PAGET DISEASE OF BONE
Lecturer: Dr. Heddie O. Sedano, DDS, Dr. Odont.
Contents:
Paget
disease of bone (PDB) was origillay described by Sir James Paget in 1877
under the name of osteitis deformans. Sir Paget's clinical description
was so acurate that it is still valid today.
PDB is a chronic metabolic disease affecting many parts of the skeleton
(polyostotic) characterized by abnormal resorption and formation of bone.
The basic defect lies in abnormalities of the osteoclasts and osteoclasts
precursor cells. There is ample evidence that points to genetic heterogeneity.
This evidence is based on several research studies that have shown that
PDB is caused by gene mutations in at least four different chromosomes.
PDB1 has been mapped to the short arm of chromosome 6 region 21.3 (6p21.3),
PDB2 has been mapped to the long arm of chromosome 18 regions 21-22 (18q21-22),
PDB3 maps to the long arm of chromosome 5 regions 5 to ter (5q35-qter)
and PDB4 maps to the long arm of chromosome 5 region 31 (5q31). The clinical
manifestations in patients with any one of these mutations are identical,
the number following PDB only indicates the particular mutation. The
gene (TNFRSF11A) which is essential for osteoclast formation maps to the
PDB2 region (18q21-22).
Osteoclasts and osteoclast precursor cells from Paget's patients are abnormal
and have been shown to contain paramyxoviral transcripts. The role that
the paramyxoviruses may play in the etiology of PDB is still to be properly
ascertain. (Osteoclasts from patients with PDB show in their cytoplasm
multiple inclusion bodies. Electron microscopy of these bodies demonstrate
whorls of tubular filaments similar to that of the paramyxoviruses, especially
measles).
Osteoporosis and PDB are the two most common metabolic diseases of bone.
Recently a decline in the severity and prevalence of PDB have been noted.
PDB is most frequently diagnosed in patients over 40 years of age and
it has a slight male predilection. It has been established that 2 to 3%
of the population over 60 years of age present radiographic changes compatible
with PDB.
SYSTEMIC
FINDINGS
Almost all bones can be involved. The major characteristic is enlargement
of the affected bone. The most frequent complaint is bone pain, severe
headache, deafness due to compression of the cochlear nerve, blindness
due to compression of the optic nerve, dizziness and weakness. A frequent
complication of these bone lesions is spontaneous fracture. Bowing of
legs is very marked and of diagnostic aid. The skin overlying affected
superficial bones become swollen and hot. The disease has a slow, chronic
course.
ORAL
FINDINGS
In about 50 percent of cases, there is involvement of jaw bones with marked
predilection for the maxilla.
Figure 1. This 67 year old woman had PDB. Note the marked enlargement of both maxilla and the protrusion of the upper lip. Also note the deformity present at the root of the nose.
When in the jaw the lesion can be observed initially in either the maxilla or mandible, most likely the maxilla. In many cases, PDB remains confined to the maxilla for a period of time before it manifests in some other bones. Maxillary and mandibular manifestations are characterized by generalized enlargement of these bones with consequent tooth diastema due to migration of teeth.
Figure 2. This is the intraoral view of the patient shown in Figure 1. Note the increase in size of the maxillary alveolar bone and the driffting of teeth.
If the patient is edentulous a generalized enlargement of either the maxillary or mandibular alveolar ridges will be observed. In this case the main complaint of the patient will be the inability to wear the old dentures.
Figure 3. Intraoral view from and edentulous patient with PDB. Note the enlargement on the right maxilla. The patient was unable to use his denture.
In the jaw, fracture as well as osteomyelitis can be associated with dental pain. Another frequent complication is the development of either an osteogenic sarcoma or a true giant cell tumor of bone.
Figure 4. This lateral X-ray from another patient with PDB shows the typical findings in the skull as well as an osteosarcoma present in the maxilla.
RADIOGRAPHIC
FINDINGS
Radiographically, PDB is characterized by the presence of areas of radiopacity
alternating with areas of radiolucency.
Figure 5. These are the intraoral serial radiographs of the patient shown in Figure 1. Note the mixture of radiopaque and radiolucent lesions around the maxillary teeth.
The term cotton-wool is used to describe the radiographic appearance of bone in PDB. In the area of the maxilla and mandible this cotton-wool image is accompanied by areas of hypercementosis.
Figure 6. This is an occlusal radiograph of the same patient. Once more note the areas of radiolucencies and radiopacity as result of bone resorption and apposition.
This radiologic appearance can be confused, in those cases confined to the jaw, with periapical cemental dysplasia.
Figure 7. This compound serial intraoral x-ray is from another patient with PDB. Note the marked areas of radiopacities similar to hypercementosis. Those areas alternate with radiolucid zones of resorption.
The radiologic image portrays the basic pathologic process in PDB, that is reabsorption and softening of bone, represented by the radiolucent areas and dysplastic new bone formation not related to functional requirements, represented by areas of marked radiopacity. Both stages can occur either simultaneously or alternatively. The cotton-wool appearance can be observed in other bones, especially those of the skull.
Figure 8. This lateral skull view from another patient with PDB shows the typical "cotton-wool" appearance.
HISTOPATHOLOGY Bone biopsies of patients with PDB are quite typical showing spicules of bones with accelerated bone formation showing active osteoblasts.
Figure 9. This photomicrograph taken from a bone biopsy from a patient with PDB shows several bone spicules in a highly vascularized connective tissue stroma.
These areas of bone formation alternate with areas of bone resorption characterized by the presence of osteoclasts. Typically, the osteoclasts are seen inside of Howship lacunae.
Figure 10. This is a higher magnification of the previous microscopy. Arrow A points to osteoclasts in Howship lacunae and arrow B points to osteoblasts in the process of bone formation.
The stroma is highly vascular. Biopsies from areas of densely calcified bone show a mosaic appearance characterized by deeply stained straight lines which represent areas of bone formation. These lines are intermixed with, also deeply stained, wavy lines (reversal lines) which represent fronts of previous bone resorption.
Figure 11. This is another photomicrograph taken from a bone biopsy from a patient with PDB from a mostly radiopaque area. Note the apposition lines and the reversal (resorption) lines. The combination of these two lines give this biopsy a mosaic appearance.
DIFFERENTIAL
DIAGNOSIS
The diagnosis becomes quite evident after obtaining a detailed clinical
history as well as several radiographs and laboratory values as explained
below. Nevertheless, in those cases which originate in the maxilla or
mandible, periapical cemental dysplasia, autosomal
dominant cemental dysplasia, sclerosing osteitis,
familial gigantiform cementoma, florid
osseous dysplasia and osteogenesis imperfecta Levine
Type should be considered in the differential diagnosis, as these
all present with similar localized clinico-radiographic pictures as PDB
without the generalized skeletal changes and no changes in alkaline phosphatase
levels.
LABORATORY
AIDS
Serum calcium, phosphorous, and acid phosphatase are within normal limits.
Alkaline phosphatase is generally markedly elevated. Values as high as
250 Bodansky units (BU) have been recorded compared to the normal range
of 1.5 to 5.0 BU. Alkaline phosphatase is elevated especially during the
osteoblastic phase of the disease and especially in patients with several
bones affected. Urinalysis will demonstrate elevated values of hydroxyproline
which originates from destruction of bone collagen.
TREATMENT
The treatment is provided by physicians specialized in bone disorders.
Presently PDB is treated with pamidronate which is a bisphosphonate specially
used to treat hypercalcemia. Pamidronate reduces the rate of bone resorption
by down regulating osteoclasts which eventuates in an increase in bone
density.
The usual total dose range of pamidronate for adults with PDB is 90 to
180 mg in an intravenous solution spread over a period of 3 to 6 weeks.
Improvements and remissions are most frequently seen in patients with
a serum level of alkaline phosphatase less than three times the upper
limit of normal (ULN) at the begining of treatment. Patients with a serum
level of alkaline phosphatase above 3 times the ULN are less likely to
go into remission.
Pamidronate is also used to treat calcium producing metastatic disease
to bones, osteogenesis imperfecta, multiple myeloma and several other
hypercalcemic states.
PRECAUTIONS
It is important to remember that if a patient with osteitis deformans
need to undergo a tooth extraction antibiotic medication is recommended
prior to and following the extraction in order to avoid the development
of osteomyelitis starting at the extraction site. The danger of bone fracture
also exists during the extraction manuvers due to the abnormal bone composition.
PERIAPICAL
CEMENTAL DYSPLASIA
Periapical cemental dysplasia (PCD) is an aberration of periapical connective
tissue in which a fibroblastic stroma is gradually replaced by cementum-like
calcified tissue. The cause of PCD is unknown and the teeth are vital.
Multiple poorly defined periapical radiolucencies are found most commonly
on the lower incisor, cuspid, and premolar teeth. This is the first or
osteolytic stage of the process and resembles the periapical radiolucency
of a periapical granuloma. In the subsequent stage, PCD develops radiopaque
flecks and more calcified material is laid down. In the final inactive
phase PCD presents as a periapical radiopacity resembling condensing osteitis.
PCD is painless. The teeth respond positively to vitality tests. There
may be, however, a suggestion of traumatic occlusion. PCD appears to have
a predilection for the lower incisor teeth of women. PCD grows to a certain
size and stops maturing with no complications.
Figure 12. These X-rays
are from a patient with periapical cemental dysplasia showing the characteristic
calcified masses around the apices of the anterior mandibular teeth. Vitality
tests were within normal limits.
PCD is to be differentiated from the true cementoma, a benign neoplasm
of cementum which continues to grow steadily by peripheral extension.
It is also differentiated from sclerosing or condensing osteitis by the
lack of pulpal involvement. It is essential to differentiate the early
osteolytic stage from periapical granuloma or cyst. Autosomal dominant
cemental dysplasia should also be considered in the differential diagnosis
as well as fibro-osseous dysplasia.
Pulp vitality tests are essential. Regular radiographic follow-up is indicated.
No surgery is indicated unless the behavior of PCD does not conform to
this picture or clinical bone expansion is found.
AUTOSOMAL
DOMINANT CEMENTAL DYSPLASIA
Autosomal dominant cemental dysplasia (ADCD), as the name implies is an
inherited condition which affects the teeth bearing areas of the maxilla
and mandible. There are no obvious clinical signs and patients with ADCD
do not have any symptomatology. ADCD represents an incidental radiographic
finding characterized by faint to obvious areas of radiopacity which are
observed around the roots of all teeth.
Figure 13. This panoramic X-ray is from one of several members of a family with autosomal dominant cemental dysplasia. Note the radiopaque masses, especially in the mandible, around teeth apices. These lesions were asymptomatic and the patient was unaware of its presence. The lesions were discovered in a routine radiographic examination and, originally, were believed to represent an example of PDB.
Vitality tests are within normal limits. There are no systemic or skeletal manifestations. Histologic and electron microscopic studies have shown those areas of abnormal calcification to be similar to cementum. There is no treatment for ADCD. The radiologic appearance of this condition is quite similar to that seen in patients with PDB as well as in patients with osteogenesis imperfecta Levine type and to some degree to familial gigantiform cementoma. Dental extractions in patients with ADCD are difficult due to the increased calcification of bone.
SCLEROSING
OSTEITIS
Sclerosing osteitis (SO) or condensing osteitis is a localized increase
in bone density as a response to a chronic inflammatory foci around the
apices of vital or non-vital teeth. SO presents as a radiopacity of varying
size, shape and contour. These lesions are generally not well-defined.
Figure 14. These are radiographs depicting sclerosing osteitis. The one to the left in an extraction site and the one to the right at the apex of a non-vital tooth. Note that there is no definite separation between the lesion and the surrounding normal bone.
The periodontal membrane's
space is seen to be occupied by the sclerotic area and the lamina dura
may be seen to have lost its integrity, as opposed to hypercementosis
where it is normal for the periodontal membrane space to be visible and
the lamina dura to surround the lesions. Acute symptoms such as pain,
swelling and drainage and lymphadenitis are absent though some degree
of periapical sclerosis may occasionally be seen associated with a draining
dental sinus. After root canal therapy or extraction of the tooth the
sclerosis may not necessarily disappear.
Depending upon the location, periapical cemental dysplasia and benign
cementoblastoma need to be considered in the differential diagnosis. PDB
should be included in the differential especially in cases of multiple
SO lesions Pulp vitality tests may be equivocal as sclerosing osteitis
may occur in teeth which may have one non-vital root canal and two vital.
Root canal therapy is the indicated treatment.
FAMILIAL
GIGANTIFORM CEMENTOMA
Familial gigantiform cementoma (FGC) is characterized by multiple, large
cemental masses found in the maxilla and mandible which are inherited
as an autosomal dominant trait. Occasionally these patients also present
radiolucent areas.
Figure 15. This panoramic X-ray is from a patient with familial gigantiform cementoma. Note the large calcified masses in the mandible with displacement of teeth. The mother of the patient had a similar radiographic appearance in her mandible.
There are no systemic or skeletal findings. These masses can produce driffting of teeth and they induce marked facial deformity. The differential diagnosis with PDB is established by the fact that FGC is inherited and also because there are no findings in other bones. Laboratory values are also normal in FGC.
FLORID
OSSEOUS DYSPLASIA
Florid osseous dysplasia (FOD), which has been described under a great
variety of names, is an abnormality of the tooth-bearing areas of the
maxilla and mandible in which large, densely calcified masses resembling
cementum are deposited in the periodontium and neighboring alveolar bone.
FOD may also be accompanied by solitary bone cysts.
Figure 16. Panoramic X-ray from a patient with florid osseous dysplasia showing radiopaque masses mixed with areas of radiolucency. The radiolucent areas represent traumatic cysts. This condition has been reported mostly in females with African heritage .
Lesions generally occur simultaneously in all four quadrants of the jaws. They present mostly as a diffuse radiopacity with a "cotton-wool" appearance on the radiograph, similar to that seen in PDB. These radiopacities may be associated with areas of radiolucency, both observed in the alveolar bone and periodontium. The non-teeth bearing areas of both jaws are not affected by the process. The lesions are not well-circumscribed and there may be gross expansion of the cortical plates resembling fibrous dysplasia or PDB. The condition appears to have a predilection for women of African heritage; however, cases have been reported in both sexes and in other races. The behavior is of a very gradual expansion over a number of years without pain. The changes are generally discovered on routine roentgenographic examination. The resistance of the bone to infection might be impaired and osteomyelitis may supervene. The expansion of bone and apparent hypercementosis may simulate PDB. Autosomal dominant cemental dysplasia has a similar radiologic appearance but it has been observed in several kindreds, segregating as a dominant genetic trait. The differences and similarities of these two entities still needs further classification. Serum calcium, phosphorus, and alkaline phosphatase appear to be within normal limits in FOD.
The treatment should be confined to cosmetic surgery and diagnostic biopsy. Rigorous dental hygiene and regular dental checkups are required to avoid the complications of dental infection.
OSTEOGENESIS
IMPERFECTA LEVINE TYPE
This rare form of osteogenesis imperfecta was described in 1985 by Levine
in several members of three families. Patients present multiple fractures
as well as multiple radiolucent-radiopaque lesions of the jaws in the
teeth bearing areas.
Figure 17. This panoramic X-ray is from one of the patients originally described by Levine. Note the radiopaque areas around the root of the teeth. Note the similarity with autosomal dominant cemental dysplasia and PDB. These jaw lesions are very similar to those seen in patients with PDB and also in patients with autosomal dominant cemental dysplasia.
Good DA et al. Linkage of Paget disease of bone to a novel region on human chromosome 18q23. Am J Hum Genet 2002;70:517-25
Laurin N et al. Paget disease of bone: mapping of two loci at 5q35-qter and 5q31. Am J Hum Genet 2001;69:528-43
Levin LS et al. Osteogenesis imperfecta with unusual skeletal lesions. Report of three families. Am J Med Genet 1985;21:256-69.
Noor M, Shoback D. Paget's disease of bone: diagnosis and treatment update. Curr Rheumatol Rep 2000;2:67-73
Paget, J. On a form of chronic inflammation of bones (osteitis deformans). Med. Chir. Trans. 1877;60: 37-64.
Reddy SV et al. Paget's disease of bone: a disease of the osteoclast. Rev Endocr Metab Disord 2001;2:195-201
Said-al-Naief NA, Surwillo E. Florid osseous dysplasia of the mandible: report of a case. Compend Contin Educ Dent 1999;20:1017-9, 1022-8
Sedano HO et al. Autosomal dominant cemental dysplasia. A new entity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1982;54:642-6.
Singer, F. R. et al. Risedronate, a highly effective oral agent in the treatment of patients with severe Paget's disease. J. Clin. Endocr. Metab. 1998;83:1906-10.
Tucci JR, Bontha S. Intravenously administered pamidronate in the treatment of Paget's disease of bone. Endocr Pract 2001;7:423-9 and 479-80.
Young SK et al. Familial gigantiform cementoma: Classification and presentation of a large pedigree. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1989;68:740-7.
Disclaimer & Disclaimer & Copyright © 1996-1998 UCLA PIC & DSH. All Rights Reserved. All prices subject to change without notice. This site was designed for dental professionals by dentists.