Mary L Bouxsein

• Beth Israel Deaconess Medical Center

Background Subject‐specific musculoskeletal models may be used to estimate spine loads that cannot be measured in vivo. Model generation methods may use detailed measurements extracted from medical imaging, but it may be possible to create accurate models without these measurements. We aimed to determine which physiological and anthropometric facto...

Bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) and adjustable gastric banding (AGB) lead to long-term deficits in bone density but are also accompanied by decreased weight, which may lower the impact force with falls. The aim of this study was to compare the long-term skeletal impact of RYGB and AGB using a biomechanical evaluation of...

We have proposed to the Food and Drug Administration (FDA) that treatment-related increases in total hip bone mineral density (TH BMD) at two years could be a surrogate endpoint for fracture risk reduction in clinical trials. The qualification of a surrogate includes a strong association of the surrogate with the clinical outcome. We compiled a lar...

Up to 40% of elite athletes experience bone stress injuries (BSIs), with 20-30% facing reinjury. Early identification of runners at high risk of subsequent BSI could improve prevention strategies. However, the complex etiology and multifactorial risk factors of BSIs makes identifying predictive risk factors challenging. In a study of 30 female recr...

Type 1 diabetes (T1D) is associated with an increased risk of hip fracture beyond what can be explained by reduced bone mineral density, possibly due to changes in bone material from accumulation of advanced glycation end-products (AGEs) and altered matrix composition, though data from human cortical bone in T1D are limited. The objective of this s...

The development of eye pathology is a serious concern for astronauts who spend time in deep space. Microgravity is a major component of the spaceflight environment which could have adverse effects on ocular health. The use of centrifugation to exert forces that partially or fully mimic Earth-level gravity in space is a possible countermeasure to mi...

Vertebral compression fractures (VFs) and spinal degeneration are both common causes of back pain, particularly in older adults. Previous cross-sectional studies have shown a potential association between these entities, but there is limited evidence on the role of VFs in spinal degeneration. In this longitudinal study, we evaluated the association...

Exposure to ionizing radiation for oncological therapy increases the risk for late-onset fractures in survivors. However, the effects of total body irradiation (TBI) on adult bone are not well-characterized. The primary aim of this study was to quantify the long-term effects of TBI on bone microstructure, material composition, and mechanical behavi...

Introduction Although bone formation has been observed in the distal tibia of trainees during Basic Combat Training (BCT), some animal studies have demonstrated greater mechanosensitivity in the juvenile compared to the mature skeleton. How age affects skeletal adaptations to military training is unknown. The purpose of this study was to determine...

Identifying individuals at risk for short-term fracture is essential to offer prompt beneficial treatment, especially since many fractures occur in those without osteoporosis by DXA-aBMD. We evaluated whether deficits in bone microarchitecture and density predict short-term fracture risk independent of the clinical predictors, DXA-BMD and FRAX. We...

Adults with type 1 diabetes (T1D) have increased hip fracture risk, yet no studies have assessed volumetric bone density or structure at the hip in older adults with T1D. Here, we used previously collected 3D CT scans of the proximal femur from older adults with longstanding T1D and non-diabetic controls to identify bone deficits that may contribut...

There is a strong association between total hip bone mineral density (THBMD) changes after 24 months of treatment and reduced fracture risk. We examined whether changes in THBMD after 12- and 18 months of treatment are also associated with fracture risk reduction. We used individual patient data (n = 122 235 participants) from 22 randomised, placeb...

Context Neuropathy and fracture are prevalent complications of type 1 diabetes (T1D). Although correlated in the clinical literature, it remains unknown whether neuropathy contributes to the initiation of bone loss at the earliest stages of disease. Methods We performed a single-center, cross-sectional study to quantify parameters of nerve and bon...

Background Computed tomography (CT) captures the quantity, density, and distribution of subcutaneous and visceral (SAT and VAT) adipose tissue compartments. These metrics may change with age and sex. Objective The study aims to provide age-, sex-, and vertebral level–specific reference values for SAT on chest CT and for SAT and VAT on abdomen CT....

Objective Less than half of servicewomen report loss of menses during initial military training. However, self-reported menstrual status may not accurately reflect hypothalamic-pituitary-ovarian (HPO) axis suppression and may underestimate reproductive health consequences of military training. Our aim was to characterise HPO axis function during US...

Randomized trials have not been performed, and may never be, to determine if osteoporosis treatment prevents hip fracture in men. Addressing that evidence gap, we analyzed data from an observational study of new hip fractures in a large integrated healthcare system to compare the reduction in hip fractures associated with standard-of-care osteoporo...

Osteoporosis and cardiovascular disease frequently occur together in older adults; however, a causal relationship between these two common conditions has not been established. By the time clinical cardiovascular disease develops, it is often too late to test whether vascular dysfunction developed before or after the onset of osteoporosis. Therefore...

Some osteoporosis drug trials have suggested that treatment is more effective in those with low BMD measured by DXA. This study used data from a large set of randomized controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments differs according to baseline BMD. We used individual patient data from 25 RCTs (103 086 subje...

Alzheimer's disease (AD) and osteoporosis often coexist in the elderly. Although observational studies suggest an association between these two diseases, the pathophysiologic link between AD and skeletal health has been poorly defined. We examined the skeletal phenotype of 5xFAD mice, an AD model with accelerated neuron-specific amyloid-β accumulat...

There is a common belief that antiosteoporosis medications are less effective in older adults. This study used data from randomized controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments and their effects on bone mineral density (BMD) differ in people ≥70 compared to those <70 years. We used individual patient data f...

Fracture risk increases with lower areal BMD (aBMD); however, aBMD-related estimate of risk may decrease with age. This may depend on technical limitations of 2-dimensional (2D) DXA which are reduced with 3D high-resolution peripheral quantitative computed tomography (HR-pQCT). Our aim was to examine whether the predictive utility of HR-pQCT measur...

With the technological advances made to expand space exploration, astronauts will spend extended amounts of time in space before returning to Earth. This situation of unloading and reloading influences human physiology, and read- aptation to full weight-bearing may significantly impact astronauts' health. On Earth, similar situations can be observe...

Diabetes, a disease marked by consistent high blood glucose levels, is associated with various complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Notably, skeletal fragility has emerged as a significant complication in both type 1 (T1D) and type 2 (T2D) diabetic patients. This review examines non-invasive imagin...

Astronauts have an increased risk of back pain and disc herniation upon returning to Earth. Thus, it is imperative to understand the effects of spaceflight and readaptation to gravity on the musculoskeletal tissues of the spine. Here we investigated whether ~6 months of spaceflight led to regional differences in bone loss within the vertebral body....

Osteocytes express parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptors and respond to the PTHrP analog abaloparatide (ABL) and to the PTH 1-34 fragment teriparatide (TPTD), which are used to treat osteoporosis. Several studies indicate overlapping but distinct skeletal responses to ABL or TPTD, but their effects on cortical bone may dif...

To understand whether the bone loss which occurs after vertical sleeve gastrectomy increases the risk of fracture, we used an engineering model to estimate risk in participants before and after surgery. We found that estimated risk decreased 1 year after surgery and remained lower, though had rebounded, at year 2. Vertical sleeve gastrectomy (VSG)...

Over 1 million Americans are currently living with T1D and improvements in diabetes management have increased the number of adults with T1D living into later decades of life. This growing population of older adults with diabetes is more susceptible to aging comorbidities, including both vascular disease and osteoporosis. Indeed, adults with T1D hav...

Disclosure: G.H. Jung: None. B. Zahedi: None. K. Lindeman: None. C.C. Rushin: None. M.C. Cheney: None. M.L. Bouxsein: None. E.W. Yu: Grant Recipient; Self; Amgen Inc. Background: Bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) and adjustable gastric banding (AGB) lead to long-term deficits in bone density but are also accompanied by dec...

The gut microbiome affects the inflammatory environment through effects on T-cells, which influence the production of immune mediators and inflammatory cytokines that stimulate osteoclastogenesis and bone loss in mice. However, there are few large human studies of the gut microbiome and skeletal health. We investigated the association between the h...

Background Loss of muscle mass is a known feature of sarcopenia and predicts poor clinical outcomes. Although muscle metrics can be derived from routine computed tomography (CT) images, sex-specific reference values at multiple vertebral levels over a wide age range are lacking. Objective The aim of this study was to provide reference values for s...

Type 1 diabetes (T1D) confers an increased risk of fracture and is associated with lower bone mineral density (BMD) and altered microarchitecture compared with controls. Adequate calcium (Ca) intake promotes bone mineralization, thereby increasing BMD. The objective of this analysis was to evaluate the associations of total daily Ca intake with bon...

Skeletal muscle size and strength are important for overall health for astronauts. However, how male and female muscle may respond differently to micro- and partial-gravity environments is not fully understood. The purpose of this study was to determine how biological sex and sex steroid hormones influence the progression of muscle atrophy after lo...

Objective To determine mechanisms contributing to impaired bone health in youth 24 months following sleeve gastrectomy (SG) Design 24-month longitudinal observational study Methods Participants included 23 youth undergoing SG and 30 non-surgical controls (NS) 13-25 years old with moderate-to-severe obesity. Subjects underwent fasting labs for bon...

The purpose of this study was to develop a machine learning model to reconstruct time series kinematic and kinetic profiles of the ankle and knee joint across six different tasks using an ankle-mounted IMU. Four male collegiate basketball players performed repeated tasks, including walking, jogging, running, sidestep cutting, max-height jumping, an...

Trunk muscle size and location relative to the spine are key factors affecting their capacity to assist in trunk movement, strength, and function. There remains limited information on how age, weight and height affect these measurements across multiple spinal levels, and prior studies had limited samples in terms of size and ethnicity. In this stud...

Introduction: Leadership skills are essential for a successful career in medical research but are often not formally taught. To address these gaps, we designed a leadership development program for early-stage investigators. Methods: A 9-month virtual program with monthly 2-hour interactive sessions was designed, covering topics such as Leadershi...

Musculoskeletal models can uniquely estimate in vivo demands and injury risk. In this study, we aimed to compare muscle activations from subject-specific thoracolumbar spine OpenSim models with recorded muscle activity from electromyography (EMG) during five dynamic tasks. Specifically, 11 older adults (mean = 65 years, SD = 9) lifted a crate weigh...

Background Sleeve gastrectomy (SG) is effective in the treatment of cardiometabolic complications of obesity but is associated with bone loss. Purpose To determine the long-term effects of SG on vertebral bone strength, density, and bone marrow adipose tissue (BMAT) in adolescents and young adults with obesity. Materials and Methods This 2-year pro...

Most fracture risk assessment tools use clinical risk factors combined with bone mineral density (BMD) to improve assessment of osteoporosis; however, stratifying fracture risk remains challenging. This study developed a fracture risk assessment tool that uses information about volumetric bone density and three-dimensional structure, obtained using...

Context: Female athletes, particularly runners, with insufficient caloric intake for their energy expenditure (low energy availability or relative energy deficiency) are at risk for impaired skeletal integrity. Data are lacking in male runners. Objective: To determine whether male runners at risk for energy deficit have impaired bone mineral den...

Sleeve gastrectomy (SG) is effective in treating cardiometabolic complications of obesity but is associated with bone loss. Our aim was to determine the effect of SG on the lumbar spine by biomechanical CT analysis in adolescents/young adults with obesity. We hypothesized that SG would lead to a decrease in strength and bone mineral density (BMD) c...

Purpose: To determine whether changes in menstruation develop in female trainees during BCT and whether changes in body mass, body composition and/or physical activity are associated with menstrual interruption during BCT. Methods: Female trainees grouped according to self-reported menstrual status in the 12 months before BCT as having regular c...

Basic Combat Training (BCT) is a physically rigorous period at the beginning of a Soldier's career that induces bone formation in the tibia. Race and sex are determinants of bone properties in young adults but their influences on changes in bone microarchitecture during BCT are unknown. Purpose: To determine the influence of sex and race on changes...

Impact microindentation (IMI) is a novel technique for assessing bone material strength index (BMSi) in vivo, by measuring the depth of a micron-sized, spherical tip into cortical bone that is then indexed to the depth of the tip into a reference material. The aim of this study was to define the reference intervals for men and women by evaluating h...

Background This study used bi-planar low-dose X-ray images to identify differences in lower extremity skeletal morphology by race and sex that might contribute to observed disparities in the occurrence of musculoskeletal disorders. Methods We enrolled a multiracial cohort of young adults (n = 172) that included Asian women (n = 29) and men (n = 31...

Static biomechanical simulations are sometimes used to estimate in vivo kinetic demands because they can be solved efficiently, but this ignores any potential inertial effects. To date, comparisons between static and dynamic analyses of spinal demands have been limited to lumbar joint differences in young males performing sagittal lifts. Here we co...

Context Visceral adipose tissue (VAT) has been recognized to be a metabolically active fat depot that may have paracrine effects on surrounding tissues, including muscle. Since many adults accumulate VAT as they age, the effect of changes in VAT on muscle is of interest. Objective We determined the association between six year changes in VAT and p...

Osteoporosis is a major public health problem. Currently, there are no orally available therapies that increase bone formation. Intermittent parathyroid hormone (PTH) stimulates bone formation through a signal transduction pathway that involves inhibition of salt-inducible kinase isoforms 2 and 3 (SIK2 and SIK3). Here, we further validate SIK2/SIK3...

The combination of denosumab and teriparatide is an effective treatment strategy in postmenopausal osteoporosis, though skeletal gains are promptly lost when these agents are discontinued. In the DATA‐HD study, we reported that a single dose of zoledronic acid (ZOL) maintains the increases in areal spine and hip bone mineral density (BMD) achieved...

Background Peptide YY (PYY) is an anorexigenic gut hormone that also has anti-osteogenic effects, inhibiting osteoblastic activity and inducing catabolic effects. It has been postulated that increases in PYY after Roux-en-Y gastric bypass (RYGB) contribute to declines in bone mineral density (BMD) and increases in bone turnover. The aim of this stu...

Context: Vertical sleeve gastrectomy (VSG) is an increasingly common tool to achieve weight loss and improve metabolic health in adolescents and young adults with obesity, although it may adversely affect bone health. Objective: To evaluate the effect of VSG on bone health in youth. Design: Observational 2-year study. Setting: Tertiary care...

The 22nd Annual Santa Fe Bone Symposium (SFBS) was a hybrid meeting held August 5-6, 2022, with in-person and virtual attendees. Altogether, over 400 individuals registered, a majority of whom attended in-person, representing many states in the USA plus 7 other countries. The SFBS included 10 plenary presentations, 2 faculty panel discussions, sate...

As part of the risk management plan for human system risks at the US National Aeronautics and Space Administration (NASA), the NASA Human Systems Risk Board uses causal diagrams (in the form of directed, acyclic graphs, or DAGs) to communicate the complex web of events that leads from exposure to the spaceflight environment to performance and healt...

Background Bariatric surgery has been shown to result in weight loss, improved hemoglobin A1C, and decreased mortality but can also lead to bone loss and increased fracture rates. Serum IGFBP-2 is elevated in patients after bariatric surgery and although it may lead to improved blood glucose, may also drive bone resorption, and inhibit IGF-I action...

Type 2 diabetes (T2D) is associated with increased risk of fractures. However, it is unclear whether current osteoporosis treatments reduce fractures in individuals with diabetes. The aim of the study was to determine whether presence of T2D influences the efficacy of antiresorptive treatment for osteoporosis using the FNIH‐ASBMR‐SABRE cohort which...

Although bone mineral density (BMD) is decreased and fracture risk increased in anorexia nervosa, BMD does not predict fracture history in this disorder. We assessed BMD, bone microarchitecture, and bone marrow adipose tissue (BMAT) in women with anorexia nervosa and found that only BMAT was associated with fracture history.IntroductionAnorexia ner...

The effects of exercise on stress fracture risk are paradoxical. Exercise can promote both bone formation and resorption, which in turn, can reduce and increase risk of stress fractures, respectively. We review classic and current literature that suggests that the processes that underlie these responses to exercise are distinct. Bone remodeling inv...

Study design: Prospective Randomized Placebo Controlled Animal Trial. Objective: Determine the effect of daily subcutaneous abaloparatide injection on the intervertebral fusion rate in rabbits undergoing posterolateral fusion. Study of background data: Despite the wide utilization of spine fusion, pseudarthrosis remains prevalent and results i...

Background Among adolescents with extremity fractures, individuals with obesity have greater representation compared with individuals of normal-weight, despite having higher areal and volumetric bone mineral density (aBMD, vBMD) than their normal-weight counterparts. The relative increase in BMD in individuals with obesity may thus be insufficient...

Opioid use is detrimental to bone health, causing both indirect and direct effects on bone turnover. While the mechanisms of these effects are not entirely clear, recent studies have linked chronic opioid use to alterations in circulating miRNAs. Here, we developed a model of opioid‐induced bone loss to understand bone turnover and identify candida...

Glucocorticoid excess suppresses osteocyte remodeling of surrounding bone mineral, causes apoptosis of osteoblasts and osteocytes, and disrupts bone remodeling, eventually leading to glucocorticoid-induced osteoporosis and bone fragility. Preventing apoptosis and preserving osteocyte morphology could be an effective means of preventing bone loss du...

Purpose: To determine whether 25-hydroxyvitamin D (25-OH D) levels are associated with bone outcomes in a multiracial cohort of young adults. Methods: This cross-sectional study included 165 participants (83 men, 82 women, 18-30y) who self-identified as Asian, Black, or White. We measured bone microarchitecture and strength of the distal radius...

Context: Sleeve gastrectomy (SG) improves metabolic endpoints but is associated with impaired bone outcomes. Objective: To determine mechanisms contributing to impaired bone health in youth following SG. Design: 12-month longitudinal observational study. Setting: Multi-disciplinary tertiary care hospital. Patients: 64 youth 13-25 years old...

Bone stress injuries (BSIs) are common among athletes and have high rates of recurrence. However, risk factors for multiple or recurrent BSIs remain understudied. Thus, we aimed to explore whether energy availability, menstrual function, measures of bone health, and a modified Female Athlete Triad Cumulative Risk Assessment (CRA) tool are associate...

Bone stress injuries, including stress fractures, are overuse injuries that lead to substantial morbidity in active individuals. These injuries occur when excessive repetitive loads are introduced to a generally normal skeleton. Although the precise mechanisms for bone stress injuries are not completely understood, the prevailing theory is that an...

For decades researchers reported that pre-menopausal women who engage in extensive endurance exercise and have menstrual dysfunction can develop low bone mineral density (BMD) or osteoporosis. More recently, low energy availability has been recognized as the initiating factor for low BMD in these women. Furthermore, the relationship between low ene...

Although the non‐selective β‐blocker, propranolol, improves bone density with PTH treatment in mice, the mechanism of this effect is unclear. To address this, we used a combination of in vitro and in vivo approaches to address how propranolol influences bone remodeling in the context of PTH treatment. In female C57BL/6J mice, intermittent PTH and p...

Purpose : Bone stress injuries (BSIs) are common in female runners, and recurrent BSI rates are high. Previous work suggests an association between higher impact loading during running and tibial BSI. However, it is unknown whether impact loading and fatigue related loading changes discriminate women with a history of multiple BSIs. This study comp...

Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a "one-size-fits-all" approach to diagnosis and management of osteoporosis may not b...

Glucocorticoid (GC)-induced osteoporosis and subsequent bone fragility are preceded by death and dysfunction at the cellular level. In particular, short-term glucocorticoid excess suppresses osteocyte remodeling of the surrounding bone mineral, causes apoptosis of osteoblasts and osteocytes, and disrupts homeostatic bone remodeling. Preventing apop...

Some osteoblasts embed within bone matrix, change shape, and become dendrite-bearing osteocytes. The circuitry that drives dendrite formation during “osteocytogenesis” is poorly understood. Here we show that deletion of Sp7 in osteoblasts and osteocytes causes defects in osteocyte dendrites. Profiling of Sp7 target genes and binding sites reveals u...

Basic combat training (BCT) is a period of novel physical training including load carriage resulting in higher risk of stress fracture compared to any other time during military service. Prior trials reported a 20% reduction in stress fracture incidence with Ca and vitamin D (Ca + D) supplementation (2000 mg Ca, 800 IU vitamin D), and greater incre...

Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analyzing exome sequencing data from the UK Biobank, we...

Higher fracture risk in White versus Black women is partly explained by lower BMD and worse bone microarchitecture in White women. However, whether rates of decline in bone density, microarchitecture and strength differ between postmenopausal Black and White women is unknown. Further, factors that influence rates of age-related bone microarchitectu...

Background: Markers of bone metabolism (MBM) play an important role in fracture evaluation, and changes have been associated with increased fracture risk. The purpose of the present study was to describe changes in MBM in premenopausal women with distal radial fractures. Methods: Premenopausal women with distal radial fractures (n = 34) and with...

Disuse-induced bone loss is seen following spinal cord injury, prolonged bed rest, and exposure to microgravity. We performed whole transcriptomic profiling of cortical bone using RNA sequencing (RNAseq) and RNA molecular barcoding (NanoString) on a hindlimb unloading (HLU) mouse model to identify genes whose mRNA transcript abundances change in re...

Background Fractures secondary to osteoporosis, particularly those of the hip and spine, are a major public health concern with high social and economic costs. The Local Osteo-Enhancement Procedure (LOEP) is an approach intended to strengthen skeletal areas that are at the highest risk for fracture due to osteoporosis. LOEP involves the implantatio...

Recent efforts have focused on further understanding female muscle physiology during exposure to muscle atrophic stimuli. A key feature of female rodent physiology is the estrous cycle. However, how such stimuli interact with the estrous cycle to influence muscle health remains uninvestigated. Aim: To investigate the impact of muscle atrophic stimu...

Background: States of chronic overnutrition and undernutrition are both associated with impaired bone health and increased fracture risk but there are no data on bone microarchitecture following short-term controlled nutritional challenges. Objective: The purpose of our study was to evaluate the impact of short-term high-caloric feeding and fast...

Motion analysis is increasingly applied to spine musculoskeletal models using kinematic constraints to estimate individual intervertebral joint movements, which cannot be directly measured from the skin surface markers. Traditionally, kinematic constraints have allowed a single spinal degree of freedom (DOF) in each direction, and there has been li...

Bone formation and resorption are typically coupled, such that the efficacy of anabolic osteoporosis treatments may be limited by bone destruction. The multi-kinase inhibitor YKL-05-099 potently inhibits salt inducible kinases (SIKs) and may represent a promising new class of bone anabolic agents. Here we report that YKL-05-099 increases bone forma...