Duchenne muscular dystrophy (DMD) is caused by dystrophin loss-of-function mutations, which impairs skeletal muscle and bone by mechanisms that are not fully understood. DMD patients exhibit high fracture rates, with 75% fracturing at 15yrs. Currently in DMD, muscle and bone are treated separately, as investigations focus on individual tissue type. Our goals are to examine if the musculoskeletal defect occurs simultaneously in both tissues and to understand the bone cellular mechanisms underlying the lifelong DMD-bone disease. Towards this end, 3mo mice lacking functional dystrophin (MDX) and WT (N=15) mice, underwent longitudinal in vivo muscle function testing and DXA from 3-8mo with endpoint ex vivo µCT, histology, and bone mechanical testing. For MDX muscle, in vivo plantarflexion testing detected decreased muscle strength (low plantarflexion torque, contraction energy, and muscle power) with dysfunctional increases in the time to contract (4mo 75-300Hz; 5-8mo 25-300Hz). Lean body mass, an index of muscle mass, was increased from 3-8mo without changing body weight, a known DMD hallmark of fibrotic infiltration in muscle. MDX muscle weights (TA, quadriceps, soleus) were markedly increased at 8mo. For bone, total bone mineral density was lower in MDX mice from 3-8mo. Cancellous bone was low and thinner in 3 and 8mo MDX vertebrae. MDX cortical bone was also low in 8mo femurs with increased marrow area and endocortical perimeter. MDX femurs permanently damaged and fractured with less force and energy than WTs’, as failure force, yield force, energy to yield, and toughness were all decreased by 3pt. bending mechanical testing. Bone resorption marker CTX was elevated, and bone formation marker P1NP was decreased in MDX sera. Von Kossa-stained MDX vertebrae showed decreased osteoblast number and low osteoid volume. To understand the MDX cellular mechanisms leading to the loss of osteoblasts and bone formation, scRNA-seq was performed on pooled cellular populations isolated from 5mo WT and MDX bones (N=2). MDX showed increases in adipoq-CAR (24 vs 28.5%) and osteo-CAR (14.7 vs 17%) cells with decreases in osteoblastic (17 vs 5.2%) cellular populations, suggesting halted osteoblastic-lineage differentiation. These findings show that DMD impairment of muscle and bone occurs simultaneously in vivo and report osteoblastic cellular population shifts as a mechanism underlying the DMD bone pathophysiology.