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DeAnn Cummings, MD January 12, 2012

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1 DeAnn Cummings, MD January 12, 2012
Osteoporosis DeAnn Cummings, MD January 12, 2012

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

3 Why Does it Matter? 50% require nursing home care after hip fracture
30% need assistance with daily activities 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 Bone strength = Bone density + Bone quality 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 T score = #standard deviations from gender-matched young adult mean Z score = #standard deviations from age and gender-matched mean T score best correlates with fracture risk

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

7 Pathophysiology Balance between bone resorption and formation (remodeling) Remodeling is in balance until about age 50 Osteoclasts resorb bone Osteoblasts form bone 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

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

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

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

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

12 Medications Glucocorticoids Lithium Chemotherapy GnRH agonist
Anticonvulsants Phenobarbital Dilantin Tegretol Valproate Methotrexate SSRIs Prolonged heparin use Coumadin (?) Cyclosporine (?) Aromatase inhibitors Excess thyroid hormone Medroxyprogesterone Vitamin A 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. PMH HTN Hyperlipidemia GERD Depression

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

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

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

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

18 Case #2 16 year old female presents for discussion of birth control options. PMH – None Family hx – No hx osteoporosis 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.

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

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

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

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

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

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

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

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

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

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

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

30 Screening – Who to Screen?
No studies showing decreased fracture risk with screening However: 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 treating asymptomatic women with osteoporosis decreases fracture risk

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

32 Screening – Who to Screen?
USPSTF recommendations continued No recommendations for or against routine screening in women <60 yrs. or women 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. 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 All recommend screening only if results will influence treatment If patient not in favor of treatment, DON’T SCREEN!

34 Screening in Men National Osteoporosis Foundation
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 Screen men ages with risk factors However, very little evidence for or against screening men

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

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

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

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

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

40 Screening – Which Test? 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) High false positive rate

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

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

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

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

45 Screening – Which Test? DEXA HOWEVER……
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
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 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 NOF recommends follow-up BMD every 2 years on treatment

48 Screening Summary Screen all high risk women Screen every 2 years
Women < 65 with significant risk factors Men with risk factors Screen every 2 years Consider using risk assessment tools to determine high risk 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 Does she need evaluation for secondary causes of osteoporosis?

50 Evaluating for Secondary Osteoporosis
AACE CBC CMP Ca, Phos 24 hour urine for Ca, Na, creatinine excretion 25-hydroxyvitamin D level 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 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? Are her results normal? 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 Is there any benefit in treating anyone else?

53 What About Osteopenia? 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 Individualize management Decrease modifiable risk factors Increase calcium and vitamin D intake Increase exercise Decrease tobacco, alcohol and caffeine use

54 What About Osteopenia? Use FRAX calculator
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 Using this calculator most pts with osteopenia will not be treated No actual studies on outcomes using FRAX

55 Treatment Options Exercise Calcium and Vitamin D Estrogen
Bisphosphonates Raloxifene Calcitonin 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” What do you recommend?

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

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

59 Calcium and Vitamin D Randomized controlled trials show improved BMD and decreased fractures with combo NNT = 48 to prevent one hip fracture after 1.5 years of treatment 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 Cost = $5/month

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

61 Calcium and Vitamin D Side effects of calcium include dyspepsia, gas, bloating and constipation(10%) May interfere with absorption of tetracycline or quinolones 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) RR of MI = 1.24 ( )

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

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

64 Vitamin D Cochrane review – April 2009
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 No evidence that analogs of vitamin D offer any advantage over native vitamin D Vitamin D2 and vitamin D3 equally effective

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

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

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

68 Phytoestrogens 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) Secondary sources are black cohosh and red clover

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

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

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

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

73 Bisphosphonates Work by inhibiting osteoclastic activity
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

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

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

76 Risedronate (Actonel)
NNT = 15 to prevent one vert. fx over 3 yrs. NNT = 91 to prevent one hip fx over 3 yrs. Dose = 5 mg/day, 35 mg/week, 150 mg/month Cost = $150/month 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

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

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

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

80 Bisphosphonates Less than 1% of each dose is absorbed
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 Do not use in patients with creatinine clearance <30 ml/min or hypocalcemia Accumulates in bone – long term effects unknown

81 Bisphosphonates Does one work better than another?
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 Alendronate showed greater increase in BMD compared to risedronate Fracture rate not assessed Both drugs tolerated equally well

82 Case #6 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. What do you say?

83 Bisphosphonates Osteonecrosis of the jaw (ONJ)
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 NOT been clearly linked with low-dose bisphosphonates used for osteoporosis Advise good oral hygiene and regular dental visits Consider holding drug for non-emergent dental surgery

84 Bisphosphonates Atrial fibrillation Systematic review – (Loke – 2009)
Results of studies were mixed 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 FDA fells this is a chance finding

85 Bisphosphonates Subtrochanteric fracture Esophageal cancer
Occur after minimal or no trauma Direct etiologic relationship not yet substantiated 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 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. What do you recommend?

87 Selective Estrogen Receptor Modulators
Raloxifene (Evista) 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 NNT = 29 to prevent one vert. fx over 3 yrs. NO evidence of decrease in hip fractures

88 Raloxifene Dose = 60 mg/day Cost = $150/month
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) Does not increase risk of endometrial hyperplasia or cancer

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

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

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

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

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

94 Parathyroid Hormone RCT – (Body–10/02) 14 months duration
Compared PTH to alendronate 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

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

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

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

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

99 Osteoporosis in Men Treatment
1000 mg/day calcium and 800 IU/day vitamin D Exercise If hypogonadism, consider testosterone 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)

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

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

102 References 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 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 Papapoulos, SE. Meta-analysis of the efficacy of alendronate for the prevention of hip fractures in postmenopausal women. Osteoporosis Int May. Delmas, PD. Daily and intermittent oral ibandronate normalize bone turnover and reduce vertebral fracture risk: results from the BONE study. Osteoporosis Int April.

103 References Calcium Supplements. The Medical Letter April 3, 2000 Osteoporosis: Parts I and II AFP March 2001 Cochrane Database Petitti, DB. The WHO Study of Hormonal Contraception and Bone Health. Ob-Gyn 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 Nov. Kelley, GA. Efficacy of resistance exercise on lumbar spine and femoral neck BMD in premenopausal women: a meta-analysis. J Womens Health April. Sato, Y. Effect of folate and mecobalamin on hip fractures in pts with stroke: a RCT. JAMA 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 Jan. Neer, RM. Effect of PTH on fractures and BMD in postmenopausal women with osteoporosis. N Engl J Med 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 Oct. Orwoll, E. Alendronate for the treatment of osteoporosis in men. N Engl J Med Aug. Orwoll, ES. The effect of teriparatide therapy in men with osteoporosis. J Bone Miner Res Jan. AACE Guidelines for Diag and Treatment of Osteoporosis

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