17032012 Pleno PakaPc3Blok DMS

Dept.Farmakologi & TherapeutikFak.Kedokteran USU

Medan

Bone• Bone composition

– 70% mineral (Ca2+ and PO4- as hydroxyapatitie)

– 22% protein (95% Type I collagen + 5% proteoglycans and other materials)

– 8% water• Two major types of bone

– Compact (cortical, i.e., long bones)• Mechanical and protective functions

– Cancellous (spongy, i.e., vertebrae)• Metabolic regulation of calcium

• Four types of cells– Osteoblasts– Osteoclasts– Osteocytes– Bone lining cells

Osteoporosis

• Defined as reduction in bone mass and micro-architecture that leads to susceptibility to fracture

Normal Osteoporotic

Issue of Peak Bone Mass

• Bone mass peaks in the 20’s, starts dropping in the late 30’s and accelerates significantly after menopause

• Risk for osteoporosis depends on peak mass and rate of loss

• Peak bone mass depends on– Genetics– Calcium, diet, exercise, etc. in youth

Two Components of the Bone• Cortical Bone

– Dense and compact– Runs the length of the long bones, forming a hollow

cylinder• Trabecular bone

– Has a light, honeycomb structure– Trabeculae are arranged in the directions of tension

and compression– Occurs in the heads of the long bones– Also makes up most of the bone in the vertebrae

Osteons

• 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

osteocytes

Bone Cells

• Osteocytes - derived from osteoprogenitor cells– Osteoblasts– Osteoclasts

• Osteocytes:• Trapped osteoblasts

– In lacunae• Keep bone matrix in good condition and can release calcium

ions from bone matrix when calcium demands increase– Osteocytic osteolysis

Osteoblasts

• Make collagen• Activate nucleation of hydroxyapatite

crystallization onto the collagen matrix, forming new bone

• As they become enveloped by the collagenous matrix they produce, they transform into osteocytes

• Stimulate osteoclast resorptive activity

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

Mineral

• A calcium phosphate/carbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2

• Hydroxyapatite crystals– Contain Mg, Na, K

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, followed by its conversion to crystalline hydroxyapatite

• Mechanisms exist to both initiate and inhibit calcification

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

Hormonal Influence

• Vitamin D• Parathyroid Hormone• Calcitonin• Estrogen• Androgen

Vitamin D

• Osteoblast have receptors for (1,25-(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

7- dehydrocholesterol Vit D3 (cholecalciferol)

UV

Vit D3 25 (OH)D3 (calcifediol)

Vit D3Exogen.

25 (OH) D3)

1,25(OH2)D3(calcitriol)

Skin

Liver

KidneyDecreased PO4. -

Exogen.Calcifediol

+

+

Calcitriol in bloodParathyroid

Blood Ca++

Biological actions +

+

+

––

Antiresorptive Therapy

• Most forms of osteoporosis are a consequence of bone loss due to an imbalance in bone remodeling such that bone resorption exceeds bone formation. By decreasing the number, activity, and life span of osteoclasts, several therapeutic agents suppress bone resorption and, indirectly, bone formation.

• These antiresorptive agents are capable of preserving bone mass, stabilizing bone structure and quality, and reducing fracture rates.

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

Parathyroid Hormone

• PTH acts directly to increase renal tubular calcium reabsorption and indirectly to enhance intestinal calcium absorption via its stimulatory action on renal 1-α cholecalciferol hydroxylase (thereby increasing circulating calcitriol). The normal physiological role of PTH on skeletal homeostasis, when secreted endogenously, is more complex but probably serves to regulate bone remodeling rather than overall skeletal mass.

• PTH exhibits potent anabolic effects on the skeleton when given exogenously by intermittent injection

• the observation that architectural improvements do occur within the skeleton after daily PTH injections

Parathyroid hormone

• Intermittent injection stimulate new bone formation CONTRAST to continuous infusion

• Teriparatide ( rhPTH[1-34] ) was approved by US-FDA for Rx of osteoporosis

• Transient dose-related hypercalcemia• Long term effects are not known

Calcitonin

• C cells of thyroid gland secrete calcitonin• Straight chain peptide - 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

• Peptide from Thyroid C cell• Direct inhibition of osteoclast activity• Less effective in cortical bone• Salmon calcitonin nasal spray• Dose 200 IU/day• calcitonin has inherent analgesic properties,

and may be useful in the early post fracture period;

Calcitonin

• Mechanism of Action: - calcitonin is potent inhibitor of osteoclastic bone resorption; - in bone, major action is inhibition of osteoclastic bone resorption; - calcitonin inhibits bone resorption and slows down rate of bone loss; - osteoclasts escape from the inhibitory effects of calcitonin following continued exposure;

Other Systemic Hormones

• Estrogens– Increase bone remodeling

• Androgens– Increase bone formation

• Growth hormone– Increases bone remodeling

• Glucocorticoids– Inhibit bone formation

• Thyroid hormones– Increase bone resorption– Increase bone formation

Local Regulators of Bone Remodeling

• Cytokines– IL-6– IL-1

• Prostaglandins• Growth factors

– IGF-I– TGF-β

Available treatment

• Calcium and vitamin D• Hormone replacement therapy• Selective estrogen receptor modulators

( SERMs )• Bisphosphonates• Calcitonin• Parathyroid hormone• Other treatments• Non-pharmacologic intervention

Calcium

1994 consensus on optimum calcium intake

Daily calcium intake

Adolescents 1200-1500 mg

Adult up to 65 years 1000 mg

Postmenopausal women

Elderly

1500 mg

Calcium preparations

Elemental calcium

Calcium citrate 60mg/300mg

Calcium lactate 80mg/600mg

Calcium gluconate

40mg/500mg

Calcium carbonate

400mg/g

Calcium carbonate + 5 mcg Vit D2

250mg/tablet

Vitamin D

• Essential for intestinal absorption of calcium

• Daily recommendation400 - 800 IU/day

Esp. Low sunlight exposure, elderly, low vitamin D intake

• ? Decreased risk of fracture in healthy elderly with normal intake & BMD

Hormone Replacement Therapy (HRT)

Estrogen Replacement TherapyMekanisme kerja: = estrogen mengurangi resorbsi tulang dg cara: -menekan transkripsi sitokin spt IL-6 yang menginduksi proliferasi,differensiasi dan aktifasi osteoklast. -juga mempercepat apoptosis osteoclast. = lifespan dari osteoblast dan osteocytes di (diperpanjang)

Estrogen tidak meningkatkan bone formation---- estrogen is more effective at preventingthan restoring.

Effek samping estrogen:

Sering menjadi masalah,sehingga pasien jadi drop-out. = reinitiation of uterine bleeding = breast pain,breast tendernessEstrogen also increases; = venous thromboembolism = long-term risk of breast cancer

National Institute of Health ( 2002):mendapati bahwa dengan HRT,terjadi: =peningkatan risiko : -penyakit kardiovaskuler - dan kanker payudara lebih berbahaya dibanding efek anti osteoporosis nya

Hormones – cont’d• As of recent WHI study,• estrogen-progesterone therapy no longer

first-line approach for osteoporosis treatment in postmenopausal women due to increased risk of breast cancer, stroke, VTEs, and possibly CAD.

• Indications: • persistent menopausal symptoms,• inability to tolerate other options,• failure to respond to other options.

• ± Rp.300.000/bulan

Risk of osteoporosis ↑

No HRT Reassess/ Year

Contraindications to HRT ?

Increassed risk ofBreast cancer ?

Consider bisphos.Raloxifene, etc.Reassess yearly

Coronary heart disease present ?

Consider bisphos.Raloxifene, etc.Reassess yearly

No Yes

No Yes

No Yes

HRT or alternativeApproaches: reassess yearly

Consider bisphos.Raloxifene, etc. Reassess yearly

No Yes

So, in case HRT is to be given:

Ask and explain carefully: = no contraindication = if neccesary; letter of consent = perform Pap’s smear before and routinely afterward = do mammography routinely

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

Merupakan kelompok obat yang: = mengikat reseptor estrogen = bersifat tissue-selective====Contoh: -raloxifene---- estrogen agonist in bone - estrogen antagonist in breast - inactive in endometrium

Note: Estrogen Receptor (ER): 1. ESR1---ERα , found in uterus,vagina,ovaries, - mammary glands,vascular 2. ESR2---- ERβ, found in prostate,bone,lung,brain - vascular

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

Raloxifene:

Increase BMD in vertebral and non-vertebral; = vertebral fracture risk decrease

= non-vertebral fracture risk ?? = lowers LDL cholesterol

However: like estrogen,raloxifene increasethe risk of venous thromboembolism

Preparation: Evista; 6o mg,once daily- Rp 500/bulan

Parathyroid Hormone (PTH)

= Principal regulator of calcium homeostasis

= Stimulates bone formation

= Used alone or in combination with antiresorptive agents

= Potent effect on fractures: reduction of 65 - 69% in vertebral fractures and 35 - 45% in nonvertebral fractures 1

Bisphosphonates

Benefit• Potent inhibitor of

bone resorption• Reduce

osteoclast recruitment&activity

• Safe• Most effective

Rx**

RiskLow oral bioavailability (1-3%)Food, calcium, iron, coffee, tea, orange juice decreased absorptionGI discomfortRarely - esophagitisHigh cost

Bisphosphonates

• The antiresorptive effects appear to result from their inhibition of the enzyme farnesyl pyrophosphate synthase (FPPS) in osteoclasts. FPPS is a key enzyme in the mevalonate pathway, which generates isoprenoid lipids utilized for the post-translational modification of small GTP-binding proteins that are essential for osteoclast function. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity.

Other treatment

• Fluoride• Vitamin K2• Strontium ranelate

Meunier PJ. The effect of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. NEJM 2004;350:459-68

• Statins

Exercise&Osteoporosis

• Exercise effectAdolescent - Increased peak

bone mass Elderly - Small increase in BMD Fitness may prevent falling ?

• Evidence-based dataReduction of hip&leg

fractures in observational studies

Effects of Exercise on Bone• Two types of studies conducted

– Compare trained athletes with sedentary people • Athletes and chronic exercisers have higher BMD• Competitive runners in 60s have ~40% greater BMD

than controls• Weight lifters have 10-35% greater spine BMD• Tennis players have 30% greater thickness of

dominant humerous– Correlate level of fitness with BMD (Effect not obvious)

• Early life experience is important (Peak BMD)– Women who get hip fractures have lower levels of

occupational or leisure activity from 15-45 years old– Significant associations between hip BMD and early-life

exercise both men and women

Consult your doctor first

Other measures

• Treat predisposing factors• Fall prevention

Correct visual impairmentAvoid drugs - BZs,

hypnotics, antidepressant, drugs cause hypotension Extrinsic factors

• External hip protectorDecrease the risk of hip

fracture by 50% in 2 small studies

Thank You.