Early Translational II
Vertebral compression fractures are the most common fractures associated with osteoporosis. Approximately 700,000 osteoporosis-related vertebral compression fractures (OVCFs) occur each year in the US. Currently, treatment is focused primarily on prevention. When fractures occur in patients with osteoporosis, treatment options are limited because open surgery with implants often fails. Recently, new therapies involving injection of cement into the vertebral body were developed. Unfortunately, these procedures do not regenerate bone tissue, but do incur risks of leakage and emboli. Hence, we need new treatments that directly address both the underlying cause of OVCFs (bone loss) and the inadequate repair mechanisms when fractures occur. We propose to develop a therapy that exploits mesenchymal stem cells (MSCs) stimulated in vivo with PTH (parathyroid hormone) to accelerate bone repair. PTH alone can accelerate fracture repair in healthy animals by activating bone marrow MSCs. However, osteoporotic patients have either decreased numbers of MSCs, dysfunctional MSCs, or both. In these patients, injection of MSCs combined with a PTH regimen could be an effective therapy for the treatment of multiple fractures. Our preliminary data in a mouse model demonstrated that this combined treatment enhances MSC homing to long-bone fracture sites and leads to increased repair. Here, we will build upon this foundation and ask whether a similar strategy is also effective in OVCFs. We hypothesize that PTH administration will lead to increased homing of MSCs to sites of bone fracture. We further hypothesize that PTH promotes the differentiation of MSCs into osteoblasts. Hence, our objective in the proposed study is to determine the effect of injection of MSCs combined with PTH therapy on bone regeneration in a multiple vertebral bone defect model in osteoporotic rats. The optimal doses of PTH and numbers of MSCs per injection also will be determined. Human bone marrow-derived MSCs will be injected into osteoporotic athymic rats with multiple lumbar vertebral bone defects. MSC homing to bone defects will be monitored using micro- and molecular imaging. Subsequent studies will test increasing dosages of PTH to define the optimal dose for maximal enhancement of MSC homing to a fracture. Bone regeneration will be monitored using micro–CT imaging and biomechanical analyses (to determine structural integrity of newly repaired bone). Subsequent studies will determine whether increasing the number of injected MSCs linearly enhances bone tissue formation. These studies will aid in the creation of an evidence base for future clinical trials that could revolutionize the treatment of vertebral fractures and other complex fractures in patients suffering from osteoporosis.
Statement of Benefit to California:
Approximately 10 million people in the United States are diagnosed as osteoporotic, while an additional 34 million are classified as having low bone mass. The lifetime incidence of fragility fractures secondary to osteoporosis in females over fifty years of age is approximately 1 in 2, and in males over the age of fifty, is 1 in 4. Osteoporosis-related vertebral compression fractures (OVCFs) are the most common fragility fractures in the United States, accounting for approximately 700,000 injuries per year, twice the rate of hip fractures. Approximately 70,000 OVCFs result in hospitalization each year with an average hospital stay per patient of 8 days. Fragility fractures due to osteoporosis also place a severe financial strain upon the health care industry. Estimates show there were approximately 1.5 million osteoporosis-related fractures in the United States in 2001, the care of which cost about $17 billion. Moreover, as the number of individuals over the age of fifty continues to increase, costs are predicted to rise to an estimated $60 billion a year by the year 2030. OVCFs have previously received limited attention from the spine care community. This oversight may be a result of the perception that OVCFs are benign, self-limited problems or that treatment options are limited. However, it has become clear that OVCFs are associated with significant physiologic and functional impairment, even in patients not presenting for medical evaluation at the time of fracture. Current treatment of osteoporotic patients is mostly focused on prevention of OVCFs. There are a few options of treatment when OVCFs actually occur. Since open surgery involves morbidity and implant failure in the osteoporotic patient population, nonoperative management, including medications and bracing, is usually recommended for the vast majority of patients. Unfortunately, large numbers of patients report intractable pain and inability to return to activities. Currently there is no efficient biological solution for the treatment of OVCFs. The proposed study will further develop a biological therapeutic solution that will accelerate repair of OVCFs. The treatment will rely upon a combination of drug and adult stem cell therapy; both are either approved for clinical use or in clinical trials. It will also involve a simple intravenous injection instead of a percutaneous injection of a polymer, which does not restore lost bone tissue. Data generated form this study could potentially revolutionize the treatment of vertebral fractures and other complex fractures in patients suffering from osteoporosis, and so benefit the citizens of California by reducing hospitalization periods, operative costs and loss of workdays, and by improving quality of life for Californians with osteoporosis that are at risk for OVCFs.
The principal investigator (PI) proposes to evaluate systemically administered mesenchymal stem cell (MSC) therapy in combination with injection of parathyroid hormone (PTH) for the treatment of osteoporosis-related vertebral compression fractures (OVCF). MSCs are a distinct population of stem cells that can be isolated from bone marrow and adipose tissue and are currently used in clinical trials. The application builds on existing evidence that the bone forming (osteogenic) potential of MSCs is beneficial in the treatment of bone fractures, and that PTH enhances both MSC homing to the fracture site and MSC differentiation into bone. In this Development Candidate Feasibility (DCF) study, the applicant proposes to evaluate the effects of PTH on homing and osteogenic differentiation of human MSC intravenously injected into an immune compromised rat model of osteoporosis with vertebral bone defects. The PI then intends to evaluate the efficacy of this combination treatment on bone repair in this model. The reviewers were enthusiastic about the proposal’s clearly presented objectives and sound rationale. While therapies exist for the prevention of osteoporosis, a systemic therapy for vertebral fractures in osteoporotic patients would have a big impact on a major clinical need, since it would allow treatment with minimal invasion and repeated administration would be possible. However, systemically infused MSCs accumulate to some extent in the lungs, and one reviewer expressed some concern that concomitant administration of an osteogenic compound could lead to ectopic bone formation from injected MSC in the lungs, a potential adverse effect that should be addressed in the studies. Taking this and other considerations into account, some reviewers were unclear why locally targeted MSC administration is not favorable. Overall, the reviewers believed that the proposed studies are feasible and the outlined milestones are achievable within the proposed timeline. The preliminary data are strong although one reviewer felt that the data on effects of PTH on MSC recruitment are not convincing. Labeled injected cells were clearly shown to accumulate at the fracture site, but it was not clear whether a greater accumulation of cells was achieved when PTH was co-administered with MSC. Quantitative analysis of this data would have clarified this issue. The preliminary results regarding cell tracking and in vivo imaging technology were described as impressive, and convinced the reviewers that this team has the necessary methodology to undertake the proposed work. The PI is a leader in the use of MSC for bone regenerative medicine. The PI and research team have a solid track record, their expertise is relevant to the field of study, and covers all necessary areas. This team is sufficiently qualified to carry out the project as proposed. The collaborations are in order, the budget seems appropriate and the host institution is clearly committed. In summary, this application describes a DCF study to evaluate the efficacy of systemic MSC and PTH administration for repair of OVCF. Although some reviewers had minor criticisms of the rationale and preliminary data, these aspects of the proposal were overall considered to be strong. In addition, the potential for impact and the highly qualified research team contributed to the reviewers’ enthusiasm and they recommended this application for funding.