|Year : 2020 | Volume
| Issue : 1 | Page : 19-25
Paget's disease of bone with special reference to dentistry: An insight
Sonia Gupta1, Manveen Kaur Jawanda2
1 Department of Oral Pathology, Rayat Bahra Dental College and Hospital, Mohali, Punjab, India
2 Department of Oral Pathology, Laxmibai Institute of Dental Sciences and Hospital, Patiala, Punjab, India
|Date of Submission||24-Jul-2014|
|Date of Decision||09-Mar-2020|
|Date of Acceptance||04-Apr-2020|
|Date of Web Publication||16-Jul-2020|
Dr. Sonia Gupta
#95/3, Adarsh Nagar, Dera Bassi, Mohali - 140 507, Punjab
Source of Support: None, Conflict of Interest: None
Paget's disease of bone (PDB) is a relatively common disorder of uncertain etiology. It is characterized by abnormal resorption and apposition of osseous tissue in one or more bones of the skeleton. Although many patients are asymptomatic, a variety of symptoms and complications may occur. Jaw involvement is seen in approximately 17% of cases, and usually, it is the maxilla that is involved. PDB begins with a period of increased osteoclastic activity and bone resorption, followed by increased osteoblast production of woven bone that is poorly mineralized. In the final phase of the disease process, dense cortical and trabecular bone deposition predominates, but the bone is sclerotic and poorly organized and lacks the structural integrity and strength of normal bone. This article discusses the prevalence, etiology, clinical features, radiography, histopathology, biochemistry, oral and dental manifestations, complications, and the treatment of PDB.
Keywords: Bone, osteoblast, osteoclast, Paget's disease, resorption
|How to cite this article:|
Gupta S, Jawanda MK. Paget's disease of bone with special reference to dentistry: An insight. Int J Oral Health Sci 2020;10:19-25
| Introduction|| |
Bone is a dynamic tissue that is constantly renewed. The cell populations that participate in this process; the osteoblasts and osteoclast are derived from different progenitor pools that are under distinct molecular control mechanisms. Together, these cells form temporary anatomical structures, called as basic multicellular units that execute bone remodeling. A number of stimuli affect bone turnover, including hormones, cytokines, and mechanical stimuli. All of these factors affect the amount and quality of the tissue produced. Paget's disease is a bone disorder characterized by excessive and abnormal remodeling of the bone, resulting in distortion and weakness of affected bones. It is the second-most common osteodystrophic condition after osteoporosis.
| Other Terms|| |
Paget's disease of bone (PDB) was first described by scientist paget in1877, who described five men who had at least two deformed areas of the skeleton and termed it as “Osteitis deformans,” as he believed the disease was caused by chronic inflammation. Weinman and Sicher(1947) used the term “Osteitis hyperplastica.”
| Epidemiology|| |
PDB appears to be more prevalent in populations of northern European origin and is thought to be rare in nonCaucasians. It is rare throughout Asia, especially in India. This disease is relatively common in older people. It has been estimated to occur in 1%–3% of people over age 55 years, and in as many as 8% of people over the age 80 of years in certain countries. The incidence of the disease increases with age. Male-to-female ratio is almost equal, but some studies revealed the predominant occurrence in males.
Juvenile form of PDB termed as “Chronic familial hyperphospatasia” is a rare metabolic bone dysplasia that is inherited as an autosomal recessive trait characterized by increased bone turnover secondary to enhanced osteoclastic activity and unrelated to classic PDB, which is seen in the elderly.
| Normal Bone Remodeling|| |
The normal adult skeleton undergoes constant remodeling, with osteoclasts removing bone and osteoblasts-forming new bone at sites of previous bone resorption in a closely coupled fashion [Figure 1]. Bone remodeling occurs in discrete areas, termed basic multicellular units and it is estimated that the entire adult skeleton is remodeled every 2–4 years.
Osteoclasts are derived from mononuclear precursor cells in the monocyte-macrophage lineage, which fuse to form multinucleated osteoclasts that are then activated to resorb bone. Normal remodeling of bone is under the control of receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL)/receptor activator of NF-κB (RANK)/osteoprotegerin (OPG) system and this system regulates the osteoclast formation and function. RANK is present on osteoclast precursors. RANKL, which is expressed in the marrow stroma and on osteoblasts, binds RANK on osteoclast precursors promoting osteoclast proliferation and differentiation, leading to the activation of a number of downstream signaling pathways, including the NF-κB, protein kinase B, c-jun N-terminal kinase, p38 mitogen-activated protein kinase, and ERK pathways. Each of these pathways has been implicated in osteoclast differentiation, function, or survival. OPG is a decoy receptor, which binds RANKL, thus preventing RANKL from binding RANK. OPG, therefore, inhibits osteoclast differentiation. Most of the osteotropic factors, including 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), interleukin (IL)-1, IL-11, and parathyroid hormone, promote osteoclast formation indirectly by binding to marrow stromal cells and inducing expression of RANKL on their surface.
| Cells Affected in Paget's Disease of Bone|| |
The osteoclast is the primary cell affected by PDB. The osteoclasts show both morphological and physiological abnormalities. Morphologically osteoclasts in PDB are increased in both number and size and contain up to 100 nuclei, in contrast to normal osteoclasts, which contain 3–20 nuclei. Another feature of pagetic osteoclasts is the characteristic nuclear inclusions, which consist of Para crystalline arrays that appear similar to nucleocapsids of paramyxoviruses. Physiological abnormalities include increased hypersensitivity of osteoclast precursors to several osteoclastogenic factors, including 1,25-(OH)2D3 and RANKL. Osteoblasts are also increased in numbers at pagetic sites, but they are morphologically normal and are not considered to be a primary pathophysiologic factor in PDB.
| Etiology|| |
The cause of PDB is currently an area of intensive investigation, with both genetic and environmental factors being implicated in the pathogenesis of this disease.
- Several genetic theories suggest that human leukocyte antigen (HLA) on chromosome 6 and the gene on chromosome arm 18q may play important roles; however, the studies on HLA have not been conclusive and the gene on chromosome arm 18q has not been shown to be the focus in all families tested, suggesting that genetic heterogeneity is likely. It has been found that 1%–40% of affected patients have a first-degree relative with PDB.
Mutations or polymorphisms have been identified in four genes that cause classical Paget's disease and related syndromes. These include TNFRSF11A, which encodes RANK, TNFRSF11B, which encodesOPG, Valocin containing protein (VCP), which encodes p97, and SQSTM1 which encodes p62. All of these genes play a role in the RANK-NF-κB signaling pathway and it is likely that the mutations predispose to PDB by disrupting normal signaling, leading to osteoclast activation [Figure 2]. Mutation in a member of NF-κB, the modulating protein family is also one of the related causes for PDB.
|Figure 2: Binding of receptor activator of nuclear factor kappa B ligand to receptor activator of nuclear factor kappa B activates the nuclear factor kappa B signaling cascade, which leads to increased osteoclastogenesis|
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- The leading hypothesis is the “slow virus theory,” The measles virus messenger RNA sequences have been found in osteoclasts and other mononuclear cells of pagetic bones. Canine distemper virus nucleocapsid antigens have also been found in osteoclasts from patients with PDB. However, the presence of these paramyxo virus-like nuclear inclusions does not prove that these are responsible for the development of pagetic lesions; rather, these inclusions may be markers of the disease itself.
- In PDB, osteoclast precursors have also been shown to be hyper-responsive to the RANKL, a member of the tumor necrosis factor-α superfamily, which promotes osteoclast genesis. One possibility is that increased expression of RANKL contributes to the localized nature of the disease. These osteoclast precursors also appear to be hyper-responsive to 1,25-(OH)2D3 and calcitonin and have up-regulation of the c-fos proto-oncogene and bcl2, the antiapoptosis gene. Treatment efficacy of bisphosphonates in Paget disease may be due to suppression of RANKL-induced bone resorption with decreases in RANKL and increased osteoprotegerin production
- Several studies have reported increased levels of IL-6 and/or macrophage colony-stimulating factor (M-CSF) in patients with PDB. Osteoclasts formed in bone marrow cultures from patients with PDB secrete large quantities of IL-6 into the conditioned media, with IL-6 levels reaching up to 2000 pg/ml. IL-6 levels are also increased in the bone marrow plasma of affected bones from Paget patients, as well as in their peripheral blood. Since IL-6 has been shown to induce osteoclast formation, it is possible that IL-6 plays a role in the enhanced osteoclast formation in PDB. Alternatively, the increased levels of IL-6 seen in patients with PDB may simply be a marker for the increased osteoclast formation
- Other associated diseases with PDB are vascular disorders, autoimmune disorders, and some connective tissue disorders
- Some studies have revealed the co-existence of some endocrinal disturbances like hypoparathyroidism with PDB.
| Pittsburg Group Model for Paget's Etiology|| |
This model involves both genetic and nongenetic factors. It is divided into three stages [Figure 3]:
In this stage, the measles virus infects pluripotent stem cells in patients with an acquired or inherited genetic predisposition for increased osteoclast activity or persistence of the measles virus. The stem cells differentiate and proliferate, giving rise to all hematopoietic lineages. The measles virus undergoes specific mutations that result in persistence of the virus in hematopoietic stem cells. When the cells differentiate toward the osteoclast lineage, a pagetic osteoclast forms.
Over time, the pagetic osteoclasts produce increased amounts of IL-6 and other cytokines, which enhance osteoclast formation and lead to changes in the marrow microenvironment, further increasing osteoclast formation. Since osteoclastic and osteoblastic activity remains coupled in PDB, thus increased osteoclastic activity results in increased osteoblast number and formation of new bone.
As the lesion progresses, the marrow microenvironment is permanently changed: increased number of osteoblasts express high levels of RANKL and other osteoclastogenetic factors M-CSF that further enhance the formation of osteoclast. The following conditions are required for the development of Paget's disease: Mutations in the measles virus nucleocapsid protein (MVNP) gene, presence of the MVNP gene in osteoclasts, and a genetic predisposition for enhanced osteoclastogenesis. As more and more bone is formed, the lesion would eventually become sclerotic.
| Pathogenesis/phases of Paget's Disease of Bone|| |
Three phases of PDB have been described [Figure 4].
Paget disease begins with the lytic phase, an increase in bone resorption with an increase in the number of osteoclasts in a space known as Howship's lacunae. Found at the site of bony involvement. This significant increase in bone resorption leads to a second phase(known as the mixed phase) of rapid increases in bone formation with numerous osteoblasts, which are increased in number but remain morphologically normal. In the final phase of PDB, known as the sclerotic phase, bone formation dominates, and the bone that is formed has a disorganized pattern (woven bone) and is weaker than normal adult bone.
| Clinical Features|| |
Most patients with PDB are asymptomatic, and some characteristic radiographic and laboratory findings provide some indication about the presence of pathology. PDB can be monostotic or polyostototic, the former being the more common form of the disease, affecting the axial skeleton. The disease manifests with severe musculoskeletal impairments with neurological and cardiac complications. The involvement of facial bones is occasionally seen and is termed as leontiasis ossia. (lion-like face). Clinical symptoms include pain, deformity, and may lead to fracture of the affected bone, even though the initial course of the disease may be asymptomatic [Table 1]. The enlarged and deformed bones may compress the surrounding nerve leading to impaired hearing.
| Oral Manifestations|| |
Jaw involvement is common in PDB with appx 17% incidence as shown by some studies. When the jaws are involved, the maxilla is more commonly affected than the mandible. The involved jaw can exhibit progressive enlargement, with the widening of the alveolar ridge [Table 1]. If teeth are present, they may become loose and migrate, producing interdental spacing. The disproportion in size between maxilla and mandible gives rise to the inverted triangle type of facial contours. Overgrowth of cementum occurs on the roots of teeth leading to hypercementosis. This leads to more difficulty in dental extractions. The healing of the extraction sites is often slow, and localized osteitis is common. A significant number of patients develop osteomyelitis secondary to the locally infected extraction sites. In pulp, dystrophic calcifications can be seen with mosaic patterns. Internal resorption of dentin can also be found. Edentulous patients with dentures complain of difficulty in wearing their appliances due to the change in the size of arches. Increased incidence of salivary calculi has also been found in patients with PDB.
| Radiographic Features|| |
The radiographic changes depend on the stage of this disease. The resorptive phase is characterized by radiolucent lesion and appositional phase by radiopacity.
The earliest lesions are osteolytic in character and are most readily appreciated in the skull. These circumscribed osteolytic skull lesions, which are commonly seen in the frontal regions are called “osteoporosis circumscripta” by schuller. The other region where osteolytic lesions are commonly observed is the long bones of the lower extremity. The lesions usually arise at either end of the bone, seldom in the diaphysis. At the junction of the lesion with normal bone, the osteolytic lesion has the shape of a flame or inverted V.
In the osteoblastic phase, the marked thickening of the inner calvarial table produces marked enlargement of the diploic space known as a “Tam O' Shanter” skull. There are areas of increased bone formation that tend to be patchy in distribution, resulting in the typical cotton-wool appearance associated with the disease. The “blade of grass” or “flame sign” in the long bones, thickened pelvic brim known as the “Brim sign” and the “picture frame,” “double contour” or “windowed” vertebral body are other classic radiographic appearances seen in various bones affected by PDB.
In jaws, the changes are generalized as compared to long bones. Dental radiographs may reveal the typical cotton-wool appearance of the bone as well as areas of hypercementosis or club-like appearance at numerous root apices. The lamina dura may be absent either in all the mandibular or all the maxillary teeth, but never in both. Occasionally, one or two teeth may display a loss of lamina dura in either or both jaws.
A radioisotope bone scan may be recommended in all patients as part of the initial diagnostic assessment to determine the distribution of the disease, in particular the involvement of sites with the potential for complications, such as the base of the skull, spine, and long bones. Extensive involvement of the mandible may occasionally reveals the uptake of the radiotracer from one condyle to another, giving rise to “Lincoln sign” or “Black beard” sign. Computed tomography or Magnetic resonance imaging may prove useful in cases of spinal stenosis, cauda equina syndrome, compression fractures, or suspected malignancy, but these studies are expensive and generally are not needed [Table 1].
| Histopathology|| |
PDB is characterized by a focal process with remarkable variation in its stage of development in separate sites [Figure 5] and [Figure 6].
|Figure 5: Histopathology of Paget's disease of bone: Arrow A denotes osteoclasts in Howship's lacunae and Arrow B denotes osteoblasts forming bone|
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|Figure 6: Histopathology of Paget's disease of bone: appositional and resorption (reversal) lines in bone giving rise to a mosaic appearance|
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In the initial lytic stage, resorption occurs within the Haversian system, mediated by an increase in the number of large (200 μm) multinucleated (200 nuclei/cell) osteoclasts. The subsequent osteoblastic stage follows with the haphazard laying of new bone matrix and formation of woven bone. Repeated episodes of bone removal and deposition results in the appearance of many small irregular shaped bony fragments that appear to be joined in jigsaw puzzle or mosaic pattern with deeply staining hematoxyphillic reversal lines. This is the histologic hallmark of PDB. As the disease progresses, osteoblastic phase predominates and excessive abnormal bone formation occurs, causing more dense and compact bone deposition. The marrow spaces are filled by loose hypervascular tissue. Normal trabecular pattern is distorted. Eventually, osteoblastic activity diminishes and burned out phase predominates. Pagetic bone is weak, hard, poorly mineralized and shows no tendency to form Haversian system. In the teeth region, irregular deposition of cellular cementum can be seen around the apices of roots. In pulp, dystrophic calcifications can be seen, with mosaic pattern. Internal resorption of dentin can also be found.
| Biochemical Assessment|| |
The radiologic and histologic evidence of increased bone resorption and formation in patients with PDB is readily assessed by measuring biochemical markers of bone turnover. In general, these tests reflect the extent and activity of the disease.
| Bone Resorption|| |
Increased osteoclastic activity in the disease results in collagen or bone matrix degradation, producing a high excretion of urinary proline and hydroxyproline The amount of hydroxyproline excreted in this disease is considerably increased from normal level of 40 mg/24 h–1 g/24 h. Subsequently, more specific indices of bone resorption have been developed, including pyridinoline and deoxypyridinoline.
| Bone Formation|| |
Markers of bone formation that are elevated are: Serum alkaline phosphatase (SAP), Serum bone-specific alkaline phosphatase, Osteocalcin, Serum N-terminal propeptide of type I collagen. SAP level may be elevated as high as over 250 Bodansky unit (BU) in the polyostotic form of this disease and up to 50 BU in monostotic form. Patients with active PDB are characterized by an abnormally high alpha/beta- carboxy-terminal collagen crosslinks (CTX) ratio, which goes down to the normal range after bisphosphonate therapy. Serum Ca andPlevels are within the normal range, even with the advancement of this disease.
| Treatment|| |
Although PDB is chronic and slowly progressive, it is seldom the cause of death. In patients with more limited involvement and no symptoms, treatment often is not required. In asymptomatic patients, systemic therapy is usually not initiated unless the SAP is more than 25%–50% above normal. When symptomatic, bone pain is noted most frequently and often may be controlled by aspirin or other analgesics. Calcitonin was the first osteoclast inhibitor to be used in the treatment of PDB. Calcitonin is effective in suppressing bone turnover and improving bone pain in PDB but is more expensive than bisphosphonates. Many patients develop side-effects such as nausea, vomiting and flushing, and resistance may also occur with repeated use. The current mainstay of treatment in PDB; however, is the second-generation nitrogen-containing bisphosphonates (disodium pamidronate, alendronate, erisedronate), which are potent inhibitors of bone resorption and provide prolonged remission of the disease in addition to a more dramatic decrease in the parameters of bone turnover compared with calcitonin. Another therapeutic agent that has been used to treat Paget disease is mithramycin, a cytotoxic antibiotic, reserved for those cases resistant to other forms of medical treatment. Surgery, including fracture stabilization, corrective osteotomy, and total joint arthroplasty, is sometimes needed for patients with PDB.
| Complications|| |
Malignant transformation is the most serious complication for PDB, and osteosarcoma is the most common malignancy arising in PDB. Sarcoma should be suspected in those patients who experience a marked increase in the intensity of bone pain or a marked elevation in the SAP level. The risk of osteogenic sarcoma in pagetic individuals over the age of 40 years is 30 times greater than in healthy persons. Compared with osteosarcomas arising in the pediatric population, these tumors have an extremely poor prognosis. Since the advent of neoadjuvant chemotherapy, the 5-year survival rate in the former group has increased to nearly 80%, while that of patients with Paget sarcoma remains at approximately 10%. Pagetic osteosarcomas seem to arise most commonly in pagetic bone during the mixed lytic/sclerotic phase of the disease. Fibrosarcomas and giant cell tumor may also arise from long-standing PDB. Eighty-two cases of neoplasms arising in PDB from the Mid-America bone tumor registry, accessioned between 1958 and 1983, were reviewed. There were 77 osteosarcomas, 3 fibrosarcomas, 1 chondrosarcoma, and 1 giant cell tumor. Other complications include renal calculi, hypercalcemia, osteomyelitis, incomplete stress fractures, pathological fractures, dry socket, degenerative joint disease, cardiovascular abnormalities like high output cardiac failure.
| Differential Diagnosis|| |
Paget's disease must be differentiated from osteitis fibrosa cystica (hyperparathyroidism), osteomyelitis, fibrous dysplasia, periapical cemental dysplasia, and other disseminated neoplasms. A definitive diagnosis depends on a correlation of the radiographic, clinical, blood chemistry, and biopsy findings.
| Conclusion|| |
PDB is a chronic progressive disease of the bone of unknown etiology. Jaw involvement is seen in approximately 17% of cases, and usually, it is the maxilla that is involved. It may be asymptomatic initially, and it can be diagnosed by its classic radiologic features, and an early diagnosis can help prevent potential complications such as pathological fracture, arthritis, hearing loss, other neurological complications, heart failure, and rarely, osteosarcoma. Advances in treatment have resulted in the availability of several potent bisphosphonate compounds, which produce normal or near-normal bone turnover indices in a majority of patients.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]