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(1)

CHAPTER 12

뼈건강 개선

(2)

Functions of Bone

• Structural

– Support – Protection – Movement

• Mineral Storage

– Calcium – Phosphate

(3)

Skeletal Problems

• Disease / genetics

– Osteoporosis (Type I) – Multiple myeloma

– Metastatic bone cancer – Rheumatoid arthritis – Paget’s Disease

• Hormone ablative therapy

• Spinal cord or nerve injury

• Surgery and rehabilitation

• Aging (Type II Osteoporosis)

• Bedrest

• Microgravity

(4)

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

(5)

제1절 골다공증 개선

(6)

1. 골다공증의 정의 및 개요

골다공증

뼈로부터 칼슘의 배출로 인해 뼈의 밀도와 강도가 약해지게 되어 골절 가능성 이 높은 상태

(7)

골다공증의 원인

- 호르몬 불균형 - 노화

- 기타 위험인자 - 뼈의 교체율 증가

(8)
(9)

골밀도의 정도

- 세계보건기구에서 정한 기준에 따라 같은 인종과 같은 성별의 젊은 사람의 평균 골밀도에서 위, 아래 표준편차를 나타내는 T값으로 표시

- T값이 -2.5 미만일 경우 골다골증으로 진단

(10)

Background

• The problem

– Osteoporosis is common

– Over 50% of women and 30-45% of men over age 50 have osteopenia/osteoporosis

– White woman over age 50: 50 % lifetime risk of osteoporotic fracture, 25% risk vertebral fracture, 15% risk of hip fracture

– Man over age 60 has 25% risk osteoporotic fracture – 70% over age 80 have osteoporosis

(11)

Background

• Hip fractures are bad

– 20% patients with hip fracture die within the year

– 25-30% need placement in skilled nursing facility

(12)

What is Osteoporosis?

• Loss in total mineralized bone

• Disruption of normal balance of bone breakdown and build up

• Osteoclasts: bone resorption, stimulated by PTH

• Calcitonin: inhibits osteoclastic bone resorption

• Major mechanisms:

– Slow down of bone build up: osteoporosis seen in older women and men (men after age 70)

– Accelerated bone breakdown: postmenopausal

• Normal loss .5% per year after peak in 20s

• Up to 5% loss/year during first 5 years after menopause

(13)

Defining Osteoporosis

• “systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a

consequent increase in fracture risk”

• True Definition: bone with lower density and higher fracture risk

• WHO: utilizes Bone Mineral Density as definition (T score <-2.5); surrogate

marker

(14)

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, heparin)

Malignancies (metastatic disease; multiple myeloma can present as osteopenia!)

Hemiplegia s/p CVA/ immobility

(15)

Diagnosing Osteoporosis

• Outcome of interest: Fracture Risk!

• Outcome measured (surrogate): BMD

– Key: Older women at higher risk of fracture than younger women with SAME BMD!

– Other factors: risk of falling, bone fragility not all related to BMD

– Osteoporosis: disease of bone that increases risk of fracture; more than BMD goes into causing a

fracture; BMD is important, but in reducing

fractures must also consider falls risk, age and other factors!!!

(16)

Reducing Fractures

• 1. Decrease osteoporosis/improve BMD

• 2. Decrease risk of break: hip protectors

• 3. Decrease risk of fall

(17)

Hip Protectors

• Padding that fits under clothing

• Multiple studies demonstrate

effectiveness at preventing hip fractures

• Likely cost effective

• Problem: adherence!

(18)

2. 기능성 평가 방법

1) 시험관 내 실험

- 세포를 이용하는 생체 외 시험방법을 통해 평가

- 사람의 유사 조골세포주를 이용하여 조골세포의 증식능력 및 분화 촉진 인 자 등을 살펴봄으로써 이루어짐

2) 동물 실험

- 흰쥐 이용 : 성장과 대사 속도가 빨라 골의 대사 변화를 신속하게 볼 수 있음 - 골다공증 치료를 위한 기능성 평가가 다양함

- Sham operation

(19)

Bone Cell Types

Osteoblasts Osteoclasts Osteocytes Bone Lining Cells

Matrix formation

Secretes Type I collagen

Regulates mineralization

Positioned above osteoid matrix

Matrix usually polarized but can surround cells

Differentiates to become osteocyte

Digests bone

Large multi- nucleated

Exhibits ruffled border and clear zone

Exhibits polarity with nuclei away from bone surface

High density of Golgi stacks, mitochondria and lysozomal vesicles

Born from

osteoblasts

Maintains bone matrix

Occupies lucunae

Extends

filopodia through canaliculi

Forms gap junctions with neighboring cells

Flat, elongated cells

Generally inactive

Cover surfaces of inactive bone

Thought to be precursor cells to osteoblasts

(20)
(21)
(22)

Haversian

System

(23)

Cancellous or Trabecular Bone

(24)
(25)

Why Remodel Bone

• Allows bone to respond to loads (stresses)

• Maintain materials properties

• Allows repair of microdamage

• Participates in serum Ca

2+

regulation

(26)

Remodeling of Bone

• Resorption accomplished by osteoclasts

– Form cutting cones to “drill” holes – Haversian system

– Filled in holes become new osteons

• Allows bone to respond to physical stress

• Allows repair of micro damage

• Participates in plasma calcium control

• Random remodelling turns over bone

– Prevent accumulation of brittle material – Skeleton is cycled every 4-5 years

(27)
(28)

Bone Remodeling – A Coupled Control System

Osteoprogenitor

cells Osteoblasts Osteoclasts Mononuclear progenitor cells

• Osteoblasts have receptors for osteolytic agents

• Osteoclasts in culture are activated by stimulating osteoblasts

• Osteoblasts deposit factors in newly formed matrix

• Osteoclasts produce factors that recruit and activate osteoblasts

• Factors released as osteoclasts age and die (apoptosis)

(29)

Bone Turnover

•Bone Turnover Relative to Development

•Formation

•Resorption

•Formation > Resorption

•High Turnover •Formation = Resorption •Formation <

•Resorption •Formation < Resorption

•Low Turnover

•Female

•Male

(30)

Bone Strength

• Determinants of strength

– Geometry

– Bone mineral density – Materials properties

• Bone growth

– Growth needed during development – Growth also needed to withstand

increased loads

(31)
(32)

Support of Osteocyte-based Mechanism

• Osteocyte network

– Large surface area in contact with bone

• 2 orders of magnitude more than any other cell type

– Provides intracellular and extracellular route of communication

• Isolated turkey ulna stimulated with loading causes significant activation of osteocytes

– 1 Hz at 500-2,000 (10-6) strain (l/l)

– Osteocytes do not appear to respond to static loads

– Intermittent stresses cause significant changes in osteocytes which suggest function as mechanosensors

(33)

Osteocyte Candidate Signaling Molecules

• Nitric Oxide

– Small molecule, diffuses quickly – Produced rapidly

– Stimulates production of IGF via both autocrine and paracrine mechanisms

• Sclerostin

– Protein produced only by osteocytes – Powerful inhibitor of osteoblasts

– In new bone (Haversian), osteocytes closer to center of channel produce most sclerostin

(34)

Summary of Bone Feedback Control System

Bone

mechanical properties

Strain

(Deformation)

Canaliculi network resistance

Osteocytes produce Nitrous oxide /

Prostaglandins Osteoblasts

External Loads

Hormones / Cytokines Osteoclasts

- +

Streamin g

flows and osteocyte s deforme d

SGPs or direct strain Hormones /

Cytokines

Osteocytes produce sclerostin

-

(35)
(36)

Stress Shielding

• Occurs with artificial implants

– Stiffness of implant much greater than natural bone

– Does not transmit stress uniformly and fully into native bone at interface – Bone becomes resorbed

at interface and implant becomes “loose”

(37)

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

(38)

Skeletal Response to Exercise

Bone density (%)

0

-40 30

Normal Range

Sedentary Moderately Active

Changes only occur with significant habitual changes in activities over several months

Spinal injury, immobolization, bed rest, space flight.

Lazy zone

(39)

Mechanisms of Exercise Effects

• Increased habitual strain causes an increase in net bone formation

– Returns bone strain to normal control setpoint

• Studies with intact bone – Mechanical loading causes:

– Formation on periosteal surface without initial resorption

– Periosteal cell proliferation

(40)

Interaction of Age with Exercise

• Increasing age causes deficits in response (I.e., gain of system goes down)

– Probably caused by multiple factors

– Women from 60-80 show BMD increase of only 5-8% with exercise

• Increases in BMD with exercise reverts to normal within a few months of terminating training

• Exercise clearly helps maintain bone as

system gain or setpoint is reduced

(41)

Osteoporosis

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

Normal Osteoporotic

(42)

Costs of Osteoporosis

• 10,000,000 cases in U.S. alone

• Affects 1 in 2 women and 1 in 8 men > 50 years old

• Causes 1.5 million fractures/year - 700,000 spine, 300,000 hip and 300,000 wrist, 25,000 deaths from complications

• Menopause is the biggest risk factor for disease

• Disease often not diagnosed until after 1 or more fractures have occurred

• Prevalence could rise to 41 million by 2015 from 28 million today

• Cost to health care estimated at $14 billion ($38M/day)

• Psychological and social effects of disease are immense

(43)

Development of Osteoporosis

• Formation takes 3-4 months to replace bone resorbed in 2-3 weeks

• Osteoclast recruitment is increased

• Osteoblast-osteoclast Coupling is interrupted

– Factors recruiting osteoclasts may not adequately recruit osteoblasts

– Lack of estrogen may lead to less IGF-1 incorporated into new bone – reduces later osteoblast recruitment – Gain or setpoint in mechanosensory feedback loop

may be reduced

(44)

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

(45)

Bone Remodeling – A Coupled Control System

(46)

Extra OPG Normal OPG

Lack of OPG

Osteoprotegerin (OPG)

• Seminal paper published in 1997

– “Osteoprotegerin: A novel secreted protein involved in the regulation of bone density”, Simonet et al, Cell, 234:137-142

• OPG member of TNF receptor superfamily – soluble receptor

• Shown to affect bone density

(47)

OPG / RANKL / RANK Receptor

• RANKL and OPG are

secreted by osteoblasts and bone marrow stromal cells

• RANKL functions to promote osteoclast formation and

activation and inhibit apoptosis

• OPG functions as a decoy receptor to prevent RANKL signaling; ratio of RANKL to OPG dictates bone mass and structural properties

• Current extensive research is elucidating the role of OPG

and RANKL in a wide variety of bone-related diseases

OPG

Osteoclast Precursor

Bone

Osteoblasts

Osteoclast

RANK Ligand

RANK Hormones

Cytokines

RANK

(48)

Figure. Schematic representation of the pathways

regulating osteoclast differentiation.

(49)

Denosumab (OPG mimetic)

• Fully human

monoclonal antibody to RANK Ligand

• IgG2

• High affinity for RANK Ligand (Kd 3 x 10–12 M)

• Does not bind to TNFα, TNFß, TRAIL, or CD40L

Monoclonal Antibody Model

Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066.

Boyle WJ, et al. Nature. 2003;423:337-342.

(50)

Mechanism of Action for Denosumab

Osteoclast Formation, Function and Survival Inhibited

Osteoclast Activation

Adapted from Boyle WJ, et al. Nature. 2003;423:337-42.

Mature Osteoclast CFU-M

Pre-Fusion Osteoclast

Multinucleated Osteoclast Growth Factors

Hormones Cytokines

RANK RANKL OPG

Bone

Denosumab

(51)
(52)

3) 임상 시험

- 정상군의 경우 폐경하지 않은 여성을 시험대상으로 선정

- 시험군의 경우 약물, 또는 에스트로겐을 복용하지 않은 폐경 여성 혹은 난소 절제 여성으로 선정

- 기본조사 : 연령, 신장, 체중, 체질량지수, 폐경 기간, 폐경 시작 나이 및 출산 횟수 - 생화학적 검사 : 골형성 및 골흡수 지표 관찰

- 조직학적 검사 : 골밀도, 방사선 관찰

(53)
(54)

(1)골형성지표 분석

①Bone alkaline phosphatase(BALP)

- 혈정에 소맥배아 응집소를 용해하고 렉틴용액을 첨가한 뒤 희석된 트리톤-X 100용액을 첨가하여 원심분리하여 상층액에 있는 ALP 수치를 측정하는 것

②오스테오칼신(Osteocalcin)

- 혈중 오스테오칼신은 osteocalcin myria 키트를 이용하여 방사면역분석 시험법에 따라 측정

③콜라겐 프로펩타이드 유형Ⅰ

- 효소면역검사법(ELISA) 키트로 측정

3) 임상 시험

(55)

(2)골흡수지표 분석

①콜라겐 텔로펩타이드 유형Ⅰ

- 뇨 중 콜라겐 텔로펩타이드 유형을 효소면역검사법 키트로 측정

②피리디놀린(pyridinoline)

- 뇨 중 피리디놀린의 측정을 콜라겐 교차결합 키트를 이용해 효소면역검사법으로 측정

③데옥시피리디놀린(deoxypyridinolin)

- 노 중 데옥시피리디놀린의 측정은 원심분리하여 뇨량을 잰 다음 pyrilinks-D 키트를 사용 하여 효소면역검사법에 의해 분석

(56)

(3)칼슘대사

- 혈청 중 칼슘 함량은 회화시킨 후 AAS로 측정한다.

- 칼슘생체이용률은 방사성동위원소(radio-isotype)를 이용하여 분석

(4)호르몬

①부갑상선호르몬(parathyroid hormone)

- DSL-8000 ACTIVE TM Intact PTH IRMA 키트를 이용하여 비경쟁적 방사 면역분석시험을 수행

②혈중 칼시토닌(calcitonin)

- DSL-7500 ACTIVE TM Calcitonine IRMA 키르를 이용하여 비경쟁적 방사 면역분석시험 을 수행

③에스트로겐(estrogen)

- 혈청 중 에스트라디올(estradiol) 함량은 estradiol RIA 키트를 이용하여 방사면역분석시 험에 따라 측정

(57)
(58)

(5)골밀도, 골무기질 함량 및 총골칼슘 측정

- 시험 후 척추 및 골반, 오른쪽 대퇴골 등과 총골칼슘량을 이중에너지 X-선 흡수계측법을 이용하여 척추 및 골반 등과 같은 체중이 실리는 부위와 전신 골밀도를 측정

(59)

hormone

(60)
(61)
(62)

3. 골다공증 개선 건강기능식품 및 효능

1) 고시형 건강기능식품

(1)칼슘

- 우유 및 유제품, 채소 및 과일, 뼈째 먹는 생선, 두류 등에 다량 함유

- 최근, 칼슘 강화 주스, 칼슘 고형두부 등과 같은 강화식품이 개발되는 추세 - “칼슘은 뼈와 치아를 형성하는 데 필요하다.”

- “칼슘은 신경과 근육의 기능을 유지하는 데 필요하다.”

- “칼슘은 정상적인 혈액응고에 필요하다.”

(63)

(2) 비타민 D

- 비타민 D는 종류가 최소 10가지 이상으로, 대표적인 것으로는 비타민

D2 (ergo-calciferol)와 비타민 D3 (cholecalciferol)가 생리적으로 중요한 기능 을 함

- “비타민 D는 칼슘과 인이 흡수되고 이용되는 데 필요하다.”

- “비타민 D는 뼈를 형성하고 유지하는 데 필요하다.”

(64)

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

(65)

Osteoporosis Treatment: Calcium and Vitamin D

• Fewer than half adults take recommended amounts

• Higher risk: malabsorption, renal disease, liver disease

• Calcium and vit D supplementation shown to decrease risk of hip fracture in older adults

• 1000 mg/day standard; 1500 mg/day in postmenopausal women/osteoporosis

• Vitamin D (25 and 1,25): 400 IU day at least;

– Frail older patients with limited sun exposure may need up to 800 IU/day

(66)

Osteoporosis Treatment: Calcitonin

• Likely not as effective as bisphosphonates

• 200 IU nasally/day (alternating nares)

• Decrease pain with acute vertebral

compression fracture

(67)

Osteoporosis Treatment:

Bisphosphonates

• Decrease bone resorption

• Multiple studies demonstrate decrease in hip and vertebral fractures

• Alendronate, risodronate

• IV: pamidronate, zolendronate (usually used for hypercalcemia of malignancy, 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

(68)

Bisphosphonates: Contraindications

• Renal failure

• Esophageal erosions

– GERD, benign strictures, most benign GI problems are NOT a contraindication

– Concern for esophageal irritation/erosions from direct irritation, 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

(69)

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

(70)

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; studies with increased density but increased fracture risk/fragility with flouride show that just building up bone is not enough!!!

(71)

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, those on

bisphophonates for 7-10 years, 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

(72)
(73)

(3) 글루코사민

- 아미노산과 당이 결합한 형태인 아미노당의 일종으로 관절의 연골을 구성하는 성분 - 새우나 게와 같은 갑각류의 껍질에 존재하는 키틴 성분으로부터 추출

- ‘관절 및 연골 건강’의 기능성이 인정됨

(4) N-아세틸글루코사민

- 새우나 게와 같은 갑각류의 껍질에 존재하는 키틴을 효소분해하여 생산 - ‘관절 및 연골 건강’의 기능성이 인정됨

(5)뮤코다당∙단백

- 동물 점액성 다당류의 일종으로 뮤코다당체, 뮤코다당질의 약칭

- 소, 돼지, 양, 사슴, 상어, 가금류, 오징어, 게, 어패류의 연골 조직을 열수 추출 및 효소 분해하여 여과, 농축, 건조 등의 공정을 거쳐 식용에 적합하도록 정제하고 건조한 것 - ‘관절 및 연골 건강’의 기능성이 인정됨

(74)
(75)
(76)

(6)프락토올리고당

- 과일 및 채소와 버섯등에 존재

- 설탕에 과당을 전이시키거나, 이눌린을 이눌레이스로 부분 가수분해하여 생성됨 - ‘칼슘 흡수에 도움’의 기능성이 인정됨

(7)대두이소플라본 추출물

- 발효된 대두 배아를 주정추출하여 생성

- 다이드제인과 제니스테인이 지표성분으로서, 둘의 총합이 30~40%가 되게 함 - “뼈 건강에 도움을 줄 수 있습니다” - 기타기능Ⅱ로 기능성이 인정됨

(77)
(78)
(79)

• Estrogens decrease

osteoclast formation by down-regulating RANKL- induced activation of

JNK and subsequent phosphorylation (and activation) the Jun

transcription factor.

• This occurs within 5 minutes of estrogen

treatment in vitro and is reversed by treatment

with estrogen antagonist.

(80)
(81)
(82)

2) 개별인정형 건강기능식품

(1)차조기 등 복합추출물(KD-28)

- 갈근, 인진 및 차조기 세가지 재료를 주정을 이용하여 추출 - 푸에라린, 스코폴레틴, 아피제닌이 각각 원료의 지표성분임

- “관절 건강에 도움을 줄 수 있습니다” - 기타기능Ⅱ 로 기능성이 인정됨

(2)로즈힙 분말

- 건조시킨 로즈힙 열매로 만든다.

- 하이페로사이드가 지표 성분으로 알려져 있다.

- “관절 및 연골 건강에 도움을 줄 수 있습니다” – 기타기능Ⅱ로 기능성이 인정됨

(3)황금 등 복합물

- 황금물추출 분말(80%), 아선약 물추출분말(20%)을 합하여 만듦 - 바이탈린과 카테킨이 지표 성분으로 각각 18%, 3%가 되도록 함

- “관절 건강에 도움이 될 수 있습니다” - 기타기능Ⅱ 로 기능성이 인정됨

(83)
(84)

(4)초록입홍합 추출 오일복합물

- 초록입홍합 초임계 추출물, 올리브오일, D-a-토코페롤 세 가지 원료를 혼합하여 만듦 - EPA, DHA, a-리놀렌산 등의 오메가-3-불포화지방산 혼합물이 지표 성분으로, 25%이

상이 되도록 함

- “관절 건강에 도움이 될 수 있습니다” - 기타기능Ⅱ 로 기능성이 인정됨

(5)기타

- 칼슘-PGA: “체내 칼슘 흡수 촉진에 도움을 줄 수 있다”로 기능성을 인정 받음 - 호프 추출물: “관절 건강에 도움을 줄 수 있다”로 기능성을 인정 받음

- 지방산복합물: “관절 건강에 도움을 줄 수 있다”로 기능성을 인정받음

(85)
(86)
(87)
(88)

reference

• Funtional food 이형주 외 수학사

• handouts

참조

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