Bone Safety assessment sits at the intersection of current advances in skeletal imaging and heightened regulatory awareness. It is an important consideration for drug sponsors given the rising numbers of anti-diabetic drugs making their way through clinical pipelines.
Increased regulatory focus on T2DM therapies
Therapies in development for Type 2 Diabetes Mellitus (T2DM) face increasing examination by the FDA regarding skeletal health studies.
This is not surprising, given the established link between existing diabetes drugs (e.g. thiazolidinediones) and bone loss. The requirement for bone safety studies has already extended to newer classes of T2DM drugs which selectively target the sodium-glucose co-transporter SGLT2 and lower renal glucose reabsorption.
Imaging Endpoints: Limitations and Challenges
Bone Mineral Density (BMD) measurements, as assessed by DXA, are routinely used in clinical trials to monitor the safety of new therapies on skeletal health. However, there may be other bone qualities, such as bone architecture, which can affect bone strength and increase fracture risk. This is exemplified by women with T2DM who have an approximately 2-fold increase in their overall risk of skeletal fractures, despite having BMD measures that are typically normal or higher than matched non-diabetics. Therefore, clinicians are 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.
Quantitative Computed Tomography (QCT), an imaging modality that provides volumetric BMD measurements (vBMD, mg/cm3) and three-dimensional images of bone structure and geometry, is now being used in clinical trials to elucidate the effect of therapeutic interventions. 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 vBMD. 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.
Even with the 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 allowing for the introduction of 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 increasingly detailed investigations of substructures within cortical bone.