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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.

Trabecular bone element eroded by osteoclasts

Normal trabecular bone of a 30 year old woman

Vertebral body trabecular bone in 75 yr old woman with osteoporosis

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 problem o 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 more gradually 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:

Oestrogen deficiency: o Menopause o Oophorectomy (surgical removal of ovary) Hypothalmic amenorrhea o 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 alkaline bone 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 o o o bone mass bone turnover fracture incidence Effective at all skeletal sites

Also helps: o o o o o Reduced cardiovascular disease Stops hot flushes Improves libido Improves cognitive function Slows onset of senile dementia

Problems of HRT are: o o o o Patient compliance (due to unwanted effects like resumption of periods) risk of breast / endometrial cancer risk of venous thrombosis 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 o o o o o Biphosphonates Selective estradiol receptor modulators (SERMs) PTH effective but v. expensive Calcitonin Monoclonal antibodies against RANK ligand 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

Calcium / vitamin D: Only effective in those people who are deficient i.e. old ladies who have been institutionalised 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 treatment o But wouldnt prescribe bisphosphonates to young people, as long-term side effects unknown.

IMAGING OF OSTEOPOROSIS Quantative, low-dose X-ray scanning systems (DEXTA) is used for monitoring 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

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

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

Characterised by overactive osteoclasts The OCs are:

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 disorganised o 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

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

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

Bone cancer is often secondary i.e. cancer in other organs has a propensity to metastasise to bone. Tumour cells often produce: o OC stimulating cytokines o Ph o PTH-related peptide This leads to increased osteoclast activity bone resobtion fractures & hypercalcaemia.

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