CHAPTER 12
뼈건강 개선
Functions of Bone
• Structural
– Support – Protection – Movement
• Mineral Storage
– Calcium – Phosphate
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
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
제1절 골다공증 개선
1. 골다공증의 정의 및 개요
골다공증
뼈로부터 칼슘의 배출로 인해 뼈의 밀도와 강도가 약해지게 되어 골절 가능성 이 높은 상태
골다공증의 원인
- 호르몬 불균형 - 노화
- 기타 위험인자 - 뼈의 교체율 증가
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
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
Background
• Hip fractures are bad
– 20% patients with hip fracture die within the year
– 25-30% need placement in skilled nursing facility
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
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
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
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!!!
Reducing Fractures
• 1. Decrease osteoporosis/improve BMD
• 2. Decrease risk of break: hip protectors
• 3. Decrease risk of fall
Hip Protectors
• Padding that fits under clothing
• Multiple studies demonstrate
effectiveness at preventing hip fractures
• Likely cost effective
• Problem: adherence!
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
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
Haversian
System
Cancellous or Trabecular Bone
Why Remodel Bone
• Allows bone to respond to loads (stresses)
• Maintain materials properties
• Allows repair of microdamage
• Participates in serum Ca
2+regulation
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
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)
Bone Turnover
•Bone Turnover Relative to Development
•Formation
•Resorption
•Formation > Resorption
•High Turnover •Formation = Resorption •Formation <
•Resorption •Formation < Resorption
•Low Turnover
•Female
•Male
Bone Strength
• Determinants of strength
– Geometry
– Bone mineral density – Materials properties
• Bone growth
– Growth needed during development – Growth also needed to withstand
increased loads
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
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
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
-
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”
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
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
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
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
Osteoporosis
• Defined as reduction in bone mass and micro-architecture that leads to susceptibility to fracture
Normal Osteoporotic
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
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
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
Bone Remodeling – A Coupled Control System
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
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
Figure. Schematic representation of the pathways
regulating osteoclast differentiation.
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.
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
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
(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
(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
(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
(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
hormone
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.”
(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.”
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
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
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, 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
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
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
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!!!
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
(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
(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
• 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.
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
(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