Uoa Endo - Metabolic Bone Disease

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OSTEOMALACIA definition :

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A generalised skeletal disorder characterised by the accumulation of osteoid matrix which fails to mineralise.

Nb

osteoid is the unmineralized, organic portion of the bone matrix that forms prior to the maturation of bone tissue. Osteoblasts begin the process of forming bone tissue by secreting the osteoid as several specific proteins.

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OSTEOMALACIA Aetiology : A wide variety of causes, which fall into three categories:

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Calcium Deficiency

Phosphate Deficiency

Osteoblast Failure

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OSTEOMALACIA Aetiology : A wide variety of causes, which fall into three categories:

Calcium Deficiency

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This group is commonly associated with abnormalities of Vitamin D metabolism

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active VitD aka calcitriol 1.25(OH)2D is made in the kidney in response to what

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increased PTH or decreased phosphate

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Calcitriol is required for normal absorption of

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calcium (and phosphate) from the gut

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The main circulating form of Vitamin D is the immediate precursor to Calcitriol - 25OHD (Calcidiol) - which is synthesised in the

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liver

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The main source of Vitamin D (the precursor of calcidiol) is the

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skin, by the action of ultraviolet light on 7-dehydrocholesterol

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Abnormalities of Vitamin D metabolism causing osteomalacia:-

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• not enough sun (elderly/institutionalised)
• inadeq. dietary Vit D (esp. if no sun)
• increased b/d of calcidiol in liver and kidney
• 1alpha hydroxylase abn. in the kidney
• receptor problem to active vitD (eg in SI)

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what type of vitamin D do you get from sun + skin and from diet

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celciferol

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the liver converts calciferol into

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calcidiol

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EXPLAIN

• increased b/d of calcidiol in liver and kidney

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This occurs as a result of chronic calcium deprivation (diet or gastrectomy or malabsorption), which produces secondary hyperparathyroidism and chronically increased calcitriol (via Ca release from bone via action of PTH).

This, in turn, promotes catabolism of 25OHD and ultimately 25OHD deficiency.

Anticonvulsant drugs can induce the liver enzymes that catabolize vitamin D precursors.

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EXPLAIN

• increased b/d of calcidiol in liver and kidney

summary

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chronic calcium deprivation = hyperPTH = increase active VitK = promotes b/d calcidiol and ultimately calcidiol deficiency.

Anticonvulsant drugs can induce the liver enzymes that catabolize vitamin D precursors.

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EXPLAIN

• 1alpha hydroxylase abn. in the kidney

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remember this enz converts calcidiol to calcitriol so if the enz has a defect = low active vit. D

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EXPLAIN

• 1alpha hydroxylase abn. in the kidney

what are the categories

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it can be:

Inherited (vitamin D dependent rickets type 1) or

Acquired (chronic renal failure)

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Explain

• Failure of 1.25(OH)2D to act due to receptor abnormality (Vitamin D dependent rickets type II).

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just a receptor problem

theres nothing wrong with active VitK, its just the receptor ie VitD receptor in the intestine not binding VitK

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define rickets

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defective mineralization or calcification of bones before epiphyseal closure due to deficiency or impaired metabolism of vitamin D, phosphorus or calcium, potentially leading to fractures and deformity.

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rickets features

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common in kids usu. suffering severe malnutrition

most common cause = vitD deficiency

it can also be caused by low diet calcium

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can rickets happen in adults

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yes, but its mainly in kids

the key is the epiphesial plates - as long as they havent closed then adults can get, when it does close the condition becomes osteomalacia

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difference b/w rickets and osteomalacia

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mainly the EPIPHYSEAL PLATES

rickets is defective mineralisation/calcificxn of bone before the epiphyseal plates close

osteomalacia is defective mineralisation/calcificn of bone after the epiphyseal plates have closed

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OSTEOMALACIA Aetiology : A wide variety of causes, which fall into three categories:

Phosphate deficiency

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Commonly associated with impaired renal tubular phosphate re-absorption

Usually congenital and involving phosphate transport alone (Vitamin D resistant rickets) or with multiple renal tubular defects (Fanconi syndrome)

Can also be acquired (tumour osteomalacia).

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whats Vitamin D resistant rickets

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congenital condition - where genetic mutation results in kidney not being able to resorb only phosphate properly

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whats fanconi syndrome

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general defect/prob. with the renal proximal tubules not being able to resorp all the stuff it normally resorbs there which end up in the urine

eg glucose, amino acids, uric acid, phosphate and bicarbonate

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OSTEOMALACIA Aetiology : A wide variety of causes, which fall into three categories:

Phosphate deficiency is commonly associated with

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impaired renal tubular phosphate re-absorption

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OSTEOMALACIA Aetiology : A wide variety of causes, which fall into three categories:

Phosphate deficiency - is caused usually by a congenital or acquired cause

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congenital

eg Vitamin K resistant rickets, Falconi syndrome

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OSTEOMALACIA Aetiology : A wide variety of causes, which fall into three categories:

Phosphate deficiency - acquired causes are rare - name one

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Tumor-induced osteomalacia, also known as oncogenic hypophosphatemic osteomalacia or oncogenic osteomalacia, is an uncommon disorder resulting in increased renal phosphate excretion, hypophosphatemia andosteomalacia

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OSTEOMALACIA Aetiology : A wide variety of causes, which fall into three categories:

Osteoblast Failure

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The osteoblasts are the cells which lay down the osteoid and are responsible for mineralising it.

Abnormal osteoblast function, either congenital (hypophosphatasia) or acquired (continuous etidronate therapy, aluminium toxicity) can also cause osteomalacia

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OSTEOMALACIA Aetiology : A wide variety of causes, which fall into three categories:

Osteoblast Failure- what are some congenital causes

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hypophosphatasia = rare, and sometimes fatal metabolic bone disease, congenital prob. with osteoblast

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OSTEOMALACIA Aetiology : A wide variety of causes, which fall into three categories:

Osteoblast Failure- what are some acquired causes

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continuous etidronate therapy, aluminium toxicity

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OSTEOMALACIA Aetiology : A wide variety of causes, which fall into three categories:

Osteoblast Failure- what are some acquired causes

discuss aluminiun toxicity

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Aluminium toxicity is most commonly seen in dialysis patients (exposure through dialysate, phosphate binding drugs, plus inability to excrete)

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clinical features of osteomalacia

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• Differ according to age.
• In the growing skeleton, osteomalacia causes the syndrome of rickets, characterised by deformity, growth retardation and painful, swollen, epiphyses.
• In adults, bone pain is the main feature.
• Osteomalacic bone is liable to fracture

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clinical features of osteomalacia

In the growing skeleton, osteomalacia causes the syndrome of rickets, characterised by

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deformity, growth retardation and painful, swollen, epiphyses

plus fracture

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clinical features of osteomalacia

in adults what the main feature of osteomalacia

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BONE PAIN

to lesser extent fracture

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Osteomalacic bone is liable to

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fracture

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Osteomalacia biochemistry results for calcium deficiency

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• Plasma Calcium = decrease
• Phosphate = N/decreased
• ALP = doubly increased
• PTH increased
• 25OHD (calcidiol) = reduced (Normal where 1 hydroxylation or 1.25(OH)2D receptor is the problem)

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Osteomalacia biochemistry results for phosphate deficiency

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Plasma calcium = normal

Phosphate = doubly decreased

ALP = doubly increased

25OHD (calcidiol) = normal

PTH = normal

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Osteomalacia biochemistry results for osteoblast failure

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Plasma calcium = normal/increased

phosphate = normal

ALP = normal/decreased

25OHD = normal

PTH = normal/decreased

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Radiology findings with osteomalacia or rickets

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 Rickets - easily recognisable, with epiphyseal abnormalities.
 In adults, osteomalacic bones may simply look osteopenic.
 Fractures are common.
 Looser‟s zones (pseudo-fractures), rare but diagnostic.

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osteomalacia tx

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tx underlying cause ie calcium deficiency, phosphate deficiency/osteoblast failure

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osteomalacia tx

Calcium deficiency

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extra calcium with either Vitamin D (where plasma 25OHD is low - just sounds like calcidiol) or with 1alpha hydroxylated derivatives (where the main problem arises as a result of defective 1.25(OH)2D production - just sounds like active vitamin D).

calcium + Vitamin D/1alpha hydroxylated derivatives

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osteomalacia tx

Phosphate deficiency

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Phosphate + 1alpha hydroxylated Vitamin D derivatives

Surgery if tumor induced osteomalacia

nb 1alpha hydroxylated Vitamin D derivatives (just sounds like active Vit. D cause its role is to enhance gut absorp.)

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osteomalacia tx

Phosphate deficiency - if its due to an acquired cause of tumour induced osteomalacia- would the tx change

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yes, do surgery

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osteomalacia tx

Osteoblast failure

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withdraw causative agent if possible.

Aluminium can be depleted from bone by desferrioxamine

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PAGET’S DISEASE

Definition

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A focal disorder characterised by greatly increased rates of bone resorption and formation in affected bones followed by disorganized bone remodeling

This causes affected bone to weaken, resulting in pain, misshapen bones, fractures and arthritis in the joints near the affected bones

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PAGET’S DISEASE

Epidemiology

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• Largely a disease of older white people

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PAGET’S DISEASE causes

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unknown

but may be genetic factors (strong familial tendency) and enviro. factors

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PAGET’S DISEASE - clinical features

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• asymp (common)
• bone pain (common)
• bone deformity/soft
• long bone fractures
• painful fissure fractures
• OA - esp hip and knee

others

• deafness +/- other cranial nerve probs
• increased vascularity over bone thus skin temp increased
• if severe = high output HF and immobilisation hypercalcemia

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PAGET’S DISEASE - clinical features common

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asymp, bone pain, soft bone, long bone fractures and OA

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PAGET’S DISEASE dx

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XR

scintigraphy - extent of disease

biochemistry - increased bone turnover markers

bone biopsy - histology reqd to confirm dx

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PAGET’S DISEASE dx - for biochemistry markers of increased bone turnover what are you looking at

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increased levels of:

• ALP,
• AST,
• Ca,
• Ph,
• urine Pyridinoline,
• serum and urinary hydroxyproline

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PAGET’S DISEASE dx - whats needed to confirm dx

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bone biopsy

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PAGET’S DISEASE - natural hx

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• one or more bones affected more or less simultaneously
• tends to spread thru a bone rather across bones
• rare but may transform to osteosarcoma

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PAGETS disease - tx aims

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• Anti-osteoclastic drugs which reduce bone resorption and produce a secondary decrease in bone formation.

• Are effective in relieving pain, reducing bone turnover and healing lytic lesions.

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PAGETS disease - tx

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• Bisphosphonates (Alendronate, Risedronate, Zoledronate are available in NZ).

oral/IV - all equally effective with right dose

tx not curative, can have relapses

surgery for fractures and joint r/t for OA

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PAGETS disease - tx: which bisphosphonates are available in NZ

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Alendronate, Risedronate, Zoledronate are available in NZ

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PAGETS disease - tx: how are bisphosphonates available in NZ administered

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oral/IV

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PAGETS disease - tx: are the bisphosphonates curative

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NO, can still get relapses, thus get repeat courses

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PAGETS disease - tx: when is surgery indicated

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fractures and joint r/t for OA (due to pagets)

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to confirm dx of pagets you need to confirm it histologically - what do you look for in the histology

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• increased Bone Resorption and Bone Formation
• increased osteoclast numbers and osteoblast numbers
• giant osteoclasts
• woven bone
• marrow fibrosis
• woven osteoid

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what are key features in biochemistry helpful in dx pagets disease

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increased β-CTX

increased alkaline phosphatase, P1NP

nb

P1NP is a marker for bone formation

β-CTX= b/d product of bone resorption

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what key features are you looking for on XR to help dx pagets disease

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• lysis
• sclerosis