Flashcards in Disease of bone and application of new markers Deck (86):
What is cortical bone?
Hard, outer layer.
What is trabecular bone?
Spongy, inner layer that houses bone marrow.
What is the bone extracellular matrix made from?
Mainly collagen. Also hydroxyapatite and minerals (calcium, phosphate)
What is the main function of osteoblasts?
Constantly producing and secreting matrix and helping with mineralisation.
What is the main function of osteoclasts?
What is the lineage of osteoblasts?
Terminally differentiated products of mesenchymal stem cells.
What is osteoid?
Non-mineralised organic matrix, consists of mainly type 1 collagen.
What are the specific functions of osteoblasts?
- Make osteoid
- Communicate with other bone cells
- Make hormones (e.g. osteocalcin), matrix proteins and alk. phosphatase
- Prerequisite for mineralisation
What name is given to osteoblasts that are buried/trapped within the matrix?
What are the morphological features of osteoclasts?
- Ruffled-resorption border
What are the specific functions of osteoclasts?
- Break down bone, critical for repair and maintenance of bone
- Produce enzymes such as tartrate resistant acid phosphatase (TRAP) and Cathepsin K - secreted breakdown extracellular matrix
- Help enhance blood calcium levels
Where are osteoclasts found?
In bone pits (resorption bays).
Which hormones regulate osteoclasts?
PTH, calcitonin, IL-6
What help with osteoclastic maturation and activity.
RANK ligand and osteoprotegrin
What are the morphological features of osteocytes?
How do osteocytes communicate with each other?
Via cytoplasmic extensions.
What are the functions of osteocytes?
- Mechanosensory properties (i.e. so we know where the bone is where it's being moved)
- Involved with regulating bone matrix turnover
How often is an adult skeleton replaced?
What tests are used in the investigation of bone disease?
Bone mass (Calcium)
- Biopsy, qCT
What are the biochemical markers of bone formation?
- Alkaline phophatase (TAP, BAP)
- Osteocalcin (OC)
- Procollagen type 1 propeptides (P1NP)
What are the biochemical markers of bone resorption?
Degradation products of bone collagen:
- Pyridinium crosslinks
- Crosslinked telopeptides of type 1 collagen (NTX, CTX)
- Tartrate-resistant acid phosphatase (TRACP 5b)
- Cathepsin K
What is alkaline phosphatase?
- Measured in LFTs and bone profiles
- In health approx 50% liver/50% bone
- Specific isoenzymes can be measured where there is diagnostic doubt
What is the function of alkaline phosphatase in bone?
Involved in mineralisation.
Which cells release alkaline phophatase?
What stimulates the release of alkaline phophatase?
Release stimulated by increased bone remodelling.
- Hyperparathyroidism (primary or secondary)
- Paget's disease
What is P1NP?
- Procollagen type 1N propeptide
- precursor molecule of type 1 collagen
- has low diurnal and intraindividual variation
- serum concentrations not affected by food intake
Which cells synthesise P1NP?
- Serum concentration increased with increased osteoblast activity
- Decreased by reduced osteoblast activity
What are NTX and CTX?
- Cross-linking molecules which are released with bone resorption, correlate highly with bone resorption
- Increased in periods of high bone turnover
- Have diurnal variation
Do NTX and CTX predict bone mineral density?
What type of collagen are collagen-related markers based primary on?
Type 1 collagen
Are changes in bone markers disease-specific?
No - reflect alterations in skeletal metabolism. Some markers vary a lot by individual.
What are the possible uses of bone markers?
Evaluation of bone turnover and loss
Evaluation of treatment effect
- CTX used to monitor response to anti-responsive treatment
Evaluation of compliance with medication
- P1NP used to monitor compliance with teriparatide
- CTX used to monitor compliance/response to anti-resorptive therapy
What do DEXA scores mean?
- 1 and above: bone density is considered normal
Between -1 and -2.5: osteopenia
- 2.5 and below: osteoporosis
What is osteoporosis?
Generalised loss of bone with propensity to fractures - spine, hip.
decreased bone mass + deranged bone micro-architecture = failure of structural integrity
What does diagnosis rely on?
- No abnormalities are seen in routine biochemical tests, perhaps because they are too insensitive
What is a fragility fracture?
A fracture caused by injury that would be insufficient to fracture a normal bone.
What should be your suspicion in a person with a history of fragility fractures?
Low bone mass
What Hx should prompt investigation for vertebral fractures?
- Unexplained loss of height
- Severe back pain
What are the endocrine causes of secondary osteoporosis?
- Early menopause
- Hormone ablation for breast/prostate cancer
What are the haematological causes of secondary osteoporosis?
- Systemic mastocytosis
What are the gastrointestinal causes of secondary osteoporosis?
- Coeliac disease
- Chronic liver disease
- Any cause of malabsorption
What are the rheumatological causes of secondary osteoporosis?
- Inflammatory arthropathies
What are the respiratory causes of secondary osteoporosis?
- Cystic fibrosis
What are the metabolic causes of secondary osteoporosis?
Which drugs may cause secondary osteoporosis?
- Steroids (prenisolone >7.5mgs daily for >3m)
What investigations might one use for the secondary causes
- Ca and bone profile
- Vit D
- Plasma viscosity (+/- myeloma screen)
- Coeliac screen
- In men: 9am testosterone, SHBG, LH, FSH and LFTs
- In young amenorrhoeic women: LH, FSH, estradiol prolactin
- Loss of height, back pain or kyphosis consider lateral X-ray T5-L5 spine
What antiresorptive treatments are available to treat osteoporosis?
- Bisphosphonates - alendronic/zolendronic acid, oral/IV
- Denosumab - monoclonal Ab to RANKL
What anabolic treatments are available?
- Terparatide SC
- Synthetic PTH
What element can be used as treatment for osteoporosis?
What is the mechanism of action for bisphophonates?
- Mimic pyrophosphate structure
- Taken up by skeleton
- Ingested by osteoclasts
- Inhibit osteoclast formation, migration and osteolytic activity, promote apoptosis
- Concentrated in newly mineralising bone and under osteoclasts
- Modulate signalling from osteoblasts to osteoclasts
What are the drawbacks of bisphosphonates?
- Poor absorption
- Difficult to take
- Can cause oeophageal/upper GI problems
- Flu-like side effects
- Osteonecrosis of the jaw
- Atypical femur fractures
What are lytic bone metastases and which cancers are they commonly associated with?
Destruction of normal bone (osteoclasts).
Which haematological malignancy is associated with lytic bone lesions?
What are sclerotic bone metastases and which cancers are they commonly associated with?
Deposition of new bone
- Breast/lung (15-25%)
What are the usual sites of metastatic spread in the skeleton?
What are the presenting symptoms of bone mets?
- Often worse at night and gets better with movement initially
- Usually becomes constant
- Pathological fractures
Numbness, paralysis, trouble urinating
- Spinal cord compression from bone mets
Loss of appetite, nausea, thirst, confusion, fatigue
- Symptoms of hypercalcaemia
- Disruption of bone marrow
What are the symptoms of hypercalcaemia?
- Mood disturbance
- Abdo pain
- Cardiac arrhythmias
What are the non-PTH mediated causes of hypercalcaemia?
- Vit D intoxication
- Chronic granulomatous disorders e.g. sarcoidosis
- Adrenal insufficiency
Which drugs can cause hypercalcaemia?
- Thiazide diuretics
- Theophylline toxicity
What are the PTH-mediated causes of hypercalcaemia?
- Sporadic primary hyperparathyroidism
- MEN1 and 2A genes
- Familial isolated hyperparathyroidism
Which cells secrete parathyroid hormone?
Chief cells of parathyroid glands
What stimulates the release of PTH?
- Low Ca and Mg
- Increased Vit D
What inhibits the release of PTH?
- Increased levels of blood Ca
What are the actions of PTH?
- Increased decomposition of bone, releasing Ca
- Increased absorption of Ca from food by intestines
- Reabsorption of Ca from urine by kidneys
What are the test results in primary hyperparathyroidism and the main causes?
- Ca: usually high
- PTH: inappropriately high
- Low phosphate and high alk phos common
- Causes: sporadic or famillial
What are the test results in secondary hyperparathyroidism and the main causes?
- Ca: Normal or low
- PTH: Appropriately high
- Phosphate high if due to CKD
- Causes: mainly CKD or Vit D deficiency
What are the test results in tertiary hyperparathyroidism and the main causes?
- Ca: usually high
- PTH: inappropriately high
- Phosphate can be high or low
- Causes - After prolonged secondary HPT, usually in CKD
What is the presentation of primary hyperparathyroidism (PHPT)?
- Previously used to present with severe hypercalcaemia and/or symptomatic renal and skeletal disease
- Now presentation much earlier so usually asymptomatic
- >45 years
- 2:1 F:M
- Inappropriately elevated PTH in the presence of high calcium suggests PHPT
What is the cause of 85% of PHPT?
- Single adenoma
- Additional 5% have multiple
- Most adenomas encapsulated and consist of parathyroid chief cells
What percentage of PHPT is caused by malignancy?
What are the features of parathyroid carcinoma?
- Features of invasion on histology
- Usually aggressive disease, with significant hypercalcaemia and possibility of distant metastases.
- What are the features of glandular hyperplasia?
- Approx 6-10% of cases of PHPT
- All 4 glands enlarged (lower glands usually larger than upper ones, usually composed of Chief cells)
- Can occur sporadically or part of genetic syndromes (MEN1, MEN2A or familial hyperparathyroidism)
- Medical or surgical therapy
- If surgery: 3-5 glands often removed
What is an ectopic adenoma?
- Rarely ectopic adenomas in mediastitinum
- Some parathyroid adenomas found in thymus gland (parathyroid cells which migrated during embryogenesis)
What are the clinical manifestations of PHPT?
- Symptoms related to hypercalcaemia (as described)
- Renal (nephrolithiasis, CKD)
- Bone disease (osteoporosis, ostoitis, fibrosa cystica)
- Proximal muscle wasting
What are the indications for surgery in PHPT?
- Symptomatic hypercalcaemia
- In asymptomatic patients with primary
- Ca > 0.25mmol/L above normal
- Renal stone disease
- Calculated creatinine clearance
What are the calcimimetics e.g. Cinacalcet)?
- Activates CaSR in the parathyroid gland
- Therefore leads to reduced PTH secretion
What are calcimimetics used for?
- Use to normalise Ca in symptomatic patients, or those who are not fit or unwilling to have surgery
- Use limited by GI side effects, particularly nausea
- Does not seem to alter bone disease
- No data on renal outcomes or quality of life
What is Paget's disease of the bone?
- Rapid bone turnover and formation leading to abnormal bone remodelling
- Polyostotic or monostotic
- Elevated alk. phos. reflecting increased bone turnover
What is the epidemiology of Paget's disease?
- >50 yo
- Higher prevalance in men
- Probable genetic and environmental triggers
- FH in 10-15%
What are the clinical features of Paget's disease of bone?
- Bone deformity
- Bone pain
- Cranial nerve defects if skull affected - hearing and vision loss
- Risk of osteosarcoma
- Most commonly affects pelvis, femur and lower lumbar vertebrae
What investigations are necessary in Paget's disease?
- Lab assessment
- Plain x-rays
- Nuclear medicine bone scans
What is osteomalacia?
Lack of mineralisation of bone due to Vit D deficiency or lack of Ca and or phosphate.
Describe the adult form of osteomalacia?
Widened osteoid seams with lack of mineralisation.
Describe the childhood form of osteomalacia (rickets)?
Widened epiphyses and poor skeletal growth.
What are the main causes of osteomalacia?
- Insufficient Ca absorption from intestine due to lack of dietary Ca or Vit D deficiency or resistance
- Excessive renal phosphate excretion - rare genetic forms (hereditary hypophosphataemic rickets)