Pilot Study to Predict Bone Strength during Osteoporosis

Investigators: Dennis R. Carter, PhD

Project Staff: Gary S. Beaupré, PhD; Robert Marcus, MD; and Christopher J. Hernandez, PhD

Project category: Osteoporosis - 2000

Osteoporosis is a disease characterized by bone loss, decreased bone strength and an increased risk of fracture. Bone loss with osteoporosis occurs as a result of an imbalance in the bone remodeling process that is associated with aging in ways that are not yet fully understood. Bone remodeling normally involves an ordered sequence of events orchestrated by groups of osteoclasts (bone resorbing cells) and osteoblasts (bone forming cells) referred to as basic multicellular units (BMUs). Factors such as hormones (estrogen, parathyroid hormone), anti-resorptive drugs (bisphosphonates, calcitonin) and nutritional supplements (calcium and vitamin D) are known to influence BMU activity.

The gold standard for assessing the changes in BMU activity during osteoporosis progression and treatment is dynamic histomorphometric analysis; a technique that typically involves the administration of a bone labeling substance such as tetracycline prior to the removal of a biopsy from the iliac crest. Histologic parameters measured or derived from such biopsies include the duration of the bone resorption and bone formation periods; the activation frequency ; and the bone balance during each remodeling cycle.

The specific objective of this pilot study is to develop a theoretical framework and computational model of bone remodeling at the BMU-level that will be used to predict changes in mineralized bone volume fraction, osteoid volume fraction, and percent bone mineralization in response to changes in metabolic stimuli. This new model for describing BMU activity is fully three-dimensional and utilizes clinical measurements of histomorphometric parameters along with an idealized representation of BMU geometry. Our preliminary investigations show that, of the ten required histomorphometric input parameters (all of which have been either measured or derived from histomorphometric analysis), three parameters are particularly influential in terms of the changes in bone mass that are seen during osteoporosis progression and treatment. Using the output from the BMU-based model we will calculate bone strength as a function of bone volume fraction and percent mineralization. We believe that volume fraction and mineralization will provide a better prediction of bone strength than is currently provided by bone apparent density alone.

This model will allow us to answer the following key questions:

• What changes in bone mass and strength are predicted by a computational model simulating bone remodeling in patients with osteoporosis and undergoing osteoporosis treatment?

• Are the trends in changes in bone mass and strength that are predicted in the short term, indicative of the changes that are predicted for longer time periods, or are the short-term changes only transient?

• Can the clinically observed differences in response between cancellous and cortical bone be explained with a BMU-based model?

The long-term objective of this proposed area of research is to improve our understanding of osteoporosis progression and treatment and to identify better treatment protocols using theoretical and computer models.

Funding Source: VA RR&D Merit Review

Funding Status: In Review