Heterotopic bone formation after joint replacement.

Bone formation outside the skeleton, heterotopic ossification (HO), is a common finding on radiographs from patients who have undergone arthroplasty of the hip, knee, shoulder, or elbow. Only a minority (5%-10%) of the patients with HO suffer from any consequence of the condition. However, because of the great number of joint replacements performed, the number of patients with decreased function that can be attributed to HO is significant. The risk for severe HO after total hip arthroplasty is increased in 1) patients who have developed HO after previous surgery, 2) men with hypertrophic osteoarthrosis and, 3) in patients with ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. The same risk factors are probably valid for other joints as well. Two preventive treatments for HO after hip arthroplasty, nonsteroidal anti-inflammatory drugs and local radiation, are effective and reasonably well documented but are associated with potential side effects. Thus, a treatment protocol to prevent HO must identify the patients at risk for severe HO and recommend them treatment with one of these two modalities. Based on the current literature, we suggest that the patients at risk for severe HO be treated with 1) nonsteroidal anti-inflammatory drugs from the day of surgery for 7-10 days or 2) preoperative (or postoperative) radiation in a single dose.

Preventive effects of ibuprofen on periarticular heterotopic ossification after total hip arthroplasty. A randomized double-blind prospective study of treatment time.

We determined the efficacy and the minimum treatment time necessary for prophylaxis with nonsteroidal anti-inflammatory drugs (NSAIDs) for periarticular heterotopic ossification (HO) after total hip arthroplasty (THA). Using a double-blind placebo controlled design, 144 patients operated on with total hip arthroplasty for primary arthrosis were treated postoperatively with (1) ibuprofen for 3 weeks, (2) ibuprofen for 1 week and placebo for the next 2 weeks or (3) placebo for 3 weeks. Radiographic occurrence of periarticular heterotopic ossification and complications of the treatment were recorded for the first year. Both ibuprofen-treated groups showed significantly less HO than the placebo-treated group. There was no difference in HO between the patients treated for 8 or 21 days postoperatively. Both 8 and 21 days of treatment with ibuprofen following THA effectively prevents clinically significant degrees of HO. No serious short-term complications of the treatment were noted.

Effects of cyclosporin A on experimental new bone formation in rats.

The effects of the immunosuppressive drug cyclosporin A (CsA) on bone induction by demineralized allogeneic (rat) bone matrix (DABM) and demineralized xenogeneic (rabbit) bone matrix (DXBM) were studied. Growing rats were implanted with three samples each of DABM and DXBM. Groups of eight rats were treated with 0.5 or 2 mg CsA/kg body weight for four weeks and compared with a placebo group. Cyclosporin A treatment enhanced bone induction in DABM implants by 40 to 50% at four weeks, whereas there was no difference from the control group at eight weeks. Demineralized xenogeneic bone matrix induced virtually no bone in control rats at four weeks, whereas the net bone formation increased four to five times in both groups of CsA-treated rats. At eight weeks, DXBM without CsA had induced some bone formation, and the amount was almost equal to that of DABM implants in CsA-treated groups. Also, the mineral accretion rates of DXBM were equal to DABM implants in CsA-treated rats. Cyclosporin A treatment doubled the uptake of 45Ca in the orthotopic skeleton (femora) at four weeks without affecting the mineral content, indicating an increased mineral turnover. Immunologic reactions may inhibit bone induction by DXBM, which can be counteracted by treatment with CsA.

Total hip arthroplasty in patients 80 years of age and older.

One hundred fifty-seven consecutive patients (162 total hip arthroplasties) 80 years of age and older were observed for one year after total hip arthroplasty (THA). Clinical results and complications were recorded. The indication for surgery was degenerative joint disease (DJD) in one half of the patients and complications to proximal femoral fractures in the other half. The mean age was 83 years old in both groups. In 80% of the patients, no complications were recorded during the first year. Three patients died during the first three months. Two deep infections occurred (1.2%). The dislocation rate was 9.2% (15/162). There was a lower dislocation rate (4/84) in the DJD group compared to the fracture group (11/78). All nine recurrent dislocations occurred in the fracture group and were treated with either trochanteric osteotomy (five) or removal of the prosthesis (four). In the patients operated on with trochanteric osteotomy, no further dislocations occurred. The mean hospital stay was 13 days. After one year, 88% (112/127) of the patients who could be observed had good or excellent results. Total hip arthroplasty in the elderly is a reasonably safe method and yields good functional results. Dislocations, however, were common in patients operated on for complications from proximal femoral fractures, and the risk for recurrent dislocation was high (9/11). In these patients, trochanteric osteotomy is recommended.

Nonsteroidal anti-inflammatory drugs for prevention of heterotopic ossification after total hip arthroplasty.

Nonsteroidal anti-inflammatory drugs (NSAID) have been proven highly effective as prophylaxis for periarticular heterotopic ossification (HO) following total hip arthroplasty (THA) both when given to patients considered to be at risk for this complication, and in consecutive double-blind studies. Treatment with a standard dosage for 10 days starting on the day of surgery seems to be adequate for the prophylactic effect. Furthermore, NSAID are effective in preventing recurrence of HO after resection.

Experimental induction of heterotopic bone.

Heterotopic bone can be induced in experimental animals by trauma to the soft tissues, by induction from living cells, or by extracts from bone and teeth. In the first two types, the mechanism of the inductive process is not known, whereas in the latter, a factor isolated from bone matrix induces bone formation. Mesenchymal cells in bone marrow are determined for development into cartilage and bone cells and only an unspecific stimulus, such as trauma or autotransplantation, is sufficient for the development into mature osteogenic tissue. Mesenchymal cells will not differentiate into bone cells unless stimulated by a specific inductive substance, bone morphogenetic protein (BMP). Implanted to a heterotopic site, BMP induces undifferentiated mesenchymal cells into a bone morphogenetic pathway of development, causing heterotopic bone formation. The quantitative inductive response is dependent on the source of the BMP, and the bone formation is also determined by the recruitment of inducible target cells and by the environment at the implantation site. Hence, the environment at the implantation site is of major importance for the amount of bone formed. BMP initiates a cascade of events that is modulated by endocrine and paracrine factors. The heterotopic bone has all the morphologic and biochemical characteristics of orthotopic bone, is subjected to turnover, and even has the intriguing ability to generate the formation of bone marrow. Experimental induction of heterotopic bone has become a most useful method to study osteoneogenesis and has supplied important information on the prerequisites for new bone formation and on the regulation of bone metabolism.

Tissue adhesives inhibit experimental new bone formation.

The effect of the cyanoacrylate tissue adhesive Histoacryl on new bone formation was studied in rats. Experimental heterotopic new bone formation was induced by implanting pieces of demineralized allogeneic bone matrix (DABM) in the abdominal wall of 10 growing Sprague-Dawley rats. This produces cartilage formation within and around the implants after 10 days, followed by enchondral ossification and the formation of an ossicle with remodelling bone and bone marrow after three weeks. Prior to implantation, the DABM-implants were treated with increasing amounts of the tissue adhesive n-Butyl-2-cyanoacrylate-monomer (Histoacryl). New bone formation was quantified at three weeks by assay of the ash content of the implants as a measure of net bone formation, by 45calcium uptake prior to sacrifice, and by histology. Treatment of DABM with the cyanoacrylate caused an intense inflammatory process with a foreign body reaction, and abolished bone induction and new bone formation. Tissue adhesives should be used with caution in fracture surgery since they inhibit new bone formation, cause a foreign body reaction, and may impede fracture healing.

Immune inhibition of repair of canine skull trephine defects implanted with partially purified bovine morphogenetic protein.

The healing of 14-mm trephine skull defects was observed in ten adult mongrel dogs. First and second set trephine operations were performed to determine whether xenogeneic bovine bone morphogenetic protein (bBMP) and associated bone matrix water-insoluble noncollagenous proteins (iNCP) incite an immunological humoral response inhibiting bone repair. The effects of immunization to BMP/iNCP were observed by serum radioimmunoassay, and by correlated roentgenographic and histological analysis of deposits of new bone. The first set implants of bBMP/iNCP induced 96% healing while the regeneration of the second set trephines was 34% less than the first set. The second set was associated with a significant increase in serum anti-BMP antibodies. While xenogeneic bBMP induced complete healing of trephine defects when implanted without previous immunization, and repair in response to a second set of bBMP/iNCP was always incomplete, further research with high purified recombinant BMP is required to measure immune effects in a statistically significant number of pure bred recipients.

Heterotopic new bone formation causes resorption of the inductive bone matrix.

The bone matrix of growing rats was labeled by multiple injections of 3H-proline, and demineralized bone matrix (DBM) was prepared. The DBM was allotransplanted heterotopically into growing rats. New bone formation was induced in and around the implants. The new bone formation was accompanied by a decrease in the content of 3H; 20 and 30 days after implantation, 72% and 46%, respectively, of the activity remained in the implants. Daily injections of indomethacin (2 mg/kg) inhibited calcium uptake by about 20% at 20 and 30 days and inhibited the release of 3H from the DBM to a similar degree. Heterotopic bone induction by DBM is accompanied by matrix resorption, and inhibition of the new bone formation decreases the resorption of DBM.

Bone resorption in orthotopic and heterotopic bone of dichloromethylene bisphosphonate-treated rats.

The effect of the bisphosphonate dichloromethylene bisphosphonate (Cl2MBP) on orthotopic and heterotopic bone, induced by implants of demineralized bone matrix (DBM) in rats, was analyzed, with special reference to bone resorption. The heterotopic bone was formed by induction for 3 weeks; at this time, the rats were given daily subcutaneous injections of 3 mg/kg of body weight of Cl2MBP or saline, until sacrifice. Prior to the start of treatment, the animals were given 45Ca and [3H]proline to label the inorganic and organic components of bone, respectively. Groups of rats were sacrificed at intervals from 1 to 31 days after isotope injection, and the net formation of bone and the elimination rates of the two isotopes were studied in the heterotopic bone, in diaphyseal and metaphyseal bone, and in teeth. The treatment with Cl2MBP caused a doubling of the daily net increase in mineral of the induced heterotopic bone, and a less pronounced increase in the ash content of tibiae. The treatment decreased the elimination rates of both isotopes in the orthotopic and heterotopic bone, showing that decreased bone resorption is the cause of the increased net bone formation.

Comparison of the effects of adriamycin and methotrexate on orthotopic and induced heterotopic bone in rats.

The effect of the two antineoplastic drugs, Adriamycin and methotrexate, on orthotopic bone, and on the induction of experimental heterotopic bone in rats was analyzed. The drugs were administered as single injections: Adriamycin in s.c. doses of 0.5 and 2 mg/kg body weight and methotrexate i.v. 100 and 250 mg/kg body weight followed by leucovorin rescue after 2 h. A passing, but significant, decrease in body weights occurred in the methotrexate-treated animals, but not in those given Adriamycin. Analysis of the amount of heterotopic bone formed 4 weeks after induction by demineralized bone matrix revealed a 30-40% decrease in the groups treated with either of the antineoplastic agents, whereas orthotopic bone was unaffected. Six weeks after the treatment the net effect on the induced bone had decreased. The present study shows that the two antineoplastic drugs Adriamycin and methotrexate inhibit heterotopic new bone formation induced by demineralized bone matrix in rats to an equal extent, although their mode of action on the cellular level is entirely different, and that the inhibitory effect of a single treatment diminishes in the presence of a continuous inductive process.

Nonsteroid anti-inflammatory drugs prevent the recurrence of heterotopic ossification after excision.

The prophylactic effect of nonsteroid anti-inflammatory drugs on the recurrence of high-grade periarticular heterotopic ossification after resection was studied in ten patients operated on for loosening of one or both components of a cemented total hip prosthesis. These drugs, given at a standard dosage for 1-3 weeks after surgery, prevented the recurrence of heterotopic ossification. In some patients the range of motion of their joint increased following surgery, while it remained unaffected in the majority. At follow-up 2-5 years after surgery, all patients walked well and there were no clinical or radiographs signs of loosening of the prosthetic components. It is concluded that treatment with NSAIDs following resection of periarticular heterotopic ossification prevents recurrence.

Stress shielding by rigid fixation studied in osteotomized rabbit tibiae.

In 48 rabbits the bone-formation rates and strength in the tibial shaft, osteotomized and treated with rigid internal plate fixation, were compared with contralateral bones, which were treated with plate fixation without osteotomy. The plate fixation alone induced a 35 percent decrease in torsional strength after 12 weeks. The healing of the osteotomy counteracted the decrease in strength induced by stress protection of the rigid plate at 6 weeks, but this effect subsided within 12 weeks. The osteotomy also induced a 2-3-fold increase in the synthesis of bone matrix and mineral accretion of the bone underlying the plate at 6 and 9 weeks when compared with the contralateral side, which was plated but not osteotomized. The bone-formation levels returned to normal within 12 weeks; and the bone underlying the plate became subject to atrophy, resulting in decreased mechanical strength.

Effect of human interferon-alpha and interferon-gamma on growth, histology, and DNA content of human osteosarcomas in nude mice.

The antitumor effect of human natural and recombinant interferon-gamma (IFN-gamma) was evaluated in human osteosarcomas grown as xenografts in nude mice. IFN-gamma was given as daily subcutaneous injections, alone or in combination with IFN-alpha. The growth of two out of three tested osteosarcomas was inhibited by 2 x 10(5) IU of natural IFN-gamma. A five times higher dose of recombinant IFN-gamma, as compared with natural (n) IFN-gamma, was needed to obtain growth inhibition of one osteosarcoma. This difference in dose-response could be explained by differences in pharmacokinetics. Hence, subcutaneously administered natural IFN-gamma gave 10 times higher serum levels than obtained with the recombinant type. Combination treatment with IFN-alpha and IFN-gamma induced a potentiation of the antitumor effect in one osteosarcoma. In another osteosarcoma, 2-4 x 10(5) IU of nIFN-gamma did not effect tumor growth and could not potentiate the antitumor effect of 2-4 x 10(5) IU of nIFN-alpha. By using DNA analysis in cell suspension and tissue section, the proportion of aneuploid tumor cells within the xenograft could be estimated. This analysis showed that the antitumor effects of IFN were more pronounced than mere measurement of tumor volume suggested. IFN-inhibited tumors were partly replaced by fibroblasts or bone tissue. In conclusion, at the doses given nIFN-gamma appeared to have similar antitumor effects as IFN-alpha in two osteosarcomas, whereas one was sensitive to only IFN-alpha. Combination IFN treatment induced a potentiation of the antitumor effect in one osteosarcoma but not in another. The differences between the osteosarcomas in obtained antitumor effect of IFN treatment probably reflects individual IFN sensitivity and demonstrates the importance of assessing several tumors of the same neoplastic entity.

Early mobilization of isolated ulnar-shaft fractures.

A consecutive series of 21 isolated ulnar-shaft fractures were treated with early mobilization. All the fractures healed with good function and without serious complications. As long as the radioulnar joints are intact, this type of fracture can safely be treated with immediate mobilization or a short period in a below-elbow cast.

Augmentation of spinal fusion with bone morphogenetic protein in dogs.

Bone morphogenetic protein (BMP) induces mesenchymal cells to differentiate into cartilage and bone. To investigate the action of BMP on the growth of host bed-derived bone in experimental spinal fusions, posterior intervertebral spinal fusions of the lower thoracic spine were performed in 13 mature mongrel dogs. Four different fusion methods were used at single intervertebral levels within each dog. Three levels in each dog were used as controls for the BMP level. The spinal columns were examined by radiohistomorphometric methods at three weeks, six weeks, and 12 weeks and showed the BMP level to have two to three times more new bone than control levels. At the BMP level, an increase in the amount of new bone was observed in the interval from three to 12 weeks, in contrast to a decrease seen at the control levels. Fusion was present in five of seven of the BMP levels compared with zero of seven, one of seven, and two of seven in the control levels. The BMP level exhibited an increased number and volume of areas of de novo cartilage and woven bone formation at all time intervals compared to all control levels. The polylactic acid polymer carrier was not resorbed and partially retained in the fusion site. The preliminary observations suggest that BMP may serve as a useful adjunct in spinal fusions, but research is required to find a rapidly degradable delivery system. The objective of BMP research is to augment the host bed capacity for bone generation and regeneration and to spare children and adults the pain and complications involved in removing excessive volumes of iliac crest bone grafts.

Tears of the medial meniscus associated with increased radionuclide activity of the proximal tibia. Report of three cases.

Three patients who presented with longstanding medial knee pain and normal radiographs had an isotope bone scan in an attempt to arrive at a diagnosis. In each case there was a well-defined area of increased uptake over the medial tibial condyle and arthroscopy subsequently revealed meniscal damage. After arthroscopic menisectomy each patient became asymptomatic and the bone scan returned to normal. We suggest that patients with incapacitating knee pain, normal radiographs and a positive bone scan undergo an arthroscopy even in the absence of clinical signs of meniscal damage.

Periarticular heterotopic ossification after total hip arthroplasty for primary coxarthrosis.

Periarticular heterotopic ossification (PHO) is a common roentgenographic finding, occurring in more than two-thirds of patients after total hip arthroplasty (THA) for coxarthrosis. In the present study, 56 patients treated with bilateral THA were analyzed to determine the correlation between heterotopic ossification on the two sides. A strong correlation was found between the grade of PHO on the two sides: patients who developed severe PHO after the first THA invariably developed considerable PHO after surgery on the other side. The incidence and grade of PHO were higher in men than in women.

Prevention of heterotopic ossification by nonsteroid antiinflammatory drugs after total hip arthroplasty.

The effect of three weeks of postoperative treatment with indomethacin or ibuprofen on the development of periarticular heterotopic ossification (PHO) after bilateral total hip arthroplasty (THA) was investigated. Widespread PHO did not occur in 31 patients who had been treated with indomethacin or ibuprofen after both operations. Thirty-eight patients had been treated after one but not the other THA. Widespread PHO occurred in 14 of 38 untreated THA, but was not found after THA on the treated side. These findings are indicative of an inhibitory effect of nonsteroid antiinflammatory drugs on the development of PHO, since the development of severe heterotopic ossification is strongly correlated between the two sides after bilateral THA.