Clinical assessment of bone loss in type 2 diabetes studies
Therapies used to treat type 2 diabetes mellitus (T2DM) face increasing examination by the FDA and often necessitate bone safety studies prior to approval. To provide increasingly accurate evaluations of skeletal health, clinicians are turning to Quantitative Computed Tomography (QCT), which provides sub-anatomical BMD distribution and insight into differential bone loss observed in T2DM patients. Colin Miller discusses during our musculoskeletal disorders focus month.
Clinical assessment of bone mineral density (BMD) is important for identifying bone loss and evaluating fracture risk in the elderly and osteoporotic patient populations. BMD measurements, as assessed by dual energy x-ray absorptiometry (DXA), are routinely used in clinical trials to monitor the safety of new therapies on skeletal health. In particular, therapies used to treat Type 2 Diabetes Mellitus (T2DM) face increasing examination by the FDA, given the established link between T2DM drugs (e.g. thiozolidinediones) and bone loss.
The T2DM market is expanding rapidly, driven in part by an increasingly obese and aging population, and reflected in the number of therapies being evaluated in nearly 2500 clinical trials. Safety studies to assess bone health have already extended to newer classes of T2DM drugs, which target the sodium glucose co-transporter SGLT2. For example, canagliflozin (Invokana), approved earlier this year for the treatment of T2DM, has an ongoing bone safety study as part of its phase III development program, with data presented to the FDA suggesting that bone health is maintained1.
Despite advances in imaging modalities which increase the tools available for collecting BMD data, clinicians are routinely faced with the challenge of identifying and developing novel endpoints which can aid in the accurate assessment of bone loss and provide information on structural deterioration. This is especially relevant for fractures seen in T2DM patients, the majority of which appear, like all osteoporotic fractures, to occur at skeletal sites of high trabecular bone, where there is a strong cortical shell contribution to overall structural integrity. Furthermore, in these patients there is data to suggest a predominant loss of cortical rather than trabecular bone.
"The T2DM market is expanding rapidly, driven in part by an increasingly obese and aging population..."
DXA provides areal BMD measurements (aBMD, g/cm2), which correlate with a patient's fracture risk. BMD is typically reported as a T or Z score, which provides evaluation of BMD compared to that of a healthy 30 year old or an age-matched normal healthy population respectively. However, recent studies in T2DM have indicated that there may be bone qualities beyond density which can affect bone strength and predict fracture risk. For example, women with T2DM have an approximately 2-fold increase in the overall risk of skeletal fractures, despite having aBMD that is typically normal or higher than matched non-diabetics2. In an attempt to understand these observations, clinicians are turning to Quantitative Computed Tomography (QCT), which provides volumetric BMD measurements (vBMD, mg/cm3) and three-dimensional images of bone structure and geometry.
An important feature of QCT is the ability to distinguish between trabecular and cortical bone compartments, enabling the determination of the sub-anatomical distribution of BMD. This information is valuable to the clinician as it provides an understanding of the role that each bone compartment plays in the pathogenesis and prognosis of fracture and provides insight for the evaluation of new therapeutic agents that affect bone metabolism. The precise definition of cortical bone is particularly important for assessing fracture risks in T2DM patients, where clinicians have observed unexplained differential bone loss patterns, as reported with the drug rosiglitazone (Avandia)3.
Even with distinction between bone compartments, precise assessment between the cortical and cancellous bone can be difficult, since the cortical shell is on the order of only a few millimeters thick in the areas of classic osteoporotic fracture. With the voxel size being approximately 1mm, the 'partial volume effect' can introduce errors in the determination of automatic cancellous-cortical bone boundaries. Furthermore, routine QCT often relies on measurements of the entire cortical shell, which may fail to detect regional bone changes. This has prompted detailed investigations of substructures within cortical bone and the development of new techniques to better define cortical bone measurements.
"...clinicians are routinely faced with the challenge of identifying and developing novel endpoints which can aid in the accurate assessment of bone loss..."
One such recently developed technique is called 'quadrant analysis'. This analysis evaluates the four quadrants of the femoral neck cortical shell for both volumetric BMD and thickness, to determine small changes in cortical bone over time. The anatomical quadrants are defined by taking four segments from a sixteen segment analysis from within the cross sectional region of interest in the mid-femoral neck. A critical component of the quadrant analysis is the ability to segment bone using a density threshold to delineate the cortical region from the periosteal and trabecular bone. This technique has been used to show that the superior cortex of the femoral neck is a stronger predictor for hip fracture than the inferior cortex4. Studies such as these demonstrate that a critical loss of bone strength might be reached when cortical thinning is greater in one region of the femoral neck versus others. More recently, the use of quadrant analysis of the femoral neck was included in a prospective multi-site clinical trial to assess T2DM treatment response, providing the first data that this endpoint may have utility in clinical trials for the evaluation of cortical bone in the femoral neck5.
As the focus on bone safety studies increases for drugs indicated for T2DM and other therapeutic areas, it has become critical to understand their effects on bone metabolism and on bone sub-compartments. Advancements in imaging technologies and analysis tools, such as QCT quadrant analysis, provide increasingly sophisticated methods for the evaluation of BMD and bone architecture in patients, enabling more precise evaluation of the safety of new therapies in clinical pipelines.
References
1. Janssen Research & Development, Canagliflozin as an adjunctive treatment to diet and exercise alone or co-administered with other antihyperglycemic agents to improve glycemic control in adults with type 2 diabetes mellitus. Advisory Committee Briefing Materials, January 10, 2013 http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM334551.pdf
2. Bonds DE, Larson JC, Schwartz AV, Strotmeyer ES, Robbins J, Rodriguez BL, Johnson KC, Margolis KL 2006 Risk of fracture in women with type 2 diabetes: the Women's Health Initiative Observational Study. J Clin Endocrinol Metab 91:3404-3410.
3. GlaxoSmithKline (GSK), Clinical trial observation of an increased incidence of fractures in female patients who received long-term treatment with Avandia (rosiglitazone maleate) tablets for type 2 diabetes mellitus (Letter to Health Care Providers), February 2007. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150833.htm
4. Johannesdottir F, Poole KE, Reeve J, Siggeirsdottir K, Aspelund T, Mogensen B, Jonsson BY, Sigurdsson S, Harris TB, Gudnason VG, Sigurdsson G 2011 Distribution of cortical bone in the femoral neck and hip fracture: a prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study. Bone 48:1268-1276.
5. Effects of Rosiglitazone on Bone: Assessing QCT Parameters in a Mechanistic Study of Postmenopausal Women with Type 2 Diabetes Mellitus (Poster). Bilezikian JP, Kravitz BG, Lewiecki EM , Miller CG, Northcutt AR, Paul G, Cobitz A, Nino AJ, Fitzpatrick LA. American Society of Bone and Mineral Research (ASBMR), October 2010.
About the author:
Dr. Miller is the Senior Vice President of Medical Affairs at BioClinica and is responsible for medical and scientific consulting for imaging-based clinical trials. Dr. Miller is a member of the American Society of Bone and Mineral Research, and an associate member of the Radiological Society of North America to name two of his six societal affiliations. Dr. Miller has written and co-authored over 40 scientific publications and is co-editor of the books "Clinical Trials in Osteoporosis," "Clinical Trials in Osteoarthritis and Rheumatoid Arthritis," and "Medical Imaging in Clinical Trials" (in press) published by Springer Ltd. Dr. Miller received his Bachelor's degree in Physiology and Zoology from the University of Sheffield, UK, and a Ph.D. from the University of Hull, UK.
How will advances in clinical trial imaging technology aid in safety evaluation of new treatments?
