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1.  Radiography Finding in the Jaws in Children Taking Bisphosphonate 
Bisphosphonates‎ inhibit osteoclasts, prevent bone resorption and decrease bone turnover. This study examined radiography finding in bisphosphonate-associated osteonecrosis of jaws.
Materials and Methods
This is a retrospective series of 12 clinically diagnosed patients between 7 to 21 year old (average 13 years). They required emergency dental conditions requiring management by dentist: non healing ‎extraction sockets and pain of bone exposure. The panoramic radiography and cone beam computed tomography was performed ‎to assess the problem.
Thickening of the lamina dura was observed in 7 patients (58.3 %). But full-thickness sclerosis was seen in 6 patients (50 %). Sclerotic changes in the mandibular canal were noted in 3 patients (25 %). 5 patients (41.6 %) had poorly healing or non-healing of socket in extracted tooth and periapical lucencies.
4 people (33.3 %) had widening of periodontal ligament (PDL) space and osteolysis. Sequestra were seen in 3 persons (25 %). Finally in 2 children (16.6 %) were found oroantral fistula. Only one child (8.3 %) had thickening of soft tissue mid periosteal reaction.
Most patients had some degree of osteosclerosis, especially in the area of alveolar bone. Thickening of the lamina dura was also seen in children. Other findings include: osteolysis, sequestra, periosteal new bone formation, widening of PDL,soft tissue thickening, non healing extraction sockets, oroantral fistula and periapical lucencies (P-value < 0.05).
Common radiographic features in patients taking bisphosphonate, was osteosclerosis. This sclerosis had different views that thickening of the lamina dura and alveolar crest were most common.
PMCID: PMC3921879  PMID: 24575282
Osteonecrosis; Jaw; Radiography; Thalassemia
2.  Use of Ultrasonic Bone Surgery (Piezosurgery) to Surgically Treat Bisphosphonate-Related Osteonecrosis of the Jaws (BRONJ). A Case Series Report with at Least 1 Year of Follow-Up 
The Open Dentistry Journal  2013;7:94-101.
This preliminary work documents the use of a powerful piezosurgery device to treat biphosphonate-related osteonecrosis of the jaw (BRONJ) in combination with classical medication therapy. Eight patients presenting 9 BRONJ sites were treated, 2 in the maxilla and 7 in the mandible. Reason for biphosphonate (BiP) intake was treatment of an oncologic disease for 5 patients and osteoporosis for 3. The oncologic and osteoporosis patients were diagnosed with BRONJ after 35-110 months and 80-183 months of BiP treatment, respectively. BRONJ 2 and 3 was found in 4 patients. Resection of the bone sequestrae was performed with a high power ultrasonic (piezo) surgery and antibiotics were administrated for 2 weeks. Soft tissue healing was incomplete at the 2-week control but it was achieved within 1 month. At the 1-year control, soft tissue healing was maintained at all patients, without symptom recurrence. One patient with paraesthesia had abated; of the 2 pa-tients with trismus, one was healed, severity of the second trismus abated. This case report series suggests that bone resection performed with a high power ultrasonic surgery device combined with antibiotics might lead to BRONJ healing. More patients are warranted to confirm the present findings and assess this treatment approach.
PMCID: PMC3772575  PMID: 24044030
Piezosurgery; Ultrasonic bone surgery; Bone infection; Osteonecrosis; Bisphosphonates; BRONJ; Biofilm; ONJ.
California Medicine  1960;92(6):418-421.
In expert testimony before the Industrial Accident Commission, all physicians are taken as equally competent. The value of their testimony depends upon the validity of their data and the reasons for the conclusions drawn. In case of conflicting opinion, the referees, who are laymen, must decide on the basis of the testimony. Therefore physicians preparing reports must see that data are complete, that all routine investigative procedures are not only applied but reported, and that the reasons for claiming connection of injury with employment are fully stated. Moreover, other recognized causes of the patient's condition should be considered and ruled out for reasons given.
The increasing number of claims for workmen's compensation in heart disease, and the increasing tendency of insurers to settle rather than contest claims, may actually be harmful to the welfare of persons with heart disease, for it deters employers from hiring them and thus risking higher insurance costs. Physicians concerned with compensation claims must develop more widely acceptable standards that properly separate the inherent risk of heart disease from that incurred through employment for which the employer may reasonably be considered liable.
PMCID: PMC1578120  PMID: 13807236
4.  Low Back Pain in Men Receiving Workmen's Compensation 
In Ontario, only about 10% of compensation patients with low back pain are disabled more than six weeks and hence tend to have chronic complaints. Six hundred and twenty-three such patients were studied to determine the distribution of diagnoses and to test the effectiveness of various programs of conservative therapy.
Two hundred and thirteen patients were assigned in rotation to one of four treatments. The results were inconclusive. In 70% of these, the pain was due to intervertebral disc degeneration with added trauma.
Two hundred and sixteen patients were assigned randomly to a treatment involving mild exercise, or one with vigorous exercise. Neither was found to be superior. In 76% of these, the pain was due to disc degeneration with added trauma.
Using 194 patients, the results of treatment in the Compensation Board Rehabilitation Centre were compared with those obtained by treatment at home. Satisfactory improvement was achieved in 15 of 95 treated at home, and in 42 of 99 in the Centre. The failure of treatment in six of each 10 cases indicates that present-day methods of management of such patients are unsatisfactory.
PMCID: PMC1935626  PMID: 4222996
5.  Bisphosphonate-Related Osteonecrosis of the Jaw Bone: Radiological Pattern and the Potential Role of CBCT in Early Diagnosis 
To systematize the clinico-radiological symptoms and course of bisphosphonate-related osteonecrosis of jaw bone and toevaluate the diagnostic potential of various radiological techniques to detect mild osteonecrosis in each stage of the disease.
Material and Methods
The sample consisted of 22 patients previously diagnosed with extraoral malignant disease. Diagnosis was based on a clinical examination in conjunction to digital panoramic radiography and cone beam computed tomography (CBCT). Two dentomaxillofacial radiologists reviewed all images.
Twenty patients showed mandibular involvement clinically, while two others had a maxillary involvement. Four stages of the disease were proposed based on the clinico-radiological findings. Subclinical cortical and lamina dura thickening was detected with only three-dimensional CBCT and periapical images, while ulceration and cortical bone thickening was detected only by three-dimensional CBCT. Mixed sclerotic, lytic bone destruction involving alveolar and basal bone with or without encroachment on the mandibular canal, pathological mandibular fractures were detected by two-dimensional panoramic and three-dimensional CBCT images. Other findings are non healing extraction sockets, periapical radiolucencies, osteolysis, sequestra, oroantral fistula, and periosteal new bone formation.
The present study showed that bisphosphonate-related osteonecrosis of jaw bone occurs in four distinct clinico-radiological stages. For mild cases, panoramic image diagnosis was much less obvious, whereas cone beam computed tomography was able to fully characterise the bony lesions and describe their extent and involvement of neighbouring structures in all cases. Thus cone beam computed tomography might better contribute to the prevention of bisphosphonate-related osteonecrosis of jaw bone as well to the disease management.
PMCID: PMC3886047  PMID: 24421968
bisphosphonates; osteonecrosis jaw; cone-beam CT; early diagnosis.
6.  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
It will be seen from the above that we have studied the conditions associated with the deposit of calcareous salts: (I) in connection with normal and pathological ossification, and (2) in pathological calcification as exhibited in (a) atheroma of the vessels; (b) calcification of caseating tubercular lesions; (c) calcification of inflammatory new growth, and (d) degenerating tumors; and we have induced experimentally deposits of calcareous salts in the lower animals: (a) within celloidin capsules containing fats and soaps; (b) in the kidney, and (c) in connection with fat necrosis. I. We have found that bone formation and pathological calcareous infiltration are wholly distinct processes. In the former there is no evidence of associated fatty change, and the cells associated with the process of deposition of calcium are functionally active. In the latter there is an antecedent fatty change in the affected areas, and the cells involved present constant evidences of degeneration. The view that would seem to account best for the changes observed in the latter case is that with lowered vitality the cells are unable to utilize the products brought to them by the blood, or which they continue to absorb, so that the normal series of decompositions associated with their metabolism fails to take place and hence they interact among themselves in the cytoplasm with the result that insoluble compounds replace soluble ones. II. Besides the fact that calcification is always preceded by fatty change within the cells, another fact should be emphasized. namely: that combination of the fats present with calcium salts to form calcium soaps tends to occur. The stages immediately preceding these are difficult to follow with anything approaching certainty, perhaps because the earlier stages vary under different conditions. In fat necrosis, for instance, the cells affected are normally storehouses for neutral fats, and as long as they remain healthy neutral fats alone are present in them. When they are subjected to the action of the pancreatic juice with its fat-splitting ferment the cells are killed and coincidently the neutral fats are decomposed, fatty acids being deposited. The fatty acids now slowly combine with the calcium salts. In degenerating lipomata the process would seem to be similar. But in other cases the cells are not obviously fat-containing in the normal state; nevertheless prior to calcification they undergo so-called fatty degeneration, which is really a form of cell degeneration accompanied by fat infiltration. As regards the source of the cell fats in general we may safely accept: 1. That fats are transported in the blood as diffusible soaps. 2. That taken up by the cells these soaps may either— (a) Be reconverted into neutral fats and become stored in the cytoplasm as such, or (b) undergo assimilation proper, becoming part and parcel of the cell substance, in which case they are not recognizable by the ordinary microchemical tests. 3. If these two possibilities be accepted it follows that the appearance of fats and soaps in the degenerating cell may be due to either— (a) Absorption or infiltration of soaps from the surrounding medium, the degenerating cell retaining the power of splitting off the fat but being unable to utilize this in metabolism. (b) Cytoplasmic disintegration with dissociation of the soap-albumen combination or, more broadly, liberation of the fats from their combination with the cytoplasm. The appearances seen in the cells of atheromatous areas indicate that the first of these does occur. III. In areas undergoing calcareous infiltration we have demonstrated. the presence of soaps, and this often in such quantities that they can be isolated and estimated by gross chemical methods. By microchemical methods also we have been able to show that after removing all the neutral fats and fatty acids by petroleum ether there remains behind a substance giving with Sudan III the reaction we associate with the presence of soap. And experimentally we have produced these soaps within the organism, more particularly by placing capsules containing fats and fatty acids within the tissues and after several days finding that the capsules contain calcium soaps and possess a calcium content far in excess of that of the normal blood and lymph. IV. While these are the facts, certain of the details of this reaction demand elucidation. The existence of sodium and it may be potassium soaps in the degenerated cells is comprehensible if we accept that these are present in the circulating lymph and simply undergoing absorption. But even then, as these are diffusible substances how is it to be explained that they become stored up in these particular areas? We have found that, as a matter of fact, in regions which give the reaction for soaps, but which give no reaction for calcium (which therefore presumably contain at most amounts of the insoluble calcium soap too small to need consideration, the ordinary solvents for potassium and sodium soaps do not forthwith remove the stainable material; they are relatively insoluble. The reason for this insolubility is suggested by the observations made in the test tube, that soap solutions mixed with solutions of white of egg or blood serum form a precipitate of combined soap and albumen, which likewise is insoluble in water and alcohol. The indications are therefore that in cells undergoing degeneration, with degeneration of the cytoplasm, certain albuminous molecules unite with the soaps present to form relatively insoluble soap-albuminate. V. With regard to calcium soaps, these are also present and in certain stages appear to be the dominating form in the affected tissues. Two questions suggest themselves, viz.: what is the source of calcium, and what is the process by which they become formed? As to the source, the amount present in well-marked calcification is far in excess of the normal calcium contents of the affected tissue. If in the kidneys of experimental calcification three hundred times as much calcium may be present as in the normal kidney (von Kossa), the calcium must be conveyed to the part by the blood and lymph, and that this is so is demonstrated, as we have pointed out, by the distribution of the infiltration in solid organs, that like ovarian fibroids have undergone necrosis, in which the earliest deposits are superficial. As to the process, there are three possibilities: 1. That sodium and potassium soaps and soap albuminates are first formed and that interaction occurs between them and the diffused calcium salts from the lymph, the less soluble-calcium replacing the sodium and potassium. 2. That under certain conditions the calcium salts act directly on the neutral fats present in the degenerating cells. 3. That the neutral fats are first broken down into fatty acids and that these react with the calcium salts to form the soaps. We are assured that the first process occurs and that because in the boundary zone of areas of calcification we can detect soapy particles devoid of calcium, identical in position and arrangement with the particles more deeply placed which give the calcium reactions. But this is not the only reaction. In case of fat necrosis we see clearly that the third process is in evidence. And we are far from being convinced that the second does not also obtain. We have been impressed by the large accumulation of neutral fats in the cells in cases of early atheroma and the absence at any stage of the process of recognizable fatty acid. While soaps, it is true, are compounds of fatty acids with alkalies, it is recognized in ordinary domestic life that they can be formed by the direct action of strong lye upon ordinary fats, and this even in the cold. It is quite possible therefore that there occurs a similar direct process in the organism. The point is worth noting, however, that this does not occur in healthy cells the seat of fatty infiltration. We therefore leave this an open question, only laying down that, as indicated by the hyalin albuminous matrix left when calcium salts are dissolved out of an area of calcification, there must exist a calcium soap- or fat-albuminate similar to the potassium and sodium soap-albuminates already mentioned—such an albuminate as we can form with calcium soaps in the test tube. VI. In old areas of calcification soaps are largely if not entirely wanting, although these are to be detected at the periphery, when the process is still advancing. The reactions given by these older areas are almost entirely those of calcium phosphate, though some calcium carbonate is at times to be made out. This seems surely to indicate that the final stage in calcification is an interaction between the calcium soap-albuminates and substances containing phosphoric and carbonic acids. Such substances, it is needless to say, are present in considerable amounts in the lymph and blood. We must conclude that the acid sodium phosphates of the lymph act on the calcium soap, the highly insoluble calcium phosphates being formed (plus the albuminous moiety of the original compound) and diffusible sodium soap being liberated, while similarly alkaline carbonates form calcium carbonate and liberate sodium and potassium soaps. Calcium phosphate and calcium carbonate thus become the insoluble earthy salts of old crystalline areas of calcification. VII. As already stated very little soap is to be found in these old areas. It is possibly worth suggestion that the soaps liberated in this last reaction, as they diffuse out, again react with diffusible calcium salts and form calcium soaps which once more react with the alkaline salts to produce the phosphates and carbonates; that, in short, they have a katalytic action. Certain it is that old calcareous areas are extraordinarily dense, and have a coarse crystalline structure, wholly at variance with the finely granular appearance of the more recent areas, and these large crystalline masses, it would seem, can only be formed by successive deposition of new material and eventual fusion, as the interspaces become filled in between the original masses.
PMCID: PMC2124594  PMID: 19867016
These studies have shown that the bones of guinea pigs given daily injections of parathormone from the age of 2 to 7 days to the age of 110 to 120 days, show relatively very little effect after receiving 20 units daily during the last 65 to 87 days of treatment. But it is probable that their bones underwent decalcification early in the treatment and that subsequently the parathormone, continued at the same dosage, did not maintain the effects on the bones. Healing finally occurred despite it. The bones of guinea pigs treated with intermittent injections of large doses of parathormone from the time they were 1 week old to the age of 95 to 145 days also showed relatively few changes at the end of the treatment. The injections were given at intervals of 7 to 11 days, and were stepped up from 60 units to 140 units. From our previous experience (1) we infer that the earlier injections of parathormone produced very extensive bone changes which healed in the intervals between the injections. As the guinea pigs became older the injections of parathormone did not produce as severe effects. We have found in our studies of experimental hyperparathyroidism that the bone changes after a single large dose of parathormone in young guinea pigs are soon healed. The study of a series of animals shows that healing begins at about the 48th hour after injection, and proceeds rapidly. Between the 8th and 14 days, callus may be observed at the costochondral junctions, where fractures had occurred. Now the endosteum may be lined by osteoblasts and the vessel canals by new formed bone. In adult guinea pigs extremely large single doses had little effect on the bones in 48 hours, even though the dose killed the animal. It was only when three doses pyramided over a period of 48 hours and totaling 2580 units of parathormone were given, that moderately severe bone resorption could be demonstrated in the adult. The elevation of serum calcium may be considered as one of the indices of calcium mobilization in experimental hyperparathyroidism. When the rate of calcium excretion exceeds the rate of its mobilization, or when the animal is on a low calcium diet, hypercalcemia may be absent. It is possible to raise the serum calcium of adult guinea pigs by large single doses of parathormone, but the resulting rise is not as great as in the young (2). This is confirmatory evidence of the fact that calcium is mobilized much less rapidly from the bones of old animals than from those of young ones. Collip pointed out that young normal dogs are more susceptible to parathormone (6). This observation was corroborated by Morgan and Garrison (7). We found that the same difference held also in experimental hyperparathyroidism produced in dogs by repeated doses of parathormone (8). In man, clinical experience likewise indicates the necessity of using relatively large doses of parathormone to raise the serum calcium of adults. The serum calcium of middle-aged or old adults does not rise significantly unless as much as 100 units or more of parathormone are given daily for a number of days. Charts VI and VII, in a recent paper by Merritt and Bauer (9), support our findings of the relative difficulty of obtaining a significant elevation of serum calcium in adults. If adult guinea pigs are given daily injections of parathormone which are rapidly stepped up, the animals may be killed by the ensuing acute hyperparathyroidism, only slight bone changes being produced. However, a careful avoidance of the induction of acute hyperparathyroidism by gradual stepping up of the parathormone dose permits the employment of doses continued over a long period of time that could not possibly have been tolerated otherwise. Furthermore, healing of the lesions thus produced may occur, in spite of the continuance of parathormone at this level. It seems likely that the difference in response of young and old guinea pigs to single doses of parathormone, as indicated by the bone changes, as well as by the serum calcium and phosphorus, is related to the more rapid rate of mineral metabolism in the young, actively growing animals. The calcium mobilizing effect of parathormone is most prominent in actively growing young animals, the calcium being withdrawn from the most readily available stores—the regions of most active new bone formation and most active bone reconstruction (10). In the adult animal the calcium reserves (in the formed bone) are less susceptible to the calcium mobilizing effect of parathormone. The adult guinea pig will show relatively slight bone changes even as a result of extremely large, fatal doses of parathormone. Repeated doses, as is well known, will produce, by pyramiding, greater effects than the entire amount administered at one time. In this type of experiment the young again show greater susceptibility of the bone than the adult. In time, however, some compensation takes place, and the effects of the same doses are decreased until finally healing may occur in spite of the continued treatment. Increase of the dose, however, again elicits the parathormone effects upon the bone, as well as upon the serum calcium and phosphorus, without toxic changes (1, 8). It would seem that some compensation sets in which may be overcome by increasing the dose. This compensation is especially evident in the experiments in which the parathormone doses were stepped up gradually from small amounts. In addition to the compensation observed in young and adult animals as a result of repeated injections of parathormone, we must also consider the possibility that there is a compensating mechanism in adult animals more effective than in the young. That compensation occurs is unquestionable but its nature is not clear. Apparently it is less effective during pregnancy, doses of parathormone which produce only slight bone changes in ordinary adults causing very severe lesions in advanced pregnancy (11). Parathormone has been shown to produce only one primary effect on bone, and that is decalcification. This may come about as the result of a change in the circulating tissue fluids, the salts being dissolved out of the organic matrix, and the latter disappearing secondarily. The process is most rapid in the vicinity of most active bone formation. The osteoblasts disappear from the surfaces of bone where dissolution is occurring, and at the same time the marrow connective tissue proliferates. Fusion of cells produces osteoclasts (12), which then proceed to remove the decalcified organic matrix, with the production of the deep lacunae of Howship. Frequently leucocytes are also observed actively phagocyting the decalcified organic matrix, and often leucocytes are observed within the osteoclasts (12). Healing is associated with the complete reversal of the process. The osteoclasts disappear, the connective tissue diminishes, osteoblasts reappear, and bone formation is resumed. As we have previously stated (13), parathormone produces a more continuous effect than experimental acidosis and greater changes than are seen in experimental osteoporosis. A pronounced decalcification results from it which, with its sequelae, simulates von Recklinghausen's disease. The emphasis which the older pathologists laid on osteoclasts as a special feature of ostitis fibrosa cystica is justified, for in the experimental condition the appearance of great numbers of osteoclasts is a constant feature, whenever decalcification occurs (13). There seems to be no doubt that the giant cell tumors found in ostitis fibrosa cystica are expressions of the same pathological response. The other features of the bone changes of hyperparathyroidism—marrow hemorrhage, cysts, fractures, and osteoid proliferation—are secondary to the primary decalcification. Progress of the pathological changes leads to circulatory stasis and cyst formation. Stresses and strains exerted on the progressively weakening bone may result in microscopical or gross fractures. Osteoid tissue is, as we have previously pointed out (13), merely reparative in nature, being laid down as support to the weakened or fractured bone, or as a part of healing. Osteoid borders appear on bone surfaces 48 hours after one large dose of parathormone. The mosaic picture which we have observed in the bones of some of our animals is produced by short and irregularly disposed cement lines resulting from rapid bone transformation. Schmorl (14) recently emphasized the mosaic-like appearance of the newly formed lamellar bone in Paget's disease (ostitis fibrosa deformans). The mosaic-like appearance of bone has also been described in local bone conditions, as e.g. syphilitic periostitis, and in bone in the vicinity of cysts and giant cell tumors in von Recklinghausen's disease (ostitis fibrosa cystica). However, Schmorl claims that in no disease is the mosaic appearance so constant and the arrangement of the cement lines so irregular as in Paget's disease. In chronic experimental hyperparathyroidism (von Recklinghausen's disease), the mosaic structure is not a prominent feature because of the progressive decalcification. But the bones of our young guinea pigs which received intermittent injections showed a mosaic-like appearance indicative of the periodic decalcifications and restorations which they had undergone.
PMCID: PMC2132070  PMID: 19869973
9.  Beta-Catenin Signaling Plays a Disparate Role in Different Phases of Fracture Repair: Implications for Therapy to Improve Bone Healing 
PLoS Medicine  2007;4(7):e249.
Delayed fracture healing causes substantial disability and usually requires additional surgical treatments. Pharmacologic management to improve fracture repair would substantially improve patient outcome. The signaling pathways regulating bone healing are beginning to be unraveled, and they provide clues into pharmacologic management. The β-catenin signaling pathway, which activates T cell factor (TCF)-dependent transcription, has emerged as a key regulator in embryonic skeletogenesis, positively regulating osteoblasts. However, its role in bone repair is unknown. The goal of this study was to explore the role of β-catenin signaling in bone repair.
Methods and Findings
Western blot analysis showed significant up-regulation of β-catenin during the bone healing process. Using a β-Gal activity assay to observe activation during healing of tibia fractures in a transgenic mouse model expressing a TCF reporter, we found that β-catenin-mediated, TCF-dependent transcription was activated in both bone and cartilage formation during fracture repair. Using reverse transcription-PCR, we observed that several WNT ligands were expressed during fracture repair. Treatment with DKK1 (an antagonist of WNT/β-catenin pathway) inhibited β-catenin signaling and the healing process, suggesting that WNT ligands regulate β-catenin. Healing was significantly repressed in mice conditionally expressing either null or stabilized β-catenin alleles induced by an adenovirus expressing Cre recombinase. Fracture repair was also inhibited in mice expressing osteoblast-specific β-catenin null alleles. In stark contrast, there was dramatically enhanced bone healing in mice expressing an activated form of β-catenin, whose expression was restricted to osteoblasts. Treating mice with lithium activated β-catenin in the healing fracture, but healing was enhanced only when treatment was started subsequent to the fracture.
These results demonstrate that β-catenin functions differently at different stages of fracture repair. In early stages, precise regulation of β-catenin is required for pluripotent mesenchymal cells to differentiate to either osteoblasts or chondrocytes. Once these undifferentiated cells have become committed to the osteoblast lineage, β-catenin positively regulates osteoblasts. This is a different function for β-catenin than has previously been reported during development. Activation of β-catenin by lithium treatment has potential to improve fracture healing, but only when utilized in later phases of repair, after mesenchymal cells have become committed to the osteoblast lineage.
In a study in mice Benjamin Alman and colleagues show that β-catenin functions differently in different stages of fracture repair; moreover, activation of β-catenin by lithium improves fracture healing when used in later phases of repair.
Editors' Summary
Most people break at least one bone during their life. If the damaged bone is immobilized with a plaster cast or with metal plates and pins, most fractures heal naturally and quickly. Soon after a bone is damaged, cells called pluripotent mesenchymal cells collect at the injury site. Here, they multiply and change (differentiate) into osteoblasts (cells that make bone) and chondrocytes (cells that make cartilage, the dense connective tissue that covers joints). Osteoblasts and chondrocytes mend the fracture by making new bone, a process called ossification. Bone healing involves two types of ossification. In intramembranous ossification, mesenchymal cells and osteoblast progenitor cells make bone directly, forming a hard “callus” within the fracture. In endochondral ossification, mesenchymal cells differentiate into chondrocytes and make cartilage at the fracture site, which osteoblasts turn into bone. Finally, the bone made by both types of ossification is remodeled so that it closely resembles the damaged bone's original shape and strength.
Why Was This Study Done?
Unfortunately, fractures do not always heal efficiently. If healing is delayed, additional surgery may be needed to repair the break. But surgery can be risky, so drug-based ways of encouraging bone repair would be very useful. To develop such treatments, researchers need to understand what controls the differentiation and activity of osteoblasts and chondrocytes during normal healing. In this study, the researchers have investigated the role of the β-catenin signaling pathway in bone repair. This pathway regulates bone formation during embryonic development, a process that closely resembles bone healing. β-catenin is usually degraded rapidly in cells. However, if a member of a particular family of proteins known as the WNT family binds to a WNT receptor on the surface of a cell, β-catenin moves into the cell's nucleus where it interacts with a protein called T cell factor (TCF). This interaction activates the transcription (the copying of DNA into messenger RNA, which is used to make proteins) of numerous genes and alters the behavior of the cell.
What Did the Researchers Do and Find?
The researchers first measured β-catenin levels in mouse and human bones. In both species, much more β-catenin was made in bones undergoing repair than in intact bones. Then they studied TCF reporter mice—animals in which TCF controls the expression of a marker gene. β-catenin-mediated TCF-dependent transcription, they report, was activated during both bone and cartilage formation after a fracture in these mice. Next, the researchers made mice that could be induced to express an inactive form of β-catenin or a stabilized (permanently active) form of β-catenin in all the cells in a bone fracture. Expression of inactive β-catenin slowed the rate of healing but, unexpectedly, so did expression of stabilized β-catenin. Osteoblast-specific expression of inactive β-catenin also delayed bone healing, whereas osteoblast-specific expression of stabilized β-catenin enhanced the process. Finally, treatment of wild-type mice with lithium (which prevents the degradation of β-catenin) enhanced bone healing if given after a fracture, but interfered with it if given before.
What Do These Findings Mean?
These findings indicate that β-catenin signaling (which, the researchers show, is mainly activated by WNT signaling) has different effects at different stages of bone repair. Early in the process, it controls the ratio of osteoblasts and chondrocytes made from the pluripotent mesenchymal cells. Consequently, too much or too little β-catenin interferes with bone healing at this stage. Later on, β-catenin promotes the differentiation of osteoblasts and enhances their ability to make bone, and so too little β-catenin at this stage prevents healing, whereas increased β-catenin levels stimulate healing. These findings need to be confirmed in people before testing agents that affect β-catenin signaling for their effects on human bone healing. Nevertheless, the researchers' final discovery that lithium improves bone healing if given at the right time is particularly encouraging; lithium is widely used to treat one form of depression so could be readily tested in clinical trials.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia contains pages on broken bones and on bone fracture repair (in English and Spanish)
Wikipedia has pages on bone fracture and on bone healing (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The UK National Health Service Direct encyclopedia provides pages on broken bones
Animations of intramembranous and endochondral ossification are available from the Ministry of Advanced Education, Training and Technology, Province of British Columbia, Canada
The American Academy of Orthopedic Surgeons has an informative discussion of fractures
The Hospital for Sick Children in Toronto (where the authors of this study are affiliated) has a Web site called SickKids, which contains a page on child physiology, including diagrams of bone development
PMCID: PMC1950214  PMID: 17676991
It will be seen at once that the mean values obtained for calcium are higher than most of those recorded in the literature, and that the values for inorganic phosphorus are perhaps lower. It is well to bear in mind, however, that the significance that may be attached to any series of determinations of calcium and inorganic phosphorus in the blood of animals depends largely upon the conditions under which the determinations are made. As is well known, there are many factors that may affect the values obtained, including inherent differences in the animal material and the method of analysis used as well as the particular procedure employed in carrying out a given method. When all other conditions are uniform, irregularities in the handling of the blood after it is drawn will give rise to surprisingly large differences in the results for both calcium and inorganic phosphorus, as permitting blood to stand tends to decrease calcium values and to increase those for inorganic phosphorus. It seems desirable, therefore, to emphasize the fact that the results recorded above are to be viewed as results obtained under certain definitely prescribed conditions which differ in several important respects from those governing determinations made by other workers in this field. Moreover, it is to be noted that the conditions varied to some extent with each of the 4 groups of animals comprising this series. For example, there was a small but definite age difference. The animals of Groups I and II were older and more mature than those of Groups III and IV at the beginning of the experiments, and this initial difference was increased by the extension of the experiments on Groups I and II over a longer period of time, so that the observations made on these animals not only included data for a more advanced age, but represented a mean age considerably above that of the observations made on the animals of Groups III and IV. There was a similar difference of experimental conditions between Groups III and IV, while the observations on Group II differed from those on Group I in that no blood analyses were made on the animals of Group II for 2 months after they were placed under observation. These particular features of the experiments are mentioned because an examination of the text-figures will show that a line of cleavage between Groups I and II on the one hand, and III and IV on the other, is traceable through all of the distribution curves and to some extent in the tabulated results. With the combined values as the axis of distribution, Groups I and II invariably hang together, or swing to one side, while Groups III and IV swing to the other. Moreover, the extreme positions are usually represented by Groups II and IV. Whether these peculiarities of the results are in reality attributable to the conditions mentioned or to some other cause, such as the length of cage life (2), or the particular period covered by the observations, the suggested relation is sufficient to indicate the extent to which even slight differences in experimental conditions may affect the results obtained for blood calcium and inorganic phosphorus. The values obtained for calcium may be regarded as showing a fairly close agreement (Tables I and II and Text-fig. 1). The extreme difference between the means for the 4 groups of animals is only 0.5 mg. or approximately 3.00 per cent of the mean for the combined groups. Still, the small absolute difference between the means for Groups I and IV is nearly 6 times its probable error and, hence, cannot be disregarded. The most important feature of these results is, however, the range of normal variation. The distribution curves (Text-fig. 1) show a remarkably close agreement in the frequency with which values of a given magnitude occurred and an unusually symmetrical distribution of all values. The coefficients of variation are comparatively small (7.09 to 8.9 per cent), but values anywhere between 14.0 and 16.0 mg. of calcium per 100 cc. of serum occurred with great frequency, while figures as low as 13.5 or as high as 17.5 mg. (Table II) were by no means rare; and the extreme limits of observation indicate a potential difference in the calcium content of the blood of normal rabbits of as much as 100 per cent. Inorganic phosphorus was found to be subject to much wider variation than calcium (Tables III and IV and Text-fig. 2). The coefficient of variation is approximately twice that for calcium (17.29 and 8.01 respectively), while the group means for phosphorus show a difference of 0.85 mg. per 100 cc. of serum. This difference is small in absolute value, but is nearly 20.0 per cent of the mean for all groups and is 15 times its probable error. It is safe to assume, therefore, that the values obtained indicate an actual difference in the inorganic phosphorus in the blood of the several groups of animals. This conclusion is borne out by the distribution frequencies (Table IV and Text-fig. 2) which show that the values obtained for Groups I and II lie at a distinctly lower level than those for Groups III and IV; the difference between modal classes is, in fact, of the same order as that shown by the means. The limits of probable variation as determined by the standard deviation of the combined results are 3.73 and 5.29 mg. per 100 cc. of serum, but one-third of all values lie outside of these limits, while the extreme limits of normal are sufficiently wide to include values that may differ by as much as 200.0 or even 300.0 per cent. From the values obtained for calcium and inorganic phosphorus, the relation existing between the two substances may be measured in a number of ways. The ratio of the calcium to the phosphorus and the product of the amounts of the two substances have received the greatest attention. In addition to these values, we have computed values for the sum and for the ratio of the product to the sum, and also for the sum of the calcium-phophorus ratio and the product-sum ratio. The value for the sum of the calcium and inorganic phosphorus in the serum is determined largely by the calcium, but as it is also affected by the phosphorus, one might expect that the constancy of the value as compared with that of calcium would be diminished unless the variations in the two substances were so related as to neutralize each other. As is well known, there is an apparent tendency in this direction and in these experiments it was found that on the whole the values for the sum showed less variation (coefficients 6.42 and 8.01 per cent) and were more uniformly distributed than those for calcium (Tables V and VI and Text-fig. 3). It is true that differences between groups were distinctly greater than in the case of calcium, but the agreement is sufficiently close to give evidence of a tendency to the maintenance of an inverse relation between serum calcium and inorganic phosphorus. Values for the product of calcium and inorganic phosphorus emphasize the phosphorus factor rather than the calcium, reversing the conditions that obtain in the case of the sum. A consideration of the product values given in Tables VII and VIII and Text-fig. 4 show that, while the order of variation is essentially the same as that of inorganic phosphorus (coefficients 17.09 and 17.29 per cent respectively), the distribution of values is more uniform. This may be attributable to the occurrence of coordinate variations in calcium and inorganic phosphorus. The situation presented by the values obtained for the ratio of calcium to inorganic phosphorus is somewhat surprising in that the ratio between the two substances proves to be less constant than the absolute amounts of either substance (Tables IX and X and Text-fig. 5). There are considerable differences between the standard values for individual groups of animals, and the distribution frequencies are inclined to be irregular. Moreover, all groups show a large standard deviation and correspondingly high coefficients of variation, but combining the results for the 4 groups of animals gives a fairly uniform and symmetrical distribution, a striking feature of which is the high frequency with which values occur over the entire range of standard variation, that is, from ratios of 2.85 to 4.29. It thus appears that, despite the evidence of a tendency to the observance of an inverse relation between the calcium and inorganic phosphorus in the blood, the ratio of one substance to the other is by no means constant. By using the product and the sum as a basis of expressing the relation between calcium and inorganic phosphorus, the form of the relation is ???
PMCID: PMC2131397  PMID: 19869430
11.  Is bisphosphonate therapy for benign bone disease associated with impaired dental healing? A case-controlled study 
Bisphosphonates are common first line medications used for the management of benign bone disease. One of the most devastating complications associated with bisphosphonate use is osteonecrosis of the jaws which may be related to duration of exposure and hence cumulative dose, dental interventions, medical co-morbidities or in some circumstances with no identifiable aggravating factor. While jaw osteonecrosis is a devastating outcome which is currently difficult to manage, various forms of delayed dental healing may be a less dramatic and, therefore, poorly-recognised complications of bisphosphonate use for the treatment of osteoporosis. It is hypothesised that long-term (more than 1 year's duration) bisphosphonate use for the treatment of post-menopausal osteoporosis or other benign bone disease is associated with impaired dental healing.
A case-control study has been chosen to test the hypothesis as the outcome event rate is likely to be very low. A total of 54 cases will be recruited into the study following review of all dental files from oral and maxillofacial surgeons and special needs dentists in Victoria where potential cases of delayed dental healing will be identified. Potential cases will be presented to an independent case adjudication panel to determine if they are definitive delayed dental healing cases. Two hundred and fifteen controls (1:4 cases:controls), matched for age and visit window period, will be selected from those who have attended local community based referring dental practices. The primary outcome will be the incidence of delayed dental healing that occurs either spontaneously or following dental treatment such as extractions, implant placement, or denture use.
This study is the largest case-controlled study assessing the link between bisphosphonate use and delayed dental healing in Australia. It will provide invaluable data on the potential link between bisphosphonate use and osteonecrosis of the jaws.
PMCID: PMC3080357  PMID: 21477374
12.  Osteonecrosis of the jaw in a Crohn’s disease patient following a course of Bisphosphonate and Adalimumab therapy: a case report 
BMC Gastroenterology  2014;14:6.
Bisphosphonates have a widespread indication for osteoporosis and are also applied in cancer patients with skeletal-related conditions. Bisphosphonate-associated osteonecrosis of the jaw (BRONJ) is a feared side effect which is hard to treat and often affects patient´s quality of life in an extensive manner. Adalimumab (Humira®), a fully human recombinant antibody specific for tumor necrosis factor- α, is approved for treatment in patients with Inflammatory Bowel Disease like ulcerative colitis or Crohn’s disease.
Case presentation
In March 2013, a 36-year-old female presented with right-sided perimandibular swelling, recurrent facial pain and exposed necrotic bone after previous extraction of tooth 47. She had the medical history of Crohn’s disease for more than one decade with chronic active enterocolitis, fistula disease as well as previous oral manifestation and was currently treated with Adalimumab since September 2008. Due to steroid-induced osteoporosis, diagnosed in 2004, she received oral Bisphosphonates (Risedronate) from 2004 until 2007 followed by two infusions of Zoledronic acid in 2008 and 2009.
This patient with a medical history of Crohn’s disease and gastrointestinal remission under Adalimumab therapy presented with osteonecrosis of the jaw after suspended oral and intravenous Bisphosphonate therapy implicating that the biologic therapy with an anti-TNF-α antibody might promote the manifestation of osteonecrosis and compromise oral healing capacity.
PMCID: PMC3890650  PMID: 24400722
Osteonecrosis of the jaw; Bisphosphonate; Adalimumab; Crohn’s disease
13.  Extensive gingival necrosis and sequestration of the alveolar bone caused by methimazole-induced neutropenia and three-year follow-up 
Methimazole is an anti-thyroid drug that can cause life-threatening neutropenia in rare situations. The aim of this case report is to describe a set of oral complications associated with methimazole-induced neutropenia and the healing of the gingiva after proper treatment.
A 31-year-old female patient hospitalized for systemic symptoms of sore throat and fever and showing extensive gingival necrosis with pain was referred to the Department of Periodontics from the Department of Endocrinology. Methimazole-induced neutropenia was diagnosed based on blood test results and her medical history. Methimazole was discontinued and a range of treatments was administered, including the injection of granulocyte colony stimulating factor.
After systemic treatment, the gingiva began to heal as the neutrophil count increased. Approximately one year later, the gingiva had returned to a normal appearance. Twenty-one months after treatment, sequestra of the alveolar bone that had broken through the gingiva were removed. Periodic supportive periodontal treatment has been continued uneventfully.
The oral manifestations of gingival necrosis and ulcerations, in combination with systemic symptoms such as fever and sore throat, are the critical signs presented in the early stages of drug-induced neutropenia. Therefore, dentists need to be aware of these oral complications in order to make an accurate diagnosis and to ensure that prompt medical intervention is provided.
Graphical Abstract
PMCID: PMC4415005  PMID: 25932342
Complications; Hyperthyroidism; Methimazole; Neutropenia
14.  Single-incision technique for the internal fixation of distal fractures of the tibia and fibula: a combined anatomic and clinical study 
To present a novel single anterior-lateral approach for the treatment of distal tibia and fibula fracture via anatomical study and primary clinical application in order to minimize soft tissue complications.
Both a gross anatomic cadaver and retrospective studies of the single-incision technique in patients recruited between June 2004 and January 2010.
Level I trauma center.
Twenty-six legs of 14 adult human cadavers and clinical recruitment of 49 patients (29 males, 20 females) with a mean age of 37.6 years (range 11–68) with fracture of distal 1/3 tibia and fibula.
A single anterior-lateral incision technique for open reduction and internal fixations of distal tibia and fibula fractures.
Main outcome measures
To identify the anatomic structures at risk in the anterolateral aspect of the lower leg and explicit the safe dissection distance from the extensor digitorum longus (EDL) to tibia and fibula, 26 legs of 14 adult human embalmed specimens were recruited in the anatomical study with the distance between the EDL and the anterior edge of the distal thirds of the tibia, as well as the distance between the EDL and the anterior edge of the distal thirds of the fibula were measured, and their mutual relationships to the surrounding anatomical structures described. Mean average standard deviations were also calculated. As for the clinical study, the quality of bone union and soft tissue healing were noted.
The mean distances between the distal tibia and the EDL were measured to be 2.96 ± 0.46 cm (proximal), 1.85 ± 0.25 cm (middle), and 2.15 ± 0.30 cm (distal), and that between the fibula and the EDL were 1.82 ± 0.28 cm (proximal), 2.09 ± 0.31 cm (middle), and 2.30 ± 0.27 cm (distal), which means the safe gap from the distal tibia to EDL was1.6–3.4 cm and from the EDL to fibula was 1.5–2.6 cm. The anterior tibial vein and artery and the deep fibular nerve lie on the anterior interosseous membrane over the lateral surface of the distal tibia were excellently visualized. Review of clinical outcomes in 49 patients with combined distal tibial and fibular fractures who underwent reduction and fixation with the single-incision technique, revealed uneventful fracture healings in 47 patients; and two cases of superficial wound necrosis which were treated and healed in 4 months. There was no case of delayed union or non-union.
Distal fibula fracture occurring with distal tibia fracture poses a challenge for stable fixation. This has necessitated the need for dual incisions on the distal leg to approach each fracture for reduction and fixation. However, a single anterolateral incision enables the safe approach to the lateral aspects of the distal tibia and fibula thus eliminating the need for two separate incisions and minimizing the soft tissue complication to some extent. Meanwhile, the neurovascular bundle at risk during operation, distal tibia and fibula is clearly exposed in the single anterior-lateral incision.
PMCID: PMC3828491  PMID: 24121655
Fracture; Distal tibia; Distal fibula; Anatomy; Incision
15.  Oral manifestations of McCune-Albright syndrome 
McCune- Albright Syndrome (MAS) is a rare fibrosseous lesion, characterized by a classic triad of polyostotic fibrous dysplasia (PFD), café –au-lait macules (CALM) and underlying endocrinopathies. We present the oral findings of an interesting case of MAS with relevant review of literature. A 30-year-old male presented to us with swelling of both jaws over a period of two years. Cutaneous examination revealed café - au – lait macule over the back, crossing the midline. Skeletal survey showed expansile, osteolytic, mixed radiolucent- radiopaque lesions in skull and jaw bones. Serum alkaline phosphatase was elevated (388 IU/L), with normal calcium, phosphorus, parathyroid hormone and 25 hydroxy vitamin D levels. Diagnosis of McCune- Albright syndrome was made and he was treated with parenteral bisphosphonates (intravenous Zoledronate 4 mg) and is under follow up for surgical recontouring of the jaws. Early recognition facilitates better treatment and improves prognosis by reducing the morbidity.
PMCID: PMC3659890  PMID: 23776876
Albright's syndrome; fibrous dysplasia of the jaws; fibroosseous lesion; polyostotic fibrous dysplasia
16.  Tuberculosis of the foot: An osteolytic variety 
Indian Journal of Orthopaedics  2012;46(2):206-211.
Foot involvement in osteoarticular tuberculosis is uncommon and isolated bony involvement of foot bones with an osteolytic defect is even more rare; diagnostic and therapeutic delays can occur, worsening the prognosis. We present a retrospective series of osteolytic variety of foot tuberculosis.
Materials and Methods:
We present 24 osteolytic variety of foot tuberculosis (Eleven calcaneus, four cuboid, two cunieforms, one talus, three metatarsals, three phalanges) out of 92 foot TB cases collected over last 20 years. There were 16 adults and eight children. Tissue diagnosis was established in 23 of 24 cases based on PCR AFB staining, culture, and histopathology. Surgical intervention was reserved for patients with either a juxtaarticular focus threatening to involve a joint or an impending collapse of a midfoot bone with cystic destruction.
Fifteen cases had an osteolytic lesion on the radiographs resembling a space-occupying lesion, five had patchy osteolysis, while four showed coke like sequestra; one patient had a lesion in two bones. Antitubercular chemotherapy after biopsy was sufficient to heal the lesion in 19 cases, while in five cases surgical debridement needed to be done. The lesions healed eventually. At an average followup of 8.3 years, (range 2-15 years) there were no recurrences and all patients were free from pain, with no restriction of movements. Six patients complained of occasional pain during walking on uneven ground.
When tuberculous pathology is limited to the bone, the prognosis is better than in articular disease, as there is less deformity, and hence, less residual pain and disability.
PMCID: PMC3308663  PMID: 22448060
Calcaneus; foot; infection; osteolytic; tuberculosis
17.  A novel model of bisphosphonate-related osteonecrosis of the jaw in rats 
Objective: To establish a rat model of bisphosphonate-related osteonecrosis of the jaw (BRONJ) that realistically mimics major clinical manifestations of the disease. Methods: Female Sprague Dawley rats received intravenous zoledronate 80 μg/kg once a week via the tail vein. Three weeks after intravenous injection, maxillary first molars were extracted under general anesthesia. Then 1, 4 and 12 weeks after tooth extraction, the rats were euthanized, and the intact maxillas were harvested en bloc. Macroscopic analysis, histological analysis and cytokine analysis were performed. Untreated rats with tooth extraction were used as controls. Results: 12 weeks after extraction, rats treated with zoledronate developed BRONJ-like disease, including characteristic features of impaired soft tissue healing, exposed necrotic bone or sequestra, increased inflammatory infiltrates, while the controls showed normal bone healing. 4 weeks after extraction, rats treated with zoledronate exhibited the decreased receptor activator of nuclear factor kappa-B ligand (RANKL) values, the increased osteoprotegerin (OPG) values and the remarkable decreased RANKL/OPG ratio when compared with the controls. Conclusion: The rats treated with zoledronate can be considered a novel, reliable and reproducible animal model to better understand the pathophysiology and pathogenesis of BRONJ and to develop a therapeutic approach.
PMCID: PMC4503084  PMID: 26191212
Bisphosphonates; BRONJ; animal model; pathogenesis; RANKL; OPG
18.  Management of firearm injuries to the facial skeleton: Outcomes from early primary intervention 
Treatment of maxillofacial firearm injuries is still controversial with regard to timing of management. We postulate that not all maxillofacial firearm injuries need be delayed and that many may be treated early. To this end, a 19-year retrospective study was undertaken seeking to evaluate patients treated for firearm injuries to the facial skeleton at our center. The criteria which dictated when to operate are presented as are the results, benefits, and outcomes of the patients treated acutely.
Patients and Methods:
From 1991 to 2010, 51 patients with maxillofacial firearm injuries were treated; 30/51 patients received early primary repair and simultaneous open reduction for facial fractures. These underwent primary debridement and arch bar placement followed by open reduction of fractures (with or without osteosynthesis) and primary wound closure. Patient age ranged from 8 to 50 years, with a mean age of 24.4±7.8 years. Primary early intervention was done when there was no gross infection, no bone comminution or extensive soft tissue avulsion (precluding wound coverage), and when general health, concomitant injuries requiring more urgent attention or those requiring major grafts did not preclude this. Primary intervention included extensive oral and extraoral irrigation (dilute hydrogen peroxide + povidone iodide), debridement of the facial wound, removal of floating fragments (teeth particles, debris, and shell fragments) precluding viable bone within the wound, access to the bone, finding the scattered bone segments and putting them back into place to restore bone continuity. Projectiles beyond the wound were not searched for. Tooth roots within the alveolus were not extracted at this stage. In addition to arch bars, titanium miniplates or wire osteosynthesis was done when necessary. All wounds were closed primarily (using local advancement flaps when necessary) and all patients were placed on antibiotics (cephalosporin + aminoglycoside or ciprofloxacin) upon admission.
Of 51 patients, 30 were treated acutely and 21 warranted delayed intervention. In the acute-treated group, 6/30 patients had minor complications such as scarring and wound discharge. Early intervention for firearm wounds to the face was effective for facial firearm injuries in selected cases. This resulted in restoration of occlusion and continuity of the jaw, fixation of luxated teeth, early return of function, prevention of segment displacement and tissue contracture, less scarring, and decreased the need for major bone graft reconstruction later on. Those treated secondarily were only debrided and had arch bars placed. Definitive treatment of hard and soft tissue management was rendered in another subsequent operation. Bone reduction was more difficult because of scarring, and displacement of remaining segments. No significant differences were noted in terms of infection or other major complications.
Firearm wounds were associated with a high incidence of maxillofacial injuries requiring surgical intervention. Many may be treated definitively and acutely with procedures designed to repair both bone and soft tissue injuries simultaneously aiming to restore bony continuity, esthetics and function using the tissues at hand (especially in the mandible). Early treatment is advocated because the course of healing is not disrupted with another subsequent operation (in the same wound) and because it may decrease hospital stay without increasing patient morbidity in selected patients. Patients with residual defects can be treated later as out-patients.
PMCID: PMC3132361  PMID: 21769208
Early intervention; facial skeleton; firearm injuries
19.  RANK/RANKL/OPG Signaling Pathways in Necrotic Jaw Bone from Bisphosphonate-Treated Subjects 
Osteonecrosis of the jaw (ONJ) is a chronic complication affecting long-term bisphosphonate-treated subjects, recognized by non-healing exposed bone in the maxillofacial region. The pathophysiological mechanism underlying ONJ has not been fully elucidated. The aim of the present study was to investigate the role of RANK/RANKL/OPG signaling pathway and, in parallel, to evaluate angiogenic and matrix mineralization processes in jaw bone necrotic samples obtained from bisphosphonate-treated subjects with established ONJ. Necrotic bone samples and native bone samples were processed for Light and Field Emission in Lens Scanning Electron Microscope (FEISEM) analyses, for Real-Time RT-PCR to evaluate the gene expression of TNFRSF11A (RANK), TNFSF11 (RANKL), and TNFSF11B (OPG) and for immunohistochemical analyses of VEGF and BSP expression. Morphological analyses performed by Light microscope and FEISEM show empty osteocytic lacunae and alteration of lamellar organization with degradation of the mineralized bone matrix in necrotic bone samples. A significant increase in TNFRSF11A, TNFSF11, TRAF6 and NFAT2 gene expression, and a reduction of TNFSF11B gene transcription level compared is also showed in necrotic bone compared to control samples. No significant difference of VEGF expression is evidenced, while lower BSP expression in necrotic bone compared to healthy samples is found. Even if the pathogenesis of bisphosphonate-associated ONJ remains unknown, a link between oral pathogens and its development seems to exist. We suppose lipopolysaccharide produced by bacteria colonizing and infecting necrotic bone and the surrounding viable area could trigger RANK/RANKL/OPG signaling pathway and, in this context, osteoclasts activation could be considered as a protective strategy carried out by the host bone tissue to delimitate the necrotic area and to counteract infection.
PMCID: PMC4378212  PMID: 25820558
Bisphosphonate; osteonecrosis of the jaw; gene expression; RANK; RANKL; OPG
20.  Health of workmen in the chromate-producing industry in Britain. 
In a follow-up study of 2715 men who had worked for at least one year at the three chromate-producing factories in Britain between 1948 and 1977 only 298 were lost to follow-up, and the average number of person-years in the study was 16.3. One hundred and sixteen deaths from lung cancer occurred in these men, with only 48.0 expected (O/E = 2.4; p less than 0.001). For men employed at the factory, which is still in operation, the relative risk of lung cancer has decreased from over 3.0 before plant modification to about 1.8 in those who have worked only since plant modification. A multivariate analysis was used in an attempt to unravel the overlapping influence of duration of employment, length of follow-up, plant modification, factory, age at entry to work, and estimated degree of chromate exposure. The major dependent factor appeared to be duration of employment; in addition the analysis suggested that modifications in the plant and work environment had been associated with an appreciable reduction of the excess risk from lung cancer.
PMCID: PMC1008833  PMID: 7236535
21.  WORKMEN'S COMPENSATION—Details of Medical Reports 
California Medicine  1957;87(2):85-87.
Attention to details of medical reporting that are required for just settlement of compensation cases can greatly facilitate proper adjudication.
PMCID: PMC1512071  PMID: 13446752
22.  Occupational hearing loss of the workmen of an open cast chromite mines 
The present work aimed at to describe hearing threshold based on audiometry data of the mine workers based on their age, work station and years of working of an open cast chromite mine in Odisha, India at high fence.
Materials and Methods:
A cross-sectional study of hearing threshold of the subjects of the chromite mine was carried out. Audiometric data of 500 subjects were taken from the hospital of the mines of Sukinda Valley, Jajpur, Odisha, India. The latest audiometry data available during the period 2002 to 2008 was used in the statistical analysis.
The age group 50-60 years is found to be the most influential age group suffering significant hearing loss on both the ears. Also, the Work Zone area is found to be most significant area affecting hearing loss on both the ears. However, the subjects having experience of 30-35 and 25-30 years have the most significant hearing loss on the left and right ears, respectively.
The hearing loss is found to be at 6 kHz, thus the working areas of the subjects working at work zone should be regularly rotated in less noisy areas to reduce the exposure duration. High frequency noise protective device should be advocated among all the subjects in general and HEMMs operators in particulars. Regular audiometry test of all the subjects should be performed to identify the hearing loss of the subjects occurring at 6 kHz. It is essential to perform periodic maintenance of all the HEMMs to keep all the vehicles in good condition those are generating noise at dominating frequency of 4 and 6 kHz.
PMCID: PMC3482703  PMID: 23112502
Asymmetry hearing loss; dip or notch; high fence; low fence; noise induced hearing loss
23.  Pathological fracture of the coronoid process secondary to medication-related osteonecrosis of the jaw (MRONJ) 
•This case reports the first case to our knowledge of pathological fracture of the coronoid process of the mandible secondary to long term use of alendronic acid.•Demonstrates the unpredictable nature of symptoms associated with medication related osteonecrosis and its management within the hospital environment.•Demonstrates the rapidly progressing and unpredictable nature of the spread of the necrotic process in medication related osteonecrosis.•Clear clinical photographs of the surgical procedure involved in the removal of necrotic bone and curettage of the surgical site in medication related osteonecrosis.
Medication-related osteonecrosis of the jaw (MRONJ) is a growing problem within the field of oral and maxillofacial surgery. It is defined as the presence of exposed necrotic alveolar bone that does not resolve over a period of 8 weeks in a patient taking bisphosphonates, who has not had radiotherapy to the jaw [1]. Since the first report in 2003 that highlighted the potential harm caused by MRONJ, many more patients have been diagnosed with the condition [2]. The growth in recent years is likely due to the more potent drugs delivered intravenously however there is some evidence that oral bisphosphonates given over longer periods of time can have similar effects. Bone exposure may occur spontaneously or most commonly occurs following an invasive dental procedure, as shown in the case below [3].
Presentation of case
This case report demonstrates the unpredictable nature of symptoms associated with medication related osteonecrosis and its management within the hospital environment.
This case demonstrastes the unpredictable nature of MRONJ and how the disease can progress to cause significant morbidity. In this case extensive surgery was required to remove the necrotic fragments of bone with no guarnatee that the necrosis will stop spreading.
It seems a matter of great importance that the lasting effects of MRONJ are known to general dental and medical practitioners alike. Nationally recognised evidence based guidelines are lacking and uniformity in the management of MRONJ is required amongst the speciality.
PMCID: PMC4429953  PMID: 25841160
24.  Bisphosphonates Inhibit Expression of p63 by Oral Keratinocytes 
Journal of Dental Research  2011;90(7):894-899.
Osteonecrosis of the jaw (ONJ), a side-effect of bisphosphonate therapy, is characterized by exposed bone that fails to heal within eight weeks. Healing time of oral epithelial wounds is decreased in the presence of amino-bisphosphonates; however, the mechanism remains unknown. We examined human tissue from individuals with ONJ and non-bisphosphonate-treated controlindividuals to identify changes in oral epithelium and connective tissue. Oral and intravenous bisphosphonate-treated ONJ sites had reduced numbers of basal epithelial progenitor cells, as demonstrated by a 13.8 ± 1.1% and 31.9 ± 5.8% reduction of p63 expression, respectively. No significant differences in proliferation rates, vessel density, or macrophage number were noted. In vitro treatment of clonal and primary oral keratinocytes with zoledronic acid (ZA) inhibited p63, and expression was rescued by the addition of mevalonate pathway intermediates. In addition, both ZA treatment and p63 shRNA knock-down impaired formation of 3D Ex Vivo Produced Oral Mucosa Equivalents (EVPOME) and closure of an in vitro scratch assay. Analysis of our data suggests that bisphosphonate treatment may delay oral epithelial healing by interfering with p63-positive progenitor cells in the basal layer of the oral epithelium in a mevalonate-pathway-dependent manner. This delay in healing may increase the likelihood of osteonecrosis developing in already-compromised bone.
PMCID: PMC3318057  PMID: 21551338
osteonecrosis; oral pathology; gingival; epithelia; keratinocytes; zoledronic acid
25.  TVR and vibration-induced timing of motor impulses in the human jaw elevator muscles. 
In order to investigate myotatic reflex involvement in jaw muscle control, an analysis was made of the motor responses induced by mechanical vibration (120-160 Hz) of the jaw elevator muscles in healthy subjects. As seen in torque measurements and mean-voltage electromyographic (EMG) recordings, the vibration caused involuntary reciprocal changes in jaw muscle tone, the contraction force increasing in jaw elevators and decreasing in antagonistic jaw opening muscles. This tonic vibration reflex (TVR) elicited from the jaw elevators exhibited many characteristics similar to those previously described for limb muscle tonic vibration reflexes: it varied in strength from one subject to the next independently of the briskness of the jaw elevator tendon jerks; it had a gradual onset with successive recruitment of jaw elevator motor units firing largely out of phase with one another and at rates much lower than the vibration frequency; it was susceptible to voluntary control--when allowed visual feed-back from the torque meter all subjects were able to suppress the TVR and keep mean contraction force constant. The results indicate that with respect to the tonic motor response to sustained inflow in the Ia afferent nerve fibres, the jaw elevators do not differ markedly from other skeletal muscles. Independently of whether a TVR was present or not, the vibration caused a timing of the motor unit discharges in the jaw elevators that could not be controlled voluntarily and that showed up in gross EMG recordings as a marked grouping of discharges synchronous with each wave of vibration. A similar but less distinct grouping of the gross EMG pattern was seen in limb muscles exposed to vibration, the dispersion increasing with the peripheral conduction distances of the reflex arcs. It is suggested that contrary to the TVR, which depends on the sustained mean level of the Ia afferent input, the timing phenomenon depends, like the tendon jerk, on the degree of synchrony in the afferent Ia volleys. Monosynaptic projections may well be involved in the dynamic timing of motor discharges during tonic firing, but this does not imply that the TVR or the tonic stretch reflex is dependent upon such projections.
PMCID: PMC492437  PMID: 134135

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