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Update on Management of Osteoporosis

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1 Update on Management of Osteoporosis
E. Michael Lewiecki, MD New Mexico Clinical Research & Osteoporosis Center University of New Mexico School of Medicine Albuquerque, NM

2 Faculty Disclosure It is the policy of the American Society for Bone and Mineral Research (ASBMR) and The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a faculty member with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The American Society for Bone and Mineral Research (ASBMR) and The France Foundation have identified and resolved any and all faculty conflicts of interest prior to the release of this activity.

3 Disclosure Grant / Research Support
Amgen, Eli Lilly, Merck, Novartis, Warner Chilcott Consultant, Advisory Board, Speakers’ Bureau, or Sponsored Speaking Events

4 Learning Objectives Improve the ability to assess risk factors for osteoporosis and apply evidence-based screening recommendations to these at-risk patients within one’s practice Develop strategies to improve the treatment of patients with osteoporosis Utilize the tools and other information provided within this initiative, including patient education tools and systems- based approaches to facilitate improving the assessment and care being provided to patients with osteoporosis

5 Postmenopausal Osteoporosis in the Primary Care Setting
What is osteoporosis? Why you should care? Whom to test and how? Whom to treat and how?

6 Definition of Osteoporosis
A skeletal disorder characterized by Compromised bone strength predisposing to An increased risk of fracture Bone strength reflects the integration of two main features: Bone density Bone quality Normal Bone The “old” definition distinguished osteoporosis (in which the makeup of bone was normal) from osteomalacia (in which mineralization was clearly abnormal). The “modern” definition introduces the importance of bone quality (micro-architecture). Although this definition dates back to 1991, there is still no clinical test of bone quality. Thus, the clinically-relevant parts of the definition are bone mass and fractures. Osteoporotic Bone 2000 NIH Consensus Development Conference

7 Osteoporosis Is a Serious Public Health Problem
At age 50, lifetime risk of fracture is 1:2 women 1:5 men Affects 10 million Americans 8 million women 2 million men Additional 34 million have low bone mass 2 million fractures yearly* Direct cost $17 billion* Distribution of Fractures *Based on figures from Cost does not include lost productivity, unpaid caregiver time, transportation and social services NOF Fast Facts. Accessed February 2013. Burge R, et al. J Bone Miner Res. 2007;22: USDHHS. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD

8 Identified Treatment Gap NCQA HEDIS
HEDIS Measure % Compliance* Beta-blocker persistence after a heart attack 81.3% Breast cancer screening 70.5% Colorectal cancer screening 62.4% Osteoporosis management after a fracture 22.8% *2011 HMO Rates NCQA State of Healthcare HMO Statistics (Commercial or Medicare data from 2011). Accessed February 2013.

9 National Osteoporosis Foundation 2013 Guidelines
Major clinical recommendations Universal (risk, diet, vitamin D, exercise, smoking, monitoring) Diagnosis (BMD, vertebral imaging, causes of secondary osteoporosis) Monitoring (BMD) Treatment (initiation criteria, options, duration) Accessed March 2013.

10 Who Should Have a Bone Density Test?
AAFP1 and NOF2 Women age 65 and older and men age 70 and older Younger postmenopausal women and men ages –69 with clinical risk factors Adults who have a fracture after age 50 Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids) associated with low bone mass or bone loss Conditions, Diseases and Medications That Cause or Contribute to Osteoporosis and Fractures Lifestyle factors Alcohol Abuse High salt intake Falling Low calcium intake Inadequate physical activity Excessive thinness Vitamin D insufficiency Immobilization Excess vitamin A Smoking (active or passive) Genetic factors Cystic fibrosis Homocystinuria Osteogenesis imperfecta Ehlers-Danlos Hypophosphatasia Parental history of hip fracture Gaucher’s disease Idiopathic hypercalciuria Porphyria Glycogen storage diseases Marfan syndrome Riley-Day syndrome Hemochromatosis Menkes steely hair syndrome Hypogonadal states Androgen insensitivity Hyperprolactinemia Premature ovarian failure Anorexia nervosa and bulimia Premature menopause Athletic amenorrhea Turner’s & Klinefelter’s syndromes Panhypopituitarism Endocrine disorders Adrenal insufficiency Cushing’s syndrome Central Adiposity Diabetes mellitus (Types 1 & 2) Hyperparathyroidism Thyrotoxicosis Gastrointestinal disorders Celiac disease Inflammatory bowel disease Primary biliary cirrhosis Gastric bypass Malabsorption GI surgery Pancreatic disease Hematologic disorders Multiple myeloma Monoclonal gammopathies Sickle cell disease Hemophilia Leukemia and lymphomas Systemic mastocytosis Thalassemia Rheumatologic and autoimmune diseases Ankylosing spondylitis Lupus Rheumatoid arthritis Other rheumatic and autoimmune diseases Central nervous system disorders Epilepsy Parkinson’s disease Stroke Multiple sclerosis Spinal cord injury Miscellaneous conditions and diseases AIDS/HIV Congestive heart failure Muscular dystrophy Alcoholism Depression Post-transplant bone disease Amyloidosis End stage renal disease Sarcoidosis Chronic metabolic acidosis Hypercalciuria Weight loss Chronic obstructive lung disease Idiopathic scoliosis Medications Aluminum (in antacids) Cyclosporine A and tacrolimus Proton pump inhibitors Anticoagulants (heparin) Depo-medroxyprogesterone (premenopausal contraception) Selective serotonin reuptake inhibitors Anticonvulsants Glucocorticoids (≥ 5 mg/d prednisone or equivalent for ≥ 3 months) Tamoxifen® (premenopausal use) Aromatase inhibitors GnRH (Gonadotropin releasing hormone) antagonists and agonists Thiazolidinediones (such as Actos® and Avandia®) Barbiturates Lithium Thyroid hormones (in excess) Cancer chemotherapeutic drugs Methotrexate Parenteral nutrition 1. Sweet MG, et al. Am Fam Physician. 2009;79(3): 2. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Accessed February 2013.

11 Reimbursement for DXA Final Rule
Since 2006, Medicare covers bone densitometry for five indications Estrogen-deficient women at clinical risk for osteoporosis Patients with vertebral abnormalities Patients receiving long-term glucocorticoids (prednisone ≥ 5 mg/d or equivalent for 3+ months) Patients with primary hyperparathyroidism Patients being monitored to assess the response to an approved drug Federal Register. 2006;71(231):

12 WHO Criteria for Postmenopausal Osteoporosis
The T-score compares an individual’s BMD with the mean value for young adults and expresses the difference as a standard deviation score. Kanis JA, et al. J Bone Miner Res. 1994;9: -2.5 and below Osteoporosis Between -1.0 to -2.5 Low bone mass (osteopenia) -1.0 and above Normal T-score Category

13 NOF Treatment Guidelines 2013
Women ≥ 65 and men ≥ 70 (younger with risk factors) DXA T-score between -1.0 and -2.5 and high fracture risk T-score ≤ -2.5 in the lumbar spine, total hip, or femoral neck or Hip or spine (clinical or radiographic) fracture ≥ 3% for hip fracture or ≥ 20% for major osteoporotic fracture FRAX 10-y fracture risk Candidate for TREATMENT YES Accessed March 2013.

14 Web Version 3.4

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20 Clinical Benefits of FRAX
Derives 10-year probability of clinical event from measurable parameters Internationally recognized and validated Based on data from multiple cohorts Easily accessible on the Internet or DXA software Helps identify patients who need treatment Curr Osteoporos Rep December; 8(4): 192–197. The Utility and Limitations of FRAX: A US Perspective Stuart L. Silverman and Andrew D. Calderon Abstract The FRAX calculator is a major achievement in terms of our understanding of measuring fracture risk. Along with being an easily accessible web-based tool, it is the only model based on extensive data on multiple cohorts. FRAX will help clinicians identify individuals who need osteoporosis treatments, while also screening out those who do not require osteoporosis treatments. However, FRAX is limited by a number of factors. Although it is web based, few physicians have the means to access it. It also assumes that body mass index and mortality are constant across different racial and ethnic groups. FRAX is further limited by the exclusion of variables known to be associated with fracture risk, lack of dose-response relationships for variables, increased subsequent fracture risk after initial fracture, restriction to only one bone mineral density site, racial and ethnic differences that may influence fracture risk, and availability of racial and ethnic fracture risk data to be used in the FRAX calculator. Finally, the values obtained from FRAX should not take the place of good clinical judgment.

21 Limitations of FRAX™ WHO Fracture Probability Tool
Not valid in patients on treatment Only hip BMD is considered Risk is “yes/no” – there is no consideration of “dose” (e.g., fractures, glucocorticoids, smoking, alcohol) Not all risk factors are included (e.g., falls) “Major osteoporotic fracture” is not the same as all osteoporotic fractures Clinical judgment is required Watts NB, et al. J Bone Miner Res 2009;24:

22 Patient Care Goals Identify patients at risk of fractures
Reduce incidence of fractures Maintain quality of life Activity Independence Health

23 Universal Recommendations
Counsel on the risk of fractures Calcium intake as follows, ideally through diet, with supplements if necessary 1000 mg per day for men 50-70 1200 mg per day for women ≥ 51 1200 mg per day for men ≥ 71 Vitamin D intake should be 800-1,000 IU per day, supplemented if necessary (age ≥50) Regular weight-bearing and muscle-strengthening exercise Fall prevention evaluation and training As highlighted by the recent US Preventive Services Task Force recommendations (http://www.uspreventiveservicestaskforce.org/uspstf/uspsvitd.htm) vitamin D and calcium remain controversial. The NOF guidelines extracted for this slide describe vitamin D insufficiency [serum 25-hydroxyvitamin D (25(OH)D) < 30 ng/ml (75 nmol/L)] as a risk factor for falls and adds that “Patients with recent fractures, multiple fractures or very low BMD should be evaluated for secondary etiologies and, when considering osteomalacia or vitamin D insufficiency, a serum 25(OH)D level should be obtained.” Thus clinical judgment should dictate whether supplementation alone or with serum monitoring is appropriate for each patient. The 2010 AACE guidelines (Watts et al are explicit about monitoring vitamin D: “Maintain adequate vitamin D intake; supplement vitamin D, if needed, to maintain serum levels of 25-hydroxyvitamin D [25(OH)D] between 30 and 60 ng/mL (Grade A; BEL 1).” Accessed March 2013.

24 FDA-approved Medications Indications
Postmenopausal Osteoporosis Glucocorticoid-induced Osteoporosis Men Drug Prevention Treatment Estrogen Calcitonin* (Miacalcin®, Fortical®) Raloxifene (Evista®) Ibandronate (Boniva®) Alendronate (Fosamax®) Risedronate (Actonel®) Risedronate (Atelvia®) Zoledronate (Reclast®) Denosumab (Prolia™) Teriparatide (Forteo®) Paget’s dose: alendronate 40 mg/day x 6 mo., risedronate 30 mg/day x 2 mo. *FDA advisory board found that evidence did not support calcitonin salmon for the treatment of osteoporosis (March 5, 2013)

25 Evidence for Fracture Reduction
Drug Vertebral Fracture Nonvertebral Fracture Hip Fracture Calcitonin (Miacalcin®, Fortical®) No effect demonstrated Raloxifene (Evista®) Ibandronate (Boniva®) Alendronate (Fosamax®) Risedronate (Actonel®, Atelvia®) Zoledronic acid (Reclast®) Denosumab (Prolia™) Teriparatide (Forteo®) Adapted from Murad MH, et al. J Clin Endocrinol Metab. 2012;97(6):

26 Bisphosphonates Side Effects/Safety Concerns
May cause esophageal irritation (oral) Can cause acute phase response (IV and high-dose oral) Contraindicated in patients with hypocalcemia Limited to patients with good kidney function (GFR > 30 or 35 mL/min) Musculoskeletal pain? Osteonecrosis of the jaw? Atypical femur fractures?

27 Bisphosphonates “Side Benefits”
Decreased risk of breast cancer1-5 Decreased risk of colorectal cancer6 Decreased risk of stroke7 Reduced risk of gastric cancer8 Decreased overall mortality9,10 1. Chlebowski RT, et al. J Clin Oncol. 2010;28: 2. Dreyfuss JH. CA Cancer J Clin. 2010;60: 3. Newcomb PA, et al. Br J Cancer. 2010;102: 4. Rennert G, et al. J Clin Oncol. 2010;28: 5. Vestergaard P, et al. Calcif Tissue Int. 2011;88: 6. Rennert G, et al. J Clin Oncol. 2011;9: 7. Kang JH, et al. Osteoporos Int. 2012;23(10): 8. Abrahamsen B, et al. J Bone Miner Res. 2012;27: 9. Center JR, et al. J Clin Endocrinol Metab. 2011;96: 10. Sambrook PN, et al. Osteoporos Int. 2011;22:

28 Bisphosphonates How Long Should Treatment Last?
Bisphosphonates have a long residence time in bone When long-term therapy is stopped, is sufficient drug available to exert a continuing benefit? Does long-term treatment create safety concerns that limit the duration of treatment? Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab Apr;95(4): Watts NB, Diab DL. CONTEXT: Bisphosphonates have been widely used in the treatment of osteoporosis. Uncommon side effects have emerged in postapproval use. Because bisphosphonates accumulate in bone and are released for months or years after treatment is stopped, it is reasonable to consider the clinical question of how long to treat. OBJECTIVE: In this personal perspective, we review the pharmacology and mechanism of action of bisphosphonates and the clinical studies that support their efficacy. We then review the literature for longer-term studies and reports of possible side effects that were not seen in clinical trials. RESULTS: Bisphosphonates have demonstrated antifracture efficacy in randomized, placebo-controlled trials of 3 and 4 yr duration and have been widely used since the initial release of alendronate in For zoledronic acid and risedronate, an early effect (fractures reduced within 6-12 months of starting therapy) has been shown. A sustained effect for risedronate has been shown through 5 yr and suggested through 7 yr. Ten-year data with alendronate and 8 yr data with risedronate indicated good tolerability and safety; it is unlikely that longer-term studies will be done. Side effects that emerged in clinical trials include esophageal irritation with oral administration and acute phase response with iv treatment or high-dose oral therapy. Uncommon side effects that have been noted with wide clinical use include osteonecrosis of the jaw, musculoskeletal complaints, and atypical fractures. The numbers of events are small, and a clear cause-and-effect relationship between these events and bisphosphonate treatment has not been established. Because bisphosphonates accumulate in bone, they create a reservoir leading to continued release from bone for months or years after treatment is stopped. Studies with risedronate and alendronate suggest that if treatment is stopped after 3-5 yr, there is persisting antifracture efficacy, at least for 1-2 yr. CONCLUSIONS: Bisphosphonates are popular and effective for treatment of osteoporosis. Because they accumulate in bone and provide some residual antifracture reduction when treatment is stopped, we recommend a drug holiday after 5-10 yr of bisphosphonate treatment. The duration of treatment and length of the holiday are based on fracture risk and pharmacokinetics of the bisphosphonate used. Patients at mild risk might stop treatment after 5 yr and remain off as long as bone mineral density is stable and no fractures occur. Higher risk patients should be treated for 10 yr, have a holiday of no more than a year or two, and perhaps be on a nonbisphosphonate treatment during that time. Porras AG, et al. Clin Pharmacokinet. 1999;36(5): Watts NB, et al. J Clin Endocrinol Metab. 2010;95(4): 28

29 Long-term Experience with Alendronate Fit Long-term Extension (FLEX) Study
Patients who received ~5 years of alendronate in the Fracture Intervention Trial signed up for a second 5-year study Re-randomized to stay on alendronate (n = 662) or changed to placebo (n = 437) For those who had 10 years of alendronate compared with stopping after 5 years Clinical vertebral fractures were reduced by 55% overall Nonvertebral fractures were reduced by 50% in women with T-scores -2.5 or below at the start of FLEX Schwartz AV, et al. J Bone Miner Res. 2010;25: 29

30 Clinical Vertebral Fractures in the FLEX Study
6 5.3% ALN 5 years  Placebo 5 years 5 Alendronate 10 years 4 RR  55% P = 0.013 Cumulative Incidence of Fractures (%) 3 2.4% 2 1 the message in the oval is that fracture risk is similar for the first 2 years after stopping therapy vs continuing treatment. 1 2 3 4 5 Years Since FIT ALN/PLB ALN/ALN Black DM, et al. JAMA. 2006;296: 30

31 Suggestions for Bisphosphonate Duration
Long-term treatment (e.g., 5–10 years) appears to be safe for most patients For lower risk patients, after 3–5 years of treatment, “drug holidays” can probably be taken without a major sacrifice of efficacy Higher risk patients should probably continue treatment for at least 10 years No evidence beyond 10 years Watts NB and Diab D. J Clin Endocrinol Metab. 2010;95(4):

32 Denosumab Fully human monoclonal antibody to RANKL; decreases osteoclast differentiation, function and survival Reduces risk of spine, hip and nonvertebral fractures For treatment of osteoporosis, SQ dosing every 6 months Does not require dose adjustment for decreased kidney function Effect is reversible within 6–12 months of stopping Denosumab is a fully human monoclonal antibody with a unique mechanism of action that binds with high affinity to, and inhibits the activity of human RANK (receptor activator of nuclear factor kappa B) ligand, the primary mediator of osteoclast activity1. Amgen scientists have confirmed the essential role of RANK Ligand pathway in the formation, activation and survival of osteoclasts, the cells that are associated with bone resorption1,2. Since RANK Ligand is part of the TNF receptor superfamily, high specificity is demonstrated by the fact that denosumab does not bind to other TNF receptors.1 The pharmacokinetics (SC administration) of denosumab in postmenopausal women were nonlinear with dose. The serum profiles were characterized by three distinct phases: 1) a prolonged absorption phase, which resulted in maximum serum concentrations that increased disproportionately greater (2.6-fold) than the increase in dose and were observed between 5 and 21 days after administration; 2) a prolonged -phase, characterized by half-lives that increased with dose to a maximum of 32 days; and 3) a more rapid terminal phase observed at concentrations <1,000 ng/mL with a half-life that increased from 5 to 10 days as dose increased from 0.01 to 3.0 mg/kg. Because of the nonlinear pharmacokinetics, the mean serum residence time increased with dose from 12 to 46 days.1 1. Bekker PJ, et al. A single-dose placebo-controlled study of AMG-162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19: 2. Boyle WJ, et al. Osteoclast differentiation and activation. Nature. 2003;423: 3. Peterson HC, et al. AMG 162 maintains serum concentrations for up to 9 months following a single subcutaneous dose in healthy postmenopausal women. J. Bone Miner. Res. 2003; 18(Suppl 2):S166. Abstract SA393 ad poster. Cummings SR, et al; FREEDOM Trial. N Engl J Med. 2009;361(8): Jiang X, et al. Menopause. 2013;20(2):

33 Differences Among Antiresorptive Agents
Pharmacology – mechanism of action, onset and offset of effect, skeletal retention Route of administration – oral (fasting or with food) or parenteral Frequency of administration – daily, weekly, monthly, quarterly, twice yearly, once yearly Side effects/tolerability – depends on agent and patient Non-skeletal effects – breast cancer reduction (raloxifene) Cost/insurance coverage – generic oral; drugs “administered by health professional” covered by Medicare Part B

34 Teriparatide Recombinant human PTH (rhPTH [1-34])
Mechanism of action different from other agents (anabolic) Daily SC injection Indicated for patients at high risk for fracture Postmenopausal women with osteoporosis Men with primary or hypogonadal osteoporosis Men and women with osteoporosis associated with sustained systemic glucocorticoid therapy Treatment limited to 2 years, follow with antiresorptive agent Forteo PI. Accessed Feb 2013. Han SL, Wan SL. Int J Clin Pract. 2012;66:

35 Monitoring Monitor with DXA every 1–2 years
Do not "over-interpret" change Be happy when BMD is stable OR increasing Why do some patients lose BMD on treatment? Poor adherence Malabsorption Underlying disorders that need to be addressed Some patients may respond to therapy yet still have unacceptably high fracture risk – consider change in therapy

36 Fall Prevention Improve lighting Remove loose rugs
Add grab bars near bathtubs, toilets and stairways Formal home safety evaluation Physical therapy for core strength and balance Eliminate medications that can affect alertness and balance Assistive device evaluation and training Sweet MG, et al. Am Fam Physician. 2009;79(3):

37 Where Are We Now? The Good News
Improved awareness Excellent diagnostic tools available Fracture risk assessment using BMD and/or clinical risk factors Safe and effective individualized treatment Better understanding of pathogenesis Federal initiatives to improve care

38 Where Are We Now? The Bad News
Declining numbers of patients on therapy Under-recognition of patients at risk for fracture Poor primary and secondary adherence Poor patient understanding of risk/benefit Decreasing access to DXA Increasing patient concerns about side effects

39 Secondary Fracture Prevention
A fracture is a sentinel event A fracture in a person over 50 is the most powerful risk factor for a future fracture Many high risk patients have the fracture successfully treated but do NOT receive subsequent medical assessment and treatment to prevent the next fracture

40 What can I Do as a PCP? Practical Steps
Patient dialog Risk communication Shared decision making Decision aids Handouts Web resources Brochures

41 What can I Do as a PCP? Practical Steps
Identify patients who are at high risk        Use EHR decision tools Flag patients with risk profile Use checklist of risk factors Identify patients who are not adherent Pharmacy refill data if available Ask questions Patients who are nonadherent to one therapy are often nonadherent to others

42 Performance-improvement CME and MOC Part IV Approved (ABFM)
PI-CME: performance improvement continuing medical education MOC: maintenance of certification ABFM: American Board of Family Medicine ABIM: American Board of Internal Medicine. https://achsos.community360.net/default.aspx. Accessed April 2013.

43 Update on Management of Osteoporosis
What is osteoporosis? Decreased bone strength predisposing to an increased risk of fracture Why you should care Common, significant cost, morbidity and mortality Whom to test and how DXA for all women by age 65, higher risk women earlier; FRAX is a useful tool Whom to treat and how Individuals at high risk of fracture; approved agents are safe and effective; treatment decisions must be individualized 43

44 Questions or Comments? WILL YOUR BONES LAST AS LONG AS YOU DO?


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