Osteoporosis

Assessment of Bone Quality in Health and Disease

Drs. Elizabeth Shane, Michael Yin, Emily Stein, Adi Cohen, Ed Guo, Alison Pack, Michael Yin, Tom Nickolas, David Dempster, John Bilezikian, and Kyle Nishiyama 

Dr. Shane is spearheading efforts to measure bone quality in various groups of healthy patients as well as disease states. She and her collaborators are applying central quantitative tomography, high resolution peripheral quantitative tomography and ultrasound to increase understanding of how various disease states affect bone microstructure and strength. We have ongoing collaborations within Columbia with the Divisions of Nephrology and Infectious Diseases, the Department of Neurology, and the Department of Biomedical Engineering of the School of Engineering and Applied Sciences of Columbia University. 

Osteoporosis in Postmenopausal Women

Dr. Ethel Siris

One research area is the epidemiology of osteoporosis, including with risk factors for fracture, perceptions of risk, quality of life, mechanisms for risk prediction, etc. from a multinational cohort called GLOW, which is a longitudinal study of approximately 60,00 postmenopausal women from 723 primary care practices in 10 countries from North America, Europe and Australia. Another epidemiology study, NORA, that originally enrolled over 200,000 US postmenopausal women has also explored risk factors for fracture. 

Other areas of research focus on the effects of treatment adherence on fracture outcomes, and a series of ongoing studies regarding a new therapeutic agent for osteoporosis, denosumab, an inhibitor of RANK-ligand. 

 

Osteoporosis in Premenopausal Women

Drs. Elizabeth Shane, Adi Cohen, Emily Stein, David Dempster, Robert Recker and Joan Lappe

Besides postmenopausal women, osteoporosis can affect young women and men. Most often, osteoporosis in premenopausal women is associated with an underlying disease or exposure to a medication that causes bone loss. Dr. Shane is the Principal Investigator of a recently completed NIH-funded, cross-sectional, 2-site study (RO1 AR 49896) that is focused on understanding the causes of low bone density and fractures in women who have not yet become menopausal. Together, she and Dr. Adi Cohen have elucidated the features of osteoporosis in women for whom no cause of bone loss can be found. The study investigated the participants’ hormonal status and also assesses bone quality and strength by a variety of noninvasive and invasive tests. Dr. Cohen is the Principal Investigator of several studies of potential causes of unexplained osteoporosis in premenopausal women, including abnormalities in growth hormones and cortisol. These studies are funded by Columbia’s Irving Institute for Clinical and Translational Research and the NIH (R03 AR 64016). 

Teriparatide for the Treatment of Idiopathic Osteoporosis in Premenopausal Women

Drs. Elizabeth Shane, Adi Cohen, Emily Stein, David Dempster, Kyle Nishiyama, Robert Recker and Joan Lappe 

This research group’s studies of premenopausal women with idiopathic osteoporosis have documented the presence of both severe microstructural defects and decreased bone formation. These findings have led to further studies to test whether teriparatide (Forteo®), a bone building medication that stimulates bone formation, improves bone density and decreases fractures in other types of osteoporosis, could be a useful treatment for premenopausal women with idiopathic osteoporosis.

Drs. Shane and Cohen have completed and published results from a pilot study of teriparatide (Forteo®) for premenopausal idiopathic osteoporosis. In addition, Dr. Shane is the Principal Investigator of a randomized study of teriparatide (Forteo®) for premenopausal idiopathic osteoporosis, supported by the FDA Orphan Diseases Branch (R01 FD003902). 

 

Parathyroid

Primary Hyperparathyroidism

Drs. John Bilezikian, Shonni Silverberg, Mishaela Rubin, Marcella Walker, Natalie Cusano, David Dempster, and Angela Carrelli

This disorder has been a focus of research in our unit since receiving a major grant from the NIH in 1984. With over 25 years of continuous funding, the research support by this research grant has defined the natural history or this disorder, elucidated the densitometric and histomorphometric features of this disease and has been instrumental in providing data to the three workshops that have been conducted on the management of this disorder since 1992. A paper from our group (Silverberg et al. Skeletal disease in primary hyperparathyroidism. JBMR 1989) was named as one of the seminal papers of the first 25 years of the Journal of Bone and Mineral Research, the premier bone research journal in the world. Well over 250 original articles, chapters, and abstracts have resulted from this work. 

Normocalcemic Primary Hyperparathyroidism

Drs. John Bilezikian, Shonni Silverberg, Mishaela Rubin, Marcella Walker, Natalie Cusano, and Angela Carrelli

As the disorder of primary hyperparathyroidism has evolved from a disease that was invariably symptomatic to one that is characterized primarily by asymptomatic hypercalcemia and elevated levels of parathyroid hormone, it is noteworthy that we have recently identified yet another phenotype of this disease, namely a presentation that is characterized by elevated levels of parathyroid hormone without hypercalcemia. It is possible that this is a earlier variant of the much more common hypercalcemic form. Our studies are designed to understand better how this disease presents and its natural history.

 

Therapeutics of Primary Hyperparathyroidism 

Drs. John Bilezikian, Shonni Silverberg, Mishaela Rubin, Marcella Walker, Natalie Cusano, David Dempster, and Angela Carrelli

The quest for alternatives to surgery in Primary Hyperparathyroidism has led to a number of studies focusing upon therapeutic agents that have the potential to preserve bone and/or reduce calcium and PTH levels in this disorder. The studies have focused upon the calcimimetic agent, cinacalcet, and the bisphosphonate, alendronate. 

Cardiovascular manifestations of primary hyperparathyroidism

Drs. Shonni Silverberg and Marcella Walker

This study is investigating the presence and extent of cardiovascular manifestations in patients with mild primary hyperparathyroidism. In addition to describing the presence of such abnormalities, we are studying the reversibility of any cardiovascular abnormalities following surgical cure of the disease.

 

Non-classical manifestations of primary hyperparathyroidism

Drs. Shonni Silverberg and Marcella Walker

While the classical target organs of primary hyperparathyroidism are the skeleton and the kidneys, other organs have been shown to be potential targets of this disorder. This project is designed to identify these other target organs and how they may be affected in this disease. 

Vitamin D deficiency in primary hyperparathyroidism

Drs. Shonni Silverberg, Emily Stein, Angela Carrelli, and Marcella Walker

This project is designed to assess the effect of co-existing vitamin D deficiency in patients with primary hyperparathyroidism. The role of vitamin D in the skeletal and metabolic abnormalities associated with this disease is being defined as well as the effect of repleting vitamin D in patients who are deficient. In addition, a trial is planned to test different doses of vitamin D to assess efficacy and safety of giving vitamin D in patients with primary hyperparathyroidism. 

 

Hypoparathyroidism

Drs. John Bilezikian, Natalie Cusano, Mishaela Rubin, Shonni Silverberg, David Dempster, Kyle Nishiyama, and Edward Guo

The research team that has been studying many different aspects of primary hyperparathyroidism has extended its inquiry to another disorder of parathyroid function, namely hypoparathyroidism. While primary hyperparathyroidism is characterized by excessive secretion of parathyroid hormone, hypoparathyroidism is characterized by insufficient or absent secretion of parathyroid hormone. The project seeks to describe in detail the skeletal and metabolic abnormalities associated with this disorder, as well as how these abnormalities are corrected by the administration of parathyroid hormone. 

Sclerostin levels in parathyroid disorders

Drs. Aline Costa, John Bilezikian, Mishaela Rubin, and Shonni Silverberg

Sclerostin, an important regulator of bone remodeling, can now be measured in the circulation. This project focuses upon its measurement in parathyroid disorders such as primary hyperparathyroidism and hypoparathyroidism. We are determining not only baseline levels but also how the removal of parathyroid hormone (after parathyroidectomy in primary hyperparathyroidism) and replacement parathyroid hormone (in hypoparathyroidism) can alter circulating sclerostin levels. 

 

Bone Quality in Parathyroid Disorders

Drs. John Bilezikian, Aline Costa, Natalie Cusano, Shonni Silverberg, and David Dempster 

Parathyroid hormone has fundamental actions on bone structure as noted by disorders associated with excessive or deficient parathyroid hormone. The hypothesis that parathyroid hormone regulates the two compartments of bone (cortical vs cancellous) and that within each compartment, the hormone has modulatory functions is being tested. 

 

Diabetes

Circulating Osteogenic Cell Precursors

Drs. Mishaela Rubin, John Bilezikian, Stavroula Kousteni, Serge Cremers, Elizabeth Shane, and Shonni Silverberg

It has been shown that in the circulating, cells can be identified that represent a lineage pathway to the osteoblast. These osteogenic cells can now be identified by number and stage of maturity, using using flow cytometry and specific antigenic determinants. Studies are ongoing to define the characteristics of these cells in several disorders including hypoparathyroidism and Type 2 Diabetes Mellitus. 

Skeletal Effects of Type 2 Diabetes Mellitus

Dr. Mishaela Rubin

This project focuses on how Type 2 Diabetes affects the structural, dynamic and material components of the skeleton. On-going studies are investigating the effects of decreasing inflammation on skeletal parameters in Type 2 Diabetes. 

 

Chronic Kidney Disease

Chronic Kidney Disease on Bone Health

Drs. Thomas Nickolas, Kyle Nishiyama, and Elizabeth Shane

Osteoporosis is a very common disorder of aging. Chronic kidney disease is also very common in older individuals. We are evaluating a new noninvasive imaging technology, ultra high-resolution peripheral quantitative computed tomography (HR-pQCT), as a biomarker of bone strength in patients with and without fracture.  We hypothesize that HR-pQCT will assess fracture status and bone strength more accurately than DXA and we are testing this hypothesis in a cross sectional study that compares the utility of DXA and HR-pQCT to classify fracture status in women over age 60. Declining kidney function commonly accompanies aging and could contribute to fracture risk. Therefore we will also assess the impact of CKD on the ability of HR-pQCT and DXA to classify fracture status. As fractures are associated with considerable morbidity and excess mortality, this research has high relevance to public health.

Chronic Kidney Disease and PTH

Drs. Emily M. Stein, Elizabeth Shane and Shonni Silverberg

This study evaluates the effects of moderate CKD on bone mass, microarchitecture and strength in the postmenopausal skeleton, through a cross-sectional, in-depth analysis of bone mineral density, microarchitecture (using high resolution peripheral quantitative computed tomography), calciotropic hormones and biochemical markers of remodeling in women, with and without stage 3 CKD (60>GFR>30 ml/min) and with and without a history of fragility fracture. Women with CKD are also compared to women with primary hyperparathyroidism (PHPT) to further explore the effects of PTH on the postmenopausal skeleton. 

 

 

Surgery and Transplantation

Bariatric Surgery

Drs. Emily Stein and Shonni Silverberg

This prospective study evaluates changes in vitamin D, markers of bone turnover, bone density and microarchitecture for two years following bariatric surgery. Patients undergoing Roux-en-Y gastric bypass, and gastric banding are enrolled. Microarchitectural changes are evaluated using high resolution peripheral computed tomography. This study will help demonstrate the changes in microstructure underlying the previously reported losses in bone density after weight loss surgery. The findings will help to elucidate whether these bone density losses are adaptations to unloading of the skeleton with weight loss or whether they represent pathology and increased risk of fracture. 

 

Osteoporosis After Organ Transplantation

Drs. Elizabeth Shane, Adi Cohen and Emily Stein

Dr. Shane has a longstanding interest in the profound bone loss and high rate of fractures that follow organ transplantation. She has conducted studies that have helped to elucidate the natural history and pathogenesis of this severe form of osteoporosis and has also helped to identify therapies that can prevent this debilitating complication of organ transplantation. Recently completed studies in this area include a randomized trial comparing a single infusion of zoledronic acid (Reclast, 5 mg) with weekly alendronate (Fosamax, 70 mg) with respect to their ability to prevent bone loss and fractures in heart and liver transplant recipients. Follow-up of study subjects over the second post-transplant year is ongoing. In addition, she and her colleagues have conducted a meta-analysis of randomized controlled clinical trials assessing the effects of bisphosphonates or active analogues of vitamin D for prevention of fractures after solid organ transplantation. 

 

Other Miscellaneous Studies

Postpartum Bone Health Study

Drs. Adi Cohen and Elizabeth Shane

This study is utilizing high resolution peripheral quantitative CT (HR-pQCT) to examine the microstructural bone changes associated with breastfeeding in women over the first 18 months postpartum. 

 

Paget's Disease of Bone

Dr. Ethel Siris 

We have been studying the genetics of Paget’s disease, in collaboration with Prof. Jacques Brown’s laboratory in Quebec, funded by a grant from the Evelyn S. Nef Foundation. We have collected data on over 70 patients with Paget’s disease from our practice in the Metabolic Bone Diseases Unit, including extensive demographic information (ethnicity, family history of Paget’s disease) as well as sites of skeletal involvement, and analyzing samples of blood for a series of candidate genes for this disease. 

 

Osteoporosis in HIV/AIDS

Drs. Elizabeth Shane, Michael Yin, Emily Stein, and John Manavalan

Patients with HIV-AIDS, particularly those receiving “Highly Active Antiretroviral Therapy” or HAART have low bone density. This observation has been made in children, young men, young women and postmenopausal women. Dr. Shane is currently participating in a randomized clinical trial that is investigating the effect of vitamin D supplementation on bone mass accrual in HIV+ children. She is consulting on the WHIS grant – a longitudinal study of bone density and bone and mineral metabolism in a largely premenopausal group of HIV+ women. She is the Principal Investigator of an NIH-funded study designed to evaluate HIV+ postmenopausal women (RO1 AI 065200-06). The goals of the WHIS study and the NIH-funded study is to understand the effects of HIV infection and its therapy on bone health in young and older women. In addition, the grant will assess the effects of vitamin D supplementation on bone density and quality, muscle strength and quality and immune parameters. 

The Effects of Antiepileptic Drugs on Bone and Reproductive Health

Drs. Elizabeth Shane and Alison Pack

Fractures, a leading cause of disability in the United States and worldwide, are increased 2-4 fold in persons with epilepsy, and epidemiological studies indicate that epilepsy and its therapy are independent risk factors for fracture. We have documented evidence of increased bone remodeling activity and increased prevalence of low bone mineral density (BMD) in persons with epilepsy. These changes have traditionally been attributed to abnormalities in the vitamin D-parathyroid hormone endocrine system and primarily associated with antiepileptic drugs (AEDs) that induce the hepatic cytochrome P450 (CYP450) system. However, adverse effects on sex steroid hormone concentrations have been described in premenopausal women with epilepsy, both in association with seizures and AED therapy. As estrogen is a key factor in achieving and maintaining peak bone mass, reduced estrogen levels could also adversely affect bone strength. We are investigating the effects of epilepsy and its therapy with CYP450 enzyme inducing AEDs on bone strength and explore potential mechanisms (vitamin D and estrogen) for these effects. 

 

Image and Data Analysis

HR-pQCT Image Analysis

Drs. Kyle Nishiyama and Elizabeth Shane

Osteoporosis is a disease characterized by loss of bone mass and structural deterioration leading to increased risk of fracture. Currently, osteoporosis is diagnosed by measurement of areal bone mineral density by dual-energy x-ray absorptiometry (DXA) which only estimates areal bone density. This work focuses on developing novel methods to analyze  3D images from high-resolution peripheral quantitative computed tomography (HR-pQCT) scanners in order to better quantify the effects of treatments and diseases and to better predict fracture risk. 

Statistical Shape Models

Drs. Kyle Nishiyama and Elizabeth Shane

This study will use advanced analyses of widely available DXA images to generate 3D shape models that incorporate bone structure and geometry. By aligning 2D DXA images to 3D image atlases, patient-specific 3D models will be reconstructed for quantitative analyses and combined with FE analysis to estimate bone strength. Machine learning models will be used to incorporate these novel measurements, demographics, and various risk factors for fracture to predict incident fractures in two very large, prospective studies. The ultimate goal of this proposal is to increase the diagnostic utility of DXA, a safe, non-invasive, and widely available technology, by applying novel image processing and statistical techniques to predict fractures more accurately.

 

Fracture Classification by Machine Learning

Drs. Kyle Nishiyama and Elizabeth Shane

Fracture is a highly complex event, influenced by various risk factors that may impact individuals differently. Recently, new tools and increased capability to process, model, and draw insights from enormous datasets have emerged. Machine learning combined with ‘big data’ is one such statistical tool that can be used to recognize patterns in large datasets. Models are trained on an existing set of data, then tested on new cases. We will use these tools together with advanced 3D analysis to analyze very large datasets from existing prospective, observational cohorts. Our ultimate clinical goal is to combine advanced image analysis and machine learning to target individuals at highest risk of fracture for therapy to prevent fractures.