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Critical Challenges in Osteoporosis and Women’s Health

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1 Critical Challenges in Osteoporosis and Women’s Health
Screen & Intervene Critical Challenges in Osteoporosis and Women’s Health Critical Challenges in Osteoporosis Prevention and Treatment         Completing the Journey From Trial- and Expert-Based Information to Clinical Application in The Primary Care Setting

2 Critical Challenges in Osteoporosis Prevention and Treatment
What Have We Learned Thus Far—A Summary Osteoporosis-An Undertreated Condition Complications of Osteoporotic Fractures Indications for Screening Interpretation of BMD Measurements Aggregate Analysis of Risk Factors

3 Critical Challenges in Osteoporosis Prevention and Treatment
What Have We Learned Thus Far—A Summary Treatment Indications and Triggers Pharmacological Therapy for Fracture Prevention Relationship between BMD changes and Vertebral/Nonvertebral Fractures Vertebral and Nonvertebral Fracture Prevention We will now discuss Adherence/Compliance, and Their Relationship to Outcomes

4 Definitions  Initiation- Getting the prescription filled. About 10% of prescriptions are never filled.     Adherence- Taking the medicine Often defined as taking more than  80% of pills over a specified period of time.     Compliance- Taking the pills correctly. Important issue with bisphosphonates.     Persistence- Still taking the pills Often measured at the one year time point.

5 Non-Adherence How Large is The Problem?
Studies of patient behavior show that LESS THAN 50% of the people who leave a doctor's office with a prescription adhere and comply with drug therapy

6 Persistence with Lipid-Lowering Therapy
Simons, et al MJA 1996; 164:208.

7 The Effects of Non-Adherence
1) Poor patient outcomes due to sub-optimal therapeutic response 2) Increased cost burden to society Osterberg L,Blaschke T, N Engl J Med 2005;353:487-97

8 Poor Patient Outcomes Increased Morbidity due to disease “exacerbations” More treatment “Failures” with potential for addition or switching of medications due to perceived inefficacy More frequent Physician Visits Increased Hospitalizations Excess Mortality Osterberg L,Blaschke T, N Engl J Med 2005;353:487-97

9 Costs To Society 10% excess in all hospital admissions
125,000 to 200,000 deaths per year Billion dollars excess cost per year in the U.S. Osterberg L,Blaschke T, N Engl J Med 2005;353:487-97

10 What Are the Possible Causes of Poor Adherence?
“Target disease" eclipsed by other chronic conditions? Complex dosing guidelines? Poor patient education (Health Illiteracy) POOR ADHERENCE Lack of positive reinforcement? Disruption to daily routine? (need for frequent dosing) Concern about side effects?

11 Health Literacy The degree to which individuals have the capacity to obtain, process, and understand basic information and make appropriate decisions about their health* 90 million people in the United States, nearly half of all adults, have difficulty understanding and using health information** *(Selden et al. 2000; Healthy People 2010, HHS 2000; Ratzan & Parker 2000) **(Institute of Medicine report- 2004)

12 Literacy Level Predicts Health Outcomes
Less knowledge of disease and self-care Worse self-management skills Lower use of screening Lower medication compliance rates Higher rates of hospitalization and morbidity Literacy level is more important than racial or ethnic group, age, employment, income or education in predicting poor outcome

13 Patient Beliefs Affect Compliance
Don’t believe diagnosis or the seriousness of the diagnosis Believe other diseases are more important Believe side effects outweigh benefits Concerned about their ability to carry out recommended action AARP Survey, 1985 National Prescription Buyers’ Survey, USA 1985

14 Lack of Communication Study of 300 medical encounters: doctors spent average 1.3 minutes giving information1 Study of 264 visits to family physicians.- during patient initial statement of the problem, physician interrupted after average of 23 seconds.2 50% of patients leave office visit not understanding what the doctor said3 Clement, Diab Care 1995;18:1204. Waitzkin. JAMA 1984;252:24411 Kravitz et al. Arch Intern Med 1993;153: Roter and Hall. Ann Rev Public Health 1989;10:163. Marvel JAMA 1999;281:283. 3

15 Physicians Contribute to Patients’ Poor Adherence By:
Prescribing complex regimens Failing to explain the benefits and side effects of a medication adequately Not giving consideration to the patient’s lifestyle or the cost of the medications Osterberg L,Blaschke T, N Engl J Med 2005;353:487-97

16 Nonadherence to Osteoporosis Medications: How Common Is It?

17 Adherence With Osteoporosis Medications Is Sub-optimal
30 25 20 15 10 5 20% to 25% of Patients Abandon Therapy Within 7 Months 26% 19% 19% Patients Abandoning Treatment (%) Hormone Replacement Therapy (n=334) Bisphosphonate (n=366) Selective Estrogen Receptor Modulator (n=256) Telephone survey of 956 randomly selected women with postmenopausal osteopenia or osteoporosis who initiated therapy in Mean follow-up was 7 months. Tosteson ANA, et al. Am J Med. 2003;115:

18 Adherence With Oral Bisphosphonates Is Suboptimal, Regardless of Dosing
Percentage of Patients on Therapy (defined as having at least 1 day of medication supply in the month) P<0.001 vs daily therapy 10 20 30 40 50 60 70 80 90 100 Oct 2002 Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct 2003 Patients on Therapy (%) Daily Bisphosphonates (n=33,767) Weekly Bisphosphonates (n=177,552) 54.6% 36.9% A HIPAA-compliant, longitudinal patient database of prescriptions dispensed from ~25% of US retail pharmacies was used to assess discontinuation of bisphosphonates over a 12-month period in women aged ≥50 years.* * Primary usage in osteoporosis; however, data may include use in other indications. Ettinger M, et al. Arthritis Rheum. 2004;50(suppl):S513-S514. Abstract 1325.

19 Long-term adherence rates with any medication are poor (~50%)
Surgeon General’s Report Cites Need to Improve Adherence With Osteoporosis Therapies Long-term adherence rates with any medication are poor (~50%) Follow-up strategies that improve adherence to should be applied to osteoporosis Simplifying the treatment regimen Counseling Addressing patient concerns about side effects Maintaining an encouraging provider-patient relationship US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, Office of the Surgeon General; 2004.

20 Potential Consequences of Poor Adherence to Osteoporosis Therapy
Poorer clinical outcomes Less effective suppression in the rate of bone turnover1 Lower gains or greater losses in bone mineral density1,2 Greater risk of fractures3 Higher medical costs4 1. Eastell R, et al. Calcif Tissue Int. 2003;72:408. Abstract P-297. 2. Finigan J, et al. Osteoporos Int. 2001;12:S48-S49. Abstract P110. 3. Caro JJ, et al. Osteoporos Int. 2004;15: 4. McCombs JS, et al. Maturitas. 2004;48:

21 Non-Adherence to Osteoporosis Medication Affects BMD
Lumbar BMD Yood R, et al Osteoporosis int 14:

22 Non-Adherence to Osteoporosis Medication Increases Fracture Risk
11,249 women suffering from osteoporosis with a mean age of 68.4 years and average follow-up of 2 years Fracture Rate % 16% decrease Caro JJ et al. Osteoporosis Int 14, 2003, Suppl 7

23 Better Long-term Compliance Reduces the Risk of Fracture
Compliance With Bisphosphonates and Fracture Risk Over 2 Years in Women ≥45 Years With Postmenopausal Osteoporosis (n=6825) % Patients With Fracture (n=3400) (n=3425) * 9.4% 12.6% * P< † Compliant is defined as taking medication ≥80% of the time over a 24-month period. Retrospective cohort study that used longitudinal medical and pharmacy claims data from Medstat MarketScan® Research Databases to assess adherence and fracture risk over 24 months ( ). Siris E, et al. Presented at: Sixth International Symposium on Osteoporosis. April 6-10, 2005; Washington, DC.

24 How Can Adherence Be Improved?

25 Improving Adherence by Reinforcing Treatment Efficacy
Patient monitoring may be helpful in demonstrating effects of treatment1-3 BMD Biochemical markers of bone turnover Frequent visits or calls from staff Clowes et al. JCEM. 2004;89: ). Deal CL. Curr Rheumatol Rep. 2001;3: 3. Chapurlat RD, Cummings SR. Osteoporos Int. 2002;13:

26 Improving Adherence Through Modifying Dosing Interval: Focus on Bisphosphonates
Survey data suggests that patients prefer more widely-spaced dosing intervals Retrospective data suggest improved adherence with once-weekly versus daily bisphosphonates To date, there are no prospective data demonstrating that extended dosing regimens improve patient adherence and clinical outcomes

27 Women Preferred Weekly over Daily
Alendronate 288 postmenopausal women with osteoporosis 4 weeks of alendronate Weekly followed by 4 weeks alendronate Daily 4 weeks of alendronate Daily followed by 4 weeks alendronate Weekly At the final visit, patients completed a preference study questionnaire: Which Treatment Routine… Patients (%) From medical department approved MCO Slide set. 38 United States Centers, randomized, open label, preference study that evaluated Fosamax 10mg once-daily versus Fosamax 70mg once-weekly. Women with postmenopausal osteoporosis were enrolled to receive 9 weeks of treatment in crossover fashion. Each woman received 4 weeks with each study regimen separated by a 1 week washout period             Page 1873  Simon JA, et al. Clin Ther. 2002;24: Do You Prefer? Is More Convenient? Would Be Easier to Comply With For a Long Period of Time? Simon JA et al Clin Ther 2002;24:

28 Women Preferred Monthly over Weekly
Patients Say They Prefer a Once-a-month Over a Once-a-week Dosing Schedule Dosing Schedule Preference (n = 367)* Once a week 33% 67% Once a month From medical department approved MCO Slide set. Standard deviations weekly (4.8%) monthly (4.8%) Patients who preferred monthly more likely to be younger p = 0.05; employed full time p =0.017; initiated therapy <3 yrs ago p = 0.009 Page 33 Simon JA et al. The Female Patient 2005;30:31-6. p <0.001 * Among women expressing a preference, 67% prefer once-a-month dosing, a statistically significantly higher proportion than the 33% who prefer once-a-week dosing Simon JA et al Female Patient 2005;30:31-6

29 BALTO- Study Design A randomized, prospective, 6 month Phase IIIB, open-label, multi-center, crossover study Primary Endpoint – Proportion (%) of patients preferring once-monthly dosing of ibandronate over once-weekly dosing of alendronate Secondary Endpoint – Proportion (%) of patients perceiving the once-monthly dosing of ibandronate to be more convenient versus once-weekly dosing of alendronate Slide summarized from slide s in BALTO Protocol Review Daiva M This was a six month prospective, randomized open-label, multi-center (48 centers), 2-period and 2-sequence crossover study. After a screening period of up to 30 days, eligible patients were randomized into either Sequence A or B (Figure 1). Patients randomized to Sequence A received oral ibandronate once-monthly 150 mg for three calendar months (Period 1), followed by oral alendronate once-weekly 70 mg for 12 weeks (Period 2). Patients assigned to Sequence B received alendronate once-weekly for 12 weeks (Period 1) followed by ibandronate once-monthly for three calendar months (Period 2). The crossover (Visit 3) took place once the patient had completed three calendar months of treatment with ibandronate (Sequence A) or 12 weeks treatment with alendronate (Sequence B). There was no wash-out period between the two treatment regimens. The study duration was approximately six months (3 months and 12 weeks). A follow-up period of 15 days after the completion of treatment was included to assure collection of additional information on safety. Emkey R et al Curr Med Res Opin Dec;21(12):

30 Patient Preference: Ibandronate Monthly vs Alendronate Weekly
(Patients Expressing Preference) Patients (%) n = 197 n = 79 Source: Boniva® (ibandronic acid) Clinical Study Report BALTO I (Protocol MA Research Report ). Pages Ibandronate CI 65.7, 76.6 The primary analysis of the primary endpoint was analyzed using Gart’s test which excluded patients who did not express an opinion for one treatment over the other (see Section ). Two hundred seventy six patients were included in this analysis and 22 patients were excluded because they did not express a preference for either treatment regimen. Of those patients who expressed a preference for one treatment over the other (92.6% of the patients declared a preference), significantly more patients preferred the 150 mg once-monthly oral ibandronate tablet (71.4%, n= 197, 95% CI 65.7, 76.6) than the 70 mg once-weekly oral alendronate tablet (28.6%, n = 79) (P<0.0001). The order of intake of the two medications did not have an impact on patient preference for once-monthly ibandronate over once-weekly alendronate (Gart-order-effect P=0.1855). Preferred Treatment * p < vs alendronate Excludes those patients who did not express a preference for one treatment / m ITT population Twenty-two patients did not express preference Emkey R et al Curr Med Res Opin Dec;21(12):

31 Patient Preference: Ibandronate Monthly vs Alendronate Weekly
(Those Expressing Convenience) Patients (%) n = 197 n = 67 Significantly more women found it more convenient to take once-monthly ibandronate than once-weekly alendronate (74.6% versus 25.4%, P<0.0001). Two hundred sixty-four patients were included in the primary analysis of convenience. Thirty-two patients (10.8%) were excluded from this analysis as they considered the two treatments to be equally convenient (Table 16). The order of the intake of the two medications did not have an impact on this opinion (Gart-Order-Effect P=0.1570). More Convenient Therapy * p < vs alendronate Excludes those patients who did not express a preference for treatment Thirty-two patients found both treatments equally convenient Emkey R et al Curr Med Res Opin Dec;21(12):

32 Principles of Evidence-Based Medicine
Acquire the Evidence Critically Appraise the Evidence Apply the Evidence to the Individual Patient

33 Evidence-Based Medicine: Integrate Findings With Clinical Expertise and Patient Needs
Clinical expertise IS important! Why? Experience with patients: improves efficiency of diagnosis and treatment Improves ability to determine applicability of research data to your patients Allows consideration of patient preferences EBM is the process of systematically finding the most recent applicable research, appraising its validity, and using it as the basis for clinical decisions. Clinical Expertise improves efficiency of Dx and Rx considers patient preferences Overestimates usefulness of therapy - Research Evidence Patient Preferences Rx Adapted from: Sackett DL et al. Evidence-Based Medicine: How to Practice and Teach EBM. 2nd ed. Churchill Livingstone; 2000

34 Summary Adherence to daily and weekly bisphosphonates is suboptimal
Poor adherence may compromise clinical outcomes and may increase healthcare utilization Need to improve communication and education of patients utilizing all available resources Among other factors, dosing frequency may be an important determinant of adherence with bisphosphonates

35 “Drugs don’t work in people that don’t take them”
C. Everett Koop, M.D.

36 Applying Evidence to Practice— Prevention and Treatment of Patients Suspected or Confirmed Osteoporosis: An Interactive Case Study Approach Case Study # 1: Low BMD in An Early Postmenopausal Woman

37 Case 1 LR is a 52 year old newly menopausal white woman
She has hot flashes but no fractures or height loss She is of average height and weight (5’2”, 137 pounds) She has an intact uterus There is no family history of OP She had never undergone BMD testing However, you ordered a DXA which showed a T-score of -1.8 in lumbar spine and -1.5 in femoral neck

38 Case 1 Diagnosed as osteopenia What would you do? Would you treat with an antiresorptive therapy?

39 Case 1 With no history of fx or FH, her absolute risk for an osteoporotic spine, hip or wrist fx over the next 5 years is very low at <0.12%/y No utility for bone markers in this age group No treatments have been proven to reduce fx risk in women in their 50s with osteopenia, although several treatments may reduce bone loss Bisphosphonates or PTH although effective would probably be unjustified based on her low absolute risk and the high NNT of 2000

40 Case 1 Consider preventive approaches
At her age with a uterus she is more likely to have an AE from HRT (VTE, MI, breast CA) than a beneficial outcome Raloxifene is an option May lower risk of breast ca May aggravate hot flashes Calcium and vitamin D

41 Case 1: What Mrs. LR Chose To Do…
Chose to decline any pharmacologic intervention Agreed to calcium supplementation 500mg bid, a MVI, and an exercise program Began to experiment with soy preparations No evidence that these agents reduce fx risk or prevent bone loss

42 Case 2. A postmenopausal woman who recently discontinued HRT but has low BMD

43 Case 2 RG is a 68-year-old woman who has been on HT since menopause
She initially took HT for hot flashes but continued when she was told of benefits for her heart and bones When she heard the WHI results she discontinued HT She has scheduled a visit with you to discuss whether she needs additional therapy to treat or prevent OP

44 Case 2: History Mrs. RG Meds: no calcium or vitamin D supplements
She takes a MVI She is lactose intolerant She has lost 2 inches in height Approximately 10 years ago she broke her forearm when she slipped on the sidewalk No FH of OP

45 Case 2: History Mrs. RG At age 65 she had a DXA which showed spine T-score of -2.0 and total hip T-score of -2.2 She has OP based on relatively low BMD and history of fracture Her absolute risk of fracture in 5 years will be high, assuming that HRT effects on bone will diminish with time

46 Need to exclude secondary OP
Case 2 Need to exclude secondary OP Serum calcium TSH 25 OH D 24 hour urinary calcium

47 Case 2: Medical Recommendations Mrs. RG
Calcium supplementation 1200 mg 800 IU vitamin D (her MVI has 400 IU) Exercise Medication options: Bisphosphonates weekly or monthly SERMS Follow-up BMD in two years

48 Case 2: What Mrs. RG Did Ibandronate 150 mg once monthly 1000 mg calcium supplementation 400 IU vitamin D plus her MVI

49 Case 3. Severe postmenopausal osteoporosis

50 Case 3: Mrs. RW 70 year old woman with low BMD and multiple vertebral fractures who has been on a weekly bisphosphonate, ca, vitamin D for two years Her lumbar spine T-score in Jan 2001 was -3.0 A repeat DXA today shows a lumbar spine T-score of -3.5, and a FN T-score of -3.0 She has significant midback pain and has new OP fx of the thoracic spine with significant deformity Vertebroplasty was recommended by her PCP

51 Case 3: MRI Series T1 T2 T2 STIR

52 Case 3: The Magnitude of the Loss is Troublesome
Consider the following: Is she a non-responder? Is she taking her bisphosphonate? Is the bisphosphonate being absorbed? Are there secondary causes of osteoporosis contributing to her bone loss and fractures? What therapeutic interventions both pharmacologic and nonpharmacologic should we consider?

53 Case 3: What Mrs. RW Did Treated aggressively with opioids
Refused vertebral body augmentation Initially switched to another oral bisphosphonate but untx was high at 55 25 OHD level 35 Calcium supplementation to 1500 mg/daily Switched to Forteo Back pain diminished 6% increase in lumbar spine BMD at 6 months

54 Case 4. Age related osteoporosis

55 Case 4: Mrs. PR An 80-year-old frail, community dwelling woman who lives alone She has no hx of fx but falls often during the year She takes 1000 mg calcium daily and a MVI She does not go out in the sun She has difficulty walking She has a long hx of GERD She has HBP treated with beta blockers BMD T-score of -2.8 at hip and -2.0 in spine

56 Case 4: Medical Recommendations Mrs. PR
Falls assessment Check vitamin D She had 25 OHD level of 8 ng/ml 50,000 U of oral vitamin D weekly for 3 months Take calcium in divided doses Exercise program Hip protectors Her risk of NVF is high 10%/year Started on a bisphosphonate

57 Case 4: What Mrs. PR Did 50,000 U ergocalciferol weekly for 3 months Chose weekly bisphosphonate PT program She refused hip protectors

58 Clinical Risk Factors Femoral neck T-score + Age
Previous low trauma fracture Current cigarette smoking Rheumatoid arthritis High alcohol intake (> 2 units/day) Parental history of hip fracture Prior or current glucocorticoid use Adapted from Kanis JA et al. Osteoporos Int. 2005;16:

59 Intervention Threshold
A fracture probability above which it is cost-effective to treat with pharmacological agents Based on statistical modeling using many medical, social, and economic assumptions

60 Case 5

61 Patient Case #5 70 year old post menopausal female
Wrist fracture at age 62 T-score lumbar spine = -0.8 T-score femoral neck and total hip = -1.5 Should she receive pharmacological therapy? What would you choose and why? Would you choose a different therapy if her T-score was –3.5?

62 Case 6

63 Patient Case #6 52 year old post menopausal female
Mother had hip fracture at age 69 T-score lumbar spine = -1.5, femoral neck -1.6 Should she receive pharmacological therapy? Would bone markers help your decision?

64 Patient Case #6 What therapy would you choose?
Hormone therapy SERM Bisphosphonate- which one? She refuses pharmacological therapy: she would like to try calcium and vitamin D alone How and how often would you monitor her?

65 Case 7

66 Patient Case #7 67 year old post menopausal female with osteoporosis
On risedronate 35 mg QW for 2 years Repeat DXA reveals 5% loss at the spine and 4.5% loss at the total hip What should you do?

67 Patient Case #7 Her DXAs were performed at the same facility: her bone loss is statistically significant according to their precision She insists that she has taken her bisphosphonate every week and has followed proper administration instructions What labs would you order?

68 Patient Case #7 Her serum calcium, phosphorus, alkaline phosphatase, albumin and creatinine are normal 24 hour urine calcium = 175 mg 25-OH vitamin D = 35 ng/ml Tissue transglutaminase- negative Would you change her treatment? What would you change her to?

69 Case 8

70 Patient Case #8 A 66 year old female has a heel ultrasound performed at a health fair Her T-score at the heel = -2.5 Does she have osteoporosis? What other tests, if any, should be performed?

71 Patient Case #8 A DXA reveals a T-score at the spine of –2.7 and at he femoral neck of –1.9 Lab workup is negative except for a 25-OH D level of 18 ng/ml What therapy would you choose? Hormone therapy SERM Teriparatide Bisphosphonate- which one?

72 Case 9

73 Patient Case #9 67 year old postmenopausal female
History: Heart disease, high cholesterol, hypertension and osteoporosis She takes alendronate 70 mg QW for OP Complains about taking multiple pills Often forgets to take her medications Requests help in simplifying her medication schedules What are some other options?

74 Patient Case #9 You offer her ibandronate 150 mg once-a-month
How can you help her remember to take her pill every month? What other methods could you use to re-inforce effectiveness of therapy and persistence? Mention MyBoniva program of letters, phone calls, faxes and s to patients that sign up for program Could perform markers after 6 months, repeat visits or calls from staff reinforcing persistence

75 Clinical Risk Factors Femoral neck T-score + Age
Previous low trauma fracture Current cigarette smoking Rheumatoid arthritis High alcohol intake (> 2 units/day) Parental history of hip fracture Prior or current glucocorticoid use Adapted from Kanis JA et al. Osteoporos Int. 2005;16:

76 Intervention Threshold
A fracture probability above which it is cost-effective to treat with pharmacological agents Based on statistical modeling using many medical, social, and economic assumptions

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