A recent multicenter prospective study showed poor radiographic outcomes in children of all ages with severe Lateral Pillar C LCPD, irrespective of nonsurgical or surgical treatment, warranting the investigation of novel therapies to prevent femoral head deformity [11
]. A pathologic repair process marked by an imbalance of bone resorption and bone formation has been recognized as a major contributor to the pathogenesis of collapse in juvenile femoral head osteonecrosis. The rationale for using BP therapy for LCPD is the potential to prevent substantial femoral head deformity during the fragmentation phase by inhibiting osteoclastic bone resorption. Our purposes in this systematic review were to determine the effect of BP therapy on the improvement of pain and function in LCPD and other juvenile osteonecrotic conditions and the prevention of femoral head collapse in clinical and experimental studies of femoral head osteonecrosis.
The limitations in the literature are numerous and primarily stem from the small number of published Level IV studies currently available for review. All studies were subject to selection bias. The patient populations represented a heterogeneous group with varying etiologies and stages of osteonecrosis. Only one study adhered to a standardized protocol for initiation and dosing of BP therapy, which is critical to understanding the effects of the drug on prevention of femoral head collapse and improving function. Furthermore, a clear radiographic classification of osteonecrosis pre- and posttreatment was not described in most studies, making it difficult to quantify the amount of deformity at the onset and conclusion of BP use. Objective radiographic data describing femoral head shape and correlative histologic information analyzing bone microarchitecture obtained from animal studies suggest BPs interfere with the pathophysiology of femoral head collapse, but these findings remain to be confirmed in humans.
Potential controversies regarding the use of BP therapy for the treatment of LCPD consist of limited distribution of the drug in necrotic bone, lack of bone anabolic effect, absence of a direct ability to enhance mechanical properties, and unknown long-term effects of therapy on the growing skeleton. It is important to recognize local bioavailability of BP for an avascular bone condition is impaired. A radioactive BP tracing study in the piglet model showed preferential binding of 14
C-ibandronate in the vascularized regions of the infracted femoral head [18
] (Fig. ). This finding explains why multiple dosing regimens are suggested for oral or intravenous administration. Local intraosseous administration has been investigated in the piglet model by injecting 14
C-ibandronate into the necrotic femoral heads and demonstrated a wide distribution of the drug with a reasonable retention over time [3
] (Fig. ). While a single local injection may effectively decrease the dose needed to exert the same desirable effect on decreasing femoral head deformity, this method also requires a secondary surgical procedure that introduces additional trauma to the ischemic bone.
Fig. 5A–B (A) Autoradiographic images show the three regions (necrotic bone, revascularized marrow space, and newly formed bone) found in the infarcted femoral heads of piglets at 6 weeks after ischemia induction. 14C-labeled ibandronate was administered (more ...)
Fig. 6A–B (A) A radiograph demonstrates an intraosseous needle placed in the central region of the femoral head used to locally deliver BP. (B) Autoradiographic sections from a control femoral head and an infarcted femoral head injected with 14C-ibandronate show (more ...)
The preservation of necrotic bone without new bone formation on the necrotic framework as observed in large-animal studies also raises the question of what effect BP therapy may have on bone formation in LCPD. An ideal biologic treatment for LCPD would restore the imbalance of bone resorption and formation that occurs during the fragmentation/resorptive phases. This prompted investigation of combined BP (antiresorptive) and BMP-2 (anabolic) therapy for femoral head osteonecrosis [45
]. In comparison to controls, the combined therapy group had a decrease in femoral head asphericity and osteoclast number and an increase in trabecular bone volume and osteoblast surface, suggesting an additive effect of BMP-2 to increase bone formation. One cautionary finding from this study was the presence of heterotopic ossification in the hip joint capsule. Adjustment of the BMP-2 dose and refinement of the injection technique is paramount before applying this therapy in the clinical setting.
Several experimental studies suggest ischemic necrosis of the immature femoral head produces mechanical weakening of the cartilage and bone [20
]. The likelihood of BP therapy to have an immediate effect on restoring the mechanical properties of the necrotic femoral head is small as this restoration depends on new bone formation that occurs over time. Since the healing process can be prolonged, especially in older patients with LCPD, a treatment regimen that combines protected weightbearing with a biologic agent to control bone resorption and formation may offer the best solution to avoiding mechanical collapse and ensuring good long-term results.
In general, severe adverse effects due to BP therapy in children are uncommon when the drug is used judiciously [4
]. The most common side effect observed after intravenous administration is transient pyrexia with flulike symptoms; gastrointestinal effects were also reported. Osteonecrosis of the jaw has not been reported in the pediatric population. One of the unresolved questions pertains to the long-term effects of administering repetitive doses of BP on the normal growing skeleton. Since LCPD is a self-limiting disease, the duration of treatment arguably will be shorter than that for chronic conditions such as osteogenesis imperfecta. The drug may be required only in the initial and resorptive stages of the disease. While some data on the systemic skeletal effects of BP therapy in children with osteogenesis imperfecta have been reported in the literature [10
], information on children with normal skeletons is scant. Decreased long-bone growth was observed in several animal studies [7
] and postulated to be a dose-dependent effect where high-dose BPs were given to fast-growing animals. Such growth inhibition has not been seen in several clinical reports. Maintenance of height z-scores was found in a small cohort of children treated for fibrous dysplasia with pamidronate for 1.2 to 9.1 years [38
] and another review of 17 patients with LCPD treated with zoledronic acid over an 18-month period [13
In conclusion, experimental studies show a potential role for BPs to protect the femoral head from collapsing in conditions of osteonecrosis. Many questions remain to be clarified regarding the optimal dose of BP, timing of treatment initiation, and mode of drug delivery. Possible limitations of BP therapy include decreased distribution within the necrotic bone after systemic administration, lack of a bone anabolic effect, and absence of an immediate enhancement of mechanical properties in the necrotic femoral head. Due to the lack of available clinical evidence, we cannot recommend the use of BP therapy in LCPD to prevent femoral head deformity and improve long-term functional outcome. Further basic science and clinical research are necessary to investigate the efficacy and safety of BP treatment in LCPD with a particular focus on the potential adverse events on remodeling of the necrotic bone and the rest of the growing skeleton. Any clinical trial must be appropriately powered and be well-defined in terms of age groups, stage of disease, and weightbearing status during the course of BP treatment. We are currently aware of one randomized clinical trial under way in Australia comparing intravenous administration of zoledronic acid to a standard care (weightbearing restriction and current treatments) for LCPD (Clinical Trial Registration ACTRN12610000407099).