Bone biology and disease

Diabetes mellitus is associated with an increased risk of fragility fractures. Here, Napoli and colleagues discuss the complex interactions between glucose homeostasis and bone fragility, the epidemiology of fractures in patients with diabetes mellitus and the effects of antidiabetic drugs on bone health.

In this Review, Weitzmann and Ofotokun examine the evolution of the field of osteoimmunology and how advances in our understanding of the immuno–skeletal interface might lead to novel approaches to prevent and treat bone loss, and avert fractures.

Osteocytes have a central role in bone homeostasis, integrating the effects of mechanical and hormonal stimuli on bone. Here, Lilian Plotkin and Teresita Bellido discuss the potential of osteocytic signalling pathways as therapeutic targets to improve bone health and maintain musculoskeletal integrity.

In this Review, Karasik et al. summarize key advances from the past 5 years in understanding the genetics of bone traits and osteoporosis. Despite the wealth of new genetic and genomic information, its application to the clinical management of osteoporosis remains in its infancy. The notable advances made in gene discovery suggest that the next decade will witness cataloguing of hundreds of genes that influence bone mass, which, in turn, will provide a roadmap for the development of new bone-focused drug targets.

Hypophosphatasia — a form of metabolic bone disease characterized by low serum alkaline phosphatase activity — results from loss-of-function mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Here, Michael Whyte discusses the aetiology, nosology, pathogenesis, diagnosis and treatment of hypophosphatasia, which is particularly timely given the recently reported successes and approvals of treating the disease using asfotase alfa, a bone-targeted, recombinant TNSALP.

Bone morphogenetic proteins (BMPs) have been implicated in almost all aspects of bone, cartilage and joint biology. Here, Valerie Salazar and colleagues discuss BMP superfamily signalling in the context of skeletal development and joint morphogenesis, and summarize the status of the BMP pathway as a therapeutic target for treating skeletal trauma and disease.

The bone marrow niche is a unique microenvironment that integrates the physiology of the skeleton and the marrow to maintain the haematopoietic stem cell pool and support whole-organism homeostasis. Reagan and Rosen examine the features of this microenvironment and the consequences of its disruption, particularly in relation to invasion by cancer cells, and discuss how better understanding of the niche could inform treatments for various disorders including skeletal diseases and malignancies.

The skeleton has a central role in the development and regulation of bone metastasis. Here, Larry Suva and colleagues review the skeletal consequences of bone metastasis from an orthopaedic perspective. The authors discuss the effects of existing cancer treatments on bone and the bone marrow microenvironment, as well as the mechanisms mediating these effects and the current utility of modern orthopaedic interventions.

Parathyroid hormone/parathyroid hormone-related peptide receptor (PTHR1) is a family B G-protein-coupled receptor and is involved in the regulation of skeletal development, bone turnover and mineral ion homeostasis. This Review discusses fundamental aspects of ligand-binding and signalling mechanisms at PTHR1, highlighting the relationship between ligand structural modification and variation in PTHR1 signalling responses. The action of these signalling mechanisms in disease states in which PTHR1 function has an important role are also discussed.

Paget's disease is a disorder of bone that manifests in one or several bones and is initiated by osteoclast-induced osteolytic lesions. In addition to a genetic cause, environmental factors, including measles virus, have been proposed to have a role in the pathogenesis of Paget's disease. Here, Frederick R. Singer discusses the present knowledge and controversies surrounding the aetiology of Paget's disease.

In this Review, Joshua Farr and Sundeep Khosla discuss changes in bone architecture during growth, placing an emphasis on skeletal changes at the distal radius, a clinically relevant site of forearm fractures. The implications of these changes for fracture risk in adolescence and later in life, and the architectural changes in bone with ageing that might contribute to increased fracture risk are also discussed.

Osteoporosis is a process operative in almost all individuals past middle age and results in fractures in a large proportion of men and women. In this Review, Ian Reid reflects on the nature of the osteoporotic process and its implications for treatment indications, and considers the pros and cons of available interventions to reduce fracture risk.

This article discusses the many heritable and nonheritable factors contributing to primary osteoporosis, focusing on osteogenesis imperfecta, juvenile osteoporosis and other monogenic disorders associated with increased bone fragility. Understanding these conditions not only illuminates the pathogenesis of osteoporosis, but could also lead to the discovery of new therapeutic targets.

The extracellular calcium-sensing receptor (CaSR) is a G protein-coupled receptor that has a key role in Ca²⁺homeostasis via its role in the parathyroid glands and kidneys. New evidence has shown that CaSR also regulates skeletal homeostasis. In this Review, David Goltzman and Geoffrey Hendy discuss the role of CaSR in chondrocytes and development of the cartilagenous growth plate, in osteoblasts and osteoclasts, and effects of CaSR on skeletal development and bone turnover.

Stromal cells and stem cells have been successfully used for bone-tissue-engineering applications in clinical trials; however, the routine use of these cells is far from being adopted into clinical practice. In this Review, Warren Grayson and colleagues discuss the scientific, technical, practical and regulatory obstacles that are preventing the widespread therapeutic use of stromal cells and stem cells to enhance skeletal repair.

Glucocorticoid therapy is associated with bone loss and increased risk of fracture, but these deleterious effects can be avoided or mitigated with appropriate treatment. When to initiate anti-osteoporosis therapy and what form this preventive therapy should take is the focus of this Review.

In this Review, the authors explore the interactions between obesity, haematopoiesis and the immune system through systemic effects and changes to the primary haematopoietic environment—the bone marrow niche. They also discuss the effects of adipocytes and adiposity on haematopoietic stem cell and progenitor cell populations, with the goal of understanding how obesity might compromise the core haematopoietic system.

In this Review, skeletal ontogeny is compared to fracture healing mechanisms. The authors describe developments in our understanding of the different stages of fracture healing as well as the latest therapies tested in animal models and in clinical trials, focusing on bone morphogenetic proteins or parathyroid hormone based treatments.