Perelman School of Medicine at the University of Pennsylvania

McKay Orthopaedic Research Laboratory

Liu Laboratory

Ongoing Research at Liu Laboratory

Osteoporosis Treatment and In Vivo Dynamic Imaging

There are two main classes of treatments for osteoporosis, anti-catabolic agents, such as bisphosphonates, and anabolic agents, such as intermittent parathyroid hormone (PTH) treatment. There are many types of anti-catabolic agents, which block osteoclast action to prevent further bone loss. PTH is the only FDA approved anabolic agent for postmenopausal osteoporosis treatment. Our lab has several ongoing studies regarding the benefits and use of PTH as a treatment either alone or in conjunction with other drugs.

Combined PTH and Bisphosphonate Therapy

One ongoing study focuses on the combination of PTH and bisphosphonate therapy. The literature has shown conflicting results regarding combined therapy. Some groups have found that bisphosphonates blunt the effects of PTH, while others show an additive effect. Our work in this area has shown promising results indicating an additive effect of combined therapy (Fig 1). However, the mechanisms through which this additive effect occurs is unclear. One hypothesis we have proposed is that PTH can promote modeling-based bone formation (Fig 2). Our lab is interested in further identifying the mechanisms through which this additive effect is achieved, and elucidating potential modeling-based formation events by in vivo micro-computed tomography (µCT) and advanced in vivo dynamic imaging techniques.

fig1Fig 1. 3D bone structure of control (VEH), bisphosphonate (ALN), parathyroid hormone (PTH), and combined (PTH+ALN) treated before and after a 12 day treatment period.

fig2Fig 2. Typically, bone remodeling is thought to be initiated by resorption (red), followed by formation (green) as shown on the bottom panel. Modeling-based formation is formation without prior resorption (top panel).

Advanced In Vivo Dynamic Imaging Techniques

Our lab focuses on longitudinal µCT imaging studies in both humans and rodents which allow us to track the same segment of bone over time. In doing this we have developed techniques to measure precise changes in the bone's micro architecture, down to the individual trabecula level. Our lab is interested in using these imaging and computational tools to gain insight into the complex physiological responses to treatment.

fig3Fig 3. 3D individual trabecular dynamics (ITD) analysis isolates individual trabecular structures and follows them over time to quantify incidences of structural deterioration and repair.

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Fig 4. 3D dynamic in vivo histomorphometry identifies areas of new bone in green and lost bone in red to quantify measures such as bone formation rate (BFR/BS) and bone resorption rate (BRR/BS).

Clinical Imaging in Patients with Idiopathic Osteoporosis (IOP)

Although PTH has been effective in treating postmenopausal osteoporosis, it is unclear if it would be effective in IOP of premenopausal women. High resolution peripheral quantitative computed tomography (HR-pQCT) allows us to visualize changes in bone in the peripheral skeleton, such as the distal tibia or distal radius. In this study we are interested in comparing changes between pre-treated and post-PTH-treated patients with IOP to observe time dependent effects on both cortical and trabecular bone. Using advanced in vivo dynamic imaging we are interested in identifying changes in cortical bone mineralization as well as trabecular micro-architecture to determine the effectiveness of PTH for treating IOP.

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Fig 5. Differential color map indicating the changes in bone mineral density (BMD) over time. Red at the periosteal surface indicates a decrease in BMD over time. Green indicates increased BMD at the endocortical surface.

Lactation Induced Bone Loss and Subsequent Bone Recovery

During pregnancy and lactation, the increased calcium demand caused by fetal/infant growth induces substantial changes in maternal calcium metabolism. This affects a variety of physiological processes, including remodeling of the maternal skeleton. In particular, lactation is known to result in dramatic bone loss that is partially recovered following weaning. However, the effects of pregnancy on maternal bone are controversial, and the precise mechanisms underlying both lactation bone loss and recovery post-weaning remain unknown. Using a rat model, combined with advanced in vivo µCT imaging techniques, our lab is working to answer some of these questions. We hope that a better understanding of reproductive bone loss will lead to improved maternal health. Additionally, we aim to draw parallels between the normal, physiological bone loss that takes place during reproduction, which is largely reversible, and the pathophysiological, irreversible bone loss occurring in post-menopausal osteoporosis.

fig6Fig 6. Longitudinal changes in the trabecular bone in the proximal tibia of a rat as a result of pregnancy, lactation, and weaning.

fig7Fig 7. Bone remodeling taking place during pregnancy, lactation, and weaning. Newly formed bone is shown in blue, while lost bone is shown in red.

3D Vascular Imaging within the rat tibiae

The bone remodeling process works in conjunction with the microvascular network within the bone marrow to regulate calcium and phosphate homeostasis. Because of their drastic effects on bone remodeling, it is likely that the bone vasculature will undergo major alterations during periods of bone loss and bone gain. However, simultaneous visualization of the effect of bone remodeling in the trabecular and vascular microstructures remains challenging. Our lab focuses on establishing a novel technique that simultaneously visualizes the 3D microstructure of bone and microvasculature using standard µCT. We can simulate bone loss due to aging using ovariectomy-induced osteoporosis (OVX) and bone gain via intermittent PTH. By combining the bone microvascular network with measures of bone formation and resorption, it can improve our understanding of the effects of bone remodeling on the bone-blood vessel functional unit.

fig8Fig 8. (Top) 3D representative bone and blood vessel images of the proximal tibia of OVX, control, and PTH groups. (Bottom) The 3D trabecular bone and blood vessel images with bone formation and resorption labeled in green and purple, respectively.

4.21.2014 updated