Nutrition, Lifestyle and Bone Health – Fake News?

Dr David J ArmstrongConsultant Rheumatologist

Clinical Lead Fracture Liaison and Osteoporosis Service

WHSCT

Disclosures

• Honoraria from Consilient Health, Internis

• Educational Grants from Lilly

• Stock in GSK

FAKE NEWS

I endorse this message…

Bone Health

Lifestyle Nutrition

Lifestyle

1. Nicotine

2. Alcohol

3. Physical Activity

Lifestyle

1. Nicotine

2. Alcohol

3. Physical Activity

Nutrition

1. Calcium

2. Vitamin D

3. Protein

4. Vitamins C, E, K, zinc etc

5. ‘Dairy Produce’ – good or bad

Alcohol

Alcohol Definitions

•Moderate alcohol consumption

•Chronic Heavy alcohol consumption

•Frequency v Total Units

• UK government advice – 14 units/week

Is Moderate Alcohol Protective?

DIAZ, N.M.; O’NEILL, T.W.; SILMAN, A.J.(1997) European Vertebral Osteoporosis Study Group. Influence of alcohol consumption on the risk of vertebral deformity. Osteoporosis Int 7:65–71

Woman >65 alcohol 5 days/week

fewer new vertebral collapse fractures

FELSON, D.T.et al. (1995) Alcohol intake and bone mineral density in elderly men and women—The Framingham Study. American Journal of Epidemiology 142:485–492

Reduced fracture risk in post-menopausal women who drank alcohol

Many confounders

Is Moderate Alcohol Protective?

Confounding factors?

Eg subjects with serious illnesses/medication less likely to drink alcohol?

What is moderate intake? Self-reporting bias?

Findings not repeated in animal studies

eg TURNER, R.T.; KIDDER, L.S.; KENNEDY, A.; et al. (2001) Moderate alcohol consumption suppresses bone turnover in adult female rats. Journal of Bone and Mineral Research 16:589–594

Heavy Chronic Alcohol

Enormous evidence for damage to bone density from heavy alcohol

Heavy alcohol intake in ADOLESCENCE and YOUNG ADULTS very damaging to bone health in later life

Animal studies in rats fed with alcohol show

reduced bone growth

reduced bone density

reduced IGF-1

reduced cartilage growth and maturation etc

Impact on final bone size as well as density

ie shorter adults

Recent nationwide surveys of alcohol and BMD

• Jang HD et al (2017) Relationship between bone mineral density and alcohol intake: A nationwide health survey analysis of postmenopausal women. PloS One 12(6):e0180132

• BMD increased from alcohol intake x0/week to x2-3/week

• Fell again with intake from x4/week and more frequently

• OR for osteoporosis NOF 1.70 heavy v moderate drinkers

Mean BMD comparisons according JangHD et al (2017) Relationship between bone mineral density and alcohol intake: A nationwide health survey analysis of postmenopausal women.PloS One 12(6):e0180132to the alcohol consumption.

BMD (g/cm2)

Total Femur Femoral neck Femoral trochanterFemoral inter-

trochanterLumbar spine

Frequency of drinking†

Non- 0.766 (0.005) 0.615 (0.005) 0.557 (0.004) 0.929 (0.007) 0.797 (0.007)

Light- 0.777 (0.006) 0.628 (0.006) 0.566 (0.004) 0.94 (0.007) 0.808 (0.008)

Heavy- 0.749 (0.016) 0.617 (0.016) 0.543 (0.011) 0.902 (0.02) 0.812 (0.023)

p 0.009**‡ 0.0081**‡ 0.0036**§ 0.0235*§ 0.1069

AUDIT scores†

< 5 0.776 (0.004) 0.625 (0.004) 0.565 (0.003) 0.940 (0.005) 0.806 (0.006)

5–9 0.779 (0.008) 0.631 (0.008) 0.565 (0.006) 0.943 (0.010) 0.819 (0.01)

> 9 0.757 (0.012) 0.610 (0.01) 0.551 (0.008) 0.916 (0.015) 0.794 (0.014)

p 0.2007 0.2328 0.2251 0.2401 0.3032

High-risk drinkers

Non-high-risk 0.799 (0.003) 0.648 (0.003) 0.582 (0.002) 0.966 (0.004) 0.826 (0.004)

High-risk 0.766 (0.019) 0.638 (0.018) 0.559 (0.012) 0.920 (0.024) 0.834 (0.026)

p 0.0941 0.5863 0.0773 0.0598 0.7617

Heavy Chronic Alcohol (2)

• Armstrong DJ, Hunter R. Different aetiologies in male and female osteoporosis in Northern Ireland. Arch Osteoporosis (2016) 11:32

• Males made up 29% of all FLS patients (50-75)

• 36% male patients alcohol dependent v 7% female FLS patients

• Marley WD, Kelly G, Thompson NW. Alcohol-Related Fracture Admissions: A Retrospective Observational Study. Ulster Med J. (2015)84:94-7

• 23% ALL fractures with alcohol in system were alcohol dependent

Conclusions - alcohol

• Small amount of alcohol may improve BMD

• Excessive alcohol, including in younger subjects, bad for bone health and fracture risk

Nicotine

Nicotine and Bone Health

• Smoking and fracture risk: a meta-analysis.

• Kanis et al 2005 Osteoporos Int. 2005 Feb;16(2):155-62

• Almost 60,000 subjects, 250,000 pt years

• Any fracture RR 1.25 (95% CI =1.15-1.36) for current smoking

• Reduces when adjusted for (lower) BMI (RR 1.13)

Nicotine and Bone Health

• Hip fracture RR=1.84 (95% CI=1.52-2.22)

• Reduces when adjusted for BMI (1.60)

• Smoking had greater effect in men (all fractures)

• Ex smokers had increased RR compared with never smokers

Quitting and bone health

• Cornuz J et al. Smoking, smoking cessation, and risk of hip fracture in women. Am J Med. (1999) 106:311-4.

• No apparent fracture benefit from quitting smoking until 10 years after cessation.

• After 10 years, former smokers had a reduced risk of hip fracture (adjusted RR = 0.7, 95% CI 0.5 to 0.9) compared with current smokers.

• Smokers have significantly lower Vit D, activated vit D and PTH

Quitting and bone health

• Oncken C et al. Impact of smoking cessation on bone mineral density in postmenopausal women. J Womens Health (Larchmt). (2006)15:1141-50

• BMD rises at hip 1 year after quitting (1.52% v 0.42%, p=0.03)

• Changes largely due to weight gain

Mechanisms of action on bone health

• Constituents of cigarette smoke

• – benzopyrene, cyanide, nitrosamines, nicotine, benzene

• - formaldehyde, carbon monoxide, toluene etc

• Effects on ca absorption Effects on bone hormones

• Effects on sex hormones Effects on adrenocorticoids

• Effects on RANKL and OPG Effects on osteoblasts

• Effects on osteoclasts Effects on vitamin D

• Other effects inc CVS

Conclusion

• Smoking is bad for you

• Better not to start

Calcium and Vitamin D

• Bone 70% mass calcium hydoxyapatite

• Up to 350mg/d excreted in urine (male)

• Up to 900mg/d excreted in faeces (male)

• Therefore adequate calcium intake appears logical step in bone health

• UK RNI 700mg/day adults

• 1000mg-1200mg if osteoporosis

Calcium alone• Fewer studies, most as an arm of a Ca v Ca&Vit D study

• Tang et al (2007) Lancet 370:657–666• Small numbers, different outcomes• RR for any fracture 0.90 (95% CI 0.80-1.00)• (Combination CaVitD in same paper RR 0.87)

• Bischoff-Ferrari (2007) Am J Clin Nutr 86:1780–1790• Prospective Cohort Studies - no benefit (RR<1.00)• Randomised Control Trials (4) – RR 1.64 (95% CI:1.02, 2.64)• Small trials, self-reported diet, ca use

Calcium Alone

• Bolland et al (2015) Calcium intake and risk of fracture: systematic review. BMJ 351:h4580

• Almost 70,000 subjects

• Calcium alone hip fracture RR = 1.51 (95%CI 0.93-2.48)

• Calcium&VitD hip fracture RR = 0.84 (95%CI 0.74-0.96)

• Conclusion

• Calcium alone – no clear overall benefit (especially hip fracture)

Calcium and Vitamin D• DIPART (2010) BMJ 340:b5463• N=68,500 RCTs (1,144 - 36,282)• All fractures – RR 0.92 (95%CI 0.86-0.99)• Hip fractures – RR 0.83 (95%CI 0.69-0.99)

• Weaver et al (2016) Calcium plus vitamin D supplementation and risk of fractures Osteoporos Int 27:367–376

• >30,000 subjects• All fractures – SRRE 0.85 (95%CI 0.73-0.98)• Hip fractures – SRRE 0.70 (95%CI 0.56-0.87)• ie 30% reduction in risk of hip fracture

Targetting high risk groups - Chapuy study

• Chapuy MC et al. Vitamin D3 and calcium to prevent hip fractures in elderly women.

• N Engl J Med. 1992 Dec 3;327(23):1637-42.• All subjects lived in nursing/residential homes, all ambulatory• 1634 females, 1200mg Ca 800iu vit D daily; 1636 females, placebo• 18 month follow-up

• Hip fractures - 43% reduced (p=0.04) • Non-vertebral fractures - 32% reduced (p=0.015)• Hip BMD increased by 2.7% v fell by 4.6%• Reproduced but not by as big margins

Vitamin D and falls

• Emerging evidence of role of vitamin D in reducing falls and improving muscle strength

• Bischoff-Ferrari (2009) BMJ (Clinical research ed) 339:b3692

• High dose vitD (700-1000iu) reduced falls RR=0.81

• Achieving serum levels >60nmol/l reduced falls RR=0.77

• Low dose or serum levels <60nmol/l – no effect

• Most effective in elderly or those with low levels initially

• Eg Beaudart et al (2014) J Clin Endocrinol Metab 99:4336–4345

• 17% improvement in global muscle strength with vitD supplements

• Only relevant in elderly and/or vitD deficiency

Summary

• The role of calcium supplementation in healthy musculoskeletal ageing. Osteoporosis International (2017) 28:447–462

• N. C. Harvey et al

• An expert consensus meeting of the (ESCEO) and (IOF)

• 1. Ca and Vit D lead to modest reduction in fracture risk – not a public health strategy

• 2. Calcium supplementation alone not supported by literature

• 3. Side-effects – renal stones and GI symptoms

• 4. Vitamin D supplementation may reduce falls risk

• 5. Assertions of increased CVS risk with Calcium supplementation are not supported by current evidence

Protein and Bone

• Protein makes up 30% bone mass

• ESA 2015 Pop Ref intake 0.83g/kg/day

• Long believed that protein intake is linked with bone strength

• Increasing protein intake causes increased urinary calcium loss

• Now believed mitigated by increased absorption from gut

• 3 large meta-analyses in last 8 years offer some clarity

• Darling (2009), Wu (2015), Shams-White (2017)

Meta-analyses of protein intake and bone

• Darling (2009) Am J Clin Nutr 90:1674-92

• Positive relationship between protein intake and BMD spine – approx only 2% of BMD

• No effect on hip fracture

• Wu (2015) Sci Rep 5:9151

• 12 prospective cohort studies >400,000 subjects

• Higher total protein consumption and hip fracture RR of 0.89 (0.82, 0.97)

• No effect on spine, limb or ‘all fracture’

• Both animal and vegetable protein of equal benefit (but only significant fracture reduction when combined)

Meta-analysis of protein intake and bone

• Shams-White (2017) AM J Clin Nutr 105:1528-43

• 36 RCT and Cohort studies

• Trends to higher BMD multiple sites; significant only at spine

• Non-significant reduction fracture

• Studies were heterogeneous, and confounding could not be excluded

Protein and Bone Health

• Conclusion

• 1. Is my patient getting near to 0.83g/kg/day of protein?

• 2. If clearly poor protein intake, consider action

Vitamin C

• Ascorbic Acid – anti-oxidant, cofactor for hydroxylases in collagen maturation

• Deficiency associated with poor bone health

• Human research mostly observational, variable quality

• Only 1 out of 13 cross-sectional studies measured serum vit C

• Others used food diaries etc

• Generally positive correlation between vit C and BMD

• Generally patients with fracture have lower vit C than controls

Vitamin C

• Hall SL, Greendale GA. The relation of dietary vitamin C intake to bone mineral density: results from the PEPI study. Calcif Tissue Int. 1998;63(3):183-9

• Each 100 mg increment in dietary vitamin C intake, was associated with a 0. 017 g/cm2 increment in BMD (p = 0.002 femoral neck; p = 0.005 total hip).

• Average intake approx 100mg-300mg/day

• Had to take at least 500mg vitamin D/day to be effective for fracture reduction

Conclusion

• Possible small benefit from vitamin C supplements

• Avoid scurvy

Vitamin E

• Important anti-oxidant, alpha- and gamma-tocopherol, mops up free radicals

• Some epidemiological evidence of link between low dietary vitamin E intake and fracture

• No convincing evidence for supplementation

Vitamin E

• COCHRANE REVIEW 2012 Bjelakovic

• Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases (2012)

• increased mortality Vit E supplements

• Hamidi MS et al. Effects of vitamin E on bone turnover markers among US postmenopausal women. J Bone Miner Res. 2012 Jun;27(6):1368-80

• 497 postmenopausal women, 45% taking alpha-tocopherol

• These subjects higher alpha/gamma ratio

• Lower osteoblast activity markers

• Higher gamma-tocopherol associated with more favourable osteoblast/osteoclast activity ratio

Conclusion

• Vitamin E supplements do not prevent fracture

Vitamin K

• Phylloquinone (K1) diet – green veg

• Menaquinone (K2) produced in gut, active in bone

• Cofactor of gamma-carboxylase – carboxylation of osteocalcin

• Carboxylated osteocalcin binds hydroxyapatite – bone mineralisation

• ucOC (‘under-carboxylated OC) does not

• ucOC used as a marker for osteoporosis in some countries

• Oral vitamin K in large doses antagonises effects of warfarin

Vitamin K

• Almost all RCTs carried out in Japan

• Oral vitamin K2 produced modest benefits for BMD

• Eg Iwamoto (2000) 2 years, spine BMD

• -0.79% Ca, +0.9% vit K and Ca

• Ishida et al (2004) 2 years, distal radius BMD

• – 3.3% placebo, -1.9% vit K

• A number of very small studies suggesting benefit for fracture BUT

• Inoue et al (2009) vit K v placebo, >2000 each arm, open label, 3 years

• – no significant effect in fracture reduction

• (5.87/100 pt years vit K v 5.74/100 pt years placebo)

• Combination with bisphosphonates?

Conclusion

• Evidence for vitamin K benefit small

Zinc

• Evidence for both promotion of osteoblast activity (Runx2) and inhibition of osteoclast activity (RANKL)

• Evidence that deficiency associated with osteoporosis

• No convincing evidence for supplementation in healthy adults preventing fracture

Is Dairy good for the bones?

Debunking the debunkers

This really is fake news

• Nutritionist website

• “…dairy foods contribute to osteoporosis by ‘acidifying’ our bodies.

• foods high in phosphate leave an ‘acid ash’ after digestion, thereby lowering serum pH.

• The body compensates for this and restores normal blood pH by stealing alkaline minerals (such as calcium) from the bones, thus decreasing bone density…”

6 key points against the acid ash dogma

• J Am Coll Nutr. 2011 Oct;30(5 Suppl 1):471S-5S. Milk and acid-base balance: proposed hypothesis versus scientific evidence. Fenton TR, Lyon AW.

• Key teaching points:

• Measurement of an acidic pH urine does not reflect metabolic acidosis or an adverse health condition.

• The modern diet, and dairy product consumption, does not make the body acidic.

• Alkaline diets alter urine pH but do not change systemic pH.

• Net acid excretion is not an important influence of calcium metabolism.

• Milk is not acid producing.

• Dietary phosphate does not have a negative impact on calcium metabolism, which is contrary to the acid-ash hypothesis.

Milk intake and risk of mortality and fractures in women and men: cohort studies

Michaelsson paper in BMJ (2014)J (2014) 349-364

• Lactose digested into D-glucose and D-Galactose (in those with gene)

• D-Galactose injection is used to ‘age’ mice – oxidative stress, chronic inflammation etc

• Multiplying up dose results in 1-2 glasses of milk per day

• 1987-90 90,303 woman aged 39-74 in Sweden invited to mammography

• Posted a food frequency questionnaire, 74% completed

• 1997 100,303 men aged 45-79 in Sweden invited to participate

• 49% returned food frequency questionnaires

• Mean follow-up 20 (female) and 11 (male) years

• At time of study, analysed urine in women (mean age 70) and serum in men (mean age 77)

• 8-iso-PGF2 alpha and IL-6 respectively

Milk intake and risk of mortality and fractures in women and men: cohort studies

Michaelsson K, Wolk A, Langenskiold S et al BMJ (2014) 349-364

• Results

• Female - >3 glasses milk/d v <1 glass/d

• adjusted mortality hazard ratio 1.93 (1.80 – 2.06)

• For each extra glass of milk, all cause adjusted mortality hazard ratio women 1.15 (1.13-1.17) men 1.03 (1.01-1.04)

• No protection per extra glass for any fracture or hip fractures

• Associations between amount of milk and 8-iso-PGF2a and IL-6• (Negative correlation between sour milk and yoghurt and 8-iso-PGF2a and IL-6)

• Conclusion: D-Galactose in milk may increase mortality

Issues

• Most studies (isocaloric) do not suggest milk increases oxidative stress

• No difference in oxidative stress when compared with alternatives such as soya milk

• WCRF – no increase in risk of cancers with milk intake (colorectal cancer ‘probable’ protective)

Issues

• Women born between 1913 and 1951 included in one sample

• Societal changes

• Dietary changes

Other studies on milk and fracture?

• Milk consumption during teenage years and risk of hip fractures in older adults D Feskanich, HA Bischoff-Ferrari, AL Frazier et al JAMA Pediatr. (2014);168(1):54-60

• No difference in women (RR=1.0)

• Extra 0.5cm in height for every glass of milk/day taken as a teenager

• Increased hip fracture in taller individuals

• Men hip fracture (RR = 1.09; 95% CI, 1.01-1.17) for every extra glass, but disappeared when corrected for height

Hip fracture and milk intake

• HA Bischoff-Ferrari, B Dawson-Hughes, JA Baron

• JBMR 26, 4, 833–839,(2011)

•Our conclusion is that in our meta-analysis of cohort studies, there was no overall association between milk intake and hip fracture risk in women

•More data are needed in men.

Calcium and Dairy Produce - Conclusions

• Basic Common Sense

1. Replace daily losses

2. 1000mg-1200mg in osteoporosis. A little more should do no harm.

3. No evidence that taking eg 3000-4000mg Calcium is of any benefit – why would it be?

4. Watch for patients with ZERO calcium intake!

5. Caution in interpreting large observational studies with self-reported data, large variations in subjects followed over more than 20 years with lots of confounders

6. BUT KEEP AN OPEN MIND

Summary

• Calcium and Vitamin D are good for your bones

• So is protein

• Avoid deficiency of other vitamins

• Don’t smoke

• Don’t drink excessive alcohol

• Sensible amount of dairy produce is good for you

Careful NowThank you