Osteoporosis Highlights from the ISFR Adelaide Conference
Written by Antonio Moroni and Amy Hoang-Kim
Wednesday, 26 July 2006
Antonio Moroni, MD ISFR Programme and Awards Secretary, OFC Research Chair
Amy Hoang-Kim, BScH, MA OFC Coordinator
Orthopaedic surgeons have traditionally been involved in the care of fragility fractures. However, there is increasing demand for them to act beyond just fixing the fractures, to provide a more holistic management of patients with respect to future injury prevention.1 Thirteen accepted papers in this year’s ISFR Biennial conference highlighted pertinent issues dealing with osteoporosis.
If the skeleton does not adequately repair bone microcracks, they accumulate resulting in decreased bone stiffness, strength and toughness, and may lead to an increased risk of fracture. Kuliwaba JS2 (Institute of Medical and Veterinary Science and Hanson Institute, Adelaide, South Australia) assessed microdamage accumulation and repair (bone resorption) in femoral trabecular bone from patients with a fragility hip fracture compared to age- and sex-matched controls. Intertrochanteric bone cores were obtained from patients undergoing hemi-arthroplasty surgery for a non-traumatic subcapital femoral fracture (6f, 2m, aged 825 yrs [mean SD]). Samples were en bloc-stained in basic fuchsin, resin-embedded, and in vivo microdamage identified in 70m sections. Trabecular bone volume, architecture, and indices of bone resorption were not different between the fracture and control groups (BV/TV[%]: Fracture: 4.7 2.3, Control: 5.8 2.3, p=NS). Linear microcrack density and crack length were similar between groups. However, bone from fracture patients had an increased density of diffuse damage (DF.Dn [#/mm2]: Fracture:1.61 (0.18-2.81), Control:0 (0-0.58), p< 0.05 [median (quartiles)], which may be associated with altered bone matrix properties, such as a change in the degree of bone mineralisation. Although the ratio of microdamage (cracks and diffuse) density to resorption site density was not statistically different between groups, the increased diffuse microdamage burden, with no bone architectural change, suggests that bone from hip fracture patients may be mechanically compromised due to a defective damage repair mechanism. Future research should investigate factors that influence bone strength in order to develop improved diagnostic techniques and more effective treatments for individuals at risk of fragility fracture.
Controlled screw insertion
Hearn TC et al3 (Flinders University, Adelaide, Australia) examined the basis for adaptive surgical control of screw tightening. Ovine cancellous bone specimens (n=91) were tested to evaluate the method given the continuously variable density and interface characteristics of bone. Significant linear regression was found between plateau current and bone density (p<0.0001) and plateau current was a strong predictor of peak current. The authors confirmed that bone density can be automatically detected through screw electromechanical rotational characteristics.
Vitamin D and secondary hyperparathyroidism
Secondary hyperparathyroidism (SHPT) due to vitamin D insufficiency has long been considered as a principal mechanism in the pathogenesis of hip fracture in older people. However, not all patients with inadequate vitamin D levels develop SHPT. In 472 consecutive patients aged 60 years and older admitted with a non-pathological minimal trauma hip fracture were assessed. The prevalence of elevated PTH (>6.5 pmol/L) was 46.1%. When patients were stratified by quartiles of serum PTH, higher PTH levels were associated with older age (p=0.010), lower 25 (0H) D (p<0.001), higher phosphate (p=0.015) and creatinine (p<0.001). Patients in the top quartile compared with the lowest more often had 25 (OH) D deficiency (<25nmol/L: 31.9% vs. 19.2% p=0.009), atrial fibrillation (33.3% vs. 11.7% p=0.008) and history of stroke (49.2% vs 10.2%, p,0.001). The correlation between PTH and 25 (OH)D was weak but significant (r=-0.1827; 0.001). The prevalence of 25 (OH)D insufficiency (<50nmol/L) was 81.7%. In 47.5% the PTH level was elevated, indicating SHPT, while in the remainder the PTH response was blunted suggesting down regulation of vitamin D receptors and/or calcium sensing receptors in parathyroid cells. Fisher et al4 (Canberra Hospital and Australian National University Medical School, Australia) further concluded that older hip fracture patients demonstrate heterogeneity in calciotropic hormone concentrations. Serum PTH and 25 (OH)D measurements may help to identify subgroups of hip fracture patients with different pathogenesis and promote individualized therapeutic and prophylactic interventions.
Inhibin A (InhA), a peptide hormone normally produced by the gonad, increases bone volume and strength in the intact adult murine skeleton, and protects against gonadectomy-induced bone loss via a mechanism that increases bone formation, since no changes in osteoclast numbers or systemic markers of bone resorption are observed. Perrien DS et al5 (University of Arkansas for Medical Sciences, Arkansas) subjected adult mice to osteotomy and eternal fixator placement, and subsequently stimulated the mice with mifepristone (MFP) pellets to selectively induce InA overexpression. There was a 3-day lag time, the mice were then distracted at a rate of 0.15mm/day and sacrificed 21 days post-osteotomy. To quantify compartment-specific effects, the 3-dimensional CT data were used to define and quantify the amount of endosteal and periosteal bone formation in the distraction gap. The results demonstrated that InhA selectively increased endosteal bone formation in the distraction osteogenesis gap without affecting the amount of periosteal bone formation. In addition, proliferating cell nuclear antigen staining was significantly increased in osteoblasts within the distraction gaps of InhA overexpressing mice.
Bisphosphonates and fracture healing
Effects of antiresorptive agents on fracture healing. Mori S et al6 (Faculty of Medicine Kagawa University, Japan) investigated the effects of the anti-resorptive agents (bisphosphonates, estrogen, SERM) on fracture healing using a rat femoral osteotomy model. In the first study, 8-week-old female rats were injected with either vehicle or incadronate (10, 100 mg/kg) for 2 weeks. The femur was osteotomized and fixed with intramedullary wire. Incadronate treatment was continued (C) until sacrifice at 25 or 29 weeks after surgery. Cross-sectional area in C-100 was the largest. Although mechanical tests showed that stiffness and ultimate load of fractured femur in C-100 were the highest, histomorphometric evaluation revealed that callus remodeling was delayed in C-groups, especially in C-100. In the second study, the authors ovariectomized 3-month-old female rats and treated them with vehicle (OVX), estrogen (0.1 mg/kg, EE2), raloxifene (1.0 mg/kg, Rlx) or alendronate (0.01 mg/kg, Aln). Four weeks later, femoral osteotomy was performed. Treatment was continued until sacrifice at 6 and 16 weeks post-fracture. By 16 weeks post-fracture, OVX calluses were smaller than at 6 weeks, while the dimensions for Aln had not changed. Aln had higher BMC and ultimate load than OVX, EE2 and Rlx. EE2 and Rlx had similar biomechanical properties similar to Sham. Aln strongly suppressed callus remodeling, resulting in the highest content of woven bone and the lowest content of lamellar bone, compared to other groups. The larger Aln callus appeared to be a remarkable, morphologic adaptation to secure the fracture with inferior material. In conclusion, OVX-stimulated bone turnover resulted in the fastest progression of fracture healing, that was most delayed with bisphosphonates treatment, consistent with marked suppression of bone turnover.
McDonald M et al7 (The Children’s Hospital Westmead & University of Technology Sydney, Australia), reported that zoledronic acid (ZA) did not delay endochondral ossification in a closed rat fracture model indicating that osteoclast function is not essential to soft callus removal. Dosing began in the rats 1 week after the fracture with harvests at 2, 4, 6, 12 and 26 weeks. Groups included saline, 0.1 mg/kg ZA as bolus or 5 divided weekly doses. QCT revealed callus bone mineral content and volume were increased in both treatment groups over saline at all time points (p < 0.01). Further, between 4-6 weeks, callus volume decreased by 8% in bolus, group (remodeling), but increased by 24% in the weekly group (no remodeling). However, by 12 weeks callus volume in both ZA groups decreased by 23-26% suggestive of continued remodeling. In contrast, the weekly group still maintained a larger callus volume over saline (12 weeks – 67%, 26 weeks 88%) compared to bolus (12 weeks- 30%, 26 weeks 47%). Thus the authors found that weekly dosing more adversely affected callus remodeling.
Animal studies have shown that alendronate (ALN) inhibits bone resorption at the bone-screw interface thereby enhancing fixation. In a clinical study, Moroni A et al8 (Rizzoli Orthopaedic Institute, Bologna, Italy) introduced another innovative approach to enhance implant fixation using hydroxyapatite-coated screws coupled with bisphosphonate therapy. Patients were randomized to therapy with either alendronate (Group A) or control (Group B) for a three-month post-operative period. Fixators were removed after 3 months in all patients. All the fractures healed. No pin loosening or infection occurred in either group and no differences between femoral neck-shaft angle at 6 months versus post-op were observed. There was no significant difference in pin insertion torque between the two groups. The combined mean extraction torque of the pins implanted at positions 1 and 2 (cancellous bone of the femoral head) was 2558 ±1103 N/mm in Group A and 1171 ± 479 N/mm in Group B (p < 0.0005). The combined mean extraction torque of the pins implanted at positions 3 and 4 (cortical bone of the femoral diaphysis) was 4327 ± 1720 N/mm in Group A and 4075 ± 1022 N/mm in Group B (ns). This is the first clinical study to show improved fixation following post-operative ALN treatment. In the future, the success of delivering pharmacological therapy through an implant device would be an exciting prospect for an orthopaedic surgeon to consider.
In “Adapted implants increase anchorage in osteoporotic vertebrae- A biomechanical study” by Goldhahn J et al9 (AO Research Institute and Schulthess Clinic, Zurich, Switzerland) two newly developed implant designs in lumbar vertebral bodies under cyclic loading were evaluated. Their enlarged implant-bone interface was designed to reduce the cut-through during perpendicular, repetitive loading. A total of 65 vertebrae were used to establish five testing groups of similar BMD distribution with eight lumbar vertebrae each. DXA scans assessed BMD and structural parameters were determined by 3D-pQCT. The specimens were loaded force-controlled sinusoidally at a frequency of 1Hz for 1000 cycles at three-load level (100, 200 and 400N). All new prototype configurations except the large cylinder survived significantly longer than the control group (p<0.005). In both large prototypes, the authors reported that the cycle number until failure significantly correlated with the preoperative distance to the upper endplates (R=-0.75 resp. R=-0.94). In conclusion, although the direct relationship between bone structure or density and mechanical breakage behaviour could not yet be conclusively proven, all the prototypes adapted for poor bone structure performed better than the comparable conventional implant.
Ekholm C and Ullman M (M Sahlgrenska University Hospital, University of Gotenburg, Molndal, Sweden) presented on “The eUloq A New System for Treatment of wrist fractures”.10 The system consists of specially contoured pins with eyelets for intra-size pinning and optional fixation with low profile screws designed for fixation in osteoporotic bone. The surgical procedure is minimally invasive and the pins usually do not require removal. The prerequisite is a non-comminuted volar cortex to maintain axial length. 68% of the fractures healed with a clinically and radiologically excellent or good result. Over-reduction and/or volar displacement was noted in 20 patients. Dorsal re-angulation and incongruent DRUJ was noted in eight patients. One postoperative infection was diagnosed. Five patients had one or more pins removed. Five patients had further surgery with plate-fixation. Extensor tendon problems were noted in six patients and two tendon ruptures were diagnosed and repaired. This contoured pin principle appears to be cost effective, clinically efficient and safe with few complications when properly used in selected patient groups. Unstable volar cortex was the underlying explanation for the cases of volar displacement seen; according to the authors this complication could have been avoided with correct pre-op assessment of X-rays.
- Goh SL and Ghabrial Y. The orthopaedic surgeon and fragility fractures: Beyond fixing the bone; an Australian perspective. Royal Newcastle Hospital, Newcastle, Australia, 027.
- Kuliwaba JS, Forwood MR, and Fazzalari NL. Is there an unrepaired microdamage burden in bone from fragility hip fracture patients? Institute of Medical and veterinary Science and Hanson Institute. Adelaide, South Australia, 046.
- Hearn TC, Reynolds KJ, and Cleek TM. Computer Assisted Tightening of cancellous bone screws to adaptive torque levels. Flinders University, Adelaide, Australia, 032.
- Fisher, AA, Davis, MW, Goh SL, Srikusalanukul W, Budge MM and Smith PN. Parathyroid Hormone (PTH) Secretion in Older People with Hip Fracture: Unrecognised heterogeneity and complexity. The Canberra Hospital and Australian National University Medical School, ACT, Australia. 047.
- Perrien, DS, Liu L, Aronson J, Suva LJ and Gaddy D. Anabolic Actions of Inhibin During Distraction Osteogenesis. University of Arkansas for Medical Sciences, Arkansas, 033.
- Mori S, Mashiba T, Komatsubara S Manabe T, Kaji Y and Kawanishi J. Mild suppression of bone turnover with estrogen and SERM has insignificant effects on the progression of fracture healing. Faculty of Medicine Kagawa University, Japan, J26.
- McDonald M, Dulai S, Godfrey C, Sztynda T, Little D. Zoledronic Acid Treatment enhances hard callus formation without delaying endochonral repair in a rat fracture model. The children’s hospital Westmead, 001.
- Moroni A, Faldini C, Hoang-Kim A, Pegreffi F and Giannini S. Alendronate improves screw fixation in osteoporotic bone: a clinical study of pertrochanteric fractures. Rizzoli Orthopaedic Institute, Bologna, Italy, J3.
- Goldhahn, J, Reinhold M, Stauber M, Suhm N, Schwieger K and Schneider E. Adapted Implants Increase Anchorage in Osteoporotic Vertebrae- A Biomechanical Study. AO Research Institute and Schulthess Clinic Zurich, Switzerland, 018.
- Ekholm C and UIlman M. The eUlog A New System for Treatment of Wrist Fractures. Sahlgrenska University Hospital, University of Gotenburg, Molndal, Sweden, 031.
Last Updated ( Wednesday, 26 July 2006 )