Calcium and Bone Disease Flashcards
Describe the features of bone turn over
Bone is an active tissue - turns over several times in a lifetime
- Increased rate of growth in childhood and puberty
- In adults rates of bone formation and resorption are coupled and matched
List the functions of calcium
Structural
– e.g. bone, teeth
Neuromuscular
– e.g. control of excitability, release of neurotransmitters, initiation of muscle contraction
Enzymic
– e.g. coenzyme for coagulation factors, trypsin
Signalling
– e.g. intracellular second messenger
Describe the distribution of plasma calcium
Ionised Calcium - around 1.0mmol/l
– Physiologically active fraction
• Cellular Effects
• Control of PTH
Bound Calcium - around 0.95mmol/l
– Physiologically inactive
– Albumin main binding protein (50%)
Complexed Calcium - around 0.05mmol/l
– Salts - calcium phosphate
Total Calcium = Ionised + Bound + Complexed = around 2.0mmol/l
Describe the laboratory measurement of calcium
Usual measurement is Total Calcium
– Cheaper
– More convenient
Doesn’t necessarily reflect ionised calcium
because:
– Total Ca affected by albumin concentration
because of protein binding
– pH influences ionised Ca more H+ ions inhibit Ca2+
binding
How does acidosis effect plasma calcium levels?
Bound calcium dissociates into ionised calcium
From around 0.95mmol/l to around 0.55mmol/l
How does alkalosis effect plasma calcium levels?
Ionised calcium changes to bound calcium
From around 1.00mmol/l to around 0.60mmol/l
Describe the evidence and clinical implications of the relationship between calcium and pH
- Direct measurement with ion specific electrodes confirms the relationship
- Alkalosis can precipitate tetany – eg carpopedal spasm (hyperventilation)
- Hypocalcaemic patients with acidosis don’t develop symptoms
Describe the pathophysiology of calcium
Disorders of homeostatic regulators
–Parathyroid hormone
–vitamin D
Disorders of the skeleton
–bone metastases
Disorders of effector organs
–gut - malabsorption
–kidney
Diet
List the calcium-regulating hormones
Parathyroid hormone
Calcitriol
Calcitonin
How does parathyroid hormone effect calcium homeostasis?
84 and 34 residue forms
• release stimulated by decrease [Ca2+]
Actions: – bone: • increased osteoclast activity • rapid calcium release • increased plasma [Ca2+]
– kidney: • increased calcium reabsorption – increased plasma [Ca2+] • decreased phosphate reabsorption – decreased plasma [Pi] • increased 1α-hydroxylase activity (calcitriol formation in kidney) – increased gut absorption Ca & Pi • decreased bicarbonate reabsorption – acidosis
Describe the actions of calcitriol
Intestine:
• increased synthesis of calcium-binding protein - calbindin D - in enterocytes
• increased uptake of dietary calcium & phosphate
• increased ECF calcium & phosphate, hence bone
mineralization
Bone:
• Binding to receptors in osteoblast - alkaline
phosphatase & osteocalcin (Ca-binding protein,
unknown function)
• High concs stimulate osteoclast activity & bone
resorption
Kidney
• Inhibits 1α-hydroxylase
• Small permissive effect with PTH on Ca reabsorption
Give examples of bone diseases related to calcium levels
Hypercalcaemia
– Metastatic disease
– Hyperparathyroidism
Hypocalcaemia
– Osteomalacia / Rickets
– Hypoparathyroidism
Eucalcaemia, but impaired bone mineralization
– Osteoporosis
– Paget’s Disease
How is bone disease investigated?
Gross Structure
– X-ray
Bone Mass / Density
(Calcium)
– DEXA (dual energy X-ray absorptiometry)
Cellular Function / Turnover
– Biochemistry - e.g. enzymes - AP
Microstructure / Cellular Function
– Biopsy
Describe clinical features of hypercalcaemic bone diseases
Common: – malignant disease • metastatic – tumour may actively dissolve bone • no apparent metastases – tumour may secrete PTH-related peptides – hyperparathyroidism (primary)
Rarer:
– thyrotoxicosis, vitamin D intoxication, thiazide diuretics etc
Describe the effects hyperparathyroidism
Commonest overall cause of hypercalcaemia
Primary / Secondary / Tertiary forms seen
• Secondary due to decreased calcitriol and plasma Ca (e.g. chronic renal disease, vitamin D deficiency)
• Tertiary - renal transplant patients
Parathyroid adenomas common - less often diffuse hyperplasia - rarely parathyroid carcinoma
Results in: • Increased bone turnover / resorption • Hypercalcaemia / Hypophosphataemia • Alkaline Phosphatase raised • Long standing damage : Osteitis Fibrosa Cystica
Give examples of hypocalcaemic bone diseases
Osteomalacia/Rickets (Vitamin D deficiency)
Renal failure
Hypoparathyroidism
– congenital (+/- immune deficiency)
– acquired (idiopathic, autoimmune, surgery (thyroidectomy) etc.
Pseudohypoparathyroidism
– failure of cAMP signalling
– increased PTH, but ineffective
Describe osteomalacia
Due to vitamin D deficiency
– dietary &/or lack of sunlight
Adult form - widened osteoid seams with lack of
mineralisation
Classic childhood rickets (before epiphyseal closure) - widened epiphyses & poor skeletal growth
Failure of vitamin D metabolism or effectiveness e.g. in renal / liver disease and some rare genetic
forms
Results in:
– Hypocalcaemia with secondary hyperparathyroidism
– Raised alkaline phosphatase
What is osteomalacia?
Rickets disease
What is the biochemistry in osteomalacia?
Low vitamin D Low calcium Increased PTH Low/N phosphate Increased Alkaline phosphatase
Give examples of metabolic bone diseases with normal plasma calcium
Osteoporosis
Paget’s disease
Describe the features of osteoporosis
- Common disease especially of elderly
- Generalised loss of bone with propensity to fractures - spine, hip
- Aetiology is largely unknown though current major research efforts are providing some clues - includes oestrogen deficiency
- No abnormalities are seen in routine biochemical tests perhaps because they are too insensitive
- Diagnosis relies almost exclusively on DEXA/X-Ray
Describe how sex hormones effect bone disease
Women who lose bone fastest post menopause have the lowest endogenous sex hormone (oestrogen) levels
- Mechanism: Osteoclast and osteoblast cells have oestrogen receptors. The binding of oestrogens causes a cytokine mediated reaction that promotes bone re-modelling.
- Changes are reversed during Oestrogen therapy
Describe how calcium levels effect bone disease
- Recommended daily allowance of Calcium is 700mg/day
- Most adults only achieve 500 mg/day
- Post menopausal women require 1400 mg/day
- Negative calcium balance and reduced intestinal absorption have been demonstrated in post menopausal women
- Studies have shown that calcium supplementation has beneficial skeletal effects in post menopausal women. It is NOT a replacement for HRT.
Describe the use of biochemistry tests in bone disease
Normal biochemical profile except a raised alkaline
phosphatase
Osteocalcin (bone formation)
Pyridinoline cross-links (marker of bone turnover/resorption):
• cross-links in collagen released on breakdown of collagen
during bone turnover
• Measurements include:
– Urinary total pyridinoline (PYD)
– Urinary free deoxypyridinoline (DPD)
