044 - bone disorders

7/31/2019 044 - Bone Disorders

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OSTEOPOROSIS: Classic disorder of bone remodelling

Primarily affecting bone which is predominantly trabecular

OCs eroision of trabecular bone plates rod-like elements

These elements can then be perforated & eventually lost

Lateral elements of bone seem to be more vulnerarble to this process.

Cortical (compact) bone loss is due to:o Endosteal resorbtion > periosteal formation

o leads with age to thinner bone shafts with increased diameter.

Osteoporosis is a massive medical, social & economic problemo Esp. in Western countries with aging populations

Osteoporosis is less common in Afro-carribeans

White people tend to have a lower bone mass/density

Osteoporosis verterbral crush fracture 25% white women +60 years suffer from vertebral crush fractures:

Height loss

Pain

Hunchback appearance Dowagers hump

Very rarely fatal

Vertebral crush fractures are 10x more common in woman than men

Due to abrupt decline in circulating oestrogens after female menopause.

Andogens which exert similar bone-preserving actions in men decline moregradually with age.

Osteoporosis femoral neck fracture Hip-fracture

Have an associated mortality of 20% within the 1st year in UK

More common over age of 70

2x as common in women

MAIN RISK FACTORS FOR OSTEOPOROSIS:

Normal trabecular bone

of a 30 year old womanVertebral body trabecular bone

in 75 yr old woman with

osteoporosis

Trabecular bone

element eroded

by osteoclasts


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Oestrogen deficiency:o Menopause

o Oophorectomy (surgical removal of ovary)

Hypothalmic amenorrheao Lack of menstration due to e.g. excessive exercise

Hypogonadism in males Genetic - risk if white european

Family history

Small build / low body weight

Sedentary lifestyle (moderate weight-bearing exercise is beneficial)

Smoking / excessive alcohol / excessive caffeine

Drugs e.g. corticosteroids

Excessive protein intake

Chronic acidosis

Chronic respiratory disease

Metabolic acidosis: Promotes osteoporosis in 2 ways:

A. Cannot form 1,25-dihydroxyvitamin D

B. pH OC activity

Perhaps because breakdown of bone by OCs release of alkalinebone material which may be last ditch attempt to correct acidosis.

TREATMENT OF OSTEOPOROSIS

HRT in postmenopausal woman is effective in prevention of osteoporosis

When oestrogen ceases to be produced after the menopause, there is

increased OC activity & decreased OB activity

HRT replaces the lost oestrogen:

o bone mass

o bone turnover

o fracture incidence

o Effective at all skeletal sites

Also helps:

o Reduced cardiovascular disease

o Stops hot flushes

o Improves libido

o Improves cognitive function

o Slows onset of senile dementia


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Problems of HRT are:

o Patient compliance (due to unwanted effects like resumption of periods)

o risk of breast / endometrial cancer

o risk of venous thrombosis

o stroke

BUT these risks are not generally large, and the benefits often greatly outweigh

the negatives.

Still, need to balance risk, as >50% of women will not be at risk of osteoporosis

Other treatment options include:

o Biphosphonates

o Selective estradiol receptor modulators (SERMs)

o PTH effective but v. expensive

o Calcitonin

o Monoclonal antibodies against RANK ligand

o Calcium cheap, safe, but not v. effective

Bisphosphonate:

Very cheap to make

Stable anologue of pyrophosphate

Covers the surface of bone and kills osteoclasts when they try to resorb it.

Very potent & very effective at treating osteoporosis (not preventing)

Zoledronate is the newest only needs to be administered once anually Oral

BUT substantial risks with bisphosphonates (probably more so than HRT):

GI side effects

Atrial fibrilation (esp. if given IV)

Osteonecrosis of jaw esp. following dental extractions

Inflammatory eye disease

Also supress bone turnover:

o body is ubable to respond to wear/tear & maintain bone

May lead to fracture of femoral shaft with little trauma


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Calcium / vitamin D:

Only effective in those people who are deficient i.e. old ladies who have beeninstitutionalised in care homes

Risks:

risk of renal stones

risk of CVD

Parathyroid hormone (PTH):

Anabolic very effective at bone density

BUT v. expensive

Monoclonal antibodies to RANK ligand:

Targets RANK ligand which is essential for the differentiation of monocytic

precursors OCs

Twice yearly, subcutanous injections

Long-term side effects unknown.

Summary of treatment options:

HRT is the best for prevention

Biphosphonates are the best for treatmento But wouldnt prescribe bisphosphonates to young people, as long-term

side effects unknown.


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IMAGING OF OSTEOPOROSIS

Quantative, low-dose X-ray scanning systems (DEXTA) is used formonitoring bone density at spine & hip

This is the gold standard

CAT scan

Bone biopsy & histology (not always representative)

Ultrasound (not very good)

Biochemical markers e.g. urinary collagen X-links

OSTEOPETROSIS Osteoclast deficiency

Due to deficiency in carbonic anhydrase OCs cannot generate protons

impaired remodelling

growth defects:o Bones too thick & heavy

o Marble bone syndrome

o Failure of tooth eruption

RICKETS / OSTEOMALACIA Result from vitamin D deficiency

Rickets: childhood disease

Osteomalacia: adult disease Note the difference between osteomalacia & osteoporosis:

o Osteomalacia:

Proportion of mineralised bone matrix is reduced

But proportion of osteoid is increased

change in the composition of bone.o Osteoporosis:

Loss of bone but no change in mineralisation

I.e. the bone which remains has a normal composition

PAGETS DISEASE Characterised by overactive osteoclasts The OCs are:


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o Very large

o Large number of nuclei

May be due to infection by paramyxovirus e.g. measels

greatly accelerated bone reabsorption at certain focal sites

To compensate:

o bone production by OB, but the bone produced is disorganisedo Rapid bone production may trigger osteosarcoma

Presentation of Pagets disease:

Painful deformities often hot to touch

Treatment of Pagets diesease:

Effective treatment with:o Calcitonin

o Biphosphonates

Distribution: Strange distribution

Non-existant in several countries

Common in NW England, especially in people who own dogs

OSTEOGENESIS IMPERFECTA Brittle bone disease

Heritable disorders of type I collagen synthesis

Mutations in genes encoding constituent 1 & 2 chains:

o Mutation of buried Gly residue Cys Triple-helix partially unfolded at N-terminal

Regular packing of tropocollagen cannot occur weaker collagen

Brittle bones & skeletal deformities.

Severity varies greatly, depending on type of mutation:o Prenatal lethality

o Impaired stature

o Impaired tooth development

o Hearing loss

o Blue sclera

o Minimal deformity

CANCERS OF BONE: Osteosarcoma:

o OB tumour

o Usually aggressive

o More common in younger individuals

Oseoclastoma:o No metastasis (benign)

o But can cause rapid local destruction of bone


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Bone cancer is often secondary i.e. cancer in other organs has a propensity tometastasise to bone.

Tumour cells often produce:o OC stimulating cytokines

o Pho PTH-related peptide

This leads to increased osteoclast activity bone resobtion

fractures & hypercalcaemia.

SCLEROSTEOSIS: Sclerostin = natural inhibitor of Wnt proteins which cause connective tissue

cells to differentiate into OBs

Sclerosteosis = rare, autosomal recessive genetic disease

Mutation in sclerostin gene no inhibiton of Wnt protein OB bone

formation bone overgrowth More common in Afrikaner families

044 - bone disorders

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