Paget’s disease

General

AKA osteitis deformans

Definition

A disorder of osteoclasts (possibly virally induced) causing increased rate of bone resorption with reactive osteoblastic overproduction of new, weaker, woven bone, producing characteristic “mosaic pattern.”

Pathophysiology

Initially there is a “hot” phase with elevated osteoclastic activity and increased intraosseous vascularity.
Osteoblasts lay down a soft, nonlamellar bone. Later a “cool” phase occurs with disappearance of the vascular stroma and osteoblastic activity leaving sclerotic, radiodense, brittle bone (“ivory bone”).
Malignant degeneration

A misnomer, since the malignant changes actually occur in the reactive osteoblastic cells.

About 1% (reported range: 1–14%) degenerate into sarcoma (osteogenic sarcoma, fibrous sarcoma, or chondrosarcoma), with the possibility of systemic (e.g. pulmonary) metastases.

Malignant degeneration is much less common in the spine than in the skull or femur.

There are three classically described stages, which are part of a continuous spectrum:

Early destructive stage

incipient active, lytic
Predominated by osteoclastic activity

Intermediate stage

Active, mixed
osteoblastic as well as osteoclastic activity

Late stage

inactive, sclerotic/blastic

Numbers

Prevalence:

3% of population > 55 years old in the U.S. and Europe
much lower in Asia

Slight male predominance.
Family history of Paget’s disease

15–30% of cases (accuracy is poor since most are asymptomatic).

Common sites of involvement

Affinity for axial skeleton, long bones, and skull. In approximate descending order of frequency:

pelvis, thoracic and lumbar spine,
skull, femur, tibia, fibula, and clavicles.

Neurosurgical involvement

Back pain:

usually not as a direct result of vertebral bone involvement

Spinal cord and/or nerve root symptoms

Compression of the spinal cord or cauda equina (relatively rare)
Spinal nerve root compression
Vascular steal due to reactive vasodilatation adjacent to involved areas

with skull involvement:

compression of cranial nerves as they exit through bony foramina: 8th nerve is most common, producing deafness or ataxia (p.1480)
Skull base involvement → basilar invagination

To ascertain diagnosis in unclear bone lesions of the spine or skull

Clinical presentation

General information

Symptomatic 30%

The overproduction of weak bone may produce

bone pain (the most common symptom),

Back pain

Most common
12% pt with paget has back pain

Painless bowing of a long bone may be the first manifestation

Fractures
Compressive syndromes:

Cranial nerve
Spinal nerve root

Symptoms that may be related to the Paget’s disease itself

Slowly progressive symptoms (usually present for > 12 months; rarely < 6 mos):

Neural compression

Causes of compression

Expansion of woven bone
Osteoid tissue
Pagetic extension into ligamentum flavum and epidural fat

Sites of compression

Spinal cord

Myelopathy or cauda equina syndrome

may be due to

spinal cord compression OR
Vascular effects (Only ≈ 100 cases had been described as of 1981)

Occlusion
Steal

due to reactive vasodilatation of nearby blood vessels

If symptomatic then generally has 3–5 adjacent vertebrae involvement

Monostotic involvement is usually asymptomatic.

Progressive quadri- or paraparesis was the most common presentation.

Sensory changes are usually the first manifestation, progressing to weakness and sphincter disturbance.
Pain was the only symptom in a neurologically intact patient in only 5.5%.

A rapid course (averaging 6 wks) with a sudden increase in pain is more suggestive of malignant degeneration.

Nerve root in neural foramen

Osteoarthritis of facet joints (Paget’s disease may precipitate osteoarthritis)

Symptoms from the following tend to progress more rapidly:

Malignant (sarcomatous) change of involved bone (rare, see above)
Pathologic fracture (pain usually sudden in onset)
Neurovascular (compromise of vascular supply to nerves or spinal cord) by

Compression of blood vessels (arterial or venous)
Pagetic vascular steal

Incidental 70%

Radiologically found when investigating Elevated alkaline phosphatase

Evaluation

lab work (serum markers may be normal in monostotic involvement):

serum alkaline phosphatase:

usually elevated (this enzyme is involved in bone synthesis

so may not be elevated in purely lytic Paget’s disease

mean 380 ± 318 IU/L (normal range: 9–44).
Bone-specific alkaline phosphatase may be more sensitive and may be useful in monostotic involvement

calcium:

usually normal (if elevated, one should R/O hyperparathyroidism)

urinary hydroxyproline:

hydroxyproline is found almost exclusively in cartilage.
Due to the high turnover of bone
urinary hydroxyproline is often increased with a mean of 280 ± 262 mg/24 hrs (normal range 18–38)

bone scan:

lights up in areas of involvement in most, but not all cases

plain X-rays:

localized enlargement of bone: a finding unique to PD (not seen in other osteoclastic diseases, such as prostatic bone mets)
cortical thickening
sclerotic changes
osteolytic areas (in skull → osteoporosis circumscripta; in long bones → “V” shaped lesions)
spinal Paget’s disease often involves several contiguous levels. Pedicles and lamina are thickened, Vertebral bodies are usually dense and compressed with increased width. Intervening
discs are replaced by bone

hypertrophic changes at the facet joints with coarse trabeculations

Treatment

Medical treatment for Paget’s disease

General information

There is no cure for Paget’s disease.
Medical treatment is indicated for

cases that are not rapidly progressive where the diagnosis is certain,
patients who are poor surgical candidates,
pre-op if excessive bleeding cannot be tolerated.

Medical therapy reverses some neurologic deficit in 50% of cases, but generally requires prolonged treatment (≈ 6–8 months) before improvement occurs, and may need to be continued indefinitely due to propensity for relapses.

Calcitonin derivatives

Parenteral salmon calcitonin (Calcimar):

Mech

reduces osteoclastic activity directly, osteoblastic hyperactivity subsides secondarily.

Relapse may occur even while on calcitonin.
Side effects include

nausea, facial flushing, and the development of antibodies to salmon calcitonin (these patients may benefit from a more expensive synthetic human preparation (Cibacalcin®) starting at 0.5mg SQ q d13).

℞ 50–100 IU (medical research council units) SQ q d × 1 month, then 3 injections per week for several months.
If used pre-op to help decrease bony vascularity, ≈ 6 months of treatment is ideal.
Doses as low as ≈ 50 IU units 3 × per week may be used indefinitely post-op or as a sole treatment (alkaline phosphatase and urinary hydroxyproline decline by 30–50% in > half of patients in 3–6 months, but they rarely normalize).

Anabolic Agents

Teriparatide (TP):

A parathyroid hormone analog
it is an anabolic (bone-forming) medication.
Perioperative TP treatment significantly

decreases complication rates (e.g., screw loosening, rod fracture, adjacent vertebral fracture, pseudarthrosis) and
improves bone union rates and time to fusion compared to bisphosphonates or no treatment.

Evidence

Studies show outcomes for osteoporotic patients treated with TP can be equivalent to those with normal BMD.

Teriparatide has demonstrated superior outcomes in spinal fusion when compared directly to bisphosphonates.

Seki 2017: A prospective study showed that patients treated with teriparatide had a significantly higher fusion rate (89%) compared to those receiving bisphosphonates (77%) in the context of spinal fusion.

Abaloparatide:

Another anabolic medication, effective in improving BMD and decreasing vertebral fractures, considered an alternative to teriparatide, though its use in spine surgery specifically is not yet in the literature.

Sardar et al. (2022) guidelines recommend Teriparatide or Abaloparatide as the first-line agents for osteoporosis in patients undergoing spinal reconstruction.

Antiresorptive Agents

Bisphosphonates (BPs):

The most common medications for osteoporosis.
General

1st line therapy for osteoporosis

Indication

Paget’s disease
Osteoporosis

Hip or vertebral fracture
T-score <2.5 at the femoral neck or spine (after exclusion of secondary causes)
Low bone mass (T-score between -1.0 and -2.5) and

10-year probability of a hip fracture ≥ 3% or greater or
10-year probability of a major osteoporosis-related fracture ≥ 20% based on WHO algorithm/FRAX

Mech:

Accumulate at sites of bone remodelling and are incorporated into bone matrix
Are released into acid environment once bone is resorbed, and are then taken up by osteoclasts

Pyrophosphate analogues that bind to hydroxyapatite crystals and inhibit reabsorption.

Decrease osteoclastic bone resorption, flattening of osteoclast ruffled border and increased osteoclast apoptosis
Exact mechanism depends on presence of nitrogen on alkyl chain

Pharmacokinetics

They are retained in bone until it is resorbed.
Oral absorption of all is poor (especially in the presence of food).
Bone formed during treatment is lamellar rather than woven.
Renal excretion without undergoing metabolism

Types

Etidronate (Didronel) (AKA EHDP):

reduces normal bone mineralization (especially at doses ≥ 20 mg/kg/d),
producing mineralization defects (osteomalacia) which may increase the risk of fracture but which tend to heal between courses.
Contraindicated in patients with

renal failure,
osteomalacia, or
severe lytic lesions of an LE.

℞ 5–10 mg/kg PO daily (average dose: 400 mg/d, or 200–300 mg/d in frail elderly patients) for 6 months, may be repeated after a 3–6 month hiatus if biochemical markers indicate relapse.

Tiludronate (Skelid):

unlike etidronate, does not appear to interfere with bone mineralization at recommended doses.
Side effects: abdominal pain, diarrhea, N/V. ℞ 400mg PO qd with 6–8 ounces of plain water > 2 hrs before or after eating × 3 months. Available: 200mg tablets.

Pamidronate (Aredia):

much more potent than etidronate.
May cause a transient acute flu-like syndrome.
Oral dosing is hindered by GI intolerance, and IV forms may be required.
Mineralization defects do not occur in doses < 180 mg/course. ℞ 90 mg/d IV × 3 days, or as weekly or monthly infusions.

Alendronate (Fosamax):

does not produce mineralization defects (p. 1051).
Some studies showed alendronate improving fusion rates and decreasing complications, while others found no effect.
Zoledronate also showed varied effects on fusion rate and complications across studies. While no negative effect has been shown,

Clodronate (Ostac, Bonefos):

℞ 400–1600 mg/d PO × 3–6 months. 300 mg/d IV × 5 days (may be available outside the U.S.).

Risedronate (Actonel):

does not interfere with bone mineralization in recommended doses.15 ℞: 30mg PO q d with 6–8 oz. of water at least 30 minutes before the first meal of the day.

Outcomes

Osteoporosis

Alendronate reduces the rate of hip, spine, and wrist fractures by 50%
Risedronate reduces vertebral and non-vertebral fractures by 40% (each) over 3 years
IV zoledronic acid reduces the rate of spine fractures by 70% and hip fractures by 40% over 3 years
When administered during the perioperative period, bisphosphonates have been associated with better clinical outcomes, higher fusion rates, and a lower incidence of vertebral compression fractures

Denosumab:

Similar to bisphosphonates, it is an antiresorptive medication. One study showed improved fusion rates when combined with teriparatide. It is well-demonstrated in preventing osteoporotic fractures.

Romosozumab:

A newer monoclonal anti-sclerostin antibody with both anabolic and anti-resorptive effects. It has significantly improved lumbar spine CTHU and decreased new vertebral fractures, though not specifically studied in spine surgery.

Antiresorptive agents such as Denosumab or Zoledronate are recommended if anabolic agents are contraindicated or not tolerated.

Vitamin D and Calcium

Optimising Vitamin D and calcium levels is an important component of medical treatment. Vitamin D deficiency is common and often undiagnosed. Higher vitamin D levels have been linked to improved clinical outcomes, including better ODI scores and reduced pain after spine surgery, and potentially improved fusion rates.

Surgical treatment

Conservative treatment of fractures in PD are associated with a high rate of delayed union.
spinal Paget’s disease

Surgical indications

Rapid progression: indicating possible malignant change or spinal instability
Spinal instability: severe kyphosis or compromise of canal by bone fragments from pathologic fracture. Although the collapse is usually gradual, sudden compression may occur
Uncertain diagnosis: especially to R/O metastatic disease (osteoblastic lesions)
Failure to improve with medications

Surgical considerations

Profuse bleeding is common:

if significant bleeding would present an unusual problem, treat for as long as feasible pre-op with a bisphosphonate or calcitonin

Use bone wax to help control bleeding
Hemostasis may be difficult

To treat resultant spinal stenosis:

decompressive laminectomy is the standard procedure in the thoracic region.
However, if most of the pathology is anterior, consideration should be given to anterior approach

Bone is often thickened, and may be fused with obliteration of interspace landmarks.

A highspeed drill is usually helpful

Post-op medical treatment may be necessary to prevent recurrences

Osteogenic sarcoma

Surgery and chemotherapy are used,

Cure is less likely than in primary osteosarcoma of nonpagetic origin

Biopsy proven of the scalp requires en-bloc excision of scalp and tumor

Surgical outcome

In 65 patients treated with decompressive laminectomy,

85% had definite but variable degrees of improvement.
Patients who had only minimal improvement were often ones with malignant changes.
One patient was worse after surgery, and the operative mortality was 7 patients (10%).
Survival with malignant degeneration is < 5.5 mos after admission.