphoma and metastic carcinoma) Systemic factors Corticosteroid therapy (long- and short-term)/Cushing’s syndrome Variable atmospheric pressures in occupation (Caisson’s disease) Alcoholism/pancreatitis Osteoporosis Systemic lupus erythematosus (with or without corticosteroids) Sickle cell disease Hereditary thrombophilia (Protein C and Protein S deficiencies) Homocystinemia from homozygosity for methylene tetrahydrofolate reductase Hereditary familial hypofibrinolysis disease Factor VLeiden gene mutation Gaucher’s disease Pregnancy/high dose estrogen therapy Disseminated intravascular coagulation (DIC) Chemotherapy for cancer Deficiency of thyroid hormone Antiphospholipid antibody syndrome Hyperlipidemia Hemodialysis Inactivity (bedridden, paraplegic, etc)

Alveolar bone and the mandibular condyles appear most susceptible to this disease, usually diagnosed under the terms neuralgia-inducing cavitational osteonecrosis (NICO) and avascular condylar necrosis.15,48 Alveolar lesions are likely to be misdiagnosed as facial neuralgias, as NICO diagnostic terminology implies. This misdiagnosis may result because the jawbones are the only bones of the human skeleton to contain large sensory nerves; thus, the level of pain is greater or the pain is different from that produced by disease in other bones. This problem is compounded by the high proportion of false-negatives on routine radiographic evaluation, and by low levels of diagnostic suspicion demonstrated by health care professionals.

Pain of osteonecrosis It has been suggested that a proportion of patients with facial neuralgia have persistent pain from trigeminal nerve damage at some distance from the brain, including nerves within inflamed jawbones. 49,50 The pain could be created by damage to peripheral nerves (neuritis, deafferentation, demyelination), and occasionally patients with NICO have certainly demonstrated degen156

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eration of myelin sheathing of intraosseous nerves.16 Some patients have even demonstrated antimyelin antibody levels consistent with chronic exposure of the immune system to damaged myelin.51,52 Ischemic osteonecrosis appears to be a significant contributor to this process from this and previous studies. However, pain, recurrence and multifocal involvement are hallmarks of osteonecrosis, regardless of the exact cause, and nerve damage is not necessary to produce the pain. Osteonecrotic pain has been shown to typically result from increased intramedullary pressure, which can be 5 times greater than normal and is routinely twice that of normal bone.7,36,53,54 This has resulted from poor outflow from the bone and is unique to ischemic osteonecrosis. Certain authorities have advocated diagnostic injection of saline in marrow of painful bones lacking obvious radiographic changes. The pain increases in patients with osteonecrosis but not in others.36 Intraosseous stasis and hypertension, first noted in osteoarthritis, is especially associated with a deep, aching pain at rest.53-55 The pain of osteonecrosis may also be due to venous distension, and the pain stimulus may originate in the vein wall.53 In addition, pain of osteonecrosis may be due to diminished blood flow from intravascular microthrombi; recent clinical research has demonstrated major pain reduction in jawbone osteonecrosis patients with anticoagulants.56 NO-liberating organic nitrates, such as nitroglycerin, have been effective in controlling pain in localized ischemic conditions of other parts of the body, such as anal fissures.57 However, these medications have not been administered for patients with NICO. Other causes of deep bone pain are associated with osteonecrosis. Infarction resulting from the complete, abrupt blockage of marrow blood vessels creates an immediate and sharp pain. Toxins and inflammatory mediators, such as prostaglandin E2 and other cytokines routinely released from necrotic tissues and local inflammatory responses, may result in a variety of different pain symptoms over an extended period.58-60 In addition, infection of cancellous bone further compromises local blood flow and enhances coagulation. New microinfarctions can occur in adjacent marrow, only to repeat the entire process again.

SPECULATION Case 1 scenario is not difficult to explain by extrapolating the results of research for other bones. Steadily increasing intramedullary hypertension from poor outflow results in painful claudication and possible tissue death, similar to pulpal events in an injured tooth. Small infarctions (microinfarctions) elicit additional pain and a corresponding inflammatory response. Inflammatory mediators further diminish local blood flow, compounding the problem and perhaps establishVOLUME 81 NUMBER 2

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ing a perpetually spiraling cycle of increasing disease and pain. Case 2 scenario, with pain beginning or recurring with tooth preparation or prosthetic placement, is more difficult to understand. Mild pulpal inflammation natural to the tooth reduction may carry inflammatory mediators into apical bone. However, this appears unlikely and alveolar osteonecrosis seldom occurs at the exact apex of a tooth. It is a disease of paradental or interdental bone, not periapical pathosis. There is a more logical explanation for the case 2 scenario. Almost all local anesthetic used in dentistry today includes a potent vasoconstrictor. In a person with seriously compromised intraosseous vascular flow, the diminished blood flow from a dental anesthetic may reduce marrow vascularity beyond recovery. This problem may be enhanced by the temporary nature of vasoconstriction because damaging free radicals (oxyradicals) are created in remarkable abundance in ischemic tissues when reperfused.61

A word of caution This investigation appears to indicate that the great majority of case 1 and case 2 scenario patients suffered from intramedullary disease, but patients were initially identified through a biopsy service, with the case-selection biases that implies. The majority of prosthetic patients, even those with pain, do not have biopsies of subpontic bone and were naturally excluded from this study. The retrospective nature of the study also did not allow experimental manipulation of investigative parameters. The frequency and incidence of ischemic osteonecrosis of the jaws is unknown. It may be that mild ischemic changes are a “natural” part of the aging process, similar to a disease process such as atherosclerosis, which becomes extremely common with increasing age. Enlow62 reported ischemic loss of osteocytes greater in the jaws of older monkeys when compared with younger monkeys. Graff-Radford63 identified numerous small marrow “cavitations” in the jawbones of elderly human cadavers without apparent histories of facial pain, although he did not control for diseases known to be associated with ischemic osteonecrosis (Table V). Through a cadaver investigation, Oikarenin63 discovered that the inferior alveolar artery showed an increasing degree of degenerative changes after 40 years of age, both age changes and arteriosclerotic changes, in the form of narrowings and tortuosity, particularly for edentulous ridges. Bone marrow is not uniformly perfused and this accentuates the blood flow dilemma.64,65 Certain areas are more susceptible to ischemic changes than other areas in close proximity within the same bone. Normal marrow has been admixed with damaged marrow in ischemic osteonecrosis and a dentist must be careful to obtain adequate tissue for a diagnosis. This may be difFEBRUARY 1999

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ficult because many patients have desiccated, hollow, medullary spaces, called “cavitations,” similar to empty spaces of a traumatic (idiopathic, unicameral) bone cyst. It may be impossible to secure a sufficient tissue sample in such a situation. Cavitations are critical diagnostic data because few diseases are capable of producing “air-filled” spaces in cancellous bone.

CONCLUSIONS This preliminary investigation strongly suggested that intraosseous ischemia, infarction and low-grade inflammation were substantial explanations for at least some, and perhaps many, patients with chronic idiopathic facial pain and subpontic phantom pain. It additionally helped to explain cases of poor bone healing of extraction sites and offered an insight into cases of chronic facial pain initiated by routine restorative procedures. The limitations of the study suggest that more extensive, prospective, case-controlled studies are necessary. If additional investigations corroborate the results of this study, the therapy for idiopathic facial pain should focus on treatment of osseous or coagulation disorders rather than on neurological diseases of unknown cause.16,56 REFERENCES 1. Sessle BJ. The neurobiology of facial and dental pain: present knowledge, future directions. J Dent Res 1987;66:962-81. 2. Bonica J. The management of pain. 2nd ed. Philadelphia: Lea & Febiger; 1990. 3. Gordon SM, Dionne RA. Prevention of pain. Compend 1997;18:239-52. 4. Jones JP Jr. Osteonecrosis. In: McCarty D, editor. Arthritis and allied conditions: a textbook of rheumatology. 11th ed. Philadelphia: Lea & Febiger; 1989. p. 1545-62. 5. Mankin HJ. Nontraumatic necrosis of bone (osteonecrosis). N Eng J Med 1992;326:1473-9. 6. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:4769. 7. Steinberg ME, Steinberg DR. Osteonecrosis. In: Kelly WN, Harris ED Jr, Ruddy S, Sledge CB, editors. Textbook of rheumatology. 4th ed. Philadelphia: WB Saunders; 1993. p. 1628-50. 8. Mazieres B. Osteonecrosis. In: Klippel JH, Dieppe PA, editors. Rheumatology. Philadelphia: Mosby; 1994. p. 7,41.1-8. 9. Simkin PA, Gardner GC. Osteonecrosis: pathogenesis and practicalities. Hosp Pract Off Ed 1994;29:73-84. 10. Sweet DE, Madewell JE. Osteonecrosis: pathogenesis. In: Resnick D, editor. Diagnosis of bone and joint disorders. 3rd ed. Philadelphia: WB Saunders; 1995. p. 3445-94. 11. Bullough PG. Orthopedic pathology. 3rd ed. Baltimore: Mosby-Wolfe; 1997. 12. Bouquot JE, Roberts AM, Person P, et al. Neuralgia-inducing cavitational osteonecrosis NICO: osteomyelitis in 224 jawbone samples from patients with facial neuralgias. Oral Surg Oral Med Oral Pathol 1992;73:307-19. 13. Ingle JI, Bakland LK. Endodontics. 4th ed. Baltimore: Williams & Wilkins; 1994. p. 581-2. 14. Langlais RP, Langland OE, Nortje CJ. Diagnostic imaging of the jaws. Baltimore: Williams & Wilkins; 1994 p. 393-5. 15. Neville B, Damm D, Allen C, Bouquot J. Oral and maxillofacial pathology. Philadelphia: WB Saunders; 1995. p. 631-2. 16. Bouquot J, Christian J. Long-term effects of jawbone curettage on the pain of facial neuralgia. J Oral Maxillofac Surg 1995;53:387-97. 17. Bouquot JE, McMahon RE. Ischemic alveolar osteonecrosis in 2,023 patients with chronic facial pain. J Orofacial Pain 1997;11:180. 18. Bouquot JE, McMahon RE. Ischemic osteonecrosis of the jaws. Part II:

157

THE JOURNAL OF PROSTHETIC DENTISTRY

19.

20. 21.

22.

23. 24. 25.

26. 27.

28.

29. 30.

31.

32.

33.

34.

35.

36.

37. 38. 39. 40.

41. 42. 43.

158

histopathologic review of NICO (neuralgia-inducing cavitational osteonecrosis), based on experience with more than 4,000 jawbone biopsy samples. Edition 1. Morgantown (WV): The Maxillofacial Center; 1997. p. 1-22. Bouquot J, Roberts A. NICO (neuralgia-inducing cavitational osteonecrosis): radiographic appearance of the “invisible” osteomyelitis. Oral Surg Oral Med Oral Pathol 1992;74:600. Rohrer MD, Kim Y, Fayos JV. The effect of cobalt-60 irradiation on monkey mandibles. Oral Surg Oral Med Oral Pathol 1979;48:424-40. McKenzie MR, Wong FL, Epstein JB, Lepawsky M. Hyperbaric oxygen and postradiation osteonecrosis of the mandible. Eur J Cancer B Oral Oncol 1993;29B:201-7. Friedman M. Atypical facial pain: the consistency of ipsilateral maxillary area tenderness and elevated temperature. J Am Dent Assoc 1995; 126:855. Denucci DJ, Dionne RA, Chen CC, Meehan SC. SPECT bone scanning in the diagnosis of chronic idiopathic jaw pain. J Dent Res 1997;76:237. Law AS, Lilly JP. Trigeminal neuralgia mimicking odontogenic pain. A report of two cases. Oral Surg Oral Med Oral Pathol 1995;80:96-100. Kim v. Thune, Orange County Court, California, 1994; Drehsler v. Frankel, District Court of Washington, DC, 1996; Fisher v. Thomas, County Court of San Diego, California, 1997. Bouquot JE. Epidemiology. In: Gnepp DR, editor. Pathology of the head and neck. Philadelphia: Churchill-Livingstone; 1988. p. 263-314. McMahon RE, Adams W, Spolnik K. Diagnostic anesthesia for referred trigeminal pain, parts I & II. Compendium Cont Educ Dent 1992;11:87081, 980-97. McMahon RE, Griep J, Marfurt C, Saven MA. Local anesthetic effects in the presence of chronic osteomyelitis/necrosis of the mandible: implications for localizing the etiologic sites of referred trigeminal pain. J Craniomand Pract 1995;13:212-26. Brown RS, Hinderstein B, Reynolds DC, Corio RL. Using anesthetic localization to diagnose oral and dental pain. J Am Dent Assoc 1995;126:633-41. Glueck CJ, Freiberg R, Glueck HI, Henderson C, Welch M, Tracy T, Stroup D, et al. Hypofibrinolysis; a common, major cause of osteonecrosis. Am J Hematol 1994;45:156-68. Glueck CJ, Glueck HI, Greenfield D, Freiberg R, Kahn A, Hamer T, Stroop D, et al. Protein C&S deficiency, thrombophilia, and hypofibrinolysis; pathophysiologic causes of Legg-Perthes disease. Pediatr Res 1994;35: 383-8. Glueck CJ, McMahon RE, Bouquot JE, Stroop D, Tracy T, Wang P, Rabinovich B. Thrombophilia, hypofibrinolysis and osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol 1996;81:557-66. Gruppo R, Glueck CJ, McMahon RE, Bouquot J, Rabinovich BA, Becker A, Tracy T, et al. The pathophysiology of osteonecrosis of the jaw: anticardiolipin antibodies, thrombophilia, and hypofibrinolysis. J Lab Clin Med 1996;127:481-8. Glueck CJ, McMahon RE, Bouquot JE, Triplett D, Gruppo R, Wang P. Heterozygosity for the Leiden mutation V gene, a common pathoetiology for osteonecrosis of the jaw with thrombophilia augmented by exogenous estrogens. J Lab Clin Med 1997;130:540-3. Glueck CJ, Freiberg R, Gruppo R. Thrombophilia and hypofibrinolysis: reversible pathogenetic etiologies of osteonecrosis in adults and in children (Legg-Perthes Disease). In: Urbaniak JR, Jones JP Jr, editors. Osteonecrosis—etiology, diagnosis, and treatment. Rosemont (IL): American Academy Orthopaedic Surgeons; 1997. p. 105-10. Arlet J, Mazieres B, editors. Bone circulation and bone necrosis. Proceedings of the Fourth International Symposium on Bone Circulation, Toulouse (France), Sept 17-19, 1987. New York: Springer-Verlag; 1990. Ono K, editor. Symposium: recent advances in avascular necrosis. Clin Orthop Related Res 1992;277:2-138. Burrell KH, Goepp RA. Abnormal bone repair in jaw, socket sclerosis: a sign of systemic disease. J Am Dent Assoc 1973;87:1206-15. Bouquot JE, McMahon RE. Ischemic osteonecrosis in facial pain syndromes. TMDiary 1996;8:32-9. Soucacos PN, Xenakis TH, Beris AE, Soucacos PK, Georgoulis A. Idiopathic osteonecrosis of the medial femoral condyle. Classification and treatment. Clin Orthopaed Rel Res 1997;341:82-9. Huebsch RF, Hansen LS. A histopathologic study of extraction wounds in dogs. Oral Surg Oral Med Oral Pathol 1969;28:187-96. Shafer WG, Hine MK, Levy BM. A textbook of oral pathology. 4th ed. Philadelphia: WB Saunders; 1983. p. 601-11. Foucar K. Bone marrow pathology. Chicago: American Society of Clinical Pathologists (ASCP) Press; 1995. p. 431-74.

BOUQUOT AND LAMARCHE

44. Adrian GM. Bone destruction not demonstrable by radiology. Br J Radiol 1951;24:107-9. 45. Bender JB, Seltzer S. Roentgenographic and direct observation of experimental lesions in bone. J Am Dent Assoc 1961;62:152-60,708-16. 46. Schwartz SF, Foster JK Jr. Roentgenographic interpretation of experimentally produced bone lesions. Oral Surg Oral Med Oral Pathol 1971;32: 606-12. 47. Vanderstelt PF. Experimentally produced bone lesions. Oral Surg Oral Med Oral Pathol 1985;59:306-12. 48. Chuong R, Piper MA, Boland TJ. Osteonecrosis of the mandibular condyle, pathophysiology and core decompression. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79:539-45. 49. Harris W. Neuritis and neuralgia. London: Oxford University Press; 1926. p. 163-5. 50. Fromm GH, Terrence CF, Maroon JC. Trigeminal neuralgia; current concepts regarding etiology and pathogenesis. Arch Neurol 1984;41:1204-7. 51. Koski CL. Humoral mechanisms in immune neuropathies. Neurol Clin 1992;10:629-49. 52. McMahon R, Bouquot J. Elevated serum peripheral nerve anti-myelin antibody titers in atypical facial pain patients with NICO. J Orofacial Pain 1994;8:106. 53. Arnoldi CC. Intraosseous engorgement-pain syndromes. The pathomechanism of pain. In: Arlet J, Mazieres B, editors. Bone circulation and bone necrosis. Proceedings of the IVth International Symposium on Bone Circulation, Toulouse (France), Sept 17-19, 1987. New York: Springer-Verlag; 1990. 54. Simkin PA, Downey DJ, Lanzer WL. Hydraulic resistance: a measure of outflow resistance in osteonecrosis. In: Arlet J, Mazieres B (editors). Bone circulation and bone necrosis. Proceedings of the IVth International Symposium on Bone Circulation, Toulouse (France), Sept 17-19, 1987. New York: Springer-Verlag; 1990. 55. Arnoldi CC, Linderholm H, Mussbichler H. Venous engorgement and intraosseous hypertension in osteoarthritis of the hip. J Bone Joint Surg [Br] 1972;54(B):409-21. 56. Glueck CJ, McMahon RE, Bouquot JE, Tracy T, Sieve-Smith L, Wang P. A preliminary pilot study of treatment of thrombophilia and hypofibrinolysis and amelioration of the pain of osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:64-73. 57. Gorfine SR. Treatment of benign anal disease with topical nitroglycerin. Dis Colon Rectum 1995;38:453-51. 58. Weksler BB. Altered hemostasis in inflammation. In: Gallin JI, Goldstein IM, Snyderman R, editors. Inflammation: basic principles and clinical correlations. New York: Raven Press; 1988. p. 543-57. 59. Wannfors K, Gazelius B. Blood flow in jawbones affected by chronic osteomyelitis. Br J Oral Maxillofac Surg 1991;29:147-53. 60. Cochrane EH, Fleming RH, McCarthy ID. Dose-dependent reduction of bone blood flow and 85Sr clearance caused by prostaglandin E2. In: Arlet J, Mazieres B, editors. Bone circulation and bone necrosis. New York: Springer-Verlag; 1990. p. 43-6. 61. Gasbarrini A, Grigolo B, Serra M, Baldini N, Scotlandi K, Gasbarrini A, Bernardi M, et al. Generation of free radicals during anoxia and reoxygenation in perfused osteoblast-like cells. Clin Orthopaed Rel Res 1997;338:247-52. 62. Enlow DH. Osteocyte necrosis in normal bone. J Dent Res 1966;45:213. 63. Graff-Radford SB, Simmons M, Fox L, et al. Are bony cavities exclusively associated with atypical facial pain and trigeminal neuralgia? Proceedings of Annual Meeting, Western USA Pain Society, Santa Fe, NM, May, 1988. 64. Oikarinen VJ. The inferior alveolar artery: a study based on gross anatomy and arteriography, supplemented by observations on age changes. Suom Hammaslaak Toim 1965;61:11-131. 65. Lausten GS, Arnoldi CC. Blood perfusion uneven in femoral head osteonecrosis. Doppler flowmetry and intraosseous pressure in 12 cases. Acta Orthop Scand 1993;64:33-6. 66. Kiaer T. Bone perfusion and oxygenation. Animal experiments and clinical observations. Acta Orthop Scand 1994;65(Suppl 257):1-41.

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