Skeletal Changes Associated with Osteoarthritis Abstract Osteoarthritis (OA) is a degenerative joint disorder in which progressive articular cartilage loss occurs alongside pathological changes in subchondral bone and other joint tissues. The pathophysiological role of bone in OA has been a point of interest for many years and has resurfaced again in recent years as a potential target for new treatments. Articular cartilage and subchondral bone together form the osteochondral unit. Its homeostasis and integrity are reliant on biochemical crosstalk and biomechanical interplay between the two. Subchondral bone, with its relatively greater stiffness and strength, provides mechanical support to the overlying cartilage and absorbs much of the mechanical force transmitted through the joint. Mechanical instability in osteoarthritic joints is thought to be a significant risk-factor in joint disease, due to the mechano-sensitive nature of many of its native tissues. Although the progression of joint disease remains incompletely understood, significant changes in subchondral bone remodelling, structure, composition, and mechanical properties have been documented in animal and human studies of OA. The purpose of this review is to explore and discuss these bony changes associated with disease and, in particular, contextualise the basic science and clinical literature on the role of subchondral bone in OA.

Socio-economic Determinants of Bone Health from Past to Present Abstract Increasing epidemiology evidence amounts for social determinants of bone health underlying musculo-skeletal conditions such as osteoporosis. Amongst different facets influencing skeletal health, socio-economic status (SES) has been identified as a critical factor determining one’s access to resources, health care, education, nutrition, and physical activity. Recent conceptual and epigenetic studies assessing SES links with DNA methylation offer further support for the adverse effects of social disadvantage in early life on bone quantity and quality in adulthood. However, this evidence for socially patterned risks in bone fragility is not restricted to the contemporary society. Data exist for ancient human skeletal samples deriving from SES stratified cemeteries that also reflect bone changes consistent with lifestyles specific to social standing. Similarly to modern data, the conclusion drawn from the ancient times has been for a negative effect of low SES on bone growth and maintenance. Some contradictory results, mirroring previously reported inconsistencies in epidemiological studies, have also been reported showing that high SES can equally result in poor bone health. It becomes clear that ancient perspectives can offer a further line of support into these ongoing epidemiological and epigenetic research efforts. Taken together, a holistic approach to clinical understanding and practice of bone health is recommended, building upon ancient and modern findings to target living groups who are most at risk of developing low bone mass and compromised bone micro-architecture.

Comparison of Efficacy of Pharmacologic Treatments in Pregnancy- and Lactation-Associated Osteoporosis Abstract Pregnancy- and lactation-associated osteoporosis (PLO) is a rare disorder characterised by the occurrence of multiple fragility fractures, particularly at vertebral columns, in the third trimester or early postpartum period. Whether implementation for pharmacologic treatments in patients with PLO remains controversial partly due to rarity of data and known indolent recovery of bone mass after fracture, various pharmacologic treatments have been reported to effectively facilitate bone mineral density (BMD) increase in anecdotal case reports or cohorts based on individualised clinical assessment of subsequent fracture risk. In this study, we aimed to summarise pharmacologic strategies and its efficacy on BMD change and subsequent fractures using individual case data or frequency-weighted group data from available literatures. Among 2438 studies identified using PubMed and Embase until Jan 2019, 30 studies which reported pharmacologic treatment (23 studies) or observation (7 studies) were included. Reported treatment options consisted of observation with calcium/vitamin D supplements (control, n = 32), bisphosphonates (BP, n = 31), teriparatide (TPTD, n = 40) and other strategies (vitamin K2 and strontium; other, n = 4). Median treatment duration and BMD follow-up duration was 27 and 35 months, respectively. Mean lumbar spine BMD measured by dual-energy x-ray absorptiometry was increased at 3-year follow-up in all groups (control, 7.9%; BP, 18.2%; TPTD, 17.0%; other, 8.6%; P < 0.05 for all), with significantly higher BMD change in BP or TPTD compared to control (Bonferroni-corrected P < 0.001 for all). Our findings suggest the potential long-term efficacy of pharmacologic treatments in individuals with PLO with high risk of subsequent fracture.

Low Bone Mineral Density in Anorexia Nervosa: Treatments and Challenges Abstract Anorexia nervosa, a psychiatric disease predominantly affecting women, is characterized by self-induced starvation and a resultant low-weight state. During starvation, a number of hormonal adaptations—including hypothalamic amenorrhea and growth hormone resistance—allow for decreased energy expenditure during periods of decreased nutrient intake, but these very same adaptations also contribute to the medical complications associated with chronic starvation, including low bone mass. Almost 90% of women with anorexia nervosa have bone mineral density (BMD) values more than one-standard deviation below the mean of healthy women at peak bone mineral density, and this disease is associated with a significantly increased risk of fracture. Although multiple therapies have been studied for the treatment of low bone mass in anorexia nervosa, there are currently no approved therapies and few promising long-term therapeutic options. This review will outline the mediators of low bone mass in anorexia nervosa, discuss therapies that have been studied for the treatment of low BMD in this disorder, and highlight the important challenges that remain, including the differences in bone modeling in adolescents with anorexia nervosa as compared to adults, necessitating that potential therapies be tested in these two populations separately, and the paucity of long-term therapeutic strategies for treating bone loss in this disorder.

Osteoporosis in Veterans with Spinal Cord Injury: an Overview of Pathophysiology, Diagnosis, and Treatments Abstract Immediately after spinal cord injury (SCI), approximately 75% of patients suffer rapid and severe loss of bone mineral density (BMD) below the lesion level (i.e., sublesional), leading to osteoporosis (OP) in ~ 60% 1-year post-injury. The distal femur (DF) and proximal tibia (PT) are most commonly involved, and 70% of SCI patients sustain a low impact fracture at some point in their lifetime, adding disability to an already physically challenged population. Unfortunately, OP treatments for post-menopausal women are not as effective for OP post-SCI. Mechanisms of new agents targeting the neurogenic etiology of bone resorption (i.e., denosumab and anti-sclerostin antibodies) may hold greater potential and are discussed. Furthermore, standardized DXA protocols with normative BMD values for the DF and PT sites have not been established, so diagnosing OP is problematic. This review will summarize the pathophysiology of sublesional OP after SCI, the unique challenges of diagnosing and managing OP in SCI patients and provide recommendations for future studies. Given the Veterans Health Administration (VA) is the largest health care system in the world for persons with SCI, it is well-equipped to add to gaps in the literature.

Bone Health in the Transgender Population Abstract It is well known that sex steroids, particularly estrogen, play a crucial role in the attainment and maintenance of peak bone density in all people. Transgender (trans) have been frequently observed to have low bone density prior to initiation of gender-affirming hormone therapy, while trans men generally do not. With pharmacologic estrogen, many studies show improving bone density in trans women. With pharmacologic testosterone, bone density in trans men remains largely unchanged although androgens have indirect effects on bone health via changes in fat and lean mass. Much remains unknown about best practices to optimize bone health, interpret DXA scans and assess fracture risk in trans adults.

Acknowledgement to Referees 2018

Fourier Transform Infrared Spectroscopy of Bone Tissue: Bone Quality Assessment in Preclinical and Clinical Applications of Osteoporosis and Fragility Fracture Abstract The pathogenesis of bone fragility is of utmost importance especially to modern societies with aging populations. Increased skeletal fragility due to aging and disease motivates researchers to investigate the contributing biological mechanisms and to find ways to inhibit them. Bone quality is a set of structural and compositional variables that contribute to bone strength and influence its ability to resist fracture. They originate from multiple bone hierarchical levels and include the morphology (mass distribution), the chemical composition, and the biomechanical properties of bone tissue such as stiffness, fatigue strength, and fracture toughness. Qualitative and quantitative measurements of bone material properties reflect the underlying health or disease status. Fourier transform infrared (FTIR) spectroscopy and imaging are able to evaluate spatially inhomogeneous structures like bone in the form of sections or homogenized powder, providing simultaneous quantitative and qualitative information from both organic and inorganic tissue components. These techniques give a snapshot of structural and material properties that essentially depend on bone turnover while they are also sensitive to tissue alterations due to metabolic and nonmetabolic diseases, and external factors like administration of drugs. In this review, we discuss the application of FTIR spectroscopy and imaging to preclinical and clinical studies. The interpretation of results emphasizes the potential of infrared spectroscopic techniques to associate bone heterogeneity with fracture risk, assess the compositional and structural properties of osteoporotic bone, and investigate bisphosphonates’ antiresorptive action and side effects.

Effects of Sympathetic Activity on Human Skeletal Homeostasis: Clinical Evidence from Pheochromocytoma Abstract Bone is a highly dynamic tissue that is continuously being renewed in a lifelong remodeling process that is guided by mechanical and biochemical signals. Imbalances between the underlying processes result in metabolic bone diseases, such as osteoporosis and osteopetrosis; therefore, all phases of bone remodeling are tightly controlled by systemic or local factors to maintain bone homeostasis. The sympathetic nervous system (SNS), one of the two main divisions of the autonomic nervous system, operates through a series of interconnected neurons and finalizes the actions by binding catecholamines, released from postganglionic neurons and from adrenal medulla to adrenergic receptors on peripheral target tissues. Because bone is a metabolically active organ with a significant neural innervation, it is reasonable to assume that neuronal control may constitute a key mechanism in bone remodeling. Pheochromocytoma is a neuroendocrine tumor arising from the chromaffin cells of the adrenal medulla and is characterized by an excessive production of catecholamines. Considering that catecholamines are the main neurotransmitters of SNS, pheochromocytoma might be an ideal human model to determine the role of sympathetic outflow on the pathogenesis of a variety of diseases. This review highlights the importance of SNS activity in human skeletal homeostasis based on insights gained from pheochromocytoma, combined with evidence from a variety of experimental studies.

Exploring the Links Between Common Diseases of Ageing—Osteoporosis, Sarcopenia and Vascular Calcification Abstract Vascular diseases account for a significant proportion of preventable deaths, particularly in developed countries. Our understanding of diseases that alter the structure and function of blood vessels such as vascular calcification and vascular stiffness has grown enormously such that we now appreciate them to be active processes that can be modified. Interest has also grown in examining the links between other diseases of ageing such as the loss of bone (osteoporosis) and muscle (sarcopenia) with the development and progression of vascular disease as these three disease states commonly co-occur in older age. Cardiovascular disease (including calcification and arterial stiffness) is highly prevalent in older populations and it appears that its progression is accelerated in patients with osteoporosis, fracture, sarcopenia and in those who are functionally impaired. Biological and clinical evidence supports a view that vascular disease (calcification/stiffness) may be both a cause and consequence of diseases of ageing including musculoskeletal decline. This review provides an overview of the development of vascular calcification and stiffness and explores the molecular and physiological mechanisms linking osteoporosis and sarcopenia to vascular disease development. This review also examines clinical evidence supporting the association of muscle and bone loss with vascular disease and concludes by reviewing the interventional and therapeutic potential of bone-active minerals and hormones (calcium and vitamin D) on cardiovascular disease biology, given that these represent potential interventions to target multiple body systems. Overall, this review will aim to highlight the underappreciated burden of cardiovascular disease in individuals in the context of musculoskeletal diseases.