The term spontaneous osteonecrosis of the knee was first used by Ahlbäck¹ in 1968. This term, and the acronym SONK (sometimes SPONK²), has subsequently been used by other authors to refer to an apparent osteonecrosis of the knee, most commonly occurring within the medial femoral condyle. SONK typically occurs in older women who usually do not have the typical osteonecrosis risk factors, such as steroid use, sickle-cell anemia, and excessive alcohol intake. Furthermore, the radiologic appearance of SONK differs from the typical avascular necrosis findings seen with radiography and magnetic resonance imaging (MRI). In particular, on MRI, the abnormality of SONK does not have the typical serpiginous margin of bone infarction, or the double-line sign indicating both sclerosis and granulation tissue.³ SONK is normally seen as a line of signal intensity on T1- and T2-weighted sequences; this line is adjacent to or parallels the subchondral bone with an adjacent area of extensive edema.

There is dispute over the cause of SONK. Yamamoto and Bullough⁴ proposed the lesion is in part a subchondral insufficiency fracture and staged it into 4 parts. Histologic findings suggest at least some SONK lesions are subchondral insufficiency fractures.⁵ Brahme and colleagues⁶ were the first to describe SONK occurring after arthroscopy, and others have documented this finding. The condition has also been referred to as osteonecrosis in the postoperative knee.^7-13 An association of postoperative SONK with cartilage loss and meniscal tear has been proposed.^7-13

We reviewed the clinical, radiologic, and MRI findings in 11 patients with evidence of postarthroscopy SONK to try to identify any risk factors that might predispose them to poor outcomes. Our study population consisted of 11 patients (12 knees) with SONK; 6 of the knees had the lesion before knee arthroscopy, and the other 6 developed the lesion after arthroscopy. We also considered MRI findings in a group of 11 age- and sex-matched patients who underwent knee arthroscopy and did not have or develop SONK. We reviewed the preoperative MRI findings of both groups for meniscal tear, meniscal extrusion, and cartilage loss. We had 2 hypotheses. First, patients with preoperative MRI findings of SONK would have articular cartilage changes, posterior root degeneration, and meniscal extrusion similar to those of patients who developed SONK after arthroscopy. Second, an age- and sex-matched group of patients who underwent arthroscopy and did not develop SONK would be similar in articular cartilage changes, posterior root degeneration or tear, and meniscal extrusion.

Materials and Methods

With institutional review board approval and waived informed consent, we reviewed all imaging studies, particularly the radiographs and MRI studies, of 11 patients (12 knees) who either had SONK before arthroscopy or developed it after arthroscopy. In all these cases, arthroscopy was performed to alleviate mechanical symptoms associated with meniscal tear.

On subsequent review by a musculoskeletal radiologist, 6 patients with SONK had an identifiable lesion before surgery. All patients’ symptoms had not improved with an earlier trial of conservative management. All preoperative and postoperative radiologic and MRI findings were reviewed. The patient group was assembled by writing to all the orthopedic surgeons who performed arthroscopy at our institution and asking for SONK cases seen in their practices. All but 2 cases were performed by a surgeon who treated a predominantly older, less active population. Clinical notes were reviewed for outcomes, and the musculoskeletal radiologist reviewed all radiologic studies. The 4 men and 7 women in the SONK group (1 woman had bilateral knee lesions) ranged in age from 43 to 74 years (mean, 63.8 years), and the 4 men and 7 women in the control group were age-matched to 43 to 75 years (mean, 63.6 years). The controls were chosen from a pool of patients who underwent knee arthroscopy at our institution.

MRI was performed using General Electric 1-T, 1.5-T, or 3-T magnets (GE Healthcare, Milwaukee, Wisconsin) or using Philips 1.5-T or open 0.7-T magnets (Philips Healthcare, Andover, Massachusetts). Imaging included sagittal and coronal proton density–weighted sequences and coronal and axial fat-suppressed T2-weighted sequences. SONK was diagnosed when a low signal line adjacent to the subchondral bone plate on the femoral or tibial condyles was present with an adjacent area of bone marrow edema in the respective condyle or when there was depression of the subchondral bone plate with adjacent edema. The MRI studies were reviewed for lesion location, and medial meniscus and lateral meniscus were reviewed for tear. Type of meniscal tear (horizontal cleavage, radial, complex degenerative) was documented, as was meniscal extrusion. The meniscus was regarded as extruded if the body extended more than 3 mm from the joint margin. Cartilage in the medial and lateral compartment was reviewed according to a modified Noyes scale listing 0 as normal, 1 as internal changes only, 2A as 1% to 49% cartilage loss, 2B as 50% to 90% loss of articular cartilage, 3A as 100% articular cartilage loss with subchondral bone plate intact, and 3B as 100% articular cartilage loss with ulcerated subchondral bone plate.¹⁴ Osteoarthritic severity was similarly classified using the Kellgren-Lawrence scale,¹⁵ where grade 0 is normal; grade 1 is unlikely to have narrowing of the joint space but potentially has osteophytic lipping; grade 2 has both definite narrowing of the joint space and osteophytes; grade 3 has narrowing of the joint space and multiple osteophytes, some sclerosis, and possible deformity of bone contour; and grade 4 has marked narrowing of the joint space, large osteophytes, severe sclerosis, and definite deformity of bone contour. Follow-up clinical notes and radiologic studies were reviewed in the assessment of patient outcomes.

All statistical analyses were performed with SAS 9.2 software (SAS Institute, Cary, North Carolina). Age data were evaluated with the Shapiro-Wilk test and graphical displays and were found to violate normality assumptions, so they are presented as medians and ranges; other variables are presented as count and column percentages. The Wilcoxon rank sum test was used to compare the 2 groups’ age distributions. Fisher exact tests were used to compare proportions between the 2 groups for the other variables. Statistical significance was set at P < .05.

Results

Table 1 lists the demographics and imaging characteristics of the 11 patients—6 had SONK before arthroscopy and 6 developed it after arthroscopy. Comparison of the 11 patients with SONK and the 11 controls is summarized with P values in Table 2. Representative cases that either presented before surgery or developed after surgery are shown in Figures 1 to 4. There were 6 prearthroscopy lesions and 6 postarthroscopy lesions—all 12 in the medial femoral condyle. Eleven of the 12 knees had a medial meniscal tear, and 1 knee had both medial and lateral meniscal tears. In 8 of the 12 knees, the lateral meniscus was normal; in 2 knees, it had mild degeneration; and, in 1 knee, it had a complex tear. Assessment of hyaline cartilage revealed medial cartilage loss ranging from 2A to 3B (median, 2B) in the patients with SONK, and lateral cartilage loss ranging from 0 to 2A (median, 0). At surgery, all knees had a partial medial meniscectomy, and 6 had a partial lateral meniscectomy. Ten of the 12 knees had chondroplasty, 9 patellar and 5 of the medial femoral condyle. Only 4 of the 11 patients with follow-up of more than 1 year went on to joint replacement. Six of the 12 had follow-up of more than 2 years. Of the 6 patients without an identifiable SONK lesion on MRI before arthroscopy, 4 had mild to moderate knee pain 0.5, 2.4, 3.5, and 4 years after surgery. For the other 2 patients, knee replacement was performed 1.5 and 1.8 years after surgery. Of the 6 patients with prearthroscopy SONK, 4 had mild to moderate knee pain 1.5, 3.7, 6.5, and 6.8 years after surgery; the other 2 had knee replacement 0.5 and 1.8 years after surgery. Articular cartilage degeneration and meniscal extrusion were similar (Table 1). In the control group, there was only 1 knee replacement, at 3 years, and the other 11 were functioning 2.6 to 5 years later. The longer follow-up resulted from selection of appropriate controls from the same year. Of the 6 SONK lesions found on preoperative MRI, 3 were read by the interpreting radiologist before surgery as possible SONK lesions, 2 were read as insufficiency fractures, and 1 was read as a possible insufficiency fracture.

Discussion

SONK is well described as a complication of arthroscopic knee surgery. However, this condition more commonly appears spontaneously in a population that has not had surgery. It has become clear that the term SONK may be misleading.¹⁶ In a recent series of postoperative subchondral fractures reported by MacDessi and colleagues,⁵ the average age of patients included in their study was 64 years. Pathologic analysis revealed subchondral fracture with callus formation in all cases. Only 2 knees had evidence of osteonecrosis, which appeared to be secondary to the fracture. Based on these findings, the authors concluded that “further investigation into the etiology of this condition is warranted.” A prominent association with medial meniscal tear has been noted, with the medial femoral condyle predominantly affected. As already mentioned, SONK differs from classical avascular necrosis on several points, including lack of the typical avascular osteonecrosis risk factors and absence of the serpiginous margin and double-line sign seen with typical bone infarction. In addition, the SONK lesions seen on radiographs and MRIs of the knee typically are in the medial femoral condyle and are very different from the typical area of infarction seen in patients with known risk factors for secondary osteonecrosis.

The cause of SONK is not known. Of more importance from a medicolegal standpoint is that these lesions are not necessarily related to arthroscopy.¹⁷ Interestingly, Pape and colleagues¹⁷ noted that some of the lesions they studied may have been present before surgery, which is what we found in 6 (50%) of the SONK knees in our study. Our data thus support the proposition that some SONK lesions are present before arthroscopy, and some cases of so-called postarthroscopy SONK may in fact have been progressing before surgery.

Our data also reinforce the importance of radiologist–orthopedic surgeon communication regarding the presence of SONK. We emphasize the importance of communicating the MRI findings clearly, whether the lesion is called SONK, SPONK, or insufficiency fracture. The orthopedic surgeons in our series may have been unaware of the presence of these lesions before arthroscopic meniscectomy, given the wide variety of terms being used in radiologic reports.

The natural history of spontaneous osteonecrosis of the medial tibial plateau has also been studied.¹⁸ There were 3 outcome patterns—acute extensive collapse of the medial tibial plateau, rapid progression to varying degrees of osteoarthritis, and complete resolution. It has been shown that resolution of SONK can occur in the early stages of the disease, within several months, but often the changes progress to bone destruction and articular cartilage collapse.¹⁹

In our series of patients, there was a female predominance, and mean age was 64 years. We investigated cartilage loss, meniscal tear, and meniscal extrusion to see if we could predict outcomes in patients who had the lesion before arthroscopy and if we could predict who might be at risk for developing the lesion after arthroscopy. Type of surgical procedure was also reviewed. For the sake of simplicity, we divided the follow-up patients into 2 groups: those managed with conservative treatment, which we deemed a reasonable outcome, and those who subsequently required knee joint replacement, which we deemed a poor outcome. As seen from our representative cases, both groups had patients with cartilage loss, meniscal tear, and meniscal extrusion to varying degrees. There were no risk factors pointing to a reasonable or poor outcome. In the group of patients with prearthroscopy lesions, we found the same problem. We were unable to identify a risk factor that might suggest a poor rather than a reasonable outcome. We must also emphasize that, in our review of patient charts, we could find no other causes for osteonecrosis. In particular, arthroscopic causes of acute chondral loss (eg, thermal wash, laser, bupivacaine pain pumps, epinephrine in irrigant) were not identified.

This study consisted of a series of cases managed at our institution over the past 8 years. Our data and this study had several limitations:

We may have been unable to identify other SONK cases that belonged in the group from our institution. In addition, we had only 11 patients for comparison with patients without SONK. Likewise, there were only 6 knees each in the prearthroscopy and postarthroscopy SONK groups. We also used images obtained from 1-T, 1.5-T, and 3-T closed MRI devices and one 0.7-T open device. These were, however, at the same institution.

Timing of our imaging was not uniform. In particular, in 3 of the patients who developed SONK after arthroscopy, preoperative MRI studies were performed quite some time before surgery. However, in these patients, more recent preoperative radiographs did not show any evidence of lesions. It can also be seen that postarthroscopy follow-up of patients varied. It is possible that, on longer follow-up, some of the cases we classified as having a reasonable outcome may have gone on to require total knee arthroplasty. One could argue that, in the patient who developed SONK within 1 year after surgery (Figure 4), the lesion was not related to the surgery. However, this patient’s radiographs 3 months after surgery did not show the SONK lesion but clearly showed prominent medial joint space narrowing—a new finding.

Only 1 musculoskeletal radiologist evaluated the radiographs, MRIs, and tomosynthesis (similar to computed tomography) studies for this investigation.

This lesion is not common, thus giving us a small group to analyze.

Despite our data limitations and the retrospective nature of this study, we compiled a reasonably representative sample of surgical SONK patients that matches other samples reported in the literature. Unfortunately, we could not identify any risk factors pointing to the likelihood of developing SONK or any risk factors pointing to either a reasonable or a poor prognosis in these patients. The etiology of the lesion remains an enigma. Our finding 6 cases of prearthroscopy lesions that did not necessarily result in a poor outcome, combined with our inability to identify any risk factors for SONK, points to the lack of a causal relationship with arthroscopy.

The term spontaneous osteonecrosis of the knee was first used by Ahlbäck¹ in 1968. This term, and the acronym SONK (sometimes SPONK²), has subsequently been used by other authors to refer to an apparent osteonecrosis of the knee, most commonly occurring within the medial femoral condyle. SONK typically occurs in older women who usually do not have the typical osteonecrosis risk factors, such as steroid use, sickle-cell anemia, and excessive alcohol intake. Furthermore, the radiologic appearance of SONK differs from the typical avascular necrosis findings seen with radiography and magnetic resonance imaging (MRI). In particular, on MRI, the abnormality of SONK does not have the typical serpiginous margin of bone infarction, or the double-line sign indicating both sclerosis and granulation tissue.³ SONK is normally seen as a line of signal intensity on T1- and T2-weighted sequences; this line is adjacent to or parallels the subchondral bone with an adjacent area of extensive edema.

There is dispute over the cause of SONK. Yamamoto and Bullough⁴ proposed the lesion is in part a subchondral insufficiency fracture and staged it into 4 parts. Histologic findings suggest at least some SONK lesions are subchondral insufficiency fractures.⁵ Brahme and colleagues⁶ were the first to describe SONK occurring after arthroscopy, and others have documented this finding. The condition has also been referred to as osteonecrosis in the postoperative knee.^7-13 An association of postoperative SONK with cartilage loss and meniscal tear has been proposed.^7-13

We reviewed the clinical, radiologic, and MRI findings in 11 patients with evidence of postarthroscopy SONK to try to identify any risk factors that might predispose them to poor outcomes. Our study population consisted of 11 patients (12 knees) with SONK; 6 of the knees had the lesion before knee arthroscopy, and the other 6 developed the lesion after arthroscopy. We also considered MRI findings in a group of 11 age- and sex-matched patients who underwent knee arthroscopy and did not have or develop SONK. We reviewed the preoperative MRI findings of both groups for meniscal tear, meniscal extrusion, and cartilage loss. We had 2 hypotheses. First, patients with preoperative MRI findings of SONK would have articular cartilage changes, posterior root degeneration, and meniscal extrusion similar to those of patients who developed SONK after arthroscopy. Second, an age- and sex-matched group of patients who underwent arthroscopy and did not develop SONK would be similar in articular cartilage changes, posterior root degeneration or tear, and meniscal extrusion.

Materials and Methods

With institutional review board approval and waived informed consent, we reviewed all imaging studies, particularly the radiographs and MRI studies, of 11 patients (12 knees) who either had SONK before arthroscopy or developed it after arthroscopy. In all these cases, arthroscopy was performed to alleviate mechanical symptoms associated with meniscal tear.

On subsequent review by a musculoskeletal radiologist, 6 patients with SONK had an identifiable lesion before surgery. All patients’ symptoms had not improved with an earlier trial of conservative management. All preoperative and postoperative radiologic and MRI findings were reviewed. The patient group was assembled by writing to all the orthopedic surgeons who performed arthroscopy at our institution and asking for SONK cases seen in their practices. All but 2 cases were performed by a surgeon who treated a predominantly older, less active population. Clinical notes were reviewed for outcomes, and the musculoskeletal radiologist reviewed all radiologic studies. The 4 men and 7 women in the SONK group (1 woman had bilateral knee lesions) ranged in age from 43 to 74 years (mean, 63.8 years), and the 4 men and 7 women in the control group were age-matched to 43 to 75 years (mean, 63.6 years). The controls were chosen from a pool of patients who underwent knee arthroscopy at our institution.

MRI was performed using General Electric 1-T, 1.5-T, or 3-T magnets (GE Healthcare, Milwaukee, Wisconsin) or using Philips 1.5-T or open 0.7-T magnets (Philips Healthcare, Andover, Massachusetts). Imaging included sagittal and coronal proton density–weighted sequences and coronal and axial fat-suppressed T2-weighted sequences. SONK was diagnosed when a low signal line adjacent to the subchondral bone plate on the femoral or tibial condyles was present with an adjacent area of bone marrow edema in the respective condyle or when there was depression of the subchondral bone plate with adjacent edema. The MRI studies were reviewed for lesion location, and medial meniscus and lateral meniscus were reviewed for tear. Type of meniscal tear (horizontal cleavage, radial, complex degenerative) was documented, as was meniscal extrusion. The meniscus was regarded as extruded if the body extended more than 3 mm from the joint margin. Cartilage in the medial and lateral compartment was reviewed according to a modified Noyes scale listing 0 as normal, 1 as internal changes only, 2A as 1% to 49% cartilage loss, 2B as 50% to 90% loss of articular cartilage, 3A as 100% articular cartilage loss with subchondral bone plate intact, and 3B as 100% articular cartilage loss with ulcerated subchondral bone plate.¹⁴ Osteoarthritic severity was similarly classified using the Kellgren-Lawrence scale,¹⁵ where grade 0 is normal; grade 1 is unlikely to have narrowing of the joint space but potentially has osteophytic lipping; grade 2 has both definite narrowing of the joint space and osteophytes; grade 3 has narrowing of the joint space and multiple osteophytes, some sclerosis, and possible deformity of bone contour; and grade 4 has marked narrowing of the joint space, large osteophytes, severe sclerosis, and definite deformity of bone contour. Follow-up clinical notes and radiologic studies were reviewed in the assessment of patient outcomes.

All statistical analyses were performed with SAS 9.2 software (SAS Institute, Cary, North Carolina). Age data were evaluated with the Shapiro-Wilk test and graphical displays and were found to violate normality assumptions, so they are presented as medians and ranges; other variables are presented as count and column percentages. The Wilcoxon rank sum test was used to compare the 2 groups’ age distributions. Fisher exact tests were used to compare proportions between the 2 groups for the other variables. Statistical significance was set at P < .05.

Results

Table 1 lists the demographics and imaging characteristics of the 11 patients—6 had SONK before arthroscopy and 6 developed it after arthroscopy. Comparison of the 11 patients with SONK and the 11 controls is summarized with P values in Table 2. Representative cases that either presented before surgery or developed after surgery are shown in Figures 1 to 4. There were 6 prearthroscopy lesions and 6 postarthroscopy lesions—all 12 in the medial femoral condyle. Eleven of the 12 knees had a medial meniscal tear, and 1 knee had both medial and lateral meniscal tears. In 8 of the 12 knees, the lateral meniscus was normal; in 2 knees, it had mild degeneration; and, in 1 knee, it had a complex tear. Assessment of hyaline cartilage revealed medial cartilage loss ranging from 2A to 3B (median, 2B) in the patients with SONK, and lateral cartilage loss ranging from 0 to 2A (median, 0). At surgery, all knees had a partial medial meniscectomy, and 6 had a partial lateral meniscectomy. Ten of the 12 knees had chondroplasty, 9 patellar and 5 of the medial femoral condyle. Only 4 of the 11 patients with follow-up of more than 1 year went on to joint replacement. Six of the 12 had follow-up of more than 2 years. Of the 6 patients without an identifiable SONK lesion on MRI before arthroscopy, 4 had mild to moderate knee pain 0.5, 2.4, 3.5, and 4 years after surgery. For the other 2 patients, knee replacement was performed 1.5 and 1.8 years after surgery. Of the 6 patients with prearthroscopy SONK, 4 had mild to moderate knee pain 1.5, 3.7, 6.5, and 6.8 years after surgery; the other 2 had knee replacement 0.5 and 1.8 years after surgery. Articular cartilage degeneration and meniscal extrusion were similar (Table 1). In the control group, there was only 1 knee replacement, at 3 years, and the other 11 were functioning 2.6 to 5 years later. The longer follow-up resulted from selection of appropriate controls from the same year. Of the 6 SONK lesions found on preoperative MRI, 3 were read by the interpreting radiologist before surgery as possible SONK lesions, 2 were read as insufficiency fractures, and 1 was read as a possible insufficiency fracture.

Discussion

SONK is well described as a complication of arthroscopic knee surgery. However, this condition more commonly appears spontaneously in a population that has not had surgery. It has become clear that the term SONK may be misleading.¹⁶ In a recent series of postoperative subchondral fractures reported by MacDessi and colleagues,⁵ the average age of patients included in their study was 64 years. Pathologic analysis revealed subchondral fracture with callus formation in all cases. Only 2 knees had evidence of osteonecrosis, which appeared to be secondary to the fracture. Based on these findings, the authors concluded that “further investigation into the etiology of this condition is warranted.” A prominent association with medial meniscal tear has been noted, with the medial femoral condyle predominantly affected. As already mentioned, SONK differs from classical avascular necrosis on several points, including lack of the typical avascular osteonecrosis risk factors and absence of the serpiginous margin and double-line sign seen with typical bone infarction. In addition, the SONK lesions seen on radiographs and MRIs of the knee typically are in the medial femoral condyle and are very different from the typical area of infarction seen in patients with known risk factors for secondary osteonecrosis.

The cause of SONK is not known. Of more importance from a medicolegal standpoint is that these lesions are not necessarily related to arthroscopy.¹⁷ Interestingly, Pape and colleagues¹⁷ noted that some of the lesions they studied may have been present before surgery, which is what we found in 6 (50%) of the SONK knees in our study. Our data thus support the proposition that some SONK lesions are present before arthroscopy, and some cases of so-called postarthroscopy SONK may in fact have been progressing before surgery.

Our data also reinforce the importance of radiologist–orthopedic surgeon communication regarding the presence of SONK. We emphasize the importance of communicating the MRI findings clearly, whether the lesion is called SONK, SPONK, or insufficiency fracture. The orthopedic surgeons in our series may have been unaware of the presence of these lesions before arthroscopic meniscectomy, given the wide variety of terms being used in radiologic reports.

The natural history of spontaneous osteonecrosis of the medial tibial plateau has also been studied.¹⁸ There were 3 outcome patterns—acute extensive collapse of the medial tibial plateau, rapid progression to varying degrees of osteoarthritis, and complete resolution. It has been shown that resolution of SONK can occur in the early stages of the disease, within several months, but often the changes progress to bone destruction and articular cartilage collapse.¹⁹

In our series of patients, there was a female predominance, and mean age was 64 years. We investigated cartilage loss, meniscal tear, and meniscal extrusion to see if we could predict outcomes in patients who had the lesion before arthroscopy and if we could predict who might be at risk for developing the lesion after arthroscopy. Type of surgical procedure was also reviewed. For the sake of simplicity, we divided the follow-up patients into 2 groups: those managed with conservative treatment, which we deemed a reasonable outcome, and those who subsequently required knee joint replacement, which we deemed a poor outcome. As seen from our representative cases, both groups had patients with cartilage loss, meniscal tear, and meniscal extrusion to varying degrees. There were no risk factors pointing to a reasonable or poor outcome. In the group of patients with prearthroscopy lesions, we found the same problem. We were unable to identify a risk factor that might suggest a poor rather than a reasonable outcome. We must also emphasize that, in our review of patient charts, we could find no other causes for osteonecrosis. In particular, arthroscopic causes of acute chondral loss (eg, thermal wash, laser, bupivacaine pain pumps, epinephrine in irrigant) were not identified.

This study consisted of a series of cases managed at our institution over the past 8 years. Our data and this study had several limitations:

We may have been unable to identify other SONK cases that belonged in the group from our institution. In addition, we had only 11 patients for comparison with patients without SONK. Likewise, there were only 6 knees each in the prearthroscopy and postarthroscopy SONK groups. We also used images obtained from 1-T, 1.5-T, and 3-T closed MRI devices and one 0.7-T open device. These were, however, at the same institution.

Timing of our imaging was not uniform. In particular, in 3 of the patients who developed SONK after arthroscopy, preoperative MRI studies were performed quite some time before surgery. However, in these patients, more recent preoperative radiographs did not show any evidence of lesions. It can also be seen that postarthroscopy follow-up of patients varied. It is possible that, on longer follow-up, some of the cases we classified as having a reasonable outcome may have gone on to require total knee arthroplasty. One could argue that, in the patient who developed SONK within 1 year after surgery (Figure 4), the lesion was not related to the surgery. However, this patient’s radiographs 3 months after surgery did not show the SONK lesion but clearly showed prominent medial joint space narrowing—a new finding.

Only 1 musculoskeletal radiologist evaluated the radiographs, MRIs, and tomosynthesis (similar to computed tomography) studies for this investigation.

This lesion is not common, thus giving us a small group to analyze.

Despite our data limitations and the retrospective nature of this study, we compiled a reasonably representative sample of surgical SONK patients that matches other samples reported in the literature. Unfortunately, we could not identify any risk factors pointing to the likelihood of developing SONK or any risk factors pointing to either a reasonable or a poor prognosis in these patients. The etiology of the lesion remains an enigma. Our finding 6 cases of prearthroscopy lesions that did not necessarily result in a poor outcome, combined with our inability to identify any risk factors for SONK, points to the lack of a causal relationship with arthroscopy.

The term spontaneous osteonecrosis of the knee was first used by Ahlbäck¹ in 1968. This term, and the acronym SONK (sometimes SPONK²), has subsequently been used by other authors to refer to an apparent osteonecrosis of the knee, most commonly occurring within the medial femoral condyle. SONK typically occurs in older women who usually do not have the typical osteonecrosis risk factors, such as steroid use, sickle-cell anemia, and excessive alcohol intake. Furthermore, the radiologic appearance of SONK differs from the typical avascular necrosis findings seen with radiography and magnetic resonance imaging (MRI). In particular, on MRI, the abnormality of SONK does not have the typical serpiginous margin of bone infarction, or the double-line sign indicating both sclerosis and granulation tissue.³ SONK is normally seen as a line of signal intensity on T1- and T2-weighted sequences; this line is adjacent to or parallels the subchondral bone with an adjacent area of extensive edema.

There is dispute over the cause of SONK. Yamamoto and Bullough⁴ proposed the lesion is in part a subchondral insufficiency fracture and staged it into 4 parts. Histologic findings suggest at least some SONK lesions are subchondral insufficiency fractures.⁵ Brahme and colleagues⁶ were the first to describe SONK occurring after arthroscopy, and others have documented this finding. The condition has also been referred to as osteonecrosis in the postoperative knee.^7-13 An association of postoperative SONK with cartilage loss and meniscal tear has been proposed.^7-13

We reviewed the clinical, radiologic, and MRI findings in 11 patients with evidence of postarthroscopy SONK to try to identify any risk factors that might predispose them to poor outcomes. Our study population consisted of 11 patients (12 knees) with SONK; 6 of the knees had the lesion before knee arthroscopy, and the other 6 developed the lesion after arthroscopy. We also considered MRI findings in a group of 11 age- and sex-matched patients who underwent knee arthroscopy and did not have or develop SONK. We reviewed the preoperative MRI findings of both groups for meniscal tear, meniscal extrusion, and cartilage loss. We had 2 hypotheses. First, patients with preoperative MRI findings of SONK would have articular cartilage changes, posterior root degeneration, and meniscal extrusion similar to those of patients who developed SONK after arthroscopy. Second, an age- and sex-matched group of patients who underwent arthroscopy and did not develop SONK would be similar in articular cartilage changes, posterior root degeneration or tear, and meniscal extrusion.

Materials and Methods

With institutional review board approval and waived informed consent, we reviewed all imaging studies, particularly the radiographs and MRI studies, of 11 patients (12 knees) who either had SONK before arthroscopy or developed it after arthroscopy. In all these cases, arthroscopy was performed to alleviate mechanical symptoms associated with meniscal tear.

On subsequent review by a musculoskeletal radiologist, 6 patients with SONK had an identifiable lesion before surgery. All patients’ symptoms had not improved with an earlier trial of conservative management. All preoperative and postoperative radiologic and MRI findings were reviewed. The patient group was assembled by writing to all the orthopedic surgeons who performed arthroscopy at our institution and asking for SONK cases seen in their practices. All but 2 cases were performed by a surgeon who treated a predominantly older, less active population. Clinical notes were reviewed for outcomes, and the musculoskeletal radiologist reviewed all radiologic studies. The 4 men and 7 women in the SONK group (1 woman had bilateral knee lesions) ranged in age from 43 to 74 years (mean, 63.8 years), and the 4 men and 7 women in the control group were age-matched to 43 to 75 years (mean, 63.6 years). The controls were chosen from a pool of patients who underwent knee arthroscopy at our institution.

MRI was performed using General Electric 1-T, 1.5-T, or 3-T magnets (GE Healthcare, Milwaukee, Wisconsin) or using Philips 1.5-T or open 0.7-T magnets (Philips Healthcare, Andover, Massachusetts). Imaging included sagittal and coronal proton density–weighted sequences and coronal and axial fat-suppressed T2-weighted sequences. SONK was diagnosed when a low signal line adjacent to the subchondral bone plate on the femoral or tibial condyles was present with an adjacent area of bone marrow edema in the respective condyle or when there was depression of the subchondral bone plate with adjacent edema. The MRI studies were reviewed for lesion location, and medial meniscus and lateral meniscus were reviewed for tear. Type of meniscal tear (horizontal cleavage, radial, complex degenerative) was documented, as was meniscal extrusion. The meniscus was regarded as extruded if the body extended more than 3 mm from the joint margin. Cartilage in the medial and lateral compartment was reviewed according to a modified Noyes scale listing 0 as normal, 1 as internal changes only, 2A as 1% to 49% cartilage loss, 2B as 50% to 90% loss of articular cartilage, 3A as 100% articular cartilage loss with subchondral bone plate intact, and 3B as 100% articular cartilage loss with ulcerated subchondral bone plate.¹⁴ Osteoarthritic severity was similarly classified using the Kellgren-Lawrence scale,¹⁵ where grade 0 is normal; grade 1 is unlikely to have narrowing of the joint space but potentially has osteophytic lipping; grade 2 has both definite narrowing of the joint space and osteophytes; grade 3 has narrowing of the joint space and multiple osteophytes, some sclerosis, and possible deformity of bone contour; and grade 4 has marked narrowing of the joint space, large osteophytes, severe sclerosis, and definite deformity of bone contour. Follow-up clinical notes and radiologic studies were reviewed in the assessment of patient outcomes.

All statistical analyses were performed with SAS 9.2 software (SAS Institute, Cary, North Carolina). Age data were evaluated with the Shapiro-Wilk test and graphical displays and were found to violate normality assumptions, so they are presented as medians and ranges; other variables are presented as count and column percentages. The Wilcoxon rank sum test was used to compare the 2 groups’ age distributions. Fisher exact tests were used to compare proportions between the 2 groups for the other variables. Statistical significance was set at P < .05.

Results

Table 1 lists the demographics and imaging characteristics of the 11 patients—6 had SONK before arthroscopy and 6 developed it after arthroscopy. Comparison of the 11 patients with SONK and the 11 controls is summarized with P values in Table 2. Representative cases that either presented before surgery or developed after surgery are shown in Figures 1 to 4. There were 6 prearthroscopy lesions and 6 postarthroscopy lesions—all 12 in the medial femoral condyle. Eleven of the 12 knees had a medial meniscal tear, and 1 knee had both medial and lateral meniscal tears. In 8 of the 12 knees, the lateral meniscus was normal; in 2 knees, it had mild degeneration; and, in 1 knee, it had a complex tear. Assessment of hyaline cartilage revealed medial cartilage loss ranging from 2A to 3B (median, 2B) in the patients with SONK, and lateral cartilage loss ranging from 0 to 2A (median, 0). At surgery, all knees had a partial medial meniscectomy, and 6 had a partial lateral meniscectomy. Ten of the 12 knees had chondroplasty, 9 patellar and 5 of the medial femoral condyle. Only 4 of the 11 patients with follow-up of more than 1 year went on to joint replacement. Six of the 12 had follow-up of more than 2 years. Of the 6 patients without an identifiable SONK lesion on MRI before arthroscopy, 4 had mild to moderate knee pain 0.5, 2.4, 3.5, and 4 years after surgery. For the other 2 patients, knee replacement was performed 1.5 and 1.8 years after surgery. Of the 6 patients with prearthroscopy SONK, 4 had mild to moderate knee pain 1.5, 3.7, 6.5, and 6.8 years after surgery; the other 2 had knee replacement 0.5 and 1.8 years after surgery. Articular cartilage degeneration and meniscal extrusion were similar (Table 1). In the control group, there was only 1 knee replacement, at 3 years, and the other 11 were functioning 2.6 to 5 years later. The longer follow-up resulted from selection of appropriate controls from the same year. Of the 6 SONK lesions found on preoperative MRI, 3 were read by the interpreting radiologist before surgery as possible SONK lesions, 2 were read as insufficiency fractures, and 1 was read as a possible insufficiency fracture.

Discussion

SONK is well described as a complication of arthroscopic knee surgery. However, this condition more commonly appears spontaneously in a population that has not had surgery. It has become clear that the term SONK may be misleading.¹⁶ In a recent series of postoperative subchondral fractures reported by MacDessi and colleagues,⁵ the average age of patients included in their study was 64 years. Pathologic analysis revealed subchondral fracture with callus formation in all cases. Only 2 knees had evidence of osteonecrosis, which appeared to be secondary to the fracture. Based on these findings, the authors concluded that “further investigation into the etiology of this condition is warranted.” A prominent association with medial meniscal tear has been noted, with the medial femoral condyle predominantly affected. As already mentioned, SONK differs from classical avascular necrosis on several points, including lack of the typical avascular osteonecrosis risk factors and absence of the serpiginous margin and double-line sign seen with typical bone infarction. In addition, the SONK lesions seen on radiographs and MRIs of the knee typically are in the medial femoral condyle and are very different from the typical area of infarction seen in patients with known risk factors for secondary osteonecrosis.

The cause of SONK is not known. Of more importance from a medicolegal standpoint is that these lesions are not necessarily related to arthroscopy.¹⁷ Interestingly, Pape and colleagues¹⁷ noted that some of the lesions they studied may have been present before surgery, which is what we found in 6 (50%) of the SONK knees in our study. Our data thus support the proposition that some SONK lesions are present before arthroscopy, and some cases of so-called postarthroscopy SONK may in fact have been progressing before surgery.

Our data also reinforce the importance of radiologist–orthopedic surgeon communication regarding the presence of SONK. We emphasize the importance of communicating the MRI findings clearly, whether the lesion is called SONK, SPONK, or insufficiency fracture. The orthopedic surgeons in our series may have been unaware of the presence of these lesions before arthroscopic meniscectomy, given the wide variety of terms being used in radiologic reports.

The natural history of spontaneous osteonecrosis of the medial tibial plateau has also been studied.¹⁸ There were 3 outcome patterns—acute extensive collapse of the medial tibial plateau, rapid progression to varying degrees of osteoarthritis, and complete resolution. It has been shown that resolution of SONK can occur in the early stages of the disease, within several months, but often the changes progress to bone destruction and articular cartilage collapse.¹⁹

In our series of patients, there was a female predominance, and mean age was 64 years. We investigated cartilage loss, meniscal tear, and meniscal extrusion to see if we could predict outcomes in patients who had the lesion before arthroscopy and if we could predict who might be at risk for developing the lesion after arthroscopy. Type of surgical procedure was also reviewed. For the sake of simplicity, we divided the follow-up patients into 2 groups: those managed with conservative treatment, which we deemed a reasonable outcome, and those who subsequently required knee joint replacement, which we deemed a poor outcome. As seen from our representative cases, both groups had patients with cartilage loss, meniscal tear, and meniscal extrusion to varying degrees. There were no risk factors pointing to a reasonable or poor outcome. In the group of patients with prearthroscopy lesions, we found the same problem. We were unable to identify a risk factor that might suggest a poor rather than a reasonable outcome. We must also emphasize that, in our review of patient charts, we could find no other causes for osteonecrosis. In particular, arthroscopic causes of acute chondral loss (eg, thermal wash, laser, bupivacaine pain pumps, epinephrine in irrigant) were not identified.

This study consisted of a series of cases managed at our institution over the past 8 years. Our data and this study had several limitations:

We may have been unable to identify other SONK cases that belonged in the group from our institution. In addition, we had only 11 patients for comparison with patients without SONK. Likewise, there were only 6 knees each in the prearthroscopy and postarthroscopy SONK groups. We also used images obtained from 1-T, 1.5-T, and 3-T closed MRI devices and one 0.7-T open device. These were, however, at the same institution.

Timing of our imaging was not uniform. In particular, in 3 of the patients who developed SONK after arthroscopy, preoperative MRI studies were performed quite some time before surgery. However, in these patients, more recent preoperative radiographs did not show any evidence of lesions. It can also be seen that postarthroscopy follow-up of patients varied. It is possible that, on longer follow-up, some of the cases we classified as having a reasonable outcome may have gone on to require total knee arthroplasty. One could argue that, in the patient who developed SONK within 1 year after surgery (Figure 4), the lesion was not related to the surgery. However, this patient’s radiographs 3 months after surgery did not show the SONK lesion but clearly showed prominent medial joint space narrowing—a new finding.

Only 1 musculoskeletal radiologist evaluated the radiographs, MRIs, and tomosynthesis (similar to computed tomography) studies for this investigation.

This lesion is not common, thus giving us a small group to analyze.

Despite our data limitations and the retrospective nature of this study, we compiled a reasonably representative sample of surgical SONK patients that matches other samples reported in the literature. Unfortunately, we could not identify any risk factors pointing to the likelihood of developing SONK or any risk factors pointing to either a reasonable or a poor prognosis in these patients. The etiology of the lesion remains an enigma. Our finding 6 cases of prearthroscopy lesions that did not necessarily result in a poor outcome, combined with our inability to identify any risk factors for SONK, points to the lack of a causal relationship with arthroscopy.

"This patient had presented 2-weeks postpartum in a manic state with psycotic features. She was screened by Ob-Gyn who collaborated with her care while she was admitted to the psychiatric inpatient unit. Patient had been non-compliant with prescribed medications prior to admission and she was started on aripiprazole from day one and the dose was tapered up to 15 mg BID by day 5. Patient's manic symptoms improved slowly as the days progressed by day 8 psychotic symptoms started to subside. As delivery was imminent, patient was transferred to Ob-Gyn service. She delivered a healthy but premature child via csection on day 12. Child did not exhibit any gross or anatomic malformations. She was continued on aripiprazole 15 mg BID after discharge and was seen weeks later in outpatient psychiatry."

Read more from the Poster Abstracts from the 2015 APA Annual Meeting

"This patient had presented 2-weeks postpartum in a manic state with psycotic features. She was screened by Ob-Gyn who collaborated with her care while she was admitted to the psychiatric inpatient unit. Patient had been non-compliant with prescribed medications prior to admission and she was started on aripiprazole from day one and the dose was tapered up to 15 mg BID by day 5. Patient's manic symptoms improved slowly as the days progressed by day 8 psychotic symptoms started to subside. As delivery was imminent, patient was transferred to Ob-Gyn service. She delivered a healthy but premature child via csection on day 12. Child did not exhibit any gross or anatomic malformations. She was continued on aripiprazole 15 mg BID after discharge and was seen weeks later in outpatient psychiatry."

Read more from the Poster Abstracts from the 2015 APA Annual Meeting

"This patient had presented 2-weeks postpartum in a manic state with psycotic features. She was screened by Ob-Gyn who collaborated with her care while she was admitted to the psychiatric inpatient unit. Patient had been non-compliant with prescribed medications prior to admission and she was started on aripiprazole from day one and the dose was tapered up to 15 mg BID by day 5. Patient's manic symptoms improved slowly as the days progressed by day 8 psychotic symptoms started to subside. As delivery was imminent, patient was transferred to Ob-Gyn service. She delivered a healthy but premature child via csection on day 12. Child did not exhibit any gross or anatomic malformations. She was continued on aripiprazole 15 mg BID after discharge and was seen weeks later in outpatient psychiatry."

Read more from the Poster Abstracts from the 2015 APA Annual Meeting

When you decided to go to medical school, did you expect that you would be seeing as many patients with mental health complaints as you are seeing now? If you have been practicing pediatrics for more than 15 years, has your patient mix significantly taken on a more behavioral flavor? Do you think that more of your patients are experiencing serious mental health issues?

If you answered yes to any or all of those questions, your perception of the mental health status of this country’s children agrees with mine and probably that of most other Americans. However, a recent study suggests that not all of our perceptions are reality based (N. Engl. J. Med. 2015;372:2029-38). The authors used a parent-scored scale of the children’s impairment and found that the rate of severe mental illness has fallen significantly over the last generation. Despite the decline in severe cases that they observed, the percentage of children receiving outpatient mental health services (including psychotherapy and psychotropic drugs) has increased. In other words, while we and other providers are indeed seeing more children and adolescents with mental health and behavioral complaints, the tip of the iceberg is shrinking.

Does that divergence make any sense? As the chief of the National Institute of Mental Health’s in-house genetic epidemiological research program observes, it is hard to make any sense of the results of this new study, or any study, because there is a plethora of agencies doing surveys often using different methodologies. In Kathleen Merikangas’ words, “It’s a nightmare” (“Severe Mental Illness Found to Drop in Young, Defying Perceptions” by Benedict Carey in the New York Times on May 20, 2015).

The situation seems to be a classic case of comparing apples and oranges. It is probably even worse because different agencies can’t even agree on whether McIntoshes and Granny Smiths should both be counted as apples. With this degree of uncertainty, the officials charged with making decisions about funding and allocating mental health services are flying blind much of the time.

When it comes to divining the trends in the prevalence of mental illness in children and adolescents, your guess is as good as mine. So ... because I happen to have the time, I’m going to give you mine.

From my lofty perch here on the rocky coast of Maine, it appears to me that the recent study in the New England Journal of Medicine is accurate in its observation that serious mental illness is not increasing and may in be decreasing. But why does it feel that our office schedules are bulging with the patients presenting with less serious behavioral problems? One answer is that many of the cases of serious physical illness that we once saw never make it to the waiting room. For example, most children with congenital heart disease are now diagnosed in utero and delivered and treated in tertiary centers. Serious infectious diseases such as meningitis and epiglottitis have been damped down by successful immunizations. The abundance of subspecialists, the tendency of some physicians to issue knee-jerk referrals, and the awareness by parents that they can self-refer has left a void in our schedules that in the blink of an eye has filled with the walking worried.

It is worry and anxiety that in my estimation is on the rise and generating a large percentage of visits. Whether this is a post 9-11 phenomenon or simply a reflection of too-much-news-too-quickly is unclear. But the bottom line is that parents are worried and as a result so are many of their children. I am less sure on whether there has been a true increase in depression. It may be that people are more willing to talk about their unhappiness or it may be a ripple effect from our national sleep deprivation.

Finally, there has been a tendency to narrow the definition of normal that goes hand in hand with the notion that if it isn’t “normal,” there must be some medication to fix the problem. Attention-deficit/hyperactivity disorder is the poster child for this schedule-filling duo.

So that’s what I think. I suspect you feel you are seeing more behavior-related problems. But is this because of a true increase in the level of mental health problems in this country? How do you explain it?

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “Coping with a Picky Eater.” E-mail him at pdnews@frontlinemedcom.com.

When you decided to go to medical school, did you expect that you would be seeing as many patients with mental health complaints as you are seeing now? If you have been practicing pediatrics for more than 15 years, has your patient mix significantly taken on a more behavioral flavor? Do you think that more of your patients are experiencing serious mental health issues?

If you answered yes to any or all of those questions, your perception of the mental health status of this country’s children agrees with mine and probably that of most other Americans. However, a recent study suggests that not all of our perceptions are reality based (N. Engl. J. Med. 2015;372:2029-38). The authors used a parent-scored scale of the children’s impairment and found that the rate of severe mental illness has fallen significantly over the last generation. Despite the decline in severe cases that they observed, the percentage of children receiving outpatient mental health services (including psychotherapy and psychotropic drugs) has increased. In other words, while we and other providers are indeed seeing more children and adolescents with mental health and behavioral complaints, the tip of the iceberg is shrinking.

Does that divergence make any sense? As the chief of the National Institute of Mental Health’s in-house genetic epidemiological research program observes, it is hard to make any sense of the results of this new study, or any study, because there is a plethora of agencies doing surveys often using different methodologies. In Kathleen Merikangas’ words, “It’s a nightmare” (“Severe Mental Illness Found to Drop in Young, Defying Perceptions” by Benedict Carey in the New York Times on May 20, 2015).

The situation seems to be a classic case of comparing apples and oranges. It is probably even worse because different agencies can’t even agree on whether McIntoshes and Granny Smiths should both be counted as apples. With this degree of uncertainty, the officials charged with making decisions about funding and allocating mental health services are flying blind much of the time.

When it comes to divining the trends in the prevalence of mental illness in children and adolescents, your guess is as good as mine. So ... because I happen to have the time, I’m going to give you mine.

From my lofty perch here on the rocky coast of Maine, it appears to me that the recent study in the New England Journal of Medicine is accurate in its observation that serious mental illness is not increasing and may in be decreasing. But why does it feel that our office schedules are bulging with the patients presenting with less serious behavioral problems? One answer is that many of the cases of serious physical illness that we once saw never make it to the waiting room. For example, most children with congenital heart disease are now diagnosed in utero and delivered and treated in tertiary centers. Serious infectious diseases such as meningitis and epiglottitis have been damped down by successful immunizations. The abundance of subspecialists, the tendency of some physicians to issue knee-jerk referrals, and the awareness by parents that they can self-refer has left a void in our schedules that in the blink of an eye has filled with the walking worried.

It is worry and anxiety that in my estimation is on the rise and generating a large percentage of visits. Whether this is a post 9-11 phenomenon or simply a reflection of too-much-news-too-quickly is unclear. But the bottom line is that parents are worried and as a result so are many of their children. I am less sure on whether there has been a true increase in depression. It may be that people are more willing to talk about their unhappiness or it may be a ripple effect from our national sleep deprivation.

Finally, there has been a tendency to narrow the definition of normal that goes hand in hand with the notion that if it isn’t “normal,” there must be some medication to fix the problem. Attention-deficit/hyperactivity disorder is the poster child for this schedule-filling duo.

So that’s what I think. I suspect you feel you are seeing more behavior-related problems. But is this because of a true increase in the level of mental health problems in this country? How do you explain it?

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “Coping with a Picky Eater.” E-mail him at pdnews@frontlinemedcom.com.

When you decided to go to medical school, did you expect that you would be seeing as many patients with mental health complaints as you are seeing now? If you have been practicing pediatrics for more than 15 years, has your patient mix significantly taken on a more behavioral flavor? Do you think that more of your patients are experiencing serious mental health issues?

If you answered yes to any or all of those questions, your perception of the mental health status of this country’s children agrees with mine and probably that of most other Americans. However, a recent study suggests that not all of our perceptions are reality based (N. Engl. J. Med. 2015;372:2029-38). The authors used a parent-scored scale of the children’s impairment and found that the rate of severe mental illness has fallen significantly over the last generation. Despite the decline in severe cases that they observed, the percentage of children receiving outpatient mental health services (including psychotherapy and psychotropic drugs) has increased. In other words, while we and other providers are indeed seeing more children and adolescents with mental health and behavioral complaints, the tip of the iceberg is shrinking.

Does that divergence make any sense? As the chief of the National Institute of Mental Health’s in-house genetic epidemiological research program observes, it is hard to make any sense of the results of this new study, or any study, because there is a plethora of agencies doing surveys often using different methodologies. In Kathleen Merikangas’ words, “It’s a nightmare” (“Severe Mental Illness Found to Drop in Young, Defying Perceptions” by Benedict Carey in the New York Times on May 20, 2015).

The situation seems to be a classic case of comparing apples and oranges. It is probably even worse because different agencies can’t even agree on whether McIntoshes and Granny Smiths should both be counted as apples. With this degree of uncertainty, the officials charged with making decisions about funding and allocating mental health services are flying blind much of the time.

When it comes to divining the trends in the prevalence of mental illness in children and adolescents, your guess is as good as mine. So ... because I happen to have the time, I’m going to give you mine.

From my lofty perch here on the rocky coast of Maine, it appears to me that the recent study in the New England Journal of Medicine is accurate in its observation that serious mental illness is not increasing and may in be decreasing. But why does it feel that our office schedules are bulging with the patients presenting with less serious behavioral problems? One answer is that many of the cases of serious physical illness that we once saw never make it to the waiting room. For example, most children with congenital heart disease are now diagnosed in utero and delivered and treated in tertiary centers. Serious infectious diseases such as meningitis and epiglottitis have been damped down by successful immunizations. The abundance of subspecialists, the tendency of some physicians to issue knee-jerk referrals, and the awareness by parents that they can self-refer has left a void in our schedules that in the blink of an eye has filled with the walking worried.

It is worry and anxiety that in my estimation is on the rise and generating a large percentage of visits. Whether this is a post 9-11 phenomenon or simply a reflection of too-much-news-too-quickly is unclear. But the bottom line is that parents are worried and as a result so are many of their children. I am less sure on whether there has been a true increase in depression. It may be that people are more willing to talk about their unhappiness or it may be a ripple effect from our national sleep deprivation.

Finally, there has been a tendency to narrow the definition of normal that goes hand in hand with the notion that if it isn’t “normal,” there must be some medication to fix the problem. Attention-deficit/hyperactivity disorder is the poster child for this schedule-filling duo.

So that’s what I think. I suspect you feel you are seeing more behavior-related problems. But is this because of a true increase in the level of mental health problems in this country? How do you explain it?

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “Coping with a Picky Eater.” E-mail him at pdnews@frontlinemedcom.com.

Nyer et al examined whether fatigue was associated with greater symptomatic burden and functional impairment in 287 college students with depressive symptoms using data from the self-report Beck Depression Inventory (BDI). Students endorsing significant symptoms of depression (BDI score ≥13) were grouped into 3 levels: no fatigue, mild fatigue, or moderate/severe fatigue. Researchers compared the 3 levels of fatigue across a battery of psychiatric and functional outcome measures.

The study found that depressed college students with symptoms of fatigue demonstrated functional impairment and symptomatic burden that worsened with increasing levels of fatigue. The authors call for more attention to assessing and treating symptoms of fatigue within this population.

Nyer et al examined whether fatigue was associated with greater symptomatic burden and functional impairment in 287 college students with depressive symptoms using data from the self-report Beck Depression Inventory (BDI). Students endorsing significant symptoms of depression (BDI score ≥13) were grouped into 3 levels: no fatigue, mild fatigue, or moderate/severe fatigue. Researchers compared the 3 levels of fatigue across a battery of psychiatric and functional outcome measures.

The study found that depressed college students with symptoms of fatigue demonstrated functional impairment and symptomatic burden that worsened with increasing levels of fatigue. The authors call for more attention to assessing and treating symptoms of fatigue within this population.

Nyer et al examined whether fatigue was associated with greater symptomatic burden and functional impairment in 287 college students with depressive symptoms using data from the self-report Beck Depression Inventory (BDI). Students endorsing significant symptoms of depression (BDI score ≥13) were grouped into 3 levels: no fatigue, mild fatigue, or moderate/severe fatigue. Researchers compared the 3 levels of fatigue across a battery of psychiatric and functional outcome measures.

The study found that depressed college students with symptoms of fatigue demonstrated functional impairment and symptomatic burden that worsened with increasing levels of fatigue. The authors call for more attention to assessing and treating symptoms of fatigue within this population.

Mortality rate is an important indicator of the severity of traumatic injuries, and these values have been described for different orthopedic injuries and fractures. Studies have identified 3 distinct trends in patient survival when compared with the age- and sex-matched uninjured population: 

1.  Hip fractures bring about a transient increase in mortality relative to age-matched controls that normalizes after a few months to 1 year.^1-10

2.  Thoracic and lumbar compression fractures are associated with an ongoing, lifelong increase in mortality rate relative to age-matched controls without an initial marked upswing.^11-15

3.  Certain injuries such as isolated rib or wrist fractures do not adversely affect survival relative to age-matched controls.^12,16-18

Understanding the mortality patterns after these injuries can help guide management and even facilitate the development of appropriate treatment algorithms.^19-21 While studies have examined mortality in specific odontoid fracture types,²² such mortality trends have not been broadly established in persons with cervical spine fractures. 

Cervical spine fractures are common: 60% of spine fractures localize to this region,^23-26 and this equates to 2% to 3% of all blunt-trauma patients.^27,28 These injuries can lead to devastating consequences, including neurologic compromise, permanent disability, and death.^29-31

Studies have estimated that up to 20% of cervical fractures involve the odontoid process.^23-26 These injuries are more common among the elderly population because of their greater prevalence of osteoporosis and likelihood of falling.³² Because of demographic similarities to those of the hip fracture population, a survival analysis of all odontoid fractures is particularly interesting. Published odontoid mortality rates vary significantly, with reports ranging from 13% to 44%.^22,33-35 Unfortunately, these studies largely evaluated survival rates specific to an individual treatment modality, such as nonoperative compared with operative, or specific to certain odontoid fracture types (eg, type II). Additionally, studies have generally only considered survivorship during initial hospitalization, have been specific to a constrained age group, or have been based solely on inpatient records that do not permit the longer-term follow-up critical to determining the effect of odontoid fractures on overall mortality.^36-39

Likewise, mortality rates after fractures of the subaxial spine (ie, the motion segments between C3 and C7) have yet to be established. In 1 study, the mortality risk of a cohort of elderly patients with cervical fractures appeared to be elevated for the first 6 to 12 months after the traumatic event.⁴⁰ However, the sample size was too small to examine mortality beyond 1 year.

In this context, the purpose of the current study was to determine the mortality rates at several time points (3 months, 1 year, and 2 years) of patients 50 years or older (start of the second mode of the bimodal age distribution of odontoid fractures^41-44) with fractures of the odontoid and subaxial cervical spine. A secondary purpose of this study was to compare survival rates of these 2 cohorts relative to each other and to the general population.

Materials and Methods

Identification of Cervical Fractures and Collection of Demographic Information

This protocol was approved by the human investigation committee of our institution. Every computed tomography (CT) scan of the cervical spine performed in the emergency department (ED) of an academic hospital between November 27, 1997, and December 31, 2006, was identified. Since the threshold for obtaining a CT scan of a patient with suspected cervical spine trauma is relatively low, it was assumed that virtually all acute cervical spine fractures during this time period would be successfully identified through this approach.

Radiology reports for all identified CT scans were reviewed for any findings consistent with acute fractures and/or dislocations of the cervical spine (Figure 1). Every study noted to be positive or equivocal for cervical trauma was directly visualized, including those that did not specifically mention the presence or absence of an injury. Scans with no signs of acute trauma or that showed fractures caused by a pathologic process or penetrating mechanism (eg, metastatic lesions or gunshot wounds) were omitted from this series. Finally, relevant demographic information, such as the medical record number, age, gender, and date of study, was recorded for every subject in this group.

Fracture Classification

Next, the level and the type of cervical injury were documented for each patient. Fractures were segregated according to their involvement with the odontoid or the subaxial vertebrae. 

Odontoid fractures were categorized into type I (limited to the tip), type II (across the base of the process) and type III (through the base with extension into the C2 vertebral body).^45,46 Since many systems for classifying subaxial cervical spine trauma require a subjective inference of the injury mechanism, which is difficult to ascertain from imaging studies alone, all of these fractures were pooled together.

A preliminary survey of the data indicated that the odontoid fractures appeared to exhibit a bimodal age distribution, with the beginning of the second cluster occurring around age 50 years (Figure 2). As noted above, this has been shown in previous studies.^41-44 As a consequence, the mortalities of those older than 50 years became the focus of this study. To control for comorbid conditions, mechanism of injury, and to allow for more direct comparison with the odontoid fractures in this study, the same age demarcation was used for subaxial cervical fractures.

Mortality Data

The mortality status of every patient diagnosed with an acute cervical injury at our institution between November 27, 1997, and December 31, 2006, was determined by referencing the National Death Index (NDI). The NDI is a computerized database of death records maintained by the National Center for Health Statistics (NCHS). The time window for the current study was selected because we had access to NDI information only through 2007 at the time of this study. Social Security numbers (SSNs), which were available for approximately half of the subjects, were used to search the NDI catalog. For individuals whose SSNs were unavailable, patient names and birthdates were considered to be sufficient to confirm a true match. Our center’s medical records of this cohort were also examined to verify whether any had died during their initial hospitalizations and to substantiate the NDI data. Finally, patient deaths were categorized as trauma (eg, motor vehicle accident, fall from a height) or medical comorbidity (eg, diabetes mellitus, cancer, congestive heart failure), based on information in the NDI listing.

Age- and Sex-Matched Controls

Age- and sex-matched controls were determined from the Wide-ranging Online Data for Epidemiologic Research (WONDER) application distributed by the Centers for Disease Control and Prevention (http://wonder.cdc.gov). Composite mortality data from the state in which the study was performed was obtained for the years between 1999 and 2007, and this information was further stratified according to gender and age to estimate the mortality rates and construct survival curves for each group. Controls were used to establish a standardized mortality ratio (SMR) for subjects 50 years and older, a value that compares the number of observed deaths with the figure expected for matched populations from the general population.

Statistical Methods

Statistical analyses were performed by using both SAS 9.2 (SAS Institute Inc., Cary, North Carolina) and R (version 2.9; www.r-project.org, Auckland, New Zealand). Relevant comparisons were planned, and all tests were 2-sided. The Wilcoxon rank sum test was applied to compare the survival times of patients with odontoid fractures with different documented causes of death, and Pearson χ² test was used to compare the age distributions of odontoid and subaxial fractures. Survival rates at 3 months, 1 year, and 2 years were estimated from Kaplan-Meier curves. The relative survival of these cohorts was compared by completing a 2-sample log-rank test. In addition, a 1-sample log-rank test was implemented to compare the mortality from either odontoid or subaxial cervical spine fractures with that of the age- and gender-matched general population. Statistical significance was defined as a 2-sided α error of less than 0.05 (P < .05).

Results

Fifty-nine patients were diagnosed with odontoid fractures (28 men, 31 women), and 233 patients were diagnosed with subaxial cervical spine fractures (168 men, 65 women).

Odontoid Fracture Patients

Odontoid fracture patients exhibited a distinct bimodal age distribution (Figure 2). In the younger population, there were 14 subjects, 3 of whom died within days of the injury (mean, 12 days; 78.6% survival). At 2-year follow-up, there were no further deaths. The fractures that caused death were high-energy injuries, and only early deaths occurred in these cases. 

Because of the significant bimodal age distribution, it was believed these cohorts could not be directly compared. As a result, the remaining analysis focused on the older age group. In the older population mode (50 years and older) were 45 patients with odontoid fractures. Of the 12 subjects who died after odontoid fracture, 5 were assigned a trauma code as the cause of death, while a medical comorbidity code was assigned for the remaining 7. Mean survival time of those who died secondary to trauma was significantly shorter than the medical comorbidity group (P = .025). 

In the cohort of subjects older than 50 years, 3-month, 1-year, and 2-year survival rates were 84.4%, 82.2%, and 72.9%, respectively. Figure 2 shows the 1- and 2-year follow-up data by age group.

Analysis was performed relative to gender. Of male patients (n = 22), the 3-month, 1-year, and 2-year survival rates were 72.7%, 72.7%, and 62.7%, respectively. Among women (n = 23), the 3-month, 1-year, and 2-year survival rates were 95.7%, 91.3%, and 82.6%, respectively.

Figure 3 shows the Kaplan-Meier survival curves of the older patients with odontoid fractures. A comparison of the curves for each gender showed no significant disparities between the male and female survival (Figure 3A, P = .124). Compared with age-matched male counterparts, the survival of male subjects with odontoid fractures was significantly worse (Figure 3B, P < .001). Men experienced an initial acute decline in survival, with the remainder of the survival curve matching that of the general male population. In contrast, odontoid fractures did not adversely affect female survival compared with the matched population (Figure 3C, P = .568). 

The 2-year SMR of 2.98 for men showed that odontoid fractures led to greater mortality compared with a sex- and age-matched population. This means that men older than 50 years who sustained an odontoid fracture had nearly 3 times the mortality rate after 2 years compared with a normal, matched population; this increase is attributed to the 3-month time point that subsequently normalized. The female rate was 1.33 times that of a matched population, a difference that is not statistically significant.

Subaxial Fracture Patients

Of the 91 patients older than 50 years with subaxial fractures, 3-month, 1-year, and 2-year survival rates were 87.9%, 85.7%, and 85.7%, respectively. Figure 4 shows the 1- and 2-year follow-up data by age group.

Gender-specific analysis was performed. For men (n = 58), the 3-month, 1-year, and 2-year survival rates were 87.9%, 84.5%, and 84.5%, respectively. Among women (n = 33), 4 deaths were recorded at all time points (87.9% survival). 

Figure 5 shows Kaplan-Meier survival curves for the older population with subaxial fractures. A comparison of the curves between genders again showed no significant differences between male and female survival (P = .683, Figure 5A). Compared with age- and gender-matched counterparts, men showed decreased relative survival (P < .0001, Figure 5B), whereas subaxial fractures did not decrease female survival (P = .554, Figure 5C).

The 2-year SMR of 2.90 for men showed higher mortality rates relative to sex- and age-matched controls. Men who were both 50 years old and sustained a subaxial fracture were 2.9 times as likely to die within 2 years of follow-up compared with their counterparts. Similar to odontoid fractures, this increase occurred by the 3-month time point and subsequently normalized. The female rate, which was 1.34 times that of the uninjured population, was not statistically significant.

Comparison of Odontoid and Subaxial Fracture Patients

The survival of subaxial injuries was not significantly different from that of odontoid fractures (P = .113, Figure 6A). When analyzed by gender and controlled for age, the rates in both male (P = .347, Figure 6B) and female (P = .643, Figure 6C) patients did not differ between fracture types.

Discussion

The US population is aging rapidly, with the demographic older than 65 years predicted to more than double in size between 2010 and 2050.⁴⁷ As our elderly population grows, the incidence of age-related injuries will rise accordingly. An understanding of mortality risks associated with different fractures will not only assist practitioners in advising patients regarding prognosis but may also lead to improvements in clinical care.^19,48-50 While we know cervical spine trauma is associated with significant morbidity,^29-31 little is known about associated moderate-term mortality rates that can be compared with other known injury patterns, such as hip fractures or osteoporotic compression fractures. 

An interesting finding of the present study is the bimodal age distribution of the 59 odontoid fractures (Figure 2). The 14 patients younger than 50 years included 3 individuals who died, all within days of their presentation from severe multisystem trauma. This is consistent with the determination that high-energy forces are required to fracture the odontoid process in younger individuals.^{38,45,46,51,52} Given the severity of their nonspinal injuries, the cause of death was likely not primarily related to their odontoid fractures. Also in line with previous studies, the majority (76%) of odontoid fractures were documented in subjects older than 50 years.^32,53,54 Within our cohort older than 50 years, the deaths appear to be spread evenly across age groups and do not seem to be skewed by the oldest portion of the population (Figure 2).

Our gender-specific analyses revealed that older men with odontoid injuries exhibited higher mortality compared with an age-matched male cohort, with 6 of the 8 deaths occurring within 3 months. However, after this exaggerated decline in survival, the rate normalized towards general population mortality rates (Figure 3B). As in the younger cohort, these earlier deaths were largely attributable to multisystem trauma, whereas medical comorbidities were implicated in those who died later. In contrast, the Kaplan-Meier curve of older women with odontoid fractures closely approximates that of age-matched women at every time point (Figure 3C), indicating that these injuries do not decrease survival as they do in their male counterparts.

When comparing the survival of older patients with subaxial cervical spine fractures with that of gender- and age-matched controls, the mortality rates of women were, once again, essentially equivalent. However, the survival of older men was significantly compromised by these injuries. In men, 7 of the 9 deaths were within 3 months, with the remaining 2 deaths occurring within 7 months. Nevertheless, beyond this initial period of elevated mortality, the survival curve again stabilized and paralleled that of the general population. As with odontoid fractures, there was no sustained increase in the mortality of male patients who lived at least 3 months after injury.

The mortality rates of odontoid and subaxial fractures were also compared in the older population. When controlled for age, there was no difference in mortality rates between these 2 groups. When individually analyzed in both men and women, the mortality rates of both fracture types matched those of the general population at all time points.

It is useful to contextualize our findings alongside the mortality of older individuals with other fracture types. Based on our results, we believe that the survival curves of geriatric men with odontoid or subaxial cervical spine fractures most closely resemble the characteristic pattern seen in hip fractures. Hip fractures have shown an early spike in mortality by as much as 8% to 49% in the first 6 to 12 months that returns to baseline after 1 year.^1-10 This presumably reflects the natural history of these injuries in response to appropriate therapeutic interventions. Interestingly, the male mortality rates for both odontoid and subaxial cervical spine fractures in this study are largely analogous to those reported by various hip fracture surveys.^1,5,55-58 In contrast, similar to prior studies of rib or wrist fractures, older women with these cervical spine fractures did not show a survival decrease after their injuries.^12,16-18

While the reasons underlying the differential effects of cervical fractures on the mortality of men and women have not been established, one explanation is that the female geriatric population is relatively more osteoporotic; thus, cervical injuries may occur after lower-energy forces, leading to less severe associated trauma that could otherwise decrease survival. Another explanation is that men are more likely to be involved in high-energy accidents,^59,60 thus decreasing their overall survival after injury.

This investigation is not without limitations. Our primary concern is the determination of survival. The NDI maintained by the NCHS is an extremely reliable tool regularly employed by epidemiologists to collect mortality data. However, it is possible that deaths may have been missed. We believe this number would be small, because the NDI database provided multiple probable matches that were carefully compared with supplemental personal information. It is also possible that deaths that were not appropriately registered with the NDI are not represented in this series. Another limitation lies in the determination of controls. As with any case–control study, the patients sustaining these odontoid fractures may differ in some significant way from the average population. A final limitation is that a small portion of patients in the study have only 1-year follow-up, because patient data was collected through 2006, although access to NDI data ended in 2007.

Conclusion

Our results indicate that the survival of older men with either odontoid or subaxial cervical spine fractures shares many of the same mortality characteristics as hip fractures, with diminished survival in the first 3 months that normalizes to the survival rate of the age-matched population. Interestingly, and perhaps because of disparate rates of osteoporosis and traumatic forces, the mortality rates in the female cohort were similar to that of the age-matched general population at all time points. These trends were nearly identical for both odontoid and subaxial cervical fractures.

Mortality rate is an important indicator of the severity of traumatic injuries, and these values have been described for different orthopedic injuries and fractures. Studies have identified 3 distinct trends in patient survival when compared with the age- and sex-matched uninjured population: 

1.  Hip fractures bring about a transient increase in mortality relative to age-matched controls that normalizes after a few months to 1 year.^1-10

2.  Thoracic and lumbar compression fractures are associated with an ongoing, lifelong increase in mortality rate relative to age-matched controls without an initial marked upswing.^11-15

3.  Certain injuries such as isolated rib or wrist fractures do not adversely affect survival relative to age-matched controls.^12,16-18

Understanding the mortality patterns after these injuries can help guide management and even facilitate the development of appropriate treatment algorithms.^19-21 While studies have examined mortality in specific odontoid fracture types,²² such mortality trends have not been broadly established in persons with cervical spine fractures. 

Cervical spine fractures are common: 60% of spine fractures localize to this region,^23-26 and this equates to 2% to 3% of all blunt-trauma patients.^27,28 These injuries can lead to devastating consequences, including neurologic compromise, permanent disability, and death.^29-31

Studies have estimated that up to 20% of cervical fractures involve the odontoid process.^23-26 These injuries are more common among the elderly population because of their greater prevalence of osteoporosis and likelihood of falling.³² Because of demographic similarities to those of the hip fracture population, a survival analysis of all odontoid fractures is particularly interesting. Published odontoid mortality rates vary significantly, with reports ranging from 13% to 44%.^22,33-35 Unfortunately, these studies largely evaluated survival rates specific to an individual treatment modality, such as nonoperative compared with operative, or specific to certain odontoid fracture types (eg, type II). Additionally, studies have generally only considered survivorship during initial hospitalization, have been specific to a constrained age group, or have been based solely on inpatient records that do not permit the longer-term follow-up critical to determining the effect of odontoid fractures on overall mortality.^36-39

Likewise, mortality rates after fractures of the subaxial spine (ie, the motion segments between C3 and C7) have yet to be established. In 1 study, the mortality risk of a cohort of elderly patients with cervical fractures appeared to be elevated for the first 6 to 12 months after the traumatic event.⁴⁰ However, the sample size was too small to examine mortality beyond 1 year.

In this context, the purpose of the current study was to determine the mortality rates at several time points (3 months, 1 year, and 2 years) of patients 50 years or older (start of the second mode of the bimodal age distribution of odontoid fractures^41-44) with fractures of the odontoid and subaxial cervical spine. A secondary purpose of this study was to compare survival rates of these 2 cohorts relative to each other and to the general population.

Materials and Methods

Identification of Cervical Fractures and Collection of Demographic Information

This protocol was approved by the human investigation committee of our institution. Every computed tomography (CT) scan of the cervical spine performed in the emergency department (ED) of an academic hospital between November 27, 1997, and December 31, 2006, was identified. Since the threshold for obtaining a CT scan of a patient with suspected cervical spine trauma is relatively low, it was assumed that virtually all acute cervical spine fractures during this time period would be successfully identified through this approach.

Radiology reports for all identified CT scans were reviewed for any findings consistent with acute fractures and/or dislocations of the cervical spine (Figure 1). Every study noted to be positive or equivocal for cervical trauma was directly visualized, including those that did not specifically mention the presence or absence of an injury. Scans with no signs of acute trauma or that showed fractures caused by a pathologic process or penetrating mechanism (eg, metastatic lesions or gunshot wounds) were omitted from this series. Finally, relevant demographic information, such as the medical record number, age, gender, and date of study, was recorded for every subject in this group.

Fracture Classification

Next, the level and the type of cervical injury were documented for each patient. Fractures were segregated according to their involvement with the odontoid or the subaxial vertebrae. 

Odontoid fractures were categorized into type I (limited to the tip), type II (across the base of the process) and type III (through the base with extension into the C2 vertebral body).^45,46 Since many systems for classifying subaxial cervical spine trauma require a subjective inference of the injury mechanism, which is difficult to ascertain from imaging studies alone, all of these fractures were pooled together.

A preliminary survey of the data indicated that the odontoid fractures appeared to exhibit a bimodal age distribution, with the beginning of the second cluster occurring around age 50 years (Figure 2). As noted above, this has been shown in previous studies.^41-44 As a consequence, the mortalities of those older than 50 years became the focus of this study. To control for comorbid conditions, mechanism of injury, and to allow for more direct comparison with the odontoid fractures in this study, the same age demarcation was used for subaxial cervical fractures.

Mortality Data

The mortality status of every patient diagnosed with an acute cervical injury at our institution between November 27, 1997, and December 31, 2006, was determined by referencing the National Death Index (NDI). The NDI is a computerized database of death records maintained by the National Center for Health Statistics (NCHS). The time window for the current study was selected because we had access to NDI information only through 2007 at the time of this study. Social Security numbers (SSNs), which were available for approximately half of the subjects, were used to search the NDI catalog. For individuals whose SSNs were unavailable, patient names and birthdates were considered to be sufficient to confirm a true match. Our center’s medical records of this cohort were also examined to verify whether any had died during their initial hospitalizations and to substantiate the NDI data. Finally, patient deaths were categorized as trauma (eg, motor vehicle accident, fall from a height) or medical comorbidity (eg, diabetes mellitus, cancer, congestive heart failure), based on information in the NDI listing.

Age- and Sex-Matched Controls

Age- and sex-matched controls were determined from the Wide-ranging Online Data for Epidemiologic Research (WONDER) application distributed by the Centers for Disease Control and Prevention (http://wonder.cdc.gov). Composite mortality data from the state in which the study was performed was obtained for the years between 1999 and 2007, and this information was further stratified according to gender and age to estimate the mortality rates and construct survival curves for each group. Controls were used to establish a standardized mortality ratio (SMR) for subjects 50 years and older, a value that compares the number of observed deaths with the figure expected for matched populations from the general population.

Statistical Methods

Statistical analyses were performed by using both SAS 9.2 (SAS Institute Inc., Cary, North Carolina) and R (version 2.9; www.r-project.org, Auckland, New Zealand). Relevant comparisons were planned, and all tests were 2-sided. The Wilcoxon rank sum test was applied to compare the survival times of patients with odontoid fractures with different documented causes of death, and Pearson χ² test was used to compare the age distributions of odontoid and subaxial fractures. Survival rates at 3 months, 1 year, and 2 years were estimated from Kaplan-Meier curves. The relative survival of these cohorts was compared by completing a 2-sample log-rank test. In addition, a 1-sample log-rank test was implemented to compare the mortality from either odontoid or subaxial cervical spine fractures with that of the age- and gender-matched general population. Statistical significance was defined as a 2-sided α error of less than 0.05 (P < .05).

Results

Fifty-nine patients were diagnosed with odontoid fractures (28 men, 31 women), and 233 patients were diagnosed with subaxial cervical spine fractures (168 men, 65 women).

Odontoid Fracture Patients

Odontoid fracture patients exhibited a distinct bimodal age distribution (Figure 2). In the younger population, there were 14 subjects, 3 of whom died within days of the injury (mean, 12 days; 78.6% survival). At 2-year follow-up, there were no further deaths. The fractures that caused death were high-energy injuries, and only early deaths occurred in these cases. 

Because of the significant bimodal age distribution, it was believed these cohorts could not be directly compared. As a result, the remaining analysis focused on the older age group. In the older population mode (50 years and older) were 45 patients with odontoid fractures. Of the 12 subjects who died after odontoid fracture, 5 were assigned a trauma code as the cause of death, while a medical comorbidity code was assigned for the remaining 7. Mean survival time of those who died secondary to trauma was significantly shorter than the medical comorbidity group (P = .025). 

In the cohort of subjects older than 50 years, 3-month, 1-year, and 2-year survival rates were 84.4%, 82.2%, and 72.9%, respectively. Figure 2 shows the 1- and 2-year follow-up data by age group.

Analysis was performed relative to gender. Of male patients (n = 22), the 3-month, 1-year, and 2-year survival rates were 72.7%, 72.7%, and 62.7%, respectively. Among women (n = 23), the 3-month, 1-year, and 2-year survival rates were 95.7%, 91.3%, and 82.6%, respectively.

Figure 3 shows the Kaplan-Meier survival curves of the older patients with odontoid fractures. A comparison of the curves for each gender showed no significant disparities between the male and female survival (Figure 3A, P = .124). Compared with age-matched male counterparts, the survival of male subjects with odontoid fractures was significantly worse (Figure 3B, P < .001). Men experienced an initial acute decline in survival, with the remainder of the survival curve matching that of the general male population. In contrast, odontoid fractures did not adversely affect female survival compared with the matched population (Figure 3C, P = .568). 

The 2-year SMR of 2.98 for men showed that odontoid fractures led to greater mortality compared with a sex- and age-matched population. This means that men older than 50 years who sustained an odontoid fracture had nearly 3 times the mortality rate after 2 years compared with a normal, matched population; this increase is attributed to the 3-month time point that subsequently normalized. The female rate was 1.33 times that of a matched population, a difference that is not statistically significant.

Subaxial Fracture Patients

Of the 91 patients older than 50 years with subaxial fractures, 3-month, 1-year, and 2-year survival rates were 87.9%, 85.7%, and 85.7%, respectively. Figure 4 shows the 1- and 2-year follow-up data by age group.

Gender-specific analysis was performed. For men (n = 58), the 3-month, 1-year, and 2-year survival rates were 87.9%, 84.5%, and 84.5%, respectively. Among women (n = 33), 4 deaths were recorded at all time points (87.9% survival). 

Figure 5 shows Kaplan-Meier survival curves for the older population with subaxial fractures. A comparison of the curves between genders again showed no significant differences between male and female survival (P = .683, Figure 5A). Compared with age- and gender-matched counterparts, men showed decreased relative survival (P < .0001, Figure 5B), whereas subaxial fractures did not decrease female survival (P = .554, Figure 5C).

The 2-year SMR of 2.90 for men showed higher mortality rates relative to sex- and age-matched controls. Men who were both 50 years old and sustained a subaxial fracture were 2.9 times as likely to die within 2 years of follow-up compared with their counterparts. Similar to odontoid fractures, this increase occurred by the 3-month time point and subsequently normalized. The female rate, which was 1.34 times that of the uninjured population, was not statistically significant.

Comparison of Odontoid and Subaxial Fracture Patients

The survival of subaxial injuries was not significantly different from that of odontoid fractures (P = .113, Figure 6A). When analyzed by gender and controlled for age, the rates in both male (P = .347, Figure 6B) and female (P = .643, Figure 6C) patients did not differ between fracture types.

Discussion

The US population is aging rapidly, with the demographic older than 65 years predicted to more than double in size between 2010 and 2050.⁴⁷ As our elderly population grows, the incidence of age-related injuries will rise accordingly. An understanding of mortality risks associated with different fractures will not only assist practitioners in advising patients regarding prognosis but may also lead to improvements in clinical care.^19,48-50 While we know cervical spine trauma is associated with significant morbidity,^29-31 little is known about associated moderate-term mortality rates that can be compared with other known injury patterns, such as hip fractures or osteoporotic compression fractures. 

An interesting finding of the present study is the bimodal age distribution of the 59 odontoid fractures (Figure 2). The 14 patients younger than 50 years included 3 individuals who died, all within days of their presentation from severe multisystem trauma. This is consistent with the determination that high-energy forces are required to fracture the odontoid process in younger individuals.^{38,45,46,51,52} Given the severity of their nonspinal injuries, the cause of death was likely not primarily related to their odontoid fractures. Also in line with previous studies, the majority (76%) of odontoid fractures were documented in subjects older than 50 years.^32,53,54 Within our cohort older than 50 years, the deaths appear to be spread evenly across age groups and do not seem to be skewed by the oldest portion of the population (Figure 2).

Our gender-specific analyses revealed that older men with odontoid injuries exhibited higher mortality compared with an age-matched male cohort, with 6 of the 8 deaths occurring within 3 months. However, after this exaggerated decline in survival, the rate normalized towards general population mortality rates (Figure 3B). As in the younger cohort, these earlier deaths were largely attributable to multisystem trauma, whereas medical comorbidities were implicated in those who died later. In contrast, the Kaplan-Meier curve of older women with odontoid fractures closely approximates that of age-matched women at every time point (Figure 3C), indicating that these injuries do not decrease survival as they do in their male counterparts.

When comparing the survival of older patients with subaxial cervical spine fractures with that of gender- and age-matched controls, the mortality rates of women were, once again, essentially equivalent. However, the survival of older men was significantly compromised by these injuries. In men, 7 of the 9 deaths were within 3 months, with the remaining 2 deaths occurring within 7 months. Nevertheless, beyond this initial period of elevated mortality, the survival curve again stabilized and paralleled that of the general population. As with odontoid fractures, there was no sustained increase in the mortality of male patients who lived at least 3 months after injury.

The mortality rates of odontoid and subaxial fractures were also compared in the older population. When controlled for age, there was no difference in mortality rates between these 2 groups. When individually analyzed in both men and women, the mortality rates of both fracture types matched those of the general population at all time points.

It is useful to contextualize our findings alongside the mortality of older individuals with other fracture types. Based on our results, we believe that the survival curves of geriatric men with odontoid or subaxial cervical spine fractures most closely resemble the characteristic pattern seen in hip fractures. Hip fractures have shown an early spike in mortality by as much as 8% to 49% in the first 6 to 12 months that returns to baseline after 1 year.^1-10 This presumably reflects the natural history of these injuries in response to appropriate therapeutic interventions. Interestingly, the male mortality rates for both odontoid and subaxial cervical spine fractures in this study are largely analogous to those reported by various hip fracture surveys.^1,5,55-58 In contrast, similar to prior studies of rib or wrist fractures, older women with these cervical spine fractures did not show a survival decrease after their injuries.^12,16-18

While the reasons underlying the differential effects of cervical fractures on the mortality of men and women have not been established, one explanation is that the female geriatric population is relatively more osteoporotic; thus, cervical injuries may occur after lower-energy forces, leading to less severe associated trauma that could otherwise decrease survival. Another explanation is that men are more likely to be involved in high-energy accidents,^59,60 thus decreasing their overall survival after injury.

This investigation is not without limitations. Our primary concern is the determination of survival. The NDI maintained by the NCHS is an extremely reliable tool regularly employed by epidemiologists to collect mortality data. However, it is possible that deaths may have been missed. We believe this number would be small, because the NDI database provided multiple probable matches that were carefully compared with supplemental personal information. It is also possible that deaths that were not appropriately registered with the NDI are not represented in this series. Another limitation lies in the determination of controls. As with any case–control study, the patients sustaining these odontoid fractures may differ in some significant way from the average population. A final limitation is that a small portion of patients in the study have only 1-year follow-up, because patient data was collected through 2006, although access to NDI data ended in 2007.

Conclusion

Our results indicate that the survival of older men with either odontoid or subaxial cervical spine fractures shares many of the same mortality characteristics as hip fractures, with diminished survival in the first 3 months that normalizes to the survival rate of the age-matched population. Interestingly, and perhaps because of disparate rates of osteoporosis and traumatic forces, the mortality rates in the female cohort were similar to that of the age-matched general population at all time points. These trends were nearly identical for both odontoid and subaxial cervical fractures.

Mortality rate is an important indicator of the severity of traumatic injuries, and these values have been described for different orthopedic injuries and fractures. Studies have identified 3 distinct trends in patient survival when compared with the age- and sex-matched uninjured population: 

1.  Hip fractures bring about a transient increase in mortality relative to age-matched controls that normalizes after a few months to 1 year.^1-10

2.  Thoracic and lumbar compression fractures are associated with an ongoing, lifelong increase in mortality rate relative to age-matched controls without an initial marked upswing.^11-15

3.  Certain injuries such as isolated rib or wrist fractures do not adversely affect survival relative to age-matched controls.^12,16-18

Understanding the mortality patterns after these injuries can help guide management and even facilitate the development of appropriate treatment algorithms.^19-21 While studies have examined mortality in specific odontoid fracture types,²² such mortality trends have not been broadly established in persons with cervical spine fractures. 

Cervical spine fractures are common: 60% of spine fractures localize to this region,^23-26 and this equates to 2% to 3% of all blunt-trauma patients.^27,28 These injuries can lead to devastating consequences, including neurologic compromise, permanent disability, and death.^29-31

Studies have estimated that up to 20% of cervical fractures involve the odontoid process.^23-26 These injuries are more common among the elderly population because of their greater prevalence of osteoporosis and likelihood of falling.³² Because of demographic similarities to those of the hip fracture population, a survival analysis of all odontoid fractures is particularly interesting. Published odontoid mortality rates vary significantly, with reports ranging from 13% to 44%.^22,33-35 Unfortunately, these studies largely evaluated survival rates specific to an individual treatment modality, such as nonoperative compared with operative, or specific to certain odontoid fracture types (eg, type II). Additionally, studies have generally only considered survivorship during initial hospitalization, have been specific to a constrained age group, or have been based solely on inpatient records that do not permit the longer-term follow-up critical to determining the effect of odontoid fractures on overall mortality.^36-39

Likewise, mortality rates after fractures of the subaxial spine (ie, the motion segments between C3 and C7) have yet to be established. In 1 study, the mortality risk of a cohort of elderly patients with cervical fractures appeared to be elevated for the first 6 to 12 months after the traumatic event.⁴⁰ However, the sample size was too small to examine mortality beyond 1 year.

In this context, the purpose of the current study was to determine the mortality rates at several time points (3 months, 1 year, and 2 years) of patients 50 years or older (start of the second mode of the bimodal age distribution of odontoid fractures^41-44) with fractures of the odontoid and subaxial cervical spine. A secondary purpose of this study was to compare survival rates of these 2 cohorts relative to each other and to the general population.

Materials and Methods

Identification of Cervical Fractures and Collection of Demographic Information

This protocol was approved by the human investigation committee of our institution. Every computed tomography (CT) scan of the cervical spine performed in the emergency department (ED) of an academic hospital between November 27, 1997, and December 31, 2006, was identified. Since the threshold for obtaining a CT scan of a patient with suspected cervical spine trauma is relatively low, it was assumed that virtually all acute cervical spine fractures during this time period would be successfully identified through this approach.

Radiology reports for all identified CT scans were reviewed for any findings consistent with acute fractures and/or dislocations of the cervical spine (Figure 1). Every study noted to be positive or equivocal for cervical trauma was directly visualized, including those that did not specifically mention the presence or absence of an injury. Scans with no signs of acute trauma or that showed fractures caused by a pathologic process or penetrating mechanism (eg, metastatic lesions or gunshot wounds) were omitted from this series. Finally, relevant demographic information, such as the medical record number, age, gender, and date of study, was recorded for every subject in this group.

Fracture Classification

Next, the level and the type of cervical injury were documented for each patient. Fractures were segregated according to their involvement with the odontoid or the subaxial vertebrae. 

Odontoid fractures were categorized into type I (limited to the tip), type II (across the base of the process) and type III (through the base with extension into the C2 vertebral body).^45,46 Since many systems for classifying subaxial cervical spine trauma require a subjective inference of the injury mechanism, which is difficult to ascertain from imaging studies alone, all of these fractures were pooled together.

A preliminary survey of the data indicated that the odontoid fractures appeared to exhibit a bimodal age distribution, with the beginning of the second cluster occurring around age 50 years (Figure 2). As noted above, this has been shown in previous studies.^41-44 As a consequence, the mortalities of those older than 50 years became the focus of this study. To control for comorbid conditions, mechanism of injury, and to allow for more direct comparison with the odontoid fractures in this study, the same age demarcation was used for subaxial cervical fractures.

Mortality Data

The mortality status of every patient diagnosed with an acute cervical injury at our institution between November 27, 1997, and December 31, 2006, was determined by referencing the National Death Index (NDI). The NDI is a computerized database of death records maintained by the National Center for Health Statistics (NCHS). The time window for the current study was selected because we had access to NDI information only through 2007 at the time of this study. Social Security numbers (SSNs), which were available for approximately half of the subjects, were used to search the NDI catalog. For individuals whose SSNs were unavailable, patient names and birthdates were considered to be sufficient to confirm a true match. Our center’s medical records of this cohort were also examined to verify whether any had died during their initial hospitalizations and to substantiate the NDI data. Finally, patient deaths were categorized as trauma (eg, motor vehicle accident, fall from a height) or medical comorbidity (eg, diabetes mellitus, cancer, congestive heart failure), based on information in the NDI listing.

Age- and Sex-Matched Controls

Age- and sex-matched controls were determined from the Wide-ranging Online Data for Epidemiologic Research (WONDER) application distributed by the Centers for Disease Control and Prevention (http://wonder.cdc.gov). Composite mortality data from the state in which the study was performed was obtained for the years between 1999 and 2007, and this information was further stratified according to gender and age to estimate the mortality rates and construct survival curves for each group. Controls were used to establish a standardized mortality ratio (SMR) for subjects 50 years and older, a value that compares the number of observed deaths with the figure expected for matched populations from the general population.

Statistical Methods

Statistical analyses were performed by using both SAS 9.2 (SAS Institute Inc., Cary, North Carolina) and R (version 2.9; www.r-project.org, Auckland, New Zealand). Relevant comparisons were planned, and all tests were 2-sided. The Wilcoxon rank sum test was applied to compare the survival times of patients with odontoid fractures with different documented causes of death, and Pearson χ² test was used to compare the age distributions of odontoid and subaxial fractures. Survival rates at 3 months, 1 year, and 2 years were estimated from Kaplan-Meier curves. The relative survival of these cohorts was compared by completing a 2-sample log-rank test. In addition, a 1-sample log-rank test was implemented to compare the mortality from either odontoid or subaxial cervical spine fractures with that of the age- and gender-matched general population. Statistical significance was defined as a 2-sided α error of less than 0.05 (P < .05).

Results

Fifty-nine patients were diagnosed with odontoid fractures (28 men, 31 women), and 233 patients were diagnosed with subaxial cervical spine fractures (168 men, 65 women).

Odontoid Fracture Patients

Odontoid fracture patients exhibited a distinct bimodal age distribution (Figure 2). In the younger population, there were 14 subjects, 3 of whom died within days of the injury (mean, 12 days; 78.6% survival). At 2-year follow-up, there were no further deaths. The fractures that caused death were high-energy injuries, and only early deaths occurred in these cases. 

Because of the significant bimodal age distribution, it was believed these cohorts could not be directly compared. As a result, the remaining analysis focused on the older age group. In the older population mode (50 years and older) were 45 patients with odontoid fractures. Of the 12 subjects who died after odontoid fracture, 5 were assigned a trauma code as the cause of death, while a medical comorbidity code was assigned for the remaining 7. Mean survival time of those who died secondary to trauma was significantly shorter than the medical comorbidity group (P = .025). 

In the cohort of subjects older than 50 years, 3-month, 1-year, and 2-year survival rates were 84.4%, 82.2%, and 72.9%, respectively. Figure 2 shows the 1- and 2-year follow-up data by age group.

Analysis was performed relative to gender. Of male patients (n = 22), the 3-month, 1-year, and 2-year survival rates were 72.7%, 72.7%, and 62.7%, respectively. Among women (n = 23), the 3-month, 1-year, and 2-year survival rates were 95.7%, 91.3%, and 82.6%, respectively.

Figure 3 shows the Kaplan-Meier survival curves of the older patients with odontoid fractures. A comparison of the curves for each gender showed no significant disparities between the male and female survival (Figure 3A, P = .124). Compared with age-matched male counterparts, the survival of male subjects with odontoid fractures was significantly worse (Figure 3B, P < .001). Men experienced an initial acute decline in survival, with the remainder of the survival curve matching that of the general male population. In contrast, odontoid fractures did not adversely affect female survival compared with the matched population (Figure 3C, P = .568). 

The 2-year SMR of 2.98 for men showed that odontoid fractures led to greater mortality compared with a sex- and age-matched population. This means that men older than 50 years who sustained an odontoid fracture had nearly 3 times the mortality rate after 2 years compared with a normal, matched population; this increase is attributed to the 3-month time point that subsequently normalized. The female rate was 1.33 times that of a matched population, a difference that is not statistically significant.

Subaxial Fracture Patients

Of the 91 patients older than 50 years with subaxial fractures, 3-month, 1-year, and 2-year survival rates were 87.9%, 85.7%, and 85.7%, respectively. Figure 4 shows the 1- and 2-year follow-up data by age group.

Gender-specific analysis was performed. For men (n = 58), the 3-month, 1-year, and 2-year survival rates were 87.9%, 84.5%, and 84.5%, respectively. Among women (n = 33), 4 deaths were recorded at all time points (87.9% survival). 

Figure 5 shows Kaplan-Meier survival curves for the older population with subaxial fractures. A comparison of the curves between genders again showed no significant differences between male and female survival (P = .683, Figure 5A). Compared with age- and gender-matched counterparts, men showed decreased relative survival (P < .0001, Figure 5B), whereas subaxial fractures did not decrease female survival (P = .554, Figure 5C).

The 2-year SMR of 2.90 for men showed higher mortality rates relative to sex- and age-matched controls. Men who were both 50 years old and sustained a subaxial fracture were 2.9 times as likely to die within 2 years of follow-up compared with their counterparts. Similar to odontoid fractures, this increase occurred by the 3-month time point and subsequently normalized. The female rate, which was 1.34 times that of the uninjured population, was not statistically significant.

Comparison of Odontoid and Subaxial Fracture Patients

The survival of subaxial injuries was not significantly different from that of odontoid fractures (P = .113, Figure 6A). When analyzed by gender and controlled for age, the rates in both male (P = .347, Figure 6B) and female (P = .643, Figure 6C) patients did not differ between fracture types.

Discussion

The US population is aging rapidly, with the demographic older than 65 years predicted to more than double in size between 2010 and 2050.⁴⁷ As our elderly population grows, the incidence of age-related injuries will rise accordingly. An understanding of mortality risks associated with different fractures will not only assist practitioners in advising patients regarding prognosis but may also lead to improvements in clinical care.^19,48-50 While we know cervical spine trauma is associated with significant morbidity,^29-31 little is known about associated moderate-term mortality rates that can be compared with other known injury patterns, such as hip fractures or osteoporotic compression fractures. 

An interesting finding of the present study is the bimodal age distribution of the 59 odontoid fractures (Figure 2). The 14 patients younger than 50 years included 3 individuals who died, all within days of their presentation from severe multisystem trauma. This is consistent with the determination that high-energy forces are required to fracture the odontoid process in younger individuals.^{38,45,46,51,52} Given the severity of their nonspinal injuries, the cause of death was likely not primarily related to their odontoid fractures. Also in line with previous studies, the majority (76%) of odontoid fractures were documented in subjects older than 50 years.^32,53,54 Within our cohort older than 50 years, the deaths appear to be spread evenly across age groups and do not seem to be skewed by the oldest portion of the population (Figure 2).

Our gender-specific analyses revealed that older men with odontoid injuries exhibited higher mortality compared with an age-matched male cohort, with 6 of the 8 deaths occurring within 3 months. However, after this exaggerated decline in survival, the rate normalized towards general population mortality rates (Figure 3B). As in the younger cohort, these earlier deaths were largely attributable to multisystem trauma, whereas medical comorbidities were implicated in those who died later. In contrast, the Kaplan-Meier curve of older women with odontoid fractures closely approximates that of age-matched women at every time point (Figure 3C), indicating that these injuries do not decrease survival as they do in their male counterparts.

When comparing the survival of older patients with subaxial cervical spine fractures with that of gender- and age-matched controls, the mortality rates of women were, once again, essentially equivalent. However, the survival of older men was significantly compromised by these injuries. In men, 7 of the 9 deaths were within 3 months, with the remaining 2 deaths occurring within 7 months. Nevertheless, beyond this initial period of elevated mortality, the survival curve again stabilized and paralleled that of the general population. As with odontoid fractures, there was no sustained increase in the mortality of male patients who lived at least 3 months after injury.

The mortality rates of odontoid and subaxial fractures were also compared in the older population. When controlled for age, there was no difference in mortality rates between these 2 groups. When individually analyzed in both men and women, the mortality rates of both fracture types matched those of the general population at all time points.

It is useful to contextualize our findings alongside the mortality of older individuals with other fracture types. Based on our results, we believe that the survival curves of geriatric men with odontoid or subaxial cervical spine fractures most closely resemble the characteristic pattern seen in hip fractures. Hip fractures have shown an early spike in mortality by as much as 8% to 49% in the first 6 to 12 months that returns to baseline after 1 year.^1-10 This presumably reflects the natural history of these injuries in response to appropriate therapeutic interventions. Interestingly, the male mortality rates for both odontoid and subaxial cervical spine fractures in this study are largely analogous to those reported by various hip fracture surveys.^1,5,55-58 In contrast, similar to prior studies of rib or wrist fractures, older women with these cervical spine fractures did not show a survival decrease after their injuries.^12,16-18

While the reasons underlying the differential effects of cervical fractures on the mortality of men and women have not been established, one explanation is that the female geriatric population is relatively more osteoporotic; thus, cervical injuries may occur after lower-energy forces, leading to less severe associated trauma that could otherwise decrease survival. Another explanation is that men are more likely to be involved in high-energy accidents,^59,60 thus decreasing their overall survival after injury.

This investigation is not without limitations. Our primary concern is the determination of survival. The NDI maintained by the NCHS is an extremely reliable tool regularly employed by epidemiologists to collect mortality data. However, it is possible that deaths may have been missed. We believe this number would be small, because the NDI database provided multiple probable matches that were carefully compared with supplemental personal information. It is also possible that deaths that were not appropriately registered with the NDI are not represented in this series. Another limitation lies in the determination of controls. As with any case–control study, the patients sustaining these odontoid fractures may differ in some significant way from the average population. A final limitation is that a small portion of patients in the study have only 1-year follow-up, because patient data was collected through 2006, although access to NDI data ended in 2007.

Conclusion

Our results indicate that the survival of older men with either odontoid or subaxial cervical spine fractures shares many of the same mortality characteristics as hip fractures, with diminished survival in the first 3 months that normalizes to the survival rate of the age-matched population. Interestingly, and perhaps because of disparate rates of osteoporosis and traumatic forces, the mortality rates in the female cohort were similar to that of the age-matched general population at all time points. These trends were nearly identical for both odontoid and subaxial cervical fractures.

NEW ORLEANS – Evidence seems to be mounting that the link between testosterone replacement therapy and increased hematocrit doesn’t lead to more cardiac or thrombotic events in men.

The association between testosterone and secondary erythrocytosis has been known for some time, Dr. Wayne J. G. Hellstrom said at the annual meeting of the American Urological Association. An increase in hematocrit almost invariably follows testosterone supplementation. “The question is, is there a causal relation between testosterone replacement therapy–induced erythrocytosis and venous thromboembolism or major cardiac events?” said Dr. Hellstrom of Tulane Medical Center, New Orleans. “The available evidence doesn’t support this claim.”

Erythrocytosis is defined as a packed red blood cell volume exceeding 125% of the age-predicted mass. This may be primary – an intrinsic alteration of the hematopoietic stem cells – or secondary. “And it may actually be a physiologically appropriate response to something, as in anemia,” Dr. Hellstrom said. “In fact, some anemias are primarily treated with testosterone.”

In the presence of exogenous testosterone, the condition may be due to a couple of things, he noted, such as:

• An overall increase in the erythropoietin set point.

• Increased availability of iron in the liver.

• The conversion of testosterone to estradiol, which tends to stimulate the bone marrow.

Erythrocytosis, obviously then, increases blood viscosity – and this is the primary concern for cardiovascular events.

Intramuscular testosterone is the only form that significantly increases hematocrit above normal levels. However, it does so strongly, with up to a 6% change from baseline. The runner-up is testosterone gel, with an average increase of 2.5% over baseline levels.

But despite concerns – which in March prompted the FDA to require on labeling a warning about the risk of cardiovascular events – the relationship has never been thoroughly investigated, Dr. Hellstrom said.

“We only have retrospective data, primarily extrapolating from the nephrology literature. When we look at the renal literature, we see that 10%-20% of kidney transplant patients develop polycythemia – an increase of both red and white cells, with hematocrit values of more than 51% or 52%.”

This has led to a recommendation by the American Society of Nephrology for frequent complete blood cell counts in the year after transplant and annual measurements thereafter.

The highest-quality mortality data for kidney transplant patients come from a 2013 study of 365 patients; the investigators found that those with polycythemia were 2.7 times more likely to die over 4 years. “But this is a true primary polycythemia,” which is often accompanied by procoagulative changes. It is not the secondary condition induced by testosterone, Dr. Hellstrom said.

Older studies suggested a significant link between increased hematocrit and cardiovascular or thrombotic events, especially after surgery. But prospective data from the Atherosclerosis Risk in Communities and Cardiovascular Health Studies have found no increased risk of cardiovascular death by increasing tertiles of either hematocrit or hemoglobin, with respective cut points of 43% and 14.5 g/dL.

In fact, a recent transgenic mouse model with hematopoietic overexpression, reaching an 85% hematocrit, found no evidence of either lung or cardiovascular thromboses. “This seems to be related to a reduction in clot strength and increased osmotic fragility in the presence of increasing hematocrit. It seems to mechanically deter the interaction of platelets and fibrin in the extravascular space and endothelium.”

He referred to an in-press mouse study showing that a short course of high-dose testosterone did raise whole blood viscosity and hematocrit. “But over time, this returned to normal, even with supraphysiolgic testosterone levels, so it seems likely that there is an adaptive mechanism that occurs in these animals.”

Additionally, he said, men who live at high altitudes develop naturally high hematocrits as a response to decreased oxygen in the atmosphere. “We routinely see men from these locations with hematocrits of 57% and 59% who have no problems at all.”

Extrapolating all these data to the testosterone/thrombosis link is confusing. The most recent study, however, provided some measure of reassurance. The large meta-analysis comprised 75 randomized, placebo-controlled trials involving about 5,500 men; they all examined cardiovascular risk and testosterone therapy.

“Our analyses, performed on the largest number of studies collected so far, indicate that testosterone supplementation is not related to any increase in cardiovascular risk, even when composite or single adverse events were considered,” wrote Dr. Giovanni Corona of the Maggiore-Bellaria Hospital, Bologna, Italy. “In randomized trials performed in subjects with metabolic derangements, a protective effect … was observed. … Our results are in agreement with a large body of literature from the last 20 years supporting testosterone supplementation of hypogonadal men as a valuable strategy in improving a patient’s metabolic profile, reducing body fat, and increasing lean muscle mass, which would ultimately reduce the risk of heart disease

“There is a definite need for large multicenter, randomized trials to determine the true risk,” Dr. Hellstrom said. However, in light of the current evidence, he recommends what he called a “conservative” approach to testosterone prescribing:

• Before prescribing, get a baseline complete blood count.

• If the baseline hematocrit is more than 47%, consider alternative treatments, but proceed if testosterone replacement therapy seems to be the best clinical option. Repeat testing at 3 and 12 months after therapy initiation and then annually.

• If hematocrit increases above 54%, discontinue treatment until there is a further clinical assessment, as detailed by the Endocrine Society.

• Closely monitor any new diagnoses of hypertension.

• If hematocrit does rise precipitously, phlebotomy rapidly resolved the problem.

Dr Hellstrom made the following financial disclosures: consultant, advisor, or leadership position for Abbvie, Allergan, American Medical Systems, Antares, Astellas, Auxilim, Allergan, Coloplast, Endo, Lilly, New England Research Institutes Inc. Pfizer, Promescent, Reros Therapeutics, and Theralogix.

msullivan@frontlinemedcom.com

NEW ORLEANS – Evidence seems to be mounting that the link between testosterone replacement therapy and increased hematocrit doesn’t lead to more cardiac or thrombotic events in men.

The association between testosterone and secondary erythrocytosis has been known for some time, Dr. Wayne J. G. Hellstrom said at the annual meeting of the American Urological Association. An increase in hematocrit almost invariably follows testosterone supplementation. “The question is, is there a causal relation between testosterone replacement therapy–induced erythrocytosis and venous thromboembolism or major cardiac events?” said Dr. Hellstrom of Tulane Medical Center, New Orleans. “The available evidence doesn’t support this claim.”

Erythrocytosis is defined as a packed red blood cell volume exceeding 125% of the age-predicted mass. This may be primary – an intrinsic alteration of the hematopoietic stem cells – or secondary. “And it may actually be a physiologically appropriate response to something, as in anemia,” Dr. Hellstrom said. “In fact, some anemias are primarily treated with testosterone.”

In the presence of exogenous testosterone, the condition may be due to a couple of things, he noted, such as:

• An overall increase in the erythropoietin set point.

• Increased availability of iron in the liver.

• The conversion of testosterone to estradiol, which tends to stimulate the bone marrow.

Erythrocytosis, obviously then, increases blood viscosity – and this is the primary concern for cardiovascular events.

Intramuscular testosterone is the only form that significantly increases hematocrit above normal levels. However, it does so strongly, with up to a 6% change from baseline. The runner-up is testosterone gel, with an average increase of 2.5% over baseline levels.

But despite concerns – which in March prompted the FDA to require on labeling a warning about the risk of cardiovascular events – the relationship has never been thoroughly investigated, Dr. Hellstrom said.

“We only have retrospective data, primarily extrapolating from the nephrology literature. When we look at the renal literature, we see that 10%-20% of kidney transplant patients develop polycythemia – an increase of both red and white cells, with hematocrit values of more than 51% or 52%.”

This has led to a recommendation by the American Society of Nephrology for frequent complete blood cell counts in the year after transplant and annual measurements thereafter.

The highest-quality mortality data for kidney transplant patients come from a 2013 study of 365 patients; the investigators found that those with polycythemia were 2.7 times more likely to die over 4 years. “But this is a true primary polycythemia,” which is often accompanied by procoagulative changes. It is not the secondary condition induced by testosterone, Dr. Hellstrom said.

Older studies suggested a significant link between increased hematocrit and cardiovascular or thrombotic events, especially after surgery. But prospective data from the Atherosclerosis Risk in Communities and Cardiovascular Health Studies have found no increased risk of cardiovascular death by increasing tertiles of either hematocrit or hemoglobin, with respective cut points of 43% and 14.5 g/dL.

In fact, a recent transgenic mouse model with hematopoietic overexpression, reaching an 85% hematocrit, found no evidence of either lung or cardiovascular thromboses. “This seems to be related to a reduction in clot strength and increased osmotic fragility in the presence of increasing hematocrit. It seems to mechanically deter the interaction of platelets and fibrin in the extravascular space and endothelium.”

He referred to an in-press mouse study showing that a short course of high-dose testosterone did raise whole blood viscosity and hematocrit. “But over time, this returned to normal, even with supraphysiolgic testosterone levels, so it seems likely that there is an adaptive mechanism that occurs in these animals.”

Additionally, he said, men who live at high altitudes develop naturally high hematocrits as a response to decreased oxygen in the atmosphere. “We routinely see men from these locations with hematocrits of 57% and 59% who have no problems at all.”

Extrapolating all these data to the testosterone/thrombosis link is confusing. The most recent study, however, provided some measure of reassurance. The large meta-analysis comprised 75 randomized, placebo-controlled trials involving about 5,500 men; they all examined cardiovascular risk and testosterone therapy.

“Our analyses, performed on the largest number of studies collected so far, indicate that testosterone supplementation is not related to any increase in cardiovascular risk, even when composite or single adverse events were considered,” wrote Dr. Giovanni Corona of the Maggiore-Bellaria Hospital, Bologna, Italy. “In randomized trials performed in subjects with metabolic derangements, a protective effect … was observed. … Our results are in agreement with a large body of literature from the last 20 years supporting testosterone supplementation of hypogonadal men as a valuable strategy in improving a patient’s metabolic profile, reducing body fat, and increasing lean muscle mass, which would ultimately reduce the risk of heart disease

“There is a definite need for large multicenter, randomized trials to determine the true risk,” Dr. Hellstrom said. However, in light of the current evidence, he recommends what he called a “conservative” approach to testosterone prescribing:

• Before prescribing, get a baseline complete blood count.

• If the baseline hematocrit is more than 47%, consider alternative treatments, but proceed if testosterone replacement therapy seems to be the best clinical option. Repeat testing at 3 and 12 months after therapy initiation and then annually.

• If hematocrit increases above 54%, discontinue treatment until there is a further clinical assessment, as detailed by the Endocrine Society.

• Closely monitor any new diagnoses of hypertension.

• If hematocrit does rise precipitously, phlebotomy rapidly resolved the problem.

Dr Hellstrom made the following financial disclosures: consultant, advisor, or leadership position for Abbvie, Allergan, American Medical Systems, Antares, Astellas, Auxilim, Allergan, Coloplast, Endo, Lilly, New England Research Institutes Inc. Pfizer, Promescent, Reros Therapeutics, and Theralogix.

msullivan@frontlinemedcom.com

NEW ORLEANS – Evidence seems to be mounting that the link between testosterone replacement therapy and increased hematocrit doesn’t lead to more cardiac or thrombotic events in men.

The association between testosterone and secondary erythrocytosis has been known for some time, Dr. Wayne J. G. Hellstrom said at the annual meeting of the American Urological Association. An increase in hematocrit almost invariably follows testosterone supplementation. “The question is, is there a causal relation between testosterone replacement therapy–induced erythrocytosis and venous thromboembolism or major cardiac events?” said Dr. Hellstrom of Tulane Medical Center, New Orleans. “The available evidence doesn’t support this claim.”

Erythrocytosis is defined as a packed red blood cell volume exceeding 125% of the age-predicted mass. This may be primary – an intrinsic alteration of the hematopoietic stem cells – or secondary. “And it may actually be a physiologically appropriate response to something, as in anemia,” Dr. Hellstrom said. “In fact, some anemias are primarily treated with testosterone.”

In the presence of exogenous testosterone, the condition may be due to a couple of things, he noted, such as:

• An overall increase in the erythropoietin set point.

• Increased availability of iron in the liver.

• The conversion of testosterone to estradiol, which tends to stimulate the bone marrow.

Erythrocytosis, obviously then, increases blood viscosity – and this is the primary concern for cardiovascular events.

Intramuscular testosterone is the only form that significantly increases hematocrit above normal levels. However, it does so strongly, with up to a 6% change from baseline. The runner-up is testosterone gel, with an average increase of 2.5% over baseline levels.

But despite concerns – which in March prompted the FDA to require on labeling a warning about the risk of cardiovascular events – the relationship has never been thoroughly investigated, Dr. Hellstrom said.

“We only have retrospective data, primarily extrapolating from the nephrology literature. When we look at the renal literature, we see that 10%-20% of kidney transplant patients develop polycythemia – an increase of both red and white cells, with hematocrit values of more than 51% or 52%.”

This has led to a recommendation by the American Society of Nephrology for frequent complete blood cell counts in the year after transplant and annual measurements thereafter.

The highest-quality mortality data for kidney transplant patients come from a 2013 study of 365 patients; the investigators found that those with polycythemia were 2.7 times more likely to die over 4 years. “But this is a true primary polycythemia,” which is often accompanied by procoagulative changes. It is not the secondary condition induced by testosterone, Dr. Hellstrom said.

Older studies suggested a significant link between increased hematocrit and cardiovascular or thrombotic events, especially after surgery. But prospective data from the Atherosclerosis Risk in Communities and Cardiovascular Health Studies have found no increased risk of cardiovascular death by increasing tertiles of either hematocrit or hemoglobin, with respective cut points of 43% and 14.5 g/dL.

In fact, a recent transgenic mouse model with hematopoietic overexpression, reaching an 85% hematocrit, found no evidence of either lung or cardiovascular thromboses. “This seems to be related to a reduction in clot strength and increased osmotic fragility in the presence of increasing hematocrit. It seems to mechanically deter the interaction of platelets and fibrin in the extravascular space and endothelium.”

He referred to an in-press mouse study showing that a short course of high-dose testosterone did raise whole blood viscosity and hematocrit. “But over time, this returned to normal, even with supraphysiolgic testosterone levels, so it seems likely that there is an adaptive mechanism that occurs in these animals.”

Additionally, he said, men who live at high altitudes develop naturally high hematocrits as a response to decreased oxygen in the atmosphere. “We routinely see men from these locations with hematocrits of 57% and 59% who have no problems at all.”

Extrapolating all these data to the testosterone/thrombosis link is confusing. The most recent study, however, provided some measure of reassurance. The large meta-analysis comprised 75 randomized, placebo-controlled trials involving about 5,500 men; they all examined cardiovascular risk and testosterone therapy.

“Our analyses, performed on the largest number of studies collected so far, indicate that testosterone supplementation is not related to any increase in cardiovascular risk, even when composite or single adverse events were considered,” wrote Dr. Giovanni Corona of the Maggiore-Bellaria Hospital, Bologna, Italy. “In randomized trials performed in subjects with metabolic derangements, a protective effect … was observed. … Our results are in agreement with a large body of literature from the last 20 years supporting testosterone supplementation of hypogonadal men as a valuable strategy in improving a patient’s metabolic profile, reducing body fat, and increasing lean muscle mass, which would ultimately reduce the risk of heart disease

“There is a definite need for large multicenter, randomized trials to determine the true risk,” Dr. Hellstrom said. However, in light of the current evidence, he recommends what he called a “conservative” approach to testosterone prescribing:

• Before prescribing, get a baseline complete blood count.

• If the baseline hematocrit is more than 47%, consider alternative treatments, but proceed if testosterone replacement therapy seems to be the best clinical option. Repeat testing at 3 and 12 months after therapy initiation and then annually.

• If hematocrit increases above 54%, discontinue treatment until there is a further clinical assessment, as detailed by the Endocrine Society.

• Closely monitor any new diagnoses of hypertension.

• If hematocrit does rise precipitously, phlebotomy rapidly resolved the problem.

Dr Hellstrom made the following financial disclosures: consultant, advisor, or leadership position for Abbvie, Allergan, American Medical Systems, Antares, Astellas, Auxilim, Allergan, Coloplast, Endo, Lilly, New England Research Institutes Inc. Pfizer, Promescent, Reros Therapeutics, and Theralogix.

msullivan@frontlinemedcom.com

Doctor and patient

Photo courtesy of NIH

In trying to estimate the global cancer burden, researchers found that cases of Hodgkin lymphoma (HL) have decreased worldwide over the last 2 decades.

The team studied 28 cancer types in 188 countries, and HL was the only malignancy whose incidence decreased from 1990 to 2013.

And the number of HL deaths in 2013 was comparatively low. When the researchers ranked cancers according to the number of global deaths, HL was 26th on the list of 28.

The researchers disclosed these results in JAMA Oncology.

The team collected data from cancer registries, vital records, verbal autopsy reports, and other sources to estimate the global cancer burden.

The data suggested that, in 2013, there were 14.9 million new cancer cases and 8.2 million cancer deaths worldwide. The proportion of cancer deaths as part of all deaths increased from 12% in 1990 to 15% in 2013.

The most common malignancy in men was prostate cancer, with 1.4 million cases in 2013. For women, it was breast cancer, with 1.8 million cases in 2013.

Tracheal, bronchus, and lung cancers were the leading cause of cancer death in men and women, with 1.6 million deaths in 2013.

Hematologic malignancies

Globally, the age-standardized incidence of HL per 100,000 people decreased by 34% during the time period studied. Cases of HL fell from about 103,000 in 1990 to 93,000 in 2013.

When the researchers ranked cancer types according to the number of global deaths in 2013, HL came in 26th. There were about 24,000 HL deaths in 2013—14,000 among men and 10,000 among women.

Non-Hodgkin lymphoma (NHL) came in 11th for global cancer deaths in 2013. There were about 226,000 NHL deaths—133,000 among men and 92,000 among women.

In addition, the incidence of NHL more than doubled from 1990 to 2013, rising from about 227,000 to 465,000. According to 2013 data, 1 in 103 men and 1 in 151 women developed NHL between birth and 79 years of age.

The researchers observed an increase in cases of multiple myeloma (MM) as well, from about 63,000 in 1990 to 117,000 in 2013.

In 2013, there were about 79,000 MM deaths—42,000 among men and 37,000 among women. MM ranked 19th on the list of global cancer deaths in 2013.

Leukemia ranked 9th on the list. There were about 265,000 leukemia deaths in 2013—149,000 among men and 116,000 among women.

Cases of leukemia increased from 297,000 in 1990 to 414,000 in 2013. According to 2013 data, 1 in 127 men and 1 in 203 women developed leukemia between birth and 79 years of age.

This research shows that cancer remains a major threat to people’s health around the world, said study author Christina Fitzmaurice, MD, of the University of Washington in Seattle.

“Cancer prevention, screening, and treatment programs are costly,” she noted, “and it is very important for countries to know which cancers cause the highest disease burden in order to allocate scarce resources appropriately.”

Doctor and patient

Photo courtesy of NIH

In trying to estimate the global cancer burden, researchers found that cases of Hodgkin lymphoma (HL) have decreased worldwide over the last 2 decades.

The team studied 28 cancer types in 188 countries, and HL was the only malignancy whose incidence decreased from 1990 to 2013.

And the number of HL deaths in 2013 was comparatively low. When the researchers ranked cancers according to the number of global deaths, HL was 26th on the list of 28.

The researchers disclosed these results in JAMA Oncology.

The team collected data from cancer registries, vital records, verbal autopsy reports, and other sources to estimate the global cancer burden.

The data suggested that, in 2013, there were 14.9 million new cancer cases and 8.2 million cancer deaths worldwide. The proportion of cancer deaths as part of all deaths increased from 12% in 1990 to 15% in 2013.

The most common malignancy in men was prostate cancer, with 1.4 million cases in 2013. For women, it was breast cancer, with 1.8 million cases in 2013.

Tracheal, bronchus, and lung cancers were the leading cause of cancer death in men and women, with 1.6 million deaths in 2013.

Hematologic malignancies

Globally, the age-standardized incidence of HL per 100,000 people decreased by 34% during the time period studied. Cases of HL fell from about 103,000 in 1990 to 93,000 in 2013.

When the researchers ranked cancer types according to the number of global deaths in 2013, HL came in 26th. There were about 24,000 HL deaths in 2013—14,000 among men and 10,000 among women.

Non-Hodgkin lymphoma (NHL) came in 11th for global cancer deaths in 2013. There were about 226,000 NHL deaths—133,000 among men and 92,000 among women.

In addition, the incidence of NHL more than doubled from 1990 to 2013, rising from about 227,000 to 465,000. According to 2013 data, 1 in 103 men and 1 in 151 women developed NHL between birth and 79 years of age.

The researchers observed an increase in cases of multiple myeloma (MM) as well, from about 63,000 in 1990 to 117,000 in 2013.

In 2013, there were about 79,000 MM deaths—42,000 among men and 37,000 among women. MM ranked 19th on the list of global cancer deaths in 2013.

Leukemia ranked 9th on the list. There were about 265,000 leukemia deaths in 2013—149,000 among men and 116,000 among women.

Cases of leukemia increased from 297,000 in 1990 to 414,000 in 2013. According to 2013 data, 1 in 127 men and 1 in 203 women developed leukemia between birth and 79 years of age.

This research shows that cancer remains a major threat to people’s health around the world, said study author Christina Fitzmaurice, MD, of the University of Washington in Seattle.

“Cancer prevention, screening, and treatment programs are costly,” she noted, “and it is very important for countries to know which cancers cause the highest disease burden in order to allocate scarce resources appropriately.”

Doctor and patient

Photo courtesy of NIH

In trying to estimate the global cancer burden, researchers found that cases of Hodgkin lymphoma (HL) have decreased worldwide over the last 2 decades.

The team studied 28 cancer types in 188 countries, and HL was the only malignancy whose incidence decreased from 1990 to 2013.

And the number of HL deaths in 2013 was comparatively low. When the researchers ranked cancers according to the number of global deaths, HL was 26th on the list of 28.

The researchers disclosed these results in JAMA Oncology.

The team collected data from cancer registries, vital records, verbal autopsy reports, and other sources to estimate the global cancer burden.

The data suggested that, in 2013, there were 14.9 million new cancer cases and 8.2 million cancer deaths worldwide. The proportion of cancer deaths as part of all deaths increased from 12% in 1990 to 15% in 2013.

The most common malignancy in men was prostate cancer, with 1.4 million cases in 2013. For women, it was breast cancer, with 1.8 million cases in 2013.

Tracheal, bronchus, and lung cancers were the leading cause of cancer death in men and women, with 1.6 million deaths in 2013.

Hematologic malignancies

Globally, the age-standardized incidence of HL per 100,000 people decreased by 34% during the time period studied. Cases of HL fell from about 103,000 in 1990 to 93,000 in 2013.

When the researchers ranked cancer types according to the number of global deaths in 2013, HL came in 26th. There were about 24,000 HL deaths in 2013—14,000 among men and 10,000 among women.

Non-Hodgkin lymphoma (NHL) came in 11th for global cancer deaths in 2013. There were about 226,000 NHL deaths—133,000 among men and 92,000 among women.

In addition, the incidence of NHL more than doubled from 1990 to 2013, rising from about 227,000 to 465,000. According to 2013 data, 1 in 103 men and 1 in 151 women developed NHL between birth and 79 years of age.

The researchers observed an increase in cases of multiple myeloma (MM) as well, from about 63,000 in 1990 to 117,000 in 2013.

In 2013, there were about 79,000 MM deaths—42,000 among men and 37,000 among women. MM ranked 19th on the list of global cancer deaths in 2013.

Leukemia ranked 9th on the list. There were about 265,000 leukemia deaths in 2013—149,000 among men and 116,000 among women.

Cases of leukemia increased from 297,000 in 1990 to 414,000 in 2013. According to 2013 data, 1 in 127 men and 1 in 203 women developed leukemia between birth and 79 years of age.

This research shows that cancer remains a major threat to people’s health around the world, said study author Christina Fitzmaurice, MD, of the University of Washington in Seattle.

“Cancer prevention, screening, and treatment programs are costly,” she noted, “and it is very important for countries to know which cancers cause the highest disease burden in order to allocate scarce resources appropriately.”

Cynomolgus monkey

Photo by Sakurai Midori

An artificial antibody that redirects T cells to target cancer cells shows promise for treating acute myeloid leukemia (AML), according to preclinical research.

The antibody, MGD006, induced tumor regression in mouse models of AML and was largely well-tolerated in cynomolgus monkeys.

Investigators say these results support clinical testing of MGD006 in AML, which is currently underway.

MGD006 is a humanized, dual-affinity re-targeting (DART) molecule that combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123.

MGD006 redirects T cells to kill cells expressing CD123, which is upregulated in AML and other hematologic diseases.

Gurunadh Chichili, PhD, of MacroGenics, Inc., in Rockville, Maryland, and his colleagues described their work with MGD006 in Science Translational Medicine. MacroGenics, the company developing MGD006, funded this research.

Because MGD006 is designed to be cleared rapidly, it requires continuous delivery. So in mice, the investigators administered the molecule continuously for up to a week via peritoneally implanted osmotic pumps.

The NSG/b2m^−/− mice had been reconstituted with human peripheral blood mononuclear cells and grafted with KG-1a cells, an AML-M0 line. The mice received MGD006 after tumors were allowed to grow to an average size of about 100 mm³.

Treated mice experienced significant tumor regression at all doses of MGD006 (P<0.005), but there was no activity in mice treated with a control DART molecule. The investigators found that 500 ng/kg of MGD006 per day was sufficient to completely eliminate leukemic cells.

The team also tested MGD006 in macaques and found the molecule binds to human and cynomolgus monkey antigens with similar affinities and redirects T cells from either species to kill CD123-expressing target cells.

The monkeys received continuous infusions of MGD006, starting at 0.1 mg/kg per day and escalating weekly to up to 1 mg/kg per day for a 4-week period. The treatment depleted circulating CD123-positive cells beginning at 72 hours and continuing throughout the infusion period.

The monkeys experienced cytokine release, but it was transient and most significant after the first dose of MDG006. After the first dose, IL-6 concentration returned to baseline by 72 hours, and the magnitude of IL-6 response decreased with each successive MGD006 infusion, even when the dose was increased.

The animals experienced reversible reductions in hematocrit and red cell mass at the highest doses of MDG006 but no neutropenia or thrombocytopenia.

“This research paved the way for our initiation of a phase 1 clinical study of MGD006 in 2014,” said Scott Koenig, MD, PhD, President and CEO of MacroGenics.

“MGD006 has demonstrated great promise as a T-cell-redirected cancer immunotherapy in preclinical studies. We are hopeful that these studies will translate into clinical trial results indicative of clinical improvement for patients with AML, myelodysplastic syndrome, and several other forms of leukemia and lymphoma.”

Cynomolgus monkey

Photo by Sakurai Midori

An artificial antibody that redirects T cells to target cancer cells shows promise for treating acute myeloid leukemia (AML), according to preclinical research.

The antibody, MGD006, induced tumor regression in mouse models of AML and was largely well-tolerated in cynomolgus monkeys.

Investigators say these results support clinical testing of MGD006 in AML, which is currently underway.

MGD006 is a humanized, dual-affinity re-targeting (DART) molecule that combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123.

MGD006 redirects T cells to kill cells expressing CD123, which is upregulated in AML and other hematologic diseases.

Gurunadh Chichili, PhD, of MacroGenics, Inc., in Rockville, Maryland, and his colleagues described their work with MGD006 in Science Translational Medicine. MacroGenics, the company developing MGD006, funded this research.

Because MGD006 is designed to be cleared rapidly, it requires continuous delivery. So in mice, the investigators administered the molecule continuously for up to a week via peritoneally implanted osmotic pumps.

The NSG/b2m^−/− mice had been reconstituted with human peripheral blood mononuclear cells and grafted with KG-1a cells, an AML-M0 line. The mice received MGD006 after tumors were allowed to grow to an average size of about 100 mm³.

Treated mice experienced significant tumor regression at all doses of MGD006 (P<0.005), but there was no activity in mice treated with a control DART molecule. The investigators found that 500 ng/kg of MGD006 per day was sufficient to completely eliminate leukemic cells.

The team also tested MGD006 in macaques and found the molecule binds to human and cynomolgus monkey antigens with similar affinities and redirects T cells from either species to kill CD123-expressing target cells.

The monkeys received continuous infusions of MGD006, starting at 0.1 mg/kg per day and escalating weekly to up to 1 mg/kg per day for a 4-week period. The treatment depleted circulating CD123-positive cells beginning at 72 hours and continuing throughout the infusion period.

The monkeys experienced cytokine release, but it was transient and most significant after the first dose of MDG006. After the first dose, IL-6 concentration returned to baseline by 72 hours, and the magnitude of IL-6 response decreased with each successive MGD006 infusion, even when the dose was increased.

The animals experienced reversible reductions in hematocrit and red cell mass at the highest doses of MDG006 but no neutropenia or thrombocytopenia.

“This research paved the way for our initiation of a phase 1 clinical study of MGD006 in 2014,” said Scott Koenig, MD, PhD, President and CEO of MacroGenics.

“MGD006 has demonstrated great promise as a T-cell-redirected cancer immunotherapy in preclinical studies. We are hopeful that these studies will translate into clinical trial results indicative of clinical improvement for patients with AML, myelodysplastic syndrome, and several other forms of leukemia and lymphoma.”

Cynomolgus monkey

Photo by Sakurai Midori

An artificial antibody that redirects T cells to target cancer cells shows promise for treating acute myeloid leukemia (AML), according to preclinical research.

The antibody, MGD006, induced tumor regression in mouse models of AML and was largely well-tolerated in cynomolgus monkeys.

Investigators say these results support clinical testing of MGD006 in AML, which is currently underway.

MGD006 is a humanized, dual-affinity re-targeting (DART) molecule that combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123.

MGD006 redirects T cells to kill cells expressing CD123, which is upregulated in AML and other hematologic diseases.

Gurunadh Chichili, PhD, of MacroGenics, Inc., in Rockville, Maryland, and his colleagues described their work with MGD006 in Science Translational Medicine. MacroGenics, the company developing MGD006, funded this research.

Because MGD006 is designed to be cleared rapidly, it requires continuous delivery. So in mice, the investigators administered the molecule continuously for up to a week via peritoneally implanted osmotic pumps.

The NSG/b2m^−/− mice had been reconstituted with human peripheral blood mononuclear cells and grafted with KG-1a cells, an AML-M0 line. The mice received MGD006 after tumors were allowed to grow to an average size of about 100 mm³.

Treated mice experienced significant tumor regression at all doses of MGD006 (P<0.005), but there was no activity in mice treated with a control DART molecule. The investigators found that 500 ng/kg of MGD006 per day was sufficient to completely eliminate leukemic cells.

The team also tested MGD006 in macaques and found the molecule binds to human and cynomolgus monkey antigens with similar affinities and redirects T cells from either species to kill CD123-expressing target cells.

The monkeys received continuous infusions of MGD006, starting at 0.1 mg/kg per day and escalating weekly to up to 1 mg/kg per day for a 4-week period. The treatment depleted circulating CD123-positive cells beginning at 72 hours and continuing throughout the infusion period.

The monkeys experienced cytokine release, but it was transient and most significant after the first dose of MDG006. After the first dose, IL-6 concentration returned to baseline by 72 hours, and the magnitude of IL-6 response decreased with each successive MGD006 infusion, even when the dose was increased.

The animals experienced reversible reductions in hematocrit and red cell mass at the highest doses of MDG006 but no neutropenia or thrombocytopenia.

“This research paved the way for our initiation of a phase 1 clinical study of MGD006 in 2014,” said Scott Koenig, MD, PhD, President and CEO of MacroGenics.

“MGD006 has demonstrated great promise as a T-cell-redirected cancer immunotherapy in preclinical studies. We are hopeful that these studies will translate into clinical trial results indicative of clinical improvement for patients with AML, myelodysplastic syndrome, and several other forms of leukemia and lymphoma.”

Blood sample collection

Photo by Juan D. Alfonso

A new approach to urine testing could make the tests more versatile and therefore decrease the need for blood tests, according to researchers.

They believe the method could also reduce costs, produce results faster than current tests, and lower the volume of urine needed for a sample.

R. Kenneth Marcus, PhD, of Clemson University in South Carolina, and his colleagues described this method in Proteomics-Clinical Applications.

Dr Marcus noted that the trouble with testing urine is that it’s awash in salt, so it can be tricky to isolate the proteins that act as biomarkers.

To overcome this problem, he and his colleagues used a string made of capillary-channeled polymer fibers. The team packed the fibers into plastic tubes and then passed urine samples through the tubes by spinning them in a centrifuge for 30 seconds.

Then, the researchers ran de-ionized water through the tubes for a minute to wash off salt and other contaminants.

As proteins are hydrophobic, they remained stuck to the fibers. The team extracted the proteins by running a solvent through the tubes in the centrifuge for 30 seconds.

When this process was complete, the researchers were left with purified proteins that could be stored in a plastic vial and refrigerated until testing time.

The team was able to extract 12 samples in about 5 minutes, limited only by centrifuge capacity.

In addition to being faster and cheaper than current urine tests, the new testing method should also make it easier to test urine samples from infants, Dr Marcus said.

One of the challenges now is getting a large enough sample, but the new method requires only a few microliters of urine.

Blood sample collection

Photo by Juan D. Alfonso

A new approach to urine testing could make the tests more versatile and therefore decrease the need for blood tests, according to researchers.

They believe the method could also reduce costs, produce results faster than current tests, and lower the volume of urine needed for a sample.

R. Kenneth Marcus, PhD, of Clemson University in South Carolina, and his colleagues described this method in Proteomics-Clinical Applications.

Dr Marcus noted that the trouble with testing urine is that it’s awash in salt, so it can be tricky to isolate the proteins that act as biomarkers.

To overcome this problem, he and his colleagues used a string made of capillary-channeled polymer fibers. The team packed the fibers into plastic tubes and then passed urine samples through the tubes by spinning them in a centrifuge for 30 seconds.

Then, the researchers ran de-ionized water through the tubes for a minute to wash off salt and other contaminants.

As proteins are hydrophobic, they remained stuck to the fibers. The team extracted the proteins by running a solvent through the tubes in the centrifuge for 30 seconds.

When this process was complete, the researchers were left with purified proteins that could be stored in a plastic vial and refrigerated until testing time.

The team was able to extract 12 samples in about 5 minutes, limited only by centrifuge capacity.

In addition to being faster and cheaper than current urine tests, the new testing method should also make it easier to test urine samples from infants, Dr Marcus said.

One of the challenges now is getting a large enough sample, but the new method requires only a few microliters of urine.

Blood sample collection

Photo by Juan D. Alfonso

A new approach to urine testing could make the tests more versatile and therefore decrease the need for blood tests, according to researchers.

They believe the method could also reduce costs, produce results faster than current tests, and lower the volume of urine needed for a sample.

R. Kenneth Marcus, PhD, of Clemson University in South Carolina, and his colleagues described this method in Proteomics-Clinical Applications.

Dr Marcus noted that the trouble with testing urine is that it’s awash in salt, so it can be tricky to isolate the proteins that act as biomarkers.

To overcome this problem, he and his colleagues used a string made of capillary-channeled polymer fibers. The team packed the fibers into plastic tubes and then passed urine samples through the tubes by spinning them in a centrifuge for 30 seconds.

Then, the researchers ran de-ionized water through the tubes for a minute to wash off salt and other contaminants.

As proteins are hydrophobic, they remained stuck to the fibers. The team extracted the proteins by running a solvent through the tubes in the centrifuge for 30 seconds.

When this process was complete, the researchers were left with purified proteins that could be stored in a plastic vial and refrigerated until testing time.

The team was able to extract 12 samples in about 5 minutes, limited only by centrifuge capacity.

In addition to being faster and cheaper than current urine tests, the new testing method should also make it easier to test urine samples from infants, Dr Marcus said.

One of the challenges now is getting a large enough sample, but the new method requires only a few microliters of urine.

Drawing of a taste bud

Image by Jonas Töle

Investigators have identified a molecular pathway that aids the renewal of taste buds, and they believe this discovery may have implications for cancer patients who suffer from an altered sense of taste during treatment.

“Taste dysfunction can . . . result from an alteration of the renewal capacities of taste buds and is often associated with psychological distress and malnutrition,” said Dany Gaillard, PhD, of the University of Colorado Anschutz Medical Campus in Aurora.

He and his colleagues decided to investigate this dysfunction using mouse models, and the group reported their findings in PLOS Genetics.

The investigators discovered that a protein in the Wnt pathway, ß-catenin, controls the renewal of taste cells by regulating separate stages of taste-cell turnover.

Previous research showed that Wnt/β-catenin signaling is crucial in developing taste buds in embryos and regulating the renewal of epithelial tissue in adults, including skin, hair follicles, the intestine, and the mouth.

“We show that activating this pathway directs the newly born cells to become, primarily, a specific taste- cell type whose role is to support the other taste cells and help them work efficiently,” said Linda Barlow, PhD, also of the University of Colorado Anschutz Medical Campus.

As chemotherapy destroys dividing precursor cells, including those that produce taste cells, the investigators believe that activating Wnt signaling may be a way to renew taste buds after chemotherapy.

New small-molecule drugs that specifically block the Wnt pathway are under development, and Drs Gaillard and Barlow predict these drugs could also cause taste dysfunction.

Dr Barlow said more research is needed to understand how taste is altered at the cellular level, but this research holds promise for developing new ways to improve cancer patients’ quality of life.

Drawing of a taste bud

Image by Jonas Töle

Investigators have identified a molecular pathway that aids the renewal of taste buds, and they believe this discovery may have implications for cancer patients who suffer from an altered sense of taste during treatment.

“Taste dysfunction can . . . result from an alteration of the renewal capacities of taste buds and is often associated with psychological distress and malnutrition,” said Dany Gaillard, PhD, of the University of Colorado Anschutz Medical Campus in Aurora.

He and his colleagues decided to investigate this dysfunction using mouse models, and the group reported their findings in PLOS Genetics.

The investigators discovered that a protein in the Wnt pathway, ß-catenin, controls the renewal of taste cells by regulating separate stages of taste-cell turnover.

Previous research showed that Wnt/β-catenin signaling is crucial in developing taste buds in embryos and regulating the renewal of epithelial tissue in adults, including skin, hair follicles, the intestine, and the mouth.

“We show that activating this pathway directs the newly born cells to become, primarily, a specific taste- cell type whose role is to support the other taste cells and help them work efficiently,” said Linda Barlow, PhD, also of the University of Colorado Anschutz Medical Campus.

As chemotherapy destroys dividing precursor cells, including those that produce taste cells, the investigators believe that activating Wnt signaling may be a way to renew taste buds after chemotherapy.

New small-molecule drugs that specifically block the Wnt pathway are under development, and Drs Gaillard and Barlow predict these drugs could also cause taste dysfunction.

Dr Barlow said more research is needed to understand how taste is altered at the cellular level, but this research holds promise for developing new ways to improve cancer patients’ quality of life.

Drawing of a taste bud

Image by Jonas Töle

Investigators have identified a molecular pathway that aids the renewal of taste buds, and they believe this discovery may have implications for cancer patients who suffer from an altered sense of taste during treatment.

“Taste dysfunction can . . . result from an alteration of the renewal capacities of taste buds and is often associated with psychological distress and malnutrition,” said Dany Gaillard, PhD, of the University of Colorado Anschutz Medical Campus in Aurora.

He and his colleagues decided to investigate this dysfunction using mouse models, and the group reported their findings in PLOS Genetics.

The investigators discovered that a protein in the Wnt pathway, ß-catenin, controls the renewal of taste cells by regulating separate stages of taste-cell turnover.

Previous research showed that Wnt/β-catenin signaling is crucial in developing taste buds in embryos and regulating the renewal of epithelial tissue in adults, including skin, hair follicles, the intestine, and the mouth.

“We show that activating this pathway directs the newly born cells to become, primarily, a specific taste- cell type whose role is to support the other taste cells and help them work efficiently,” said Linda Barlow, PhD, also of the University of Colorado Anschutz Medical Campus.

As chemotherapy destroys dividing precursor cells, including those that produce taste cells, the investigators believe that activating Wnt signaling may be a way to renew taste buds after chemotherapy.

New small-molecule drugs that specifically block the Wnt pathway are under development, and Drs Gaillard and Barlow predict these drugs could also cause taste dysfunction.

Dr Barlow said more research is needed to understand how taste is altered at the cellular level, but this research holds promise for developing new ways to improve cancer patients’ quality of life.