Metabolic Bone Disease 2- Clinical Biochemical Features of Bone Disease
- Explain how basic biochemical tests can be used to assess mineral metabolism and bone turnover.
- Explain how Bone Densitometry can be used to diagnose Osteoporosis, and to monitor response to treatment.
- Describe the biochemical and clinical features of osteoporosis, osteomalacia, Paget’s disease and hyperparathyroidism; and the basics of treatment
Metabolic bone diseases are characterised by a decrease in bone density and bone strength either by increasing bone reabsorption or decreasing its formation (or both).
Bone is metabolically active tissue consisting of an interaction between osteocytes and osteoblasts.
Osteoblasts synthesise bone matrix, regulate the deposition of hydroxyapatite (calcium-containing mineral of bone) and secrete molecules to control the proliferation and action of osteoclasts. They arise from pluripotential mesenchymal cells.
Osteoclasts breakdown and reabsorb bone, dentine and calcified cartilage. They play an important role in the modelling of growing bone, and maintenance of shape. They are also activated by parathyroid hormone to regulate the levels of calcium in the blood.
Assessing Bone Function
Radiology e.g. osteomalacia, Paget’s disease
Bone mineral densitometry, e.g. osteoporosis
- corrected calcium
- parathyroid hormone
- 25-hydroxy vitamin D
- NTX (Cross-linked N-telopeptides of type I collagen)
The majority of the calcium in the body is stored in bone however, that which is stored in the blood is stored:
- 46% bound to proteins
- 46% free ionised
- 7% complexed
The level is controlled, minute by minute by parathyroid hormone.
Parathyroid hormone is an 84 amino acid peptide but only N1-34 are active. It is dependent on Mg and has a plasma half life of around 8 minutes. It activates receptors in bone, kidney and the gastrointestinal tract – these receptors can also be activated by PTHrP – parathyroid hormone related protein.
The varying rate and amount of release of PTH is a steep inverse sigmoidal function in relation to Cao2+ in vivo.
MINIMUM- at this level, there is still a baseline release of PTH SET POINT – this is half the level of suppression of PTH, and at this point, even small peturbances in Ca2+ cause large changes in PTH.
Hyperparathyroidism: primary hyperparathyroidism is caused mainly by a pituitary adenoma, or hyperplasia. It is occasionally caused by an inherited syndrome. It can cause
1. Increase serum calcium, by absorption from bone/gut/kidney
2. Decrease serum PO4, as increased absorption is overcome by marked renal excretion
3. Increase urine calcium excretion, as increased renal resorption is overcome by the hugely increased filtered load
4. Increase markers of bone resorption, thus secondarily formation
- Stones : Renal colic, nephrocalcinosis, CRF
- Abdominal moans: Dyspepsia, pancreatitis Constipation, nausea, anorexia
- Psychic groans: Depression, impaired concentration, Drowsy, coma.
- Thirst Polydipsia
- Polyuria due to impaired reabsorption of water and sodium.
- Muscle weakness
- Increased susceptibility to fractures.
Management of Hyperparathyroidism
- BMD (bone mineral density) for osteoporosis
- Ultrasound for renal stones
- 24hr CrCl for renal failure.
Can treat either with surgery or with use of bisphosphonates and calcimimetics.
Osteomalacia: inadequate Vitamin D activity leads to defective mineralisation of the cartilaginous growth plate (before a low calcium).
- Bone pain and tenderness (axial)
- Muscle weakness (proximal)
- Lack of play
- Age dependent deformity
- Short stature
- Tenderness on percussion
DietaryLack of sunlight
Decreased production with age.
GastrointestinalSmall bowel malabsorption/ bypass
Drugs- phenytoin, phenobarbitone
RenalChronic renal failure – renal phosphate loss.
Vitamin D dependent rickets type I (autosomal recessive, no 1a-hydroxylation)
ResistanceVitamin D dependent rickets type II (autosomal recessive, VDR defect)
Patients should be X-rayed and ultrasound scanned.
NB: if calcium and vit D levels are normal then the cause could be renal phosphate loss, either from X-linked hypophosphataemic Rickets (a disease caused by mutation in PHEX) or oncogenic osteomalacia (caused by a mesenchymal tumour).
Age Related Changes in Bone Mass
The graph shows an increased loss of bone mass and density in post-menopausal women. This is associated with oestrogen levels:
• Increases the number of remodelling units
• Causes remodelling imbalance with increased bone resorption (90%) compared to bone formation (45%)
• Enhanced osteoclast survival and activity
• Remodelling errors. Deeper and more resorption pits lead to trabecular perforation and cortical excess Haversian excavation
• Decreased osteocyte sensing.
Tests in Osteoporosis
Check Vitamin D levels
Check for secondary endocrine causes of diease
- Hyperparathyroidism – high PTH
- Hyperthyroidism – high T3, low TSH
- Hypogonadis – low testosterone
Exclude multiple myeloma
Check urine calcium (may be high in osteoporosis)
“Gold standard” for BMD is D.X.A (Dual energy X-ray absorptiometry): Measures transmission through the body of X-rays of two different photon energies. It enables densities of two different tissues to be inferred, i.e. bone mineral, soft tissue
Osteoporosis is defined by patients T-score
T-score =-2.5 OSTEOPOROSIS
T-score = measured BMD – young adult mean BMD
Young adult standard deviation
Complications of Osteoporosis
The most common problem is increase in fracture risk. The most common fracture is that of the spine, and then the hip.
Treatment for Osteoporosis
Treatment for osteoporosis is decided by Z-score:
Z-score =measured BMD – aged-matched mean BMD
aged-matched standard deviation
The result is compared to a healthy normal subject matched for age, gender and ethnic origin. However, certain Situations can interfere with the interpretation of the scores:
• Degenerative change, osteoarthritis
• Vertebral fractures
• Metal artefacts
• Vascular calcification
• Paget’s disease
The criteria for measurement is dependent on age and complications.
We can use bone markers to give us an idea of bone activity rather than using bone mineralisation density. It is a dynamic test.
In bone formation the 2 ‘Alpha 1’ and 1 ‘Alpha 2’ chains of type I collagen that are produced by the osteoblast are joined together.
3 hydroxylysine molecules on adjacent tropocollagen fibrils then condense to form a PYRIDINIUM ring linkage ; DPD, PYD
The products produced by the collagen breakdown are useful markers for bone reabsorption as they directly correlate with the amount of bone reabsorbed. These include:
Pyridinium (DPD; PYD not bone specific)
N-terminal telopeptide (NTX)
C-terminal telopeptide (CTX)
They can be used in the diagnosis of the disease, to predict fracture risk and also to monitor treatment. Bone markers are higher in osteoporotic patients. There are however certain problems with the use of bone markers including their reproducibility, the association with age, the need to correct the levels for Cr, and the diurnal variation in level.
Measurement of osteoblast function is also useful:
- serum alkaline phosphatase
- propeptides of type 1 collagen
- carboxyterminal PICP
- aminoterminal PINP
- BSAP – bone specific alkaline phosphatase: NB increased in Paget’s disease, osteomalacia, bone metastases, hyperparathyroidism and hyperthyroidism
Treatment of Osteoporosis
1. Optimise calcium and vitamin D
800 units vitamin D3
2. Prevent bone resorption
3. Increase bone formation
Paget’s Disease: Chronic disorder of excess focal exaggerated bone remodelling.
There are 2 main causes of Paget’s disease, viral and genetic.
Total Alkaline phosphatase only one needed
Bone-specific if normal total alk-p or liver disease
to confirm diagnosis
to diagnose complications
to assess extent of disease at diagnosis
Should be treated with bisphosphonates.