1. Susan Broy MD FACP FACR CCD Professor of Clinical Medicine Rosalind Franklin School of Medicine, Chicago Medical School

2. No disclosures to report

3.  Introduction – what is bone strength?  Bone density  Bone quality  Measuring bone “quality”  Invasive  Imaging ▪ CT and MRI, including finite element analysis (FEA) ▪ DXA ▪ Hip structural analysis (HSA) ▪ Trabecular bone score (TBS)

4. 4 Healthy bone “A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture.” “Bone strength is a composite of bone density and bone quality” NIH Consensus Development Panel JAMA 2001;285:785

5.  Bone “quality”  Matrix properties ▪ Damage accumulation ▪ Collagen quality ▪ Mineralization (eg. crystal size)  Macroarchitecture ▪ Bone size ▪ Bone shape  Microarchitecture  Bone density  Explains 60-80% of bone strength in cadaveric studies 1,2 1 Cheng XG et al. J Bone Miner Res 1997;12:1721-8 2 Bousson V et al. Osteoporos Int 2006;17:855-64

6.  Invasive  Mechanical studies of cadaveric bone = direct measurement of bone strength  Bone biopsy – tetracycline labeled ▪ Bone metabolism and structure Important in research but not clinically useful

7.  Invasive  Imaging by CT/MRI  HR-pQCT, µMRI: microarchitecture  QCT: ▪ 3-D geometry ▪ Finite element analysis (FEA)  Imaging by DXA  HSA – hip structural analysis ▪ Measures size and shape of femur i.e. macroarchitecture  TBS – trabecular bone score ▪ Evaluates microarchitecture of vertebrae Research Dr Engelke

8. Cylinder B has less bone but the same strength as cylinder A A larger bone (e.g. in a man) is a stronger bone than a smaller bone with the same volumetric density 1 1 Bruno AG et al. J Bone Miner Res 2014;29(3):562-569

9. Source: NHANES III courtesy Dr. Anne Looker, National Center for Health Statistics, CDC Images courtesy of Tom Beck CSA does not decrease as much as BMD because of an increase in femoral neck width

10. 20406080100 Age Density Section modulus Inner and Outer Bone Diameters expand with age Slide courtesy of Dr Thomas Beck

11. Bending AxialCompression Uniform across bone surface, proportional to cross-surface area (CSA) Non-uniform across bone surface. Maximal at outer surfaces. Quantified by section modulus (SM) Axial Compression Bending

12. Males Females Aging leads to decreased BMD but periosteal expansion helps preserve section modulus, especially in males Beck TJ et al, J Bone Miner Res 2000;15:2297

13.  CSA: cross-sectional area  CSMI: cross-sectional moment of inertia  SM: section modulus  BR: buckling ratio  OD: outer diameter  HAL: hip axis length  NSA: neck-shaft angle Software programs HSA™ (Hologic) AHA™ (GE)

14. Line of pixels defines a cut plane through the bone Mass projected in cut plane describes bone cross-section Outer diameter CSA CSMI, Sm BR = Sm/length Profile and Cross-section have equal: OD

15. Mineral profiles are extracted from DXA images by software and used to estimate geometric properties. BMD, outer diameter, CSA and CSMI measured from profiles Sm and BR calculated Requires assumptions about bone shape and distribution of cortical and trabecular bone at each site. Image courtesy of Thomas J. Beck, ScD..

16. OD: Subperiosteal width CSA: cross-sectional area CSMI: cross-sectional moment of inertia Z = section modulus CT: cortical thickness BR: buckling ratio HAL : Hip axis length greater trochanter to inner pelvic rim NSA: neck-shaft angle (NSA)

17. Neck-shaft angle Outer diameter d1, d2: measurements of femoral neck length d3 = outer diameter y: measurement of radius at minimum CSMI alpha: angle femoral shaft to vertical theta: neck-shaft angle Yoshikawa T et al J Bone Miner Res 1994; 9:1053-64 Faulkner KG et al Osteoporos Int 2006;17:593-9 Strength index (SI) = estimated strength/ expected stress

18.  Multiple studies have shown that hip geometry parameters are associated with risk of hip fracture  Hip geometry parameters (especially Sm, BR, HAL and NSA) are associated with hip fracture in postmenopausal women 1,2  NSA is associated with hip fracture in men and women 3  Measurements change with condition or treatment  Aging 4  Exercise 5  Pharmacologic therapy: estrogen, raloxifene, alendronate, denosumab, teriparatide 1 Kaptoge S et al. J Bone Miner Res 2008;23:1892 4 Beck TJ et al J Bone Miner Res 2000;15;:297 2 Leslie WD et al. Osteoporos Int 2009;20:1767 5 Hind K et al. Bone 2007;40:14-27 3 Faulkner KG et al. Osteoporos Int 2006;17:593

19. 19 Buckling Ratio BMDCSACortical Thickness Section Modulus Mean Change From Baseline, % ALNRIS ALNRIS ALNRISALNRISALNRIS *P<0.05. † P<0.005. ALN = alendronate. RIS = risedronate. CSA = cross-sectional area. † * † † † † † † † † † † † † † † † † † † † † † † † † † Reproduced from Bonnick SI et al. Poster presented at the 28th Annual Meeting of the American Society for Bone and Mineral Research; September 16, 2006; Philadelphia, PA. Poster SA345. Alendronate 70 mg once weekly for 2 years Risedronate 35 mg once weekly for 2 years – – – –

20.  Pros  FDA-approved software ▪ HSA™ ▪ AHA ™  Can do at same time as DXA  Evidence correlates with fracture risk in women  Cons  Variable precision – depends on image quality, positioning  Except for HAL, not clear if fracture risk is independent of BMD  Need universally accepted standards for use ▪ Need cut-off points ▪ Can geometric measurements be incorporated into FRAX calculations? ISCD Position Development Conference addressing these issues

21.  Bone “quality”  Matrix properties ▪ Damage accumulation ▪ Collagen quality ▪ Mineralization (eg. crystal size)  Macroarchitecture ▪ Bone size ▪ Bone shape  Microarchitecture  Bone density  Explains 60-80% of bone strength in cadaveric studies* *Cheng XG et al. J Bone Miner Res 1997;12:1721-8 Bousson V et al. Osteoporos Int 2006;17:855-64

22. NormalLoss ofLoss of Quantity andQuantityArchitecture Architecture Loss BMDNo change in BMD

23. Normal Dempster 2000 Microarchitectural Changes in Osteoporosis Osteoporotic Horizontal Disconnections

24.  Bone biopsy  HR-pQCT  Micro-MRI  TBS Research

25.  Textural index: DXA software that extracts bone texture information from a regular AP spine DXA scan image  Gray-level variations in the image provide an indirect assessment of microarchitecture  Has been shown to be related to bone microarchitecture and fracture risk  Provides information independent of BMD

26. Well-structured trabecular bone Degraded trabecular bone Pothuaud et al. Bone 2008;42:775-87 Hans et al. JCD 2011;14:302-12 Winzenrieth et al. JCD 2013; 16:287-96 Experimental variogram of pixel gray-levels DXA image

27. TBS = 1.459 TBS = 1.243 BMD=0.972 BMD=0.969 Silva BC at al. J Bone Miner Res 2014;29(3):518-30 Low variability, high amplitude Large variability, small amplitude

28. Normative database for USA: Simonelli C et al. J Clin Densitom 2014

29.  Many studies  61 entries for TBS in PubMed (November 2014)  1 ASBMR abstract in 2011, 19 in 2012, 33 in 2013, 22 in 2014  Correlates with mechanical behavior of cadaveric vertebrae 1  Correlates with microarchitectural parameters  Cadaveric vertebrae 1,2  In vivo µCT 3  Predicts fracture 3 1 Roux JP et al. Osteoporos Int 2013;24(9):2455-60 2 Hans D et al. J Clin Densitom 2011;14(3):302-12 3 Silva BC at al. J Bone Miner Res 2014;29(3):518-30

30. Pothaud ‘09 Winzenreith ‘10 Rabier ‘10 Krueger’13 Lamy’12 Del Rio ‘13 Pothaud ‘09 Krueger ‘13 Lamy ‘12 Cross-sectional studiesProspective studies* Manitoba ’11 JPOS ‘13 OPUS ’13 Manitoba ‘11 OFELY ’13 OPUS Silva BC at al. J Bone Miner Res 2014;29(3):518-30 * F/U 4.7 – 8years

31. Hans D et al. J Bone Miner Res 2011;26:2762-9 Manitoba, Canada N=29,407 women >50 Mean F/U 4.7 years 1668 major osteoporotic fractures (MOF)* *MOF = spine, hip, humerus or radius

32. ControlDiabetic with fracture Link TM Skeletal Radiol 2010;39:943-55 HR-pQCT Distal Tibia Postmenopausal Women

33. Leslie WD et al. J Clin Endocrinol Metab 2013;98:602-9 Odds ratios (95% CI bars) for BMD or TBS measurement in the lowest vs highest tertile according to presence of diabetes. TBS predicted fracture in those with diabetes as well as those without diabetes.

34.  Pros  FDA-approved in 2012  Can do at same time as DXA  EvidenceTBS correlates with ▪ Mechanical strength ▪ Microarchitectural parameters ▪ Fracture risk (cross-sectional and prospective studies )  Provides information independent of BMD  Might be helpful in cases of secondary osteoporosis ▪ Type 2 diabetes 1  Cons  No reimbursement  Need universally accepted standards for use ▪ Need cut-off points ▪ Can TBS be incorporated into FRAX calculations? 2 ▪ German osteoplogy society (DVO) 2014 guidelines include a TBS offset for FRAX calculations 1 Leslie WD et al. J Clin Endocrinol Metab 2013;98:602-9 2 Johannson H et al. IOF meeting 2013 Hong Kong ISCD PDC addressing these issues

35.  Bone strength includes bone density and bone “quality”  Bone “quality” can be assessed by  Invasive: mechanical studies of cadaveric bone, bone biopsy  Research: HR-pQCT, µMRI (microarchitecture), 3-D QCT (macroarchitecture)  Possible clinical use: ▪ FEA ▪ HSA (geometry i.e. macroarchitexture) ▪ TBS (microarchitecture) ISCD Position Development Conference Will review the evidence and develop official positions on the clinical utility of non DXA BMD measures of fracture risk