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1.  Histology of 8 atypical femoral fractures 
Acta Orthopaedica  2014;85(3):280-286.
Background and purpose
The pathophysiology behind bisphosphonate-associated atypical femoral fractures remains unclear. Histological findings at the fracture site itself may provide clues.
Patients and methods
Between 2008 and 2013, we collected bone biopsies including the fracture line from 4 complete and 4 incomplete atypical femoral fractures. 7 female patients reported continuous bisphosphonate use for 10 years on average. 1 patient was a man who was not using bisphosphonates. Dual-energy X-ray absorptiometry of the hip and spine showed no osteoporosis in 6 cases. The bone biopsies were evaluated by micro-computed tomography, infrared spectroscopy, and qualitative histology.
Incomplete fractures involved the whole cortical thickness and showed a continuous gap with a mean width of 180 µm. The gap contained amorphous material and was devoid of living cells. In contrast, the adjacent bone contained living cells, including active osteoclasts. The fracture surfaces sometimes consisted of woven bone, which may have formed in localized defects caused by surface fragmentation or resorption.
Atypical femoral fractures show signs of attempted healing at the fracture site. The narrow width of the fracture gap and its necrotic contents are compatible with the idea that micromotion prevents healing because it leads to strains within the fracture gap that preclude cell survival.
PMCID: PMC4062796  PMID: 24786905
2.  Denosumab and atypical femoral fractures 
Acta Orthopaedica  2014;85(1):1.
PMCID: PMC3940980  PMID: 24171676
3.  Atypical fracture of the femur in a patient using denosumab – a case report 
Acta Orthopaedica  2014;85(1):6-7.
PMCID: PMC3940983  PMID: 24460109
4.  Dichotomous location of 160 atypical femoral fractures 
Acta Orthopaedica  2013;84(6):561-564.
Background and purpose
The risk of atypical fracture of the femur is associated with bisphosphonate use. While characterizing atypical fractures from a previous nationwide study in radiographic detail, we had the impression that the fractures were located either in the subtrochanteric region or in the shaft. We determined whether there is a dichotomy in this respect.
Patients and methods
The distance between the atypical fractures and the lesser trochanter was measured on plain radiographs from 129 of 160 patients with atypical fractures, taken from 2008 through 2010. Analysis of the distances measured showed 2 clusters, which were then analyzed with regard to bisphosphonate use and age.
The distribution of the distances would be best described as 2 clusters, with a dichotomy at 8 cm. The proximal (subtrochanteric) cluster comprised 25 patients who were generally younger (median 71 years) than the 104 patients in the cluster with shaft fractures (median 80 years). The 95% CI for the difference between medians was 4–11 years. Of the patients with subtrochanteric fractures, 18 of 25 used bisphosphonates as compared to 89 of 104 with shaft fractures.
The younger age and possibly smaller proportion of bisphosphonate users in the subtrochanteric cluster may be compatible with a greater influence of mechanical stress in the underlying pathophysiology of proximal fractures.
PMCID: PMC3851670  PMID: 24286566
5.  Distal radial fractures heal by direct woven bone formation 
Acta Orthopaedica  2013;84(3):297-300.
Descriptions of fracture healing almost exclusively deal with shaft fractures and they often emphasize endochondral bone formation. In reality, most fractures occur in metaphyseal cancellous bone. Apart from a study of vertebral fractures, we have not found any histological description of cancellous bone healing in humans.
Patients and methods
We studied histological biopsies from the central part of 12 distal radial fractures obtained during surgery 6–28 days after the injury, using routine hematoxylin and eosin staining.
New bone formation was seen in 6 cases. It was always in the form of fetal-like, disorganized woven bone. It seldom had contact with old trabeculae and appeared to have formed directly in the marrow. Cartilage was scarce or absent. The samples without bone formation showed only necrosis, scar, or old cancellous bone.
The histology suggests that cells in the midst of the marrow respond to the trauma by direct formation of bone, independently of trabecular surfaces.
PMCID: PMC3715812  PMID: 23570338
6.  Bisphosphonate-coated external fixation pins appear similar to hydroxyapatite-coated pins in the tibial metaphysis and to uncoated pins in the shaft 
Acta Orthopaedica  2013;84(3):314-318.
Background and purpose
External fixation pins tend to loosen with time, especially from cancellous bone. A coating that releases a bisphosphonate has been shown to improve the fixation of dental implants in humans. We now tested a bisphosphonate coating on steel pins for external fixation. The primary hypothesis was that coated pins would be better fixed in the diaphysis.
20 patients with medial knee osteoarthritis underwent proximal tibial correction osteotomy with hemicallotasis. They received a pair of pins (Orthofix) in the tibial shaft, one bisphosphonate-coated and one uncoated. Another pair of pins was inserted in the metaphysis, near the joint. This pair was a bisphosphonate-coated pin and an HA-coated pin. All pins were inserted according to a random list. The pins were removed after the osteotomy had healed (8–15 weeks), and extraction torque served as the predetermined main outcome variable.
No pins showed clinical signs of loosening. Removal torque for the shaft pins was 6.6 Nm (SD 2.2) for the bisphosphonate and 6.0 Nm (SD 2.5) for the uncoated (difference = 0.5, 95% CI: –0.03 to 1.3). Removal torque for the metaphyseal pins was 4.4 Nm (SD 1.3) for the bisphosphonate-coated and 4.2 Nm (SD 1.6) for the HA-coated (difference = 0.2, 95% CI: –0.5 to 1.0).
We could not show any improved cortical fixation, but the metaphyseal findings are striking. In a previous study on 19 patients with a similar layout, HA-coated and uncoated pins were compared. In the metaphysis, all 19 uncoated pins loosened before removal. It was concluded that uncoated pins could not be used in the metaphyseal region. The present results suggest that a bisphosphonate coating enables metaphyseal fixation similar to that of hydroxyapatite coatings, with no difference from uncoated pins in cortical bone.
PMCID: PMC3715817  PMID: 23621808
7.  Annotation: Parathyroid hormone and fracture healing 
Acta Orthopaedica  2013;84(1):4-6.
This annotation describes some early rat studies which conclude that parathyroid hormone (PTH) has more dramatic stimulatory effects on bone repair than on untraumatized bone. It also suggests, based on the effects of PTH on osteoblasts, that it is more likely to accelerate normal fracture healing than to prevent non-union. The only 2 controlled clinical trials that have been published are critically discussed. Although both are encouraging and appear to show acceleration of normal fracture healing, they have methodological shortcomings that preclude definitive conclusions.
PMCID: PMC3584600  PMID: 23368745
8.  Tourniquet use in total knee replacement does not improve fixation, but appears to reduce final range of motion 
Acta Orthopaedica  2012;83(5):499-503.
Background and purpose
Although a tourniquet may reduce bleeding during total knee replacement (TKA), and thereby possibly improve fixation, it might also cause complications. Migration as measured by radiostereometric analysis (RSA) can predict future loosening. We investigated whether the use of a tourniquet influences prosthesis fixation measured with RSA. This has not been investigated previously to our knowledge.
50 patients with osteoarthritis of the knee were randomized to cemented TKA with or without tourniquet. RSA was performed postoperatively and at 6 months, 1 year, and 2 years. Pain during hospital stay was registered with a visual analog scale (VAS) and morphine consumption was measured. Overt bleeding and blood transfusions were registered, and total bleeding was estimated by the hemoglobin dilution method. Range of motion was measured up to 2 years.
RSA maximal total point motion (MTPM) differed by 0.01 mm (95% CI –0.13 to 0.15). Patients in the tourniquet group had less overt bleeding (317 mL vs. 615 mL), but the total bleeding estimated by hemoglobin dilution at day 4 was only slightly less (1,184 mL vs. 1,236 mL) with a mean difference of –54 mL (95% CI –256 to 152). Pain VAS measurements were lower in the non-tourniquet group (p = 0.01). There was no significant difference in morphine consumption. Range of motion was 11° more in the non-tourniquet group (p = 0.001 at 2 years).
Tourniquet use did not improve fixation but it may cause more postoperative pain and less range of motion.
PMCID: PMC3488177  PMID: 22974220
9.  Elevated plasma levels of TIMP-1 in patients with rotator cuff tear 
Acta Orthopaedica  2012;83(5):523-528.
Background and purpose
Extracellular matrix remodeling is altered in rotator cuff tears, partly due to altered expression of matrix metalloproteinases (MMPs) and their inhibitors. It is unclear whether this altered expression can be traced as changes in plasma protein levels. We measured the plasma levels of MMPs and their tissue inhibitors (TIMPs) in patients with rotator cuff tears and related changes in the pattern of MMP and TIMP levels to the extent of the rotator cuff tear.
Blood samples were collected from 17 patients, median age 61 (39–77) years, with sonographically verified rotator cuff tears (partial- or full-thickness). These were compared with 16 age- and sex-matched control individuals with sonographically intact rotator cuffs. Plasma levels of MMPs and TIMPs were measured simultaneously using Luminex technology and ELISA.
The plasma levels of TIMP-1 were elevated in patients with rotator cuff tears, especially in those with full-thickness tears. The levels of TIMP-1, TIMP-3, and MMP-9 were higher in patients with full-thickness tears than in those with partial-thickness tears, but only the TIMP-1 levels were significantly different from those in the controls.
The observed elevation of TIMP-1 in plasma might reflect local pathological processes in or around the rotator cuff, or a genetic predisposition in these patients. That the levels of TIMP-1 and of certain MMPs were found to differ significantly between partial and full-thickness tears may reflect the extent of the lesion or different etiology and pathomechanisms.
PMCID: PMC3488181  PMID: 23043271
10.  Etanercept does not impair healing in rat models of tendon or metaphyseal bone injury 
Acta Orthopaedica  2012;83(3):305-310.
Background and purpose
Should blockade of TNF-α be avoided after orthopedic surgery? Healing of injuries in soft tissues and bone starts with a brief inflammatory phase. Modulation of inflammatory signaling might therefore interfere with healing. For example, Cox inhibitors impair healing in animal models of tendon, ligament, and bone injury, as well as in fracture patients. TNF-α is expressed locally at increased levels during early healing of these tissues. We therefore investigated whether blocking of TNF-α with etanercept influences the healing process in established rat models of injury of tendons and metaphyseal bone.
Rats were injected with etanercept, 3.5 mg/kg 3 times a week. Healing of transected Achilles tendons and bone healing around screws implanted in the tibial metaphysis were estimated by mechanical testing. Tendons were allowed to heal either with or without mechanical loading. Ectopic bone induction following intramuscular BMP-2 implants has previously been shown to be stimulated by etanercept in rodents. This was now tested as a positive control.
Tendon peak force after 10 days was not significantly influenced by etanercept. Changes exceeding 29% could be excluded with 95% confidence. Likewise, screw pull-out force was not significantly influenced. More than 25% decrease or 18% increase could be excluded with 95% confidence. However, etanercept treatment increased the amount of bone induced by intramuscular BMP-2 implants, as estimated by blind histological scoring.
Etanercept does not appear to impair tendon or metaphyseal bone healing to any substantial degree.
PMCID: PMC3369160  PMID: 22616743
11.  Under-reported complications related to BMP use in spine surgery 
Acta Orthopaedica  2011;82(5):511-512.
PMCID: PMC3242945  PMID: 21992083
12.  Anti-sclerostin antibody and mechanical loading appear to influence metaphyseal bone independently in rats 
Acta Orthopaedica  2011;82(5):628-632.
Background and purpose
Sclerostin is produced by osteocytes and is an inhibitor of bone formation. Thus, inhibition of sclerostin by a monoclonal antibody increases bone formation and improves fracture repair. Sclerostin expression is upregulated in unloaded bone and is downregulated by loading. We wanted to determine whether an anti-sclerostin antibody would stimulate metaphyseal healing in unloaded bone in a rat model.
10-week-old male rats (n = 48) were divided into 4 groups, with 12 in each. In 24 rats, the right hind limb was unloaded by paralyzing the calf and thigh muscles with an injection of botulinum toxin A (Botox). 3 days later, all the animals had a steel screw inserted into the right proximal tibia. Starting 3 days after screw insertion, either anti-sclerostin antibody (Scl-Ab) or saline was given twice weekly. The other 24 rats did not receive Botox injections and they were treated with Scl-Ab or saline to serve as normal-loaded controls. Screw pull-out force was measured 4 weeks after insertion, as an indicator of the regenerative response of bone to trauma.
Unloading reduced the pull-out force. Scl-Ab treatment increased the pull-out force, with or without unloading. The response to the antibody was similar in both groups, and no statistically significant relationship was found between unloading and antibody treatment. The cancellous bone at a distance from the screw showed changes in bone volume fraction that followed the same pattern as the pull-out force.
Scl-Ab increases bone formation and screw fixation to a similar degree in loaded and unloaded bone.
PMCID: PMC3242963  PMID: 22103277
13.  Where did bone come from? 
Acta Orthopaedica  2011;82(4):393-398.
Bone is specific to vertebrates, and originated as mineralization around the basal membrane of the throat or skin, giving rise to tooth-like structures and protective shields in animals with a soft cartilage-like endoskeleton. A combination of fossil anatomy and genetic information from modern species has improved our understanding of the evolution of bone. Thus, even in man, there are still similarities in the molecular regulation of skin appendages and bone. This article gives a brief overview of the major milestones in skeletal evolution. Some molecular machineries involving members of core genetic networks and their interactions are described in the context of both old theories and modern genetic approaches.
PMCID: PMC3237026  PMID: 21657973
14.  Wnt signaling and orthopedics, an overview 
Acta Orthopaedica  2011;82(2):125-130.
Wnt signaling is a ubiquitous system for intercellular communication, with multiple functions during development and in homeostasis of the body. It comprises several ligands, receptors, and inhibitors. Some molecules, such as sclerostin, appear to have bone-specific functions, and can be targeted by potential drugs. Now, ongoing clinical trials are testing these drugs as treatments for osteoporosis. Animal studies have also suggested that these drugs can accelerate fracture healing and implant fixation. This brief overview focuses on currently available information on the effects of manipulations of Wnt signaling on bone healing.
PMCID: PMC3235279  PMID: 21438671
15.  Overtreatment of cruciate ligament injuries 
Acta Orthopaedica  2010;81(5):524-525.
PMCID: PMC3214738  PMID: 20929420
17.  Fluid pressure and flow as a cause of bone resorption 
Acta Orthopaedica  2010;81(4):508-516.
Unstable implants in bone become surrounded by an osteolytic zone. This is seen around loose screws, for example, but may also contribute to prosthetic loosening. Previous animal studies have shown that such zones can be induced by fluctuations in fluid pressure or flow, caused by implant instability.
To understand the roles of pressure and flow, we describe the 3-dimensional distribution of osteolytic lesions in response to fluid pressure and flow in a previously reported rat model of aseptic loosening. 50 rats had a piston inserted in the proximal tibia, designed to produce 20 local spikes in fluid pressure of a clinically relevant magnitude (700 mmHg) twice a day. The spikes lasted for about 0.3 seconds. After 2 weeks, the pressure was measured in vivo, and the osteolytic lesions induced were studied using micro-CT scans.
Most bone resorption occurred at pre-existing cavities within the bone in the periphery around the pressurized region, and not under the piston. This region is likely to have a higher fluid flow and less pressure than the area just beneath the piston. The velocity of fluid flow was estimated to be very high (roughly 20 mm/s).
The localization of the resorptive lesions suggests that high-velocity fluid flow is important for bone resorption induced by instability.
PMCID: PMC2917576  PMID: 20718695
18.  Teriparatide improves early callus formation in distal radial fractures 
Acta Orthopaedica  2010;81(2):234-236.
Background Teriparatide (parathyreoid hormone; PTH 1-34) increases skeletal mass in humans and improves fracture healing in animals. A recent randomized multicenter trial of nonoperated distal radial fractures showed a moderate shortening of the time to restoration of cortical continuity by treatment with 20 μg (low-dose) teriparatide per day, but not with 40 μg (high-dose). As radiographic cortical continuity appears late in the healing process, perhaps too late for clinical relevance, we studied the qualitative appearance of the callus 5 weeks after fracture.
Methods One third of the patients of the international trial were treated at Linköping University Hospital. The multicenter trial did not evaluate early callus formation. We therefore made a blinded qualitative scoring of the callus at 5 weeks in our 27 patients. Callus formation was arbitrarily classified as rich, intermediate, or poor.
Results 9 patients were classified as rich (none had received placebo, 3 low-dose teriparatide, and 6 high-dose teriparatide). 9 patients were classified as intermediate (1 had received placebo, 5 low-dose, and 3 high-dose). 9 patients were classified as poor (7 had received placebo, 1 low-dose, and 1 high-dose) (p < 0.001).
Interpretation This is a post hoc subgroup analysis of an outcome variable, which was not in the official protocol. The results must therefore be interpreted with caution. However, in combination with the results of the larger trial, the data suggest that radiographic quality at an early time point might be a sensitive variable, perhaps better than time to cortical continuity. Moreover, teriparatide appeared to improve early callus formation in distal radial fractures.
PMCID: PMC2895344  PMID: 20367417
19.  Metalloproteinases and their inhibitors—diagnostic and therapeutic opportunities in orthopedics 
Acta Orthopaedica  2009;80(6):693-703.
Matrix metalloproteinases (MMPs) and related enzymes (ADAMs, ADAMTS) and their inhibitors control matrix turnover and function. Recent advances in our understanding of musculoskeletal conditions such as tendinopathy, arthritis, Dupuytren's disease, degenerative disc disease, and bone and soft tissue healing suggest that MMPs have prominant roles. Importantly, MMPs are amenable to inhibition by cheap, safe, and widely available drugs such as the tetracycline antibiotics and the bisphosphonates. This indicates that these MMP inhibitors, if proven effective for any novel indication, may be quickly brought into clinical practice.
PMCID: PMC2823312  PMID: 19968600
20.  Incidence of stress fractures of the femoral shaft in women treated with bisphosphonate 
Acta Orthopaedica  2009;80(4):413-415.
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 (Black et al. 1996).
PMCID: PMC2823197  PMID: 19568963
21.  Black holes in bone – irresistible attractors of foreign materials? 
Acta Orthopaedica  2009;80(1):2-3.
PMCID: PMC2823249  PMID: 19297784
22.  Once-weekly oral medication with alendronate does not prevent migration of knee prostheses 
Acta Orthopaedica  2009;80(1):41-45.
Background and purpose Early migration of joint replacements is an effect of poor fixation and can predict late loosening. By reducing the bone resorption after implantation of a joint replacement, it should be possible to enhance the initial fixation of the implant. We studied the effect of once-weekly treatment with alendronate after knee replacement.
Patients and methods We recruited 60 patients (60 knees) with gonarthrosis who were scheduled for a total knee replacement. They were operated on with identical implants and uncemented fixation. 30 patients were treated with a bisphosphonate (alendronate) and 30 patients underwent placebo treatment. The treatment started postoperatively and continued on a weekly basis for 6 months. The fixation of the implants was measured with repeated radiostereometry for 2 years.
Results There was no difference in migration of implants between the two groups.
Conclusion With uncemented fixation of knee implants, no benefit of once-weekly treatment with alendronate, starting postoperatively, could be seen during a 2-year follow-up period.
PMCID: PMC2823246  PMID: 19297788
23.  Celecoxib does not appear to affect prosthesis fixation in total knee replacement 
Acta Orthopaedica  2009;80(1):46-50.
Background and purpose After joint replacement, a repair process starts at the interface between bone and cement. If this process is disturbed, the prosthesis may never become rigidly fixed to the bone, leading to migration—and with time, loosening. Cox-2 inhibitors are widely used as postoperative analgesics, and have adverse effects on bone healing. This could tamper prosthesis fixation. We investigated whether celecoxib, a selective Cox-2 inhibitor, increases prosthesis migration in total knee replacement (TKR).
Methods 50 patients were randomized to either placebo or celecoxib treatment, 200 mg twice daily, for 3 weeks after TKR (NexGen; Zimmer). Maximum total point motion (MTPM) of the tibial component was measured after 2 years using radiostereometric analysis (RSA). In addition, range of motion, pain, and, subjective outcome were evaluated.
Results No differences in prosthesis migration, pain scores, range of motion, and subjective outcome were found after 2 years. Confidence intervals were narrow.
Interpretation It is unlikely that Celecoxib increases the risk of loosening, and it may be used safely in conjunction with TKR.
PMCID: PMC2823240  PMID: 19234885
24.  Bisphosphonates and implants 
Acta Orthopaedica  2009;80(1):119-123.
PMCID: PMC2823231  PMID: 19234893

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