Distraction osteogenesis is a powerful stimulus for new bone (and tissue) generation (anabolism). Biomechanical stimulation by distraction of the regenerate region results in a high rate of tissue and bone production. However, catabolism (bone resorption) can also occur, the process potentially accentuated in a stress-shielded environment of an external fixator. Regenerate insufficiency can result in regenerate bending or fracture after frame removal. Experimental evidence has demonstrated that bisphosphonates may mediate improved local limb bone mineral density (BMD) and regenerate strength in animal models. Seven patients who had undergone limb lengthening using an Ilizarov device were found to have regenerate insufficiency. Poor regenerate quality led to consideration for intervention. With informed consent, patients received a therapeutic regime of intravenous pamidronate (n = 3) or zoledronic acid (n = 4).The mean age was 13.8 years (SD, +/-3.6 years), with a minimum follow-up period of 4 months after fixator removal. The sites of regenerate insufficiency were the proximal tibia (n = 6) and the distal femur (n = 1). The mean time interval in the fixator before bisphosphonate treatment was 170 days (range, 124-252 days), with an average length increase of 4.8 cm (SD, +/-1.1 cm). At time of intravenous bisphosphonate treatment, dual-energy x-ray absorptiometry measurements demonstrated a reduced BMD (mean, 62.1%; SD, +/-12.6%) in the bone adjacent to the lengthening site of the nonoperated side. Mean healing index was high at 79.6 days/cm (range, 64.4-108.0 days/cm), reflecting the observed regenerate insufficiency. No significant systemic complications were encountered. Six of the patient's fixators were removed without requirement for other intervention, demonstrating a rapid and sustained improvement in local BMD, increasing to a mean of 85.6% (SD, +/-13.3%) of the healthy side. One patient did not respond and subsequently healed after percutaneous osteogenic protein 1 (bone morphogenetic protein 7) and bone marrow injection. Most failed regenerate cases maintain some underlying anabolic activity and can be treated successfully with bisphosphonate therapy, which reduces catabolism. Only 1 case required percutaneous administration of an anabolic therapy to achieve union. These minimally invasive approaches may lessen the need for surgery in a group where significant surgical reintervention could otherwise be required.