Disclosures Diagnostic Challenges in Osteoporosis: Whom To Treat Ethel S. Siris, MD Columbia University Medical Center New York, NY Consultant on scientific issues for: AgNovos Amgen Eli Lilly Merck Novartis Osteoporosis Definition: NIH Consensus Conference A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture Bone strength = Bone Quantity (BMD) + Bone Quality (micro-architecture, etc) 1 Projections for Osteoporosis and Low BMD at Lumbar Spine or Femoral Neck (millions, female and male >50) Wright et al JBMR doi:10.1002/jbmr2269 Normal Osteoporosis 1 NIH Consensus Conference, 2000. 2 Source: Dempster DW, et al. J Bone Miner Res. 1986:1:15-21 Reprinted with permission from the American Society of Bone and Mineral Research 1
Sporadic Factors Heredity Local Factors Menopause Aging Pathogenesis of Osteoporotic Fractures Low Peak Bone Mass Increased Bone Loss Reduced Bone Quantity (and Quality) Trauma FRACTURES Consequences of Osteoporosisassociated Fractures in the United States 2 million fractures in 2005 1 29% occurred in men 14% occurred in nonwhites Fractures Negatively impact quality of life 2 Impose physical and functional limitations 3 Increase mortality (vertebral and hip) 4,5 In 2005, osteoporosis related fractures in the U.S. were estimated to be $17 $19 billion 1, 6 Wrist 19% Pelvis 7% Vertebra 27% Other 33% Humerus Clavicle Hands/Fingers Patella Tibia/Fibula Hip 14% 1. Burge R et al, J Bone Miner Res. 2007;22:465 475. 2. Tosteson AN, et al. Osteoporos Int. 2001;12:1042 1049. 3. Fink HA, et al. Osteoporos Int. 2003;14:69 76. 4. Bliuc D, et al. JAMA. 2009;301:513 521. 5. Tosteson AN, et al. Osteoporos Int. 2007;18:1463 1472. 6. National Osteoporosis Foundation. Osteoporosis Fast Facts. 2008 http://www.nof.org/osteoporosis/diseasefacts.htm#prevalencen Accessed 23 July, 2009. Figure adapted from: Burge R et al, J Bone Miner Res. 2007;22:465 475. FDA Approved Medications Drug FDA Indication Dose and Regimen Estrogen PMO prevention Multiple formulations and regimens; oral, topical; cyclic, continuous BZA/CEE PMO prevention BZA 20/CEE 0.45 Raloxifene PMO prevention and treatment 60 mg PO daily Calcitonin (??) Alendronate Risedronate PMO treatment in women >5 years postmenopause PMO prevention PMO, male, GIOP treatment PMO treatment Male treatment PMO, GIOP prevention PMO, male, GIOP treatment 200 IU intranasally once daily (alternate nostrils) 100 IU SQ every other day Prevention: 5 mg PO daily or 35 mg PO weekly Treatment 10 mg PO daily or 70 mg PO weekly Treatment 70 mg PO weekly* Treatment 70 mg PO weekly* Ibandronate PMO prevention and treatment 150 mg PO monthly 3 mg IV every 3 months Zoledronic acid PMO, GIOP prevention PMO, male, GIOP treatment 5 mg PO daily; 35 mg PO weekly; 150 mg PO monthly Delayed release/enteric Coated form 35 mg PO weekly after breakfast Prevention: 5 mg IV every 2 nd year Treatment: 5 mg IV once yearly Denosumab PMO, male treatment 60 mg SQ every 6 months Teriparatide PMO, male, GIOP treatment 20 mcg SQ daily (for maximum 2 years lifetime) PMO = Post menopausal; GIOP Glucocorticoid induced osteoporosis Data from prescribing information *Effervescent for individual tablet medications (in water) Prevention vs. Treatment: FDA Drugs for prevention of osteoporosis inhibit the bone loss in postmenopausal women with low bone mass that might lead in time to the development of osteoporosis, i.e. a T score 2.5. Drugs approved for treatment of osteoporosis lower risk for fracture in postmenopausal women with osteoporosis (diagnosed by T score, or by fracture history). 2
Current Conundrums Emphasis today is to treat those women at high risk for fracture The drugs used for prevention of osteoporosis all have problems with respect to risk benefit issues: e.g., estrogen/progestin and breast cancer risk; bisphosphonates and ONJ and AFF; raloxifene and DVT or fatal stroke Prevention drugs also raise cost effectiveness issues. The Osteopenia Problem Osteopenia, i.e. low bone mass, is not a disease it is a risk factor for future fracture Some women with osteopenia are at high short term risk for fracture due to advanced age and other risk factors Younger postmenopausal women with osteopenia are at relatively low short term risk for fracture, though they may be at high long term risk since they have many years to lose bone and may develop additional risk factors This is where FRAX is useful Secondary Fracture Prevention There is truly no controversy about the need for treatment in older patients who have already fractured. Currently, however, only 20% of such patients receive treatment to prevent the next fracture. Half of patients who have a hip fracture had a previous fracture, but no treatment was given despite that red flag. 3
Fracture Liaison Service (FLS) Model of Care: Getting the Post-fracture Patient Treated A coordinated preventive care model which operates under the supervision of bone health specialists and collaborates with the patient s orthopedist and primary care physician Coordinates post-fracture care through a FLS coordinator (a nurse or other allied health professional) who ensures individuals who fracture receive appropriate diagnosis, treatment and support FLS coordinators link the fracture fixers in orthopedics with the fracture preventers who will medically manage the patient FLS programs have been successful in a number of closed and open settings, both in the U.S. and abroad (most notably in the U.K. and Canada) These programs have greatly reduced the number of costly and serious recurrent fractures by identifying and appropriately treating post-fracture patients, recognizing that this group has the highest risk of future fractures The Clinical Diagnosis of Osteoporosis The National Bone Health Alliance recently published recommendations to expand the criteria for making a diagnosis of osteoporosis, to reflect better the disease definition a disorder of reduced bone strength that predisposes to fractures. The goal is to identify all those who are at elevated risk for fracture to increase both patient and physician awareness, clarify the patient s status with payers and assure appropriate management The main barrier: paying the salary of the FLS coordinator The Clinical Diagnosis of Osteoporosis The diagnosis of osteoporosis should be made in postmenopausal women and in men over 50 who have one of the following characteristics: T score 2.5 at spine or hip (total hip or femoral neck) Hip fracture, with or without BMD testing Low trauma vertebral, proximal humerus or pelvis fracture in the presence of osteopenia Some distal radius fractures in presence of osteopenia FRAX scores (in those with osteopenia) that meet the NOF Guide treatment intervention threshold: 10 year risk for hip fracture 3%, or for major osteoporotic fracture 20% 4
Pharmacologic Intervention for Those With Significant Fracture Risk: NOF Guide Postmenopausal women and men age 50 and older presenting with the following should be considered for treatment: A hip or vertebral (clinical or morphometric) fracture T -score -2.5 at the femoral neck or spine after appropriate evaluation to exclude secondary causes Low bone mass (T -score between -1.0 and -2.5 at the femoral neck, total hip, or spine), and 10-yr probability of hip fracture 3% or 10-yr probability of major osteoporotic fracture 20% based on the US-adapted WHO algorithm National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2010. NOF Guide: How Many Would be Treated? The Dawson Hughes paper, using data from NHANES estimates that the number of people who meet the current NOF Guide criteria for treatment would include 33% of women and 19% of men age 50 and older Adding the other fracture types in addition to spine and hip as noted in the Clinical Diagnosis of Osteoporosis paper (osteopenia plus pelvis, proximal humerus, and some distal forearm fractures) the proportion treated would not increase significantly, based upon an analysis of NHANES data that is currently underway Caveats Most of the current therapies that have been shown to reduce fracture risk enrolled either women with PMO by T score at the spine or hip or postmenopausal women with at least low bone mass who had a prevalent spine or hip fracture Do the drugs reduce fracture outcomes if the elevated fracture risk (or diagnosis of OP) is based on FRAX? Other aspects of treatment e.g. fall risk reduction, lifestyle factors (stop smoking, decrease alcohol), calcium and D sufficiency are always needed and especially when diagnosis is based on FRAX 5
Another Caveat: The Need for Adherence Initiating therapy is of little value if the patient stops taking it. Many studies have indicated that about half of patients discontinue treatment within a year of starting it. The medicines don t work if they aren t taken, as former Surgeon General C. Everett Koop once pointed out. Effect of treatment compliance on probability of fracture over 24 months for bisphosphonate treated subjects Probability of Fracture 0.120 0.115 0.110 0.105 0.100 0.095 0.090 0.085 0.080 0.075 0.070 eg, 1 out of 2 wks Refill Compliance (MPR) Adapted from Siris et al., Mayo Clin Proc 81:1013, 2006 eg, 3 out of 4 wks eg, 11 out of 12 mos 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Whom to Treat? Treatment is clearly indicated in postmenopausal women and older men with osteoporosis, based upon the expanded diagnostic criteria. The choice of treatment may vary based upon the evidence of a treatment effect in each of the diagnostic categories Treatment is especially critical in the patient who has already fractured When to Prevent? A period of therapy with an agent approved for prevention of bone loss may be indicated in postmenopausal women with low bone mass who have added risk factors for fractures (e.g. use of corticosteroids, AIs; diseases that adversely affect bone such as diabetes), or who undergo surgical or chemotherapy induced menopause, or abruptly stop estrogen. Clinical judgment and patient preferences are very important in this setting. 6
Nothing is Forever Whenever a drug is provided for bone health, a review of the reasons for giving it and the need to continue it must be re evaluated periodically; similarly in untreated older women periodic reassessment to see if treatment should be initiated (or re initiated) due to new events or risk factors needs to occur. Thank you for your attention! 7