Medicine chapters
Paget disease of bone and osteopetrosis
Two disorders of bone remodelling: Paget disease, where overactive osteoclasts and osteoblasts make large, weak bone with a raised alkaline phosphatase, and osteopetrosis, where failed osteoclasts make dense but brittle "marble" bone.
- Paget disease = focal overactive bone turnover in people over 40: osteoclasts first, then disorganised woven bone that is thick but weak.
- Classic picture: older patient with bone pain, bowed tibia, enlarging skull, deafness, very high alkaline phosphatase with normal calcium and phosphate; rare osteosarcoma; treat with IV zoledronic acid.
- Osteopetrosis = failed osteoclast resorption → dense "marble bones" that fracture easily, with marrow failure and cranial nerve palsies in the severe recessive form; cure by bone marrow transplant.
On this page
Overview
Bone is constantly broken down by osteoclasts and rebuilt by osteoblasts. Two exam favourites show what happens when this balance goes wrong:
- Paget disease of bone: remodelling is too fast and chaotic. Bone becomes bigger but weaker.
- Osteopetrosis: osteoclasts fail, so old bone is never removed. Bone becomes denser but brittle.
Paget disease of bone (osteitis deformans)
Definition
A focal disorder of bone remodelling. Excess osteoclastic resorption comes first and is followed by a compensatory burst of new bone formation. The new bone is woven (disorganised), vascular and mechanically weak, so it deforms and fractures.
Epidemiology and cause
- Rare before 40 years; becomes steadily more common with age.
- Common in Britain, western Europe, North America and Australia; uncommon in Asia and Africa.
- Genetic: family history in about 15%; mutations in SQSTM1 (p62 protein in osteoclasts).
- Viral theory: paramyxovirus-like inclusions (measles, RSV, canine distemper) in osteoclasts; still unproven.
- Osteoclasts are huge with many nuclei (up to 100).
Phases
| Phase | What happens |
|---|---|
| Lytic (vascular) | Giant osteoclasts resorb bone; spaces fill with vascular fibrous tissue |
| Mixed | Resorption and chaotic new bone formation together |
| Sclerotic (burnt-out) | Thick, dense but brittle bone; activity settles |
Histology: irregular cement lines give a mosaic (jigsaw) pattern.
Sites
- Monostotic (one bone, about 15%) or polyostotic.
- Commonest sites: pelvis, femur, lumbar spine, skull and tibia.
- Hands and feet are rarely involved.
Clinical features
- Most patients have no symptoms (60–80%). Found by chance from a raised alkaline phosphatase or an X-ray taken for another reason.
- Bone pain: deep, constant ache, often worse at night and when warm.
- Deformity: bowed tibia (anterior bowing) and femur (anterolateral); bone feels thick and warm (increased blood flow).
- Skull: enlarging head ("hat no longer fits"), frontal bossing; platybasia (flattened skull base).
- Kyphosis and loss of height.
Complications
| Complication | Mechanism or note |
|---|---|
| Deafness | Most common nerve problem: compression of the VIII nerve and changes in the ossicles |
| Other cranial nerves | II, V, VII palsies |
| Spinal stenosis / cord compression | Vertebral enlargement; steal of blood from the cord |
| Hydrocephalus | Basilar invagination blocking CSF flow |
| Pathological fractures | Weight-bearing long bones; transverse "banana" fractures; non-union in the femur |
| Secondary osteoarthritis | Hip and knee next to diseased bone |
| High-output cardiac failure | Greatly increased bone blood flow (now rare) |
| Hypercalcaemia | Only after immobilisation or fracture |
| Osteosarcoma | In under 1%; suspect if pain and swelling suddenly increase; very poor prognosis |
Deafness is the classic neurological complication of skull Paget disease.
An elderly person with a new osteosarcoma very likely has underlying Paget disease.
Investigations
| Test | Finding |
|---|---|
| Serum alkaline phosphatase | Raised (often very high): reflects osteoblast activity and extent of disease; used to monitor treatment |
| Serum calcium and phosphate | Normal (calcium rises only with immobilisation) |
| PTH | Normal |
| Urine hydroxyproline, N-telopeptide | Raised (bone resorption markers) |
| Vitamin D | Check and correct before bisphosphonates |
| X-ray | Early: lytic lesions, osteoporosis circumscripta (skull), flame-shaped (blade of grass) lytic front in long bones. Later: bone enlargement, thick cortex, coarse trabeculae, sclerosis, "cotton-wool" skull |
| Isotope bone scan | Shows the extent of disease (hot spots); cannot reliably tell Paget from sclerotic metastases (prostate, breast) |
| Biopsy | Only if malignancy is suspected |
Paget = "ALP up, calcium normal". Old man, big head, bent shin, deaf.
A raised ALP with normal calcium and phosphate in an elderly man = Paget. Osteomalacia gives raised ALP with low calcium and phosphate; primary hyperparathyroidism gives high calcium and low phosphate; osteoporosis has normal ALP, calcium and phosphate.
An isotope bone scan shows how much of the skeleton is involved, but hot spots look the same in sclerotic metastases from prostate or breast cancer. Correlate with X-ray, ALP, PSA and, if needed, biopsy.
Differential diagnosis
- Sclerotic bone metastases (prostate, breast).
- Fibrous dysplasia, hyperparathyroid bone disease, osteomalacia.
Management
- Asymptomatic patients: usually no treatment. Treat if there is a high risk of complications (weight-bearing bone, skull with risk of deafness, spine) or before surgery on pagetic bone (to reduce bleeding).
- Indications for treatment: bone pain, deformity progressing, fractures, nerve compression, high-output heart failure, hypercalcaemia of immobilisation, and before orthopaedic surgery.
- Bisphosphonates are the mainstay:
- IV zoledronic acid: the drug of choice; a single infusion over 15 minutes can give long remission.
- IV pamidronate (less potent), or high-dose oral risedronate or alendronate (less effective).
- First-dose flu-like reaction (fever 24–48 hours); correct vitamin D first to avoid hypocalcaemia.
- Calcitonin is an older option, now rarely used.
- After treatment, new bone is lamellar rather than woven. Response is followed with ALP.
- Simple analgesia or NSAIDs for pain, especially when it is from secondary OA.
- Surgery: fixation of fractures, joint replacement, osteotomy, spinal decompression. Expect heavy bleeding because the bone is so vascular.
Osteopetrosis (marble bone disease, Albers-Schonberg disease)
Definition and cause
- A group of inherited disorders where osteoclasts fail to resorb bone.
- Bone keeps being laid down but is never remodelled, so the skeleton becomes very dense.
- One cause is carbonic anhydrase II deficiency: osteoclasts cannot make the acid needed to dissolve bone. This variant also gives renal tubular acidosis and cerebral calcification.
Types
| Feature | Autosomal recessive (congenital, malignant) | Autosomal dominant (tarda, benign) |
|---|---|---|
| Onset | Birth or infancy | Adolescence or adulthood, often by chance |
| Severity | Severe; often fatal in childhood | Mild; may have no symptoms |
| Marrow | Pancytopenia, anaemia, infections, hepatosplenomegaly (extramedullary haemopoiesis) | Usually normal |
| Nerves | Optic atrophy (blindness), deafness, facial palsy, hydrocephalus | Occasional cranial nerve compression |
| Bones | Fractures, osteomyelitis (e.g. of the jaw after tooth extraction) | Fractures that heal slowly |
Why the features occur
- Fractures: bone is dense but poorly organised and brittle ("chalk-like").
- Anaemia, low platelets and white cells: bone fills the marrow cavity (myelophthisis), so blood is made in the liver and spleen.
- Cranial nerve palsies: narrowed skull foramina compress nerves II, VII and VIII.
- Osteomyelitis: poor blood supply to the dense bone.
Investigations
- X-ray: generalised increased bone density; thick cortex with no clear medullary cavity; Erlenmeyer flask widening of the lower femur; "bone within bone" appearance and dense end-plates giving sandwich vertebrae.
- Blood: pancytopenia in the severe form; calcium usually normal.
- Genetic testing.
Management
- Allogeneic bone marrow (haemopoietic stem cell) transplant for the severe infantile form. Osteoclasts come from the monocyte-macrophage line, so donor marrow supplies working osteoclasts.
- Interferon-gamma may help.
- Supportive: transfusion, treatment of infections and fractures, decompression of nerves.
- The adult (benign) form usually needs only treatment of fractures.
Osteopetrosis is the opposite of osteoporosis: bone mass is high, yet the bones still break easily.
Comparison
| Feature | Paget disease | Osteopetrosis |
|---|---|---|
| Basic fault | Osteoclasts overactive, then chaotic repair | Osteoclasts underactive |
| Age | Over 40 years | Infancy (recessive) or young adults (dominant) |
| Bone | Enlarged, deformed, weak | Dense, brittle |
| ALP | High | Usually normal |
| Marrow | Normal | Crowded out (pancytopenia) in severe form |
| Nerves | Deafness, spinal stenosis | Blindness, deafness, facial palsy |
| Treatment | Bisphosphonates | Bone marrow transplant |
Expect: raised ALP with normal calcium and phosphate, commonest sites (pelvis, femur, spine, skull, tibia), bowed tibia and enlarging skull, deafness from VIII nerve compression, osteosarcoma as rare malignant change, osteoporosis circumscripta and mosaic histology, IV zoledronic acid as drug of choice, and in osteopetrosis the osteoclast defect, dense but fragile bone, marrow failure, cranial nerve palsies and bone marrow transplant.
Quick revision
- Paget: fast chaotic remodelling; osteoclasts first.
- Most are asymptomatic; found by high ALP.
- Pelvis most common; bowed tibia; large skull; deafness.
- ALP high; calcium and phosphate normal.
- X-ray: lytic flame front, osteoporosis circumscripta, then thick sclerotic bone.
- Osteosarcoma under 1%.
- IV zoledronic acid; monitor ALP.
- Osteopetrosis: osteoclast failure; marble bones that fracture.
- Severe form: pancytopenia, hepatosplenomegaly, blindness, deafness; marrow transplant.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Apley's System of Orthopaedics and Fractures).
FAQ
Why is alkaline phosphatase raised in Paget disease?
It comes from the very active osteoblasts making new bone, and its level reflects how active and extensive the disease is.
Is serum calcium high in Paget disease?
Usually not. Calcium and phosphate are normal unless the patient is immobilised, for example after a fracture.
What is the drug of choice for symptomatic Paget disease?
An intravenous bisphosphonate, usually a single infusion of zoledronic acid.
Why does bone marrow transplant cure severe osteopetrosis?
Osteoclasts develop from blood monocyte-macrophage cells, so healthy donor marrow supplies working osteoclasts that can remodel bone.
Why do dense bones break easily in osteopetrosis?
The bone is never remodelled, so it is thick but poorly organised and brittle, like chalk.