1. 2010 Guidelines
Case Study #1 Mrs. DT

2. Case Presentation
Age 59: nine years post-menopause with treated osteoporosis
Has always enjoyed excellent health with no past medical or surgical history
Comes in for her periodic health exam— concerned about calcium and cardiovascular risk

3. Physical Examination Height = 154 cm (60.5 in.)
Weight = 55.5 kg (122 lbs.)
No significant changes in height, weight, posture, or gait from previous visits
Changes in height and weight can be signs of vertebral fractures

4. Medications
Risedronate 35 mg weekly for past six years
Calcium 600 mg + vitamin D 400 IU (single-tablet supplement)

5. History of Osteoporosis: T-scores and Treatment Decisions
Age
BMD T-scores
Action taken 53
Spine: -1.8
Femoral neck: -2.4
Ruled out secondary causes of osteoporosis
Initiated risedronate 35 mg weekly
Educated on importance of dietary calcium
Initiated calcium 1500 mg daily
Initiated vitamin D 400 IU daily

6. Current Risk Factor Assessment
Non-smoker, no regular alcohol consumption
No previous history of fracture
No parental history of hip fracture
No history of systemic glucocorticoid use
No comorbidities
Diet rich in calcium (1200 mg daily from foods)
High caffeine intake

7. Question
Were the diagnosis and treatment initiation in line with today's guideline recommendations?

8. Reflections on the Decision-making Process
Previous diagnosis and treatment decisions were largely based on bone density T-scores
2010 osteoporosis guidelines advocate making decisions based on an assessment of overall 10-year fracture risk
Tools endorsed: CAROC and FRAX
Current recommendations for:
Calcium: 1200 mg from diet and supplement combined
Vitamin D: 800 – 2000 IU daily for age over 50

9. Should This Patient Have Been Receiving Treatment
Should This Patient Have Been Receiving Treatment? FRAX 10-year Risk Assessment
Age
BMD
FRAX-calculated 10-year risk 53
Spine: -1.8
Femoral neck: -2.4
6.0% for major osteoporotic fracture

10. FRAX Calculation of Original Risk (Age 53 – Six Years Ago)

11. Mrs. DT: Reflection on Diagnosis
Six years ago, the diagnosis and therapy were appropriate, given the low BMD at the femoral neck (-2.4) and two minor risk factors (weight < 57kg, high caffeine intake)
With today's tools (e.g., CAROC, FRAX), however, Mrs. DT would have been low risk
Treatment would not have been recommended under the current system

12. Question
Would you consider using a risk-assessment tool to check Mrs. DT's current level of risk on treatment?

13. Absolute Fracture Risk Tools
Calculate risk for treatment-naïve patients only
Cannot be used to monitor response to therapy
Using CAROC or FRAX in a patient on therapy only reflects the theoretical risk of a hypothetical patient who is treatment naïve and does not reflect the risk reduction associated with therapy
One could use these tools to assess what the risk might be for a woman like Mrs. DT who had never been treated

14. FRAX Calculation of Risk for a Woman Like Mrs
FRAX Calculation of Risk for a Woman Like Mrs. DT, but Who Had Never Been Treated

15. Question What would you do in this case?
Would you continue or discontinue treatment with risedronate?
Discuss the rationale for your decision

16. Mrs. DT: Conclusions
Diagnosis and treatment decisions should now be based on 10-year assessment of risk using a validated tool
Patients at low risk (10-year risk < 10%) should not be receiving treatment
Her current risk level is not known:
10-year absolute risk tools were developed to assess patients who are treatment naive
Mrs. DT currently gets adequate calcium from her diet (~1200 mg daily)
Calcium supplementation should be stopped
Vitamin D supplementation should continue

17. Additional slides that can be accessed from hyperlinks on case slides
Back-up Material
Additional slides that can be accessed from hyperlinks on case slides
Case 1 – Mrs. DT

18. Potential Risks of Calcium Supplementation
High-dose calcium supplementation has been associated with
Renal calculi in older women
Cardiovascular events in older women
Prostate cancer in older men
Speaker notes
There is controversy regarding the potential adverse effects of high-dose calcium supplementation on renal calculi and cardiovascular events in older women and on prostate cancer in older men.1-3
References
1. Bolland MJ, Grey AB, Gamble GD, et al. Effect of osteoporosis treatment on mortality: A meta-analysis. J Clin Endocrinol Metab 2010; 95(3):
2. Bolland MJ, Barber AP, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ 2008; 336(7638):
3. Reid IR, Bolland MJ, Grey A, et al. Effect of calcium supplementation on hip fractures. Osteoporos Int 2008; 19(8):
1. Bolland MJ, et al. J Clin Endocrinol Metab 2010; 95(3):
2. Bolland MJ, et al. BMJ 2008; 336(7638):
3. Reid IR, et al. Osteoporos Int 2008; 19(8):
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19. Importance of Weight
In men > 50 years and in postmenopausal women, the following are associated with low BMD and fractures
Low body weight (< 60 kg)
Major weight loss (> 10% of weight at age 25)
Speaker notes
In postmenopausal women and men 50 years and older, low body weight (< 60 kg) and major weight loss (>10% of weight at age 25) are associated with low BMD and fractures.1-6
References
1. Papaioannou A, Kennedy CC, Ioannidis G, et al. The impact of incident fractures on health-related quality of life: 5 years of data from the Canadian Multicentre Osteoporosis Study. Osteoporos Int 2009; 20(5):
2. Waugh EJ, Lam MA, Hawker GA, et al. Risk factors for low bone mass in healthy year old women: A systematic review of the literature. Osteoporos Int 2009; 20:1-21.
3. Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1995; 332(12):
4. Papaioannou A, Joseph L, Ioannidis G, et al. Risk factors associated with incident clinical vertebral and nonvertebral fractures in postmenopausal women: the Canadian Multicentre Osteoporosis Study (CaMos). Osteoporos Int 2005; 16(5):
5. Kanis J, Johnell O, Gullberg B, et al. Risk factors for hip fracture in men from southern Europe: the MEDOS study. Mediterranean Osteoporosis Study. Osteoporos Int 1999; 9:45-54.
6. Morin S, Tsang JF, Leslie WD. Weight and body mass index predict bone mineral density and fractures in women aged 40 to 59 years. Osteoporos Int 2009; 20(3):
1. Papaioannou A, et al. Osteoporos Int 2009; 20(5):
2. Waugh EJ, et al. Osteoporos Int 2009; 20:1-21.
3. Cummings SR,et al. N Engl J Med 1995; 332(12):
4. Papaioannou A, et al. Osteoporos Int 2005; 16(5):
5. Kanis J, et al. Osteoporos Int 1999; 9:45-54.
6. Morin S, et al. Osteoporos Int 2009; 20(3):
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20. Importance of Height Loss
Increased risk of vertebral fracture:
Historical height loss (> 6 cm)1,2
Measured height loss (> 2 cm)3-5
Significant height loss should be investigated by a lateral thoracic and lumbar spine X-ray
Speaker notes
Historical height loss (difference between the tallest recalled height and current measured height)1,2 and measured height loss (from two or more office visits)3-5 are associated with the presence of vertebral fractures. Prospective loss of > 2 cm over three years should be investigated by a lateral thoracic and lumbar spine X-ray.
References
1. Siminoski K, Warshawski RS, Jen H, et al. The accuracy of historical height loss for the detection of vertebral fractures in postmenopausal women. Osteoporos Int 2006; 17(2):
2. Briot K, Legrand E, Pouchain D, et al. Accuracy of patient-reported height loss and risk factors for height loss among postmenopausal women. CMAJ 2010; 182(6):
3. Moayyeri A, Luben RN, Bingham SA, et al. Measured height loss predicts fractures in middle-aged and older men and women: the EPIC-Norfolk prospective population study. J Bone Miner Res 2008; 23:
4. Siminoski K, Adachi JG, Hanley DA, et al. Accuracy of height loss during prospective monitoring for detection of incident vertebral fractures. Osteoporos Int 2005; 16(4):
5. Kaptoge S, Armbrecht G, Felsenberg D, et al. When should the doctor order a spine x-ray? Identifying vertebral fractures for osteoporosis care: results from the European Prospective Osteoporosis Study (EPOS). J Bone Miner Res 2004; 19:
1. Siminoski K, et al. Osteoporos Int 2006; 17(2):
2. Briot K, et al. CMAJ 2010; 182(6):
3. Moayyeri A, et al. J Bone Miner Res 2008; 23:
4. Siminoski K, et al. Osteoporos Int 2005; 16(4):
5. Kaptoge S, et al. J Bone Miner Res 2004; 19:
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21. First Line Therapies with Evidence for Fracture Prevention in Postmenopausal Women*
Type of Fracture
Antiresorptive therapy
Bone formation therapy
Bisphosphonates
Denosumab
Raloxifene
Hormone therapy (Estrogen)**
Teriparatide
Alendronate
Risedronate
Zoledronic acid
Vertebral 
Hip -
Non- vertebral+
Speaker notes
The following agents have level 1 evidence to support their use for prevention of vertebral fracture: alendronate, denosumab, estrogen, raloxifene, risedronate, teriparatide and zoledronic acid. For hip fracture prevention, the following therapies have level 1 evidence: alendronate, denosumab, estrogen, risedronate, zoledronic acid. For non-vertebral fracture prevention, there is level 1 evidence for alendronate, denosumab, estrogen, teriparatide and zoledronic acid.
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* For postmenopausal women,  indicates first line therapies and Grade A recommendation. For men requiring treatment, alendronate, risedronate, and zoledronic acid can be used as first line therapies for prevention of fractures [Grade D].
+ In clinical trials, non-vertebral fractures are a composite endpoint including hip, femur, pelvis, tibia, humerus, radius, and clavicle.
** Hormone therapy (estrogen) can be used as first line therapy in women with menopausal symptoms.

22. 10-year Risk Assessment: CAROC
Semiquantitative method for estimating 10-year absolute risk of a major osteoporotic fracture* in postmenopausal women and men over age 50
Stratified into three zones (Low: < 10%, moderate, high: > 20%)
Basal risk category is obtained from age, sex, and T-score at the femoral neck
Other fractures attributable to osteoporosis are not reflected; total osteoporotic fracture burden is underestimated
Speaker notes
This risk assessment model provides a semiquantitative (ordinal risk category) method for estimating 10-year absolute risk of a major osteoporotic fracture in postmenopausal women and men over age 50.1 An individual’s 10-year absolute fracture risk (combined risk for fractures of the proximal femur, vertebra [clinical], forearm, and proximal humerus) is stratified into three 10-year absolute fracture-risk zones designated low risk (< 10%), moderate risk (10% – 20%), and high risk (> 20%), similar to the absolute risk categories already used for cardiovascular risk assessment.2 Other fractures attributable to osteoporosis (e.g., pelvic fractures and undiagnosed vertebral fractures) are not reflected in the CAROC or FRAX predictions, which will therefore underestimate the total osteoporotic fracture burden.
References
1. Siminoski K, Leslie WD, Frame H, et al. Recommendations for bone mineral density reporting in Canada. Can Assoc Radiol J 2005; 56(3):
2. McPherson R, Frohlich J, Fodor G, et al. Canadian Cardiovascular Society position statement—Recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease. Can J Cardiol 2006; 22(11):
* Combined risk for fractures of the proximal femur, vertebra [clinical], forearm, and proximal humerus
Siminoski K, et al. Can Assoc Radiol J 2005; 56(3):

23. 10-year Risk Assessment for Women (CAROC Basal Risk)
Speaker notes
An initial (basal) risk category is obtained from age, sex, and T-score at the femoral neck. The spine BMD is not considered in the initial risk assessment for either CAROC or FRAX. However when determining the risk category, a patient with a T-score of the spine or hip < -2.5 should not be considered low risk (i.e., should be classified having at least moderate risk).
Reference
Papaioannou A, Leslie WD, Morin S, et al Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada. CMAJ 2010 Oct 12. [Epub ahead of print].
Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

24. 10-year Risk Assessment for Women (CAROC Basal Risk)
Age
Low Risk
Moderate Risk
High Risk 50
above -2.5
-2.5 to -3.8
below -3.8 55 60
above -2.3
-2.3 to -3.7
below -3.7 65
above -1.9
-1.9 to -3.5
below -3.5 70
above -1.7
-1.7 to -3.2
below -3.2 75
above -1.2
-1.2 to -2.9
below -2.9 80
above -0.5
-0.5 to -2.6
below -2.6 85
above +0.1
+0.1 to -2.2
below -2.2
Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

25. 10-year Risk Assessment for Men (CAROC Basal Risk)
Speaker notes
An initial (basal) risk category is obtained from age, sex, and T-score at the femoral neck. The spine BMD is not considered in the initial risk assessment for either CAROC or FRAX. However when determining the risk category, a patient with a T-score of the spine or hip < -2.5 should not be considered low risk (i.e., should be classified having at least moderate risk).
Reference
Papaioannou A, Leslie WD, Morin S, et al Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada. CMAJ 2010 Oct 12. [Epub ahead of print].
Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

26. 10-year Risk Assessment for Men (CAROC Basal Risk)
Age
Low Risk
Moderate Risk
High Risk 50
above -2.5
-2.5 to -3.9
below -3.9 55 60
-2.5 to -3.7
below -3.7 65
above -2.4
-2.4 to -3.7 70
above -2.3
-2.3 to -3.7 75
-2.3 to -3.8
below -3.8 80
above -2.1
-2.1 to -3.8 85
above -2.0
-2.0 to -3.8
Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

27. Risk Assessment with CAROC: Important Additional Risk Factors
Factors that increase CAROC basal risk by one category (i.e., from low to moderate or moderate to high)
Fragility fracture after age 40*1,2
Recent prolonged systemic glucocorticoid use**2
Speaker notes
Certain clinical factors increase fracture risk independently of BMD, the most important being: fragility fractures after age 40 (especially vertebral compression fractures1,2 and recent prolonged systemic glucocorticoid use (e.g., at least three months cumulative during the preceding year at a prednisone equivalent dose of at least 7.5 mg daily).2
References
1. Siminoski K, Leslie WD, Frame H, et al. Recommendations for bone mineral density reporting in Canada. Can Assoc Radiol J 2005; 56(3):
2. Kanis JA, Johansson H, Oden A, et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 2004; 19(6):
* Hip fracture, vertebral fracture, or multiple fracture events should be considered high risk
** >3 months use in the prior year at a prednisone-equivalent dose ≥ 7.5 mg daily
1. Siminoski K, et al. Can Assoc Radiol J 2005; 56(3):
2. Kanis JA, et al. J Bone Miner Res 2004; 19(6):
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28. Risk Assessment Using FRAX
Uses age, sex, BMD, and clinical risk factors to calculate 10-year fracture risk
BMD must be femoral neck
FRAX also computes 10-year probability of hip fracture alone
This system has been validated for use in Canada1
There is an online FRAX calculator with detailed instructions at:
Speaker notes
The WHO Collaborating Centre has identified clinical risk factors which, in addition to age and sex, contribute to fracture risk independently of BMD.1 The FRAX tool, released in 2008, computes 10-year probability of major osteoporotic fracture (composite of hip, vertebra forearm, and humerus) from sex, age, BMI, prior fracture, parental hip fracture, prolonged corticosteroid use, rheumatoid arthritis (or secondary causes of osteoporosis), current smoking, alcohol intake (three or more units daily) and femoral neck BMD.2 FRAX has been validated in Canada.3
Although FRAX also computes 10-year probability of hip fracture alone, the primary designation of risk for clinical decision-making should be the global assessment of major osteoporotic fracture probability. The online FRAX calculator and more details on how it is used is at: You can also type FRAX into a search engine (e.g., Google) and find this main FRAX site.
 References
1. Kanis JA, Johansson H, Oden A, et al. Assessment of fracture risk. Eur J Radiol 2009; 71(3):
2. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int 2007; 18(8):
3. Leslie WD, Lix LM, Langsetmo L, et al. Construction of a FRAX® model for the assessment of fracture probability in Canada and implications for treatment. Osteoporos Int; In press.
* composite of hip, vertebra, forearm, and humerus
1. Leslie WD, et al. Osteoporos Int; In press.

29. FRAX Tool: Online Calculator
Speaker notes
As fracture rates are known to vary by more than an order of magnitude worldwide,1 calibration for the FRAX tool is population/country specific. Using national fracture data, a FRAX model for Canada was recently constructed for the prediction of hip-fracture risk and major osteoporotic fracture risk with and without use of BMD. Performance of this system was independently assessed in CaMos (4778 women and 1919 men) and a clinical cohort from Manitoba (36,730 women and 2873 men).2 The Canadian FRAX tool generated fracture risk predictions that were generally consistent with observed fracture rates across a wide range of risk categories.2,3
Fracture discrimination using FRAX with BMD was better than FRAX without BMD or BMD alone, as has been seen in other cohorts.
In addition to the free on-line calculator, shown here, there is also an iphone app, which is available for a fee.
References
1. Kanis JA, Johnell O, De Laet C, et al. International variations in hip fracture probabilities: implications for risk assessment. J Bone Miner Res 2002; 17(7):
2. Leslie WD, Lix LM, Langsetmo L, et al. Construction of a FRAX® model for the assessment of fracture probability in Canada and implications for treatment. Osteoporos Int; In press.
3. Leslie WD, Lix LM, Johansson H, et al. Independent clinical validation of a Canadian FRAX® Tool: Fracture prediction and model calibration. J Bone Miner Res 2010; Apr 30. [Epub ahead of print].

30. FRAX Clinical Risk Factors
Parental hip fracture
Prior fracture
Glucocorticoid use
Current smoking
High alcohol intake
Rheumatoid arthritis
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31. Recommended Vitamin D Supplementation
Group
Recommended Vitamin D Intake (D3)
Adults < 50 without osteoporosis or conditions affecting vitamin D absorption
400 – 1000 IU daily
(10 mcg to 25 mcg daily)
Adults > 50 or high risk for adverse outcomes from vitamin D insufficiency (e.g., recurrent fractures or osteoporosis and comorbid conditions that affect vitamin D absorption)
800 – 2000 IU daily
(20 mcg to 50 mcg daily)
Speaker notes
There is evidence that vitamin D supplementation is associated with increases in bone mineral density1-3 and reductions in fractures,4 particularly when combined with adequate calcium intake.5
 A recent review and guideline statement from Osteoporosis Canada6 recommends increased vitamin D supplementation for low-risk adults (without osteoporosis or conditions affecting vitamin D absorption) from 10 mcg (400 IU) daily to 10 – 25 mcg (400 – 1000 IU) daily. In those at high risk for adverse outcomes from vitamin D insufficiency (e.g., recurrent fractures or osteoporosis and comorbid conditions that affect vitamin D absorption) recommendations have been increased from 20 mcg (800 IU)/day to 20 – 50 mcg (800 – 2000 IU) daily; some of these patients need doses higher than 50 mcg (2000 IU) daily, and monitoring of the serum 25-OH-D response is appropriate. The optimal level of serum 25OH-D for musculoskeletal benefits is estimated to be at least 75 nmol/L.6
 References
1. Dawson-Hughes B, Harris SS, Krall EA, et al. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997; 337(10):
2. Grados F, Brazier M, Kamel S, et al. Effects on bone mineral density of calcium and vitamin D supplementation in elderly women with vitamin D deficiency. Joint Bone Spine 2003; 70(3):
3. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354:
4. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005; 293(18):
5. Tang BM, Eslick GD, Nowson C, et al. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007; 370(9588):
6. Hanley DA, Cranney A, Jones G, et al. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada. CMAJ 2010; Jul 26. [epub before print].
Hanley DA, et al. CMAJ 2010; Jul 26. [epub before print].

32. Vitamin D: Optimal Levels
To most consistently improve clinical outcomes such as fracture risk, an optimal serum level of 25-hydroxy vitamin D is probably > 75 nmol/L
For most Canadians, supplementation is needed to achieve this level
Speaker notes
The optimal level of serum 25OH-D for musculoskeletal benefits is estimated to be at least 75 nmol/L.6
Reference
Hanley DA, Cranney A, Jones G, et al. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada. CMAJ 2010; 182:E610-E618.
Hanley DA, et al. CMAJ 2010; 182:E610-E618.

33. When to Measure Serum 25-OH-D
In situations where deficiency is suspected or where levels would affect response to therapy
Individuals with impaired intestinal absorption
Patients with osteoporosis requiring pharmacotherapy
Should be checked no sooner than three months after commencing standard-dose supplementation in osteoporosis
Monitoring of routine supplement use and routine screening of otherwise healthy individuals are not necessary
Speaker notes
Serum 25-OH-D should only be measured in situations where deficiency is suspected, or would affect response to therapy; e.g., individuals with impaired intestinal absorption, or in patients with osteoporosis requiring pharmacologic therapy. The half-life of 25-OH-D in the body is 15 – 20 days1 and the serum 25-OH-D response to standard-dose supplementation plateaus after 3 – 4 months.2 Therefore, serum 25-OH-D should be checked no sooner than three months after commencing standard-dose supplementation in patients who have osteoporosis. Monitoring of routine supplement use and routine testing of otherwise healthy individuals as a screening procedure are not necessary.3
References
1. Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 2008; 88(2):582S-586S.
2. Heaney RP, Davies KM, Chen TC, et al. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003; 77(1):
3. Hanley DA, Cranney A, Jones G, et al. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada. CMAJ 2010; 182:E610-E618.
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Hanley DA, et al. CMAJ 2010; 182:E610-E618.

34. Recommended Calcium Intake
From diet and supplements combined: 1200 mg daily
Several different types of calcium supplements are available
Evidence shows a benefit of calcium on reduction of fracture risk1
Concerns about serious adverse effects with high-dose supplementation2-4
Speaker notes
Dietary calcium exerts a mild suppressive effect on bone turnover and this has a beneficial impact on BMD.1,2 In a meta-analysis, it was concluded that calcium, with or without vitamin D, resulted in fewer fractures (both hip [shown] and vertebral).3
Health Canada defines adequate calcium intake (from diet and supplements) as 1200 mg daily with an upper tolerable level of 2500 mg per day for adults 50 and older. The upper tolerable levels were derived from historical concerns over the development of milk-alkali syndrome in individuals who consumed large doses of calcium. High doses of calcium supplements are difficult to achieve as individuals experience gastrointestinal symptoms such as constipation. There is also controversy regarding the potential adverse effects of high-dose calcium supplementation on renal calculi and cardiovascular events in older women and on prostate cancer in older men.4-6
These symptoms may have contributed to compliance rates of 40% or less in the majority of randomized controlled trials on calcium supplementation.1,7 Therefore, we have revised our recommendation on total (diet plus supplements) daily calcium intake from 1500 mg to 1200 mg.
References
1. Reid IR, Bolland MJ, Grey A, et al. Effect of calcium supplementation on hip fractures. Osteoporos Int 2008; 19(8):
2. Moschonis G, Katsaroli I, Lyritis GP, et al. The effects of a 30-month dietary intervention on bone mineral density: The Post-menopausal Health Study. Br J Nutr 2010; 104(1):100-7.
3. Tang BM, Eslick GD, Nowson C, et al. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007; 370(9588):
4. Bolland MJ, Grey AB, Gamble GD, et al. Effect of osteoporosis treatment on mortality: A meta-analysis. J Clin Endocrinol Metab 2010; 95(3):
5. Bolland MJ, Barber AP, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ 2008; 336(7638):
6. Reid IR, Bolland MJ, Grey A, et al. Effect of calcium supplementation on hip fractures. Osteoporos Int 2008; 19(8):
7. Prince RL, Devine A, Dhaliwal SS, et al. Effects if calcium supplementation on clinical fractures and bone structure: results of a 5-year double-blind placebo controlled trial in elderly women. Arch Intern Med 2006; 166:
1. Tang BM, et al. Lancet 2007; 370(9588):
2. Bolland MJ, et al. J Clin Endocrinol Metab 2010; 95(3):
3. Bolland MJ, et al. BMJ 2008; 336(7638):
4 Reid IR, et al. Osteoporos Int 2008; 19(8):
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