Osteitis Deformans (Paget Disease of Bone)

BASICS

DESCRIPTION

Focal disorder of hyperactive bone resorption followed by excessive bone formation (remodeling) that is stimulated by abnormal osteoclasts
Results in enlarged, disorganized, weakened, and highly vascularized mosaic of bone
Painful condition, with easily deformed bone that is subject to fractures from minimal trauma
Most commonly affected sites:
- Pelvis, spine, skull, extremities
Cranial and vertebral involvement can lead to neurologic deficits.
Synonym(s): Paget disease of bone; osteodystrophia deformans

EPIDEMIOLOGY

Predominant age: >50 years
- Less common in patients from ages 20 to 50 years
- Does not occur in children (juvenile Paget disease is unrelated to the adult disease)
Predominant sex: males > females (1.8:1)

Prevalence

Prevalence increases with increasing age
- 2% among 55- to 59-year-old men, 20% among men >85 years (1)[C]
More common if Caucasian, especially in United Kingdom, France, Germany, Italy, United States, Australia, or New Zealand
- 3% of Caucasians >50 years have at least one gene focus.
Rare in African Americans and Asians
Incidence and prevalence have decreased in recent years; likely due to genetic and environmental factors

ETIOLOGY AND PATHOPHYSIOLOGY

Unknown, although several theories proposed:
- Slow viral infection (controversial): due to paramyxovirus, respiratory syncytial virus, canine distemper virus, measles causing expression develops over years
- Zoonotic infections
- Toxin occupational exposure
- Childhood malnutrition " ”vitamin D deficiency or low dietary calcium
Three pathologic phases:
- Lytic phase: Osteoclasts are large, contain 10 to 100 nuclei, and have abnormal configuration.
- Mixed phase: Excessive osteoblastic bone formation predominates from increase in number of osteoblasts; nonlinear collagen deposition results
- Sclerotic phase: sclerotic bone " “containing cement lines form a mosaic pattern (woven bone), with vasculature infiltration and fibrous connective tissue deposition

Genetics

At least seven genetic loci have been identified that are associated with Paget disease of bone.
Mutations in SQSTM1, predominately ubiquitin-binding associated (UBA) domain and P392L, are associated. Product of SQSTM1 affects osteoclast differentiation and activation.

RISK FACTORS

First-degree relative with osteitis deformans (OD)
- 15 " “30% of patients note a family history of OD.
Caucasian and European ethnicity

GENERAL PREVENTION

Fracture reduction: Avoid excessive mechanical stress on afflicted bones. ‚

COMMONLY ASSOCIATED CONDITIONS

Hyperparathyroidism
Gout
Secondary osteoarthritis
Peyronie disease
Accelerated atherosclerosis
Osteoporosis circumscripta
Frontotemporal dementia (rare)
Hereditary inclusion body myopathy (rare)
Bone sarcoma (rare)

DIAGNOSIS

HISTORY

Frequently asymptomatic (70 " “90% of patients); often noted as incidental finding (2)[B]
Resting or nocturnal bone pain is most common complaint.
Secondary osteoarthritis
Hearing loss (cranial nerve VIII compression)
Headaches
Head enlargement (e.g., increase in hat size)
Pathologic fractures
Muscle weakness (due to nerve root compression)

PHYSICAL EXAM

Neurologic examination
- Test hearing with whisper test or tuning fork.
- Visual field study for visual impairment (if cranial involvement)
- Peripheral neuropathies
Asymmetric skeletal deformities
- Enlarged maxilla or frontal bossing
- Bowed legs
Flank or CVA tenderness secondary to renal calculi
Warmth over affected areas of bone
Carpal/tarsal tunnel syndromes may manifest as positive Tinel and Phalen tests.
Ophthalmic examination may reveal mottled retinal degeneration (rare).
Cardiovascular effects resulting in valvular/endocardial calcification and high-output congestive heart failure (rare)

DIFFERENTIAL DIAGNOSIS

Osteoporosis
Osteoarthritis
Polyostotic fibrous dysplasia
Primary bone neoplasms
Osteitis fibrosis cystica (skeletal hyperparathyroidism)
Osteolytic or osteoblastic metastases

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Serum alkaline phosphatase (total or bone-specific) typically elevated (~95% of patients)
Serum calcium, phosphorus, parathyroid hormone levels usually normal
Serum ˇ ³-glutamyl transpeptidase often normal
Other elevated lab findings: serum osteocalcin (binary ghost-pulse constraint); urinary pyridinoline collagen crosslinks; serum and urinary N- and C-telopeptide (collagen crosslinks)
Drugs that may alter laboratory results
- Vitamin D and its metabolites
- Hepatotoxic drugs
Disorders that may alter lab results
- Osteomalacia
- Liver disorders
- Traumatic fractures
X-rays may demonstrate various Pagetic elements
- Radiolucent resorptive fronts with osteolysis
- "Framed vertebrae " ¯ (enlarged vertebral bodies, thickened cortices, vertical striations)
- "Brim sign " ¯ (thickened iliopectineal line)
- "Cotton wool " ¯ skull pattern
- "Blade of grass " ¯ (V-shaped pattern demarcating Pagetic from normal bone)
Radionuclide bone scans more sensitive than plain radiographs
- Show intense uptake in focal pattern
CT and MRI demonstrate extra-bony extension when sarcomatous degeneration is present. Renal calculi may be incidentally noted due to increased serum calcium and uric acid.

Diagnostic Procedures/Other

Audiogram may demonstrate sensorineural or conductive hearing loss (if suspect skull involvement).
Bone biopsy is rarely needed.

Test Interpretation
Electron photomicroscopy demonstrates nuclei and cytoplasm contain myriad inclusion bodies resembling viral nucleocapsids. ‚

TREATMENT

GENERAL MEASURES

Shoe orthoses to counteract limb shortening
Hearing aids for severe sensorineural deafness
Rarely, splints for severely resorbed areas with high risk of fracture

MEDICATION

Goals are to relieve bone pain and prevent progression of disease leading to skeletal deformities and other complications. ‚
First Line
Bisphosphonates inhibit osteoclastic activity. They are the mainstay of treatment, especially the amino bisphosphonate subclass (including alendronate, risedronate, pamidronate, and zoledronic acid). Older bisphosphonates (e.g., etidronate, tiludronate) are not usually recommended for patients with osteitis deformans (3)[C] ‚

Alendronate (Fosamax) 40 mg/day PO (taken on an empty stomach) for 6 months; OR
Risedronate (Actonel) 30 mg/day PO (taken on an empty stomach) for 2 months; OR
Pamidronate (Aredia) 60 mg/day (or alternatively 30 mg IV over 4 hours daily for 3 days); OR
Zoledronic acid (Reclast) 5 mg infusion over 15 minutes once. Give 1,500-mg elemental calcium (divided) and 1,000 IU vitamin D per day for minimum of 2 weeks after infusion. Zoledronic acid has demonstrated 2 times higher rates of serum alkaline phosphatase normalization in comparison to pamidronate after 6 months of use.
Contraindications:
- History of allergy or hypersensitivity
- For alendronate and risedronate: esophageal dysfunction, severe upper GI tract symptoms, gastroesophageal reflux disease, creatine clearance <35 mL/min
Precautions:
- Alendronate and risedronate: heartburn, epigastric pain, and musculoskeletal pain. Take on an empty stomach with copious water. No food, beverages, or other medications for the following 30 to 60 minutes; remain upright for 1 hour.
- Pamidronate disodium: transient fever, leukopenia, hypocalcemia, headache, malaise, loss of appetite
- Osteonecrosis of the jaw is a very rare but serious complication of bisphosphonates. Extensive dental work is a risk factor and should be performed prior to treatment with bisphosphonates whenever possible.
IV bisphosphonate therapy improves serum alkaline phosphatase levels more than oral therapy. Studies have demonstrated, however, that IV bisphosphonate treatment provides no significant difference in clinical manifestations of osteitis deformans compared to symptomatic management.

Second Line

Calcitonin is recommended for patients who are unable to tolerate the aminobisphosphonates. Calcitonin is given as a synthetic injectable (Miacalcin), at a starting dose of 100 IU SC/IM daily with maintenance afterward at 3 times weekly. The intranasal form is not approved for treatment of OD.
NSAIDs or COX-2 inhibitors for pain management

SURGERY/OTHER PROCEDURES

Total joint replacement (hip, knee) may restore mobility and ameliorate pain.
Osteotomy for extreme deformity
Decompression procedures (skull, spinal column) for acute neurologic deficits (rarely needed)
Extirpative surgery for sarcomatous complications
Open reduction and fixation of pathologic fractures

COMPLEMENTARY & ALTERNATIVE MEDICINE

Physiotherapy, hydrotherapy, or transcutaneous electrical nerve stimulation may be used to treat pain. ‚

INPATIENT CONSIDERATIONS

OD is generally treated on an outpatient basis, except when surgery or IV bisphosphonate treatment is used.
Bisphosphonates are indicated preoperatively to mitigate surgical blood loss and reduce risk of implant loosening in the setting of a total joint replacement.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Full activity to maintain function
Avoid excessive mechanical stress on involved bones.

Patient Monitoring

Follow-up visits every 2 to 4 months during drug therapy; yearly when drugs not being used
- Alkaline phosphatase level (total or bone-specific) before each visit
Repeat x-rays and bone scan every 3 to 5 years or as needed.

DIET

Sufficient dietary intake of calcium and vitamin D is crucial, especially for those on bisphosphonates. ‚

PATIENT EDUCATION

The Paget Foundation, PO Box 24432, Brooklyn, NY 11202; Toll Free: 800-23-PAGET; e-mail: PagetFdn@aol.com
NIH Osteoporosis and Related Bone Diseases National Resources Center http://www.niams.nih.gov/Health_Info/Bone/Pagets/
MedlinePlus http://www.nlm.nih.gov/medlineplus/pagetsdiseaseofbone.html
PubMed Health http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001451/

PROGNOSIS

Generally good, if diagnosed and treated early
Untreated disease has a slow progression with significant morbidity.
Significant amelioration of symptoms ( ≥85%) with treatment
Poor prognosis if bone sarcoma develops (5-year survival <6%).

COMPLICATIONS

Fractures
Severe bony deformities
Head circumference enlargement
Acetabular protrusion
Arthritis
Neurologic deficits
Deafness
Visual impairment
Nephrocalcinosis
Peyronie syndrome
Bone tumors (<1% of cases)

REFERENCES

11 Walker ‚ J. Pathogenesis, diagnosis and management of Paget 's disease of the bone. Nurs Older People. 2014;26(8):32 " “38. doi:10.7748/nop.26.8.32.e626.22 Singer ‚ FR, Bone ‚ HGIII, Hosking ‚ DJ, et al. Paget 's disease of bone: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(12):4408 " “4420.33 Tan ‚ A, Ralston ‚ SH. Clinical presentation of Paget 's disease: evaluation of a contemporary cohort and systematic review. Calcif Tissue Int. 2014;95(5):385 " “392. doi:10.1007/s00223 " “014-9904-1.

ADDITIONAL READING

Corral-Gudino ‚ L, Borao-Cengotita-Bengoa ‚ M, Del Pino-Montes ‚ J, et al. Epidemiology of Paget 's disease of bone: a systematic review of meta-analysis of secular changes. Bone. 2013;55(2):347 " “352.
Cundy ‚ T, Reid ‚ IR. Paget 's disease of bone. Clin. Biochem. 2012;45(1 " “2):43 " “48.
Langston ‚ AL, Campbell ‚ MK, Fraser ‚ WD, et al. Randomized trial of intensive bisphosphonate treatment versus symptomatic management in Paget 's disease of bone. J Bone Miner Res. 2010;25(1):20 " “31.
Ralston ‚ SH, Langston ‚ AL, Reid ‚ IR, et al. Pathogenesis and management of Paget 's disease of bone. Lancet. 2008;372(9633):155 " “163.
Reid ‚ IR. Pharmacotherapy of Paget 's disease of bone. Expert Opin Pharmacother. 2012;13(5):637 " “646.
Rubin ‚ DJ, Levin ‚ RM. Neurologic complications of Paget disease of bone. Endocr Pract. 2009;15(2):158 " “166.
Wegrzyn ‚ J, Pibarot ‚ V, Chapurlat ‚ R, et al. Cementless total hip arthroplasty in Paget 's disease of bone: a retrospective review. Int Orthop. 2010;34(8):1103 " “1109.

CODES

ICD10

M88.9 Osteitis deformans of unspecified bone
M88.88 Osteitis deformans of other bones
M88.1 Osteitis deformans of vertebrae
M88.0 Osteitis deformans of skull
M90.60 Osteitis deformans in neoplastic diseases, unspecified site

ICD9

731.0 Osteitis deformans without mention of bone tumor
731.1 Osteitis deformans in diseases classified elsewhere

SNOMED

osteitis deformans (disorder)
Paget 's disease of pelvis (disorder)
Paget 's disease of skull (disorder)
Osteitis deformans in neoplastic disease (disorder)

CLINICAL PEARLS

Osteitis deformans (Paget disease of bone) is often asymptomatic. When symptomatic, bone pain is the most common complaint.
Osteolysis and thickened bony cortices are common radiographic findings in osteitis deformans.
Elevated alkaline phosphatase is the most common laboratory finding.
Patients with osteitis deformans are at increased risk of sarcomatous transformation.

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