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1.  Osteogenic Protein-1 for Long Bone Nonunion 
Executive Summary
To assess the efficacy of osteogenic protein-1 (OP-1) for long bone nonunion.
Clinical Need
Although most fractures heal within a normal period, about 5% to 10% do not heal and are classified as delayed or nonunion fractures. Nonunion and segmental bone loss after fracture, reconstructive surgery, or lesion excision can present complex orthopedic problems, and the multiple surgical procedures often needed are associated with patient morbidity and reduced quality of life.
Many factors contribute to the pathogenesis of a delayed union or nonunion fractures, including deficiencies of calcium, vitamin D, or vitamin C, and side effects of medications such as anticoagulants, steroids, some anti-inflammatory drugs, and radiation. It has been shown that smoking interferes with bone repair in several ways.
Incidence of Nonunion and Delayed Union Cases
An estimated 5% to 10% of fractures do not heal properly and go on to delayed union or nonunion. If this overall estimate of incidence were applied to the Ontario population1, the estimated number of delayed union or nonunion in the province would be between 3,863 and 7,725.
Treatment of Nonunion Cases
The treatment of nonunion cases is a challenge to orthopedic surgeons. However, the basic principle behind treatment is to provide both mechanical and biological support to the nonunion site.
Fracture stabilization and immobilization is frequently used with the other treatment modalities that provide biological support to the fractured bone. Biological support includes materials that could be served as a source of osteogenic cells (osteogenesis), a stimulator of mesenchymal cells (osteoinduction), or a scaffold-like structure (osteoconduction).
The capacity to heal a fracture is a latent potential of the stromal stem cells, which synthesize new bone. This process has been defined as osteogenesis. Activation of the stem cells to initiate osteogenic response and to differentiate into bone-forming osteoblasts is called osteoinduction. These 2 properties accelerate the rate of fracture healing or reactivate the ineffective healing process. Osteoconduction occurs when passive structures facilitate the migration of osteoprogenitor cells, the perivascular tissue, and capillaries into these structures.
Bone Grafts and Bone Graft Substitutes
Bone graft and bone graft substitutes have one or more of the following components:
Undifferentiated stem cells
Growth factors
Structural lattice
Undifferentiated stem cells are unspecialized, multipotential cells that can differentiate into a variety of specialized cells. They can also replicate themselves. The role of stem cells is to maintain and repair the tissue in which they are residing. A single stem cell can generate all cell types of that tissue. Bone marrow is a source of at least 2 kinds of stem cells. Hematopoietic stem cells that form all types of blood cells, and bone marrow stromal stem cells that have osteogenic properties and can generate bone, cartilage, and fibrous tissue.
Bone marrow has been used to stimulate bone formation in bone defects and cases of nonunion fractures. Bone marrow can be aspirated from the iliac crest and injected percutaneously with fluoroscopic guidance into the site of the nonunion fracture. The effectiveness of this technique depends on the number and activity of stem cells in the aspirated bone marrow. It may be possible to increase the proliferation and speed differentiation of stem cells by exposing them to growth factor or by combining them with collagen.
Many growth factors and cytokines induced in response to injury are believed to have a considerable role in the process of repair. Of the many bone growth factors studied, bone morphogenetics (BMPs) have generated the greatest attention because of their osteoinductive potential. The BMPs that have been most widely studied for their ability to induce bone regeneration in humans include BMP-2 and BMP-7 (osteogenic protein). Human osteogenic protein-1 (OP-1) has been cloned and produced with recombinant technology and is free from the risk of infection or allergic reaction.
The structural lattice is osteoconductive; it supports the ingrowth of developing capillaries and perivascular tissues. Three distinct groups of structural lattice have been identified: collagen, calcium sulphate, and calcium phosphate. These materials can be used to replace a lost segment of bone.
Grafts Used for Nonunion
Autologous bone graft is generally considered the gold standard and the best material for grafting because it contains several elements that are critical in promoting bone formation, including osteoprogenitor cells, the matrix, and bone morphogenetic proteins. The osteoconductive property of cancellous autograft is related to the porosity of bone. The highly porous, scaffold-like structure of the graft allows host osteoblasts and host osteoprogenitor cells to migrate easily into the area of the defect and to begin regeneration of bone. Sources of cancellous bone are the iliac crest, the distal femur, the greater trochanter, and the proximal tibia. However, harvesting the autologous bone graft is associated with postoperative pain at the donor site, potential injury to the surrounding arteries, nerves, and tissues, and the risk of infection. Thus the development of synthetic materials with osteoconductive and osteoinductive properties that can eliminate the need for harvesting has become a major goal of orthopedic research.
Allograft is the graft of tissue between individuals who are of the same species but are of a disparate genotype. Allograft has osteoconductive and limited osteoinductive properties. Demineralized bone matrix (DBM) is human cortical and cancellous allograft. These products are prepared by acid extraction of allograft bone, resulting in the loss of most of the mineralized component while collagen and noncollagenous proteins, including growth factors, are retained. Figures 1 to 5 demonstrate the osteogenic, osteoinduction, and osteoconduction properties of autologous bone graft, allograft, OP-1, bone graft substitutes, and bone marrow.
Autologous Bone Graft
Osteogenic Protein-1
Allograft bone and Demineralized Bone Matrix
Bone Graft Substitutes
Autologous Bone Marrow Graft
New Technology Being Reviewed: Osteogenic Protein-1
Health Canada issued a Class IV licence for OP-1 in June 2004 (licence number 36320). The manufacturer of OP-1 is Stryker Biotech (Hapkinton, MA).
The United States Food and Drug Administration (FDA) issued a humanitarian device exemption for the application of the OP-1 implant as an “alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and alternative treatments have failed.” Regulatory agencies in Europe, Australia, and New Zealand have permitted the use of this implant in specific cases, such as in tibial nonunions, or in more general cases, such as in long bone nonunions.
According to the manufacturer, OP-1 is indicated for the treatment of long bone nonunions. It is contraindicated in the patient has a hypersensitivity to the active substance or collagen, and it should not be applied at the site of a resected tumour that is at or near the defect or fracture. Finally, it should not be used in patients who are skeletally immature (< 18 years of age), or if there is no radiological evidence of closure of epiphysis.
Review Strategy
To summarize the safety profile and effectiveness of OP-1 in the treatment of cases of long bone nonunion and bone defects
To compare the effectiveness and cost effectiveness of OP-1 in the treatment of long bone nonunions and bone defects with the alternative technologies, particularly the gold standard autologous bone graft.
Literature Search
International Network of Agencies for Health Technology Assessments (INAHTA), the Cochrane Database of Systematic Reviews and the CCTR (formerly Cochrane Controlled Trials Register) were searched for health technology assessments. MEDLINE, EMBASE, Medline In Process and Other Non-Indexed Citations were searched from January 1, 1996 to January 27, 2004 for studies on OP-1. The search was limited to English-language articles and human studies. The search yielded 47 citations. Three studies met inclusion criteria (2 RCTs and 1 Ontario-based study presented at an international conference.
Summary of Findings
Friedlaender et al. conducted a prospective, randomized, partially blinded clinical trial on the treatment tibial nonunions with OP-1. Tibial nonunions were chosen for this study because of their high frequency, challenging treatment requirements, and substantial morbidity. All of the nonunions were at least 9 months old and had shown no progress toward healing over the previous 3 months. The patients were randomized to receive either treatment with autologous bone grafting or treatment with OP-1 in a type-1 collagen carrier. Both groups received reduction and fixation with an intramedullary rod. Table 1 summarizes the clinical outcomes of this study.
Outcomes in a Randomized Clinical Trial on Tibial Nonunions: Osteogenic Protein-1 versus Autologous Bone Grafting
Clinical success was defined as full weight-bearing, loss of severe pain at the fracture site on weight-bearing, and no further surgical treatment to enhance fracture repair.
The results of this study demonstrated that recombinant OP-1 is associated with substantial clinical and radiographic success for the treatment of tibial nonunions when used with intramedullary rod fixation. No adverse event related to sensitization was reported. Five per cent of the patients in the OP-1 group had circulating antibodies against type 1 collagen. Only 10% of the patients had a low level of anti-OP-1 antibodies, and all effects were transient. Furthermore, the success rate with the OP-1 implant was comparable with those achieved with autograft at 9 and 24 months follow-up. Eighty-two per cent of patients were successful at 24 months follow-up in both groups.
Statistically significant increased blood loss in the group treated with the autograft was observed (P = .049). Patients treated with autograft had longer operation and hospitalization times. All patients in the autograft group had pain at the donor site after surgery, and more than 80% judged their postoperative pain as moderate or severe. At their 6-month visit, 20% of the patients in the autograft group had persistent pain, mild or moderate in nature, at the donor site. This number fell to 13% at 12 months.
All patients in each of the groups had at least 1 adverse event that wasn’t serious, such as fever, nausea and vomiting, leg edema, discomfort, and bruising at the operative site. The incidence of these events was similar in both groups. Serious adverse events were observed in 44% of both groups, none of which were considered related to the OP-1 implant or autograft.
On the basis of this data, the FDA issued a humanitarian device exemption for the application of OP-1 implant as an alternative to autograft in recalcitrant long bone nonunions when the use of autograft is unfeasible and alternative treatments have failed.
Study on Fibular Defects
Geesink et al. investigated the osteogenic activity of OP-1 by assessing its value in bridging fibular defects made at the time of tibial osteotomy for varus or valgus deformity of the knee. This study had 2 phases and included 12 patients in each phase. Each phase included 12 patients (6 in each group). Patients in the first phase received either DBM or were left untreated. Patients in the second phase received either OP-1 on collagen type-1 or collagen type-1 alone.
Radiological and Dual Energy X-ray Absorptiometry (DEXA) evaluation showed that in patients in whom the defect was left untreated, no formation of bone occurred. At 12 months follow-up, new bone formation with bridging occurred in 4 of the 6 patients in DMB group, and 5 of the 6 patients in OP-1 group. One patient in OP-1 group did not show any evidence of new bone formation at any point during the study.
Ontario Pilot Study
A prospective pilot study was conducted in Ontario, Canada to investigate the safety and efficacy of OP-1 for the treatment of recalcitrant long bone nonunions. The study looked at 15 patients with complex, recalcitrant, long bone nonunions whose previous treatment had failed. The investigators concluded that this bone graft substitute appears to be safe and effective in providing sufficient biological stimulation in difficult to treat nonunions. Results of a more complete study on 70 patients are ready for publication. According to the principal investigator, OP-1 was 90% effective in inducing bone formation and bone healing in this sample.
Alternative Technologies
The Medical Advisory Secretariat conducted a literature search from January 1, 2000 to February 28, 2005 to identify studies on nonunions/bone defects that had been treated with alternative technologies. A review of these studies showed that, in addition to the gold standard autologous bone marrow grafting, bone allografts, demineralized bone matrices, bone graft substitutes, and autologous bone marrow have been used for treatment of nonunions and bone defects. These studies were categorized according to the osteoinductive, osteoconductive, and osteogenesis properties of the technologies studied.
A review of these studies showed that bone allografts have been used mostly in various reconstruction procedures to restore the defect after excavating a bone lesion. Two studies investigated the effectiveness of DBM in healing fracture nonunions. Calcium phosphate and calcium sulphate have been used mostly for repair of bone defects.
Several investigators have looked at the use of autologous bone marrow for treatment of long bone nonunions. The results of these studies show that method of percutaneous bone marrow grafting is highly effective in the treatment of long bone nonunions. In a total of 301 fractures across all studies, 268 (89%) healed with a mean healing time of 2.5 to 8 months. This healing time as derived from these case series is less than the timing of the primary end point in Friedlaender’s study (9 months). Table 2 summarizes the results of these studies. Table 2 summarizes the results of these studies.
Studies that used Percutaneous Bone Marrow Grafting for Treatment of Nonunions
Economic Analysis
Based on annual estimated incidence of long-bone nonunion of 3,863 - 7,725, the annual hospitalization costs associated with this condition is between $21.2 and $42.3 million based on a unit cost of $5,477 per hospital separation. When utilized, the device, a single vial of OP-1, is approximately $5,000 and if adopted universally in Ontario, the total device costs would be in the range of $19.3 - $38.6 million annually. The physician fee for harvest, insertion of bone, or OP-1 is $193 and is $193 for autologous bone marrow transplantation. Total annual physician costs are expected to be in the range of from $0.7 million to $1.3 million per year. Expenditures associated with long-bone nonunion are unlikely to increase since incidence of long-bone nonunion is unlikely to change in the future. However, the rate of uptake of OP-1 could have a significant impact on costs if the uptake were large.
The use of OP-1 and autologous bone marrow transplantation may offset pain medication costs compared with those associated with autologous bone harvest given that the former procedures do not involve the pain associated with the bone harvest site. However, given that this pain is normally not permanent, the overall offset is likely to be small. There are likely to be smaller OHIP costs associated with OP-1 than bone-harvest procedures given that only 1, rather than 2, incisions are needed when comparing the former with the latter procedure. This offset could amount to between $0.3 million to $0.7 million annually.
No data on the cost-effectiveness of OP-1 is available.
PMCID: PMC3382627  PMID: 23074475
2.  Autologous bone graft versus demineralized bone matrix in internal fixation of ununited long bones 
Non-unions are severe complications in orthopaedic trauma care and occur in 10% of all fractures. The golden standard for the treatment of ununited fractures includes open reduction and internal fixation (ORIF) as well as augmentation with autologous-bone-grafting. However, there is morbidity associated with the bone-graft donor site and some patients offer limited quantity or quality of autologous-bone graft material. Since allogene bone-grafts are introduced on the market, this comparative study aims to evaluate healing characteristics of ununited bones treated with ORIF combined with either iliac-crest-autologous-bone-grafting (ICABG) or demineralized-bone-matrix (DBM).
Methods and results
From 2000 to 2006 out of sixty-two consecutive patients with non-unions presenting at our Level I Trauma Center, twenty patients had ununited diaphyseal fractures of long bones and were treated by ORIF combined either by ICABG- (n = 10) or DBM-augmentation (n = 10). At the time of index-operation, patients of the DBM-group had a higher level of comorbidity (ASA-value: p = 0.014). Mean duration of follow-up was 56.6 months (ICABG-group) and 41.2 months (DBM-group). All patients were clinically and radiographically assessed and adverse effects related to bone grafting were documented. The results showed that two non-unions augmented with ICABG failed osseous healing (20%) whereas all non-unions grafted by DBM showed successful consolidation during the first year after the index operation (p = 0.146). No early complications were documented in both groups but two patients of the ICABG-group suffered long-term problems at the donor site (20%) (p = 0.146). Pain intensity were comparable in both groups (p = 0.326). However, patients treated with DBM were more satisfied with the surgical procedure (p = 0.031).
With the use of DBM, the costs for augmentation of the non-union-site are more expensive compared to ICABG (calculated difference: 160 €/case). Nevertheless, this study demonstrated that the application of DBM compared to ICABG led to an advanced outcome in the treatment of non-unions and simultaneously to a decreased quantity of adverse effects. Therefore we conclude that DBM should be offered as an alternative to ICABG, in particular to patients with elevated comorbidity and those with limited availability or reduced quality of autologous-bone graft material.
PMCID: PMC2801473  PMID: 20003511
3.  Injection of Demineralized Bone Matrix With Bone Marrow Concentrate Improves Healing in Unicameral Bone Cyst 
Unicameral bone cysts are benign lesions that usually spontaneously regress with skeletal maturity; however, the high risk of pathologic fractures often justifies treatment that could reinforce a weakened bone cortex. Various treatments have been proposed but there is no consensus regarding the best procedure.
We compared the healing rates and failures of two methods of cure based on multiple injections of corticosteroid or a single injection of demineralized bone matrix (DBM) in association with bone marrow concentrate (BMC).
We retrospectively reviewed 184 patients who had one of the two treatments for unicameral bone cysts with cortical erosion. Clinical records were reviewed for treatment failures and radiographs for healing in all patients. The minimum followup was 12 months for the Steroids Group (mean, 48 months; range, 12–120 months) and 12 months for the DBM + BMC Group (mean, 20 months; range, 12–28 months).
After one treatment we observed a lower healing rate of cysts treated with multiple injections of steroids compared with the healing after the first injection of DBM + BMC (21% versus 58%, respectively). At last followup, 38% healed with steroids and 71% with DBM + BMC. The rate of failure after one steroid injection was higher than after a single injection of BDM + BMC (63% versus 24%, respectively). We observed no difference in fracture rates after treatment between the two groups.
A single injection of DBM added with autologous bone marrow concentrate appears to provide a higher healing rate with a lower number of failures compared with a single injection of steroids.
Level of Evidence
Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2947677  PMID: 20568027
4.  Minimal invasive surgery for unicameral bone cyst using demineralized bone matrix: a case series 
Various treatments for unicameral bone cyst have been proposed. Recent concern focuses on the effectiveness of closed methods. This study evaluated the effectiveness of demineralized bone matrix as a graft material after intramedullary decompression for the treatment of unicameral bone cysts.
Between October 2008 and June 2010, twenty-five patients with a unicameral bone cyst were treated with intramedullary decompression followed by grafting of demineralized bone matrix. There were 21 males and 4 female patients with mean age of 11.1 years (range, 3–19 years). The proximal metaphysis of the humerus was affected in 12 patients, the proximal femur in five, the calcaneum in three, the distal femur in two, the tibia in two, and the radius in one. There were 17 active cysts and 8 latent cysts. Radiologic change was evaluated according to a modified Neer classification. Time to healing was defined as the period required achieving cortical thickening on the anteroposterior and lateral plain radiographs, as well as consolidation of the cyst. The patients were followed up for mean period of 23.9 months (range, 15–36 months).
Nineteen of 25 cysts had completely consolidated after a single procedure. The mean time to healing was 6.6 months (range, 3–12 months). Four had incomplete healing radiographically but had no clinical symptom with enough cortical thickness to prevent fracture. None of these four cysts needed a second intervention until the last follow-up. Two of 25 patients required a second intervention because of cyst recurrence. All of the two had a radiographical healing of cyst after mean of 10 additional months of follow-up.
A minimal invasive technique including the injection of DBM could serve as an excellent treatment method for unicameral bone cysts.
PMCID: PMC3475132  PMID: 22839754
5.  Grafting Using Injectable Calcium Sulfate in Bone Tumor Surgery: Comparison with Demineralized Bone Matrix-based Grafting 
Clinics in Orthopedic Surgery  2011;3(3):191-201.
Injectable calcium sulfate is a clinically proven osteoconductive biomaterial, and it is an injectable, resorbable and semi-structural bone graft material. The purpose of this study was to validate the clinical outcomes of injectable calcium sulfate (ICS) grafts as compared with those of a demineralized bone matrix (DBM)-based graft for filling in contained bony defects created by tumor surgery.
Fifty-six patients (41 males and 15 females) with various bone tumors and who were surgically treated between September 2003 and October 2007 were included for this study. The patients were randomly allocated into two groups, and either an ICS graft (28 patients) or a DBM-based graft (28 patients) was implanted into each contained defect that was developed by the surgery. The radiographic outcomes were compared between the two groups and various clinical factors were included for the statistical analysis.
When one case with early postoperative pathologic fracture in the DBM group was excluded, the overall success rates of the ICS and DBM grafting were 85.7% (24/28) and 88.9% (24/27) (p > 0.05), respectively. The average time to complete healing was 17.3 weeks in the ICS group and 14.9 weeks in the DBM group (p > 0.05). Additionally, the ICS was completely resorbed within 3 months, except for one case.
Although the rate of resorption of ICS is a concern, the injectable calcium sulfate appears to be a comparable bone graft substitute for a DBM-based graft, with a lower cost, for the treatment of the bone defects created during surgery for various bone tumors.
PMCID: PMC3162199  PMID: 21909466
Injectable calcium sulfate; Demineralized bone matrix; Bone tumor
6.  Bone Mesenchymal Stem Cells with Growth Factors Successfully Treat Nonunions and Delayed Unions 
HSS Journal  2015;11(2):104-111.
While the gold standard of treatment of nonunion is open autologous bone grafting, studies have shown that injecting bone marrow aspirate concentrates (BMAC) is effective in treating tibial nonunions with fracture gaps less than 5 mm.
We aim to demonstrate that combining BMAC with osteoinductive agents can effectively treat delayed or nonunion regardless of fracture gap size, nonunion site, or osteoinductive agent used.
In this non-randomized retrospective-prospective cohort study, 49 patients with tibial nonunion met the inclusion criteria and underwent BMAC injection with demineralized bone matrix (DBM) and/or recombinant human bone morphogenic protein-2 (rhBMP-2). Radiologic healing of the fracture was the primary outcome. Patients were followed until radiographic union was achieved or another procedure was performed. Radiographic healing was defined as bridging of three out of four cortices on anteroposterior and lateral films.
There was no difference in the healing rate (p = 0.81) between patients with fracture gaps less than and greater than 5 mm. On multivariate analysis, the use of rhBMP-2 was associated with a lower healing rate compared to DBM (p = 0.036). Patients who underwent early intervention (within 6 months of fixation) had higher union rates (p = 0.04).
This study shows that percutaneous BMAC injection combined with either DBM and/or rhBMP-2 is a safe and effective treatment for delayed or nonunion regardless of the fracture gap size or fracture site. DBM may be superior to rhBMP-2 in this procedure.
Electronic supplementary material
The online version of this article (doi:10.1007/s11420-015-9432-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4481261  PMID: 26140028
modified Hernigou technique; nonunion; delayed union; BMAC (concentrated autogenous iliac crest bone marrow aspirate); demineralized bone matrix; bone morphogenic protein
7.  Does Fracture Affect the Healing Time or Frequency of Recurrence in a Simple Bone Cyst of the Proximal Femur? 
Studies have focused on intramedullary nailing of femoral simple bone cysts but have not clarified the recurrence frequency or management of recurrent cysts. In particular, the affect of pathologic fractures on cyst healing, recurrence, and complications of treatment have not been reported.
We performed a retrospective comparative study to examine whether there were differences between simple bone cysts in the proximal femur nailed after pathologic fracture and those without pathologic fracture in terms of (1) healing time, (2) frequency and timing of recurrence, and (3) complications.
From 1995 to 2005, 54 patients diagnosed with femoral simple bone cysts were treated and followed for a minimum of 8 years. Flexible nails were inserted in a retrograde fashion in 25 patients with fractures and 29 patients without fractures. The healing period, degree of radiographic consolidation based on the criteria of Capanna et al., recurrence frequency, and final bony abnormalities were analyzed. The mean followups were 107 months (range, 96–124 months) and 103 months (range, 96–140 months) in the groups with and without fractures, respectively. With the numbers available, a post hoc calculation showed that this study had 80% power to detect a difference of 7 months of healing time as significant with a probability less than 0.05.
With the numbers available, the mean healing period was not different between groups (25 versus 30 months in the groups with and without fractures, respectively; p = 0.16). Complete healing was observed at 19 versus 18 months, incomplete healing at 5 versus 8 months, and recurrence was observed in one and three patients in the groups with and without fractures, respectively. No differences were found in the distribution of healing grade based on the criteria of Capanna et al. A second surgery was performed using intramedullary nails in two patients with an open physis and compression hip screw fixation was performed in two patients with a closed physis. Finally, the recurrent cysts were classified as completely healed in three patients and incompletely healed in one.
Whether a pathologic fracture had occurred before surgical treatment, intramedullary nailing of femoral simple bone cysts resulted in reliable healing, and the frequency of recurrence did not differ. Because this was a retrospective study, the optimal treatment for recurred cysts after intramedullary nailing should be further investigated through a comparative or prospective study.
Level of Evidence
Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.
PMCID: PMC4160469  PMID: 25002216
8.  Is DBM Beneficial for the Enhancement of Bony Consolidation in Distraction Osteogenesis? A Randomized Controlled Trial 
BioMed Research International  2015;2015:281738.
The aim of the present study was to compare the radiographic and clinical outcomes of DBM injection and conventional treatment during tibial lengthening over an intramedullary nail in adult patients with short stature. Twenty-nine patients were randomized to receive DBM injection (n = 14) or conventional treatment without any injection (n = 15) and evaluated. The outcome was measured on the basis of the pixel value ratio (PVR) in the digital radiographs during the consolidation period; healing index; clinical assessment; and the rate of complications. In the DBM group, the mean PVR of 1 (mineral density of the callus is comparable to the adjacent bone) was reached by 40 weeks in anterior and medial cortices which was significantly different than that in the control group (P = 0.03 for anterior cortex; P = 0.04 for medial cortex). The average healing index in the DBM group was 39.8 ± 5.3 days/cm compared to 44.3 ± 5.8 days/cm in the control group (P = 0.05). There were no significant differences in clinical outcomes (P = 0.23) and functional status (P = 0.47) including complications (P = 0.72) between two groups. In this randomized clinical trial, injection of DBM at the time of initial operation enhanced consolidation of regenerate callus without interfering with clinical outcomes compared to that with conventional treatment.
PMCID: PMC4326219  PMID: 25705653
9.  The Role of the Orthopaedic Surgeon 
Treatment for patients with vertebral compression fractures (VCFs) should address pain and mobility, and aim to prevent further fractures. Restoration of vertebral height to improve the spinal deformity is also of primary importance. Traditionally, osteoporosis-induced VCFs have been treated with bed rest, narcotic analgesics, braces, and physical therapy. However, immobility is known to have a negative impact on muscle strength and bone mass and may cause serious general health complications, narcotics can worsen mood and mentation problems, and brace wear is not well tolerated by the elderly. These fractures have a considerable impact on quality of life, and although most of them heal, the height loss and deformity remain uncorrected. Vertebroplasty and balloon kyphoplasty are minimally invasive treatment options for VCFs. Kyphoplasty is designed to reduce and stabilise the fracture in a controlled way, to correct the spinal deformity and to provide immediate pain relief, mobility, and an improved quality of life. The main differences between balloon kyphoplasty and vertebroplasty are the greater potential of the kyphoplasty procedure to restore the vertebral height and kyphosis angle of the fractured vertebra and (although the clinical significance of this has not yet been demonstrated) its lower percentage of cement extravasation; the latter is related to lower injection pressures, and facilitated by a higher cement viscosity and by the cavity created in the fractured vertebrae.
Worldwide, over 95,000 VCFs in 75,000 patients have been treated with balloon kyphoplasty. Accordingly, the orthopaedic surgeon today plays a leading role in the “Fracture Unit”, not only on the therapeutic side, but also on the diagnostic side. The kyphoplasty kit can allow percutaneous bone biopsy, often very important in order to obtain a correct diagnosis. In order to justify resource allocation and patient selection for new osteoporotic fracture treatment technologies, it is also becoming increasingly important to determine the cost-effectiveness of treatments. In a recent study we highlighted why spine surgery is important in VCFs, comparing the efficacy and safety of kyphoplasty and of non-surgical management for the treatment of acute osteoporotic VCFs. Our aim was to test the hypothesis that kyphoplasty would result in greater improvement in quality of life with a better cost-effectiveness ratio at 24 months’ follow up. Between January 2005 and September 2008, we randomly assigned 60 patients with one fresh (< 6 weeks) painful osteoporotic VCF to undergo either percutaneous surgical treatment with Medtronic Kyphoplasty (Group A, n=32) or conservative treatment (Group B, n=28), preceded by 40 days of bed rest and followed by 40 days of hyperextension back brace wear (type C35). The baseline characteristics were similar in the two groups: the average age was 67 years and 7 months, min. 62 - max. 89 years, in Group A, and 66 years and 5 months, min. 64 - max. 78 years, in Group B. The fractured levels were T12=10, L1=11, L2=5, L3=6 in Group A and T12=7, L1=13, L2=5, L3=3 in Group B. According to the Magerl classification the VCFs in both groups were prevalently A1.2 (13 cases in A and 16 in B) and A1.3 (14 cases in A and 8 in B). In all cases standing lateral spinal radiographs were taken at baseline, 3 months, 6 months, 12 months and 24 months to evaluate vertebral kyphosis (VK) and regional kyphosis (RK). Vertebral kyphosis was measured from the superior endplate to the inferior endplate of the fractured vertebra. Regional kyphosis was measured from the inferior endplate of the intact adjacent distal vertebra to the superior endplate of the intact adjacent proximal vertebra. Pain was evaluated at baseline, 3 months, 6 months, 12 months and 24 months with the VAS pain scale. Each patient had a card to be used for recording medical and non-medical costs sustained in the course of the 24 months.
The primary endpoint was the difference, between the groups, in VK and VAS pain scale score changes from baseline to 3, 6, 12 and 24 months: the surgical treatment group always showed better results. Mean VK was 11.50 degrees at baseline, 6.50 degrees at 3 months, 6.37 degrees at 6 months, and 6.38 degrees at 12 and 24 months in Group A and 12.6 degrees at baseline, 10.50 degrees at 3 months, 10.70 degrees at 6 months, and 11.80 degrees at 12 and 24 months in Group B. The VAS pain score was 9 (baseline), 2 (3 mths), 1 (6 mths), 2 (12 and 24 mths) in Group A and 9 (baseline), 7 (3 mths), 4 (6 mths), 5 (12 and 24 mths) in Group B.
The secondary endpoint was the difference, between surgical and conservative treatments, in medical (hospitalisation, surgical procedure, convalescence and 24-months follow up) and non-medical costs sustained. Group A recorded higher hospitalisation costs (average 9 days, € 4551) than Group B (average 5 days, € 2681). For the surgically treated group there was also an additional surgical procedure cost (average € 4,483.09).
The convalescence was longer in Group B (average 95 days, medical costs: € 2018,59) than in Group A (average 15 days, medical costs: € 192,92). Obviously, non-medical costs were also higher in Group B (€ 3390,00) than in Group A (€ 210,00). Between 3 and 24 months we recorded three cases of back pain Group A and 17 in Group B, with an additional cost of € 47,53 in the first group and € 1319,56 in the second. Therefore, on the whole, the surgical treatment had an average cost of € 9484,54 while the conservative treatment had an average cost of € 9409,15. However it is important to underline that in the second group there was also another non-medical cost that is difficult to quantify: that of family caregiving, which corresponds to 1 person’s days of absence from work (average 14 days, min. 5, max. 22).
The cost-effectiveness relationship becomes even better for the surgically treated group if we analyse the complications. In the first group we recorded seven asymptomatic minor complications (3 cases of vein leakage and 4 of intradiscal leakage) that did not generate supplementary medical or non-medical costs; instead, in the second group we recorded 13 complications (6 cases of decubitus ulcers and 7 cases of bronchitis) generating an additional cost of ⇔ 4325. Therefore, this study confirmed that kyphoplasty may today be the gold standard in the treatment of fresh osteoporotic VCFs. Accordingly, orthopaedic surgeon is destined to play an ever more important role within a superspecialist team.
PMCID: PMC3213845
10.  Comparison of titanium elastic intramedullary nailing versus injection of bone marrow in treatment of simple bone cysts in children: a retrospective study 
Simple bone cysts are common benign lytic bone lesions in children. The main goals of treatment for bone cysts are to prevent pathological fractures, support the healing process, and prevent recurrence. This retrospective study compared fixation with titanium elastic intramedullary nailing (TEN) versus aspiration and injection of autogenous bone marrow (ABM) for the treatment of simple bone cysts in children.
Forty-six patients (mean follow-up, 62 months; range, 34–71 months) who presented with bone cysts (30 in the humerus, 16 in the femur) from January 2006 to December 2012 were retrospectively evaluated. Patients were treated with either TEN or ABM injection. Radiographs were evaluated according to previously established criteria. Clinical evaluations of pain, infection, additional fractures, and range of motion were performed.
After treatment, all patients were pain-free and had normal range of motion in adjacent joints. In the ABM group, 14 (60.9 %) bone cysts completely healed, six (26.1 %) healed with small residuals after two injections, and three (13.0 %) recurred. In the TEN group, 16 (69.6 %) bone cysts completely healed, four (17.4 %) healed with small residuals, and three (13.0 %) recurred. There were no significant differences in radiographic outcomes between groups at the final follow-up (P > 0.05). Three patients developed skin irritation as a result of the nail ends. Additional fractures occurred in four patients who underwent ABM injection and in two patients who underwent TEN. No significant associations were found between pathological fractures and cyst activity, location, or treatment outcomes in the patients studied.
Both TEN and ABM injection are safe and effective treatment for bone cysts. ABM injection promotes osteogenic differentiation of bone marrow stromal cells; multiple injections can reduce the likelihood of recurrence. TEN stabilizes the affected bone and thus allows early limb mobilization. It also reduces pressure in the capsule wall by continuous decompression to promote cyst healing. ABM injections can be used to treat cyst recurrence after previous TEN, with favorable results.
PMCID: PMC4986274  PMID: 27527751
Simple bone cyst; Elastic intramedullary nailing; Bone marrow; Long bones; Children
11.  Efficacy of platelet rich fibrin in the treatment of human intrabony defects with or without bone graft: A randomized controlled trial 
To evaluate the efficacy of platelet rich fibrin (PRF) with or without bone graft [demineralized bone matrix (DBM) graft] in the treatment of intrabony defects based on clinical and radiographic parameters.
Materials and Methods:
Thirty six intrabony defects in 36 patients were randomly divided into three different groups and were treated with group A (PRF with DBM) or group B (PRF alone) or group C [open flap debridement (OFD)]. Clinical parameters such as plaque index (PI), gingival index (GI), probing depth (PD), relative attachment level (RAL), and gingival recession (GR) were assessed at baseline and 9 months postoperatively; radiographic parameters such as linear bone growth (LBG) and percentage in bone fill (%BF) were calculated by using the image analysis software. Comparisons of groups were analyzed using Kruskal–Wallis analysis of variance test. Pair-wise comparison of groups was done by Mann-Whitney U test.
Mean PD reduction and RAL gain were greater in group A (4.25 ± 1.48, 3.92 ± 0.90) and group B (3.82 ± 0.75, 3.27 ± 0.65) than control (3.00 ± 1.21, 2.25 ± 0.62). Furthermore, statistically significant improvement in LBG and %BF was found in group A (3.47 ± 0.53, 61.53 ± 4.54) compared to group B (2.55 ± 0.61, 49.60 ± 14.08) and group C (1.21 ± 0.80, 24.69 ± 15.59).
The study demonstrated that PRF improves clinical and radiological parameters compared to OFD alone in intrabony defects. Addition of DBM enhances the effects of PRF in RAL gain and radiographic defect fill.
PMCID: PMC5022394  PMID: 27652249
Chronic periodontitis; clinical trial; periodontal attachment loss; platelet-derived growth factor; regeneration
12.  Demineralized Bone Matrix Injection in Consolidation Phase Enhances Bone Regeneration in Distraction Osteogenesis via Endochondral Bone Formation 
Clinics in Orthopedic Surgery  2015;7(3):383-391.
Distraction osteogenesis (DO) is a promising tool for bone and tissue regeneration. However, prolonged healing time remains a major problem. Various materials including cells, cytokines, and growth factors have been used in an attempt to enhance bone formation. We examined the effect of percutaneous injection of demineralized bone matrix (DBM) during the consolidation phase on bone regeneration after distraction.
The immature rabbit tibial DO model (20 mm length-gain) was used. Twenty-eight animals received DBM 100 mg percutaneously at the end of distraction. Another 22 animals were left without further procedure (control). Plain radiographs were taken every week. Postmortem bone dual-energy X-ray absorptiometry and micro-computed tomography (micro-CT) studies were performed at the third and sixth weeks of the consolidation period and histological analysis was performed.
The regenerate bone mineral density was higher in the DBM group when compared with that in the saline injection control group at the third week postdistraction. Quantitative analysis using micro-CT revealed larger trabecular bone volume, higher trabecular number, and less trabecular separation in the DBM group than in the saline injection control group. Cross-sectional area and cortical thickness at the sixth week postdistraction, assessed using micro-CT, were greater in the regenerates of the DBM group compared with the control group. Histological evaluation revealed higher trabecular bone volume and trabecular number in the regenerate of the DBM group. New bone formation was apparently enhanced, via endochondral ossification, at the site and in the vicinity of the injected DBM. DBM was absorbed slowly, but it remained until the sixth postoperative week after injection.
DBM administration into the distraction gap at the end of the distraction period resulted in a significantly greater regenerate bone area, trabecular number, and cortical thickness in the rabbit tibial DO model. These data suggest that percutaneous DBM administration at the end of the distraction period or in the early consolidation period may stimulate regenerate bone formation and consolidation in a clinical situation with delayed bone healing during DO.
PMCID: PMC4553289  PMID: 26330963
Bone substitute; Osteogenesis; Distraction; Bone development
13.  Treatment of nontraumatic osteonecrosis of the femoral head using bone impaction grafting through a femoral neck window 
International Orthopaedics  2009;34(5):635-639.
Nontraumatic osteonecrosis of the femoral head (non-ONFH) is a disorder that can lead to femoral head collapse and the need for total hip replacement. Various head-preserving procedures have been used for this disease to avert the need for total hip replacement. These include various vascularised and nonvascularised bone grafting procedures. We examined the effect of bone-grafting through a window at the femoral head-neck junction known as the “light bulb” approach for the treatment of osteonecrosis of the femoral head with a combination of demineralised bone matrix (DBM) and auto-iliac bone. The study included 110 patients (138 hips; 41 females, 69 males; mean age 32.36 years, range 17–54 years) with stage IIA–IIIA nontraumatic avascular necrosis of the femoral head according to the system of the ARCO (Association Research Circulation Osseous). The bone grafting procedure is called “light bulb” procedure in which the diseased bone was replaced by a bone graft substitute (combination of DBM and auto-iliac bone).The outcome was determined by the changes in the Harris hip score, by progression in radiographic stages, and by the need for hip replacement. The mean follow-up was 25.37 months (range 7–42 months). All data were processed by a statistics analysis including Cox risk model analysis and Kaplan-Meier survival analysis. Pre- and postoperative evaluations showed that the mean Harris hip score increased from 62 to 79. Clinically, 94 of 138 hips (68%) were successful at the latest follow-up, and radiological improvement was noted in 100% of patients in stage IIA, 76.67% of patients in stage IIB and 50.96% of patients in stage IIC and IIIA cases. Excellent and good results according to the Harris score were obtained in 100% of cases in stage IIA, 93.33% in stage IIB and 59.62% in stages IIIA and IIC stage, with a survivorship of 85% in stages IIA and IIB and 60% in stage IIIA and IIC cases. Cox risk model analysis showed that the clinical success rate correlated with both pre-operation stage and the necrotic area of the femoral head. The complications included ectopic ossification, lateral femoral cutaneous nerve lesion and joint infection. This procedure may be effective at avoiding or forestalling the need for total hip replacement in young patients with early to intermediate stages of osteonecrosis of the femoral head. Therefore, it may be the treatment of choice particularly in nontraumatic osteonecrosis of the femoral head of pre-collapse stage with small and middle area (<30%, or the depth of collapse <2 mm).
PMCID: PMC2903158  PMID: 19529935
14.  Demineralized Bone Matrix Add-On for Acceleration of Bone Healing in Atypical Subtrochanteric Femoral Fracture: A Consecutive Case-Control Study 
BioMed Research International  2016;2016:4061539.
Background. Delayed union and nonunion are common complications in atypical femoral fractures (AFFs) despite having good fracture fixation. Demineralized bone matrix (DBM) is a successfully proven method for enhancing fracture healing of the long bone fracture and nonunion and should be used in AFFs. This study aimed to compare the outcome after subtrochanteric AFFs (ST-AFFs) fixation with and without DBM. Materials and Methods. A prospective study was conducted on 9 ST-AFFs patients using DBM (DBM group) during 2013-2014 and compared with a retrospective consecutive case series of ST-AFFs patients treated without DBM (2010–2012) (NDBM group, 9 patients). All patients were treated with the same standard guideline and followed up until fractures completely united. Postoperative outcomes were then compared. Results. DBM group showed a significant shorter healing time than NDBM group (28.1 ± 14.4 versus 57.9 ± 36.8 weeks, p = 0.04). Delayed union was found in 4 patients (44%) in DBM group compared with 7 patients (78%) in NDBM group (p > 0.05). No statistical difference of nonunion was demonstrated between both groups (DBM = 1 and NDBM = 2, p > 0.05). Neither postoperative infection nor severe local tissue reaction was found. Conclusions. DBM is safe and effective for accelerating the fracture healing in ST-AFFx and possibly reduces nonunion after fracture fixation. Trial registration number is TCTR20151021001.
PMCID: PMC4789057  PMID: 27022610
15.  The Effect of Poloxamer 407-Based Hydrogel on the Osteoinductivity of Demineralized Bone Matrix 
Clinics in Orthopedic Surgery  2014;6(4):455-461.
Demineralized bone matrix (DBM) is used for bone healing due to its osteoinductivity, but it requires a carrier for clinical application. Here, we report the effects on the osteoinductivity of DBM by use of a poloxamer 407-based hydrogel as the carrier, compared to sterile water.
DBM-W and DBM-H represent 27 wt% of DBM with sterile water and DBM with a poloxamer 407-based hydrogel, respectively. Both of the compositions were applied to human mesenchymal stem cell (MSC) cultures, and monitored for alkaline phosphatase (ALP) staining and ALP activity. Six 10-week-old athymic nude rats were used for abdominal muscle grafting with either DBM-W or DBM-H, and were tested by plane radiography, microfocus X-ray computed tomography (CT), and decalcified histology to evaluate ectopic bone formation.
The DBM-W group showed stronger ALP staining at 7, 14, and 21 days of treatment, and significantly higher ALP activity at 7 and 14 days of treatment, compared to the DBM-H group. Plane radiography could not confirm the radio-opaque lesions in the rat ectopic bone formulation model. However, ectopic bone formation was observed in both groups by micro-CT. Compared to the DBM-H group, the DBM-W group showed higher bone volume, percent bone volume and trabecular number, and the difference in percent bone volume was statistically significant. Decalcified histology found bony tissue with lamellation in both groups.
Our results suggest that poloxamer 407-based hydrogel has efficacy as a DBM carrier since it shows ectopic bone formation, but its effects on the quality and quantity of osteoblastic differentiation in rat abdominal ectopic bone and MSC are considered negative.
PMCID: PMC4233226  PMID: 25436071
Demineralized bone matrix; Osteoinductivity; Carrier; Poloxamer 407-based hydrogel
16.  Adipose-derived Mesenchymal Stem Cells Are Phenotypically Superior for Regeneration in the Setting of Osteonecrosis of the Femoral Head 
Bone marrow-derived mesenchymal stem cells (bmMSCs) have been used as a cellular therapeutic option for treatment of osteonecrosis of the femoral head. However, use of bmMSCs as a treatment adjuvant for orthopaedic disorders in general has achieved limited success. Adipose-derived MSCs (aMSCs) may be a more-efficient regenerative cell source given their greater quantity and protection from physiologic stress.
We asked the following questions in a paired analysis of MSCs from patients with osteonecrosis: (1) Is there a difference in proliferation potential between aMSCs and bmMSCs? (2) Is there a difference in osteogenic differentiation potential between aMSCs and bmMSCs? (3) Are genetic pathways differentially expressed between aMSCs and bmMSCs that may govern functional phenotypic discrepancies?
Periarticular samples of adipose tissue and bone marrow from the femoral canal were obtained from 15 patients undergoing hip replacement for late-stage (Steinberg Stages III-VI) osteonecrosis. MSCs were isolated from both tissue sources and taken through a standardized 20-day cell division protocol to establish cumulative cell count. They also were grown in osteogenic differentiation media for 14 days with subsequent measurement of alkaline phosphatase in units of optical density. RNA was isolated from aMSCs and bmMSCs in five patients to assess differentially expressed genetic pathways using the Affymetrix GeneChip® Human Transcriptome Array 2.0 platform.
Proliferation capacity was increased by fourfold in aMSCs compared with bmMSCs after 20 days in culture. The mean difference in cumulative cell count was 3.99 × 108 cells (SD = 1.67 × 108 cells; 95% CI, 3.07 × 108–4.92 × 108 cells; p < 0.001). Bone differentiation efficiency as measured by optical density was increased by 2.25-fold in aMSCs compared with bmMSCs. The mean difference in optical density was 1.27 (SD = 0.34; 95% CI, 1.08–1.46; p < 0.001). RNA transcriptome analysis showed 284 genes that met statistical (p < 0.05) and biological (fold change > 1.5) significance cutoffs for differential expression between cell populations. Subsequent network topology of differentially expressed genes showed alterations in pathways critical for musculoskeletal tissue development in addition to many nonspecific findings.
aMSCs outperform bmMSCs in growth rate and bone differentiation potential in the setting of osteonecrosis, suggesting they may provide a more-potent regenerative therapeutic strategy in this population. Differential expression of genes and cellular pathways highlighted in this study may provide therapeutic targets for cellular optimization or acellular treatment strategies.
Clinical Relevance
aMSCs may provide a more robust cellular therapeutic than bmMSCs for treatment of osteonecrosis. Ideally, a well-designed prospective study will be able to evaluate the efficacy of these cellular therapies side-by-side in patients with bilateral early stage disease.
PMCID: PMC4562944  PMID: 26070774
17.  Outcome analysis of retrograde nailing and less invasive stabilization system in distal femoral fractures: A retrospective analysis 
Indian Journal of Orthopaedics  2011;45(3):243-250.
Two major therapeutic principles can be employed for the treatment of distal femoral fractures: retrograde intramedullary (IM) nailing (RN) or less invasive stabilization on system (LISS). Both operative stabilizing systems follow the principle of biological osteosynthesis. IM nailing protects the soft-tissue envelope due to its minimally invasive approach and closed reduction techniques better than distal femoral locked plating. The purpose of this study was to evaluate and compare outcome of distal femur fracture stabilization using RN or LISS techniques.
Materials and Methods:
In a retrospective study from 2003 to 2008, we analyzed 115 patients with distal femur fracture who had been treated by retrograde IM nailing (59 patients) or LISS plating (56 patients). In the two cohort groups, mean age was 54 years (17–89 years). Mechanism of injury was high energy impact in 57% (53% RN, 67% LISS) and low-energy injury in 43% (47% RN, 33% LISS), respectively. Fractures were classified according to AO classification: there were 52 type A fractures (RN 31, LISS 21) and 63 type C fractures (RN 28, LISS 35); 32% (RN) and 56% (LISS) were open and 68% (RN) and 44% (LISS) were closed fractures, respectively. Functional and radiological outcome was assessed.
Clinical and radiographic evaluation demonstrated osseous healing within 6 months following RN and following LISS plating in over 90% of patients. However, no statistically significant differences were found for the parameters time to osseous healing, rate of nonunion, and postoperative complications. The following complications were treated: hematoma formation (one patient RN and three patients LISS), superficial infection (one patient RN and three patients LISS), deep infection (2 patients LISS). Additional secondary bone grafting for successful healing 3 months after the primary operation was required in four patients in the RN (7% of patients) and six in the LISS group (10% of patients). Accumulative result of functional outcome using the Knee and Osteoarthritis Outcome (KOOS) score demonstrated in type A fractures a score of 263 (RN) and 260 (LISS), and in type C fractures 257 (RN) and 218 (LISS). Differences between groups for type A were statistically insignificant, statistical analysis for type C fractures between the two groups are not possible, since in type C2 and C3 fractures only LISS plating was performed.
Both retrograde IM nailing and angular stable plating are adequate treatment options for distal femur fractures. Locked plating can be used for all distal femur fractures including complex type C fractures, periprosthetic fractures, as well as osteoporotic fractures. IM nailing provides favorable stability and can be successfully implanted in bilateral or multisegmental fractures of the lower extremity as well as in extra-articular fractures. However, both systems require precise preoperative planning and advanced surgical experience to reduce the risk of revision surgery. Clinical outcome largely depends on surgical technique rather than on the choice of implant.
PMCID: PMC3087226  PMID: 21559104
Distal femoral fractures; osteosynthesis; minimally invasive techniques; retrograde intramedullary nailing; angular stable plating
18.  Utilization of DXA Bone Mineral Densitometry in Ontario 
Executive Summary
Systematic reviews and analyses of administrative data were performed to determine the appropriate use of bone mineral density (BMD) assessments using dual energy x-ray absorptiometry (DXA), and the associated trends in wrist and hip fractures in Ontario.
Dual Energy X-ray Absorptiometry Bone Mineral Density Assessment
Dual energy x-ray absorptiometry bone densitometers measure bone density based on differential absorption of 2 x-ray beams by bone and soft tissues. It is the gold standard for detecting and diagnosing osteoporosis, a systemic disease characterized by low bone density and altered bone structure, resulting in low bone strength and increased risk of fractures. The test is fast (approximately 10 minutes) and accurate (exceeds 90% at the hip), with low radiation (1/3 to 1/5 of that from a chest x-ray). DXA densitometers are licensed as Class 3 medical devices in Canada. The World Health Organization has established criteria for osteoporosis and osteopenia based on DXA BMD measurements: osteoporosis is defined as a BMD that is >2.5 standard deviations below the mean BMD for normal young adults (i.e. T-score <–2.5), while osteopenia is defined as BMD that is more than 1 standard deviation but less than 2.5 standard deviation below the mean for normal young adults (i.e. T-score< –1 & ≥–2.5). DXA densitometry is presently an insured health service in Ontario.
Clinical Need
Burden of Disease
The Canadian Multicenter Osteoporosis Study (CaMos) found that 16% of Canadian women and 6.6% of Canadian men have osteoporosis based on the WHO criteria, with prevalence increasing with age. Osteopenia was found in 49.6% of Canadian women and 39% of Canadian men. In Ontario, it is estimated that nearly 530,000 Ontarians have some degrees of osteoporosis. Osteoporosis-related fragility fractures occur most often in the wrist, femur and pelvis. These fractures, particularly those in the hip, are associated with increased mortality, and decreased functional capacity and quality of life. A Canadian study showed that at 1 year after a hip fracture, the mortality rate was 20%. Another 20% required institutional care, 40% were unable to walk independently, and there was lower health-related quality of life due to attributes such as pain, decreased mobility and decreased ability to self-care. The cost of osteoporosis and osteoporotic fractures in Canada was estimated to be $1.3 billion in 1993.
Guidelines for Bone Mineral Density Testing
With 2 exceptions, almost all guidelines address only women. None of the guidelines recommend blanket population-based BMD testing. Instead, all guidelines recommend BMD testing in people at risk of osteoporosis, predominantly women aged 65 years or older. For women under 65 years of age, BMD testing is recommended only if one major or two minor risk factors for osteoporosis exist. Osteoporosis Canada did not restrict its recommendations to women, and thus their guidelines apply to both sexes. Major risk factors are age greater than or equal to 65 years, a history of previous fractures, family history (especially parental history) of fracture, and medication or disease conditions that affect bone metabolism (such as long-term glucocorticoid therapy). Minor risk factors include low body mass index, low calcium intake, alcohol consumption, and smoking.
Current Funding for Bone Mineral Density Testing
The Ontario Health Insurance Program (OHIP) Schedule presently reimburses DXA BMD at the hip and spine. Measurements at both sites are required if feasible. Patients at low risk of accelerated bone loss are limited to one BMD test within any 24-month period, but there are no restrictions on people at high risk. The total fee including the professional and technical components for a test involving 2 or more sites is $106.00 (Cdn).
Method of Review
This review consisted of 2 parts. The first part was an analysis of Ontario administrative data relating to DXA BMD, wrist and hip fractures, and use of antiresorptive drugs in people aged 65 years and older. The Institute for Clinical Evaluative Sciences extracted data from the OHIP claims database, the Canadian Institute for Health Information hospital discharge abstract database, the National Ambulatory Care Reporting System, and the Ontario Drug Benefit database using OHIP and ICD-10 codes. The data was analyzed to examine the trends in DXA BMD use from 1992 to 2005, and to identify areas requiring improvement.
The second part included systematic reviews and analyses of evidence relating to issues identified in the analyses of utilization data. Altogether, 8 reviews and qualitative syntheses were performed, consisting of 28 published systematic reviews and/or meta-analyses, 34 randomized controlled trials, and 63 observational studies.
Findings of Utilization Analysis
Analysis of administrative data showed a 10-fold increase in the number of BMD tests in Ontario between 1993 and 2005.
OHIP claims for BMD tests are presently increasing at a rate of 6 to 7% per year. Approximately 500,000 tests were performed in 2005/06 with an age-adjusted rate of 8,600 tests per 100,000 population.
Women accounted for 90 % of all BMD tests performed in the province.
In 2005/06, there was a 2-fold variation in the rate of DXA BMD tests across local integrated health networks, but a 10-fold variation between the county with the highest rate (Toronto) and that with the lowest rate (Kenora). The analysis also showed that:
With the increased use of BMD, there was a concomitant increase in the use of antiresorptive drugs (as shown in people 65 years and older) and a decrease in the rate of hip fractures in people age 50 years and older.
Repeat BMD made up approximately 41% of all tests. Most of the people (>90%) who had annual BMD tests in a 2-year or 3-year period were coded as being at high risk for osteoporosis.
18% (20,865) of the people who had a repeat BMD within a 24-month period and 34% (98,058) of the people who had one BMD test in a 3-year period were under 65 years, had no fracture in the year, and coded as low-risk.
Only 19% of people age greater than 65 years underwent BMD testing and 41% received osteoporosis treatment during the year following a fracture.
Men accounted for 24% of all hip fractures and 21 % of all wrist fractures, but only 10% of BMD tests. The rates of BMD tests and treatment in men after a fracture were only half of those in women.
In both men and women, the rate of hip and wrist fractures mainly increased after age 65 with the sharpest increase occurring after age 80 years.
Findings of Systematic Review and Analysis
Serial Bone Mineral Density Testing for People Not Receiving Osteoporosis Treatment
A systematic review showed that the mean rate of bone loss in people not receiving osteoporosis treatment (including postmenopausal women) is generally less than 1% per year. Higher rates of bone loss were reported for people with disease conditions or on medications that affect bone metabolism. In order to be considered a genuine biological change, the change in BMD between serial measurements must exceed the least significant change (variability) of the testing, ranging from 2.77% to 8% for precisions ranging from 1% to 3% respectively. Progression in BMD was analyzed, using different rates of baseline BMD values, rates of bone loss, precision, and BMD value for initiating treatment. The analyses showed that serial BMD measurements every 24 months (as per OHIP policy for low-risk individuals) is not necessary for people with no major risk factors for osteoporosis, provided that the baseline BMD is normal (T-score ≥ –1), and the rate of bone loss is less than or equal to 1% per year. The analyses showed that for someone with a normal baseline BMD and a rate of bone loss of less than 1% per year, the change in BMD is not likely to exceed least significant change (even for a 1% precision) in less than 3 years after the baseline test, and is not likely to drop to a BMD level that requires initiation of treatment in less than 16 years after the baseline test.
Serial Bone Mineral Density Testing in People Receiving Osteoporosis Therapy
Seven published meta-analysis of randomized controlled trials (RCTs) and 2 recent RCTs on BMD monitoring during osteoporosis therapy showed that although higher increases in BMD were generally associated with reduced risk of fracture, the change in BMD only explained a small percentage of the fracture risk reduction.
Studies showed that some people with small or no increase in BMD during treatment experienced significant fracture risk reduction, indicating that other factors such as improved bone microarchitecture might have contributed to fracture risk reduction.
There is conflicting evidence relating to the role of BMD testing in improving patient compliance with osteoporosis therapy.
Even though BMD may not be a perfect surrogate for reduction in fracture risk when monitoring responses to osteoporosis therapy, experts advised that it is still the only reliable test available for this purpose.
A systematic review conducted by the Medical Advisory Secretariat showed that the magnitude of increases in BMD during osteoporosis drug therapy varied among medications. Although most of the studies yielded mean percentage increases in BMD from baseline that did not exceed the least significant change for a 2% precision after 1 year of treatment, there were some exceptions.
Bone Mineral Density Testing and Treatment After a Fragility Fracture
A review of 3 published pooled analyses of observational studies and 12 prospective population-based observational studies showed that the presence of any prevalent fracture increases the relative risk for future fractures by approximately 2-fold or more. A review of 10 systematic reviews of RCTs and 3 additional RCTs showed that therapy with antiresorptive drugs significantly reduced the risk of vertebral fractures by 40 to 50% in postmenopausal osteoporotic women and osteoporotic men, and 2 antiresorptive drugs also reduced the risk of nonvertebral fractures by 30 to 50%. Evidence from observational studies in Canada and other jurisdictions suggests that patients who had undergone BMD measurements, particularly if a diagnosis of osteoporosis is made, were more likely to be given pharmacologic bone-sparing therapy. Despite these findings, the rate of BMD investigation and osteoporosis treatment after a fracture remained low (<20%) in Ontario as well as in other jurisdictions.
Bone Mineral Density Testing in Men
There are presently no specific Canadian guidelines for BMD screening in men. A review of the literature suggests that risk factors for fracture and the rate of vertebral deformity are similar for men and women, but the mortality rate after a hip fracture is higher in men compared with women. Two bisphosphonates had been shown to reduce the risk of vertebral and hip fractures in men. However, BMD testing and osteoporosis treatment were proportionately low in Ontario men in general, and particularly after a fracture, even though men accounted for 25% of the hip and wrist fractures. The Ontario data also showed that the rates of wrist fracture and hip fracture in men rose sharply in the 75- to 80-year age group.
Ontario-Based Economic Analysis
The economic analysis focused on analyzing the economic impact of decreasing future hip fractures by increasing the rate of BMD testing in men and women age greater than or equal to 65 years following a hip or wrist fracture. A decision analysis showed the above strategy, especially when enhanced by improved reporting of BMD tests, to be cost-effective, resulting in a cost-effectiveness ratio ranging from $2,285 (Cdn) per fracture avoided (worst-case scenario) to $1,981 (Cdn) per fracture avoided (best-case scenario). A budget impact analysis estimated that shifting utilization of BMD testing from the low risk population to high risk populations within Ontario would result in a saving of $0.85 million to $1.5 million (Cdn) to the health system. The potential net saving was estimated at $1.2 million to $5 million (Cdn) when the downstream cost-avoidance due to prevention of future hip fractures was factored into the analysis.
Other Factors for Consideration
There is a lack of standardization for BMD testing in Ontario. Two different standards are presently being used and experts suggest that variability in results from different facilities may lead to unnecessary testing. There is also no requirement for standardized equipment, procedure or reporting format. The current reimbursement policy for BMD testing encourages serial testing in people at low risk of accelerated bone loss. This review showed that biannual testing is not necessary for all cases. The lack of a database to collect clinical data on BMD testing makes it difficult to evaluate the clinical profiles of patients tested and outcomes of the BMD tests. There are ministry initiatives in progress under the Osteoporosis Program to address the development of a mandatory standardized requisition form for BMD tests to facilitate data collection and clinical decision-making. Work is also underway for developing guidelines for BMD testing in men and in perimenopausal women.
Increased use of BMD in Ontario since 1996 appears to be associated with increased use of antiresorptive medication and a decrease in hip and wrist fractures.
Data suggest that as many as 20% (98,000) of the DXA BMD tests in Ontario in 2005/06 were performed in people aged less than 65 years, with no fracture in the current year, and coded as being at low risk for accelerated bone loss; this is not consistent with current guidelines. Even though some of these people might have been incorrectly coded as low-risk, the number of tests in people truly at low risk could still be substantial.
Approximately 4% (21,000) of the DXA BMD tests in 2005/06 were repeat BMDs in low-risk individuals within a 24-month period. Even though this is in compliance with current OHIP reimbursement policies, evidence showed that biannual serial BMD testing is not necessary in individuals without major risk factors for fractures, provided that the baseline BMD is normal (T-score < –1). In this population, BMD measurements may be repeated in 3 to 5 years after the baseline test to establish the rate of bone loss, and further serial BMD tests may not be necessary for another 7 to 10 years if the rate of bone loss is no more than 1% per year. Precision of the test needs to be considered when interpreting serial BMD results.
Although changes in BMD may not be the perfect surrogate for reduction in fracture risk as a measure of response to osteoporosis treatment, experts advised that it is presently the only reliable test for monitoring response to treatment and to help motivate patients to continue treatment. Patients should not discontinue treatment if there is no increase in BMD after the first year of treatment. Lack of response or bone loss during treatment should prompt the physician to examine whether the patient is taking the medication appropriately.
Men and women who have had a fragility fracture at the hip, spine, wrist or shoulder are at increased risk of having a future fracture, but this population is presently under investigated and under treated. Additional efforts have to be made to communicate to physicians (particularly orthopaedic surgeons and family physicians) and the public about the need for a BMD test after fracture, and for initiating treatment if low BMD is found.
Men had a disproportionately low rate of BMD tests and osteoporosis treatment, especially after a fracture. Evidence and fracture data showed that the risk of hip and wrist fractures in men rises sharply at age 70 years.
Some counties had BMD utilization rates that were only 10% of that of the county with the highest utilization. The reasons for low utilization need to be explored and addressed.
Initiatives such as aligning reimbursement policy with current guidelines, developing specific guidelines for BMD testing in men and perimenopausal women, improving BMD reports to assist in clinical decision making, developing a registry to track BMD tests, improving access to BMD tests in remote/rural counties, establishing mechanisms to alert family physicians of fractures, and educating physicians and the public, will improve the appropriate utilization of BMD tests, and further decrease the rate of fractures in Ontario. Some of these initiatives such as developing guidelines for perimenopausal women and men, and developing a standardized requisition form for BMD testing, are currently in progress under the Ontario Osteoporosis Strategy.
PMCID: PMC3379167  PMID: 23074491
19.  Does Adjunctive Chemotherapy Reduce Remission Rates Compared to Cortisone Alone in Unifocal or Multifocal Histiocytosis of Bone? 
Langerhans cell histiocytosis (LCH) is a rare disorder that can affect almost any organ, including bone. Treatment options include local corticosteroid infiltration in isolated bone lesions and oral corticosteroids and chemotherapy in multifocal bone lesions. Several studies show local corticosteroid injection in unifocal bone lesions heal in more than 75% of patients with minimal side effects. Therefore, it is unclear whether chemotherapy adds materially to the healing rate.
We therefore compared overall survival, remission rate, and recurrence rate in patients with bone LCH treated with chemotherapy and corticosteroids or corticosteroids alone.
We retrospectively reviewed the records of 198 patients with LCH since 1950. Median age at diagnosis was 5 years, male-to-female ratio was 1.33, and the most frequent symptom was local pain (95%). We recorded the disease presentation, demographics, treatment, and clinical evolution of each patient. Minimum followup was 4 months (median, 24 months; range, 4–360 months).
The survival rate of the systemic disease group was 76.5% (65 of 85) while the survival rate in the unifocal and multifocal bone involvement groups was 100% at a median 5-year followup. All patients with unifocal bone involvement and 40 of 43 (93%) with multifocal bone involvement had complete remission. One of 30 patients with multifocal bone involvement treated with chemotherapy and oral corticosteroids did not achieve remission whereas two of six receiving only corticosteroids did not achieve remission.
Our observations suggest intralesional corticosteroid injection without adjunctive chemotherapy achieves remission in unifocal bone LCH but may not do so in multifocal single-system bone involvement. Larger series would be required to confirm this observation.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3270175  PMID: 22052526
20.  Surgical treatment of aseptic nonunion in long bones: review of 193 cases 
The surgical treatment of aseptic nonunion often represents a more challenging situation for the orthopaedic surgeon than treatment of the primary fracture. In fact, it may be necessary not only to "rivitalize" the nonunion area, but also to exchange the bone fixation devices and to place some refill material in the bone gap. Several surgical techniques and different kinds of bone gap refills have been reported in the literature for the treatment of long bone nonunion. We present the results of 193 cases of long bone nonunion that have been treated in a period of 11 years (1992–2003) by a mostly open approach to the nonunion site with or without autologous bone graft interposition. The site (27 humerus, 44 forearm, 48 femur, 74 tibia) and the type of nonunion (179 atrophic, 19 hypertrophic) were considered in the surgical planning as were the mechanic and biological problems. New osteosynthesis was performed in 139 cases: with plate and screws in 82 cases, with intramedullary nails in 31 cases, with external fixators in 15 cases and with other devices in 11 cases (e.g. interfragmentary screws, k-wires). Cancellous or corticocancellous bone graft, always autologous from the iliac crest or from the anterior tibial tuberosity, was used in 183 cases (94.8%). Healing of the nonunion was successful in 179 cases (92.7%) in a mean time of 5.8 months. 14 patients (7.2%), all atrophic nonunion, healed with further surgery in a mean time of 19.2 months. Best results were obtained by the use of the intramedullary nail (31 cases): 99% healed in 5.2 months for the lower limb and 100% healed in 7.4 months for the upper limb. Good results have been achieved by plate (82 cases): 89.5% healed in 4.5 months for the lower limb and 94.1% in 6 months for the upper one. The worst results were observed with external fixation (15 cases). However, this device was used in the most complex situations, when severe soft tissue sufference was present. In this group, the mean healing time was 7.1 months (69.2% of cases) in the lower limb and 8 months (50%) in the upper one. Bone graft alone (54 cases) led to healing in 34 of 35 cases (97%) in the lower limb in 6 months and in 17 of 19 cases (89.4%) in 6.4 months in the upper limb.
PMCID: PMC4874976
Nonunion; Bone graft; Osteosynthesis; Fracture
21.  Revision Surgery Occurs Frequently After Percutaneous Fixation of Stable Femoral Neck Fractures in Elderly Patients 
Femoral neck fractures are a major public health problem. Multiple-screw fixation is the most commonly used surgical technique for the treatment of stable femoral neck fractures.
We determined (1) the proportion of hips that had conversion surgery to THA, and (2) the proportion of hips that underwent repeat fracture surgery after percutaneous screw fixation of stable (Garden Stages I and II) femoral neck fractures in patients older than 65 years and the causes of these reoperations.
We performed a retrospective study of all patients older than 65 years with stable femoral neck fractures secondary to low-energy trauma treated surgically at our institution between 2005 and 2008. We identified 121 fractures in 120 patients older than 65 years as stable (Garden Stage I or II); all were treated with percutaneous, cannulated screw fixation in an inverted triangle without performing a capsulotomy or aspiration of the fracture hematoma at the time of surgery. The average age of the patients at the time of fracture was 80 years (range, 65–100 years). Radiographs, operative reports, and medical records were reviewed. Fracture union, nonunion, osteonecrosis, intraarticular hardware, loss of fixation, and conversion to arthroplasty were noted. Followup averaged 11 months (range, 0–5 years) because all patients were included, including those who died. The mortality rate was 40% for all patients at the time of review.
Twelve patients (10%) underwent conversion surgery to THA at a mean of 9 months after the index fracture repair (range, 2–24 months); the indications for conversion to THA included osteonecrosis, nonunion, and loss of fixation. Two others had periimplant subtrochanteric femur fractures treated by surgical repair with cephalomedullary nails and two patients had removal of hardware.
Revision surgery after osteosynthesis for stable femoral neck fractures was more frequent in this series than previously has been reported. The reasons for this higher frequency of reoperation may be related to poor bone quality, patient age, and some technical factors, which leads us to believe other treatment options such as nonoperative management or hemiarthroplasty may be viable options for some of these patients.
Level of Evidence
Level IV, therapeutic study.
PMCID: PMC4397802  PMID: 25256623
22.  Static or Dynamic Intramedullary Nailing of Femur and Tibia 
Medical Archives  2015;69(2):110-113.
The basic principle of non-surgical fracture treatment is to restore the original anatomical position of fractured fragments by different techniques, without direct access to the bone and without further traumatizing of tissues. Intramedullary nailing is synthesis and consolidation of fracture fragments with the main goal to gain strength and permanent placement of the implants. Two techniques of intramedullary osteosynthesis are used: with dynamic or with static intramedullary nail. Dynamization include conversion of static nail by removing screws from the longest fragment.
The aim of this study is to determine whether there is a difference in the speed and quality of healing of the type A and B fractures of the femur and tibia treated by static or dynamic intramedullary nails and to compare the results.
Material and methods:
The study was conducted at the Clinic for Orthopaedics and Traumatology, Clinical Center University Sarajevo from January 2004 to June 2009. The study was retrospective-prospective, manipulative, controlled and it was conducted on a total of 129 patients with closed fractures of the diaphysis of the femur and tibia type A and type B, with different segments of bone, regardless of sex and age structure, with the exception of children under 14 years of age.
Precisely there were 47 patients with femoral fractures and 82 patients with tibial fractures. The average number of weeks of healing femoral and tibial fractures was slightly in advantage of static intramedullary osteosynthesis, it was 17.08 weeks (SD=3.382). The average number of weeks of healing in 23 patients with fractures of the femur, treated by dynamic intramedullary osteosynthesis was 17.83 (SD=2.978). We can conclude that static intramedullary nailing osteosynthesis unable movements between fragments which directly stimulates bone formation and formation of minimal callus.
Static intramedullary osteosynthesis resolve the problem of stabilizing the fracture, limb shortening and rotation of fragments.
PMCID: PMC4430006  PMID: 26005261
fracture healing; intramedullary nailing; dynamic and static intramedullary nail
23.  Internal femoral osteosynthesis after external fixation in multiple-trauma patients 
In this study the authors evaluate the results of internal synthesis of femoral fractures in polytraumatised patients initially treated by external fixation (EF). From January 2002 to December 2005, 39 femurs in 37 polytraumatised patients (average age 34.2 years, range 18-44) with closed fractures and an ISS>20 were initially treated with EF. There were three groups: Group A, 13 cases when conversion to internal osteosynthesis occurred after 4-7 days (average 5.6 days); Group B, 11 cases with a 4-6-month interval before internal osteosynthesis, and after investigation using MRI and scintigraphy with labelled leucocytes; Group C, the remaining cases treated definitively with EF. Time of healing, lower limb function, time of return to previous activities and short and long-term complications were evaluated at the follow-up. The average time of follow-up was 23 months. In Group A the time of bone healing was 123 days; there were no events of embolism but one case of pseudoarthrosis and one case of instrument failure. In Group B the time of bone healing was 274 days, with one case of pseudoarthrosis and one case of deep infection. In Group C the average healing time was 193 days, with 3 cases of screw (half-pin) osteolysis. Functional recovery was delayed by the presence of other fractures. EF is a simple, quick and safe procedure to stabilise fractures in polytraumatised patients. According to damage control orthopaedic (DCO) concepts, it is possible to replace EF with internal synthesis after an interval as this reduces the risks of internal osteosynthesis when performed in the emergency period. EF can also be maintained as definitive treatment but should a change to internal synthesis be needed, it is possible to do it safely after excluding bone infection.
PMCID: PMC2321719  PMID: 18427913
Femoral fractures; Damage control orthopaedics; Internal femoral osteosynthesis; External fixation
24.  Internal femoral osteosynthesis after external fixation in multiple-trauma patients 
In this study the authors evaluate the results of internal synthesis of femoral fractures in polytraumatised patients initially treated by external fixation (EF). From January 2002 to December 2005, 39 femurs in 37 polytraumatised patients (average age 34.2 years, range 18-44) with closed fractures and an ISS>20 were initially treated with EF. There were three groups: Group A, 13 cases when conversion to internal osteosynthesis occurred after 4-7 days (average 5.6 days); Group B, 11 cases with a 4-6-month interval before internal osteosynthesis, and after investigation using MRI and scintigraphy with labelled leucocytes; Group C, the remaining cases treated definitively with EF. Time of healing, lower limb function, time of return to previous activities and short and long-term complications were evaluated at the follow-up. The average time of follow-up was 23 months. In Group A the time of bone healing was 123 days; there were no events of embolism but one case of pseudoarthrosis and one case of instrument failure. In Group B the time of bone healing was 274 days, with one case of pseudoarthrosis and one case of deep infection. In Group C the average healing time was 193 days, with 3 cases of screw (half-pin) osteolysis. Functional recovery was delayed by the presence of other fractures. EF is a simple, quick and safe procedure to stabilise fractures in polytraumatised patients. According to damage control orthopaedic (DCO) concepts, it is possible to replace EF with internal synthesis after an interval as this reduces the risks of internal osteosynthesis when performed in the emergency period. EF can also be maintained as definitive treatment but should a change to internal synthesis be needed, it is possible to do it safely after excluding bone infection.
PMCID: PMC2321719  PMID: 18427913
Femoral fractures; Damage control orthopaedics; Internal femoral osteosynthesis; External fixation
25.  The Fracture Unit Model. A Model for Implementation in Italy: “Multidisciplinary Approach for the Prevention and Treatment of Osteoporotic Vertebral Compression Fractures: VCF Unit” 
Reduced BMD is a risk factor for vertebral fractures (VFs). Every one SD increase in BMD is associated with a 2- to 2.5-fold increase in the risk of VFs. The presence of a previous fracture, vertebral or of other districts, is another important predictor of an increased risk of future fractures, independently of the association between BMD and fracture risk. Thus, the presence of both a low BMD and a previous fracture dramatically increases fracture risk. The definition of osteopo-rotic VFs has undergone considerable variations over the years, going from initial clinical sign of OP, through the now superseded definition of VFs as a disease, to a complication of OP resulting from bone fragility. The prevalence of VFs increases with age in both sexes, and it is calculated that at the age of 80 years, 37% of Caucasian women will have at least one radiographically evident VF. It has been estimated, again in Caucasian women, that the percentage incidence of fractures is 0.5% in those aged 50-55 years, 1.4% in those aged 65-69 years, and over 2% in women older than 75. However, two factors prevent an accurate assessment of the epidemiology of VFs. First, most VFs escape clinical diagnosis. Second, the absence of a “gold standard” radiographic definition of VFs has given rise to different ways of defining these lesions. VFs are rarely a cause of mortality, but they are associated with increased impairment of general conditions. Recurrent VFs have irreversible clinical consequences, such as reduction of height and chronic vertebral pain, which provoke an intensification of the pain and a greater degree of disability due to accentuation of kyphosis. The presence of VFs and kyphosis leads to a reduced thoracic volume and, consequently, to a loss of lung volume, in some cases severe enough to result in respiratory insufficiency. The consequences of the intense pain are: reduced range of motion, loss of balance, slowed gait and greater difficulty carrying out normal daily activities. In rare cases, lower limb pain and weakness may appear, caused by compression of the spinal medulla by the deformed vertebral body. The main aim of treatment is to restore the patient to his/her pre-trauma levels of functioning. This can be achieved through recourse to mini-invasive percutaneous techniques, vertebroplasty and kyphoplasty, with the aim of reducing the pain caused by osteo-porotic vertebral compression fractures, of preventing progression of the vertebral collapse and of rapidly re-establishing functional activity. Most fracture patients are discharged without undergoing a thorough bone metabolism assessment that could identify the causal factor of the fracture. In a high percentage (up to 95%) of patients with recent fractures, BMD is not measured and, therefore, a diagnosis of OP is not made. Consequently, these patients are not prescribed drugs capable of effectively reducing the risk of further fractures. Specialist orthopaedic centres need to introduce protocols designed to ensure application of the current procedures for diagnosing and treating OP.
On the basis of these considerations, we undertook to develop, in collaboration with the Department of Specialist Surgical Sciences of the University of Florence, the Orthopaedics and Traumatology Units 1, 2 and 3, the Recovery and Functional Re-education Unit, the Neurosurgery Unit, and the third Radiodiagnostics Unit of the Careggi Hospital in Floren-ce, a protocol that involves a range of specialists in assessing the introduction of variable, outcome-targeted medical therapies for osteoporotic patients submitted to kyphoplasty following fragility fractures of the vertebra. To choose the appropriate medical therapy, and to monitor its effects, the patients will be submitted to a series of clinical investigations. The “appropriate” therapy could include calcium and vitamin D supplementation, biphosphonates, SERMs, bone anabolic agents and combinations of drugs. The safety of the medical therapy and any adverse effects will be monitored at each follow-up visit through an appropriate questionnaire. This study aims to compare the outcomes of the group following a traditional pathway with those following a modified pathway (prescription of a targeted medical therapy), by means of metabolic, instrumental and functional tests performed at 2 months, 6 months, 1 year and 2 years. The general aim of the study will be to evaluate the efficacy and safety of a modified versus a traditional pathway in the care of osteoporotic patients undergoing kyphoplasty for VFs. The primary endpoint of the study will be the percentage of successes in the modified compared with the traditional pathway group. Secondary endpoints will be: change in femoral and lumbar BMD, changes in biochemical markers of bone remodelling and quality of life, assessment of safety parameters: overall and symptomatic cement leakage, pulmonary embolism, spinal medulla compression, radicular pain, radiculopathies and assessment of total procedure-related, cement-related and access-related adverse events. The ultimate aim of the study will be to prepare guidelines for the management, in terms of metabolic diagnosis and relative medical therapy, of patients with OP complicated by VFs.
PMCID: PMC3213825

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