This study evaluated factors influencing fracture (n 197) and osteotomy (n 200) healing in children with moderate to severe OI. Pamidronate treatment was associated with delayed healing after osteotomy, but not after fracture. The data suggest that both pamidronate and mechanical factors influence bone healing in this cohort. Introduction: Intravenous pamidronate is widely used to treat children with moderate to severe osteogenesis imperfecta (OI). However, the effect of this treatment on bone healing is not well characterized. We therefore retrospectively analyzed the healing of lower limb fractures and osteotomies in children with moderate to severe OI, both before and after the start of pamidronate treatment. Materials and Methods: Bone healing was evaluated on standard radiographs after 197 lower limb fractures (132 femur and 65 tibia) in 82 patients (age at fracture, 0.0 -19.9 years) and 200 intramedullary rodding procedures in 79 patients (age at surgery, 1.2-19.8 years). Delayed healing was diagnosed when a fracture or osteotomy line was at least partially visible 12 months after the event. Results: Delayed fracture healing was observed more frequently during than before pamidronate treatment. However, the effect of pamidronate was no longer significant when age differences were taken into account (odds ratio (OR), 1.76; 95% CI, 0.61-5.10). Better mobility status was a strong independent predictor of delayed healing after fractures that occurred during pamidronate treatment. After osteotomies, delayed healing was more frequent when pamidronate had been started before surgery (OR, 7.29; 95% CI, 2.62-20.3), and this effect persisted after adjustment for multiple confounders. During pamidronate treatment, older age (OR per year of age, 1.25; 95% CI, 1.06 -1.47) and osteotomy of the tibia (OR, 3.51; 95% CI, 1.57-7.82) were independent predictors of delayed healing. Conclusions: This study suggests that pamidronate therapy is associated with delayed healing of osteotomy sites after intramedullary rodding procedures. Better mobility status, but not pamidronate treatment, seems to be predictive of delayed healing after fractures. J Bone Miner Res 2004;19:1779-1786. Published online on August 23, 2004; doi: 10.1359/JBMR.040814

https://onlinelibrary.wiley.com/doi/pdf/10.1359/JBMR.040814

Delayed Osteotomy but Not Fracture Healing in Pediatric Osteogenesis Imperfecta Patients Receiving Pamidronate

Micro-computed tomography assessment of fracture healing: Relationships among callus structure, composition, and mechanical function

We hypothesized that ZA treatment would bolster fracture repair. In a rat model for closed fracture healing, a single dose of ZA at 0, 1, or 2 wk after fracture significantly increased BMC and strength of the healed fracture. Delaying the dose (1 or 2 wk after fracture) displayed superior results compared with dosing at the time of fracture. Introduction: Bisphosphonates are known to increase bone strength and thus the resistance to fracture by decreasing osteoclastic bone resorption. These properties may enable bisphosphonates to also increase the strength of fracture repair. Zoledronic acid (ZA) is a potent bisphosphonate with a high affinity for bone mineral, allowing bolus intraveous dosing in a range of indications. In this study, we examined the application of bolus dose ZA in endochondral fracture repair. Materials and Methods: Carbon-14 labeled ZA was used in a closed rat fracture model. Rats were divided into five treatment groups (n 25 per group): saline control, local ZA (0.01 mg/kg), and three systemic bolus ZA groups (0.1 mg/kg) with different administration times: at fracture, 1 wk after fracture, and 2 wk after fracture. Rats were killed 6 wk postoperatively. Postmortem analyses included radiography, QCT, CT, biomechanical testing, scintillation counting, autoradiography, and histology. Results: Single-dose systemic ZA administration significantly increased callus volume, callus BMC, and me- chanical strength. Perioperative treatment increased mechanical strength by 30% compared with controls (p < 0.05). Administering the systemic dose at 1 or 2 wk after fracture further increased mechanical strength compared with controls by 44% and 50%, respectively (p < 0.05). No significant differences in mechanical parameters were seen with local injection at the dose studied. Autoradiographic analysis indicated that ZA binds significantly to bone that is present at the time of administration. ZA quantification indicated that delayed administration significantly increased the uptake efficiency in the callus. Histological and CT analy- sis showed that ZA treated calluses had a distinctive internal structure consisting of an intricate network of retained trabecular bone. Conclusions: The timing of a single systemic dose of ZA plays an important role in the modulation of callus properties in this rat fracture model; delaying the single dose produces a larger and stronger callus. J Bone Miner Res 2007;22:867-876. Published online on March 19,2 007; doi: 10.1359/JBMR.070318

Optimal Timing of a Single Dose of Zoledronic Acid to Increase Strength in Rat Fracture Repair

Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling

Bone mineral composition, crystallinity, and bone mineral content of osteoporotic patients are different from those of normal subjects We review the evidence that these mineralization parameters contribute to the strength (fracture resistance) of bone and the methods that have been used to examine them A specific example is provided from analysis of biopsies from the Multiple Outcomes in Raloxifene Evaluation trial For the analyses, randomly selected biopsies from placebo, low-dose, and high-dose groups (n = 5 per group) obtained at time zero and 2 years after treatment were examined by infrared imaging spectroscopy In all cases, comparable increases in mineral content were found, but there were no significant variations in mineral crystallinity

/pdf/mineral-changes-in-osteoporosis-a-review-3uqxxrqi74.pdf

Mineral Changes in Osteoporosis: A Review

Clinicians have been concerned that fractures do not heal properly in individuals exposed to bisphosphonate treatment, a treatment that strongly affects bone metabolism. The current study attempted to clarify the long-term effects of clodronate (dichloromethylene bisphosphonate) treatment on fracture healing in growing rats. Clodronate was administered subcutaneously twice a week in a dose of 2 mg/kg or 10 mg/kg. Physiologic saline served as a control. After 24 weeks of treatment, the tibiae were fractured, and the treatment was continued for another 4 weeks and 8 weeks. At both end points the cross-sectional areas of the callus, measured by peripheral quantitative computed tomography, were greater in the clodronate-treated rats than in controls, but there were no significant differences in bone mineral density. There were no significant differences between treatments in radiologic healing, histomorphometry, or in mechanical failure load of the callus with the exception of increased tensile stiffness at a dose of 2 mg/kg at 4 weeks. Clodronate treatment does not seem to prolong the fracture healing process, even when administered on a long-term basis before the fracture. Clodronate increases the size of the callus, but has only a minor effect on its biomechanical properties. The current results suggest that long-term clodronate treatment does not inhibit fracture healing.

Long-term administration of clodronate does not prevent fracture healing in rats.

Fracture healing and callus formation have traditionally been evaluated by using X-ray radiography Here we compared X-ray radiography and peripheral quantitative computed tomography (pQCT) in evaluating the healing callus of standardized tibial fractures in 141 female rats after a 4- or 8-week follow-up The results were compared with the tensile (4-week) and compressive (8-week) failure load of the callus The projectional size of callus, as defined from lateral ex vivo radiographs, correlated significantly with the pQCT-defined cross-sectional area (CSA) of mid-callus This relationship was dependent on the pQCT attenuation threshold, being higher for the CSA of compact bone (r = 085, P < 00001) than for the total bone CSA (r = 068, P < 00001) Radiographically defined callus projectional area also correlated strongly with bone mineral content (BMC) (r = 084–086, P < 00001) The mean optical density of the callus analyzed from the radiographs had only a weak correlation with the pQCT-defined bone mineral density (BMD) of callus A weak negative relationship was found between CSA and BMD The optical density analyzed from lateral radiographs did not correlate with the tensile or compressive failure load of callus Callus size, BMC, and BMD were associated with the compressive failure load, whereas both radiographs and pQCT were poor in explaining the failure load in tension

Comparison of Radiographic and pQCT Analyses of Healing Rat Tibial Fractures

Daily oral clodronate treatment was evaluated in Sprague-Dawley rats for its ability to inhibit estrogen-deficiency-induced changes in femoral neck, femoral diaphysis, and lumbar vertebrae (L4-L5). Six-month-old ovariectomized (OVX) rats were administered by gavage a vehicle (Veh) or clodronate (100 or 500 mg/kg/day). Sham-operated (SHAM) control rats received the vehicle (n = 15/group). Treatment was started on the day of operation and continued for 3 months. Trabecular bone volume (BV/TV) and structural variables (trabecular number, Tb.N; thickness, Tb.Th; separation, Tb.Sp; and trabecular bone pattern factor, Tb.Pf) were assessed on secondary spongiosa of the right femoral neck Furthermore, cantilever bending test of the left femoral neck and compression test of L4, ash weight of L5, and morphometric studies of femoral diaphysis were carried out, and serum and urinary markers of bone turnover were determined. The OVX/Veh group had higher levels of serum osteocalcin and alkaline phosphatase and higher urinary excretion of deoxypyridinoline/creatinine than the SHAM/Veh group at 3 months postsurgery, and clodronate reduced these changes. BV/TV of femoral neck, bone mass of L5, and the maximum loads of the femoral neck and L4 were lower after OVX than SHAM operation. Although clodronate prevented trabecular bone loss in the femoral neck and preserved Tb.Pf at the SHAM control level, it failed to preserve the mechanical strength at the femoral neck However, in lumbar vertebrae, clodronate prevented the loss of bone mass and mechanical properties. Furthermore, there was a good positive correlation between maximum load of L4 and the ash weight of L5 (n = 58, r = 0.69, p < 0.001). In the femoral neck (n = 55), Tb.Pf correlated negatively with BV/TV and Tb.N (r = -0.59 and r = -0.55;p < 0.001, respectively) and positively with Tb.Sp (r = 0.61, p < 0.001). In femoral mid-diaphysis, there were no significant changes in cortical bone geometry in any of the groups. We conclude that orally administered clodronate suppresses the enhanced bone turnover in adult OVX rats and preserves trabecular bone volume and connectivity in the femoral neck In the axial skeleton, clodronate has a beneficial effect on lumbar vertebral bone mass and strength.

Clodronate Prevents Osteopenia and Loss of Trabecular Connectivity in Estrogen-Deficient Rats†

The aim of this study was to evaluate the ability of the bisphosphonate compounds clodronate and etidronate to prevent ovariectomy-induced bone changes. Three-month-old Sprague-Dawley rats were either ovariectomized (OVX) or sham-operated (SHAM) and further divided into groups receiving either vehicle (n = 30), 25 mg/kg/week of clodronate (n = 25) or 25 mg/kg/week of etidronate (n = 25). The subcutaneous drug administration was started immediately after the surgery and was continued for 12 weeks. OVX rats had accelerated bone turnover rates compared with the SHAM animals, as indicated by the results of dynamic histomorphometry and biochemical markers in serum and urine. Femoral and vertebral mineralized trabecular bone volume and maximum loads in compressions of the femoral neck and lumbar vertebra were lower after OVX compared with the SHAM operation. Both clodronate and etidronate prevented the decrease in trabecular bone volume and suppressed the increase in the bone turnover rate. Clodronate and etidronate also blocked the loss of bone strength in the femoral neck and lumbar vertebra of OVX rats. Both compounds resulted in an absence of double fluorochrome labels on the endocortical surface of the femoral metaphysis, which seemed, however, to be a dose-dependent response. Furthermore, etidronate also lowered serum osteocalcin and diaphyseal endocortical bone formation below the vehicle level both in the OVX and SHAM rats. In conclusion, clodronate and etidronate were effective in preventing the estrogen deficiency-induced decreases in trabecular bone volume and bone strength in rats. Treatment with a high dose of clodronate induced minor signs of abnormally low bone formation but not any impairment of bone mineralization, whereas both of these events were seen with high-dose etidronate administration.

Bisphosphonates clodronate and etidronate in the prevention of ovariectomy-induced osteopenia in growing rats†

Bisphosphonates inhibit bone resorption. Short-term bisphosphonate treatment at therapeutical dosage has been shown to be safe, but there are only a few studies concerning the long-term effects of bisphosphonates on the non-osteoporotic skeleton. Here, we studied the bone effects of 32 weeks' treatment with clodronate on growing rats, using a therapeutical dose of 2 mg/kg and a high dose of 10 mg/kg. We used biomechanical, densitometrical, and, histomorphometrical analyses to examine the rat tibia, femur, and vertebra and also tested some hematological and biochemical parameters. Tibial length was significantly lower in the high clodronate group compared with the controls. No differences were found in tibial or vertebral ash weights. The L4 vertebra compression failure load was higher in the high clodronate group compared with the therapeutical clodronate group, but not compared with the controls. The mechanical strength of the femoral shaft or femoral neck was not affected by clodronate. Cortical BMD in the L4 vertebra was significantly higher in both clodronate groups compared with controls. Histomorphometrical analysis indicated that the trabecular number of vertebra was increased in the therapeutical clodronate group. The mineral apposition rate was not significantly affected by the treatment. Hematological analyses showed a decreased number of platelets at the high dosage. A slight increase in liver enzyme activity was seen in both groups. We conclude that long-term administration of clodronate has no harmful but rather some beneficial effects on bone at the therapeutical dosage. However, a fivefold dose of clodronate causes a slight decrease in the growth of tibial length.

K. Kippo

Papers

Long-term administration of clodronate does not prevent fracture healing in rats.

Comparison of Radiographic and pQCT Analyses of Healing Rat Tibial Fractures

Clodronate Prevents Osteopenia and Loss of Trabecular Connectivity in Estrogen-Deficient Rats†

Bisphosphonates clodronate and etidronate in the prevention of ovariectomy-induced osteopenia in growing rats†

Effects of long-term administration of clodronate on growing rat bone.