51 - Diseases of the Bone and New Markers Flashcards
Bone composition
Cortical - hard, outer layer
Trabecular bone - spony, inner layer
Cells - forming + resorbing
Extracellular - organic matrix of collagen + inorganic components
What inorganic components are there of bone?
Hydroxypatite
Minerals - Ca, phosphate
Bone is called what before mineralisation
Osteoid
What is the matrix mineralised by
Hydroxyapatite (calcium-phosphate-hydroxide salt)
What are osteoblasts?
Terminally differentiated products of mesenchymal stem cells which make osteoids
What are osteoids?
Non-mineralised organic matrix, consists of mainly type 1 collagen
Functions of osteoblasts
Communicate with other bone cells
Make hormones (osteocalcin), matrix proteins and alkaline phosphatase
Prerequisite for mineralisation
Osteoblasts can be osteoclasts
What are osteoclasts?
Osteoblasts that are buried/trapped within the matrix
Osteoclasts appearance
Large, multinucleated
Ruffled-resorption border
Found in bone pits (resorption bays)
Osteoclast function
Break down bone
Produce enzymes which breakdown extracellularly matrix
Help enhance blood Ca levels
Regulated by hormones
Osteocytes
Star shaped Trapped osteoblasts Communicate via cytoplasmic extensions Mechanosensory properties Involved with regulating bone matrix turnover
Test for gross structure of bone
X ray
Test for bone mass
DEXA scan
Test for cellular function/turnover
Biochemistry
Test for microstructure/cellular function
Biopsy, qCT
Biomarkers for bone formation
Alkaline phosphatase (TAP, BAP) Osteocalcin Procollagen type I (P1NP) - but loads of cells have type one collagen
Biomarkers for bone resorption
Hydroxyproline
Pyridinium crosslinks
Crosslinked telopeptides for of type I collagen
Osteoclast enzymes
Tartrate-resistant acid phosphatase
Cathepsin K
Alkaline phosphatase facts
Measured in LFTs and Bone profiles
50% liver and 50% bone
Specific isoenzymes can be measured if diagnostic doubt
What releases and stimulate alkaline phosphatase?
Osteoblasts
Childhood/pubertal growth spurts, fractures, hyperparathyroidism, Paget’s disease
P1NP - made where, describe activity
Osteoblasts make it - precursor for type one collagen
Low diurnal and intraindividual variation
[Serum] not affected by food intake
Increase with increased osteoblast activity
Decreased with reduced osteoblast activity
Collagen cross-links (NTX, CTX)
Cross-linking molecules which are released with bone resorption
Increased in periods of high bone turnover
Diurnal variation, do not predict bone mineral density, decrease with anti-resorptive therapy
Usefulness of bone markers
Collagen one - not specific but can detect changes in bones
Indication of bone turnover and/or loss
Evaluation of treatment effect (CTX)
Evaluation of medication compliances (P1NP)
DEXA gives what score
T-scores
- 1 and above = normal
- 1 and -2.5 = osteopenia
- 2.5 and below = osteoporosis
Bone disorders
Metastatic disease Hyperparathyroidism Osteomalacia/Rickets Osteoporosis Paget's disease
What happens to the spine of a patient with osteoporosis?
Increase in biconcavity of lower thoracic bodies
Osteoporosis symptoms
Propensity to fractures - spine or hip
No abnormal routine biochemical tests
Diagnosis relies on DEXA/Xray
Osteoporosis definition
Decreased bone mass with deranged bone micro architecture
Antiresorptive treatments
Bisphosphonates (most common)
Oral/IV
Alendronic acid/zoledronic acid
Denosumab - RANKL monoclonal antibody
Raloxifene
Anabolic treatment
Terparatide SC
Synthetic PTH
Efficacy of treatment for osteoporosis
50-70% reduction in vertebral fractures
25-35% reduction in hip fractures
How do bisphosphonates work
Mimic pyrophosphate structure
Taken up by skeleton
Ingested by osteoclasts
Bisphosphonates - problems
Poor absorption Difficult to take - sat up for hours Can cause oesophageal/upper GI problems Flu-like side effects Osteonecrosis of jaw Atypical femur fracture
Types of bone mets
Lytic
Sclerotic/osteoblastic
Usual sites of spread inc. spine, pelvis, femur, humerus, skull
Lytic bone mets
Destruction of normal bone (osteoclasts)
Breast/lung
Kidney/thyroid
Sclerotic/osteoblastic mets
Deposition of new bone
Prostate
Lymphoma
Breast/lung (15-25%)
Bone mets - clinical presentation
pain - worse and night and gets better with movement
Broken bones
Numbness, paralysis, trouble urinating
Loss of appetite, nausea, thirst, confusion, fatigue (from hypercalcaemia)
Anaemia from bone marrow disruption
Symptoms of mild hypercalcaemia
Polyuria, polydipsia Mood disturbance Anorexia Nausea Fatigue Fatigue Constipation
Symptoms of severe hypercalcaemia
Abdo pain Vomiting Coma Pancreatitis Dehydration Cardiac arrythmias
Causes of hypercalcaemia
Either non-PTH mediated or PTH-mediated
Mainly malignancy and sporadic 1° hyperparathyroidism respectively
Parathyroid hormone
PTH
Secreted by chief cells of parathyroid gland
stimulated by high blood calcium
Primary hyperparathyroidism
Ca: high
PTH: inappropriately high
Low phosphate and high alk phos common
Sporadic or familial
Secondary hyperparathyroidism
Ca: normal or low
PTH: appropriately high
Phosphate high if due to chronic kidney infection
Causes: mainly CKD or vit D deficiency
Tertiary hyperparathyroidism
Ca: usually high
PTH: inappropriately high
Phosphate can high or low
Causes: after prolonged secondary HPT, usually in CKD
Primary hyperparathyroidism - clinical presentation
Severe hypercalcaemia +/- symptomatic renal/skeletal disease
Primary hyperparathyroidism - who?
> 45
Women>M
Primary hyperparathyroidism - benign cancers
Adenomas (benign) - 85% of cases have single adenoma
5% have double
Most encapsulated and consist of parathyroid chief cells
Primary hyperparathyroidism - malignant cancers
Parathyroid carcinoma
1-2% of all HPT
Invasion seen in histology
Usually aggressive with significant hypercalcaemia and possibility of distant mets
Primary hyperparathyroidism - hyperplasia
6-10% of HPT cases
All 4 glands enlarged
Can occur sporadically or part of genetic syndromes (MEN1, MEN2A or familial hyperparathyroidism)
Medial or surgical therapy e.g. 3.5 glands removed
Primary hyperparathyroidism - which genetic syndromes?
MEN1
MEN2
Familial hyperparathyroidism
Primary hyperparathyroidism - ectopic adenomas
Rarely ectopic adenomas in mediastinum
Some parathyroid adenomas found in thymus gland (due to embryological migration)
Primary hyperparathyroidism - classical clinical presentation
Hypercalcaemia
Renal disease
Bone disease
Proximal muscle wasting
Primary hyperparathyroidism - investigations
Radiography - ectopic PT tissue in mediastinum
Primary hyperparathyroidism - indications for surgery
Symptomatic hypercalcaemia
In asymptomatic patients: Ca>0.25mmol/l above normal.
Renal stone disease
Calculated creatinine clearnace (
Calcimimetics
Activates CaSR in PT gland - reducing PTH secretion
Paget’s disease - what is it
rapid bone turnover and formation leading to abnormal bone remodelling
Paget’s disease - who?
Over 50 Higher prevalence in men Genetic + enviro FH in 10-15% of cases Polyostotic or monostotic Elevated alk. phos. reflecting increased bone turnover
Paget’s disease - clinical presentation
Bone pain Bone deformity Fractures Arthritis Cranial nerve defects if skull affected Risk of osteosarcoma Most commonly affects pelvis, femur and lower lumbar vertebrae
Paget’s disease - managment
Labs
Plain X-rays
Nuclear medicine bone scan
Osteomalacia - pathogenesis
lack of mineralisation of bone due to vitamin D deficiency or lack of calcium and/or phosphate
Osteomalacia - adult form, childhood
Widened osteoid seams with lack of mineralisation
Child - rickets - widened epiphyses & poor skeletal growth
Osteomalacia - main causes
Insufficient Ca absorption from intestine (lack of dietary Ca/vit D)
Excessive renal phosphate excretion (rare genetic)
Osteomalacia - clinical features
Diffuse bone pains - symmetrical
Muscle weakness
Bone weakness
High alk phos, low vit D, possibly low Ca and high PTH
Osteomalacia - who?
Ageing pop
Nursing home residents
Asian (hijab/burka wearing)
Malabsorption
Pic on slide 71
is good summary
