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Umar Zein

Two Components of the Bone

Cortical Bone
 Dense and compact
 Runs the length of the long bones, forming a hollow
Trabecular bone
 Has a light, honeycomb structure
 Trabeculae are arranged in the directions of tension and
 Occurs in the heads of the long bones
 Also makes up most of the bone in the vertebrae


Principal organizing feature of compact bone
 Haversian canal – place for the nerve blood
and lymphatic vessels
 Lamellae – collagen deposition pattern
 Lacunae – holes for osteocytes
 Canaliculi – place of communication between

Bone Cells

Osteocytes - derived from
osteoprogenitor cells
 Osteoblasts
 Osteoclasts


Trapped osteoblasts
 In lacunae

Keep bone matrix in good condition and can release
calcium ions from bone matrix when calcium demands

Osteocytic osteolysis

Osteoblasts     Make collagen Activate nucleation of hydroxyapatite crystallization onto the collagen matrix. they transform into osteocytes Stimulate osteoclast resorptive activity . forming new bone As they become enveloped by the collagenous matrix they produce.

Osteoclasts      Resorb bone matrix from sites where it is deteriorating or not needed Digest bone matrix components Focal decalcification and extracellular digestion by acid hydrolases and uptake of digested material Disappear after resorption Assist with mineral homeostasis .

Chemistry of the Bone Matrix  Mineral  .

Matrix .Osteoid    Collagen type I and IV Layers of various orientations (add to the strength of the matrix) Other proteins 10% of the bone protein  Direct formation of fibers  Enhance mineralization  Provide signals for remodeling .

K .Mineral   A calcium phosphate/carbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2 Hydroxyapatite crystals  Imperfect  Contain Mg. Na.

followed by its conversion to crystalline hydroxyapatite Mechanisms exist to both initiate and inhibit calcification .Mineralization of the Bone   Calcification occurs by extracellular deposition of hydroxyapatite crystals  Trapping of calcium and phosphate ions in concentrations that would initiate deposition of calcium phosphate in the solid phase.

Bone Remodeling Process  Proceeds in cycles – first resorption than bone formation  The calcium content of bone turns over with a half-life of 1-5 years .

Bone Remodeling Process .

Coordination of Resorption and Formation  Phase I  Signal from osteoblasts  Stimulation of osteoblastic precursor cells to become osteoclasts  Process takes 10 days .

Coordination of Resorption and Formation   Phase II  Osteoclast resorb bone creating cavity  Macrophages clean up Phase III  New bone laid down by osteoblasts  Takes 3 months .

Pathways of Differentiation of Osteoclasts and Osteoblasts .

Hormonal Influence      Vitamin D Parathyroid Hormone Calcitonin Estrogen Androgen .

25-(OH)2-D) Increases activity of both osteoblasts and osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased intestinal calcium absorption Feedback action of (1.25-(OH)2-D) represses gene for PTH synthesis .Vitamin D      Osteoblast have receptors for (1.

Parathyroid Hormone     Accelerates removal of calcium from bone to increase Ca levels in blood PTH receptors present on both osteoblasts and osteoclasts Osteoblasts respond to PTH by  Change of shape and cytoskeletal arrangement  Inhibition of collagen synthesis  Stimulation of IL-6. macrophage colony-stimulating factor secretion Chronic stimulation of the PTH causes hypocalcemia and leads to resorptive effects of PTH on bone .

32 aa Synthesized from a large preprohormone Rise in plasma calcium is major stimulus of calcitonin secretion Plasma concentration is 10-20 pg/ml and half life is 5 min .Calcitonin      C cells of thyroid gland secrete calcitonin Straight chain peptide .

Actions of Calcitonin    Osteoclasts are target cells for calcitonin Major effect of calcitonin is rapid fall of plasma calcium concentration caused by inhibition of bone resorption Magnitude of decrease is proportional to the baseline rate of bone turnover .

Definition A systemic skeletal disease characterized by low bone mass and micro architectural deterioration of bone tissue lead to bone fragility and susceptibility to fracture .

J Bone Miner Res.1997 Melton L.1992 . J. J Bone Miner Res.Prevalence of osteoporosis Osteopenia Osteoporosis Female Age > 50 year 37-50% 13-18% Male Age > 50 year 28-47% 3-6% NHANES III.

Incidence of osteoporotic Fx Vertebral Fracture Forearm Fracture Hip Fracture .

No Bones About It 25 .

” 26 .Typical comments from people with osteoporosis “I’ve lost six inches in height and none of my clothes fit me anymore.

.Pathogenesis Q ui ckT i me™ and a TI FF ( Uncompressed) decompressor are needed to see thi s pi ct ure.

Pathogenesis .

Pathogenesis Quic kTime™ and a TIF F (Unc ompressed) dec ompressor are needed to see this pic ture. Microdamage Peak bone mass Quic kTime™ and a TIF F (Unc ompressed) dec ompressor are needed to see this pic ture. Precipitating factors Loss of Estrogen .

Diagnosis of osteoporosis .

Diagnosis of Osteoporosis   Physical examination Measurement of bone mineral content Dual X-ray absorptiometry (DXA) Ultrasonic measurement of bone CT scan Radiography .

Physical examination        Osteoporosis Height loss Body weight Kyphosis Humped back Tooth loss Skinfold thickness Grip strength Vertebral fracture Arm span-height difference Wall-occiput distance Rib-pelvis distance .

Green.Physical examination Amanda D. JAMA 2001 vol.292(23) .

1 WO distance > 0 cm 4.6 2.9-7.4 1.Physical examination LR +ve 95% CI Wt < 51 kg 7.2-4.8 2.0-10.3 5.1 Amanda D.0 2.4-8.292(23) .0 RP distance < 2 FB 3. JAMA 2001 vol.3 Humped backed 3. Green.8 Tooth < 20 3.9-5.

Green.292(23) . JAMA 2001 vol.Physical examination No single maneuver is sufficient to rule in or rule out osteoporosis or vertebral fracture without further testing Amanda D.

Dual X-ray absorptiometry 2-dimensional study BMD = Amount of mineral Area Accuracy at hip > 90% Low radiation exposure Error in Osteomalacia Osteoarthritis Previous fracture .

Dual X-ray absorptiometry WHO criteria .Hip BMD Normal Low bone mass (Osteopenia) Osteoporosis Severe osteoporosis .

5 .5 SD below PLUS Fracture </= -2.5 SD below < -1 > -2.5 Osteoporosis >/= 2.5 SD below Severe osteoporosis >/= 2.Dual X-ray absorptiometry Normal Low bone mass ( Osteopenia ) BMD compare with young adult female T score < 1 SD below >/= -1 1-2.

Ultrasonic measurement Broad-band ultrasound attenuation or ultrasound velocity No radiation exposure Cannot be used for diagnosis Preferred use in assessment of fracture risk .

CT scan True volumetric study Most useful in cancellous bone assessment Avoid effect of degenerative disease Drawback High cost .

Plain radiography Q ui ckT i me™ and a TI FF (Uncompressed) decompressor are needed to see thi s pi ct ure. Low sensitivity High availability Subclinical vertebral fracture is a strong risk factor for subsequent fractures at new vertebral site and other sites .

heparin) Malignancies (metastatic disease.Who Gets Osteoporosis?                   Age Estrogen deficiency Testosterone deficiency Family history/genetics Female sex Low calcium/vitamin D intake Poor exercise Smoking Alcohol Low body weight/anorexia Hyperthyroidism Hyperparathyroidism Prednisone use Liver and renal disease (think about vit d synthesis) Low sun exposure Medications (antiepileptics. multiple myeloma can present as osteopenia!) Hemiplegia s/p CVA/ immobility .

Fracture Reduction   Goal: prevent fracture. not just treat BMD Osteoporosis treatment options       Calcium and vitamin D Calcitonin Bisphosphonates Estrogen replacement Selective Estrogen Receptor Modulators Parathyroid Hormone .

1500 mg/day in postmenopausal women/osteoporosis Vitamin D (25 and 1.Osteoporosis Treatment: Calcium and Vitamin D      Fewer than half adults take recommended amounts Higher risk: malabsorption. renal disease.  Frail older patients with limited sun exposure may need up to 800 IU/day . liver disease Calcium and vit D supplementation shown to decrease risk of hip fracture in older adults 1000 mg/day standard.25): 400 IU day at least.

Osteoporosis Treatment: Calcitonin    Likely not as effective as bisphosphonates 200 IU nasally/day (alternating nares) Decrease pain with acute vertebral compression fracture .

Osteoporosis Treatment: Bisphosphonates       Decrease bone resorption Multiple studies demonstrate decrease in hip and vertebral fractures Alendronate. risodronate IV: pamidronate. malignancy related fractures. and multiple myeloma related osteopenia) Ibandronate (boniva): once/month Those at highest risk of fracture (pre-existing vertebral fractures) had greatest benefit with treatment . zolendronate (usually used for hypercalcemia of malignancy.

Bisphosphonate Associated Osteonecrosis (BON)     Jaw osteonecrosis Underlying significant dental disease Usually associated with IV formulations Case reports associated with oral formulations .

benign strictures.Bisphosphonates: Contraindications   Renal failure Esophageal erosions    GERD. recommendations to drink water after and not lie down at least 30 minutes Reality: no increased GI side effects compared to placebo group in multiple studies . most benign GI problems are NOT a contraindication Concern for esophageal irritation/erosions from direct irritation.

Osteoporosis Treatment: Estrogen Replacement    Reduction in bone resorption Proven benefits in treatment FDA approval. cancer) . now limited because of recent concerns from HERS trial and other data suggesting possible increased cardiac risk.

Osteoporosis Treatment: Selective Estrogen Receptor Modulators      Raloxifene FDA recommended Decrease bone resorption like estrogen No increased risk cancer (decrease risk breast cancer) Increase in vasomotor symptoms associated with menopause .

studies with increased density but increased fracture risk/fragility with flouride show that just building up bone is not enough!!! .Osteoporosis Treatment: PTH    Teriparatide Why PTH when well known association with hyperparathyroidism and osteoporosis??? INTERMITTENT PTH: overall improvement in bone density  Optimal bone strength relies upon balance between bone breakdown and bone build up.

those who can not tolerate oral bisphosphonate Optimal effect requires bone uptake Not for use in combination with Bisphosphonate!  May need to stop bisphosphonate up to 1 year prior . those on bisphophonates for 7-10 years.Intermittent PTH: Teriparatide       Studies suggest improved BMD and decreased fractures risk osteosarcoma with prolonged use (over 2 years): studies with rats SQ. expensive Option for severe osteoporosis.

Decrease risk of break: hip protectors 3.Reducing Fractures    1. Decrease osteoporosis/improve BMD 2. Decrease risk of fall .

Hip Protectors     Padding that fits under clothing Multiple studies demonstrate effectiveness at preventing hip fractures Likely cost effective Problem: adherence! .

Falls Reduction   Falls are a marker of frailty Hip fracture is a marker of frailty   Mortality after hip fracture:?due to hip fracture or hip fracture as marker for those who are declining? Increased risk of falls:         Prior fall (fear of falling) Cognitive decline Loss of vision Peripheral neuropathy Weakness Stroke Medications: anticholinergics. benzos… ETOH . tcas.

Hip Fracture Prevention: Falling How do Younger Adults Fall? 56 .

Hip Fracture Prevention: Falling How do Older Adults Fall? 57 .

Hip Fracture Prevention: Hip Protectors 58 .