Daily subcutaneous Teriparatide injection increased bone mineral density of newly formed bone after tibia distraction osteogenesis, a randomized study

Highlights

• We present a randomized prospective trial investigating the effect of Teriparatide on bone formation in patients undergoing tibia bone transport.

• The study population was young patients with tibia bone defect after tibia osteomyelitis.

• Teriparatide doubled the mineralisation rate of the bone formed after distraction osteogenesis with the Ilizarov method.

Abstract

Long bone defects are often treated by bone segment transport with the Ilizarov method requiring months spent with fixator mounted until bony consolidation of the newly formed bone. Shortening of consolidation would allow earlier fixator removal and earlier return to work. In pre-clinical studies parathyroid hormone, increased bone mineral density and mechanical properties of regenerate bone formed during distraction osteogenesis. Clinical studies showed that Teriparatide accelerated fracture healing in patients with osteoporotic fracture of the pelvis, hip, wrist and shoulder. We hypothesized that rhPTH(1-34) (Teriparatide) administered to patients who had undergone distraction osteogenesis, would increase mineralization of the regenerate formed during the consolidation phase.

Sixteen patients with tibial defects after infection, underwent bone segment transport and at the time of docking the transport segment, were randomized to 8 weeks treatment with daily subcutaneous 0.20-μg Teriparatide injection followed by 8 weeks with no treatment, or to 8 weeks with no treatment followed by 8 weeks with daily subcutaneous 0.20 μg Teriparatide injection. Bone mineral density (BMD) of the regenerate was measured at the time of docking, 8 weeks after docking and 16 weeks after docking with DEXA. Functional evaluation was performed after one year. The design was a cross-over study.

Overall BMD increased 0.14 g/cm² in 8 weeks without treatment and 0.33 g/cm² under Teriparatide treatment. After adjustment for a potential phase difference, 8 weeks of Teriparatide treatment led to an additional 0.19 g/cm² BMD increase (95%-CI:[0.11,0.28], p < 0.001). The ratio of the BMD increase between the two treatments was 0.33/0.14 = 2.43 (CI: [1.21,3.65]).

Teriparatide treatment during the consolidation phase of distraction osteogenesis doubled the mineralization rate of the regenerate when compared to no treatment.

Introduction

Bone loss after tumor or infection is often treated by bone segment transport, a process where long bones, stabilized by an external or internal fixator, are first osteotomized and then lengthened at a rate of 0.5 mm–1 mm each day. The metaphysis is osteotomized and a controlled series of micro fractures through the callus of the osteotomy gap followed by distraction of the gap produces competent bone with properties identical to parent bone [1]. After lengthening is completed, consolidation of the newly formed bone requires continuation of external or internal fixation until the bone can be fully loaded. On average the adult patient spends 35 days with the bone stabilized in a fixator for every 1 cm elongation [2]. I.e. 10 cm of lengthening requires 100 days of lengthening and 250 days of consolidation, thus almost one year of fixation. Shortening the consolidation phase by even one month would reduce patient morbidity, increase patient satisfaction and allow earlier return to work.

Teriparatide (rhPTH(1-34)) is the active fragment (1-34) of endogenous human parathyroid hormone (1-84)(PTH). Once-daily administration of PTH increases apposition of new bone on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. In an experimental femoral bone lengthening model in rats, PTH increased callus size and strength [3], and in an experimental tibia lengthening model in rabbits PTH increased biomechanical properties, bone mineral content and callus size [4]. In a more recent and similar study, biomechanical properties of the regenerate increased more rapidly in rabbits receiving intermittent PTH, and after 10 weeks there was no longer any difference between the control group and the PTH treated group [5]. There are no human studies investigating the effects of PTH treatment during bone lengthening. We are aware of 11 controlled clinical studies investigating the effect of Teriparatide on fracture healing after osteoporotic fracture. There were 2 pelvic fracture studies, 2 spine, 3 proximal femur, 1 distal femur, 2 wrist and 1 shoulder fracture study. In all studies, daily subcutaneous injections of 20 μg Teriparatide was used except in one study where daily injections of 20 μg were compared to 40 μg injections. Duration of the therapy was 4 weeks to 11 months. In all but one study, Teriparatide either increased fracture healing, reduced pain or improved functional performance [6]. Teriparatide (rhPTH(1-34)) is registered in all EU countries for the prevention of osteoporosis in postmenopausal women and in men, but its use to accelerate fracture healing still is experimental. We hypothesized that Teriparatide treatment of patients undergoing bone lengthening of the tibia after infection would lead to increased bone mineralization in the zone of newly formed bone during the consolidation phase of distraction osteogenesis.