This document discusses challenges that can arise after starting treatment for osteoporosis, including motivating patients to adhere to their medication regimen and monitoring them to ensure benefits are achieved. It also reviews evidence on how adherence impacts outcomes and strategies to improve adherence through patient education, communication, and nurse monitoring. Biomarkers like bone mineral density and bone turnover markers are discussed as tools to monitor treatment response, but they have limitations in clinical practice.

1. What To Do After Starting Treatment E. Michael Lewiecki, MD, FACP, FACE New Mexico Clinical Research & Osteoporosis Center Albuquerque, NM

2. Fracture Risk Assessment Will I end up like my mother? Fracture Risk Reporting Intervention Thresholds Follow-up Strategies Treatment Decisions Clinical Factors

3. Clinical Challenges after Starting Treatment Motivating the patient to fill the prescription and take it correctly, regularly, and for a sufficient amount of time to benefit Determining how (or if) to follow and monitor the patient to assure that benefit is achieved Deciding when (if ever) to stop or change therapy Knowing when (if ever) to restart, if treatment is stopped Managing side effects, perceived side effects, and fear of side effects

4. Evidence Based Medicine

5. Evidence Based Medicine “Conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.” “Good doctors use both individual clinical expertise and the best available external evidence, and neither alone is enough.” Sackett DL et al. BMJ. 1996;312:71-72.

6. Combining Medical Evidence and Clinical Judgment “ Without clinical expertise, practice risks becoming tyrannised by evidence, for even excellent external evidence may be inapplicable or inappropriate for an individual patient.” “ Without current best evidence, practice risks becoming rapidly out of date, to the detriment of patients.” Sackett DL et al. BMJ. 1996;312:71-72.

7. NOF Clinician’s Guide “ Its recommendations are not intended as rigid standards of practice.” “ Clinicians should tailor their recommendations and, in consultation with their patients, devise individualized plans for osteoporosis prevention and treatment.” “ This guide cannot and should not be used to govern health policy decisions.” NOF Clinician’s Guide. 2008.

8. National Institute for Health and Clinical Excellence (NICE) “ In general, doctors, nurses and other healthcare professionals in the NHS are expected to follow NICE’s clinical guidelines.” “ There will be times when the recommendations will not be suitable for someone because of his or her specific medical condition, general health, wishes or a combination of these.” http://www.nice.org.uk/nicemedia/pdf/AboutGuidance.pdf#null.

9. Differences Between Clinical Trials and Clinical Practice Clinical trial subjects vs. patients Subjects- Homogenous, screened for secondary factors, educated, highly motivated, rewarded for adherence, closely monitored Patients- Heterogeneous (age, sex, ethnicity), co-morbidities, variable motivation, education, follow-up, adherence often poor Definitions may vary (e.g., “bone loss”) Research- Bone loss often defined as a change in BMD of less than 0.0% Practice- Bone loss means a decrease in BMD that is at least as great as the least significant change (LSC) with a 95% level of confidence

11. Retrospective chart review of 120 consecutive women with T-scores < -2.0 and/or fragility fractures, seen as new patients at an academic osteoporosis center Evaluated for eligibility in 4 typical RCTs of drugs for treatment of osteoporosis Inclusion criteria varied by age range, skeletal site of BMD measurement, T-score, type and number of prevalent fractures, etc. Exclusion criteria varied by allowable drugs, washout periods, co-morbidities, etc. Dowd R et al. Osteoporos Int. 2000;11:533-536.

12. Eligibility for Treatment or RCT Dowd R et al. Osteoporos Int. 2000;11:533-536. Standard Criteria for Drug Therapy Eligible for Participation in Drug Study A B C D 100% 3% 4% 21% 7% Reasons for Exclusion from Drug Studies Too young 28% Too old 8% Disease too severe 19% Co-morbid conditions 60% Medications 60% Other 3%

13. Adherence in Clinical Trials * Definition of adherence and dropout varies by study Study Drug Time Adherence* Dropout* FIT-I + FIT-II Alendronate 3-4 yrs 86% 4% VERT-NA Risedronate 3 yrs >85% 42% MORE Raloxifene 3 yrs 92% 23% PROOF Calcitonin 5 yrs >90% 59% PEPI Estrogen 3 yrs 77% 3% Neer Teriparatide 1.8 yrs 82% 19%

14. Seeman E et al. Osteoporos Int. 2007;18;711-719. Cramer JA et al. Curr Med Res Opin.2005;21:1453-1460.

15. Lewiecki EM. South Med J. 2007;100:1190-1191.

16. Consequences of Poor Adherence Poorer clinical outcomes Less effective suppression of bone turnover 1 Lower gains or greater losses in BMD 1,2 Greater risk of fractures 3 Higher medical costs 4 Up to 69% of all medication-related admissions are due to poor medication adherence $100 billion per year in USA 5 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;15:1003-1008. 4. McCombs JS et al. Maturitas. 2004;48:271-287.5. 5.Osterberg L et al. N Engl J Med. 2005;5:353:487-497.

17. Fracture Risk Decreases with Improved Compliance Adapted from Siris E et al. Mayo Clin Proc. 2006;81:1013-1022, in Seeman E et al. Osteoporos Int. 2007;18;711-719.

18. Why don’t patients take their medicine? Patient Factors Cost Side effects Fear of side effects Depression Inconvenience Cultural issues Poor understanding Physician Factors Male Lack of interest Poor communication Poor pt. education No handouts Inadequate follow-up No monitoring

19. Adherence and Patient Beliefs 6 focus groups with elderly African American and non-Hispanic white women Adherence was associated with belief that: Non-adherence had serious consequences Therapy had beneficial effects Drugs were not harmful Fracture risk was significant Physician was competent Drugs were affordable Unson CG et al. J Women’s Health. 2003;12:1037-1045.

20. Patient Misconceptions No need to treat a silent asymptomatic disease 1 Medications will “cancel each other out” 2 Treatment benefits do not outweigh side effects 3 No risk of osteoporosis if no family history 2 Falling without a fracture means future fall will not cause fracture 2 Hip fracture is preferable to taking more medications 2 1. Lombas C et al. J Bone Miner Res. 2001;16(suppl):529. Abstract M406. 2. Unson CG et al. J Womens Health. 2003;12:1037-1045. 3. Tosteson ANA et al. Am J Med. 2003;115:209-216.

21. Improving Adherence to Therapy Longer dosing intervals Less complex administration Injectable therapy? Patient education Ongoing communication Nurse monitoring

22. Impact of Nurse Visits on Adherence Postmenopausal Women Treated with Raloxifene Clowes JA et al. J Clin Endocrinol Metab. 2004;1117-1123. (Refill at 6 mo.) (Nurse visit at 3,6,9 mo.) (Nurse visit with markers at 3,6,9 mo.) Adherence = > 75% of pills taken P<0.05 P<0.05 Adherent patients had better BMD and marker response than non-adherent patients.

23. Typical Responses in Treatment and Placebo Arms of Successful Clinical Trials BMD Fracture Risk BTM, Antiresorptive Rx BTM, Anabolic Rx Percent Change Percent Change Percent Change Fracture Rate (%)

24. BMD Response to Alendronate Concept from EPIC data. Personal communication Dr. Mike McClung. Shaded area shows estimated least significant change (LSC).

25. BMD Change & VF Risk Relative Risk of Vertebral Fracture Wasnich RD, Miller PD. J Clin Endo Metab. 2000;85(1):231-236. A - Alendronate H - Hormone Replacement C - Calcitonin R - Raloxifene E - Etidronate T - Tiludronate T A A A A A H E E R R R C C C T T T 22% 54% Risk Reduction Line = No effect C 13 RCT’s with alendronate, risedronate, ERT, calcitonin, etidronate, raloxifene, tiludronate.

26. Change in BTM & Fracture Risk Pooled data in 6186 women from FIT1 + FIT2 Bauer DC et al. J Bone Miner Res. 2004;19:1250-1258. * * * * * P < 0.01 compared to placebo. Change in BSAP at 1-Year Predicts Fracture Risk over 3.6 Years. Type of Fracture

27. Biomarker Change and Fracture Risk Reduction with Treatment Bouxsein ML, Delmas PD. J Bone Miner Res. 2008;23:1155-1167. NR = No relationship, data exist ND = No data QCT = quantitative computed tomography Micro-arch = micro-architecture hr = high resolution pCT = peripheral computed tomography MRI = magnetic resonance imaging FEA = finite element analysis DXA BMD BTM QCT Micro-arch (hr pCT or MRI) QCT FEA Raloxifene NR + ND ND ND Bisphosphonates ++ +++ ND ND ND Teriparatide + ND ND ND ND Strontium ranelate ++ ND ND ND ND

28. Summary of Clinical Trials BMD changes explain some but not all of the fracture risk reduction with most drugs Changes in BTMs are correlated with BMD change and fracture risk reduction with some drugs Controversy on relationship between magnitude of BMD and BTM change and fracture risk reduction Other biomarkers are promising but need validation before using in clinical practice

29. Goals of Treatment Reduce fracture risk Increase bone strength Reduce fall risk Reduce force applied to bone Prevent bone loss and irreversible changes in bone structure

30. Monitoring Drug Therapy Limitations Bone strength, fracture risk, and microarchitecture of bone cannot be measured in individual patients in clinical practice Fractures may occur in responders or non-responders Surrogate markers (“biomarkers”) Bone mineral density (BMD) DXA Bone turnover markers (BTMs) Resorption- uNTX, sNTX, sCTX Formation- Alk Phos, BSAP, Osteocalcin, P1NP

31. Clinical Considerations for Biomarkers *Least Significant Change = smallest change in a measurement that is likely to represent a genuine change and not a measurement error or biological variation DXA BMD BTM LSC* with 95% CI ~3% (Must be measured for each facility) ~20-40% (biological and analytical variability) Signal-Noise Ratio (biological change/LSC) >1 (varies by skeletal site and drug) >1 (not clear which BTM best for which drug) Time to reach LSC 1-2 years (varies by skeletal site and drug) 3 months (within several days for some drugs) Medicare coverage 1-2 years (varies by Medicare carrier) 2 baseline, 1 f/u per yr Guidelines for clinical use Yes No

32. Serial BMD Testing DXA must be performed and interpreted at a qualified facility with known LSC Predictive of fracture risk reduction Guidelines often recommend repeat 1-2 years after starting therapy Widely available and generally affordable

33. Bone Turnover Markers Predictive of BMD response Associated with fracture risk reduction No clinical practice guidelines Potentially helpful Many uncertainties Biological and analytical variability LSC in clinical practice Best marker for which drug

34. Monitoring in Clinical Practice BMD Measure 1-2 years after starting therapy Goal is stability or increase If BMD is stable, measure a BTM to assure metabolic effect BTMs Measure about 3 months after starting therapy or when BMD response is not as expected Goal is significant decrease with antiresorptive agent and increase with anabolic agent Optimal method of monitoring, best skeletal site to measure, and best BTM may vary according to drug used Significant loss of BMD, lack of expected change in BTM, or fracture on therapy is cause for concern and consideration of further evaluation Personal Opinion.

35. Bisphosphonate Bone-Losers in Clinical Practice Lewiecki EM, Rudolph LA. J Bone Miner Res. 2002;17(Suppl 1):S367. 90.4% Stable or Increased BMD 9.6% Bone Losers 50% Contributing Factors Identified 50% No Contributing Factors Identified 104 patients age 65 and over with baseline and F/U DXA

36. Case Study: Non-response to Treatment for Osteoporosis 65 year-old retired university professor has osteoporosis (L1-L4 T-score = -3.3) Treatment with an oral bisphosphonate results in a significant BMD increase at L1-L4 1 year later Next DXA shows BMD loss He sees you for evaluation of non-response to therapy What do you do?

37. Quiz: What do you do? Change therapy to an injectable bisphosphonate Stop alendronate and start teriparatide Order lab studies to evaluate for factors contributing to bone loss Other

38. L1-L4 Scans Baseline 0.729 g/cm 2 Follow-up #1 +0.038 (+5.3%) Follow-up #2 -0.037 (-5.1%)

39. Correct Answer is D Follow-up scan #2 has vertebral bodies labeled differently than in the first 2 scans When it was re-analyzed and labeled the same as the others, BMD was stable Patient was responding to therapy and needed no further evaluation Serial DXA studies must be carefully reviewed to assure that the comparison is valid

40. Quantitative Comparison Same instrument at same facility (unless cross-calibration has been done) Compare “apples with apples,” e.g., same skeletal site, same ROI, same bone area Precision assessment and least significant change (LSC) known

41. Considerations in a Non-responder Initiation Adherence Calcium / Vitamin D Co-morbidities Absorption Metabolism Dose Dosing Interval Efficacy / Resistance

42. Management of a Non-responder Address contributing factors Consider change to IV bisphosphonate in a patient with poor response to oral bisphosphonate Consider switch to teriparatide if poor response to antiresorptive agent and at high risk for fracture and Consider combination therapy (?) Consider no change in therapy and re-evaluate in 1 year Personal Opinion.

43. How Long to Treat

44. Offset of Effect Estrogen, raloxifene, salmon calcitonin Short half-life Rapid offset of effect when stopped Teriparatide Short half-life Limited to 18-24 months by FDA “ Anabolic window” may be <18 or >24 mo. Bisphosphonates Long skeletal-retention time Persistence of effect may vary by drug

45. FLEX: Lumbar Spine BMD 2 4 6 8 10 12 14 3.7% Year P <0.001 Mean Percent Change From FIT Baseline, % 16 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5 0 F 0 F 1 F 2 F 3 F 4 FLEX 5 years Time Between FIT and FLEX 1 to 2 years FIT 3 to 4.5 years Black DM et al. JAMA. 2006;296:2927-2938. = ALN/placebo (n = 437) = ALN/ALN (pooled 5-mg and 10-mg groups: n = 662)

46. FLEX: Serum CTX 0.05 0.25 0.10 0.15 0.20 Mean Absolute Value, ng/mL 0.00 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5 F 0 F 1 F 2 F 3 F 4 Year 56% P <0.0001 FLEX 5 years Time Between FIT and FLEX 1 to 2 years FIT 3 to 4.5 years Black DM et al. JAMA. 2006;296:2927-2938. = ALN/placebo (n = 97) = ALN/ALN (pooled 5-mg and 10-mg groups: n = 139)

47. FLEX: Incidence of Fractures ARR = 2.9% P = 0.013 RR = 0.9 CI (0.6, 1.2) RR = 1.0 CI (0.8, 1.3) 5% 2% 11% 10% 19% 19% Fracture Incidence, % Clinical Vertebral Vertebral Morphometric Nonvertebral RR = 0.45 CI (0.2, 0.8) Hip 3% 3% RR = 1.0 CI (0.5, 2.1) Black DM et al. JAMA. 2006;296:2927-2938. ALN/PLB (n = 437) ALN/ALN (n = 662)

48. FLEX Summary ALN for 10 years is safe and effective Discontinuation of ALN after 5 years is associated with decreased BMD, increased BTMs, and greater risk of clinical VFs Morphometric VFs, non-VFs, and hip fractures similar in both groups Limitations: small sample size, selection bias (33% of women randomized to receive ALN in FIT included in FLEX analysis), weakly powered to detect difference in fractures, mean FLEX baseline FN T-score = -2.2 (T-score < -3.5 excluded)

49. When to Consider a Bisphosphonate Holiday When patient never needed treatment in the first place Retrospective application of NOF guide After good response (BMD/BTM) to at least 3-5 years treatment and fracture risk no longer high Estimate fracture risk with baseline FRAX™ and adjustment for treatment effect Continue treatment in high risk patients Previous fractures, very low BMD Personal Opinion.

50. When to End a Bisphosphonate Holiday Not clear Possible approaches Arbitrarily restart treatment after 1-2 years Monitor BMD/BTM every 6-12 months and restart treatment when significant decrease in BMD or increase in BTM Reconsider treatment plan if fracture or change in clinical status Personal Opinion.

51. Adverse Events Side-effect An undesirable condition that is clearly caused by the drug Ex- severe heartburn 1 hour after oral bisphosphonate Perceived side-effect Attributed to drug but may or may not be caused by drug Ex- itchy scalp 6 months after IV zoledronate Fear of side-effect Often rare high profile conditions that may or may not be caused by drug Ex- rotten jaw, brittle bones, spontaneous fractures, atrial fib, heart attacks, bone cancer, etc.

52. Selected Adverse Events Bisphosphonates Raloxifene Teriparatide Calcitonin GI irritation VTE Osteosarcoma in rats Nasal irritation Acute phase reaction Fatal stroke Leg cramps Chronic muscle and bone pain Leg cramps Nausea Renal effects Vasomotor symptoms Headaches Uveitis/iritis/scleritis Fatal stroke Hypercalcemia Hypocalcemia ONJ Unusual fractures? Atrial fib?

53. Comparative Risks Kanis JA et al. Osteoporos Int. 2001;12:417-427. Pharmcoepidemiol Drug Saf. 2003;12:195-202. National Center for Health Statistics. JADA. 2006;137:1144-1150. www.nssl.noaa.gov/papers/techmemos/NWS-SR-193/techmemo-sr193-4.html (1) Women age 65-69 (from Swedish National Bureau of Statistics and database of Olmsted County, MN, USA.)

54. Managing Adverse Events Before starting therapy, address patient concerns and discuss AEs that are common, serious, or high profile For uncertain side effect, consider stopping drug and re-challenging later For clear side effect, stop drug and re-treat later, usually with drug of different class

55. Summary Learn from RCTs but do not be tyrannized by them Use CPGs as tools but not mandates for treatment decisions Listen to patients, learn from them, educate them, and individualize their care Respect your good clinical judgment