1. Metabolic Bone Disease – Histopathology Flashcards
What are the three main functions of bones?
Mechanical – support and site for muscle attachment
Protective
Metabolic – reserve of calcium
What are the two main components of bone and what are their relative proportions?
Inorganic (65%) – calcium hydroxyapatite (store of 99% of the body’s calcium, 85% of the phosphorous and 65% of Na and Mg)
Organic (35%) – bone cells and protein matrix
Describe the classification of bone as cortical and cancellous.
Cortical Long bones 80% of skeleton Appendicular skeleton 80-90% calcified Mainly mechanical and protective role Cancellous Vertebrae and pelvis 20% of skeleton Axial 15-25% calcified Mainly metabolic Large surface
What are the indications for bone biopsy?
Evaluate bone pain or tenderness Investigate abnormality seen on X-ray For bone tumour diagnosis To determine the cause of unexplained infection To evaluate therapy
What are the two types of bone biopsy?
Closed – needle – core biopsy with Jamshidi needle
Open – for sclerotic or inaccessible lesions
What are the three types of bone cell?
Osteoblast – build bone by laying down osteoid
Osteoclast – multinucleate cells of the macrophage family that resorb bone
Osteocyte – osteoblast like cells
Where are osteocytes found?
Lacunae
What cytokine is important for stimulating the differentiation of osteoclast precursors into pre-osteoclasts?
M-CSF (this is produced by osteoblasts)
Which cells produce RANKL and what is its effect?
Pre-osteoblasts
It stimulates the maturation of osteoclasts
What do mature osteoblasts produce that blocks the RANK/RANKL binding?
Osteoprotegrin
How are bones classified anatomically?
Flat
Long
Cuboid
What type of ossification leads to the formation of:
a. Long Bones
b. Flat Bones
a. Long bones
Endochondral ossification
b. Flat bones
Intramembranous ossification
How else can bone be classified?
Trabecular (cancellous) or compact (cortical)
Woven (immature) or lamellar (mature)
What is metabolic bone disease?
- Disordered bone turnover due to imbalance of various chemicals in the body (vitamins, hormones, minerals etc.)
- Overall effect is reduced bone mass (osteopaenia) + strength often resulting in fractures from little or no trauma
What are the three main categories of metabolic bone disease?
Related to endocrine abnormality (e.g. Vit D and PTH)
Non-endocrine (e.g. age-related osteoporosis)
Disuse osteopaenia
Describe the staining of calcified and uncalcified bone.
Calcified – green
Uncalcified – orange
What are the primary causes of osteoporosis?
Age
Post-menopause
What are the secondary causes of osteoporosis?
Drugs
Systemic disease
Describe the histology of osteoporotic bone.
Weak trabecular bridging
Holes and cysts
What is osteomalacia and what can it be caused by?
Defective mineralisation of normally synthesized bone matrix
(Rickets in children)
caused by:
- Vitamin D deficiency
- Phosphate deficiency (usually related to chronic renal disease)
What are the metabolic and endocrine consequences of vitamin D deficiency (Osteomalacia)?
Secondary hyperparathyroidism –> increased bone resorption
Hypocalcaemia – neuronal excitability causing muscle twitching, spasms, tingling and numbness
Describe the histology of osteomalacia.
No calcification of bone
More uncalcified osteoid
Bones are very bendy and cannot carry musculature very easily
What are the clinical consequences of osteomalacia?
- Bone pain/tenderness
- Fracture (horizontal fractures at Looser’s zone at the neck of the femur are commonly seen)
- Proximal weakness
- Bone deformity
What is used to investigate mineralisation?
Fluorescent tetracycline labelling
What are the consequences of hyperparathyroidism?
- Hypercalcaemia (increased Ca2+ reabsorption)
- Hypophosphataemia (increased phosphate excretion in the urine)
- Osteitis fibrosa cystica (due to increased osteoclast activity)
- Overall increased Ca, and PO4 excretion in urine
List the four organs that are directly or indirectly affected by parathyroid hormone to control calcium metabolism.
Parathyroid glands
Bones
Kidneys
Proximal small intestine
State some causes of primary hyperparathyroidism.
Parathyroid adenoma
Chief cell hyperplasia
State some causes of secondary hyperparathyroidism.
Chronic renal insufficiency
Vitamin D deficiency
What are the symptoms of hyperparathyroidism?
Stones, Bones, Abdominal Groans and Psychic Moans Stones – calcium oxalate renal stones Bones – osteitis fibrosa cystica Abdominal Groans – acute pancreatitis Psychic Moans – psychosis and depression
What is the most important investigation for hyperparathyroidism and what will it show in someone with hyperparathyroidism?
X-ray of the hand
Subperiosteal bone erosions
Brown cell tumours – small areas of resorption in the long bones of the fingers that are filled with osteoclasts
What are the five features of renal osteodystrophy?
Skeletal changes resulting from chronic renal disease
- Increased bone resorption (osteitis fibrosa cystica)
- Osteomalacia
- Osteoporosis
- Osteosclerosis
- Growth retardation
What are the consequences of renal osteodystrophy?
Hyperphosphataemia Hypocalcaemia as a result of a decrease in vitamin D metabolism Secondary hyperparathyroidism Metabolic acidosis Aluminium deposition
What is Paget’s disease?
Disorder of bone turnover (there is a lack of proper communication between the cells)
What are the three stages of Paget’s disease?
- Osteolytic
- Osteolytic-osteosclerotic
- Quiescent osteosclerotic
Describe the histology of Paget’s disease.
Prominent reversal lines
Masses of osteoclasts in the same site as osteoblasts
In which ethnicities is Paget’s disease rare?
Asian
African
Which sites does Paget’s disease most commonly affect?
Skull Sternum Spine Humerus Pelvis Femur Tibia
List some clinical features of Paget’s disease.
Pain Microfractures Nerve compression Skull changes (may put medulla at risk) Deafness Haemodynamic changes Cardiac failure Hypercalcaemias Development of sarcoma in the area of involvement
What are Howship’s Lacunae?
Pits in the bone surface where osteoclasts are found (also called resorption bays)
Describe cortical bone microanatomy.
What are the different lamellae?
What is a Haversian canal?
- cortical bone is made of parallel osteons (0.2mm diameter), which are structured circular layers of lamellar bone surrounding a haversian canal/ central canal containing blood vessels
- Circumferential lamellae: at periosteum, goes aorund whole bone
- Interstitial lamellar: between osteons
- Trabecular lamellae: do not surround central channels but are organized into layers
- Osteocytes in lacunae have dendritic structures
Describe bone remodelling cycle.
- osteoblasts regulate osteoclast formation and activity by producing RANK-L and M-CSF, and RANKL decoy receptor OPG
- osteocytes sense damage and signal to osteoclasts by producing RANKL as they apoptose
- reversal phase
When is transilliac bone biopsy used?
- If reason to get tissue is general and not bone specific
- transiliac biopsy allows core sample with plenty of cortical and trabecular bone
List the histological stains and explain when they are used.
- H&E- for majority, staining on decalcified samples
- Masson-Goldner Trichrome- amount of mineralised (green) vs unmineralised bone (orange)
- Tetracycline/Calcein labelling- allow dynamic histomorphometry to measure rates of bone formation and turnover
Which mutations can cause Paget’s Disease?
Describe its pattern of inheritance.
SQSTM1/ RANK
Autosomal with incomplete penetrance
