Bone manifestations are frequent in Gaucher disease (GD), the most prevalent lysosomal storage disorder. Currently, therapy with enzyme replacement (ERT) or substrate reduction (SRT) is available. We investigated changes of laboratory parameters associated with bone metabolism in GD patients switching from ERT to SRT. Seven GD patients consecutively treated with ERT and SRT were studied. All patients had different degrees of bone involvement. Laboratory results were acquired at the time of change from ERT to SRT (0 months) and while on SRT (6 months, 12–18 months). Markers of GD activity remained stable or showed statistically insignificant increases. Six patients had stable skeletal manifestations and reported no bone-associated symptoms. One patient presented progressive bone manifestations on magnetic resonance imaging and experienced increasing bone pain. Osteocalcin, alkaline phosphatase, and C-terminal telopeptide of collagen I were initially within the lower part of the normal range and decreased during SRT (alkaline phosphatase P = 0.0169, osteocalcin nonsignificant, C-terminal telopeptide of collagen I nonsignificant). Tartrate-resistant acid phosphatase 5b was initially normal or slightly increased, and macrophage colony-stimulating factor was within the normal lower range; both parameters remained stable. Interleukin-6 was elevated only in the patient with progressive bone disease. Macrophage inflammatory protein 1α (MIP-1α) was elevated without change after switching to SRT. MIP-1β was within the normal range, and no values were above 85 ng/mL, indicative of active skeletal disease. From a clinical and metabolic point of view, most skeletal manifestations and bone-associated laboratory parameters remain stable after switch from ERT to SRT.