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Muscle and Bone (Bone (CHANGES WITH AGE: (Lose ability to differentiate…
Muscle and Bone
Bone
COMPOSITION:
206 BONES
- Bone Minerals
- Calcium (about 1kg)
- Phosphorus (also 1kg - Forms crystalline structure with calcium - HYDROXYAPATITE)
- Mg, F, Zn, Si
- Organic component forms a matrix with collagen - about 50% of body content
- 50% Body is protein (collagen etc), 50% Mineral
BONE CELLS:
- Osteoclasts - contains powerful lysosomal enzymes and acid which break down mineral bone components and reabsorb. - High surface area. - COMES FROM BLOOD STEM CELLS.
- Osteoblasts - Synthesizes and secrtes collagen to build the bone matrix.
- Osteogenic cells - develop into osetoblasts
- Osteocytes - main cells in bone tissue - exchange nutrients, mineralisation, and waste products.
TYPES OF BONE:
- Cortical/Compact – few spaces between hard components – forms external layers of bones and bulk of diaphyses of long bones – 80% composition
- Trabecullar/Cancellous – arranged in a thin irregular lattice – trabeculae. Major component of short, flat or irregular shaped bone – 20% composition
- Cancellous bone more sensitive to resorption and remodeling as there is a higher surface area (3-10 times faster than cortical)
MEASUREMENT:
- DEXA - Dual-energy x-ray absorptiometry
- CT - Quantitative Computed Tomography, Ultrasound / Radiography.
- FRAX TOOL - Risk of fracture.
FACTORS AFFECTING BONE MASS:
- Gender - women have lower bone density than men.
- Age - Bone formation increases until mid 20s, then stabilises, then reduces after mid-40s.
- Race - Caucasians and Asians have lower bone mineral density than Africans
- Frame size - smaller frame = lower bone mass.
BONE DISEASES:
- Rickets - Vit D deficiency - problems with forming bones.
- Osteomalacia - Vit D deficiency - problems with remodelling.
- Osteoporosis - Ca/Vit D/ Vit K Def - higher bone reabsorption than formation.
- Paget's disease - Increased rate of bone renewal.
RICKETS AND OSETOMALACIA
- Osteomalacia in adults
- Rickets in children
- Both occur as a result of vitamin D deficiency or impaired metabolism
SYMPTOMS:
- Bone pain and tenderness - osteomalacia
- Deformity and muscle weakness - rickets
- Enlarged epiphyses – rickets = abnormalities at growing end of bones
- Non-mineralised osteoid tissue cannot support body weight – bow legs; knock-knees; pelvic deformity
- CHONDROCYTE PROLIFERATION - Vitamin D induces differentiation - makes cartilage
- Vit D deficiency stop differentiation - causes the cartilage to not become mineralised - bone weakness.
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- Osteoclasts and blasts talk to each other via RANKL - vit D stimulates this - important for bone breakdown.
OSTEOPOROSIS:
- Increased rate of bone resorption
- Lower bone mass
- Lower bone mineral content
- More porous bone tissue
- Lower structural integrity
- Increased fragility fractures
- fall from standing height
- cough, sneeze
- Skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture
- Bone strength primarily reflects the integration of bone density and bone quality
- Common sites: Spine, neck of femur, wrist
- England/Wales:
- over 2 million women have osteoporosis (correl: menopause)
- 180,000 osteoporosis-related fractures occur annually
- 1 in 3 women over 50 years of age will sustain a vertebral fracture
- Men: 1 in 5 !!
- 2 million bed days annually are a result of fractures
- annual social and hospital care costs £1.8 billion
TREATMENT:
Anti-catabolic agents
- Bisphosphonates – 1 st line therapy: suppress
osteoclast activity
- Hormone replacement therapy (HRT)
- Selective Estrogen Receptor Modulators (SERMs)
- Calcitonin (opposite to PTH)
Anabolic agents
- Strontium Ranelate – stimulates CaSR
- Parathyroid hormone
Other considerations
- Calcium and Vitamin D
- Denosumab – monoclonal Ab to RANKL
- Increased Mechanical Loading
- Senolytics
PROTEIN
- Protein forms ~ 50% of bone volume
- Positive effects of protein on bone synthesis in children & adolescents – Weaver et al Osteoporos Int 2016;27:1281–386.
- High protein diet increases urinary Ca excretion (but more than dietary intake - so is probably lost from bone)
- Hypothesized that due to increased metabolic acid load -> metabolic acidosis -> demineralisation of bone -> excreted in urine.
- Is dietary protein beneficial for bone health or a risk factor for osteoporosis?
- Shams-White AJCN 2017 SR & MA
- RCTs and prospective cohort studies examining bone health effects of “high versus low” protein intake
- Moderate evidence that higher protein intake may have a protective effect on lumbar spine BMD
- Current evidence shows no adverse effects of higher protein intakes.
- DID THEY SPLIT BY TYPE OF PROTEIN?
- Shams-White PLOS One 2018 SR & MA
- Seven RCTs examining animal vs. soy protein intake in 633 healthy peri-menopausal and post-menopausal women
- No difference in BMD, bone turnover markers
- These results do not support soy protein consumption as more advantageous than animal protein, or vice versa
pH
- No evidence that it improves bone health or protects from osteoporosis
- SOME evidence that it can activate Vitamin D and reduce muscle wasting.
SOY ISOFLAVONES
- Age-related oestrogen deficiency leads to accelerated bone resorption.
- RCTs support that oestrogen therapies as effective preventative treatment of accelerated bone resorption
- There is evidence that isoflavones may exert beneficial effect
- Isoflavones may work directly on oestrogen receptor -> less bone breakdown and inhibit inflammatory pathways which lead to bone breakdown
- Lambert 2017 AJCN SR & MA
- Isoflavone treatments exert a moderately beneficial effect against oestrogen-deficient bone loss in women.
- Epidemiological studies and clinical trials:
- soy isoflavones have beneficial effects on BMD in postmenopausal women.
- Conflicting results:
- differences in study design
- oestrogen status
- The long-term safety of soy isoflavone supplements remains to be demonstrated
- Current evidence is not sufficient to make recommendations regarding the effects of soy on bone health
VIT K
- Vitamin K: cofactor for the enzyme gammaglutamyl carboxylase - converts glutamate to gamma-carboxy-glutamate residues
• Vitamin K dependent proteins have calciumbinding properties - involved in blood coagulation; mineralization of bone, cartilage, and other soft tissues
• Vit K deficiency = under carboxylated osteocalcin – associated with low BMD and increase fracture risk
• Osteocalcin – secreted by osteoblasts: gamma-carboxylated form binds hydroxyapatite and therefore important in bone mineralisation
• Limited RCT evidence supporting the protective effect of vitamin K1 or K2 supplements against fractures prevention
- Palermo 2017 SR
- Low VK intake associated with bone deterioration
- Potential positive effect of VK on bone health
- Routine VK supplementation is not globally recommended yet in postmenopausal women affected by osteoporosis
- Low quality cross sectional and RCTs have provided contrasting evidence
- Limitations in existing studies - findings should be treated with caution
- QUERCETIN MAY BE USED TO TARGET BONE CELL SENESCENCE
CALCIUM AND VITAMIN D
- Ca and Vit D
- Low Ca intake during growth may affect PBM – increased fracture risk in later life. Achieving PBM earlier is associated with lower risk of fracture.
- Calcium supplements >5 yrs post-menopause can reduce bone loss in those with low habitual Ca intake (DawsonHughes et al 1990)
- Benefits of Ca supplements in early menopause less convincing
- Vitamin D supplements in young post-menopausal women – little effect on BMD (Bischoff-Ferrari 2006)
- Vit D supplements in elderly – no significant effect on fracture unless given at high levels: ~20µg/d (BischoffFerrari 2005)
- Vit D & Ca in combination can reduce fracture rates in institutionalised elderly (Bischoff-Ferrari 2005)
CALCIUM STUDIES
- Tai et al 2015 SR & MA
- Older people recommended 1000-1200 mg/day calcium
- Supplements commonly used; but safety concerns
- Increasing food calcium may be preferable
- This study:
- Increasing calcium intake either by dietary sources or supplements = small increase in bone density
- effects are unlikely to reduce fractures
- Increasing dietary calcium increased BMD by 0.6-1.0% at the total hip and total body at one year
- Calcium supplements increased BMD at 5 skeletal sites by 0.7-1.4% at one year
- Bolland et al BMJ 2015 SR
- Dietary calcium (2 RCTs; 44 cohort studies)
- no association between calcium intake and fracture
- Supplemental calcium (26 RCTs)
- Reduced risk of total and vertebral fracture, but not hip or forearm
- publication bias in some RCTs
- RCTs at lowest risk of bias – no effects on fractures
- Dietary calcium not associated with risk of fracture
- Ca supplements small inconsistent benefits on fracture risk
- Increasing calcium intake, should not be recommended for fracture prevention
VITAMIN D STUDIES
- Reid et al Lancet 2014 - SR and MA
- Small benefit at the femoral neck (weighted mean difference 0·8%, 95% CI 0·2–1·4) with heterogeneity among trials (I²=67%, p<0·00027).
- No effect at any other site was reported, including the total hip.
- Continuing widespread use of vitamin D for osteoporosis prevention in community-dwelling adults without specific risk factors for vitamin D deficiency inappropriate.
- Zhao et al 2017 - JAMA, SR & MA
- Findings don't support use of supplements in older adults in terms of reducing risk of fracture or loss in bone mineral.
RISK FACTORS:
- Eight times more common in women than men
- Lower calcium intake than men
- Less bone mass because of smaller frame
- Bone resorption begins earlier and accelerates after menopause
- Pregnancy and breastfeeding deplete woman’s skeletal reserve of calcium
- Longevity increases likelihood of osteoporosis; women live longer than men
Non-modifiable
- Female gender
- Increasing age
- Family history
- White or Asian ethnicity
- Small stature
- Early menopause
Modifiable
- Diet
- Excess alcohol intake
- Cigarette smoking
- Anorexia
- Oophorectomy
- Sedentary lifestyle
- Medications – steroids
- Low testosterone (hypogonadism in men)
Diet
NUTRIENTS:
- Calcium - provides rigidity and strength.
- Phosphorus - Forms hydroxyapatite with calcium.
- Vitamin D - Regulates calcium and phosphorus absorption and controls bone growth in infancy AND can mobilise calcium from bone during deficiency.
- Magnesium - Maintains bone rigidity.
- Fluoride - Strengthens bones and teeth and there is evidence to suggest it stimulates osteoblast activity.
HORMONES:
- Parathyroid hormone stimulates bone breakdown.
CHANGES WITH AGE:
- Lose ability to differentiate cells with age
BONE FORMATION:
- Intramembranous ossification
- bone formed directly from precursors e.g. flat bones of skull, calvaria, clavicle
- Bone formed in “membrane” or “condensation”
- direct formation of OB precursors
- formation of periosteum
- differentiation to osteoblasts
- matrix deposition, mineralisation
- vascularisation, blood vessels
- continued growth and remodelling
- Endochondral ossification
- bone formed via cartilage intermediate e.g. long bones, vertebrae
- Formation of cartilage model, perichondrium
- Cartilage mineralisation
- Formation of bony collar, periosteum
- Capillary invasion, osteoclast migration and invasion
- Primary ossification center
- Secondary ossification center, epiphyseal growth plate
BONE REMODELLING:
- (I) Calcium homeostasis
- Focus is to maintain blood calcium through Gut, Kidney, and Bone.
- (II) Skeletal homeostasis/bone mass
- Steady state between resorption and formation.
- (III) Adaptation – mechanical forces - Bone Stress - microfractures
- Activation-Resorption-Formation (ARF)
- Quiescence -> Osteoclasts
- Resorption -> Osetoblasts arrive, Osteoclasts leave or die
- Reversal -> Matrix-formation
- Formation -> Osteocutes -> Mineralisation
- This is done at a rate of 10% per year.
CONTROLLED BY:
- Systemic hormones - PTH, Vitamin D3 etc
- Growth factors and cytokines - Transforming growth factor, IGF1
- Local Factors - Prostaglandins (PGE2)
- Transcription Factors - NFkB, Fos
- Osetoblasts mediate osteoclast differentiation
- Increased mechanical loading increased bone formation
CHANGES WITH AGE
- Osteoclasts: lack of Estrogen (eg. menopause) enhances resorption
- Osteoblasts: Mesenchymal Stem Cells
- Reduction in number, proliferative capacity and differentiation potential
- Differentiation: altered lineage distribution
- osteoblast vs adipocyte
- reduction in osteogenic,
- increase in adipogenic potential
** Also impacts fracture healing
• Increased senescence
Muscle
Ageing muscle
MUSCLE:
- Normally 25% efficient - rest lost as heat
- Has many roles in the body - function - movement - brake - heat - metabolic regulator
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- Increase in muscle strength and gradual decrease with age - decrease to a certain level = loss of independence. BUT CAUSE IS UNKNOWN.
- Illness or falls can further reduce muscle strength
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- As you get older - meeting the same strength requirements come at a slower pace.
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GENERALLY LOSS OF FUNCTION = LOSS OF TISSUE MASS.
Sarcopenia
- Loss of muscle = muscle mass / height2 is 2 SDs below young subjects. (working def)
- Decrease in number of muscle fibres AND decrease in type 2 (fast-twitch) muscle fibre size.
- BUT increase in hybrid fibres
- FACTORS ASSOCIATED
- Changes in circulating “anabolic” hormones - (e.g. GH/IGF-I, Testosterone, etc)
- Metabolic dysregulation ( reactive O2
species)
- Inflammation (“inflamageing”) ( degradation) - Massive loss in muscle mass with each day spent in intensive care. Also have much higher rates of muscle inflammation (e.g. IL-6)
- “Anabolic resistance” to feeding and exercise – ( protein synthesis) - Muscle protein synthesis seems to be the same rate between young and old. BUT there is a lower saturation point of amino acids.
- ↓ regeneration from exercise induced damage – (compromised satellite cell behaviour) - older muscle takes longer to repair
- Problem with satellite cells? - Yes there are less but the function seems fine.
- Problem with environment in which satellite cells are activated? - Age of muscle is not important, it's the age of the host which makes the difference in some, but not all papers. - Imbalance of Notch and TNF-B leads to impaired satellite cells.
- TNF-B can inhibit differentiation.
Calcium
- Ca release, ATPase, and re-uptake in slower in older age.
Decrease in specific force is related to decrease activity NOT ageing necessarily.
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- Age-related changes from increased sedentary behaviour (increased mutations and increased ROS production).
- ABSOLUTE DIFFERENCES
- Aged muscle are more fatiguable in absolute terms, but this is lost when you adjust for initial weakness.
- ↓ athletic performance*
– ↓ VO2 max with age (~10% per decade)
– ↑ %VO2 max required for given work load
- ↓ ability to repetitively lift an absolute load
- BUT - reduction is not as low as previously thoguht - as teher is loss of muscle mass there is loss of function - however adjusting for this loss means VO2 decline is less than originally thought (14% rather than 33%)
– ↑ % maximum strength required to lift given load
- Similarly - when taking a muscle fibre form young and old - they perform exactly the same.
Effect of exercise
- Differences between 'Ageing' and the study of older people. BUT CANNOT BE FOCUS ON SEDENTARY BEHAVIOUR AS THIS IS A CONFOUNDER.
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- Humans were not designed to be sedentary. Physical activity is the body's default position.
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- 'Set point' of exercise which leads to compressed morbidity. - Harridge and Lazarus 2017. Opinion Paper.
- When comparing the effect amoung ACTIVE elderly, then you can see a more true result (we still don't know about diet/smoking etc). WHEN YOU COMPARE TO SEDENTARY - THEY ARE MUCH LOWER. 45 year old sedentary person has same VO2 as an 80 year old active person.
- There is so much heterogeneity between people, comparing predictions based on age (from cross-sectional evidence, may not be useful).
- Lung function measures such as FEV1/FVC may not be useful as those who are active will have lower outcome values due to higher than average FEV/FVC values.
- Similarly, sarcopenia is not useful for slimmer people as the average data is different.
- Pollock 2018 - master cyclists between 55-80 have no significant negative differences compared to young people. ASSUMPTIONS MADE ON OLDER PEOPLE ARE BASED ON A SEDENTARY LIFESTYLE.
Similarly Porter 1010 - exercise is protective against negative effects of sedentary lifestyle in ageing.