: Macrophages are present in nearly all tissues and are critical for development, homeostasis, and regeneration. Resident tissue macrophages of bone, termed osteal macrophages, are recently classified myeloid cells that are distinct from osteoclasts. Osteal macrophages are located immediately adjacent to osteoblasts, regulate bone formation, and play diverse roles in skeletal homeostasis. Genetic or pharmacological modulation of macrophages in vivo results in significant bone phenotypes, and these phenotypes depend on which macrophage subsets are altered. Macrophages are also key mediators of osseous wound healing and fracture repair, with distinct roles at various stages of the repair process. A central function of macrophages is their phagocytic ability. Each day, billions of cells die in the body and efferocytosis (phagocytosis of apoptotic cells) is a critical process in both clearing dead cells and recruitment of replacement progenitor cells to maintain homeostasis. Recent data suggest a role for efferocytosis in bone biology and these new mechanisms are outlined. Finally, although macrophages have an established role in primary tumors, emerging evidence suggests that macrophages in bone support cancers which preferentially metastasize to the skeleton. Collectively, this developing area of osteoimmunology raises new questions and promises to provide novel insights into pathophysiologic conditions as well as therapeutic and regenerative approaches vital for skeletal health. © 2015 American Society for Bone and Mineral Research.

Intermittent administration of teriparatide, a drug composed of the first 34 amino acids of parathyroid hormone, has anabolic effects on bone. Although teriparatide has been evaluated for the treatment of osteoporosis and for the healing of fractures, clinical trials evaluating it for the treatment of osseous conditions of the oral cavity in humans are lacking. A total of 40 patients with severe, chronic periodontitis underwent periodontal surgery and received daily injections of teriparatide (20 μg) or placebo, along with oral calcium (1000 mg) and vitamin D (800 IU) supplementation, for 6 weeks. The patients were followed for 1 year. The primary outcome was a radiographic linear measurement of alveolar bone level. Secondary outcomes included clinical variables, bone turnover markers in serum and oral fluid, systemic bone mineral density, and quality of life. Radiographic linear resolution of osseous defects was significantly greater after teriparatide therapy than after placebo beginning at 6 months, with a mean linear gain in bone at 1 year of 29% as compared with 3% (P<0.001). Clinical improvement was greater in patients taking teriparatide than in those taking placebo, with a reduction in periodontal probing depth of 33% versus 20% (2.42 mm vs. 1.32 mm) and a gain in clinical attachment level of 22% versus 7% (1.58 mm vs. 0.42 mm) in target lesions at 1 year (P=0.02 for both comparisons). No serious adverse events were reported; however, the number of patients in the study was small. No significant differences were noted with respect to the other variables that were assessed. Teriparatide, as compared with placebo, was associated with improved clinical outcomes, greater resolution of alveolar bone defects, and accelerated osseous wound healing in the oral cavity. Teriparatide may offer therapeutic potential for localized bone defects in the jaw. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00277706.)

Significance: Cellular subpopulations in the bone marrow play distinct and unexplored functions in the regulation of the skeleton. A type of blood cell that resides in the bone marrow termed “osteal macrophage” was found to play a role in bone homeostasis by supporting bone formation and mediating parathyroid hormone-dependent bone regeneration. Furthermore, induction of cell death in mature macrophages activated the specialized process of efferocytosis (clearance of dead and dying cells), leading to a marrow microenvironment that supported bone formation.

Twenty-five years ago a “new” protein was identified from cancers that caused hypercalcemia. It was credited for its ability to mimic parathyroid hormone (PTH), and hence was termed parathyroid hormone-related protein (PTHrP). Today it is recognized for its widespread distribution, its endocrine, paracrine, and intracrine modes of action driving numerous physiologic and pathologic conditions, and its central role in organogenesis. The multiple biological activities within a complex molecule with paracrine modulation of adjacent target cells present boundless possibilities. The protein structure of PTHrP has been traced, dissected, and deleted comprehensively and conditionally, yet numerous questions lurk in its past that will carry into the future. Issues of the variable segments of the protein, including the enigmatic nuclear localization sequence, are only recently being clarified. Aspects of PTHrP production and action in the menacing condition of cancer are emerging as dichotomies that may represent intended temporal actions of PTHrP. Relative to PTH, the hormone regulating calcium homeostasis, PTHrP “controls the show” locally at the PTH/PTHrP receptor throughout the body. Great strides have been made in our understanding of PTHrP actions, yet years of exciting investigation and discovery are imminent. © 2012 American Society for Bone and Mineral Research.