Introduction: Bone loss occurs in the regional bone following tibial shaft fracture. An earlier cross-sectional study showed that measurements made at the metaphyseal region of the tibia using peripheral quantitative computed tomography (pQCT) and the ultradistal region of the tibia using dual-energy X-ray absorptiometry (DXA) were the most responsive at monitoring this bone loss. Biochemical markers of bone turnover enable us to assess the activity of bone formation and resorption during fracture healing. The aim of this longitudinal study was to determine the pattern and distribution of bone loss and bone turnover following a tibial shaft fracture treated with either plaster cast or intramedullary nail. Methods: Eighteen subjects underwent bone mass measurements using DXA at the tibia and hip and quantitative ultrasound (QUS) at the tibia and calcaneus of both limbs at 2 weeks, 8 weeks, 12 weeks and 24 weeks following fracture, with hip and tibia DXA measurements also performed at 52 weeks. Nine of the patients treated with plaster cast had pQCT measurements at the tibia at 24 weeks. We measured three bone formation markers, bone alkaline phosphatase (bone ALP), osteocalcin (OC) and procollagen type 1 N-terminal peptide (PINP), a marker of bone resorption, serum C-telopeptides of type 1 collagen (β-CTX) and a marker of collagen III turnover, procollagen type III N-terminal peptide (PIIINP) at 1 day, 3 days and 7 days and at 2, 4, 8, 12, 16 and 24 weeks following fracture. The greatest bone losses were observed at the ultradistal region of the tibia using DXA (28%, p <0.001) and the metaphyseal region of the tibia using pQCT (26–31%, p <0.001) at 24 weeks. In the hip, the greatest loss was in the trochanter region at 24 weeks (10%, p <0.001). The greatest loss at the calcaneus measured using QUS was for broadband ultrasound attenuation (BUA) measured using CUBA Clinical at 24 weeks (13%, p =0.01). Results: At 1 year, there was a small recovery in bone loss (ultradistal tibia DXA, 20%, p <0.01; trochanter DXA 9%, p <0.001). Bone turnover increased following fracture (PINP +72±21%, p <0.0001, bone ALP +199±22%, p =0.004, β-CTX +105±23%, p <0.0001, all at 24 weeks). There was a smaller +33±10% increase in osteocalcin at 24 weeks. PIIINP concentration peaked at week 8 (+57±9%, p <0.0001). The bone resorption marker β-CTX showed an earlier rise (week 2, 139±33%) than the bone formation markers. Conclusions: We conclude that: (1) bone loss following tibial shaft fracture occurs both proximal and distal to the fracture; (2) the decreased BMD is largest for trabecular bone in the tibia with similar measurements using DXA and pQCT; (3) there is limited recovery of bone lost at the hip and tibia at 1 year; (4) tibial speed of sound (SOS) demonstrated a greater decrease than calcaneal SOS when comparing z -scores; (5) BUA is the QUS variable that shows the biggest decrease of bone mass at the calcaneus; (6) increase in bone turnover occurs following fracture with an earlier increase in bone resorption markers and a later rise in bone formation markers.