PAGET’S DISEASE

G. Greco

 University Milano Bicocca Milano, Italy

*Correspondence to:
Dr Gildo Greco
Lecturer Dental School
University Milano Bicocca
Milano, Italy
e-mail: gildo.grecomail.com

Received: 10 April 2021 Accepted: 28 May 2021

ISSN: 2279-5855 Copyright © by BIOLIFE 2021 This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Extramammary Paget disease, also known as EMPD, is a rare clinical disorder. The intervention is linked to numerous types of Paget disease. Paget disease of the bones prevents the body’s normal recycling process, in which new bone tissue gradually replaces old bone tissue. As a result, bones tend to degrade and distort over time. The mutations that are responsible for Paget diseases are TNFRSF11A, SQSTM1, and TNFRSF11B. The long-term consequences of bisphosphonates on the progression of the disease are not well researched, but they have been proven to cure radiological abnormalities and restore normal histologically. In addition, bisphosphonate therapy is quite successful at slowing down bone turnover. Therefore, this article has been designed to review the diagnosis, histology, and treatment of Paget diseases.

KEYWORDS: Paget’s disease, bones, diagnosis, fracture, syndrome

INTRODUCTION

The clinical condition known as extramammary Paget disease, or EMPD, is extremely uncommon. There are several forms of Paget’s disease. The body’s natural recycling mechanism, in which young bone tissue progressively replaces old bone tissue, is hampered by Paget’s disease of the bones. As a result, bones tend to deteriorate and deform over the period. The pelvis, head, spine, and limbs are the most frequently impacted areas (1).

Paget disease of the bones has an enigmatic origin. A combination of hereditary and environmental factors may cause the condition. Several genes seem to be connected to developing the condition. Paget’s disease could be linked to a bone infection caused by a “slow virus,” a condition that lasts for many years until symptoms manifest. Four genes which induce Paget’s illness and associated disorders have mutations that have been found, suggesting that genetic factors play a significant role in this disease. Sequestosome 1 or SQSTM1, a scaffold enzyme in the nuclear factor-B (NF-B) signalling pathway, is the most significant of these (2). Patients with SQSTM1 mutations experience severe Paget’s disease of the bones, which is very penetrant as they age. The early-onset variant of Paget’s disease of bones is brought on by TNFRSF11A mutations (3). Bone remodelling is a typical process in which old bone is destroyed, and new bone is produced to replace it. The TNFRSF11A, SQSTM1, and TNFRSF11B genes are implicated in this process (4).

A chronic inflammatory disease condition called Paget’s disease of the bone causes a rise in bone re-absorption (5). Environmental elements also have a role. Most studies have concentrated on paramyxovirus infections as a potential cause, but there is inconsistent data to support this idea. Insufficient intake of calcium and repeated mechanical stressing of the bones are two additional possible culprits. Inhibition of osteoclastic bone resorption, such as bisphosphonates, is the mainstay of medical care for Paget’s disease of the bone. Patients who experience bone pain due to increased energy metabolism in afflicted bones should receive bisphosphonate medication (6). Paget disease of the bones is currently incurable but treatable. The sooner Paget’s illness may be identified and treated, the lower the risk of problems developing from the condition. Before the age of 40, it is rare to be diagnosed; in most series, men make up the majority. Familial aggregation is found in most succession, and its distribution pattern is uneven, with pockets of high occurrence (7).

Research is currently being conducted to see if bisphosphonate intervention in asymptomatic people with early illness will stop development and avoid consequences, allowing a better diagnosis and understanding of the disease.

Epidemiology

Its geographic distribution is asymmetrical, with high prevalence in places where familial aggregation is frequently found in series. People of British ancestry are most frequently affected by Paget’s illness. British immigrants to nations like New Zealand, Australia, and North America and European nations such as Germany, France,  Spain, and Italy, are also susceptible to the illness (8). According to Poór et al. study, which examined the prevalence of the Paget disease of bone in eight European cities, Innsbruck, Austria, had the lowest high prevalence, 0.2%, among hospital patients under the age of 55 (9).

The disease can affect one or more places throughout the skeleton and is characterised by localised anomalies of accelerated bone turnover. Predominantly affecting the axial skeleton, the skull (42% of cases), pelvis (70% of cases), lumbar spine (53% of cases), femur (55% of cases), and tibia (32% of cases), are typical sites of involvement. Paget’s disease is significantly more common as people age, and figures from the United Kingdom indicate that by the eighth decade of life, the condition affects roughly 8% of men and 5% of women (10). In addition, the frequency of the disease varies significantly by ethnicity and location. Paget’s disease of the bones is most prevalent in the United Kingdom but also widespread in southern and western Europe and among British immigrants to South Africa, Australia, and New Zealand.

On the other hand, this illness is uncommon in the Indian subcontinent, Scandinavia, Japan, China, with other Southeast Asian nations. These findings imply that genetic factors play a significant role in disease susceptibility. However, evidence also points to the importance of environmental issues, given that the occurrence and medical severity of the disease have significantly decreased over the past 25 years in the United Kingdom (Ralston et al., 2008).

Diagnosis and clinical presentation

In Paget’s disease of bones, the diagnostic evaluation of bone measurements, a comprehension of the healthy skeletal dispersion, and the structure of cancellous bone have to be interpreted.  Peripheral and axial assessment locations and small portions of both exhibit considerable variances, showing that the trabecular bone density at the femoral neck is denser in normal patients than at the lumbar region or the iliac crest. It is essential to notice that the iliac crest’s trabecular microarchitecture systematically varies, with the anterior region having the largest bone mass and the middle and dorsal parts having lower amounts (11).

When patients are being evaluated for other conditions, incidental discovery of elevated serum alkaline phosphatase and abnormal radiography is a common manifestation of Paget’s disease. Patients may also display particular characteristics, such as bone discomfort and deformity. This disease’s bone pain is typically reported as being present during rest, at night, and when using an affected limb. However, in clinical settings, Pagetic bone pain is frequently challenging to identify from tertiary osteoarthritis pain and from concurrent musculoskeletal conditions such as degenerative spinal degeneration. Localisation over an afflicted location where there is pharmacological and scintigraphic evidence of ongoing metabolic activity is one of the clinical characteristics supporting a Pagetic origin.

Pain that is restricted to the joint instead of the bone and gets worse with the movement of the joint are characteristics that rule out a Pagetic aetiology. A Pagetic aetiology is supported by the reduction of bone pain following a treatment trial of bisphosphonate medication (6).

If a patient has deformed weight-bearing limbs and experiences sudden, localised bone pain, they likely have a pseudofracture. The convex aspect of the bones in a malformed limb is where pseudofractures almost often occur and do not respond well to antiresorptive treatment. Bone deformities characterise severe Paget’s disease, and in individuals with metabolically active illness, the temperature sensor may be elevated over the affected joints (12).

Histology

The iliac crest bone or the vertebrae have received the majority of attention in investigations on the histology of Paget’s disease of bones. As previously indicated, Osteoclasts, the main cellular anomaly in Paget’s disease of bones, are larger, more numerous, and have many more nuclei per cell than normal osteoclasts (13). In their histological analysis of Pagetic iliac crest samples by using Hamburger Bone Registry, Seitz et al. reported that trabecular bone seemed predominantly solitary and had an ungainly composition. The authors also noted a typical appearance of extensive resorption lacunae with a swallowtail pattern. They also observed an increase in osteoblastic surfaces and activated cuboidal osteoblasts as indicators of faster bone development, and they noted that collagen fibres did not have a uniform dispersion indicative of collagenous fibres (14). Histologically speaking, these anomalies can result in a “mosaic look” or a combination of woven with lamellar bone. In Pagetic bone lesions, osteoclasts are larger and more numerous than in healthy bone, and they also have many more nuclei than is typical. Additionally, these osteoclasts include distinctive nuclear complexes, which are tiny, cylindrical formations that mimic virus particles in specific ways. These bodies have been observed in pycnodysostosis, osteopetrosis, and even macrophages from individuals with hereditary oxalosis, so they are not exclusive to Pagetic osteoclasts (15).

Treatment

Paget’s disease of the bones is currently incurable but treatable. The sooner Paget’s illness may be identified and treated, the lower the risk of problems developing from the condition. Treatment involves a long-considered standard of care. The primary sign that Paget’s disease of the bones needs medical attention is localised bone pain that is believed to be caused by enhanced metabolic activity. Analgesics and non-steroidal anti-inflammatory drugs can also treat pagetic bone pain symptomatology. Bisphosphonates or calcitonin, which prevents osteoclastic bone resorption, are effective treatments for pagetic bone pain (16).

The bone disease Paget’s can be treated with a variety of drugs. Bisphosphonates are the most prevalent kind. Zoledronate is the bisphosphonate that works the best. This medication frequently causes the condition to go into long-term remission with just one dose; however, it cannot treat bony deformities. Paget disease’s bone problems can be treated or improved without surgery. Some operations include knee and joint replacements, realigning malformed bones, and facilitating improved bone fracture healing (7). Many clinicians believe that aminobisphosphonates, such as risedronate, pamidronate,  and zoledronic acid, are recommended in Paget’s disease because they are more efficient at lowering bone resorption than previous bisphosphonates, like etidronate and tiludronate (17).

Older patients with Paget’s disease frequently have dietary calcium and vitamin D shortage; it is crucial to address this deficiency before beginning bisphosphonate medication to prevent problems like hypocalcemia, which is a danger following injectable bisphosphonate therapy. Patients who received injectable pamidronate for Paget’s disease may also get focal osteomalacia, a side effect linked to etidronate therapy (Reid et al., 2005). Treatments with activated vitamin D metabolites cannot reverse this mineralisation problem, which appears to be a direct consequence of bisphosphonates rather than vitamin D insufficiency. There have not yet been any reports of mineralisation problems concerning treating individuals with Paget’s disease of the bones with risedronate,  tiludronate, alendronate, and zoledronic acid (18).

There is a considerable risk of delayed union when treating fractures conservatively in patients with Paget’s disease. Patients with severe knee or hip osteoarthritis and Paget’s disease frequently gain from unilateral surgical intervention. Rarely an osteotomy procedure is required to treat a long bone’s bending deformity. Neurosurgical treatment will be necessary for patients with a neurological condition of the spine who has not improved while taking bisphosphonates. Because of the increased vasculature of the diseased bone, surgery on pagetic bone is challenging; hence treatment with bisphosphonate and calcitonin must begin before any non-urgent procedure is carried out (19).

CONCLUSIONS

The faster Paget’s disease can be discovered and treated, the less likely complications may arise. Unfortunately, it is uncommon to be diagnosed before age 40, and in most studies, men predominate. Most successions have familial aggregation, which has an uneven geographical distribution with areas of high occurrence. The use of bisphosphonates in asymptomatic individuals with the early disease is now being studied to determine whether it can halt development and prevent negative effects; this will provide a more accurate diagnosis and comprehension of the condition. Additionally, it will make some alternative treatments to surgeries and incisions available.

REFERENCES

1. Audet, M.-C.; Jean, S.; Beaudoin, C.; Guay-Bélanger, S.; Dumont, J.; Brown, J.P.; Michou, L. Environmental Factors Associated with Familial or Non-Familial Forms of Paget’s Disease of Bone. Joint Bone Spine 2017, 84, 719–723, doi:1016/j.jbspin.2016.11.010.
2. Layfield, R.; Hocking, L.J. SQSTM1 and Paget?S Disease of Bone. Calcified Tissue International 2004, 75, 347–357, doi:1007/s00223-004-0041-0.
3. Chung, P.Y.J.; Beyens, G.; Riches, P.L.; Van Wesenbeeck, L.; de Freitas, F.; Jennes, K.; Daroszewska, A.; Fransen, E.; Boonen, S.; Geusens, P.; et al. Genetic Variation in the TNFRSF11A Gene Encoding RANK Is Associated with Susceptibility to Paget’s Disease of Bone. Journal of Bone and Mineral Research 2010, 25, 2592–2605, doi:1002/jbmr.162.
4. Daroszewska, A.; Hocking, L.J.; McGuigan, F.E.; Langdahl, B.; Stone, M.D.; Cundy, T.; Nicholson, G.C.; Fraser, W.D.; Ralston, S.H. Susceptibility to Paget’s Disease of Bone Is Influenced by a Common Polymorphic Variant of Osteoprotegerin. Journal of Bone and Mineral Research 2004, 19, 1506–1511, doi:1359/jbmr.040602.
5. Cundy, T.; Bolland, M. Paget Disease of Bone. Trends in Endocrinology & Metabolism 2008, 19, 246–253, doi:1016/j.tem.2008.06.001.
6. Ralston, S.H.; Langston, A.L.; Reid, I.R. Pathogenesis and Management of Paget’s Disease of Bone. The Lancet 2008, 372, 155–163, doi:1016/s0140-6736(08)61035-1.
7. Dhillon, S. Zoledronic Acid (Reclast®, Aclasta®): A Review in Osteoporosis. Drugs 2016, 76, 1683–1697, doi:1007/s40265-016-0662-4.
8. Lojo Oliveira, L.; Torrijos Eslava, A. Treatment of Paget’s Disease of Bone. Reumatología Clínica (English Edition) 2012, 8, 220–224, doi:1016/j.reumae.2011.06.006.
9. Poór, G.; Donáth, J.; Fornet, B.; Cooper, C. Epidemiology of Paget’s Disease in Europe: The Prevalence Is Decreasing. Journal of Bone and Mineral Research 2006, 21, 1545–1549, doi:1359/jbmr.060704.
10. Van Staa, T.P.; Selby, P.; Leufkens, H.G.M.; Lyles, K.; Sprafka, J.M.; Cooper, C. Incidence and Natural History of Paget’s Disease of Bone in England and Wales. Journal of Bone and Mineral Research 2002, 17, 465–471, doi:1359/jbmr.2002.17.3.465.
11. Amling, M.; Herden, S.; Pösl, M.; Hahn, M.; Ritzel, H.; Delling, G. Heterogeneity of the Skeleton: Comparison of the Trabecular Microarchitecture of the Spine, the Iliac Crest, the Femur, and the Calcaneus. Journal of Bone and Mineral Research 2009, 11, 36–45, doi:1002/jbmr.5650110107.
12. Redden, J.F.; Dixon, J.; Vennart, W.; Hosking, D.J. Management of Fissure Fractures in Paget’s Disease. International Orthopaedics 1981, 5, 103–106, doi:1007/bf00267839.
13. Nebot Valenzuela, E.; Pietschmann, P. Epidemiology and Pathology of Paget’s Disease of Bone – a Review. Wiener Medizinische Wochenschrift 2016, 167, 2–8, doi:1007/s10354-016-0496-4.
14. Seitz, S.; Priemel, M.; Zustin, J.; Beil, F.T.; Semler, J.; Minne, H.; Schinke, T.; Amling, M. Paget’s Disease of Bone: Histologic Analysis of 754 Patients. Journal of Bone and Mineral Research 2009, 24, 62–69, doi:1359/jbmr.080907.
15. Neale, S.D.; Smith, R.; Wass, J.A.H.; Athanasou, N.A. Osteoclast Differentiation from Circulating Mononuclear Precursors in Paget’s Disease Is Hypersensitive to 1,25-Dihydroxyvitamin D3 and RANKL. Bone 2000, 27, 409–416, doi:1016/s8756-3282(00)00345-8.
16. Altman, R.D.; Johnston, C.C.; Khairi, M.R.A.; Wellman, H.; Serafini, A.N.; Sankey, R.R. Influence of Disodium Etidronate on Clinical and Laboratory Manifestations of Paget’s Disease of Bone (Osteitis Deformans). New England Journal of Medicine 1973, 289, 1379–1384, doi:1056/nejm197312272892601.
17. Reid, I.R.; Miller, P.; Lyles, K.; Fraser, W.; Brown, J.P.; Saidi, Y.; Mesenbrink, P.; Su, G.; Pak, J.; Zelenakas, K.; et al. Comparison of a Single Infusion of Zoledronic Acid with Risedronate for Paget’s Disease. New England Journal of Medicine 2005, 353, 898–908, doi:1056/nejmoa044241.
18. Woo, S.-B.; Hellstein, J.W.; Kalmar, J.R. Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws. Annals of Internal Medicine 2006, 144, 753, doi:7326/0003-4819-144-10-200605160-00009.
19. Langston, A.L. Management of Paget’s Disease of Bone. Rheumatology 2004, 43, 955–959, doi:1093/rheumatology/keh243.