A major problem with the use of diagnostic thresholds is that defining osteoporosis on the basis of a T-score < –2.5 does not identify many patients at risk for fracture. We have seen several instances in which BMD provides insufficient information to assess an individual patient’s fracture risk.
Risk factors for hip fracture can be categorized as either skeletal or non-skeletal. Some individuals have osteoporosis or other skeletal factors as their major risk for hip fracture. Others are at risk because of falls or frailty - even if they do not have osteoporosis.
If asked whether low incidence of non-vert fractures was a determinant for non-vertebral efficacy in the placebo populations and whether this affected the drug’s effectiveness across clinical studies, you can answer; This slides shows the placebo fracture incidence, shown on the x axis, across all pivotal trials of currently approved anti-resorptive therapies. The relative risk, shown on the y axis, is a measure of the drug efficacy. The dotted line represents a relative risk of 1 which means no effect. Key points from this slide: First, the Bone study has a similar fracture incidence as the vert-NA study (8.2% vs 8.4% respectively), yet the BONE study did not demonstrate non-vert fracture efficacy while the VERT-NA study did. Second, the ability to directionally show non-vert fracture efficacy in clinical studies appears to be independent of the study’s non-vert fracture incidence. Looking across studies ( in particular VERT-NA and VERT-MN since these studies are evaluating the same drug), non-vert fracture efficacy is not correlated with higher fracture incidence. Third, BONE is the only clinical study that shows an increase in non-vert fractures compared to the placebo group (relative risk>1.0). The results from the 2.5mg (relative risk of 1.1) and 20mg groups (relative risk of 1.09, not shown) supports the drugs consistent lack of efficacy in reducing non-vert fractures. Note, the average drug exposure is similar between the 2.5 mg daily and 20 mg intermittent doses (75 mg/month vs. 80 mg/month respectively).
On the whole, it is beginning to look as if all ONJ has a triggering event related to local conditions in the mouth. What is new here is to implicate chronic severe periodontitis.
Zoledronic Acid: Key Pharmacological Characteristics The unique pharmacologic profile of zoledronic acid may explain why it is possible to achieve profound and sustained suppression of bone resorption with a single, low dose of bisphosphonate: Zoledronic acid has a high binding affinity for bone mineral. 1 This maximizes the amount of drug that binds to bone and is likely to minimize the amount of drug that diffuses from bone after binding. Zoledronic acid is a potent inhibitor of FPP synthase. 2 This maximizes the antiresorptive potential of the drug and minimizes the total amount of drug required in each dose. Zoledronic acid has a high therapeutic ratio (resorption inhibition:mineralization inhibition) 3 and good renal tolerability. 4 This maximizes the safety of this bisphosphonate and allows the patient’s total annual dose to be delivered in a single administration. References 1. Nancollas GH, Tang R, Phipps RJ, et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone . 2006, in press. 2. Dunford JE, Thompson K, Coxon FP, et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther . 2001;296:235-242. 3. Widler L, Jaeggi KA, Glatt M, et al. Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa). J Med Chem . 2002;45:3721-3738. 4. Green JR, Seltenmeyer Y, Jaeggi KA, et al. Renal tolerability profile of novel, potent bisphosphonates in two short-term rat models. Pharmacol Toxicol . 1997;80:225-230.
Median ranges Table 7.1, p 34
Osteoporosis Management: the Science and the Art Robert Lindsay, MD, PhD Chief of Medicine Helen Hayes Hospital Professor of Clinical Medicine Columbia University New York
Competing Interests• Consultant – Amgen, Eli Lilly, Azelon• Speaker – Amgen, Eli Lilly
Learning ObjectivesUpon completion of this educational activity, theparticipant should be able to:• Outline the signs and symptoms of osteoporosis thatwarrant further evaluation.• Delineate the risk of osteoporosis among patients ofdifferent races.• Describe how to utilize guideline-recommendedstrategies for the prevention and treatment ofosteoporosis.• Describe methods for improving patient adherence topharmacotherapies and other strategies designed toprevent or slow the progression of osteoporosis.
Osteoporosis• A serious and common disease that causes (through fractures) significant mortality and high morbidity• Despite that, only about 21% of Medicare hip fracture patients get assessed, diagnosed, or treated! NCQA 2011 benchmarks and thresholds
“If you can get people to askthe wrong questions, you don’thave to worry about what theanswers are.”Pynchon T. Proverbs for paranoids. In: Gravity’s Rainbow. New York:Penguin; 1995.
Question 1• For persons with osteoporosis, should only fractures that occur on modest trauma be considered “osteoporotic”?
Answer• Fractures are never osteoporotic, only bones can be osteoporotic• A person with osteoporosis is at higher risk of fracture – any fracture (exceptions finger toes skull and facial bones)• The level of trauma needed to fracture is lower, thus at higher levels of trauma fracture is more likely
Fractures in patient with osteoporosis Trauma required to break a normal boneTrauma level Trauma required to break a bone that is osteoporotic
Question 2• You can only have osteoporosis when BMD falls below the normal range?
• Osteoporosis is diagnosed by fracture and/or BMD testing• BMD osteoporosis is determined when BMD falls below the normal range (a T- score of =/< -2.5)• The lower BMD is the greater the fracture risk
• Osteoporosis is diagnosed by fracture and/or BMD testing• BMD osteoporosis is determined when BMD falls below the normal range (a T- score of =/< -2.5)• But is risk much different at a T score of -2.4?
BMD and Fracture RiskOsteoporotic Fracture Risk 40 Age (% per 10 Years) 30 80 70 20 60 50 10 0 _3 _2.5 _2 _1.5 _1 _0.5 0 0.5 1 BM D T-S core Kanis JA, et al. Osteoporos Int. 2001;12:989–995.
Speculation?• The increased fragility in the skeleton occurs mostly because of loss of tissue and thus deteriorating architecture• Coupled to that is the increase in risk of injury that occurs with aging
Thank you for referring Ms Smith (at age 65 yrs) for bone density evaluation. Her T- score is -2.0 which increases her risk of fracture by 4 times.
Thank you for referring Ms Smith (at age 65 yrs) for bone density evaluation. Her T- score is -2.0 which increases her risk of fracture by 4 times.A convenient retrospectoscope tells us her BMD T-score at age 40 was +1.0
Thank you for referring Ms Jones (at age 65 yrs) for bone density evaluation. Her T- score is -2.0 which increases her risk of fracture by 4 times.But what if her BMD T-score at BMD T-score at age 40 was -2.0
Risk Assessment• For the first Ms Smith, risk is increased because of loss of mass and, concurrently, architecture• For the second, risk may be elevated because she is likely to be slim! (bones are thus small)
• This is not an advertisement for obesity!• Overweight folks are not immune from fracture risk, but small slim bones like pencils break more easily• There is nothing we can do about small slim bones
Thank you for referring Ms Jones (at age 85 yrs) for bone density evaluation. Her T- score is -2.0 which increases her risk of fracture by 4 times.
Fracture Risk Treatment Threshold Age Recommendations for treatment are based onOsteoporotic Fracture 40 absolute risk of an (% per 10 Years) 80 individual patient, based on BMD and other 30 70 important risk factors 1 Risk 20 60 50 10 0 0 1 -0.5 0.5 BMD T-Score Core data from Kanis JA, et al. Osteoporos Int. 2001;12:989–995. 1 Kanis JA, et al. Bone. 2002;31:26–31. Bone.
Thank you for referring Ms Smith for bone density evaluation. Her T-score is -2 which increases her risk of fracture by 4 times.4 times what and over what time?
• One in a million?• One in ten?• One year?• Lifetime?
“Absolute” Risk Assessment• Defines the likelihood that an event will occur specifically for an individual over a reasonable horizon (e.g. a 20% risk in next 10 years)• Model built from epidemiologic data bases• Includes common risk factors + BMD to calculate risk• Intervention depends on absolute risk and threshold depends on cost effectiveness
• Thank you for referring Ms Smith for BMD evaluation. Given her age, fracture history, weight, cigarette use, family history, and BMD, her estimated risk of fracture in the next five years is 25% with a variance of +/- 5% (range 20-30%)
Fracture Risk Treatment Threshold Age Recommendations for treatment are based onOsteoporotic Fracture 40 absolute risk of an (% per 10 Years) 80 individual patient, based 30 High Fracture Risk on BMD and other 70 important risk factors 1 Risk 20 60 50 10 0 0 1 -0.5 0.5 BMD T-Score Core data from Kanis JA, et al. Osteoporos Int. 2001;12:989–995. 1 Kanis JA, et al. Bone. 2002;31:26–31. Bone.
The Problems: The clinical community is still not equating most fractures with osteoporosis – nor is the publicDefining osteoporosis as a T-score below –2.5 does not effectively capture many patients at risk for fracture It has been difficult for clinicians to identify personswith elevated fracture risk but with T-score above -2.5
Fracture Rates, Population BMD Distribution and Number of Fractures Primary Care Arm Fracture rate per 1000 person-years 60 450 BMD distribution 400 50 350 40 300 # Fractures 250 30 200 20 150 100 10 50 0 0 0.5 to 0.0 –0.5 to –1.0 –1.5 to –2.0 –2.5 to –3.0 >1.0 1.0 to 0.5 0.0 to –0.5 –1.0 to –1.5 –2.0 to –2.5 –3.0 to –3.5 < –3.5 BMD T-scoresAdapted from Siris ES, et al.JAMA. 2001;286:2815-22. al.JAMA.
Fracture Rates, Population BMD Distribution and Number of Fractures Primary Care ArmFracture rate per 1000 person-years 60 450 BMD distribution Fracture Rate 400 50 350 40 300 # Fractures 250 30 200 20 150 100 10 50 0 0 0.5 to 0.0 –0.5 to –1.0 –1.5 to –2.0 –2.5 to –3.0 –3.5 >1.0 1.0 to 0.5 0.0 to –0.5 –1.0 to –1.5 –2.0 to –2.5 –3.0 to –3.5 <-3.5 BMD T-scores Adapted from Siris ES, et al.JAMA. 2001;286:2815-22. al.JAMA.
Fracture Rates, Population BMD Distribution and Number of Fractures Primary Care Arm Fracture rate per 1000 person-years 60 450 BMD distribution Fracture Rate 400 50 # Fractures 350 40 300 # Fractures 250 30 200 20 150 100 10 50 0 0 0.5 to 0.0 –0.5 to –1.0 –1.5 to –2.0 –2.5 to –3.0 >1.0 1.0 to 0.5 0.0 to –0.5 –1.0 to –1.5 –2.0 to –2.5 –3.0 to –3.5 < –3.5 BMD T-scoresAdapted from Siris ES, et al. JAMA. 2001;286:2815-22.
Hip Fractures in Women without Osteoporosis 160 Total n = 8065 140 Hip Fractures = 243 120 (54%) above -2.5No of subjects (*10) 100 80 Hip Fractures 60 Subjects 40 20 0 -4 -3 -2 -1 0 Total hip BMD T-Score Modified from Wainwright et al JCEM 90 2787 2005
Let’s shift gears• What about the persons who present with fracture over age 50 yrs?• These are our patients at the highest risk of future fractures!
Osteoporosis, Fracture Risk Vary by Ethnicity • Ethnic differences in BMD are strongly influenced by body weight • Fracture risk is strongly influenced by BMD in each group • Ethnic differences in absolute fracture risk remain, which may warrant ethnic-specific clinical recommendationsBarrett-Connor E, et al. J Bone Miner Res. 2005; 20:185-194.
Odds of Osteoporosis (T score −2.5 and 95% CI) by EthnicityBarrett-Connor E, et al. J Bone Miner Res. 2005; 20:185-194.
Confirmed: Prevalent Vertebral Fractures Predict Future Fracture RR = Fractures in Patients With Prevalent Fractures vs Those Without 8 7.4 7 6 5.0 4.5 Relative 5 4.0 Risk 4 (RR) 3 2 1 0 Black 99 McClung 99 Ross 93 Risedronate vs Placebo Patients 3.7 years 3 years 3 years 3 yearsBlack DM, et al. J Bone Min Res. 1999;14:821-828.McClung M, et al. Abstract.Ross PD, et al. Osteoporos Int. 1993;3:120-126.Data on File. Procter & Gamble Pharmaceuticals Inc.
Fracture Risk is Higher Immediately Following an Incident Fracture 20% Will Fracture Again Within 1 Year of Incident Fracture 24 20% 20 16 Patients (%) 12 8 7% 4 0 Incidence of Vertebral Incidence Within 1 Year Fracture in Year 0-1 Following First FractureLindsay R, et al. JAMA. 2001;285:320-323.
• Bones break when load exceeds strength• Low BMD and architecture contribute to strength• Loads are dependent on other things (Falls, frailty, height, weight, nutrition, co- morbidities, medicines etc)
Risk Factors for Fracture Falls Osteoporosis and TraumaTherapy: Bisphosphonates Calcium and Vitamin Injury prevention D
Reducing Fall Risk• Eliminate sedatives• Monitor antihypertensives• Ensure adequate vitamin D intake• Modify environment (i.e., lighting, floor coverings, pets, grab-bars, etc.)• Gait and transfer training• Exercises (i.e., Tai Chi)• Correct vision and hearing problems• Use proper footwear
What about treatment?• Background therapy refers to calcium and vitamin D• What do we know about these as nutrients and for D a hormone?
The calcium controversy• Having too little calcium in the diet increases bone remodeling which when imbalanced leads to bone loss• Diets with averages of less than 800-1000mg/day cited as too low.• Calcium intakes above this do not produce further skeletal effects• Higher intakes, especially with supplements may be harmful
The calcium controversy• An adequate diet with average intakes between 1000 and 1500mg/day is sufficient• Supplements should only be used when these averages cannot be met from diet, and only enough to bring total intake to that level• For calcium calculator go to nof.org
The vitamin D story• Vitamin D has become the vitamin of the decade• There is a lot of basic science evidence supporting the effects of 1,25(OH)2D on multiple tissues• Most human studies are observational• IOM recommendations may be set too low for many older individuals
Vitamin D• A large study is now underway to evaluate non-skeletal outcomes of vitamin D intake
Pharmacology• How well do we understand available treatments?
Pharmacology• All treatments reduce bone remodeling, except teriparatide which stimulates formation and remodeling in bone• Teriparatide is used only for a maximum of 2 yrs in any lifespan• Most patients will require long-term treatment• How do you choose the treatment for any particular patient?
Drug Therapy Classes 1 Antiresorptive Agents Reduce the risk of all fractures: • Calcium +/- vitamin D • Hormone therapy (ET/HT) • Bisphosphonates – Alendronate Risedronate Zoledronate • RANK-L Inhibitor - Denosumab Reduce vertebral fracture risk: • Selective Estrogen Receptor Modulators (SERMs) • Ibandronate • CalcitoninAll drug therapies are usually given in conjunction with lifestylemodification, calcium and vitamin D.
Non-vertebral fracture efficacyWHI Not head to head studies 1.4 BONE PROOF 1.3 1.2 RELATIVE RISK 1.1 1.0 --------------------------------------------------------------------------------------------- 0.9 0.8 MORE * 0.7 HIP 0.6 * Zoledronate FIT2 FIT1 0.5 Liberman 0.4 VERT-MN VERT-NA 0.3 2 8 9 10 11 12 13 14 15 16 17 18 PLACEBO FRACTURE INCIDENCE [%] * stat sigTREATMENT: Aln Ris Ibn Ral Calcitonin Adapted from Boonen S et al. OI 2005; 16: 1291
Bisphosphonates• Concern about long term adverse events Esophageal cancer ONJ Subtrochanteric fractures• Led to concept of “drug holiday”• Evidence to support this mostly lacking
Bisphosphonates and esophageal cancer: what is more likely?*• Incidence of esophageal cancer in women over 65: 111/ million/year• Alendronate: 35 million years of experience• If consider 20% who take Alendronate for more than 5 years• Expected number of cases based upon epidemiology should be around 800, not 23!• Similar data for Risedronate (Unpublished data, Klemes et al, 2009) *Siris E, Oster M, Bilezikian JP, NEJM Ltr , 2009
Definition of ONJAn area of exposed bone in the maxillofacial region inwhich there is no healing over 8 weeks after beingrecognized by a healthcare provider Related conditions: • Usually a triggering event/condition: – Recent tooth extraction or oral surgical procedure – Abrasion in trauma-vulnerable anatomical location (eg, mylohyoid ridge [edentulous patients], tori) – smoldering infection (eg, chronic severe periodontitis) May be: • symptomatic or asymptomatic • infected or non-infected
ONJ and Comparative Risks1-4 Any Fragility Fracture (1) 2668 Hip Fracture (1) 387 Anaphylaxis from PCN Shot 32 Death by MVA 11 Death by Murder 6 ONJ- Osteoporosis Patient 0.7 Death by Lightning Strike in NM 0.6 (1) Women age 65–69 (from Swedish National Bureau of Statistics and 0 10 20 30 40 50 60 70 80 90 100 database of Olmsted County, MN ) Risk per 100,000 People per Year1. Kanis JA et al. Osteoporosis Int. 2001;12:417-427.2. Kaufman DW. Pharmcoepidemiol Drug Saf. 2003;12:195-202.3. National Center for Health Statistics. JADA. 2006;137:1144-1150.4. NOAA Web site. www.nssl.noaa.gov/papers/techmemos/NWS-SR-193/techmemo-sr193-4.html. Accessed September 2008.
Subtrochanteric Fractures• Epidemiology mostly unknown at present• Publications mostly case series or from data derived from claims databases• Shorter use of BPs• Suggest incidence about 1/20 that of hip fracture• No time trend toward increased incidence
Hip and Subtrochanteric Fractures in the United States ’96 ’’98 ’00 ’02 ’04 ‘06 p Women* Hip 546 489 497 449 445 428 <.001 SubT** 56 68 63 65 65 53 NS Men* Hip 274 327 265 252 261 248 <.03 SubT** 36 27 27 27 28 32 NS *per 100,000 **Includes Subtrochanteric, femoral shaft, and distal femur fracturesNieves et al.Osteoporosis International 2010
Potential Mechanisms• Prolonged residence in the skeleton non-metabolized• Irreversible functional osteoclast deficiency and OC apoptosis• Atypical non-functional large inactive osteoclast forms• Dramatic suppression of remodeling – increased secondary mineralization, crystal size and tissue mineral density – loss of heterogenity in tissue mineral density causes increased stiffness and perhaps propagation of micro- cracks – Aged collagen- weakened bone – Accumulated microdamage• Heterozygous osteopetrosis profile with intermediate degree of osteoclast dysfunction
Bisphosphonates: Key Pharmacological Characteristics Binding to Hydroxyapatite1 4 • Binding affinity for bone in KL (L/mol x 106) 3 vitro 2 – Determines attachment to bone and duration of effect 1 0 CLO ETD RIS IBA ALN ZOL • FPP synthase inhibition in rhFPP synthase2 vitro 50 40 – Determines antiresorptive 30 IC50 (nM) potential 20 10 0.0 ALN IBA RIS ZOL1. Nancollas GH, et al. Bone. 2006;38: 617-627.2. Dunford JE, et al. J Pharmacol Exp Ther. 2001;296:235-242.
LOC NOCInactive Osteoclast vs. Normal Osteoclast 50 µm 50 µm < 22 nuclei/cell profile < 8 nuclei/cell profile Dempster et al ASBMR Abstract 2007
1-34hPTH increases trabecular connectivity and cortical widthCt.Th: 0.32 mm Ct.Th: 0.42 mmCD: 2.9/mm3 CD: 4.6/mm3 Dempster et al JBMR 2001
Who should get Teriparatide?• Persons with high fracture risk Patients with osteoporosis related fractures Patients with very low BMD Patients who fail other therapies(?)• How long to treat? Label – not more then 2 years in any lifetime Treat and review after one year
Tetracycline Labels After 6 Months in Cancellous Bone Zoledronic Acid TeriparatideMS/BS = 0.20% MS/BS = 5.38% These samples are representative of the median values for MS/BS for each treatment group (0.16%, zoledronic acid vs 5.60%, teriparatide) 65
Patients already on treatment• Mostly bisphosphonate treated, and effects linger after BP discontinuation• One study implies that patients should stay on BP while on TPTD
What are the Possible Causes of Poor Adherence? • Cost • Osteoporosis eclipsed by other chronic conditions • Concern about side effects • Poor patient education • Disruption to daily routine • Complex dosing guidelines • Lack of positive reinforcementSebalt, et al. J Bone Miner Res. 2004:19(Suppl 1): Abstract M423.
THE FUTURE BELONGSTO THOSE WHO BELIEVE IN THE BEAUTY OF THEIR DREAMS Eleanor Roosevelt
BODY IMAGE IT’S A MULTIFACTORIAL MENTAL CONSTRUCTDYNAMICALLY SHAPED LIFELONG ROOTED BOTH IN THE PSYCHOLOGICAL AND BIOLOGICAL DOMAIN PSYCHOLOGY WITHOUT BODY & MEDICINE WITHOUT SOUL
LIFE EXPECTANCY (LE) VS HEALTH EXPECTANCY(HE)Country LE HE DifferenceCanada 73.0 67.0 6.0U.K. 71.8 58.7 13.1France 70.7 61.9 8.8United States 70.1 55.5 14.6Poland 67.0 60.0 7.0China 66.6 61.6 5.1 from Bruno Lunefeld, Aging for men, 2000
Conclusions• Bones break when load exceeds strength• Low BMD and architecture contribute to skeletal strength• Loads are dependent on other things (Trauma, falls, frailty, height, weight, nutrition, co-morbidities, medicines etc)• Persons with high fracture risk encompass either or both
Conclusions 2• Any fracture in a person over 50 yrs, should trigger an osteoporosis evaluation• Risk assessment (e.g. FRAX) is one method of evaluating the need for treatment• Treatment must include risk reduction as well as pharmacology