THYROID TREATMENT AND VITAMIN D UPDATEA CPMC Regional CME Event

- An Integrated Approach

Saturday October 27, 2012

VITAMIN D AND CALCIUM SUPPLEMENTATION IN

OSTEOPOROSIS

Diana M. Antoniucci, MD, MASSutter Pacific Medical Foundation

Division of Endocrinology, Diabetes and OsteoporosisAssistant Clinical Professor Medicine

University of California, San Francisco

OSTEOPOROSIS

• Osteoporosis characterized by reduced bone mineral density (BMD) and bone mass

• First step in prevention of osteoporosis- Ensuring adequate nutrition- Adequate intake of calcium and vitamin D

CALCIUM AND VITAMIN D

• Indispensable for normal skeletal homeostasis

• Vitamin D enhances absorption of calcium

• Calcium balance related to calcium intake:- Less calcium intake more negative

calcium balance and in PTH- Generally, calcium balance becomes

positive at an average calcium intake 1000 mg/d 1 1Heaney et al. J Lab Clin Med 1978; 92:

953

PRODUCTION, METABOLISM, AND BIOLOGICAL FUNCTION OF VITAMIN D

S

k

i

n

Mi

lk

Milk

1,25(OH)2D3 1,25(OH)2D3

Vitamin D3 25(OH)D3Prostate, Breast, Colon

Calcium

Homeostasis

Muscle Health

Bone Health

Immuno-modulation

(prevention of

autoimmune

diseases)

Regulation of

Cell Growth

(cancer prevention)

Liver

Kidney

25(OH)D3=25-hydroxyvitamin D3; 1,25(OH)2D3= 1,25-dihydroxyvitamin D3.2Holick MF. J Cell Biochem. 2003;88:296–307 4

Skin

Milk Milk

TYPES OF VITAMIN DVitamin D2 (Ergocalciferol)• Form of vitamin D found in plants• Provided by some dietary sources and

multivitamins• Biologically inert• Conversion (OH) in liver and kidneys

produces active form• D2 may be less potent than D3

Vitamin D3 (Cholecalciferol)• Naturally occurring form in humans• Formed by action of ultraviolet light on

vitamin D precursors in skin• Present in certain nutrients• Biologically inert• Conversion (OH) in liver and kidneys

produces active form

CONSEQUENCES OF VITAMIN D INSUFFICIENCY

• Calcium absorption- With D sufficiency – we absorb 30-50% of

ingested dietary calcium- With D deficiency – absorb 10-15% of ingested

dietary calcium• PTH

- Insufficient vitamin D stimulates increased release of PTH and bone resorption

• BMD- vitamin D inadequacy may decrease BMD and

increase risk of fracture

DEFINITION OF VITAMIN D SUFFICIENCY

• No consensus…• 25OHD concentration to maximally

suppress PTH: 27.5-30 ng/ml• Institute of Medicine (IOM): >20 ng/ml• Others (Endocrine Society, NOF, IOF,

American Geriatric Society): >30 ng/ml• Aim for 30-40 ng/ml based on skeletal

health, fracture reduction and safety

VITAMIN D STATUS IN OUTPATIENTS• Prevalence of insufficiency - 9 to 50%

depending on the study population- Postmenopausal women with low spine BMD: 9%

had 25OHD<15 ng/ml1 - Postmenopausal women with osteoporosis in US:

29.3 % had 25OHD <25 ng/ml2 - Healthy community dwellers in Canada: 34% had

25OHD<16 ng/ml3- Women with acute hip fracture: 50% with

25OHD<12 ng/ml4- Among postmenopausal women on osteoporosis

therapy, 18.2% had 25OHD<20 ng/ml, and 52% a 25OHD<30 ng/ml5

1Villareal 1991 JCEM ; 2Lips JCEM 2001; 3Rucker 2002 CMAJ; 4LeBoff 1999 JAMA; 5Holick, 2005 JCEM

VITAMIN D STATUS IN OSTEOPOROSIS

• Reasonable to check levels• Goal is 25OHD>30 ng/ml• Replete first if 25OHD<30 ng/ml

- 25OHD <10 ng/ml• 50,000 IU vitamin D/ twice a week x 8 weeks

- 25OHD between 10 and 25 ng/ml• 50,000 IU vitamin D/week x 6 weeks

- 25OHD >25 ng/ml• Start 1000 IU/day

ROLE VITAMIN D IN NON-SKELETAL HEALTH• Epidemiologic data indicate increased risk of

cancer, infectious, autoimmune, cardiovascular and metabolic diseases when 25OHD<20 ng/ml

• No RCT confirming that vitamin D supplements decrease these risks back to baseline. NIH sponsored trial ongoing at Harvard to establish some of these causalities

• Until results available:- Treat for osteoporosis or fall prevention- Treat true deficiency- Otherwise be cautious

VITAMIN D AND OSTEOPOROSIS

• BMD increases with increasing 25OHD levels in population studies until plateau of 30 ng/ml3

• Increased hip fracture risk in elderly with low but not severely deficient vitamin D4

• Randomized controlled trials of vitamin D and/or calcium supplementation:- Somewhat mixed results- Pay attention to:

• Age, living situation and vitamin D status of study populations• Dose of vit. D • In combination with calcium or not

3Bischoff-Ferrari HA et al. J Bone Miner Res 2009;24:9354Lai JK et al BMC Public Health 2010;10:331

VITAMIN D AND CALCIUM SUPPLEMENTATION & RISK OF FALLING

• 122 women in long term care• Age: 63–99• Mean serum 25(OH)D 12 ng/ml

at baseline• Randomized, double-blind,

controlled trial- Calcium 1200 mg/day- Calcium 1200 mg/day

+ vitamin D 800 IU/day• 12-week duration• Some other evidence for Vit. D

decreasing falls among nursing home patients

Adapted from Bischoff HA et al J Bone Miner Res 2003;18:343–351.

Calcium only(n=44)

Calcium + vitamin D(n=45)

Fall

risk

0.0

0.2

0.4

0.6

0.8

1.0

1.2

–49%

Reduction in falls

p=0.01

CALCIUM AND VITAMIN D IN LONG TERM CARE RESIDENTS

• N=3270 men and women in institutional living setting

• Mean age 80 years• 3 years• Calcium (1000 mg) + Vitamin D3 (800 IU) vs. PLBO• 30% decrease in hip fracture risk• Vitamin D levels VERY low in small subset measured

Chapuy et al N Engl J Med 1992 Dec 3;327(23):1637-42

HIGH DOSE VITAMIN D 3 X YEAR• Entire study done by “post” (in UK)• N=2686• Age 65–85• Vitamin D3 = 100,000 IU once every four months

(equivalent to ~ 800 IU/day)• Five-year randomized, double-blind, controlled trial• Men and women living in the community• Compliance: about 75% took > 80% of pills (12/15)

Trivedi D et al BMJ 2003;326:469.

HIGH DOSE VITAMIN D 3X/YEAR

Trivedi D et al BMJ 2003;326:469.

Frac

ture

rela

tive

risk

(hip

, wris

t, fo

rear

m,

spin

e)–33%

Untreated(n=1341)

Treated(n=1345)

p=0.02

0.0

0.2

0.4

0.6

0.8

1.0

1.2

WOMEN’S HEALTH INITIATIVE (WHI)• 36,282 postmenopausal women 50-69 yo• Randomized to 1000 mg/d calcium plus 400

IU vitamin D or placebo• Note –they allowed personal supplementation

of up to 1000 mg calcium and 600 IU vitamin D, bisphosphonate, calcitonin and HRT use.

• 7 year f/u on avg.• Hip Fracture risk:

- 0.88 (95% CI 0.72-1.08) for Ca+D vs placebo- 0.71 (95% CI 0.52-0.97) for Ca+D vs placebo when

only included women taking >80% meds

ALL THESE STUDIES… TAKE HOME MESSAGE• Supplementation with Vitamin D (even 400

IU/day or 2800 IU/wk) can raise Vitamin D levels (data now shown)

• Vitamin D supplementation lowers fracture risk and fall risk in many but not all trials

• Greater benefit in:- Elderly- Institutionalized- Vitamin D/Ca-deficient people- People who take the supplements (compliance >50-

60%)

DAILY INTAKE RECOMMENDATIONS

• 2011 US IOM report:- 600 IU/d if >1 yo and <70 yo- 800 IU if > 70 yo- Sufficiency= 25OHD>20 ng/ml

• US Endocrine Society- 600-1000 IU/d for kids- Up to 1500-2000 IU/d in adults >19 yo- Sufficiency = 25OHD>30 ng/ml

SPECIAL CASES FOR VITAMIN D REPLETION• In pregnancy, replete more gingerly - 800 -1000 IU/d

- Data on safety of high doses are lacking • Consider referral to Endocrinology for:

- Patients with known malabsorption (celiac dz, IBD)- Post weight loss surgeries- Obesity- Difficulty repleting despite 2-3 courses of high dose

repletion• Do not routinely order refills on ergocalciferol 50,000

iu prescriptions - Toxicity can occur- Renal failure, hospitalization for severe hypercalcemia

US PREVENTIVE TASK FORCE

• Vitamin D With or Without Calcium Supplementation for Prevention of Cancer and Fractures: An Updated Meta-analysis - Combined vitamin D and calcium supplementation can

reduce fracture risk- The effects may be smaller among community-dwelling

older adults than among institutionalized elderly- Appropriate dose and dosing regimens, require further

study. - Evidence is not sufficiently robust to draw conclusions

regarding the benefits or harms of vitamin D supplementation for the prevention of cancer.

Ann Intern Med. 2011;155:827-838

WHAT ABOUT CALCIUM?• Standard diet relatively low in calcium

especially if dairy free• NHANES 2003-2006:

- Males: ~1000 mg/d- Females: ~850 mg/d

- BUT:• <50% men over 50 yo and women in all ages meet

RDI from diet• <25% of women >50 achieved recommended

dietary intake• Men >70: 872-952 mg/d• Women >70: 750-788 mg/d

DRI Men Women 19-50

1000 mg

1000 mg

51-70

1000 mg

1200 mg

>70 1200 mg

1200 mg

SUPPLEMENT TYPES

• Calcium carbonate- Best absorbed with meals- Ok for most people- 40 % elemental (1250 mg = 500 mg elemental)

• Calcium citrate- Absorbed fasting and with meals- Best in setting of achlorydria

• Elderly• Pts on PPI and H2 blockers

- 21% elemental (1500 mg = 315 mg elemental)• DRI refers to elemental calcium

CALCIUM INTAKE AND RISK CVD

• Prospective studies and RCT 1966-2010- Meta-analysis prospective observational studies (5)

• CVD in highest vs lowest calcium supplement use RR: 1.01 (95% CI 0.78-1.3)

• Stroke RR: 0.8 (95% CI 0.63-1.01)- No RCT designed for this outcome. 2ary analyses

from RCTs• CVD RR: 1.14 (95% CI 0.92-1.41) calcium vs pbo (n=3)• CVD RR 0.99 (95% CI 0.79-1.22) calcium with D vs

double placebos (n=2)- No RCT with this outcome as primary, but overall,

no evidence that calcium deleterious to CVD

Wang et al Am J Cardiovasc Drugs 2012: 12(2): 105

CALCIUM INTAKE AND RISK CVD• Trials of calcium with D vs pbo – n=9

- incl WHI participants not taking personal calcium supplements

- Incl unpublished data• RR MI: 1.21 (1.01-1.44) p: 0.04• Criticisms:

- Interaction b/c women using calcium at baseline differed from thos not using calcium in several factors that affect CVD risk (obesity, HRT, age, BMI, BP, hx of CV dz and CVA)

- Randomization did not take this into account- Incl unpublished data- Results driven by WHI dataset b/c so large

Bolland MJ et al BMJ 2011: 342:d2040

THE JUNE 2012 PUBLICATION…

• 23980 EPIC-Heidelberg participants- Food frequency questionnaire for dietary calcium- Questionnaire “supplements daily in past 4

weeks”. No dosage info• Total dietary calcium intake no overall

association with CV risk - likely reduction MI risk with moderately higher

dairy intake (3rd quartile vs 1st, but not 4th vs 1st…)

• MI risk increased with calcium supplements: HR 2.17 (95% CI 1.06-4.42)

Kuanrong L et al Heart 2012, 98: 9250

RECOMMENDATIONS

• Encourage dietary calcium over supplements- Supplements increase serum calcium- Diet does not

• Limit supplements to 500-600 mg/d• Remainder from diet to get 1200 mg/d

if osteoporosis

PEARLS

• Vitamin D- Aim for sufficiency >30 ng/ml- Normalize levels with high dose at first, then chronic

repletion- Typically 1000 IU/d- Avoid intoxication- Most important in elderly and institutionalized- Refer if difficult to replete

• Calcium- Dietary is best- Mild benefit in fracture prevention- Most important in elderly and institutionalized

SIDE EFFECTS

• Constipation• Affects levothyroxine absorption• Cardiovascular risk effects?