Publications

As human space exploration advances, understanding how different gravity levels affect skeletal muscle is critical for long-term health. Among the major organ systems, skeletal muscle is particularly sensitive to gravitational unloading, yet the gravity threshold required to maintain homeostasis remains unclear. Using the Multiple Artificial-gravity Research System aboard the International Space Station, mice were exposed to graded gravity levels, microgravity, 0.33g, 0.67g, and 1g, and their muscles were analyzed postflight. In the gravity-sensitive soleus, the cross-sectional area was preserved at 0.33g, while the slow-to-fast myofiber transition was partially suppressed at 0.33g and fully prevented at 0.67g. Functional measures, including forelimb grip strength and electrical impedance myography, indicated that 0.67g was sufficient to maintain muscle performance. Plasma metabolomics identified 11 metabolites with gravity-dependent changes, suggesting potential biomarkers for monitoring physiological adaptation. Collectively, these results identify 0.67g as a critical threshold for mitigating spaceflight-induced muscle atrophy and myofiber type transitions.

Bone density and microarchitecture measurements from high-resolution peripheral computed tomography (HR-pQCT) are increasingly being used to predict fracture risk and to gain insight into the pathophysiology of skeletal fragility. Using the first-generation HR-pQCT scanner, we previously showed that extraosseous soft tissue can impact HR-pQCT measurements. Yet similar data is not available for the second-generation scanner. Thus, we aimed to determine the impact of increased soft tissue on bone density, microarchitecture and strength measurements acquired using the second-generation HR-pQCT scanner. We performed HR-pQCT scans on a hydroxyapatite phantom and in human volunteers (n = 12) with no soft tissue covering, and with a thin (0.5 cm) and thick (1 cm) layer of soft tissue surrounding the phantom or limb. We found that density values of the phantom were minimally affected by the thin layer of soft tissue. In contrast, with the thick (1 cm) layer of soft-tissue, bone density was significantly lower than baseline (no bolus), with greater deficits as the density of the rod increased (-1% to -3.6%, p < 0.01 for all). In human volunteers, soft tissue layering influenced measures of both cortical and trabecular microarchitecture at the distal tibia and radius, with larger differences observed in trabecular versus cortical measures and at the tibia compared to the radius. For example, at the tibia, Tt.BMD was lower than the baseline scan under both soft tissue layering conditions (thin: -1.3%, p < 0.001; thick: -2.4%, p = 0.003), while at the radius Tt.BMD was only significantly lower for the thick layer (-1.2%, p = 0.004). Ct.BMD followed a similar pattern, with slightly greater magnitude of BMD decline with increased soft tissue (thin: -1.5%, p < 0.001, thick -2.8%, p < 0.001 at the tibia) compared to Tt.BMD. Altogether our results indicate that HR-pQCT measurements at both the metaphyseal and diaphyseal sites must be interpreted carefully when comparing subjects with varying body composition, or when assessing longitudinal changes in individuals who experience marked changes in weight and/or body composition as true differences to these measures may be more or less extreme than they appear.

Dedicator of Cytokinesis 7 (DOCK7) has recently emerged as a regulator of skeletal homeostasis, but existing Dock7 mutant models harbor only global mutations and are incompatible with tissue-specific deletion studies. We previously generated a Dock7-floxed allele in which exons 3-4 are flanked by LoxP sites. To validate the utility of this allele for future conditional strategies, we globally deleted exons 3-4 to generate Dock7 em2/em2 mice and characterized their skeletal phenotype. Dock7 em2/em2 mice exhibited a diluted coat color and white belly spot, consistent with spontaneous Dock7 mutations. Bone microarchitecture was assessed in 21-week-old males and females. Global deletion of Dock7 exons 3-4 resulted in a 30-37% reduction in trabecular bone volume in the distal femur and L5 vertebrae. Cortical bone thickness was unchanged in both sexes; however, male Dock7 em2/em2 mice displayed reduced total femoral area, whereas females showed increased medullary area. These data suggest altered appositional bone growth with mutation of Dock7. To assess osteoblast function, bone marrow stromal cells (BMSCs) were differentiated in vitro. Dock7 em2/em2 BMSCs exhibited reduced mineralization and decreased Bglap expression, indicating attenuated osteoblast differentiation. These findings demonstrate that Dock7 exons 3-4 are required for normal trabecular bone acquisition and osteoblast function. Loss of these exons disrupts DOCK7 activity, supporting the Dock7 em2/em2 line as a valid loss-of-function model. The Dock7 em2/em2 mouse provides a foundation for future tissue-specific deletion studies to define the cellular roles of DOCK7 in regulating bone formation and trabecular architecture.

PURPOSE: This study investigated the effect of bone metastasis on the biomechanical environment of human vertebrae in patients with metastatic spine disease through the metric of load-to-strength ratio (LSR). Specifically, we compared the patients' LSRs to age and sex-similar noncancer controls from the Framingham Heart Study.

METHODS: Derived from clinical CT data of 135 metastatic spine disease patients planned for radiotherapy and 246 normative controls from the Framingham Heart Study, individualized spinal musculoskeletal models and vertebral strength estimates were used to compute level-specific LSR under natural standing and three weight-holding conditions (standing + weight, flexion + weight, and lateral bending + weight).

RESULTS: Adjusted for age, BMI, and spinal region, osteosclerotic and mixed lesion vertebrae had higher strength than osteolytic and control vertebrae. The musculoskeletal models suggested breast, prostate, and male lung cancer patients had higher compressive vertebral loading, and female lung cancer patients had lower compressive vertebral loading than controls. Male patients had higher standardized LSRs in natural standing, while female patients had lower LSRs for all activities than controls. Independent of sex, vertebrae with osteosclerotic and mixed bone metastasis had lower LSRs than controls, while, for osteolytic bone lesions, males had higher and females lower LSRs than controls. Vertebrae with no observed lesion on CT had higher LSRs than controls in males and lower LSRs in females.

DISCUSSION: Our findings highlighted that primary cancer and lesion type differentially affected task-specific vertebral loading and strength, thus modifying the vertebral LSRs. Sex-mediated differences in LSRs between FHS controls and vertebrae with no observed metastatic lesions suggest that considering the latter as "normal" should be taken with care. Our initial assessment supports further examination of whether vertebral LSR measurements are associated with vertebral risk and, if so, what threshold values indicate risk.

LEVEL OF EVIDENCE: 3.

Both bone and muscle function decline with age and are anatomically and functionally related. However, whether and to what extent muscle function (ie, strength and power) may predict longitudinal changes in bone microarchitecture and strength is unclear. The Osteoporotic Fractures in Men (MrOS) Study included assessments of peak jump power (W) from a force plate and maximum grip strength (kg) from a dynamometer, both normalized to body weight at Visit 4 (2014-2016). We investigated associations of jump power and grip strength with annual % change in volumetric bone mineral density (BMD), microarchitecture, and strength at the distal tibia (DT) and radius (DR) from high-resolution peripheral quantitative computed tomography (HR-pQCT) between Visit 4 and Visit 5 (2020-2022; 6.2 ± 0.6 yr follow-up; N = 225; age 82.8 ± 3.0 yr; 89% White). Mean jump power was 22.9 ± 5.6 W/kg and grip strength was 0.49 ± 0.1 kg/kg. During follow-up (median[IQR]), failure load (-0.88[-1.71,-0.31]%), total BMD (-0.57[-1.12,-0.18]%), cortical BMD (-1.24[-2.03,-0.67]%), trabecular BMD (-0.05[-0.47,0.20]%), and trabecular thickness (-0.37[-0.64,-0.12]%) declined at the DT, while at the DR, failure load (-1.02[-2.19,-0.04]%), total BMD (-0.64[-1.20,-0.18]%), and cortical BMD (-1.38[-2.15,-0.71]%) declined (all p ≤ .05). Significant increases were observed for total area at both skeletal sites (DT: 0.04[0.01,0.08]%; DR: 0.07[-0.06,0.16]%; both p ≤ .05). Multivariable linear regression models were adjusted for age, White race, clinic site, respective HR-pQCT initial values, % weight change, alcohol consumption, medication count, chronic disease history, falls, and hip pain. Higher grip strength was significantly associated with a smaller %/year increase in total area at the DT (p ≤ .05) but not at the DR. Neither jump power nor grip strength were associated with change in failure load, BMD, or trabecular thickness at either skeletal site. Associations between grip strength and changes in tibial bone geometry provide insight into potential mechanisms for bone loss and targets for musculoskeletal interventions to reduce fracture risk.

Current fracture risk assessment does not directly include fall probability, despite most hip fractures resulting from falls. Additionally, the role of trochanteric soft tissue thickness (TST) in hip fracture risk remains unclear. This study aimed to develop a subject-specific fall risk tool and test whether incorporating fall probability and TST improves hip fracture prediction beyond FRAX alone in older adults from the AGES-Reykjavik study. Baseline data from 3242 individuals (58% women) were used to predict repeated falls (≥2 in 12 months) at follow-up ( 5 years later) via multivariate logistic regression, considering age, sex, fall history, neuromuscular function, dynamic balance, and medication use. In a case-cohort study (698 hip fractures, 1348 controls; median follow-up 10 years), Cox proportional hazards models assessed hip fracture risk. We compared the predictive value of fall probability and TST combined with FRAX against FRAX alone using time-dependent AUC at 5-, 10-, and 16-year follow-up. At follow-up, 295 individuals had ≥2 falls in the past year. The best model for future falls included a timed up-and-go test, fall history, and grip strength. The probability of falling predicted incident hip fracture and improved hip fracture prediction beyond FRAX, in both men and women. The improved predictive value of fall risk was greater among men than women (e.g. AUC for predicting 10 yrs hip fracture risk, 0.83 (95%CI 0.79-0.87) in men vs 0.75 (95%CI 0.72-0.78) in women). Lower TST was linked to higher hip fracture risk in women but not men. However, adding TST to a model with fall probability and FRAX among women did not enhance time-dependent AUC (p>0.10). In conclusion, fall probability significantly improves hip fracture prediction beyond FRAX, particularly in men. Thus, subject-specific fall risk assessment may enhance clinical evaluation of hip fracture risk in older adults.

CONTEXT: Preclinical studies demonstrate that treatment with calcitriol attenuates skeletal complications in mice with X-linked hypophosphatemia (XLH).

OBJECTIVE: To assess serum markers of mineral metabolism, nephrocalcinosis, skeletal microarchitecture, growth, and evidence of rickets following calcitriol monotherapy in children and adults with XLH.

DESIGN: A 1-year prospective single-arm open-label study comparing baseline and 12-month outcomes.

SETTING: Participants were recruited from outpatient endocrinology clinics in the United States. Data were collected in a research unit.

PARTICIPANTS: Eligible participants were ≥ 4 years old, not pregnant, with baseline 25-hydroxyvitamin D ≥20 ng/mL and normal serum calcium.

INTERVENTION: Participants were treated with calcitriol, with dose based on serum and urinary calcium concentrations, for 1 year.

MAIN OUTCOME MEASURES: The primary endpoints were change in serum phosphate and nephrocalcinosis (all participants) and rickets severity score (children). Secondary endpoints included changes in additional markers of mineral metabolism, skeletal microarchitecture parameters via high-resolution peripheral quantitative computed tomography (all participants), and height z-scores (children).

RESULTS: Serum phosphate did not change over 12 months of optimized calcitriol treatment. Rickets improved in 2 of 4 children with open epiphyses; height z-scores were unchanged. Nephrocalcinosis scores remained stable. Adults had increased cortical thickness at the radius diaphysis (p=0.012). Serum alkaline phosphatase decreased in children (p=0.021) and parathyroid hormone trended lower in both children (p=0.065) and adults (p=0.063). 4 participants developed mild hypercalcemia and 2 developed hypercalciuria which resolved with calcitriol titration.

CONCLUSIONS: Calcitriol monotherapy is safe and well-tolerated in XLH, with modest benefits on laboratory indices of mineral metabolism and rickets.