Recurrent Proximal Femur Fractures in a Teenager With Osteogenesis Imperfecta on Continuous Bisphosphonate Therapy: Are We Overtreating?

Abstract

Long-term bisphosphonate (BP) therapy in adults with osteoporosis is associated with atypical femoral fractures, caused by increased material bone density and prolonged suppression of bone remodeling which may reduce fracture toughness. In children with osteogenesis imperfecta (OI), long-term intravenous BP therapy improves bone structure and mass without further increasing the already hypermineralized bone matrix, and is generally regarded as safe. Here we report a teenage girl with OI type IV, who was started on cyclical intravenous pamidronate therapy at age 6 years because of recurrent fractures. Transiliac bone biopsy revealed classical structural features of OI but unusually low bone resorption surfaces. She made substantial improvements in functional ability, bone mass, and fracture rate. However, after 5 years of pamidronate therapy she started to develop recurrent, bilateral, nontraumatic, and proximal femur fractures, which satisfied the case definition for atypical femur fractures. Some fractures were preceded by periosteal reactions and prodromal pain. Pamidronate was discontinued after 7 years of therapy, following which she sustained two further nontraumatic femur fractures, and continued to show delayed tibial osteotomy healing. Despite rodding surgery, and very much in contrast to her affected, untreated, and normally mobile mother, she remains wheelchair-dependent. The case of this girl raises questions about the long-term safety of BP therapy in some children, in particular about the risk of oversuppressed bone remodeling with the potential for microcrack accumulation, delayed healing, and increased stiffness. The principal concern is whether there is point at which benefit from BP therapy could turn into harm, where fracture risk increases again. This case should stimulate debate whether current adult atypical femoral fracture guidance should apply to children, and whether low-frequency, low-dose cyclical, intermittent, or oral treatment maintenance regimens should be considered on a case-by-case basis.

BPS804 Anti-Sclerostin Antibody in Adults With Moderate Osteogenesis Imperfecta: Results of a Randomized Phase 2a Trial

“…However, it is still unclear whether the effects of bisphosphonates on bone metabolism are favorable for bone regeneration and bone material properties on a molecular level, particularly when considering the need for long‐term treatment regimens. Furthermore, the apparent significant decrease in the incidence of fractures associated with bisphosphonates remains a matter of debate . Hence, the bone‐remodeling‐based concept of anti‐sclerostin treatment may provide a promising approach to cover relevant treatment periods as part of a long‐term medication strategy that enables phases of bone regeneration and formation.…”

Elevated platelet counts in a cohort of children with moderate-severe osteogenesis imperfecta suggest that inflammation is present

“…However, studies have struggled to determine any true benefit in terms of fracture rate, quality of life or mobility in patients with OI on bisphosphonate treatment 21 22. Concerns have also been raised about the long-term use of bisphosphonates, particularly with regard to the risk of atypical femur fracture in OI 23. This study’s finding of one or more potential inflammatory pathways active in OI could help in the development of more targeted and effective treatments for OI.…”

A Subtrochanteric Femoral Stress Fracture following Bisphosphonate Treatment in an Adolescent Girl

“…In this series, 14/16 femoral fractures in the bisphosphonate-treated cohort occurred within the subtrochanteric location, in contrast to a widespread fracture pattern in the historical controls [5]. Hegazy et al reported a series of 6 bisphosphonate-treated children with OI who sustained minimally traumatic subtrochanteric and diaphyseal femoral fractures over preexisting intramedullary rods [4], and Vasanwala et al similarly reported an adolescent OI patient with recurrent, atraumatic femoral fractures following bisphosphonate treatment [6]. The contribution of the underlying collagen defect in the development of femoral fractures in these series is unknown, and to our knowledge there have been no reports of subtrochanteric femoral fractures in non-OI children treated with bisphosphonates.…”

“…Case series of children with osteogenesis imperfecta (OI), a disorder of bone fragility due to abnormalities in type I collagen, report a potential association between bisphosphonate treatment and proximal femoral fractures [4–6]. To date, there have been no reports of AFFs in children or adolescents without primary collagen defects.…”