Age-related chronic diseases are an enormous burden to modern societies worldwide. Among these, osteoporosis, a condition that predisposes individuals to an increased risk of fractures, substantially contributes to increased mortality and health-care costs in elderly. It is now well accepted that advanced chronical age is one of the main risk factors for chronical diseases. Hence, targeting fundamental aging mechanisms such as senescence has become a promising option in the treatment of these diseases. Moreover, for osteoporosis, the main pathophysiological concepts arise from menopause causing estrogen deficiency, and from aging. Here, we focus on recent advances in the understanding of senescence-related mechanisms contributing to age-related bone loss. Furthermore, treatment options for senile osteoporosis targeting senescent cells are reviewed.
Rheumatoid arthritis (RA), an autoimmune disease, is characterized by the presence of symmetric polyarthritis predominantly of the small joints that leads to severe cartilage and bone destruction. Based on animal and human data, the pathophysiology of osteoporosis, a frequent comorbidity in conjunction with RA, was delineated. Autoimmune inflammatory processes, which lead to a systemic upregulation of inflammatory and osteoclastogenic cytokines, the production of autoantibodies, and Th cell senescence with a presumed disability to control the systemic immune system’s and osteoclastogenic status, may play important roles in the pathophysiology of osteoporosis in RA. Consequently, osteoclast activity increases, osteoblast function decreases and bone metabolic and mechanical properties deteriorate. Although a number of disease-modifying drugs to treat joint inflammation are available, data on the ability of these drugs to prevent fragility fractures are limited. Thus, specific treatment of osteoporosis should be considered in patients with RA and an associated increased risk of fragility fractures.
Metabolic bone disease is a devastating condition in critically ill patients admitted to an intensive care unit (ICU). We investigated the effects of early administration of the antiresorptive drug denosumab on bone metabolism in previously healthy patients. Fourteen patients with severe intracerebral or subarachnoid hemorrhage were included in a phase 2 trial. Within 72 hours after ICU admission, they were randomized in a 1:1 ratio to receive denosumab 60 mg or placebo subcutaneously. The primary endpoint was group differences in the percentage change of C-terminal telopeptide of type 1 collagen (CTX-1) levels in serum from denosumab/placebo application to 4 weeks thereafter. Changes in serum levels of bone formation markers and urinary calcium excretion were secondary outcome parameters. Regarding serum levels of CTX-1, changes over time averaged À0.45 ng/mL (95% confidence interval [CI] À0.72, À0.18) for the denosumab group and 0.29 ng/mL (95% CI À0.01, 0.58) for the placebo group. The primary endpoint, the group difference in changes between baseline and secondary measurement, adjusted for baseline serum levels and baseline neurological status, averaged À0.74 ng/mL (95% CI À1.14, À0.34; p = 0.002). The group difference in changes between baseline and secondary osteocalcin measurement averaged À5.60 ng/mL (95% CI À11.2, À0.04; p = 0.049). The group difference in averaged change between baseline and secondary measurement of 24-hour urine calcium excretion was significant (À1.77 mmol/L [95% CI À3.48, À0.06; p = 0.044]). No adverse events could be attributed to the study medication. The investigation proved that a single application of denosumab early after admission to an ICU prevents acute immobilization-associated increase in bone resorption among previously healthy individuals.
This narrative review focuses on the evolution and history of osteoimmunology, which is a research field that investigates the interactions between bone and components of the immune system. Looking at the evolution of bone, bone development dates back approximately 540 million years. Osteoimmune aspects can also be found in different bone-related diseases like osteoporosis, which is a frequent age-related disease and was first recognized in 1751. Moreover, rheumatoid arthritis is known as the prototype of an osteoimmune disease, which was first clinically described in 1800. A further important component of this field are osteoclasts, a term that was coined by Kölliker in 1873. For the treatment of osteoporosis different therapeutic options are available, among which 2 antibodies (denosumab and romosozumab) were currently approved by the European Medicines Agency in 2010 and 2019, respectively, thus showing the importance of osteoimmunological research for patients’ sake.
By expressing different genes and proteins that regulate osteoclast as well as osteoblast formation, osteocytes orchestrate bone metabolism. The aim of this project was the evaluation of the differences in the osteocytes’ secretory activity in the low bone mass mouse strain C57BL/6J and the high bone mass strain C3H/J. The femura of eight- and sixteen-week-old male C57BL/6J and C3H/J mice—six animals per group—were analyzed. Using immunohistochemistry, osteocytes expressing dickkopf 1, sclerostin, periostin, fibroblast growth factor 23 (FGF23), and osteoprotegerin were detected. By means of the OsteoMeasure-System, 92.173 osteocytes were counted. At the age of eight weeks, approximately twice as many cortical and trabecular osteocytes from the C57BL/6J mice compared to the C3H/J mice expressed dickkopf 1 (p < 0.005). The number of cortical osteocytes expressing sclerostin was also higher in the C57BL/6J mice (p < 0.05). In contrast, the cortical and trabecular osteocytes expressing periostin were twice as high in the C3H/J mice (p < 0.005). The dickkopf 1 expressing osteocytes of the C57BL/6J mice decreased with age and showed a strain-specific difference only in cortical bone by 16 weeks of age (p < 0.05). In the C3H/J mice, the amount of osteocytes expressing periostin tended to increase with age. Thus, strain-related differences were maintained in 16-week-old rodents (p < 0.005). No strain-specific differences in the expression of FGF23 or osteoprotegerin in the cortical compartment could be detected. This experimental study showed that the osteocytes’ protein expression reflects differences in bone characteristics and strain-related differences during skeletal maturation. Besides the osteocytes’ expression of sclerostin, their expression of dickkopf 1 and periostin seems to be important for bone properties as well.
It remains uncertain which skeletal sites and parameters should be analyzed in rodent studies evaluating bone health and disease. In this cross-sectional mouse study using micro-computed tomography (µCT), we explored: (1) which microstructural parameters can be used to discriminate female from male bones and (2) whether it is meaningful to evaluate more than one bone site. Microstructural parameters of the trabecular and/or cortical compartments of the femur, tibia, thoracic and lumbar vertebral bodies, and skull were evaluated by µCT in 10 female and 10 male six-month-old C57BL/6J mice. The trabecular number (TbN) was significantly higher, while the trabecular separation (TbSp) was significantly lower in male compared to female mice at all skeletal sites assessed. Overall, bone volume/tissue volume (BV/TV) was also significantly higher in male vs. female mice (except for the thoracic spine, which did not differ by sex). Most parameters of the cortical bone microstructure did not differ between male and female mice. BV/TV, TbN, and TbSp at the femur, and TbN and TbSp at the tibia and lumbar spine could fully (100%) discriminate female from male bones. Cortical thickness (CtTh) at the femur was the best parameter to detect sex differences in the cortical compartment (AUC = 0.914). In 6-month-old C57BL/6J mice, BV/TV, TbN, and TbSp can be used to distinguish male from female bones. Whenever it is not possible to assess multiple bone sites, we propose to evaluate the bone microstructure of the femur for detecting potential sex differences.
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV2) infection has been associated with musculoskeletal manifestations, including a negative effect on bone health. Bone formation was found to be reduced in coronavirus disease 2019 (COVID‐19) patients. The aim of this case–control study was to determine whether bone metabolism is coupled or uncoupled in COVID‐19 patients with moderately severe disease, the latter expressed by the requirement of hospitalization but not intensive care treatment, no need for mechanical ventilation, and a C‐reactive protein level of (median [quartiles], 16.0 [4.0; 52.8]) mg/L in serum. Besides standard biochemical markers, serum levels of C‐terminal telopeptide of type 1 collagen, tartrate‐resistant acid phosphatase, osteocalcin, bone‐specific alkaline phosphatase, sclerostin, dickkopf‐1, and osteoprotegerin were evaluated in COVID‐19–infected patients at the time of hospital admission, along with those of age‐ and sex‐matched noninfected controls. The median age of the 14 female and 11 male infected patients included in the matched‐pair analysis was (67 [53; 81]) years. C‐terminal telopeptide of type 1 collagen was significantly lower in COVID‐19 patients (0.172 [0.097; 0.375] ng/mL) than in controls (0.462 [0.300; 0.649] ng/mL; p = 0.011). The patients' osteocalcin levels (10.50 [6.49; 16.26] ng/mL) were also lower than those of controls (15.33 [11.85, 19.63] ng/mL, p = 0.025). Serum levels of sclerostin and dickkopf‐1 were significantly higher in infected patients relative to controls. The remaining parameters did not differ between cases and controls. A limitation of the study was that patients and controls were recruited from different hospitals. Nevertheless, due to the geographical proximity of the two centers, we assume that this fact did not influence the results of the study. Given this limitation, the investigation showed that bone metabolism is altered but remains coupled in patients with moderately severe COVID‐19. Therefore, it is important to evaluate bone turnover markers and fracture risk in these patients during the postinfection period. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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