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Osteoporosis DeAnn Cummings, MD January 12, 2012.

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1 Osteoporosis DeAnn Cummings, MD January 12, 2012

2 Why Does it Matter? 44 million people in U.S. with low bone mass 44 million people in U.S. with low bone mass 2 million osteoporotic fractures per year 2 million osteoporotic fractures per year $17 billion spent per year on osteoporotic fractures and their complications $17 billion spent per year on osteoporotic fractures and their complications 20% increased mortality over 5 years following a vertebral fracture 20% increased mortality over 5 years following a vertebral fracture 10-30% increased mortality over one year following a hip fracture 10-30% increased mortality over one year following a hip fracture 17% for women 17% for women 30% for men 30% for men

3 Why Does it Matter? 50% require nursing home care after hip fracture 50% require nursing home care after hip fracture 30% need assistance with daily activities 30% need assistance with daily activities Only 20% return to previous level of functioning Only 20% return to previous level of functioning

4 Definition A microarchitectural deterioration of bone tissue resulting in decreased bone strength which predisposes to an increased risk of fracture A microarchitectural deterioration of bone tissue resulting in decreased bone strength which predisposes to an increased risk of fracture Bone strength = Bone density + Bone quality Bone strength = Bone density + Bone quality Bone mineral density (BMD) is usually used as a surrogate to assess bone strength Bone mineral density (BMD) is usually used as a surrogate to assess bone strength

5 Bone Mineral Density Fracture risk increases 2-3 times for each standard deviation below gender-matched young adult mean Fracture risk increases 2-3 times for each standard deviation below gender-matched young adult mean T score = #standard deviations from gender- matched young adult mean T score = #standard deviations from gender- matched young adult mean Z score = #standard deviations from age and gender-matched mean Z score = #standard deviations from age and gender-matched mean T score best correlates with fracture risk T score best correlates with fracture risk

6 World Health Organization Definitions Normal – T score greater than or equal to -1.0 Normal – T score greater than or equal to -1.0 Osteopenia – T score between -1.0 and -2.5 Osteopenia – T score between -1.0 and -2.5 Osteoporosis – T score less than or equal to -2.5 Osteoporosis – T score less than or equal to -2.5 Established osteoporosis – T score < -2.5 and at least one fragility fracture Established osteoporosis – T score < -2.5 and at least one fragility fracture

7 Pathophysiology Balance between bone resorption and formation (remodeling) Balance between bone resorption and formation (remodeling) Remodeling is in balance until about age 50 Remodeling is in balance until about age 50 Osteoclasts resorb bone Osteoclasts resorb bone Osteoblasts form bone Osteoblasts form bone Estrogen inhibits osteoclastic bone resorption Estrogen inhibits osteoclastic bone resorption Peak bone mass is established by age 20 for the hip and during the early 30’s for the spine Peak bone mass is established by age 20 for the hip and during the early 30’s for the spine

8 Pathophysiology Women have increased incidence of osteoporosis compared to men due to: Women have increased incidence of osteoporosis compared to men due to: Lower peak bone mass Lower peak bone mass Greater bone loss after menopause (10% bone loss) Greater bone loss after menopause (10% bone loss) Men and non-white women have higher peak bone mass than white women Men and non-white women have higher peak bone mass than white women Genetic factors – 70-80% of peak bone mass is genetically determined Genetic factors – 70-80% of peak bone mass is genetically determined Pregnancy and lactation cause transient bone loss Pregnancy and lactation cause transient bone loss

9 Pathophysiology Bone quality Bone quality Disruption of microarchitectural elements of trabecular bone Disruption of microarchitectural elements of trabecular bone Cortical thinning Cortical thinning Decrease in degree of mineralization Decrease in degree of mineralization May be important in the future May be important in the future

10 Types of Osteoporosis Primary osteoporosis Primary osteoporosis Related to aging and/or decreased gonadal function Related to aging and/or decreased gonadal function Aging bone loss is slower than menopausal Aging bone loss is slower than menopausal Menopause related bone loss lasts about 10 yrs Menopause related bone loss lasts about 10 yrs Secondary osteoporosis Secondary osteoporosis Due to medications or chronic illnesses that accelerate bone loss Due to medications or chronic illnesses that accelerate bone loss Consider secondary osteoporosis if Z-score is low Consider secondary osteoporosis if Z-score is low

11 Chronic Diseases Cushing’s syndrome Cushing’s syndrome Hyperparathyroidism Hyperparathyroidism Hyperthyroidism Hyperthyroidism Multiple myeloma Multiple myeloma Lymphoma Lymphoma Chronic liver disease Chronic liver disease Chronic renal disease Chronic renal disease Malabsorption syndromes Malabsorption syndromes Paraplegics, quadriplegics Paraplegics, quadriplegics Hypogonadism Hypogonadism Anorexia nervosa Anorexia nervosa Athletic amenorrhea Athletic amenorrhea Diabetes mellitus Diabetes mellitus Hemochromatosis Hemochromatosis Hyperprolactinemia Hyperprolactinemia Osteogenesis imperfecta Osteogenesis imperfecta Rheumatoid arthritis Rheumatoid arthritis Lupus Lupus Psoriatic arthritis Psoriatic arthritis Vitamin D and Calcium deficiency Vitamin D and Calcium deficiency

12 Medications Glucocorticoids Glucocorticoids Lithium Lithium Chemotherapy Chemotherapy GnRH agonist GnRH agonist Anticonvulsants Anticonvulsants Phenobarbital Phenobarbital Dilantin Dilantin Tegretol Tegretol Valproate Valproate Methotrexate Methotrexate SSRIs SSRIs Prolonged heparin use Prolonged heparin use Coumadin (?) Coumadin (?) Cyclosporine (?) Cyclosporine (?) Aromatase inhibitors Aromatase inhibitors Excess thyroid hormone Excess thyroid hormone Medroxyprogesterone Medroxyprogesterone Vitamin A Vitamin A Proton pump inhibitors Proton pump inhibitors

13 Case #1 70 year old female presents with a new vertebral compression fracture after slipping on the ice. She has never had BMD testing. 70 year old female presents with a new vertebral compression fracture after slipping on the ice. She has never had BMD testing. PMH PMH HTN HTN Hyperlipidemia Hyperlipidemia GERD GERD Depression Depression

14 Case #1 MEDS MEDS Lisinopril Lisinopril Zocor Zocor Protonix Protonix Celexa Celexa Family hx – No hx osteoporosis known Family hx – No hx osteoporosis known Social hx – Non-smoker, no ETOH Social hx – Non-smoker, no ETOH

15 Case #1 Should her SSRI be stopped? Should her SSRI be stopped? Should her PPI be stopped? Should her PPI be stopped? Should she have received BMD testing prior to starting these meds? Should she have received BMD testing prior to starting these meds?

16 SSRIs and Osteoporosis Canadian Multicenter Osteoporosis Trial – 2006 Canadian Multicenter Osteoporosis Trial – 2006 Prospective cohort of 5008 adults 50 years old or greater, followed over 5 years for fractures Prospective cohort of 5008 adults 50 years old or greater, followed over 5 years for fractures 137 were on SSRIs 137 were on SSRIs Risk of fragility fracture was increased 2 fold for pts on SSRIs Risk of fragility fracture was increased 2 fold for pts on SSRIs Relative risk = 2.1 (1.3-3.4) Relative risk = 2.1 (1.3-3.4) Relative risk for corticosteroids = 1.33-2.6 Relative risk for corticosteroids = 1.33-2.6 Study did not evaluate duration of SSRI use Study did not evaluate duration of SSRI use

17 PPIs and Osteoporosis Prospective trial – (Roux 1/09) Prospective trial – (Roux 1/09) 1211 post-menopausal women 1211 post-menopausal women For women on omeprazole the relative risk for vertebral fractures was 3.5 (1.14-8.44) For women on omeprazole the relative risk for vertebral fractures was 3.5 (1.14-8.44) Need more studies Need more studies FDA recommends considering shorter duration or lower dose of PPI FDA recommends considering shorter duration or lower dose of PPI PPI may interfere with calcium absorption PPI may interfere with calcium absorption Consider calcium citrate supplementation Consider calcium citrate supplementation No studies on initial BMD testing prior to starting med No studies on initial BMD testing prior to starting med

18 Case #2 16 year old female presents for discussion of birth control options. 16 year old female presents for discussion of birth control options. PMH – None PMH – None Family hx – No hx osteoporosis Family hx – No hx osteoporosis Social hx – No smoking, ETOH or drugs Social hx – No smoking, ETOH or drugs Pt really wants Depo Provera but her Mom is concerned about side effects – she has heard that it weakens bones. Pt really wants Depo Provera but her Mom is concerned about side effects – she has heard that it weakens bones.

19 DepoProvera Cross-sectional studies show decreased BMD in Depo users Cross-sectional studies show decreased BMD in Depo users No studies have shown increased fracture risk with depo-users No studies have shown increased fracture risk with depo-users Bone mass increases with cessation of Depo Bone mass increases with cessation of Depo FDA recommends stopping Depo after 2 years unless no other viable birth control options FDA recommends stopping Depo after 2 years unless no other viable birth control options FDA suggests evaluating BMD for use greater than 2 years FDA suggests evaluating BMD for use greater than 2 years

20 History – Risk Factors History of fractures, esp. vertebra, hip or wrist History of fractures, esp. vertebra, hip or wrist Family history of osteoporosis or fragility fxs. Family history of osteoporosis or fragility fxs. Menstrual history – history of estrogen deficiency Menstrual history – history of estrogen deficiency Nutrition Nutrition Exercise Exercise Habits – tobacco, alcohol and caffeine use Habits – tobacco, alcohol and caffeine use

21 History and Physical Exam No reliable history or physical findings to identify patients with osteoporosis No reliable history or physical findings to identify patients with osteoporosis Look for risk factors and signs of occult vertebral fractures Look for risk factors and signs of occult vertebral fractures Look for possible secondary causes of osteoporosis Look for possible secondary causes of osteoporosis Consider further laboratory tests only if signs of a secondary cause Consider further laboratory tests only if signs of a secondary cause

22 History – Vertebral Fractures Back pain – acute or chronic Back pain – acute or chronic Loss of height (>1 inch) Loss of height (>1 inch) Restrictive lung disease symptoms (exertional dyspnea, decreased exercise tolerance) Restrictive lung disease symptoms (exertional dyspnea, decreased exercise tolerance) Symptoms of reduced abdominal cavity (early satiety) Symptoms of reduced abdominal cavity (early satiety) Symptoms of depression, anxiety and fear Symptoms of depression, anxiety and fear

23 Physical Exam Measure height and body weight Measure height and body weight Look for spinal tenderness and deformities (dowager’s hump) Look for spinal tenderness and deformities (dowager’s hump) Look for tooth loss Look for tooth loss Look for protuberant abdomen Look for protuberant abdomen Signs of secondary osteoporosis Signs of secondary osteoporosis Consider home visit to assess risk for falling Consider home visit to assess risk for falling

24 Risk Factors for Osteoporosis Non-modifiable Non-modifiable Female gender Female gender Increased age Increased age White or Asian race White or Asian race Family history of osteoporosis Family history of osteoporosis Personal history of fracture Personal history of fracture Previous hyperthyroidism Previous hyperthyroidism Rheumatoid arthritis Rheumatoid arthritis Secondary osteoporosis Secondary osteoporosis

25 Risk Factors for Osteoporosis Modifiable Modifiable Tobacco use Tobacco use Sedentary lifestyle Sedentary lifestyle Caffeine use (tea is OK) Caffeine use (tea is OK) Low calcium and vitamin D intake Low calcium and vitamin D intake Alcohol use (> 2 drinks per day) Alcohol use (> 2 drinks per day) Hormone deficiency states Hormone deficiency states Low weight (BMI<21) Low weight (BMI<21) Elevated homocysteine levels Elevated homocysteine levels Corticosteroid use (5 mg prednisone daily for 3 months) Corticosteroid use (5 mg prednisone daily for 3 months)

26 Risk Factors for Fractures History of falling History of falling Poor physical condition Poor physical condition Neurological disorders Neurological disorders Impaired vision and hearing Impaired vision and hearing Certain meds – sedatives, anti-hypertensives Certain meds – sedatives, anti-hypertensives Environmental hazards Environmental hazards

27 Environment Modification Remove throw rugs Remove throw rugs Decrease clutter Decrease clutter Handrails on stairs Handrails on stairs Improve lighting, night lights Improve lighting, night lights Handrails in tubs and showers, non-skid surfaces Handrails in tubs and showers, non-skid surfaces Cane or walker if needed Cane or walker if needed Consider hip protectors Consider hip protectors Wear supportive, low-heeled shoes Wear supportive, low-heeled shoes Tape down electric cords Tape down electric cords

28 Case #3 63 year old female presents for a physical 63 year old female presents for a physical PMH PMH HTN HTN GERD GERD Anxiety Anxiety Meds Meds Metoprolol Metoprolol Omeprazole Omeprazole

29 Case #3 Social hx – smokes 1ppd, minimal ETOH Social hx – smokes 1ppd, minimal ETOH Family hx – No osteoporosis or hip fractures Family hx – No osteoporosis or hip fractures BMI = 23, Ht = 5-4 BMI = 23, Ht = 5-4 Should she be screened for osteoporosis? Should she be screened for osteoporosis?

30 Screening – Who to Screen? No studies showing decreased fracture risk with screening No studies showing decreased fracture risk with screening However: However: Good evidence for increasing risk of osteoporosis and fracture with age Good evidence for increasing risk of osteoporosis and fracture with age Good evidence that bone mineral density accurately predicts fracture risk (RR=2.6 for -1SD) Good evidence that bone mineral density accurately predicts fracture risk (RR=2.6 for -1SD) Good evidence that treating asymptomatic women with osteoporosis decreases fracture risk Good evidence that treating asymptomatic women with osteoporosis decreases fracture risk

31 Screening – Who to Screen? US Preventive Services Task Force recommendations based on current evidence US Preventive Services Task Force recommendations based on current evidence Screen all women > or equal to 65 years Screen all women > or equal to 65 years Screen women 60-65 yrs. if at increased risk Screen women 60-65 yrs. if at increased risk Lower body wt. is best predictor of low BMD Lower body wt. is best predictor of low BMD Consider using FRAX Consider using FRAX Grade B recommendations – fair to good evidence to support recommendation, benefits outweigh risks Grade B recommendations – fair to good evidence to support recommendation, benefits outweigh risks

32 Screening – Who to Screen? USPSTF recommendations continued USPSTF recommendations continued No recommendations for or against routine screening in women <60 yrs. or women 60-64 yrs. with no increased risk No recommendations for or against routine screening in women <60 yrs. or women 60-64 yrs. with no increased risk Screening women at lower risk for osteoporosis can identify additional women who might benefit from treatment but would prevent smaller # fractures. Screening women at lower risk for osteoporosis can identify additional women who might benefit from treatment but would prevent smaller # fractures. Grade C recommendation – balance of benefits to harms is too close to make recommendation Grade C recommendation – balance of benefits to harms is too close to make recommendation

33 Screening – Who to Screen? USPSTF guidelines agree with guidelines of the National Osteoporosis Foundation and the American Association of Clinical Endocrinologists USPSTF guidelines agree with guidelines of the National Osteoporosis Foundation and the American Association of Clinical Endocrinologists All recommend screening only if results will influence treatment All recommend screening only if results will influence treatment If patient not in favor of treatment, DON’T SCREEN! If patient not in favor of treatment, DON’T SCREEN!

34 Screening in Men National Osteoporosis Foundation National Osteoporosis Foundation Recommends screening all men over age 70 regardless of risk factors Recommends screening all men over age 70 regardless of risk factors Evaluate for risk factors and discuss calcium and vitamin D intake in all men >50 Evaluate for risk factors and discuss calcium and vitamin D intake in all men >50 Screen men ages 50-69 with risk factors Screen men ages 50-69 with risk factors However, very little evidence for or against screening men However, very little evidence for or against screening men

35 Screening Disadvantages Cost Cost Potential radiation exposure Potential radiation exposure Potential unnecessary treatment for false positive or misinterpreted results Potential unnecessary treatment for false positive or misinterpreted results Increased anxiety and perceived vulnerability – can lead to increase in sedentary habits Increased anxiety and perceived vulnerability – can lead to increase in sedentary habits

36 Risk Factor Assessment Which are best at predicting osteoporotic fractures? Which are best at predicting osteoporotic fractures? May help decide who to screen May help decide who to screen

37 Risk Factor Assessment Age, weight and history of previous fracture correlate the best with low BMD Age, weight and history of previous fracture correlate the best with low BMD FRAX = Fracture Risk Assessment tool FRAX = Fracture Risk Assessment tool Developed by WHO – 2008 Developed by WHO – 2008 Estimates 10 year probability of major osteoporotic fractures and hip fracture Estimates 10 year probability of major osteoporotic fractures and hip fracture www.shef.ac.uk/FRAX/ www.shef.ac.uk/FRAX/

38 Risk Factor Assessment FRAX FRAX Age Age Gender Gender Prior fracture Prior fracture Low BMI Low BMI Oral steroids Oral steroids Rheumatoid arthritis Rheumatoid arthritis Secondary osteoporosis Secondary osteoporosis Parental hx of hip fracture Parental hx of hip fracture Smoking Smoking ETOH ETOH

39 Case #3 Decision is made to screen this patient Decision is made to screen this patient Which test is the best test? Which test is the best test?

40 Screening – Which Test? Conventional x-rays – osteopenia not detected until bone mass 40% decreased Conventional x-rays – osteopenia not detected until bone mass 40% decreased Bone turnover markers – experimental, expensive and no good evidence to support use (human osteocalcin, bone alkaline phosphatase) Bone turnover markers – experimental, expensive and no good evidence to support use (human osteocalcin, bone alkaline phosphatase) High false positive rate High false positive rate

41 Screening – Which Test? All tests below have equivalent fracture risk predictability All tests below have equivalent fracture risk predictability Dual-energy x-ray absorptiometry (DEXA) Dual-energy x-ray absorptiometry (DEXA) Quantitative CT Quantitative CT Calcaneal ultrasonography Calcaneal ultrasonography

42 Screening – Which Test? Calcaneal ultrasonography Calcaneal ultrasonography Usually tests calcaneus only Usually tests calcaneus only Reflects other aspects of bone quality Reflects other aspects of bone quality More portable test More portable test No radiation No radiation Low cost Low cost Low precision Low precision Difficult to apply measurements to treatment protocols Difficult to apply measurements to treatment protocols

43 Screening – Which Test? Quantitative CT Quantitative CT Usually tests spine and hip Usually tests spine and hip High radiation High radiation High cost High cost Good precision Good precision

44 Screening – Which Test? DEXA DEXA Best validated test in studies and therefore considered gold standard Best validated test in studies and therefore considered gold standard Results vary by 6-15% when using machines from different manufacturers Results vary by 6-15% when using machines from different manufacturers Usually test spine, hip or wrist (lateral spine) Usually test spine, hip or wrist (lateral spine) Low radiation Low radiation Intermediate cost Intermediate cost Excellent precision – best if same machine is used and same technician Excellent precision – best if same machine is used and same technician

45 Screening – Which Test? DEXA DEXA HOWEVER…… HOWEVER…… DEXA identifies fewer than half the people that go on to have an osteoporotic fracture DEXA identifies fewer than half the people that go on to have an osteoporotic fracture

46 Case #3 Her DEXA reveals a T-score = -1.5 Her DEXA reveals a T-score = -1.5 When should she be retested if at all? When should she be retested if at all?

47 Screening – How Often? Screening more often than every 2 years will not show accurate change in BMD Screening more often than every 2 years will not show accurate change in BMD Repeat screening more likely to be beneficial in older women and women with risk factors Repeat screening more likely to be beneficial in older women and women with risk factors No evidence about follow-up BMD testing after initiation of treatment No evidence about follow-up BMD testing after initiation of treatment NOF recommends follow-up BMD every 2 years on treatment NOF recommends follow-up BMD every 2 years on treatment

48 Screening Summary Screen all high risk women Screen all high risk women Women > 64 Women > 64 Women < 65 with significant risk factors Women < 65 with significant risk factors Men with risk factors Men with risk factors Screen every 2 years Screen every 2 years Consider using risk assessment tools to determine high risk Consider using risk assessment tools to determine high risk DEXA scan is best test (BUT not perfect) DEXA scan is best test (BUT not perfect)

49 Case #3 She gets repeat screening with DEXA in two years and the T-score is now -2.5 She gets repeat screening with DEXA in two years and the T-score is now -2.5 Does she need evaluation for secondary causes of osteoporosis? Does she need evaluation for secondary causes of osteoporosis?

50 Evaluating for Secondary Osteoporosis AACE AACE CBC CBC CMP CMP Ca, Phos Ca, Phos 24 hour urine for Ca, Na, creatinine excretion 24 hour urine for Ca, Na, creatinine excretion 25-hydroxyvitamin D level 25-hydroxyvitamin D level Above eval detects 90% of secondary osteoporosis Above eval detects 90% of secondary osteoporosis

51 Case #4 71 year old female presents for a review of her DEXA results which reveal a T-score of -2.0. She has no hx of fractures and no family hx of fractures. She does not smoke. Her BMI=25. 71 year old female presents for a review of her DEXA results which reveal a T-score of -2.0. She has no hx of fractures and no family hx of fractures. She does not smoke. Her BMI=25. Do you tell her she has osteoporosis? Do you tell her she has osteoporosis? Are her results normal? Are her results normal? Do you recommend treatment for osteoporosis and if so what? Do you recommend treatment for osteoporosis and if so what?

52 Who to Treat? Definite reduction in fractures for treatment of BMD <-2.5 and for pts with history of fragility fractures Definite reduction in fractures for treatment of BMD <-2.5 and for pts with history of fragility fractures Is there any benefit in treating anyone else? Is there any benefit in treating anyone else?

53 What About Osteopenia? T score between -1.0 and -2.5 T score between -1.0 and -2.5 RCTs show no reduction in fracture risk for patients with T scores -1.6 to -2.5 RCTs show no reduction in fracture risk for patients with T scores -1.6 to -2.5 Individualize management Individualize management Decrease modifiable risk factors Decrease modifiable risk factors Increase calcium and vitamin D intake Increase calcium and vitamin D intake Increase exercise Increase exercise Decrease tobacco, alcohol and caffeine use Decrease tobacco, alcohol and caffeine use

54 What About Osteopenia? Use FRAX calculator Use FRAX calculator If assessed risk of hip fracture is >3% for the next ten years, consider treatment If assessed risk of hip fracture is >3% for the next ten years, consider treatment If risk of major osteoporotic fracture (wrist, vertebral, hip or proximal humerus) is >20% for the next ten years, consider treatment If risk of major osteoporotic fracture (wrist, vertebral, hip or proximal humerus) is >20% for the next ten years, consider treatment Using this calculator most pts with osteopenia will not be treated Using this calculator most pts with osteopenia will not be treated No actual studies on outcomes using FRAX No actual studies on outcomes using FRAX www.shef.ac.uk/FRAX/ www.shef.ac.uk/FRAX/

55 Treatment Options Exercise Exercise Calcium and Vitamin D Calcium and Vitamin D Estrogen Estrogen Bisphosphonates Bisphosphonates Raloxifene Raloxifene Calcitonin Calcitonin Parathyroid hormone Parathyroid hormone

56 Case #5 65 year old, very healthy female has just found out she has osteoporosis. She does not want to “pollute her body with chemicals” and will only use “natural remedies” 65 year old, very healthy female has just found out she has osteoporosis. She does not want to “pollute her body with chemicals” and will only use “natural remedies” What do you recommend? What do you recommend?

57 Exercise Weight-bearing activity – walking, running, aerobics, stair-climbing, strength training, dancing, court and field sports Weight-bearing activity – walking, running, aerobics, stair-climbing, strength training, dancing, court and field sports No data on cycling, skating or skiing No data on cycling, skating or skiing Exercise 3x/week for 30-60 minutes duration Exercise 3x/week for 30-60 minutes duration Strength training reduces risk of falling also Strength training reduces risk of falling also Short term exercise increases BMD by 2% in meta-analysis of 16 trials Short term exercise increases BMD by 2% in meta-analysis of 16 trials

58 Exercise Cochrane review 2002 Cochrane review 2002 18 RCTs of BMD in postmenopausal women 18 RCTs of BMD in postmenopausal women Increased BMD of spine with any exercise Increased BMD of spine with any exercise Increased BMD of hip with walking Increased BMD of hip with walking Meta-analysis 4/2004 (Kelley, et al) Meta-analysis 4/2004 (Kelley, et al) 143 premenopausal women 143 premenopausal women Resistance exercise did not increase or maintain BMD Resistance exercise did not increase or maintain BMD

59 Calcium and Vitamin D Randomized controlled trials show improved BMD and decreased fractures with combo Randomized controlled trials show improved BMD and decreased fractures with combo NNT = 48 to prevent one hip fracture after 1.5 years of treatment NNT = 48 to prevent one hip fracture after 1.5 years of treatment Need 1200 mg Ca/day and 800 IU vit. D/day Need 1200 mg Ca/day and 800 IU vit. D/day Calcium better absorbed if taken with food and 600 mg or less at a time Calcium better absorbed if taken with food and 600 mg or less at a time Cost = $5/month Cost = $5/month

60 Calcium and Vitamin D Calcium citrate is slightly better absorbed than Ca carbonate Calcium citrate is slightly better absorbed than Ca carbonate Consider using Ca citrate if patient on acid blocker med Consider using Ca citrate if patient on acid blocker med Ca carbonate – Oscal, Caltrate, Tums, Viactiv Ca carbonate – Oscal, Caltrate, Tums, Viactiv Ca citrate - Citracal Ca citrate - Citracal

61 Calcium and Vitamin D Side effects of calcium include dyspepsia, gas, bloating and constipation(10%) Side effects of calcium include dyspepsia, gas, bloating and constipation(10%) May interfere with absorption of tetracycline or quinolones May interfere with absorption of tetracycline or quinolones If history of kidney stones evaluate for hypercalciuria prior to giving calcium If history of kidney stones evaluate for hypercalciuria prior to giving calcium Recent meta-analysis based on WHI showed slight increase in MI and stroke in pts taking Ca with or without vitamin D (Bolland 4/11) Recent meta-analysis based on WHI showed slight increase in MI and stroke in pts taking Ca with or without vitamin D (Bolland 4/11) RR of MI = 1.24 (1.07-1.45) RR of MI = 1.24 (1.07-1.45)

62 Calcium Cochrane review – 2004 Cochrane review – 2004 15 RCTs, 1806 subjects 15 RCTs, 1806 subjects Small improvement in bone density after 2-3 yrs Small improvement in bone density after 2-3 yrs Trend toward decrease in vertebral fractures Trend toward decrease in vertebral fractures Unclear if calcium alone decreases non-vertebral fractures Unclear if calcium alone decreases non-vertebral fractures

63 Vitamin D Vitamin D deficiency Vitamin D deficiency Decreased calcium absorption Decreased calcium absorption PTH-mediated increase in bone resorption PTH-mediated increase in bone resorption Decreased muscle strength and increased falls Decreased muscle strength and increased falls

64 Vitamin D Cochrane review – April 2009 Cochrane review – April 2009 Vitamin D alone showed no sig. effect on hip or vertebral fracture rate Vitamin D alone showed no sig. effect on hip or vertebral fracture rate Vitamin D with calcium slightly reduced non- vertebral fractures, but no effect on vertebral fractures Vitamin D with calcium slightly reduced non- vertebral fractures, but no effect on vertebral fractures No evidence that analogs of vitamin D offer any advantage over native vitamin D No evidence that analogs of vitamin D offer any advantage over native vitamin D Vitamin D2 and vitamin D3 equally effective Vitamin D2 and vitamin D3 equally effective

65 Vitamin D National Osteoporosis Foundation National Osteoporosis Foundation Recommends 800 – 1000 IU daily Recommends 800 – 1000 IU daily Consider testing in pts at risk for deficiency Consider testing in pts at risk for deficiency Elderly Elderly Malabsorption diseases Malabsorption diseases Chronic kidney disease Chronic kidney disease Housebound patients Housebound patients Test serum 25(OH)D level should be between 30- 60 (toxicity > 100) Test serum 25(OH)D level should be between 30- 60 (toxicity > 100)

66 Folate and Vitamin B12 RCT (Sato – 3/2005) RCT (Sato – 3/2005) 628 pts, s/p stroke 628 pts, s/p stroke 5 mg folate and 1500 mcg of B12 vs placebo 5 mg folate and 1500 mcg of B12 vs placebo Decreased hip fractures in treated group Decreased hip fractures in treated group NNT = 14 NNT = 14

67 Magnesium Often taken by patients Often taken by patients No studies show decrease in fracture rate or increase in BMD No studies show decrease in fracture rate or increase in BMD

68 Phytoestrogens Act as weak estrogens but also have anti- estrogen effects Act as weak estrogens but also have anti- estrogen effects Primary source of phytoestrogens is isoflavones which are found in soybeans(less in tofu) and lignans (flaxseed; some cereals, fruit, vegetables, and legumes) Primary source of phytoestrogens is isoflavones which are found in soybeans(less in tofu) and lignans (flaxseed; some cereals, fruit, vegetables, and legumes) Secondary sources are black cohosh and red clover Secondary sources are black cohosh and red clover

69 Phytoestrogens Small studies show some decrease in hot flushes and vaginal dryness Small studies show some decrease in hot flushes and vaginal dryness No human studies showing effect on bone No human studies showing effect on bone Dosage, purity, and adverse effects unknown Dosage, purity, and adverse effects unknown Estreven and Remifemin are combinations of isoflavones, black cohosh and red clover Estreven and Remifemin are combinations of isoflavones, black cohosh and red clover

70 Estrogen Replacement Therapy WHI (Women’s Health Initiative Study) WHI (Women’s Health Initiative Study) NNT = 2000 to prevent one hip fracture after 5 years of treatment NNT = 2000 to prevent one hip fracture after 5 years of treatment Not as effective for treatment but has definite benefit for prevention Not as effective for treatment but has definite benefit for prevention Strongest benefit for ERT is for women < 60 Strongest benefit for ERT is for women < 60 HERS showed no sig. decrease in fracture rate over 4 years HERS showed no sig. decrease in fracture rate over 4 years FDA approved only for prevention FDA approved only for prevention

71 ERT Transdermal and oral forms equally effective Transdermal and oral forms equally effective MUST use progesterone with estrogen if patient has intact uterus MUST use progesterone with estrogen if patient has intact uterus Estrogen with or without progesterone is equally as effective Estrogen with or without progesterone is equally as effective Cost = $14-28/month Cost = $14-28/month Secondary benefit of decreasing menopausal symptoms Secondary benefit of decreasing menopausal symptoms

72 ERT - Harms WHI study WHI study Small increased risk of 22% for cardiovascular events (7 additional cases/10,000/yr) Small increased risk of 22% for cardiovascular events (7 additional cases/10,000/yr) 26% increased risk of invasive breast cancer (8 additional cases/10,000/yr) 26% increased risk of invasive breast cancer (8 additional cases/10,000/yr) 41% increased risk of stroke (8 additional cases/10,000/yr) 41% increased risk of stroke (8 additional cases/10,000/yr) 2-fold increased risk of pulmonary embolism 2-fold increased risk of pulmonary embolism SE’s – Vag. Bleeding, nausea, headache, mood alterations, breast tenderness, bloating SE’s – Vag. Bleeding, nausea, headache, mood alterations, breast tenderness, bloating

73 Bisphosphonates Work by inhibiting osteoclastic activity Work by inhibiting osteoclastic activity RCT’s show significant and rapid reduction in fracture risk for women with previous fracture and osteoporosis RCT’s show significant and rapid reduction in fracture risk for women with previous fracture and osteoporosis Evidence not as good for women without previous fracture Evidence not as good for women without previous fracture

74 Alendronate (Fosamax) NNT = 34 to prevent one vert. fx over 3 yrs. NNT = 34 to prevent one vert. fx over 3 yrs. NNT = 86 to prevent one hip fx over 3 yrs. NNT = 86 to prevent one hip fx over 3 yrs. Dose = 5-10 mg/day or 35-70 mg/week Dose = 5-10 mg/day or 35-70 mg/week Forms – oral solution, Fosamax with D weekly Forms – oral solution, Fosamax with D weekly Cost = $95/month Cost = $95/month SE’s – nausea, dyspepsia, esophageal ulcer, esophagitis SE’s – nausea, dyspepsia, esophageal ulcer, esophagitis Weekly dosing showed equivalent increase in BMD to daily dosing (no data on fractures) Weekly dosing showed equivalent increase in BMD to daily dosing (no data on fractures)

75 Alendronate Meta-analysis of RCTs – (Papapoulos – 5/05) Meta-analysis of RCTs – (Papapoulos – 5/05) Post-menopausal women Post-menopausal women Dose = 5-10 mg/day for 1-4.5 yrs Dose = 5-10 mg/day for 1-4.5 yrs Overall risk reduction for hip fractures of 55% in pts with osteoporosis Overall risk reduction for hip fractures of 55% in pts with osteoporosis Clinically sig decrease in hip fractures Clinically sig decrease in hip fractures

76 Risedronate (Actonel) NNT = 15 to prevent one vert. fx over 3 yrs. NNT = 15 to prevent one vert. fx over 3 yrs. NNT = 91 to prevent one hip fx over 3 yrs. NNT = 91 to prevent one hip fx over 3 yrs. Dose = 5 mg/day, 35 mg/week, 150 mg/month Dose = 5 mg/day, 35 mg/week, 150 mg/month Cost = $150/month Cost = $150/month SE’s – abdominal pain, nausea, diarrhea but not sig. different from placebo SE’s – abdominal pain, nausea, diarrhea but not sig. different from placebo No sig. GI adverse events even in patients with history of ulcers, GERD, or taking NSAIDS No sig. GI adverse events even in patients with history of ulcers, GERD, or taking NSAIDS

77 Risedronate Cochrane systematic review – 8/2003 Cochrane systematic review – 8/2003 8 RCTs 8 RCTs Postmenopausal women received 5 mg/day, compared to Ca or placebo Postmenopausal women received 5 mg/day, compared to Ca or placebo Increased BMD after 3 yrs Increased BMD after 3 yrs Decreased vertebral and non-vertebral fractures Decreased vertebral and non-vertebral fractures No difference in side effects compared to placebo No difference in side effects compared to placebo

78 Ibandronate (Boniva) BONE study – (Delmas – 9/2003) BONE study – (Delmas – 9/2003) Large multi-national RCT Large multi-national RCT Oral Ibandronate Osteoporosis Vertebral Fracture Trial in N. America and Europe Oral Ibandronate Osteoporosis Vertebral Fracture Trial in N. America and Europe 2946 post-menopausal women 2946 post-menopausal women Daily or intermittent ibandronate vs placebo Daily or intermittent ibandronate vs placebo Decreased risk for vertebral fractures by 50-62% Decreased risk for vertebral fractures by 50-62% NO decreased risk of non-vertebral fractures NO decreased risk of non-vertebral fractures

79 Zoledronic Acid (Reclast) Given IV every 12 months Given IV every 12 months Decreases both vertebral and hip fractures Decreases both vertebral and hip fractures Expensive Expensive Consider only in certain high risk pts Consider only in certain high risk pts

80 Bisphosphonates Less than 1% of each dose is absorbed Less than 1% of each dose is absorbed Optimize absorption by taking with full glass of water and 30 mins prior to breakfast Optimize absorption by taking with full glass of water and 30 mins prior to breakfast Avoid GI problems by standing or sitting for 30 mins after taking med Avoid GI problems by standing or sitting for 30 mins after taking med Do not use in patients with creatinine clearance <30 ml/min or hypocalcemia Do not use in patients with creatinine clearance <30 ml/min or hypocalcemia Accumulates in bone – long term effects unknown Accumulates in bone – long term effects unknown

81 Bisphosphonates Does one work better than another? Does one work better than another? Head to head RCT of alendronate 70 mg/week and risedronate 35 mg/week (Rosen-1/2005) Head to head RCT of alendronate 70 mg/week and risedronate 35 mg/week (Rosen-1/2005) Total of 1053 postmenopausal women with osteoporosis, studied over 12 months Total of 1053 postmenopausal women with osteoporosis, studied over 12 months Alendronate showed greater increase in BMD compared to risedronate Alendronate showed greater increase in BMD compared to risedronate Fracture rate not assessed Fracture rate not assessed Both drugs tolerated equally well Both drugs tolerated equally well

82 Case #6 72 year old female with T-score = -2.7 and no hx fracture. 72 year old female with T-score = -2.7 and no hx fracture. You have recommended starting a bisphosphonate but she has heard that these drugs cause cancer and a jaw problem. You have recommended starting a bisphosphonate but she has heard that these drugs cause cancer and a jaw problem. What do you say? What do you say?

83 Bisphosphonates Osteonecrosis of the jaw (ONJ) Osteonecrosis of the jaw (ONJ) Canadian Consensus Practice Guidelines (6/2008) Canadian Consensus Practice Guidelines (6/2008) ONJ has been clearly associated with use of high dose IV bisphosphonates in the treatment of cancer ONJ has been clearly associated with use of high dose IV bisphosphonates in the treatment of cancer ONJ has NOT been clearly linked with low-dose bisphosphonates used for osteoporosis ONJ has NOT been clearly linked with low-dose bisphosphonates used for osteoporosis Advise good oral hygiene and regular dental visits Advise good oral hygiene and regular dental visits Consider holding drug for non-emergent dental surgery Consider holding drug for non-emergent dental surgery

84 Bisphosphonates Atrial fibrillation Atrial fibrillation Systematic review – (Loke – 2009) Systematic review – (Loke – 2009) Results of studies were mixed Results of studies were mixed There may be a link with bisphosphonates and atrial fib but data was too heterogeneous to make a determination There may be a link with bisphosphonates and atrial fib but data was too heterogeneous to make a determination No increase in stroke risk or cardiovascular mortality No increase in stroke risk or cardiovascular mortality FDA fells this is a chance finding FDA fells this is a chance finding

85 Bisphosphonates Subtrochanteric fracture Subtrochanteric fracture Occur after minimal or no trauma Occur after minimal or no trauma Direct etiologic relationship not yet substantiated Direct etiologic relationship not yet substantiated Esophageal cancer Esophageal cancer Incidence went from 1 case per 1000 in untreated pts to 2 cases per 1000 in those treated with bisphosphonates for 5 years or more Incidence went from 1 case per 1000 in untreated pts to 2 cases per 1000 in those treated with bisphosphonates for 5 years or more Consider drug holiday of 1-2 years after 3-5 years of therapy Consider drug holiday of 1-2 years after 3-5 years of therapy

86 Case #7 75 year old female with hx osteoporotic vertebral fx cannot tolerate the bisphosphonates. She has hx of severe GERD and peptic ulcer disease. 75 year old female with hx osteoporotic vertebral fx cannot tolerate the bisphosphonates. She has hx of severe GERD and peptic ulcer disease. What do you recommend? What do you recommend?

87 Selective Estrogen Receptor Modulators Raloxifene (Evista) Raloxifene (Evista) Blocks action of cytokines which stimulate bone resorption Blocks action of cytokines which stimulate bone resorption RCT’s show sig. decrease in new vertebral fractures for women with previous history of fracture and osteoporosis RCT’s show sig. decrease in new vertebral fractures for women with previous history of fracture and osteoporosis NNT = 29 to prevent one vert. fx over 3 yrs. NNT = 29 to prevent one vert. fx over 3 yrs. NO evidence of decrease in hip fractures NO evidence of decrease in hip fractures

88 Raloxifene Dose = 60 mg/day Dose = 60 mg/day Cost = $150/month Cost = $150/month Secondary benefit may be reduction of breast cancer risk Secondary benefit may be reduction of breast cancer risk SE’s – leg cramps(3%), hot flashes(6%), risk of venous thromboembolism (1 in 465 women/yr) SE’s – leg cramps(3%), hot flashes(6%), risk of venous thromboembolism (1 in 465 women/yr) Does not increase risk of endometrial hyperplasia or cancer Does not increase risk of endometrial hyperplasia or cancer

89 Salmon Calcitonin Calcitonin nasal spray (Miacalcin) Calcitonin nasal spray (Miacalcin) Large RCT showed decreased new vertebral fractures in women with previous history of osteoporotic vertebral fx. Large RCT showed decreased new vertebral fractures in women with previous history of osteoporotic vertebral fx. No effect reported for hip fractures No effect reported for hip fractures No definite effect for women with no previous osteoporotic fx. No definite effect for women with no previous osteoporotic fx. Increased BMD less than that seen with bisphosphonates or estrogen Increased BMD less than that seen with bisphosphonates or estrogen

90 Salmon Calcitonin Dose = 200 IU/day, 1 spray in 1 nostril qd Dose = 200 IU/day, 1 spray in 1 nostril qd Cost = $112/month Cost = $112/month SE’s – rhinitis(5%), epistaxis, sinusitis SE’s – rhinitis(5%), epistaxis, sinusitis Alternate nostrils to decrease SE’s Alternate nostrils to decrease SE’s Secondary benefit of decreased pain from vertebral fractures Secondary benefit of decreased pain from vertebral fractures

91 Parathyroid Hormone Stimulates bone formation Stimulates bone formation Teriparatide (Forteo) – recombinant PTH Teriparatide (Forteo) – recombinant PTH RCT shows 1/3 decreased incidence of vert. fx and ½ decreased incidence of non-vert. fx RCT shows 1/3 decreased incidence of vert. fx and ½ decreased incidence of non-vert. fx Dose = 20 mcg SC qd Dose = 20 mcg SC qd Less convenient Less convenient More expensive - $1000/month More expensive - $1000/month SEs – nausea, headache, hypercalcemia, dizziness, leg cramps, ? risk osteosarcoma SEs – nausea, headache, hypercalcemia, dizziness, leg cramps, ? risk osteosarcoma Measure Ca, vitamin D and PTH levels prior to treatment Measure Ca, vitamin D and PTH levels prior to treatment

92 Parathyroid Hormone FDA black box warning FDA black box warning Teriparatide caused osteosarcoma in rats using much higher doses of the drug Teriparatide caused osteosarcoma in rats using much higher doses of the drug Drug is contraindicated in pts at risk for osteosarcoma Drug is contraindicated in pts at risk for osteosarcoma Pagets disease of bone Pagets disease of bone Hx of irradiation involving the skeleton Hx of irradiation involving the skeleton Unexplained elevation of alkaline phosphatase Unexplained elevation of alkaline phosphatase Safety after 2 years duration is unknown Safety after 2 years duration is unknown

93 Parathyroid Hormone RCT – (Neer – 5/01) RCT – (Neer – 5/01) 1637 post-menopausal women with prior vertebral fractures 1637 post-menopausal women with prior vertebral fractures Average T-score = -2.6 Average T-score = -2.6 20 or 40 mcg PTH vs placebo 20 or 40 mcg PTH vs placebo NNT = 11 to prevent one vertebral fracture NNT = 11 to prevent one vertebral fracture 40 mcg dose worked a little better but had more side effects (hypercalcemia) 40 mcg dose worked a little better but had more side effects (hypercalcemia)

94 Parathyroid Hormone RCT – (Body–10/02) RCT – (Body–10/02) 14 months duration 14 months duration Compared PTH to alendronate Compared PTH to alendronate PTH increased BMD in hip and spine more than alendronate (12.2% vs 5.6%) PTH increased BMD in hip and spine more than alendronate (12.2% vs 5.6%) Non-vertebral fracture rate was lower in the PTH group Non-vertebral fracture rate was lower in the PTH group

95 Denosumab Monoclonal antibody against RANKL Monoclonal antibody against RANKL Decreases osteoclastic activity Decreases osteoclastic activity Brand name – Prolia Brand name – Prolia 60 mg SQ every 6 months 60 mg SQ every 6 months Studies show reduced fractures of the hip, spine and non-vertebral sites Studies show reduced fractures of the hip, spine and non-vertebral sites SEs – Skin infections, dermatitis, ? osteonecrosis of the jaw SEs – Skin infections, dermatitis, ? osteonecrosis of the jaw

96 Combination Therapy No studies demonstrating reduction in fracture risk No studies demonstrating reduction in fracture risk More improvement in BMD with combined estrogen and alendronate More improvement in BMD with combined estrogen and alendronate RCT of combined PTH and alendronate showed no improvement over PTH alone (Finkelstein-2003) RCT of combined PTH and alendronate showed no improvement over PTH alone (Finkelstein-2003) AACE does not recommend combined therapy AACE does not recommend combined therapy

97 Treatment Monitoring AACE guidelines AACE guidelines DEXA every 1-2 years until stable DEXA every 1-2 years until stable BMD should be stable or increasing and there should be no fractures BMD should be stable or increasing and there should be no fractures If this is not the case consider different treatment If this is not the case consider different treatment

98 Osteoporosis in Men 30% of hip fractures occur in males 30% of hip fractures occur in males 1.5 million men >65 have osteoporosis 1.5 million men >65 have osteoporosis May have higher mortality rate compared to females May have higher mortality rate compared to females 2/3 have secondary osteoporosis 2/3 have secondary osteoporosis Hypogonadism, glucocorticoid use, etc. Hypogonadism, glucocorticoid use, etc. Risk increases with age but later than in women Risk increases with age but later than in women

99 Osteoporosis in Men Treatment Treatment 1000 mg/day calcium and 800 IU/day vitamin D 1000 mg/day calcium and 800 IU/day vitamin D Exercise Exercise If hypogonadism, consider testosterone If hypogonadism, consider testosterone Bisphosphonates – RCT of alendronate 10 mg/day showed sig increase in BMD and decrease in vertebral fractures (Orwoll – 8/2000) Bisphosphonates – RCT of alendronate 10 mg/day showed sig increase in BMD and decrease in vertebral fractures (Orwoll – 8/2000) PTH – RCT of PTH 20mcg/day showed increased BMD (Orwoll – 1/2003) PTH – RCT of PTH 20mcg/day showed increased BMD (Orwoll – 1/2003)

100 Prevention Summary Start adequate calcium and vitamin D intake in childhood Start adequate calcium and vitamin D intake in childhood Encourage exercise Encourage exercise Decrease risk factors for osteoporosis Decrease risk factors for osteoporosis Decrease risk factors for falling Decrease risk factors for falling Consider bisphosphonate for prevention if high risk Consider bisphosphonate for prevention if high risk

101 Treatment Summary AACE recommendations AACE recommendations 1 st line – alendronate, risedronate, zoledronic acid, denosumab 1 st line – alendronate, risedronate, zoledronic acid, denosumab 2 nd line – ibandronate, raloxifene 2 nd line – ibandronate, raloxifene Last line – calcitonin Last line – calcitonin Teriparatide only for pts that fail above Teriparatide only for pts that fail above No combination therapy No combination therapy

102 References Prevention and Treatment of Osteoporosis in Postmenopausal Women. JFP October 2002 Prevention and Treatment of Osteoporosis in Postmenopausal Women. JFP October 2002 Screening for Osteoporosis in Postmenopausal Women: Recommendations and Rationale, US Preventive Services Task Force. Ann. Intern. Med. 17 Sept. 2002 Screening for Osteoporosis in Postmenopausal Women: Recommendations and Rationale, US Preventive Services Task Force. Ann. Intern. Med. 17 Sept. 2002 Radiologic Bone Assessment in the Eval. of Osteoporosis. AFP April 2002 Radiologic Bone Assessment in the Eval. of Osteoporosis. AFP April 2002 Cauley, JA. Effects of HRT on clinical fractures and ht loss(HERS). Am J Med. 2001. Cauley, JA. Effects of HRT on clinical fractures and ht loss(HERS). Am J Med. 2001. Papapoulos, SE. Meta-analysis of the efficacy of alendronate for the prevention of hip fractures in postmenopausal women. Osteoporosis Int. 2005 May. Papapoulos, SE. Meta-analysis of the efficacy of alendronate for the prevention of hip fractures in postmenopausal women. Osteoporosis Int. 2005 May. Delmas, PD. Daily and intermittent oral ibandronate normalize bone turnover and reduce vertebral fracture risk: results from the BONE study. Osteoporosis Int. 2004 April. Delmas, PD. Daily and intermittent oral ibandronate normalize bone turnover and reduce vertebral fracture risk: results from the BONE study. Osteoporosis Int. 2004 April.

103 References Calcium Supplements. The Medical Letter April 3, 2000 Calcium Supplements. The Medical Letter April 3, 2000 Osteoporosis: Parts I and II AFP March 2001 Osteoporosis: Parts I and II AFP March 2001 Cochrane Database Cochrane Database Petitti, DB. The WHO Study of Hormonal Contraception and Bone Health. Ob-Gyn. 2000 May. Petitti, DB. The WHO Study of Hormonal Contraception and Bone Health. Ob-Gyn. 2000 May. Orr-Walker, BJ. The effect of past use of the injectable contraceptive depot medroxyprog. acetate on bone mineral density in normal post-menopausal women. Clin Endocrinol. 1998 Nov. Orr-Walker, BJ. The effect of past use of the injectable contraceptive depot medroxyprog. acetate on bone mineral density in normal post-menopausal women. Clin Endocrinol. 1998 Nov. Kelley, GA. Efficacy of resistance exercise on lumbar spine and femoral neck BMD in premenopausal women: a meta-analysis. J Womens Health. 2004 April. Kelley, GA. Efficacy of resistance exercise on lumbar spine and femoral neck BMD in premenopausal women: a meta-analysis. J Womens Health. 2004 April. Sato, Y. Effect of folate and mecobalamin on hip fractures in pts with stroke: a RCT. JAMA. 2005 March. Sato, Y. Effect of folate and mecobalamin on hip fractures in pts with stroke: a RCT. JAMA. 2005 March.

104 References Bauer, DC. Use of statins and fracture: results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials. Arch Intern Med. 2004 Jan. Neer, RM. Effect of PTH on fractures and BMD in postmenopausal women with osteoporosis. N Engl J Med. 2001 May Body, JJ. A randomized double-blind trial to compare the efficacy of teriparatide with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002 Oct. Orwoll, E. Alendronate for the treatment of osteoporosis in men. N Engl J Med. 2000 Aug. Orwoll, ES. The effect of teriparatide therapy in men with osteoporosis. J Bone Miner Res. 2003 Jan. AACE Guidelines for Diag and Treatment of Osteoporosis - 2010


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