2010 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

2010 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada
Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

Strategies for Fracture Prevention
2010 Guidelines Strategies for Fracture Prevention Speaker notes Section Five

Modalities Used to Prevent Fracture
Lifestyle modifications Vitamin D Calcium Exercise Falls prevention Pharmacologic therapy Bisphosphonates Other anti-resorptives Calcitonin Denosumab Hormone therapy Raloxifene Parathyroid hormone Combination therapy Speaker notes There are many non-pharmacologic interventions available to promote bone health and pharmacologic therapies to reduce fracture risk. Available therapeutic options can reduce the risk of future fractures in high-risk individuals by up to 40% – 60% but are dependent on the site of fracture and nature of the treatment. 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.

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; 182:E610-E618. Hanley DA, et al. CMAJ 2010; 182:E610-E618.

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.

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 an adequate supplementation dose 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 three to four 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. Click here for more information on vitamin D. Hanley DA, et al. CMAJ 2010; 182:E610-E618.

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 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 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, Dick IM. 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):

Summary Statements for Calcium & Vitamin D
Strength Vitamin D3 with calcium supplementation increases bone density in postmenopausal women and men over age 50 and reduces the risk of fractures Level 1 Vitamin D3 at daily doses of 800 IU (20 mcg) with calcium (1000 mg) reduces the risk of hip and non-vertebral fractures in elderly populations in institutions The evidence in community-dwelling individuals is less strong Level 2 There is evidence that daily 800 IU (20 mcg) vitamin D3 reduces fall risk, particularly in trials that adequately ascertained falls A daily intake of 1000 IU vitamin D3 (25 mcg)—a commonly available safe dose—will raise serum 25-OH-D level on average by 15 – 25 nmol/L Click here for a summary of the grading system for levels of evidence.

Summary Statement for Other Nonpharmacologic Therapies
Strength Weight bearing, balance and strengthening exercises can improve outcomes in individuals with osteoporosis Level 2 Exercise-focused interventions improve balance and reduce falls in community-dwelling older people Hip protectors may reduce the risk of hip fractures in long-term care residents; however adherence with their use may pose a challenge for the older adult

Medications Indicated for Osteoporosis in Canada
Bisphosphonates—oral and IV Calcitonin Denosumab (RANK ligand inhibitor) Hormone therapy Raloxifene (SERM) Teriparatide (PTH analogue)

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. * 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.

Reduction in Mortality with Anti-osteoporotic Medication
Zoledronic acid has demonstrated a 28% relative reduction in mortality after hip fracture1 Absolute risk reduction: 3.7% Meta-analysis has shown a 10% relative reduction in mortality with anti-osteoporosis therapies in older individuals at high risk of fracture2 Absolute risk reduction: 0.4% Speaker notes The only evidence, from a single trial, that fracture prevention can reduce mortality is in participants receiving zoledronic acid within 90 days of hip fracture.1 Mortality was analyzed as a secondary outcome and biases may have limited the validity of the results (e.g., not all participants were followed for the entire 36 months). However, a recent meta-analysis also reported a 10% reduction in mortality in older individuals at high risk of fractures treated with anti-osteoporosis therapies.2 References 1. Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357(18): 2. Bolland MJ, Grey AB, Gamble GD, et al. Effect of osteoporosis treatment on mortality: A meta-analysis. J Clin Endocrinol Metab 2010; 95(3): 1. Lyles KW, et al. N Engl J Med 2007; 357(18): 2. Bolland MJ, et al. J Clin Endocrinol Metab 2010; 95(3):

Summary Statements for Pharmacotherapy
Strength Alendronate prevents vertebral, non-vertebral, hip, and wrist fractures in post-menopausal women Level 1 Cyclical etidronate prevents vertebral fractures, but has not demonstrated risk reductions for other non-vertebral fracture types Risedronate prevents vertebral, non-vertebral, and hip fractures in post-menopausal women

Summary Statements for Pharmacotherapy (Cont'd)
Strength Zoledronic acid prevents vertebral, non-vertebral, hip fractures in men and women Level 1 Hormone therapy prevents vertebral, non-vertebral, and hip fractures, but is recommended for women with moderate to severe vasomotor symptoms Raloxifene and calcitonin reduce vertebral fractures, but have not demonstrated risk reductions for non-vertebral fractures

Summary Statements for Pharmacotherapy (Cont'd)
Strength Teriparatide reduces vertebral and non-vertebral fractures Level 1 Denosumab reduces vertebral, non-vertebral, and hip fractures

Recommendations for High-risk Individuals
Grade For menopausal women requiring osteoporosis treatment, alendronate, denosumab, risedronate, and zoledronic acid can be used as first-line therapies for prevention of hip, non-vertebral, and vertebral fractures A For menopausal women requiring osteoporosis treatment, teriparatide can be used as a first-line therapy for prevention of non-vertebral and vertebral fractures For menopausal women requiring osteoporosis treatment, raloxifene can be used as a first-line therapy for prevention of vertebral fractures Click here for a summary of the system for grades of recommendations.

Recommendations for High-risk Individuals (Cont'd)
Grade For menopausal women requiring osteoporosis treatment and who require treatment for vasomotor symptoms, hormone therapy can be used as a first-line therapy for prevention of hip, non-vertebral, and vertebral fractures A Clinicians should avoid prescribing more than one anti-resorptive agent concurrently for fracture reduction For menopausal women intolerant of first-line therapies, calcitonin or etidronate can be considered for prevention of vertebral fractures B For men requiring osteoporosis treatment, alendronate, risedronate, and zoledronic acid can be used as first-line therapies for prevention of fractures D

Recommendation for Duration of Therapy
Grade Individuals at high risk for fracture should continue osteoporosis therapy without a drug holiday D Speaker notes There is very little evidence to support any recommendation regarding the questions of how long to treat, use of drug holidays, and the effectiveness of resuming treatment after discontinuation of therapy. No studies have compared the effects of various drug holiday regimens and holiday lengths, and no studies have examined the effectiveness of resuming therapy after a holiday. The possible benefits of a drug holiday include reduction of potential adverse events and costs. In the FLEX (Fracture Intervention Trial Long-Term Extension) trial, after five years of treatment with alendronate, participants either continued on alendronate for an additional five years, or were randomized to placebo for five years.1 At the end of the extension phase, the five-year clinical vertebral fracture rates were decreased by 55% in those who continued on alendronate (for a total of 10 years) compared to those randomized to placebo (i.e., received five years alendronate and five years placebo). There were no differences in non-vertebral fractures or radiographic vertebral fractures. In a RCT with risedronate, participants who had been on treatment for three years (risedronate or placebo) discontinued their study medication and continued on calcium and vitamin D for an additional year.2 At the end of one year off treatment, BMD decreased in those who had been on risedronate previously, but remained higher than baseline in placebo treated subjects. References 1. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 2006; 296(24): 2. Watts NB, Chines A, Olszynski WP, et al. Fracture risk remains one year after discontinuation of risedronate. Osteoporos Int 2008; 19(3): Evidence supporting recommendations for duration of treatment is limited Data for the above recommendation come from the FLEX study (long-term alendronate treatment)1 and the risedronate discontinuation study2 1. Black DM, et al. JAMA 2006; 296(24): 2. Watts NB, et al. Osteoporos Int 2008; 19(3):

Summary Statements ≥≥for Special Groups
Strength Osteoporosis therapies including alendronate, risedronate, and teriparatide reduce the risk of vertebral fractures and maintain BMD in those prescribed glucocorticoids for 3 months or longer Level 1 Etidronate, zoledronic acid, and calcitonin maintain BMD in those prescribed glucocorticoids for 3 months or longer Level 2 Bisphosphonates and denosumab maintain BMD in women prescribed aromatase inhibitors and men prescribed androgen- deprivation therapy

Summary Statements on Treatment Initiation
Strength Multiple fractures confer greater risk than a single fracture Level 1 Prior fractures of the hip and vertebra carry greater risk than other fracture sites Pharmacologic intervention, when based on prior fragility fractures affecting the vertebra or hip, has shown fracture benefit in clinical trials

Summary Statements on Treatment Initiation (Cont'd)
Strength In patients who initiated glucocorticoids, fractures can occur quickly (within three to six months) with prednisone doses as low as 2.5 – 7.5 mg daily with a rapid decline in fracture risk toward baseline after cessation Level 1 Rapid BMD loss in untreated individuals may be an independent risk for fracture Level 2

Recommendations on Treatment Initiation
Grade In individuals over age 50, fragility fracture of the hip or vertebra, or more than one fragility fracture event, constitutes a high risk for future fracture and such individuals should be offered pharmacologic therapy A For those at moderate risk (10% – 20% probability for major osteoporotic fracture over 10 years), lateral radiographs or Vertebral Fracture Assessment (VFA) of the thoracolumbar spine is recommended for further risk stratification and in clinical decision-making regarding pharmacologic interventions

Recommendations on Treatment Initiation (Cont'd)
Grade Pharmacologic therapy should be offered to patients at high absolute risk (> 20% probability for major osteoporotic fracture over 10 years) D For those at moderate fracture risk, patient preference and additional clinical risk factors that are not already incorporated in the risk assessment system should be used to guide pharmacologic management decisions

Testosterone in Men: Summary Statement and Recommendation
Strength Testosterone maintains BMD in hypogonadal men but has not been shown to reduce the risk of fractures Level 2 Recommendation Grade Testosterone is not recommended for the treatment of osteoporosis in men B

Recommendation for Adverse Events
Grade Potential benefits and risks of the prescribed agent should be discussed with each patient prior to initiating therapy to support informed decision-making D Click here for more information on adverse events.

Considerations for Monitoring
Rationale for monitoring: To identify individuals with continued BMD loss, despite appropriate osteoporosis treatment Aspects of monitoring Serial BMD measurements Assessment of adherence Bone turnover markers (BTMs)? Speaker notes The major objective of follow-up testing is to identify individuals with continued BMD loss, despite appropriate osteoporosis treatment. Serial BMD measurement is an important aspect of follow-up, as is assessment of adherence. Assessment of bone turnover markers (BTMs) may also be an important element of monitoring, although further research is still required.

When to Refer to Specialist Care: General
Fracture on first-line therapy with optimal adherence Significant loss on follow-up BMD on first-line therapy with optimal adherence Intolerance of first- and second-line agents Speaker notes Recognizing that there may be situations in which the management of osteoporosis can be complicated, primary care physicians should consider referral where specialized consultation and care is required.

When to Refer to Specialist Care: Special Populations
Referrals to physicians with an interest or expertise in osteoporosis Secondary causes of osteoporosis outside the comfort zone of the individual primary care physician Patients with extremely low BMD Referrals to other specialists Complex individuals with multiple comorbidities, such as those with frequent falling, Alzheimer’s disease, stroke, and Parkinson’s disease Speaker notes Recognizing that there may be situations in which the management of osteoporosis can be complicated, primary care physicians should consider referral where specialized consultation and care is required.

Integrated Approach to Management of Patients Who Are at Risk for Fracture
Encourage basic bone health for all individuals over age 50, including regular active weight-bearing exercise, calcium (diet and supplementation) 1200 mg daily, vitamin D IU (20-50µg) daily and fall-prevention strategies Age < 50 yr Age yr Age > 65 yr Fragility fractures Use of high-risk medications Hypogonadism Malabsorption syndromes Chronic inflammatory conditions Primary hyperparathyroidism Other disorders strongly associated with rapid bone loss or fractures Fragility fracture after age 40 Prolonged use of glucocorticoids or other high-risk medications Parental hip fracture Vertebral fracture or osteopenia identified on radiography High alcohol intake or current smoking Low body weight (< 60 kg) or major weight loss (> 10% of body weight at age 25) Other disorders strongly associated with osteoporosis All men and women Initial BMD Testing

Integrated Approach, Continued
Initial BMD Testing Assessment of fracture risk Low risk (10-year fracture risk < 10%) Moderate risk (10-year fracture risk 10%-20%) High risk (10-year fracture risk > 20% or prior fragility fracture of hip or spine or > 1 fragility fracture) Unlikely to benefit from pharmacotherapy Reassess in 5 yr Lateral thoracolumbar radiography (T4-L4) or vertebral fracture assessment may aid in decision-making by identifying vertebral fractures Always consider patient preference Factors warranting consideration of pharmacologic therapy… Good evidence of benefit from pharmacotherapy

Moderate risk (10-year fracture risk 10%-20%) Lateral thoracolumbar radiography (T4-L4) or vertebral fracture assessment may aid in decision-making by identifying vertebral fractures Factors warranting consideration of pharmacologic therapy: Additional vertebral fracture(s) (by vertebral fracture assessment or lateral spine radiograph) Previous wrist fracture in individuals aged > 65 or those with T-score < -2.5 Lumbar spine T-score much lower than femoral neck T-score Rapid bone loss Men undergoing androgen-deprivation therapy for prostate cancer Women undergoing aromatase inhibitor therapy for breast cancer Long-term or repeated use of systemic glucocorticoids (oral or parenteral) not meeting conventional criteria for recent prolonged use Recurrent falls (> 2 in the past 12 mo) Other disorders strongly associated with osteoporosis, rapid bone loss or fractures Good evidence of benefit from pharmaco-therapy Repeat BMD in 1-3 yr and reassess risk

Moderate risk (10-year fracture risk 10%-20%) Lateral thoracolumbar radiography (T4-L4) or vertebral fracture assessment may aid in decision-making by identifying vertebral fractures Factors warranting consideration of pharmacotherapy: Additional vertebral fracture(s) (by vertebral fracture assessment or lateral spine radiograph) Previous wrist fracture in individuals aged > 65 or those with T-score < -2.5 Lumbar spine T-score much lower than femoral neck T- score Rapid bone loss Men on ADT for prostate cancer Women on AI for breast cancer Long-term or repeated use of systemic glucocorticoids (oral or parenteral) not meeting conventional criteria for recent prolonged use Recurrent falls (> 2 in the past 12 mo) Other disorders strongly associated with osteoporosis, rapid bone loss or fractures Good evidence of benefit from pharmaco-therapy Repeat BMD in 1-3 yr and reassess risk

Additional slides that can be accessed from hyperlinks on core slides
Back-up Material Additional slides that can be accessed from hyperlinks on core slides Section Five – Fracture Risk Assessment

Classification of Vitamin D Status by Serum Level of 25-OH-D
Serum 25-OH-D, nmol/L*† Category Level of evidence < 25 Vitamin D deficiency 3 25 – 75 Vitamin D insufficiency‡ 2 > 75 Desirable vitamin D status > 250 Potential adverse effects * Assumes that serum 25-OH-D is measured by a clinical laboratory participating in an external quality assurance program. †2.5 nmol/L = 1 ng/mL. ‡ ”Insufficiency” is a milder form of deficiency and should preferably be termed “suboptimal vitamin D status.” Hanley DA, et al. CMAJ 2010; 182:E610-E618.

Vitamin D Supplementation (D3) and Reduced Non-vertebral Fracture Risk
Speaker notes A meta-analysis that combined data five trials (N = 9829) that used 17.5 – 20 µg (700 – 800 IU) of vitamin D3 reported a 23% reduction in non-vertebral fractures. A fracture risk reduction was associated with higher serum 25-OH-D levels, particularly when these exceeded 75 nmol/L. Reference 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): Bischoff-Ferrari HA, et al. JAMA 2005; 293(18):

Fracture Risk Reduction with Vitamin D and Calcium
Speaker notes An update of the 2005 meta-analysis (previous slide) found that the combined relative risk from six trials (N = 45,509) of vitamin D3 (10 – 20 µg [400 – 800 IU]) combined with calcium was 0.82 (95% CI, 0.71, 0.94), consistent with an 18% (95% CI, 6-29) reduction in hip fractures. Reference Boonen S, Lips P, Bouillon R, et al. Need for additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab 2007; 92(4): Boonen S, et al. J Clin Endocrinol Metab 2005; 293(18):

Vitamin D: Reduction of Falls in the Elderly
Speaker notes Supplemental vitamin D of at least 700 IU daily has also been found to reduce falls risk by 19% in both community and institutionalized elderly. Reference Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 2009; 339:b3692. Return to main presentation Bischoff-Ferrari HA, et al. BMJ 2009; 339:b3692.

Return to main presentation
Calcium Supplements Supplement type Notes Calcium carbonate Can be refined from limestone, natural elements of the earth, or may come from shell sources, usually oyster Shell sources are often described on the label as a "natural" source Calcium carbonate from oyster shells is not "refined" and can contain variable amounts of lead Chelated calcium Refers to a special way in which calcium is chemically combined with another substance Calcium citrate, calcium lactate, calcium gluconate are examples of chelated preparation Powdered bone (bonemeal) Not recommended, as it may contain contaminants Dolomite A mineral found in rock Speaker notes Calcium supplements are tablets, capsules, or liquids containing the mineral calcium from a non-food source. These sources include: Calcium carbonate, which can be refined from limestone, natural elements of the earth, or may come from shell sources, usually oyster. Shell sources are often described on the label as a "natural" source. Calcium carbonate from oyster shells is not "refined" and can contain variable amounts of lead. Chelated calcium, which refers to a special way in which calcium is chemically combined with another substance. Calcium citrate is an example of such a chelated preparation. Calcium may also be combined with other substances to form preparations such as calcium lactate or calcium gluconate. Powdered bone (bonemeal) or dolomite, a mineral found in rock. (Bonemeal is not recommended, as it may contain contaminants.) Reference Osteoporosis Canada. How much calcium do we need? Accessed on-line at Accessed September 2010. Return to main presentation Accesssed September 2010.

Association of Calcium Intake with Hip Fracture Risk
Speaker notes In a meta-analysis, it was concluded that calcium, with or without vitamin D, resulted in fewer fractures (both hip [shown] and vertebral). Reference 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): Return to main presentation Tang BM, et al. Lancet 2007; 370(9588):

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 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): Return to main presentation

Benefits of Exercise: Fractures and Bone Health
Programs > 1 year including aerobic exercises and strength training have demonstrated positive effects on BMD and thoracic kyphosis but have limited evidence for fracture reduction1 Moderate to vigorous exercise has demonstrated an ability to reduce hip fracture risk2 Speaker notes Exercise is often recommended for individuals with osteoporosis. Programs that are at least one year in duration and include aerobic exercises and strength training have demonstrated positive effects on BMD but have limited evidence for fracture reduction. A systematic review found these programs ranged from two to five days a week with session durations from 20 to 60 minutes, and included strength training for the extremities and trunk, jumping, aerobic exercise (such as walking), stretching, and balance.1 A meta-analysis of cohort studies has demonstrated that moderate to vigorous exercise has demonstrated reduced hip fractures and supports the importance of healthy lifestyle promotion for bone health.2 References 1. De Kam D, Smulders E, Weerdesteyn V, et al. Exercise interventions to reduce fall-related fractures and their risk factors in individuals with low bone density: a systematic review of randomized controlled trials. Osteoporos Int 2009; 20(12): 2. Moayyeri A. The association between physical activity and osteoporotic fractures: a review of the evidence and implications for future research. Ann Epidemiol 2008; 18: 1. De Kam D, et al. Osteoporos Int 2009; 20(12): 2. Moayyeri A. Ann Epidemiol 2008; 18: Return to main presentation

Nonpharmacologic Interventions Associated with Reduction in Falls
Exercise-focused interventions for community-dwelling older people1 Tai chi, gait, and balance training1-3 Home safety assessment (only effective in those at high risk for falls)1 Cataract removal3 Speaker notes An integrated approach to osteoporosis treatment and falls interventions is also beneficial for exercise interventions. In a systematic review, exercise-focused interventions reduced falls for community-dwelling older people.1 Tai chi, gait, and balance training were effective in reducing falls.1-3 Home safety assessment was only effective in those with severe visual impairment and in others at high risk for falls.1 Removal of the first cataract has been demonstrated to reduce falls. References 1. Gillespie LD, Robertson MC, Gillespie WJ, et al. Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev 2009; CD 2. Cameron ID, Murray GR, Gillespie LD, et al. Interventions for preventing falls in older people in nursing care facilities and hospitals. Cochrane Database Syst Rev 2010; 1(CD005465). 3. McClure RJ, Turner C, Peel N, et al. Population-based interventions for the prevention of fall-related injuries in older people. Cochrane Database Syst Rev 2008; 1(CD004441). 1. Gillespie LD, et al. Cochrane Database Syst Rev 2009; CD 2. Cameron ID, et al. Cochrane Database Syst Rev 2010; 1(CD005465). 3. McClure RJ, et al. Cochrane Database Syst Rev 2008; 1(CD004441). Return to main presentation

Benefit of Hip Protectors in Long-term Care
A modest reduction in hip fractures in elderly long-term care residents1,2 Cost effective for fracture reduction in long-term care3 Compliance poses a challenge1 Not effective for older adults residing in the community1,4 Speaker notes Hip protectors have been shown to be ineffective for those older adults residing in the community.1,2 A modest reduction in hip fractures was demonstrated in two meta-analyses of elderly long-term care residents.1,3 A recent Canadian analysis found hip protectors were cost effective in reducing hip fractures in long-term care.4 Compliance with wearing hip protectors poses a challenge and may be responsible for the ineffectiveness of this intervention.1 References 1. Sawka AM, Boulos P, Beattie K, et al. Hip protectors decrease hip fracture in elderly nursing home residents: a Bayesian meta-analysis. J Clin Epidemiol 2007; 60(4): 2. Parker MJ, Gilliespie WJ, Gillespie LD. Effectiveness of hip protectors for preventing hip fractures in elderly people: systematic review. BMJ 2006; 332(7541): 3. Oliver D, Connelly JB, Victor CR, et al. Strategies to prevent falls and fractures in hospitals and care homes and effect of cognitive impairment: systematic review and meta-analysis. BMJ 2006; 334:82-87. 4. Canadian Agency for Drugs and Technologies in Health. Hip Protectors in Long-Term Care Policy Guidance and Implementation Ottawa, Health Technology Inquiry Service (HTIS). Rapid Review. 1. Sawka AM, et al. J Clin Epidemiol 2007; 60(4): 2. Oliver D, et al. BMJ 2006; 334:82-87. 3. Canadian Agency for Drugs and Technologies in Health. Health Technology Inquiry Service (HTIS). Rapid Review. 4. Parker MJ, et al. BMJ 2006; 332(7541): Return to main presentation

Oral Bisphosphonates: Summary
Drug (Brand name) Dosing Schedules Alendronate (Fosamax®, Fosavance®) 10 mg daily 70 mg weekly Risedronate (Actonel®) 5 mg daily mg weekly 150 mg monthly Etidronate (Didrocal®) Cyclical therapy of daily 200 mg for 14 days followed by calcium supplements for 10 weeks Speaker notes Alendronate and risedronate must be taken first thing in morning with plain water, at least 30 minutes before eating. It is best to avoid taking a calcium supplement with breakfast on that day. Patients must refrain from lying down following the intake of the medication. These medications are contraindicated in patients whose creatinine clearance is below 30 mL/min. Adverse events associated with oral bisphosphonates include: upper gastrointestinal symptoms (established association, 10% of trial participants); severe bone, joint and/or muscle pains, distinct form the acute flu-like reaction that sometimes accompanies the initial administration of IV bisphosphonates (established association, rare); esophageal ulceration (established association, rare); esophageal cancer (uncertain association, very rare); osteonecrosis of the jaw (probable association, very rare in patients who take bisphosphonates for osteoporosis, less than 1 per 100,000 patient-years); atypical subtrochanteric and diaphyseal femoral fractures (uncertain association,very rare). Recent re-analysis by the Food and Drug Administration of data from all clinical trials on bisphosphonates found no association between bisphosphonate use and atrial fibrillation. See notes page for information on patient instructions, precautions and adverse events Return to main presentation

IV Bisphosphonate: Summary
Drug (Brand name) Dosing Schedule Zoledronic Acid (Aclasta®) 5 mg intravenously once yearly Speaker notes Vitamin D must be administered in appropriate doses for a minimum of two weeks prior to the infusion. This medication is contraindicated in patients with hypocalcemia and in those whose creatinine clearance is below 35 mL/min. Patients should be warned about the possibility of flu-like symptoms; acetaminophen can be given prior to the infusion and up to 48 hours after, to reduce (or prevent) the severity of the reaction. Elderly patients, those on diuretics or who have impaired renal function should be encouraged to drink 500 mL of water prior to or during the infusion. Adverse events associated with oral bisphosphonates include: acute flu-like reaction (acute phase response) (established association, 10% of trial participants following the first infusion. Incidence decreases with subsequent infusions); severe bone, joint and/or muscle pains distinct form the acute flu-like reaction (established association, rare); hypocalcemia (established association, less than 1% of trial participants); osteonecrosis of the jaw (probable association, very rare in patients who take bisphosphonates for osteoporosis; less than 1 per 100,000 patient-years); atypical subtrochanteric and diaphyseal femoral fractures (uncertain association, very rare) Recent re-analysis by the Food and Drug Agency of data from all clinical trials on bisphosphonates found no association between bisphosphonate use and atrial fibrillation. See notes page for information on patient instructions, precautions and adverse events Return to main presentation

Other Medications: Summary
Drug (Brand name) Dosing Schedule Calcitonin (Miacalcin®) 200 IU intranasally daily Calcium (many formulations) Many dosing schedules Denosumab (Prolia®) 60 mg subcutaneous injection every six months Hormone therapy (many formulations) Raloxifene (Evista®) 60 mg daily Teriparatide (Forteo®) 20 μg subcutaneously daily Speaker notes Calcitonin: well tolerated. Calcium: Total daily intake of calcium (from diet and supplements) should not exceed 1200 mg per day. Adverse events associated with calcium include: cardiovascular events, mostly myocardial infarctions but also stroke (uncertain association, rare) and renal calculi (established association, rare if total intake less than 1500 mg daily). Denosumab: latest agent to be approved for use in Canada. Its product monograph includes discussions of infection risk and dermatologic adverse events. Hormone therapy: still indicated for use to prevent fractures, but due to concerns about malignancies and cardiovascular risk with long-term use, these agents are typically not prescribed for osteoporosis alone. Raloxifene: contraindicated in women who have a history of thromboembolic events. Adverse events associated with oral bisphosphonates include: hot flashes and leg cramps (established association, < 10% of trial participants); and venous thromboembolic events (established association, 0.02% – 0.5% of trial participants). Teriparatide (human parathyroid hormone) is contraindicated in patients who have a history of bone malignancy, hypercalcemia, and active hyperparathyroidism. There is warning on this medication’s package (black box warning) about very rare occurrences of osteosarcomas in growing rats that were given high doses of teriparatide during preclinical studies. Extensive post-marketing surveillance has not documented excess osteosarcomas in patients prescribed this medication compared to the general population. Adverse events associated with teriparatide include: headaches, nausea, and dizziness (established association, 3% – 8% of trial participants); asymptomatic hypercalcemia (established association, 10% of trial participants); and renal calculi (established association, 0.37% –1.4% of trial participants). See notes page for information on patient instructions, precautions and adverse events Return to main presentation

Zoledronic Acid Hip Fracture Trial: Reduction in Mortality
Speaker notes The only clinical trial evidence (from a single trial) that fracture prevention can reduce mortality is in participants receiving zoledronic acid within 90 days of hip fracture.1 Mortality was analyzed as a secondary outcome and biases may have limited the validity of the results (e.g., not all participants were followed for the entire 36 months). This randomized, double-blind, placebo-controlled trial included 2127 patients who had undergone repair of a hip fracture and were unable or unwilling to take an oral bisphosphonate. They were randomized to receive yearly IV zoledronic acid (at a dose of 5 mg) or placebo. All patients (mean age, 74.5 years) received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture. Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357(18): Return to main presentation Lyles KW, et al. N Engl J Med 2007; 357(18):

Meta-analysis of Anti-osteoporosis Medication: Reduction in Mortality
Studies included RR (95% CI) p value Primary Eight studies of four agents (risedronate, strontium ranelate, zoledronic acid, and denosumab) 0.89 (0.80 – 0.99) 0.036 Secondary Ten studies of five agents (as above, plus two studies of alendronate in which the dose changed during the studies) 0.90 (0.81 – 1.0) 0.044 Speaker notes A recent meta-analysis reported a 10% reduction in mortality in older individuals at high risk of fractures treated with anti-osteoporosis therapies. The meta-analysis included randomized placebo-controlled trials of approved doses of medications with proven efficacy in preventing both vertebral and nonvertebral fractures, in which the study duration was longer than 12 months and there were more than 10 deaths. Trials of estrogen and selective estrogen-receptor modulators were specifically excluded. The eight eligible studies in the primary analysis included four agents (risedronate, strontium ranelate, zoledronic acid, and denosumab). During two alendronate studies, the treatment dose changed; those studies were only included in secondary analyses. In the primary analysis, treatment was associated with an 11% reduction in mortality (relative risk, 0.89; 95% CI, 0.80 – 0.99; p = 0.036). In the secondary analysis, the results were similar (relative risk, 0.90; 95% CI, 0.81 – 1.0; p = 0.044). Mortality reduction was not related to age or incidence of hip or nonvertebral fracture, but was greatest in trials conducted in populations with higher mortality rates. Reference Bolland MJ, Grey AB, Gamble GD, et al. Effect of osteoporosis treatment on mortality: A meta-analysis. J Clin Endocrinol Metab 2010; 95(3): Return to main presentation Bolland MJ, et al. J Clin Endocrinol Metab 2010; 95(3):

Clinical Vertebral Fractures in Patients Continuing or Stopping Alendronate Therapy: FLEX Study Speaker notes In the FLEX (Fracture Intervention Trial Long-Term Extension) trial, after five years of treatment with alendronate, participants either continued on alendronate for an additional five years, or were randomized to placebo for five years.1 At the end of the extension phase, the five-year clinical vertebral fracture rates were decreased by 55% in those who continued on alendronate (for a total of 10 years) compared to those randomized to placebo (i.e., five years alendronate and five years placebo). There were no differences in non-vertebral fractures or radiographic vertebral fractures. Reference Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 2006; 296(24): Return to main presentation Black DM, et al. JAMA 2006; 296(24):

New Vertebral Fractures in Those Stopping or Continuing Risedronate Therapy Continued risedronate Stopped Speaker notes In a RCT with risedronate, participants who had been on treatment for three years (risedronate or placebo) discontinued their study medication and continued on calcium and vitamin D for an additional year. At the end of one year off treatment, BMD decreased in those who had been on risedronate previously, but remained higher than baseline in placebo-treated subjects. Reference Watts NB, Chines A, Olszynski WP, et al. Fracture risk remains one year after discontinuation of risedronate. Osteoporos Int 2008; 19(3): Return to main presentation Watts NB, et al. Osteoporos Int 2008; 19(3):

Evidence with Pharmacotherapies for Patients using Long-term Glucocorticoids Both alendronate1,2 and risedronate3,4 reduce risk of vertebral fracture Etidronate is protective against bone loss at the spine but does not prevent fractures5,6 Zoledronic acid improves lumbar spine BMD more effectively than risedronate7 Study not powered to detect differences in fracture reduction Teriparatide reduces radiographic vertebral fractures compared to alendronate8 Calcitonin prevents bone loss at the spine but not at the hip compared to placebo; no effect on fracture risk1,9 Speaker notes Both alendronate1,2 and risedronate3,4 have demonstrated a reduction in morphometric vertebral fractures compared to placebo in patients who are treated with glucocorticoids. There is evidence that etidronate is protective against bone loss at the spine but does not prevent fractures.5,6 A non-inferiority study comparing zoledronic acid to risedronate demonstrated a greater improvement in lumbar spine BMD with zoledronic acid; however the study was not powered to detect differences in fracture reduction.7 Other therapeutic options include teriparatide and calcitonin. Teriparatide treatment resulted in fewer new radiographic vertebral fractures compared to those receiving alendronate (absolute risk reduction, 5.5%), although the incidence of non-vertebral fractures was not significantly different between the groups.8 A meta-analysis of trials with calcitonin compared to placebo did not find a significant effect for the prevention of vertebral or non-vertebral fractures for individuals treated with glucocorticoids.5 There was evidence that calcitonin prevented bone loss at the spine but not at the hip compared to placebo.1,9 References 1. Adachi JD, Saag KG, Delmas PD, et al. Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum 2001; 44(1): 2. Saag KG, Emkey R, Schnitzer TG, et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med 1998; 339(5): 3. Wallach S, Cohen S, Reid DM, et al. Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int 2000; 67(4): 4. Reid DM, Hughes RA, Laan RF, et al. Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study. J Bone Miner Res 2000; 15(6): 5. MacLean C, Newberry S, Maglione M, et al. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 2008; 148(3): 6. Qaseem A, Snow V, Shekelle P, et al. Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2008; 149(6): 7. Reid DM, Devogelaer JP, Saag K, Roux C, Lau CS, Reginster JY et al. Zoledronic acid and risedronate in the prevention of treatment of glucocorticoid-induced osteoporosis (HORIZON): a multi-centre, double-blind, double dummy, randomized controlled trial. Lancet 2009; 373(9671): 8. Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 2007; 357: 9. Cranney A, Welch V, Adachi JD, et al. Calcitonin for the treatment and prevention of corticosteroid-induced osteoporosis. Cochrane Database Syst Rev 2000; (2):CD Return to main presentation 5. MacLean C, et al. Ann Intern Med 2008; 148(3): 6. Qaseem A, et al. Ann Intern Med 2008; 149(6): 7. Reid DM, et al. Lancet 2009; 373(9671): 8. Saag KG, et al. N Engl J Med 2007; 357: 9. Cranney A, et al. Cochrane Database Syst Rev 2000; (2):CD 1. Adachi JD, et al. Arthritis Rheum 2001; 44(1): 2. Saag KG, et al. N Engl J Med 1998; 339(5): 3. Wallach S, et al. Calcif Tissue Int 2000; 67(4): 4. Reid DM, et al. J Bone Miner Res 2000; 15(6):

Evidence for Zoledronic Acid in Women with Breast Cancer Receiving AIs
Reduces aromatase inhibitors (AI)-associated BMD loss Prevents bone loss in postmenopausal women with osteoporosis or low bone mass starting letrozole1 When used upfront, prevents AI-associated BMD loss with early breast cancer more effectively than delaying therapy until BMD loss or fracture occurs2 When added to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer3 Speaker notes Women with breast cancer receiving aromatase-inhibitor (AI) therapy may have increased BMD loss and fractures.1-3 Zoledronic has been demonstrated to reduce AI-associated BMD loss. Zoledronic acid prevents bone loss in postmenopausal women with osteoporosis or low bone mass starting letrozole.4 Up-front zoledronic acid prevented AI-associated BMD loss with early breast cancer more effectively than delaying therapy until BMD loss or fracture occurs.5 As well, the addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer.6 References 1. Saad F, Adachi JD, Brown JP, et al. Cancer treatment-induced bone loss in breast and prostate cancer. Journal of Clinical Oncology 2008; 26(33): 2. Reid DM, Doughty J, Eastell R, et al. Guidance for the management of breast cancer treatment-induced bone loss: A consensus position statement from a UK Expert Group. Cancer Treatment Reviews 2008; 34 Suppl 1:S3-S18. 3. Tsoi D, Khan A, Nowak AK, et al. Bisphosphonates for prevention of bone loss in women with early breast cancer. Cochrane Database Syst Rev 2009; Issue 3. Art. No.:CD 4. Hines SL, Sloan JA, Atherton PJ, et al. Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy. Breast 2010; 19(2):92-96. 5. Brufsky AM, Bosserman LD, Caradonna RR, et al. Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-month follow-up results. Clinical Breast Cancer 2009; 9(2):77-85. 6. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360(7): 1. Hines SL, et al. Breast 2010; 19(2):92-96. 2. Brufsky AM, et al. Clinical Breast Cancer 2009; 9(2):77-85. 3. Gnant M, et al. N Engl J Med 2009; 360(7):

Evidence for Risedronate in Women with Breast Cancer Receiving AIs
Reduces AI-associated bone loss Associated with a significant increase in lumbar spine and total hip BMD Speaker notes Women with breast cancer receiving AI therapy may have increased BMD loss and fractures.1-3 Risedronate has been demonstrated to reduce AI-associated BMD loss. For patients taking adjuvant anastrozole for early breast cancer, risedronate resulted in significant increase in lumbar spine and total hip BMD.4 References 1. Saad F, Adachi JD, Brown JP, et al. Cancer treatment-induced bone loss in breast and prostate cancer. Journal of Clinical Oncology 2008; 26(33): 2. Reid DM, Doughty J, Eastell R, et al. Guidance for the management of breast cancer treatment-induced bone loss: A consensus position statement from a UK Expert Group. Cancer Treatment Reviews 2008; 34 Suppl 1:S3-S18. 3. Tsoi D, Khan A, Nowak AK, et al. Bisphosphonates for prevention of bone loss in women with early breast cancer. Cochrane Database Syst Rev 2009; Issue 3. Art. No.:CD 4. Van Poznak C, Hannon RA, Mackey JR, et al. Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE trial. J Clin Oncol 2010; 28(6): Return to main presentation Van Poznak C, et al. J Clin Oncol 2010; 28(6):

Evidence for Treatment in Men Receiving Androgen-deprivation Therapy for Prostate Cancer Insufficient fracture data in studies with bisphosphonates and selective estrogen receptor modulators (SERMs) Denosumab showed a decreased cumulative incidence of new vertebral fractures at 36 months (absolute risk reduction, 2.4%)1 Speaker notes Men who receive androgen-deprivation therapy (ADT) for prostate cancer are at higher risk for fracture1,2 and should be assessed for pharmacologic therapy.3 There was insufficient fracture data in studies with bisphosphonates and SERMs; however, denosumab showed a decreased cumulative incidence of new vertebral fractures at 36 months (ARR 2.4%).4 References 1. Lau YK, Lee E, Prior HJ, et al. Fracture risk in androgen deprivation therapy: a Canadian population based analysis. Can J Urol 2009; 16(6): 2. Higano CS. Androgen-deprivation therapy-induced fractures in men with nonmetastatic prostrate cancer: what do we really know? Nat Clin Pract Urol 2008; 5:24-34. 3. Ito K, Elkin EB, Girotra M, et al. Cost-effectiveness of fracture prevention in men who receive androgen deprivation therapy for localized prostate cancer. Ann Intern Med 2010; 152(10): 4. Smith MR, Egerdie B, Hernandez TN, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009; 361(8): Return to main presentation 1. Smith MR, et al. N Engl J Med 2009; 361(8):

Factors that Warrant Consideration for Pharmacological Therapy in Moderate Risk Patients
Additional vertebral fracture(s) (> 25% height loss with end-plate disruption) identified on VFA or lateral spine X-ray Previous wrist fracture in individuals > 65 or those with T-score < -2.5 Lumbar spine T-score much lower than femoral neck T-score Rapid bone loss Men on androgen deprivation therapy for prostate cancer Women on aromatase inhibitor therapy for breast cancer Long-term or repeated systemic glucocorticoid use (oral or parenteral) that does not meet the conventional criteria for recent prolonged systemic glucocorticoid use (i.e., > 3 months cumulative during the preceding year at a prednisone equivalent dose > 7.5 mg daily) Recurrent falls defined as falling 2 or more times in the past 12 months Other disorders strongly associated with osteoporosis, rapid bone loss or fractures

Disorders Associated with Osteoporosis and Increased Fracture Risk
Primary hyperparathyroidism Type I diabetes Osteogenesis imperfecta Untreated long-standing hyperthyroidism, hypogonadism, or premature menopause (< 45 years) Cushing’s disease Chronic malnutrition or malabsorption Chronic liver disease Chronic obstructive pulmonary disease Chronic inflammatory conditions (e.g., rheumatoid arthritis, inflammatory bowel disease ) Return to main presentation

Adverse Events of Osteoporosis Therapies
Consult individual product monographs for adverse event information for approved therapies (click on drug names below to link to online resources) Bisphosphonates: alendronate, risedronate, zoledronic acid Calcitonin Denosumab Raloxifene Teriparatide

Bisphosphonates and Osteonecrosis of the Jaw
Definition: The presence of exposed bone in the maxillofacial region that did not heal within eight weeks after identification by a health care provider1 Incidence Oral bisphosphonates: Between 1 in 10,000 and < 1 in 100,000 patient-treatment years IV bisphosphonates: two cases reported in RCTs in postmenopausal osteoporosis (one in placebo group)2 Information on incidence of Osteonecrosis of the Jaw (ONJ) is rapidly evolving: the true incidence may be higher1 Speaker notes Osteonecrosis of the jaw (ONJ) is defined as an area of exposed alveolar bone in the mandible or maxilla that does not heal after eight weeks.1-3 Case series reported ONJ typically occurs in those with underlying malignancy. Osteonecrosis, while extremely rare in patients undergoing osteoporosis therapy, has on occasion been linked to bisphosphonate use in patients with cancer.4-7 Concerns about ONJ and limitations of studies prompted the American Society of Bone and Mineral Research (ASBMR) in 2007 to publish a position paper addressing the case definition, the association with bisphosphonate use, and its treatment.1 This position paper has been endorsed by Osteoporosis Canada. ONJ can occur following tooth extraction or spontaneously, may not be painful, or associated with symptoms and signs of infection. Pain and infection are neither individually nor collectively sufficient for a diagnosis of bisphosphonate associated ONJ, in the absence of exposed jaw bone. Only two cases of ONJ have been reported in randomized controlled trials with IV bisphosphonates given to treat postmenopausal osteoporosis, with the two cases being equally divided between placebo and control.8 The incidence of ONJ is rare in patients undergoing osteoporosis therapy and has been estimated to be no greater than 1 in 10,000 patient-years and is probably less than 1 per 100,000 patient-years.8 The risk is likely much higher in those with underlying malignancy, chemotherapy and radiation, who receive high-dose bisphosphonates for the prevention of skeletal complications, in those individuals on corticosteroids, or with a history diabetes, poor dental hygiene, or invasive dental procedures. References: 1. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res 2009; 22(10): 2. Shane E, Goldring S, Christakos S, et al. Osteonecrosis of the jaw: More research needed. J Bone Miner Res 2006; 10: 3. Sambrook P, Olver I, Goss A. Bisphosphonates and osteonecrosis of the jaw. Australian Family Physician 2006; 35: 4. Cartsos VM, Zhu S, Zavras AI. Bisphosphonate use and the risk of adverse jaw outcomes: a medical claims study of 714,217 people. Journal of the American Dental Association 2008; 139:23-30. 5. Friedrich RE, Blake FA. Avascular mandibular osteonecrosis in association with bisphosphonate therapy: a report on four patients. Anticancer Research 2007; 27(1841):1846. 6. Vieillard MH, Maes JM, Penel G, et al. Thirteen cases of jaw osteonecrosis in patients on bisphosphonate therapy. Joint Bone Spine 2008; 75:34-40. 7. Wutzl A, Biedermann E, Wanschitz F, et al. Treatment results of bisphosphonate-related osteonecrosis of the jaws. Head & Neck 2008; 30: 8. Grbic JT, Landesberg R, Lin SQ, et al. Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial Research Group. J Am Dent Assoc 2008; 139:32-40. . 1. Khosla S, et al. J Bone Miner Res 2009; 22(10): 2. Grbic JT, et al. J Am Dent Assoc 2008; 139:32-40.

Bisphosphonates and Atypical Fracture
Case series reported increased incidence of subtrochanteric fractures with long-term use of bisphosphonates1 15 women treated with alendronate Causation not proven Recent case-control study reported no increase in the incidence in subtrochanteric fractures among patients taking bisphosphonates versus controls2 Increased incidence of subtrochanteric fractures has not been reported with the use of other bisphosphonates Speaker notes A recent case series reported an increased incidence of subtrochanteric fractures associated with long-term use of bisphosphonates.1 The authors identified 15 women with subtrochanteric fractures who had been treated with alendronate. They noted that bisphosphonate use was observed in 37% of all patients presenting with this type of fracture and that in their group of patients these fractures represent only 6% of all hip fractures. Limitations of this report included the small number of women identified with these atypical fractures, the unknown number of patients who sustained these types of fracture who never received alendronate therapy, and the fact that this was not a prospective randomized controlled trial—as such it is not possible to state that alendronate caused the atypical fractures. Further, a recent case-control study reported no increase in the incidence in subtrochanteric fractures among patients taking bisphosphonates compared with controls.2 An increased incidence of subtrochanteric fractures has not been reported with the use of other bisphosphonates. This area is the focus of further research activities. References 1. Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 2008; 358: 2. Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: A register-based national cohort study. J Bone Miner Res 2009; 24: 1. Lenart BA, et al. N Engl J Med 2008; 358: 2. Abrahamsen B, et al. J Bone Miner Res 2009; 24: Return to main presentation

Interpretation of Serial BMD Measurements
Measurement error must be considered when interpreting serial BMD assessments Each centre should determine its precision error in order to estimate the least significant change (LSC)1 Continued BMD loss exceeding the LSC may reflect: Poor adherence to therapy Failure to respond to therapy Previously unrecognized secondary causes of osteoporosis Most anti-osteoporosis therapies do not cause large BMD increases2 Stable BMD is consistent with successful treatment Speaker notes Measurement error must be considered when interpreting serial BMD assessments in order to determine whether the change is real and not simply random fluctuation or artifact. Each centre should determine its precision error in order to estimate the least significant change (i.e., the change in BMD required to have 95% confidence that the change is real).1 Continued BMD loss exceeding the least significant change may reflect poor adherence to therapy, failure to respond to therapy, or previously unrecognized secondary causes of osteoporosis (e.g., vitamin D insufficiency). However, most osteoporosis therapies do not cause large increases in BMD, and the anti-fracture effect of treatment is only partly explained by the relatively small changes in BMD.2 Stable BMD is consistent with successful treatment. References 1. Baim S, Wilson CR, Lewiecki EM, et al. Precision assessment and radiation safety for dual-energy X-ray absorptiometry: position paper of the International Society for Clinical Densitometry. J Clin Densitom 2005; 8(4): 2. Chen P, Krege JH, Adachi JD, et al. Vertebral fracture status and the World Health Organization risk factors for predicting osteoporotic fracture risk. J Bone Miner Res 2009; 24(3): 1. Baim S, et al. J Clin Densitom 2005; 8(4): 2. Chen P, et al. J Bone Miner Res 2009; 24(3):

Recommendations for Frequency of BMD Testing
Usually repeated every 1 – 3 years, with a decrease in testing once therapy is shown to be effective In those at low risk without additional risk factors for rapid BMD loss, a longer testing interval (5 – 10 years) may be sufficient Speaker notes BMD scans are usually repeated every 1 to 3 years, with a decrease in testing once therapy is shown to be effective. In those at low risk without additional risk factors for rapid BMD loss, a longer testing interval (5 to10 years) may be sufficient. Return to main presentation

Importance of Adherence in Treatment Success
The expectation is that treated patients will experience anti-fracture benefits similar to those reported in clinical trials Suboptimal adherence reduces or eliminates anti-fracture benefits1-3 Speaker notes Once a decision to initiate osteoporosis drug therapy has been made, the expectation is that patients will experience anti-fracture benefits similar to those reported in clinical trials. Therapeutic benefit is reduced or eliminated if there is suboptimal adherence to the regimen.1-3 References 1. Silverman S. Adherence to medications for the treatment of osteoporosis. Rheum Dis Clin North Am 2006; 32(4): 2. McCombs JS, Thiebaud P, Laughlin-Miley C, et al. Compliance with drug therapies for the treatment and prevention of osteoporosis. Maturitas 2004; 48(3): 3. Gold DT, Silverman S. Review of adherence to medications for the treatment of osteoporosis. Curr Osteoporos Rep 2006; 4(1):21-27. 1. Silverman S. et al. Rheum Dis Clin North Am 2006; 32(4): 2. McCombs JS, et al. Maturitas 2004; 48(3): 3. Gold DT, et al. Curr Osteoporos Rep 2006; 4(1):21-27.

Poor Adherence Leaves Patients at Higher Risk of Fracture
50% adherence leaves patients at approximately the same fracture risk as no therapy 0.12 0.11 0.10 0.09 0.08 0.07 0.00 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Probability of fracture MPR Siris E, et al. Mayo Clin Proc 2006; 81:

Types and Rates of Non-adherence in Osteoporosis Therapy
Types of non-adherence:1-3 Frequently missed doses Failing to take the medication correctly to optimize absorption and action Discontinuation of therapy Reported one-year adherence rates: 25% –50%1,3 Marginally better with less frequent dosing regimens Speaker notes Types of non-adherence to anti-osteoporosis therapy include frequently missed doses, failing to take the medication correctly to optimize absorption and action, or discontinuation of therapy.1-3 Compliance rates at one year in the range 25% – 50% with oral anti-osteoporosis agents are commonly reported, and are only marginally better with less frequent dosing regimens.1,3 References 1. Silverman S. Adherence to medications for the treatment of osteoporosis. Rheum Dis Clin North Am 2006; 32(4): 2. McCombs JS, Thiebaud P, Laughlin-Miley C, et al. Compliance with drug therapies for the treatment and prevention of osteoporosis. Maturitas 2004; 48(3): 3. Gold DT, Silverman S. Review of adherence to medications for the treatment of osteoporosis. Curr Osteoporos Rep 2006; 4(1):21-27. 1. Silverman S. et al. Rheum Dis Clin North Am 2006; 32(4): 2. McCombs JS, et al. Maturitas 2004; 48(3): 3. Gold DT, et al. Curr Osteoporos Rep 2006; 4(1):21-27.

Approaches for Optimizing Adherence
Reminders Patient information Counselling Simplification of the dosing regimen Self-monitoring Speaker notes Several approaches can be considered to ensure that patients are adherent to therapy and to confirm treatment response. These include a combination of reminders, information, counseling, simplifying dosing regimen, and self-monitoring. Return to main presentation

Desirability of Serial BTMs
Have the potential to provide earlier evidence of treatment effects (within first three to six months) Further clinical trial validation is required Measurement variability between individuals may limit clinical utility Speaker notes BTMs have the potential to provide evidence of treatment effect much earlier than BMD (within the first three to six months), though further confirmation in clinical trials and overcoming challenges of measurement variability within individuals are required before these can be endorsed as a clinical routine. Return to main presentation

Criteria Used to Assign Levels of Evidence: Studies of Diagnosis
1 i Independent interpretation of test results ii Independent interpretation of the diagnostic standard iii Selection of people suspected, but not known to have the disorder iv Reproducible description of the test and diagnostic standard v At least 50 people with and 50 people without the disorder 2 Meets four of the Level 1 criteria 3 Meets two of the Level 1 criteria 4 Meets one or two of the Level 1 criteria

Criteria Used to Assign Levels of Evidence: Studies of Treatment and Intervention
1+ Systematic overview of meta-analysis of RCTs 1 One RCT with adequate power 2+ Systematic overview or meta-analysis of Level 2 RCTs 2 RCT that does not meet Level 1 criteria 3 Non-RCT or cohort study 4 Before/after study, cohort study with non-contemporaneous controls, case-control study 5 Case series without controls 6 Case report or case series of < 10 patients RCT = randomized, controlled study

Criteria Used to Assign Levels of Evidence: Studies of Prognosis
1 i Inception cohort of patients with the condition of interest, but free of the outcome of interest ii Reproducible inclusion and exclusion criteria iii Follow-up of at least 80% of participants iv Statistical adjustment for confounders v Reproducible description of the outcome measures 2 Meets criterion i and three of the other four Level 1 criteria 3 Meets criterion i and two of the other four Level 1 criteria 4 Meets criterion i and one of the other four Level 1 criteria Return to main presentation

Criteria Used to Assign Grades of Recommendation
Level Criteria A Need supportive level 1 or 1+ evidence plus consensus* B Need supportive level 2 or 2+ evidence plus consensus* C Need supportive level 3 evidence plus consensus D Any lower level of evidence supported by consensus * As appropriate level of evidence was necessary, but not sufficient to assign a grade in recommendation; consensus was required in addition. Return to main presentation

2010 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

Similar presentations

Presentation on theme: "2010 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print]."— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

2010 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

Similar presentations

Presentation on theme: "2010 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print]."— Presentation transcript:

Similar presentations

About project

Feedback