Per Aspenberg

Bisphosphonate use and atypical fractures of the femoral shaft.

BACKGROUND Studies show conflicting results regarding the possible excess risk of atypical fractures of the femoral shaft associated with bisphosphonate use. METHODS In Sweden, 12,777 women 55 years of age or older sustained a fracture of the femur in 2008. We reviewed radiographs of 1234 of the 1271 women who had a subtrochanteric or shaft fracture and identified 59 patients with atypical fractures. Data on medications and coexisting conditions were obtained from national registries. The relative and absolute risk of atypical fractures associated with bisphosphonate use was estimated by means of a nationwide cohort analysis. The 59 case patients were also compared with 263 control patients who had ordinary subtrochanteric or shaft fractures. RESULTS The age-adjusted relative risk of atypical fracture was 47.3 (95% confidence interval [CI], 25.6 to 87.3) in the cohort analysis. The increase in absolute risk was 5 cases per 10,000 patient-years (95% CI, 4 to 7). A total of 78% of the case patients and 10% of the controls had received bisphosphonates, corresponding to a multivariable-adjusted odds ratio of 33.3 (95% CI, 14.3 to 77.8). The risk was independent of coexisting conditions and of concurrent use of other drugs with known effects on bone. The duration of use influenced the risk (odds ratio per 100 daily doses, 1.3; 95% CI, 1.1 to 1.6). After drug withdrawal, the risk diminished by 70% per year since the last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38). CONCLUSIONS These population-based nationwide analyses may be reassuring for patients who receive bisphosphonates. Although there was a high prevalence of current bisphosphonate use among patients with atypical fractures, the absolute risk was small. (Funded by the Swedish Research Council.).

Teriparatide for acceleration of fracture repair in humans: A prospective, randomized, double‐blind study of 102 postmenopausal women with distal radial fractures

Animal experiments show a dramatic improvement in skeletal repair by teriparatide. We tested the hypothesis that recombinant teriparatide, at the 20 µg dose normally used for osteoporosis treatment or higher, would accelerate fracture repair in humans. Postmenopausal women (45 to 85 years of age) who had sustained a dorsally angulated distal radial fracture in need of closed reduction but no surgery were randomly assigned to 8 weeks of once‐daily injections of placebo (n = 34) or teriparatide 20 µg (n = 34) or teriparatide 40 µg (n = 34) within 10 days of fracture. Hypotheses were tested sequentially, beginning with the teriparatide 40 µg versus placebo comparison, using a gatekeeping strategy. The estimated median time from fracture to first radiographic evidence of complete cortical bridging in three of four cortices was 9.1, 7.4, and 8.8 weeks for placebo and teriparatide 20 µg and 40 µg, respectively (overall p = .015). There was no significant difference between the teriparatide 40 µg versus placebo groups (p = .523). In post hoc analyses, there was no significant difference between teriparatide 40 µg versus 20 µg (p = .053); however, the time to healing was shorter in teriparatide 20 µg than placebo (p = .006). The primary hypothesis that teriparatide 40 µg would shorten the time to cortical bridging was not supported. The shortened time to healing for teriparatide 20 µg compared with placebo still may suggest that fracture repair can be accelerated by teriparatide, but this result should be interpreted with caution and warrants further study.

Platelet concentrate injection improves Achilles tendon repair in rats

BACKGROUND Blood platelets release a cocktail of growth factors when activated, some of which are thought to initiate and stimulate repair. EXPERIMENT AND FINDINGS We studied whether a platelet concentrate injection would improve Achilles tendon repair in an established rat model. The Achilles tendon was transected and a 3 mm segment removed. After 6 h, a platelet concentrate was injected percutaneously into the hematoma. This increased tendon callus strength and stiffness by about 30% after 1 week, which persisted for as long as 3 weeks after the injection. At this time, the mechanical testing indicated an improvement in material characteristics--i.e., greater maturation of the tendon callus. This was confirmed by blinded histological scoring. INTERPRETATION Platelet concentrate may prove useful for the treatment of Achilles tendon ruptures.

How can one platelet injection after tendon injury lead to a stronger tendon after 4 weeks?: Interplay between early regeneration and mechanical stimulation

Background Mechanical stimulation improves the repair of ruptured tendons. Injection of a platelet concentrate (platelet-rich plasma, PRP) can also improve repair in several animal models. In a rat Achilles tendon transection model, 1 postoperative injection resulted in increased strength after 4 weeks. Considering the short half-lives of factors released by platelets, this very late effect calls for an explanation. Methods We studied the effects of platelets on Achilles tendon regenerates in rats 3, 5 and 14 days after transection. The tendons were either unloaded by Botulinum toxin A (Botox) injections into the calf muscles, or mechanically stimulated in activity cages. No Botox injections and ordinary cages, respectively, served as controls. Repair was evaluated by tensile testing. Results At 14 days, unloading (with Botox) abolished any effect of the platelets and reduced the mechanical properties of the repair tissue to less than half of normal. Thus, some mechanical stimulation is a prerequisite for the effect of platelets at 14 days. Without Botox, both activity and platelets increased repair independently of each other. However, at 3 and 5 days, platelets improved the mechanical properties in Botox-treated rats. Interpretation Platelets influence only the early phases of regeneration, but this allows mechanical stimulation to start driving neo-tendon development at an earlier time point, which kept it constantly ahead of the controls.

Randomized Radiostereometric Study Comparing Osteogenic Protein-1 (BMP-7) and Autograft Bone in Human Noninstrumented Posterolateral Lumbar Fusion : 2002 Volvo Award in Clinical Studies

Study Design. Randomized efficacy trial comparing two types of noninstrumented posterolateral fusion between L5 and S1 in patients with L5 spondylolysis and vertebral slip less than 50%, as evaluated by radiostereometric analysis. Objective. To determine whether osteogenic protein-1 (BMP-7) in the OP-1 Implant yields better stabilizing bony fusion than autograft bone. Summary of Background Data. Animal studies of osteoinductive proteins in noninstrumented posterolateral fusions have shown high fusion rates. No similar conclusive study on humans has been performed. Methods. For this study, 20 patients were randomized to fusion with either OP-1 Implant or autograft bone from the iliac crest, 10 in each group. The patients were instructed to keep the trunk straight for 5 months after surgery with the aid of a soft lumbar brace. At surgery 0.8-mm metallic markers were positioned in L5 and the sacrum, enabling radiostereometric follow-up analysis during 1 year. The three-dimensional vertebral movements, as measured by radiostereometric analysis induced by positional change from supine posture to standing and sitting, were calculated with an accuracy of 0.5 to 0.7 mm and 0.5° to 2.0°. Conventional radiography was added. Results. No significant difference was noted between the radiostereometric and radiographic results of fusion with the OP-1 Implant and fusion with autograft bone. There was a significant relation between reduced vertebral movements and better bone formation. No adverse effects of the OP-1 Implant occurred. Persistent minor pain at the iliac crest was noticed in one patient. Conclusions. There was no significant difference between the two fusion versions. Thus, the OP-1 Implant did not yield better stabilizing bony fusion than autograft bone.

Enhanced tendon healing with GDF 5 and 6

Between ruptured tendon ends, undifferentiated mesenchymal cells invade the hematoma and differentiate to form a tendon regenerate. This differentiation is partly directed by mechanical stimuli, which are difficult to apply and control clinically. For example, closed treatment of Achilles tendon ruptures is associated with a risk of rerupture of the regenerate. Improved tendon healing by exogenous growth factors has not previously been reported. Three proteins in the Bone Morphogenetic Protein (BMP) family--namely Growth and Differentiation Factors (GDFs) 5, 6 and 7--have recently been shown to induce a tendon- or ligament-like tissue after intramuscular implantation in rats, indicating a new way to improve tendon healing. We transected the Achilles tendon in 66 rats and denervated the calf muscle. Denervation served to reduce the mechanical stimulation to the tendon callus by eliminating muscle contractions. GDF 5 or 6 were implanted on collagen sponges in the tendon defects in two doses and compared to collagen sponges alone. The rats were killed after 2 weeks and the tensile strength of the tendon regenerate was found to be increased by both proteins in a seemingly dose-dependent manner.

Autologous Platelets Have No Effect on the Healing of Human Achilles Tendon Ruptures A Randomized Single-Blind Study

Background: Animal studies have shown that local application of platelet-rich plasma (PRP) stimulates tendon repair. Preliminary results from a retrospective case series have shown faster return to sports. Hypothesis: Autologous PRP stimulates healing of acute Achilles tendon ruptures. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: Thirty patients were recruited consecutively. During surgery, tantalum beads were implanted in the Achilles tendon proximal and distal to the rupture. Before skin suture, randomization was performed, and 16 patients were injected with 10mL PRP (10 times higher platelet concentration than peripheral blood) whereas 14 were not. With 3-dimensional radiographs (roentgen stereophotogrammetric analysis; RSA), the distance between the beads was measured at 7, 19, and 52 weeks while the patient resisted different dorsal flexion moments over the ankle joint, thereby estimating tendon strain per load. An estimate of elasticity modulus was calculated using callus dimensions from computed tomography. At 1 year, functional outcome was evaluated, including the heel raise index and Achilles Tendon Total Rupture Score. The primary effect variables were elasticity modulus at 7 weeks and heel raise index at 1 year. Results: The mechanical variables showed a large degree of variation between patients that could not be explained by measuring error. No significant group differences in elasticity modulus could be shown. There was no significant difference in heel raise index. The Achilles Tendon Total Rupture Score was lower in the PRP group, suggesting a detrimental effect. There was a correlation between the elasticity modulus at 7 and 19 weeks and the heel raise index at 52 weeks. Conclusion: The results suggest that PRP is not useful for treatment of Achilles tendon ruptures. The variation in elasticity modulus provides biologically relevant information, although it is unclear how early biomechanics is connected to late clinical results.

Simvastatin improves fracture healing in mice

Recently, several articles have been published dealing with the anabolic effects on bone by statins. Mundy and associates discovered that several statins were able to activate the promotor of bone morphogenetic protein (BMP) 2. Additionally, oral simvastatin and lovastatin increased the cancellous bone volume in rats, presumably an effect of the increase of BMP‐2. Other studies have followed, with conflicting results; some have found a positive bone metabolic effect of statins and others have not. Studies published so far have focused on osteoporosis. In this study, femur fractures were produced in 81 mature male BALB/c mice and stabilized with marrow‐nailing. Forty‐one mice were given a diet prepared with simvastatin, so that each mouse received an approximate dose of 120 mg/kg of body weight per day. The remaining mice received the same diet with the exception of the simvastatin. Bilateral femurs were harvested at 8, 14, and 21 days postoperatively (po), the marrow‐nail was extracted, and diameters were measured. Biomechanical tests were performed on 42 mice, by way of three‐point bending. Histological specimens were prepared using standard techniques. For statistical analysis, ANOVA with Scheffés post hoc test was used. At 8 days, the fracture callus was too soft for meaningful biomechanical testing. At 14 days, the callus of the simvastatin‐treated mice had a 53% larger transverse area than controls (p = 0.001), the force required to break the bone was 63% greater (p = 0.001), and the energy uptake was increased by 150% (p = 0.0008). Stiffness and modulus of elasticity were not significantly affected. At 21 days, the fractures were histologically healed and the mechanical differences had disappeared. The contralateral unbroken bone showed a slight increase in transverse area because of the simvastatin treatment, but there was no significant effect on the force required to break the bone or on energy uptake. These results point to a new possibility in the treatment of fractures.

Bone allografts pretreated with a bisphosphonate are not resorbed

Bisphosphonates bind to bone surfaces and inactivate osteoclasts when they start to resorb the bone. Therefore, immersion of a bone graft in a bisphosphonate solution before implantation may protect it from resorption. We implanted frozen cancellous bone allografts into bilateral bone chambers for 6 weeks in 10 rats. One graft in each pair had been immersed in an alendronate solution (1 mg/mL) for 10 minutes, and then rinsed in saline. Controls underwent the same treatment with saline only. Results were evaluated with histomorphometry. Control grafts were almost entirely resorbed, but alendronate-treated grafts seemed intact. In the treated specimens, two thirds of the space behind the bone ingrowth frontier consisted of graft or host bone, but in the controls, only one fifth. Local graft treatment with a bisphosphonate before insertion seems to be risk-free, and may prevent mechanical graft failure due to resorption in patients.

Incidence of stress fractures of the femoral shaft in women treated with bisphosphonate

Background Recent case reports have identified an association between long-term bisphosphonate treatment and stress fractures of the femoral shaft. The risk of such fractures in bisphosphonate users has not been determined. Methods We identified women over 55 years of age with the specific fracture pattern by searching the operation registry of the hospitals in 2 healthcare districts. Prevalence of bisphosphonate treatment was provided by a Swedish national registry covering all drugs delivered to all individuals since 2005. Results The number of women on bisphosphonate treatment was 3,087. Of these, 5 had femoral stress fractures. They had been taking bisphosphonates for 3.5 to 8.5 years. The incidence density for a patient on bisphosphonate was 1/1,000 per year (95% CI: 0.3–2). In the remaining 88,869 women who were not taking bisphosphonates, there were 3 stress fractures. Thus, their risk (without correction for inhomogeneity in age distribution) was 46 times less (95% CI: 11–200). Interpretation These results are rough estimations based on a comparatively small material. Still, a treatment-associated incidence density of 1/1,000 is acceptable, considering that bisphosphonate treatment is likely to reduce the incidence density of any fracture by 15/1,000 according to a large randomized trial ().