Introduction The effects of caloric restriction (CR) on the skeleton are well studied in adult rodents, and include lower cortical bone mass but higher trabecular bone volume. Much less is known about how CR affects bone mass in young, rapidly growing animals. This is an important problem because low caloric intake during skeletal acquisition in humans, as in anorexia nervosa, is associated with low bone mass, increased fracture risk, and osteoporosis in adulthood. To explore this question, we tested the effect of caloric restriction on bone mass and microarchitecture during rapid skeletal growth in young mice. Methods At 3 wks of age we weaned male C57Bl/6J mice onto 30% caloric restriction (CR, 10% Kcal/fat) or normal diet (N, 10% Kcal/fat). Outcomes at 6 (N=4/group) and 12 wks of age (N=8/group) included body mass, femur length, serum leptin and IGF-1, whole body bone mineral density (WBBMD, g/cm2), cortical and trabecular bone architecture at the midshaft and distal femur, bone formation and cellularity, and marrow fat measurement. Results Compared to N, CR mice had 52% and 88% lower serum leptin and 33% and 39% lower serum IGF-1 at 6 and 12 wks of age (p<0.05 for all). CR mice were smaller, with lower bone mineral density, trabecular and cortical bone properties. Bone formation indices were lower, while bone resorption indices were higher (p<0.01 for all) in CR vs. N. Despite having lower %body fat, bone marrow adiposity was dramatically elevated in CR vs. N (p<0.05). Conclusion Caloric restriction in young, growing mice is associated with impaired skeletal acquisition, low leptin and IGF-1 levels, and high marrow adiposity. These results support the hypothesis that caloric restriction during rapid skeletal growth is deleterious to cortical and trabecular bone mass and architecture, in contrast to potential skeletal benefits of CR in aging animals.

How reliable are reconstructions of body mass and joint function based on articular surface areas? While the dynamic relationship between mechanical loading and cross-sectional geometry in long bones is well-established, the effect of loading on the subchondral articular surface area of epiphyses (hereafter, articular surface area, or ASA) has not been experimentally tested. The degree to which ASA can change in size and shape is important, because articular dimensions are frequently used to estimate body mass and positional behavior in fossil species. This study tests the hypothesis that mechanical loading influences ASA by comparing epiphyses of exercised and sedentary sheep from three age categories: juvenile, subadult, and adult (n = 44). ASA was measured on latex molds of subchondral articular surfaces of 10 epiphyses from each sheep. Areas were standardized by body mass, and compared to diaphyseal cross-sectional geometrical data. Nonparametric statistical comparisons of exercised and control individuals found no increases in ASA in response to mechanical loading in any age group. In contrast, significant differences in diaphyseal cross-sectional geometry were detected between exercised and control groups, but mostly in juveniles. The conservatism of ASA supports the hypothesis that ASA is ontogenetically constrained, and related to locomotor behavior at the species level and to body mass at the individual level, while variations in diaphyseal cross-sectional geometry are more appropriate proxies for individual variations in activity level.

SUMMARY Wolff's law of trajectorial orientation proposes that trabecular struts align with the orientation of dominant compressive loads within a joint. Although widely considered in skeletal biology, Wolff's law has never been experimentally tested while controlling for ontogenetic stage, activity level,and species differences, all factors that may affect trabecular bone growth. Here we report an experimental test of Wolff's law using a within-species design in age-matched subjects experiencing physiologically normal levels of bone strain. Two age-matched groups of juvenile guinea fowl Numida meleagris ran on a treadmill set at either 0° (Level group) or 20° (Incline group), for 10 min per day over a 45-day treatment period. Birds running on the 20° inclined treadmill used more-flexed knees than those in the Level group at midstance (the point of peak ground reaction force). This difference in joint posture enabled us to test the sensitivity of trabecular alignment to altered load orientation in the knee. Using a new radon transform-based method for measuring trabecular orientation, our analysis shows that the fine trabecular bone in the distal femur has a high degree of correspondence between changes in joint angle and trabecular orientation. The sensitivity of this response supports the prediction that trabecular bone adapts dynamically to the orientation of peak compressive forces.

Obesity and osteoporosis are two of the most common chronic disorders of the 21st century. Both are accompanied by significant morbidity. The only place in the mammalian organism where bone and fat lie adjacent to each other is in the bone marrow. Marrow adipose tissue is a dynamic depot that likely exists as both constitutive and regulated compartments. Adipocytes secrete cytokines and adipokines that either stimulate or inhibit adjacent osteoblasts. The relationship of marrow adipose to other fat depots is complex and may play very distinct roles in modulating metabolic homeostasis, hematopoiesis and osteogenesis. Understanding the relationship between bone and fat cells that arise from the same progenitor within the ‘niche’ provides insight into the pathophysiology of age-related osteoporosis, diabetes mellitus and obesity.

PurposeIndividuals with cerebral palsy (CP) are at increased risk for frailty and chronic disease due to factors experienced throughout the lifespan, such as excessive sedentary behaviors and malnutrition. However, little is known about noncommunicable diseases (NCDs) and multimorbidity profiles in young adults with CP. The study objective was to compare NCD and multimorbidity profiles between young adults with and without CP.MethodsA clinic-based sample of adults (18–30 years) with (n=452) and without (n=448) CP was examined at the University of Michigan Medical Center. The prevalence and predictors of 13 NCDs were evaluated, including existing diagnoses or historical record of musculoskeletal, cardiometabolic, and pulmonary morbidities. The level of motor impairment was determined by the Gross Motor Function Classification System (GMFCS) and stratified by less vs more severe motor impairment (GMFCS I–III vs IV–V). Logistic regression was used to determine the odds of NCD morbidity and multimorbidity in adults with CP compared to adults without CP, and for GMFCS IV–V compared to GMFCS I–III in those with CP, after adjusting for age, sex, body mass index, and smoking.ResultsAdults with CP had a higher prevalence of osteopenia, osteoporosis, hypertension, myocardial infarction, hyperlipidemia, asthma, and multimorbidity compared to adults without CP, and higher odds of musculoskeletal (odds ratio [OR]: 6.97) and cardiometabolic morbidity (OR: 1.98), and multimorbidity (OR: 2.67). Adults with CP with GMFCS levels IV–V had a higher prevalence of osteopenia/osteoporosis, osteoarthritis, hypertension, other cardiovascular conditions, pulmonary embolism, and multimorbidity, and higher odds of musculoskeletal (OR: 3.41), cardiometabolic (OR: 2.05), pulmonary morbidity (OR: 1.42), and multimorbidity (OR: 3.45) compared to GMFCS I–III.ConclusionYoung adults with CP have a higher prevalence of chronic NCDs and multimorbidity compared to young adults without CP, which is pronounced in those with more severe motor impairment. These findings reiterate the importance of early screening for prevention of NCDs in CP.

Emerging evidence points to a critical role for the skeleton in several homeostatic processes including energy balance. The connection between fuel utilization and skeletal remodeling begins in the bone marrow with lineage allocation of mesenchymal stromal cells into adipocytes or osteoblasts. Mature bone cells secrete factors that influence insulin sensitivity and fat cells synthesize cytokines that regulate osteoblast differentiation. The emerging importance of the bone-fat interaction suggests that novel molecules could be used as targets to enhance bone formation and possibly prevent fractures. In this review, we discuss three pathways that could favor pharmacologic intervention with the ultimate goal of enhancing bone mass and reducing osteoporotic fracture risk. Not surprisingly, because of the complex interactions across homeostatic networks, other pathways will likely be activated by this targeting and these could prove to be beneficial or detrimental for the organism. Hence a more complete picture of energy utilization and skeletal remodeling will be required to bring these potential agents into any future clinical armamentarium.

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