Paget Disease


Article Author:
Philip Bouchette


Article Editor:
Sameh Boktor


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
3/2/2019 8:26:13 AM

Introduction

Paget disease is a skeletal growth disorder in which abnormalities such as unusual bone growth can occur in several multifactoral ways. This is often manifested by diffuse pain throughout the musculoskeletal system.[1][2][3][4]

Etiology

Some literary sources suggest that the family of paramyxoviruses solely causes Paget. However, many studies have come to determine that the osteoclast generation of a unique cytokine found exclusively in the bone marrow of patients diagnosed with Paget disease may be the primary insult. This cytokine is known as IL-6.

Epidemiology

Paget disease is usually seen in individuals older than 50 years. It is common in Caucasians of northern European descent. Paget disease is equally common in males and females.

Pathophysiology

Paget disease occurs when there's an increase of bone resorption that leads to a decrease in bone mass and lytic structures. This process gives rise to osteoblasts from the bone utilizing a sensing system that allows them to increase its activity.

Paget disease pathological process occurs in four stages. Briefly, it begins with osteoclastic activity followed by a hybrid osteoclastic/osteoblastic process. The third stage is where osteoblastic activity is observed and culminates in the final stage, where malignant degeneration will be seen.

Histopathology

The key histopathological features of Paget disease involve the bone architecture and includes the three phases of the disease: mixed, osteolytic, and osteosclerotic. These phases may occur at the same time or separately. The osteolytic phase has areas of resorption due to a large increase in the number of abnormal osteoclasts that contain dozens of nuclei. The osteoblastic phase that follows is disorganized. The bone development is fragmented and irregular. The presence of irregularly shaped bone particles appear like a jigsaw and are a hallmark feature of  Paget disease. As the disorder advances, the osteoblastic phase becomes dominant, resulting in excessive bone formation which is fibrous and coarse. The marrow space is filled with vascularized fibrous tissue, which accounts for the persistence warmth and fever.

The bone in Paget disease does not have centralized blood vessels or Haversian systems. Once the osteoblastic phase subsides, the new bone is poorly mineralized and is devoid of any structural integrity.[5][6][7]

History and Physical

Many patients that present to clinic with pathognomonic features associated with Paget disease are usually symptomatic. Majority of patients with the condition are often diagnosed by an incidental finding on an x-ray study.

Examples include:

  • Pain involving the bones and joints
  • Diffuse joint stiffness
  • Abnormally enlarged skull
  • Musculoskeletal deformities
  • Loss of hearing
  • Migraines
  • Fractures

Evaluation

Tests to assist in the diagnosis of Paget disease include:

  • Bone scan
  • Bone x-ray
  • Elevated markers of bone breakdown like N-telopeptide

 This disease also may affect the results of the following: 

  • Elevated ALP (alkaline phosphatase) 
  • Normal Serum calcium and Phosphate

Treatment / Management

Some patients diagnosed with Paget disease may not require treatment. [8][9][10] This patient cohort includes:

  • Patients with abnormal blood test
  • Patients who have no active signs of the disease and those who are asymptomatic

The most commonly treated patients diagnosed with Paget disease include:

  • Those with abnormal bone defects
  • When weight-bearing bones are involved
  • Those with skull deformities
  • When there’s evidence of a rapidly progressing bone changes
  • Patients with complaints of diffuse pain

There are several treatment regimens that aid in prophylactically preventing bone breakdown and the subsequent formation.  Some of the more common drug therapies include:

  • Bisphosphonates, which has been proven as the first-line treatment option, secondary to its influence in bone remodeling.
  • Calcitonin is usually second-line treatment. This drug is assisted in bone absorption
  • Supplements such as calcium and vitamin D have been known to provide some symptomatic benefit
  • Pain management achieved with either NSAIDs or acetaminophen

Indications for surgery is usually offered as an option to patients diagnosed with Paget disease when there is a progression into osteosarcoma. Majority of patients diagnosed with osteosarcoma are often offered palliative options such as amputation of the affected limb. In many cases, clinicians are often tasked with the job of making judgment calls about which treatment options to offer the wide spectrum of patients that may be diagnosed. For example, younger patients are usually offered surgical procedure where they could potentially salvage the limb by resecting the tumor with wide margins. This may not be a viable alternative for an elderly patient with multiple comorbidities and risk factors. Patients may also develop pathological fractures that may need radiation and internal fixation to relieve pain burden. Chemotherapy has been shown to be an ineffective option for patients diagnosed with a sarcoma. It is important to note that surgical failure rates are high in this group of patients. Often, revision surgery is indicated.

Differential Diagnosis

The differential diagnosis includes:

  • Osteomalacia
  • Osteoporosis
  • Malignancy
  • Renal osteodystrophy
  • Osteoarthritis
  • Osteopenia
  • Fibrous dysplasia

Pearls and Other Issues

Diet and Activity

  • While there is no specific diet for patients with Paget disease, those who are prescribed bisphosphonates should ensure adequate intake of calcium and vitamin D.
  • Aggressive physical activity is not recommended, as the risk of fractures is high. However, muscle strengthening exercise at a low level is recommended

Deterrence

To date, there is no way to prevent Paget disease since the cause remains unknown. For family members of a patient with Paget disease, some physicians do recommend monitoring levels of alkaline phosphatase levels every 2 years. If the levels are within the normal range, then imaging of the bone may also be performed.

Guidelines Summary

Current endocrine guidelines for Paget disease:

  • Obtain plain x-rays of the affected body part
  • Determine extent of bone involvement with a radionuclide scan
  • Measure levels of serum alkaline phosphatase to assess bone formation/resorption to assess response to treatment or follow untreated patients
  • Patients at risk for complications like fracture should be started on bisphosphonates
  • Another option is a single 5 mg dose of intravenous zoledronate if there are no contraindications
  • If a patient has normal alkaline phosphatase levels, monitor disease with a specific marker for bone formation
  • One can follow patients with serial bone scans to assess disease of bone markers are all normal
  • Use of bisphosphonates is effective in slowing progress of disease or hearing loss
  • If patients with Paget disease need surgery, consider pre-treatment with bisphosphonates.

Enhancing Healthcare Team Outcomes

The diagnosis and management of Paget disease is with a multidisciplinary team that consists of a rheumatologist, neurologist, audiologist, internist, nurse practitioner, and a pathologist. Asymptomatic patients do not require treatment. Symptomatic patients usually can be managed by bisphosphonates, calcitonin and vitamin D supplements. A pain specialist should be involved as these patients have moderate to severe bony pain that is often disabling.

Indications for surgery is usually offered as an option to patients diagnosed with Paget disease when there is a progression into osteosarcoma. Majority of patients diagnosed with osteosarcoma are often offered palliative options such as amputation of the affected limb. Patients may also develop pathological fractures that may need radiation and internal fixation to relieve pain burden. Chemotherapy has been shown to be an ineffective option for patients diagnosed with a sarcoma. It is important to note that surgical failure rates are high in this group of patients. [2][11]


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Paget Disease - Questions

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Which statement is false about Paget disease of the bone?



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Which of the following bone disorders has been associated with tinnitus?



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What is the most common symptom in patients with Paget disease of bone?



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Which bone does Paget disease most commonly affect?



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Which of the following viruses may be a trigger for Paget disease of the bone?



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Which of the following rarely is affected by Paget disease?



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Which of the following complications is known to occur in patients with Paget disease of bone?



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Which protein is frequently used to assess bone resorption in patients with Paget disease of bone?



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What is the most common neurological presenting feature of patients with Paget disease?



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A 56-year-old with pelvic pain undergoes radiographs of his pelvis, which shows the blade of grass and brim signs. What is the most likely diagnosis?



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An African American with Paget disease has a femur radiograph showing a sunburst appearance. What has he developed?



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Which of the following is included in the treatment of Paget disease?



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A 64-year-old with weight loss and severe headaches is found to have a large, sharply demarcated "punched out" lesion on a skull radiograph. Blood work reveals elevated levels of alkaline phosphatase and urinalysis shows high levels of telopeptides. What disease is most likely for this patient?



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A 55-year-old patient with a Paget cancer measuring 4 cm, with nipple retraction, is at which stage of cancer?



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Which of the following diseases may be suggested by multiple "punched out" lesions seen on the skull by radiograph?



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Which of the following is often indicated by platybasia?



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Which of the following is an indication for starting therapy in a 55-year-old with Paget disease?



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A 55-year old with Paget disease of bone should initially be investigated with which method?



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Select the indication for starting therapy for Paget disease.



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What is the most common symptom of Paget disease?



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What is the treatment of choice for Paget disease?



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A patient is diagnosed with Paget disease and has an alkaline phosphatase of 160 U/L, normal levels of calcium and phosphate, and no bone pain. Select the appropriate treatment.



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An older female has routine labs drawn at the time of her physical. She has a history of hypertension and is taking hydrochlorothiazide, calcium, and vitamin D. Her physical is normal. All her labs are normal except her alkaline phosphatase is three times normal. Her Gamma-glutamyl transpeptidase is normal. What is the most likely cause of the abnormality?



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Select the true statement about Paget disease of the bone.



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Select the true statement about Paget disease.



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Which of the following is seen in Paget disease of the bone?



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What disease process is associated with cotton wool appearance on plain radiograph?



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A 65-year-old undergoes a skull x-ray which the radiologist report as having cotton wool' appearance. He may have which disorder?



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What chemical marker is abnormal in Paget disease?



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A 60-year-old presents with vague dull pain in his hips for the past 2 months. the pain is often worse at night. Lately he has been having headaches and difficulty hearing. he denies any trauma. Physical reveals bossing of the skull and localized pain around the hips. The patient also appears to have a hearing deficit and has an abnormal gait. Two weeks ago he was admitted for heart failure. Which laboratory value may provide a hint to his diagnosis?



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A 65-year-old male has an enlarged skull with frontal bossing. The temporal arteries are dilated and bruits are audible over the bone. What is the most likely diagnosis?



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A 65-year-old G2P2 female with a past medical history of hypertension presents to the breast clinic for evaluation of an "itchy rash" involving her right breast. She has been on hormone replacement therapy for symptomatic management of hot flashes since 49 years of age. She has no family history of breast or ovarian cancer and has received annual mammograms since 50 years of age. Her last breast imaging was 10 months ago and was negative for suspicious findings. On further questioning, she admits to the presence of a coarse-textured, itchy rash of her right nipple for the past four months that has now spread to the areola. She was treated for eczema with topical steroids by her primary care provider with no relief, so has now been referred to the breast clinic for evaluation. She denies nipple discharge but occasionally notes some blood inside her bra that she attributes to the skin irritation. On examination, the right nipple and entire areola are reddened, with a dry, thickened, peeling appearance. A small, 1 cm fixed mass in the ten o'clock position approximately 1 cm from the edge of the areola is present. A small amount of bloody fluid can be expressed from the nipple. Which of the following is the most likely diagnosis?



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Paget Disease - References

References

Lillemon JN,Nardos R,Kaul MP,Johnson AN,Choate A,Clark AL, Complex Female Pelvic Pain: A Case Series From a Multidisciplinary Clinic in Urogynecology and Physiatry. Female pelvic medicine     [PubMed]
Ralston SH,Corral-Gudino L,Cooper C,Francis RM,Fraser WD,Gennari L,Guañabens N,Javaid MK,Layfield R,O'Neill TW,Russell RGG,Stone MD,Simpson K,Wilkinson D,Wills R,Zillikens MC,Tuck SP, Diagnosis and Management of Paget's Disease of Bone in Adults: A Clinical Guideline. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2019 Feb 25;     [PubMed]
McLaughlin MB,Jialal I, Calcitonin 2018 Jan;     [PubMed]
Mantovani G,Fagotti A,Franchi M,Scambia G,Garganese G, Reviewing vulvar Paget's disease molecular bases. Looking forward to personalized target therapies: a matter of CHANGE. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2019 Jan 23;     [PubMed]
Appelman-Dijkstra NM,Papapoulos SE, Paget's disease of bone. Best practice     [PubMed]
Adams C,Banks KP, Bone Scan 2018 Jan;     [PubMed]
Kravets I, Paget's Disease of Bone: Diagnosis and Treatment. The American journal of medicine. 2018 Nov;     [PubMed]
Buske C,Sadullah S,Kastritis E,Tedeschi A,García-Sanz R,Bolkun L,Leleu X,Willenbacher W,Hájek R,Minnema MC,Cheng M,Bilotti E,Graef T,Dimopoulos MA, Treatment and outcome patterns in European patients with Waldenström's macroglobulinaemia: a large, observational, retrospective chart review. The Lancet. Haematology. 2018 Jul;     [PubMed]
Muschitz C,Feichtinger X,Haschka J,Kocijan R, Diagnosis and treatment of Paget's disease of bone : A clinical practice guideline. Wiener medizinische Wochenschrift (1946). 2017 Feb;     [PubMed]
Guay-Bélanger S,Simonyan D,Bureau A,Gagnon E,Albert C,Morissette J,Siris ES,Orcel P,Brown JP,Michou L, Development of a molecular test of Paget's disease of bone. Bone. 2016 Mar;     [PubMed]
Cherian KE,Kapoor N,Shetty S,Jebasingh FK,Asha HS,Hephzibah J,Prabhu AJ,Rajaratnam S,Thomas N,Paul TV, Paget's Disease of Bone: An Entity Still Exists in India. Indian journal of endocrinology and metabolism. 2018 May-Jun;     [PubMed]

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