Kerri Wachter

“The first thing you think of when a patient [like this one] walks into your office is medial meniscal tear just because meniscal lesions are so common in a patient in this age group,” said Dr. Hollis G. Potter, chief of magnetic resonance imaging at the Hospital for Special Surgery in New York. “You might also suspect that she might have some early medial osteoarthritis.”

“There wasn't anything glaring in her presentation that directed them to think that she had an inflammatory arthropathy,” said Dr. Potter.

Upon magnetic resonance imaging (MRI), the patient was found to have severe synovial expansion with an inflammatory synovitis. “It was pretty clear that even if her meniscus had been torn—which it wasn't—that wouldn't be the cause of her pain. The cause was really the fact that she had an inflammatory synovitis,” said Dr. Potter.

The synovial proliferation extended into the medial and lateral gutters (see arrows in first image). The patient also had early marginal bony erosion (see arrow in second image) affecting the medial tibial plateau. Together, the synovial proliferation and bony erosion indicated rheumatoid arthritis (RA).

The images were obtained using a cartilage-sensitive sequence used for evaluating articular cartilage.

“We do this for all patients routinely,” said Dr. Potter. The technique allows physicians to noninvasively evaluate the morphologic integrity of the cartilage. “When we find articular lesions, I find it drives patient management more than anything else.”

“It's always been my sense that the purpose of MRI is to find what physicians are not clinically suspecting,” said Dr. Potter, who is also a professor of radiology at Cornell University, New York.

“I find that if the MRI doesn't in fact change the management or affect the management in some way, it's a very expensive test that really hasn't helped anybody at all,” Dr. Potter told RHEUMATOLOGY NEWS in an interview.

Based on the imaging findings, the patient underwent serologic testing and was placed on appropriate clinical management. This patient was identified with RA early in the disease progression when disease-modifying antirheumatic drugs can make a big difference in slowing disease progression.

Dr. Potter and her colleagues have found another use for MRI in rheumatology: They are investigating synovial recruitment patterns in patients with early, clinically suspected, inflammatory RA—patients who meet the American College of Rheumatology criteria for inflammatory arthritis. In an ongoing, prospective pilot study, they are using MR angiography with a contrast agent to assess neovascularity in areas of inflammatory synovium. The hope is that work like this will help better define patients who are good candidates for therapy with biologic agents, said Dr. Potter.

Synovial expansion with an inflam-matory synovitis (arrows) suggests RA.

Marginal bony erosion (arrow) suggests RA. There is no evidence of meniscal tear. Photos courtesy Dr. Hollis G. Potter

“The first thing you think of when a patient [like this one] walks into your office is medial meniscal tear just because meniscal lesions are so common in a patient in this age group,” said Dr. Hollis G. Potter, chief of magnetic resonance imaging at the Hospital for Special Surgery in New York. “You might also suspect that she might have some early medial osteoarthritis.”

“There wasn't anything glaring in her presentation that directed them to think that she had an inflammatory arthropathy,” said Dr. Potter.

Upon magnetic resonance imaging (MRI), the patient was found to have severe synovial expansion with an inflammatory synovitis. “It was pretty clear that even if her meniscus had been torn—which it wasn't—that wouldn't be the cause of her pain. The cause was really the fact that she had an inflammatory synovitis,” said Dr. Potter.

The synovial proliferation extended into the medial and lateral gutters (see arrows in first image). The patient also had early marginal bony erosion (see arrow in second image) affecting the medial tibial plateau. Together, the synovial proliferation and bony erosion indicated rheumatoid arthritis (RA).

The images were obtained using a cartilage-sensitive sequence used for evaluating articular cartilage.

“We do this for all patients routinely,” said Dr. Potter. The technique allows physicians to noninvasively evaluate the morphologic integrity of the cartilage. “When we find articular lesions, I find it drives patient management more than anything else.”

“It's always been my sense that the purpose of MRI is to find what physicians are not clinically suspecting,” said Dr. Potter, who is also a professor of radiology at Cornell University, New York.

“I find that if the MRI doesn't in fact change the management or affect the management in some way, it's a very expensive test that really hasn't helped anybody at all,” Dr. Potter told RHEUMATOLOGY NEWS in an interview.

Based on the imaging findings, the patient underwent serologic testing and was placed on appropriate clinical management. This patient was identified with RA early in the disease progression when disease-modifying antirheumatic drugs can make a big difference in slowing disease progression.

Dr. Potter and her colleagues have found another use for MRI in rheumatology: They are investigating synovial recruitment patterns in patients with early, clinically suspected, inflammatory RA—patients who meet the American College of Rheumatology criteria for inflammatory arthritis. In an ongoing, prospective pilot study, they are using MR angiography with a contrast agent to assess neovascularity in areas of inflammatory synovium. The hope is that work like this will help better define patients who are good candidates for therapy with biologic agents, said Dr. Potter.

Synovial expansion with an inflam-matory synovitis (arrows) suggests RA.

Marginal bony erosion (arrow) suggests RA. There is no evidence of meniscal tear. Photos courtesy Dr. Hollis G. Potter

“The first thing you think of when a patient [like this one] walks into your office is medial meniscal tear just because meniscal lesions are so common in a patient in this age group,” said Dr. Hollis G. Potter, chief of magnetic resonance imaging at the Hospital for Special Surgery in New York. “You might also suspect that she might have some early medial osteoarthritis.”

“There wasn't anything glaring in her presentation that directed them to think that she had an inflammatory arthropathy,” said Dr. Potter.

Upon magnetic resonance imaging (MRI), the patient was found to have severe synovial expansion with an inflammatory synovitis. “It was pretty clear that even if her meniscus had been torn—which it wasn't—that wouldn't be the cause of her pain. The cause was really the fact that she had an inflammatory synovitis,” said Dr. Potter.

The synovial proliferation extended into the medial and lateral gutters (see arrows in first image). The patient also had early marginal bony erosion (see arrow in second image) affecting the medial tibial plateau. Together, the synovial proliferation and bony erosion indicated rheumatoid arthritis (RA).

The images were obtained using a cartilage-sensitive sequence used for evaluating articular cartilage.

“We do this for all patients routinely,” said Dr. Potter. The technique allows physicians to noninvasively evaluate the morphologic integrity of the cartilage. “When we find articular lesions, I find it drives patient management more than anything else.”

“It's always been my sense that the purpose of MRI is to find what physicians are not clinically suspecting,” said Dr. Potter, who is also a professor of radiology at Cornell University, New York.

“I find that if the MRI doesn't in fact change the management or affect the management in some way, it's a very expensive test that really hasn't helped anybody at all,” Dr. Potter told RHEUMATOLOGY NEWS in an interview.

Based on the imaging findings, the patient underwent serologic testing and was placed on appropriate clinical management. This patient was identified with RA early in the disease progression when disease-modifying antirheumatic drugs can make a big difference in slowing disease progression.

Dr. Potter and her colleagues have found another use for MRI in rheumatology: They are investigating synovial recruitment patterns in patients with early, clinically suspected, inflammatory RA—patients who meet the American College of Rheumatology criteria for inflammatory arthritis. In an ongoing, prospective pilot study, they are using MR angiography with a contrast agent to assess neovascularity in areas of inflammatory synovium. The hope is that work like this will help better define patients who are good candidates for therapy with biologic agents, said Dr. Potter.

Synovial expansion with an inflam-matory synovitis (arrows) suggests RA.

Marginal bony erosion (arrow) suggests RA. There is no evidence of meniscal tear. Photos courtesy Dr. Hollis G. Potter

Risedronate appears to be no better than placebo at improving symptoms and slowing structural changes associated with osteoarthritis, but the drug did significantly reduce markers of bone resorption and cartilage degradation, providing some measure of hope that the drug may still prove useful in treating this disorder.

“In the groups that were receiving placebo, there was worsening of their cartilage degradation marker [C-terminal crosslinking telopeptide of type II collagen, or CTX-II], whereas there was a dose-dependent reduction in all of the rise dronate treated patients. To date, CTX-II is the leading biomarker for osteoarthritis in terms of one that may be predictive of patients who are at risk for progression,” Dr. Clifton O. Bingham III, the study's lead author and a rheumatologist at Johns Hopkins University, Baltimore, said.

Whether these changes in biomarkers will translate into a later clinically relevant change in joint preservation is unknown. “The fact that we are able to now show that certain treatments can affect this biomarker is really a very important piece for us in order to move forward in the development of therapeutics,” said Dr. Bingham, who reported receiving consulting fees from Procter & Gamble Pharmaceuticals Inc., maker of risedronate (Actonel).

The study was conducted at 42 sites in North America and at 44 sites in the European Union (Arthritis Rheum. 2006;54:3494–507). Patients were randomized to receive placebo or oral risedronate in dosages of 5 mg/day, 15 mg/day, 35 mg/week (Europe only), or 50 mg/week (North America only).

Patients aged 40–80 years were screened for inclusion if they had signal knee pain resulting from osteoarthritis (OA) most days during at least 1 month in a 3-month period, and had one of the following: morning knee stiffness lasting more than 30 minutes, or knee crepitus according to the American College of Rheumatology criteria for knee OA.

Patients were excluded if they had known inflammatory arthritis; body mass index (kg/m

All patients underwent radiography of the knee to confirm OA. For inclusion, patients had to have at least one osteophyte and minimal joint space width of 2–4 mm, inclusive, in the medial tibiofemoral compartment, and a medial compartment that was narrower than the lateral. Radiographic assessment was performed at baseline, 1 year, and 2 years.

Nonnarcotic analgesics, NSAIDs, or COX-2 inhibitors were allowed and monitored during the study. Patients underwent a stepped reduction and washout period for these medications prior to study visits, including the baseline visit. Patients were provided with 500 mg acetaminophen (North America) or paracetamol (Europe) and 50 mg diclofenac to be used as needed from 5 to 3 days prior to a visit. All pain medications were stopped 2 days prior to a visit.

The two primary end points were the effect of risedronate on structure and symptoms compared with placebo after 2 years. Patient symptoms were measured by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index and by Patient Global Assessment (PGA) scores. Structure was assessed by measuring joint-space narrowing in the medial tibiofemoral compartment.

Joint-space narrowing of the target knee was evaluated at the narrowest point in the medial tibiofemoral compartment at baseline and at 1 and 2 years follow-up. Radiographs were performed using a semiflexed view of the knee (fluoroscopically assisted). Radiographs were obtained at 13 regional radiographic facilities in Europe and 12 in the United States. All radiographs were sent to a quality control center in Amsterdam for review and then to the central analysis facility in London, where films were digitized and semiautomated computer measurements of minimal medial joint-space width were performed. The test-retest standard deviation—the difference between radiographs obtained 2 days apart—for this technique was approximately 0.2 mm.

Urine samples were also collected at baseline and at 6 months, 12 months, and 24 months. Samples were analyzed for N-terminal crosslinking telopeptide of type I collagen (NTX-I) to assess bone resorption and for CTX-II.

In the North American cohort, 301 participants were randomized to placebo, 306 to 5 mg/day risedronate, 302 to 15 mg/day, and 314 to 50 mg/week. In the European cohort, 312 participants were randomized to placebo, 322 to 5 mg/day risedronate, 307 to 15 mg/day, and 310 to 35 mg/week.

“In both the European and North American studies, no significant differences between treatment groups were noted in the mean change from baseline in total WOMAC score, scores for WOMAC components, or PGA scores,” the researchers said. Notably, those patients treated with placebo had a mean reduction of about 20% from baseline in total WOMAC scores.

“In all treatment groups, including the placebo, there was a clinically detectable improvement in pain that occurred at the 6-month point and was maintained over 2 years,” said Dr. Bingham. The results for the placebo patients highlight the importance of accounting for placebo benefit in osteoarthritis studies. Not only did placebo improvement occur, but it was maintained over time.

So either improvement is part of the natural course of the disease or there is a clinical benefit simply in entering a clinical trial. Regardless, this effect needs to be taken into consideration in designing future osteoarthritis trials, said Dr. Bingham, who is also with the division of allergy and immunology at Johns Hopkins University.

In terms of structure, 13% of participants had radiographic progression. There were no statistically significant differences in any treatment group in either cohort.

“When you looked at the people who were showing what was unequivocally progression … there was no drug effect that was demonstrated but interestingly that group of people was only a very small percentage of the entire study population,” said Dr. Bingham.

The radiographic findings also have implications for future trial design: If only a small number of people are going to show substantial worsening in terms of joint structure, then—in order to study an OA drug by looking at structure as an outcome—greater numbers of patients are needed to be able to demonstrate a potential treatment effect, he said.

In both cohorts, a dose-dependent decrease in the level of NTX-I was observed within 6 months for those on risedronate, and it continued through 24 months. The mean percent change from baseline to 24 months for all dosages of risedronate was statistically different from the placebo group. In the North American group, those on placebo had a mean increase in NTX-I of 7.3%, whereas those on risedronate at dosages of 5 mg/day, 15 mg/day, and 50 mg/week had NTX-I level decreases of 21.6%, 39.2%, and 29.2%, respectively. In the European cohort, those on placebo had a mean increase in NTX-I of 3.0%, whereas those on risedronate at dosages of 5 mg/day, 15 mg/day, and 35 mg/week had NTX-I level decreases of 29.0%, 41.7%, and 28.2%, respectively.

The results for CTX-II levels were similar, with those on placebo having increases over 24 months, whereas those on risedronate had early decreases. At 15 mg/day risedronate, reductions of 17.9% and 19.6% from baseline were seen in North American and European patients respectively. In comparison, the North American and European placebo groups had increases of CTX-II levels of 26.3% and 10.1%, respectively.

The biomarker results suggest—from a pathobiologic perspective—that an agent that acts on subchondral bone, interrupts the turnover of bone, and improves bone structure can consequently improve cartilage stability. This suggests a fundamental interaction between bone and cartilage. This could be important because treatments already are available that interrupt bone turnover.

These study results indicate that “potentially the bone is an important therapeutic target in patients with osteoarthritis,” said Dr. Bingham.

Risedronate appears to be no better than placebo at improving symptoms and slowing structural changes associated with osteoarthritis, but the drug did significantly reduce markers of bone resorption and cartilage degradation, providing some measure of hope that the drug may still prove useful in treating this disorder.

“In the groups that were receiving placebo, there was worsening of their cartilage degradation marker [C-terminal crosslinking telopeptide of type II collagen, or CTX-II], whereas there was a dose-dependent reduction in all of the rise dronate treated patients. To date, CTX-II is the leading biomarker for osteoarthritis in terms of one that may be predictive of patients who are at risk for progression,” Dr. Clifton O. Bingham III, the study's lead author and a rheumatologist at Johns Hopkins University, Baltimore, said.

Whether these changes in biomarkers will translate into a later clinically relevant change in joint preservation is unknown. “The fact that we are able to now show that certain treatments can affect this biomarker is really a very important piece for us in order to move forward in the development of therapeutics,” said Dr. Bingham, who reported receiving consulting fees from Procter & Gamble Pharmaceuticals Inc., maker of risedronate (Actonel).

The study was conducted at 42 sites in North America and at 44 sites in the European Union (Arthritis Rheum. 2006;54:3494–507). Patients were randomized to receive placebo or oral risedronate in dosages of 5 mg/day, 15 mg/day, 35 mg/week (Europe only), or 50 mg/week (North America only).

Patients aged 40–80 years were screened for inclusion if they had signal knee pain resulting from osteoarthritis (OA) most days during at least 1 month in a 3-month period, and had one of the following: morning knee stiffness lasting more than 30 minutes, or knee crepitus according to the American College of Rheumatology criteria for knee OA.

Patients were excluded if they had known inflammatory arthritis; body mass index (kg/m

All patients underwent radiography of the knee to confirm OA. For inclusion, patients had to have at least one osteophyte and minimal joint space width of 2–4 mm, inclusive, in the medial tibiofemoral compartment, and a medial compartment that was narrower than the lateral. Radiographic assessment was performed at baseline, 1 year, and 2 years.

Nonnarcotic analgesics, NSAIDs, or COX-2 inhibitors were allowed and monitored during the study. Patients underwent a stepped reduction and washout period for these medications prior to study visits, including the baseline visit. Patients were provided with 500 mg acetaminophen (North America) or paracetamol (Europe) and 50 mg diclofenac to be used as needed from 5 to 3 days prior to a visit. All pain medications were stopped 2 days prior to a visit.

The two primary end points were the effect of risedronate on structure and symptoms compared with placebo after 2 years. Patient symptoms were measured by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index and by Patient Global Assessment (PGA) scores. Structure was assessed by measuring joint-space narrowing in the medial tibiofemoral compartment.

Joint-space narrowing of the target knee was evaluated at the narrowest point in the medial tibiofemoral compartment at baseline and at 1 and 2 years follow-up. Radiographs were performed using a semiflexed view of the knee (fluoroscopically assisted). Radiographs were obtained at 13 regional radiographic facilities in Europe and 12 in the United States. All radiographs were sent to a quality control center in Amsterdam for review and then to the central analysis facility in London, where films were digitized and semiautomated computer measurements of minimal medial joint-space width were performed. The test-retest standard deviation—the difference between radiographs obtained 2 days apart—for this technique was approximately 0.2 mm.

Urine samples were also collected at baseline and at 6 months, 12 months, and 24 months. Samples were analyzed for N-terminal crosslinking telopeptide of type I collagen (NTX-I) to assess bone resorption and for CTX-II.

In the North American cohort, 301 participants were randomized to placebo, 306 to 5 mg/day risedronate, 302 to 15 mg/day, and 314 to 50 mg/week. In the European cohort, 312 participants were randomized to placebo, 322 to 5 mg/day risedronate, 307 to 15 mg/day, and 310 to 35 mg/week.

“In both the European and North American studies, no significant differences between treatment groups were noted in the mean change from baseline in total WOMAC score, scores for WOMAC components, or PGA scores,” the researchers said. Notably, those patients treated with placebo had a mean reduction of about 20% from baseline in total WOMAC scores.

“In all treatment groups, including the placebo, there was a clinically detectable improvement in pain that occurred at the 6-month point and was maintained over 2 years,” said Dr. Bingham. The results for the placebo patients highlight the importance of accounting for placebo benefit in osteoarthritis studies. Not only did placebo improvement occur, but it was maintained over time.

So either improvement is part of the natural course of the disease or there is a clinical benefit simply in entering a clinical trial. Regardless, this effect needs to be taken into consideration in designing future osteoarthritis trials, said Dr. Bingham, who is also with the division of allergy and immunology at Johns Hopkins University.

In terms of structure, 13% of participants had radiographic progression. There were no statistically significant differences in any treatment group in either cohort.

“When you looked at the people who were showing what was unequivocally progression … there was no drug effect that was demonstrated but interestingly that group of people was only a very small percentage of the entire study population,” said Dr. Bingham.

The radiographic findings also have implications for future trial design: If only a small number of people are going to show substantial worsening in terms of joint structure, then—in order to study an OA drug by looking at structure as an outcome—greater numbers of patients are needed to be able to demonstrate a potential treatment effect, he said.

In both cohorts, a dose-dependent decrease in the level of NTX-I was observed within 6 months for those on risedronate, and it continued through 24 months. The mean percent change from baseline to 24 months for all dosages of risedronate was statistically different from the placebo group. In the North American group, those on placebo had a mean increase in NTX-I of 7.3%, whereas those on risedronate at dosages of 5 mg/day, 15 mg/day, and 50 mg/week had NTX-I level decreases of 21.6%, 39.2%, and 29.2%, respectively. In the European cohort, those on placebo had a mean increase in NTX-I of 3.0%, whereas those on risedronate at dosages of 5 mg/day, 15 mg/day, and 35 mg/week had NTX-I level decreases of 29.0%, 41.7%, and 28.2%, respectively.

The results for CTX-II levels were similar, with those on placebo having increases over 24 months, whereas those on risedronate had early decreases. At 15 mg/day risedronate, reductions of 17.9% and 19.6% from baseline were seen in North American and European patients respectively. In comparison, the North American and European placebo groups had increases of CTX-II levels of 26.3% and 10.1%, respectively.

The biomarker results suggest—from a pathobiologic perspective—that an agent that acts on subchondral bone, interrupts the turnover of bone, and improves bone structure can consequently improve cartilage stability. This suggests a fundamental interaction between bone and cartilage. This could be important because treatments already are available that interrupt bone turnover.

These study results indicate that “potentially the bone is an important therapeutic target in patients with osteoarthritis,” said Dr. Bingham.

Risedronate appears to be no better than placebo at improving symptoms and slowing structural changes associated with osteoarthritis, but the drug did significantly reduce markers of bone resorption and cartilage degradation, providing some measure of hope that the drug may still prove useful in treating this disorder.

“In the groups that were receiving placebo, there was worsening of their cartilage degradation marker [C-terminal crosslinking telopeptide of type II collagen, or CTX-II], whereas there was a dose-dependent reduction in all of the rise dronate treated patients. To date, CTX-II is the leading biomarker for osteoarthritis in terms of one that may be predictive of patients who are at risk for progression,” Dr. Clifton O. Bingham III, the study's lead author and a rheumatologist at Johns Hopkins University, Baltimore, said.

Whether these changes in biomarkers will translate into a later clinically relevant change in joint preservation is unknown. “The fact that we are able to now show that certain treatments can affect this biomarker is really a very important piece for us in order to move forward in the development of therapeutics,” said Dr. Bingham, who reported receiving consulting fees from Procter & Gamble Pharmaceuticals Inc., maker of risedronate (Actonel).

The study was conducted at 42 sites in North America and at 44 sites in the European Union (Arthritis Rheum. 2006;54:3494–507). Patients were randomized to receive placebo or oral risedronate in dosages of 5 mg/day, 15 mg/day, 35 mg/week (Europe only), or 50 mg/week (North America only).

Patients aged 40–80 years were screened for inclusion if they had signal knee pain resulting from osteoarthritis (OA) most days during at least 1 month in a 3-month period, and had one of the following: morning knee stiffness lasting more than 30 minutes, or knee crepitus according to the American College of Rheumatology criteria for knee OA.

Patients were excluded if they had known inflammatory arthritis; body mass index (kg/m

All patients underwent radiography of the knee to confirm OA. For inclusion, patients had to have at least one osteophyte and minimal joint space width of 2–4 mm, inclusive, in the medial tibiofemoral compartment, and a medial compartment that was narrower than the lateral. Radiographic assessment was performed at baseline, 1 year, and 2 years.

Nonnarcotic analgesics, NSAIDs, or COX-2 inhibitors were allowed and monitored during the study. Patients underwent a stepped reduction and washout period for these medications prior to study visits, including the baseline visit. Patients were provided with 500 mg acetaminophen (North America) or paracetamol (Europe) and 50 mg diclofenac to be used as needed from 5 to 3 days prior to a visit. All pain medications were stopped 2 days prior to a visit.

The two primary end points were the effect of risedronate on structure and symptoms compared with placebo after 2 years. Patient symptoms were measured by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index and by Patient Global Assessment (PGA) scores. Structure was assessed by measuring joint-space narrowing in the medial tibiofemoral compartment.

Joint-space narrowing of the target knee was evaluated at the narrowest point in the medial tibiofemoral compartment at baseline and at 1 and 2 years follow-up. Radiographs were performed using a semiflexed view of the knee (fluoroscopically assisted). Radiographs were obtained at 13 regional radiographic facilities in Europe and 12 in the United States. All radiographs were sent to a quality control center in Amsterdam for review and then to the central analysis facility in London, where films were digitized and semiautomated computer measurements of minimal medial joint-space width were performed. The test-retest standard deviation—the difference between radiographs obtained 2 days apart—for this technique was approximately 0.2 mm.

Urine samples were also collected at baseline and at 6 months, 12 months, and 24 months. Samples were analyzed for N-terminal crosslinking telopeptide of type I collagen (NTX-I) to assess bone resorption and for CTX-II.

In the North American cohort, 301 participants were randomized to placebo, 306 to 5 mg/day risedronate, 302 to 15 mg/day, and 314 to 50 mg/week. In the European cohort, 312 participants were randomized to placebo, 322 to 5 mg/day risedronate, 307 to 15 mg/day, and 310 to 35 mg/week.

“In both the European and North American studies, no significant differences between treatment groups were noted in the mean change from baseline in total WOMAC score, scores for WOMAC components, or PGA scores,” the researchers said. Notably, those patients treated with placebo had a mean reduction of about 20% from baseline in total WOMAC scores.

“In all treatment groups, including the placebo, there was a clinically detectable improvement in pain that occurred at the 6-month point and was maintained over 2 years,” said Dr. Bingham. The results for the placebo patients highlight the importance of accounting for placebo benefit in osteoarthritis studies. Not only did placebo improvement occur, but it was maintained over time.

So either improvement is part of the natural course of the disease or there is a clinical benefit simply in entering a clinical trial. Regardless, this effect needs to be taken into consideration in designing future osteoarthritis trials, said Dr. Bingham, who is also with the division of allergy and immunology at Johns Hopkins University.

In terms of structure, 13% of participants had radiographic progression. There were no statistically significant differences in any treatment group in either cohort.

“When you looked at the people who were showing what was unequivocally progression … there was no drug effect that was demonstrated but interestingly that group of people was only a very small percentage of the entire study population,” said Dr. Bingham.

The radiographic findings also have implications for future trial design: If only a small number of people are going to show substantial worsening in terms of joint structure, then—in order to study an OA drug by looking at structure as an outcome—greater numbers of patients are needed to be able to demonstrate a potential treatment effect, he said.

In both cohorts, a dose-dependent decrease in the level of NTX-I was observed within 6 months for those on risedronate, and it continued through 24 months. The mean percent change from baseline to 24 months for all dosages of risedronate was statistically different from the placebo group. In the North American group, those on placebo had a mean increase in NTX-I of 7.3%, whereas those on risedronate at dosages of 5 mg/day, 15 mg/day, and 50 mg/week had NTX-I level decreases of 21.6%, 39.2%, and 29.2%, respectively. In the European cohort, those on placebo had a mean increase in NTX-I of 3.0%, whereas those on risedronate at dosages of 5 mg/day, 15 mg/day, and 35 mg/week had NTX-I level decreases of 29.0%, 41.7%, and 28.2%, respectively.

The results for CTX-II levels were similar, with those on placebo having increases over 24 months, whereas those on risedronate had early decreases. At 15 mg/day risedronate, reductions of 17.9% and 19.6% from baseline were seen in North American and European patients respectively. In comparison, the North American and European placebo groups had increases of CTX-II levels of 26.3% and 10.1%, respectively.

The biomarker results suggest—from a pathobiologic perspective—that an agent that acts on subchondral bone, interrupts the turnover of bone, and improves bone structure can consequently improve cartilage stability. This suggests a fundamental interaction between bone and cartilage. This could be important because treatments already are available that interrupt bone turnover.

These study results indicate that “potentially the bone is an important therapeutic target in patients with osteoarthritis,” said Dr. Bingham.

PHILADELPHIA — Weekly parathyroid hormone increases bone mineral density and bone formation biomarkers, but only slightly, Dennis M. Black, Ph.D., reported at the annual meeting of the American Society for Bone and Mineral Research.

Spine bone mineral density (BMD) increased 2.1% in women on parathyroid hormone (PTH) at the end of 1 year, compared with women receiving no treatment, a significant finding. Trabecular spine volumetric BMD assessed with quantitative CT increased 3.8% in women in the treatment group, compared with those in the control group, though this result was not significant, Dr. Black said. There also were trends toward increases in trabecular number and cortical thickness, though these were not statistically significant.

In the PTH Once Weekly Research (POWR) study, 50 women were randomized evenly to treatment with PTH (1–84) at a dosage of 100 mcg daily for 1 month followed by 11 months of once weekly PTH (also 100 mcg) or no treatment. All women also received 500 mg calcium and 400 IU vitamin D per day, reported Dr. Black, professor of epidemiology and biostatistics at the University of California, San Francisco. Women had to be postmenopausal and aged between 45 and 70 years, with minimal previous use of bisphosphonates. They also had to have a femoral neck BMD T score between −1 and −2 and a spine BMD T score greater than −2.5.

The primary end point was spine BMD measured by dual-energy x-ray absorptiometry (DXA). Secondary end points included BMD at the hip, trabecular, and cortical bone measured by quantitative CT at the spine and hip and bone biomarkers. Based on injection diaries, 94% of the women were found to have at least an 80% compliance with the injection regimen, he said.

Bone formation during daily treatment with PTH, as measured by procollagen type 1 N-propeptide (P1NP) levels, increased roughly 100% compared with untreated women. However, levels slowly decreased during weekly injections, remaining 15% greater than for untreated women at 12 months. There were no significant changes in resorption markers in either group.

He compared the results of this pilot study with those for daily PTH treatment at 12 months from the Parathyroid Hormone and Alendronate (PaTH) study (N. Engl. J. Med. 2005;353:555–65).

Once-weekly PTH following daily PTH for 1 month significantly increased spine BMD. However, compared with daily PTH in the PaTh study, “there was no significant increase in trabecular BMD, a small increase in DXA spine BMD, a smaller increase in bone formation markers, and generally a smaller anabolic response,” he said.

Once weekly PTH may not be frequent enough. A longer loading period may be necessary, he noted. In terms of adverse events, there was one case of chest pain in the placebo group, and there were four mild cases of hypercalcemia in the PTH group.

Dr. Black disclosed that he has significant financial relationships with Novartis, Merck & Co., Hoffmann-La Roche Inc., and GlaxoSmithKline.

PHILADELPHIA — Weekly parathyroid hormone increases bone mineral density and bone formation biomarkers, but only slightly, Dennis M. Black, Ph.D., reported at the annual meeting of the American Society for Bone and Mineral Research.

Spine bone mineral density (BMD) increased 2.1% in women on parathyroid hormone (PTH) at the end of 1 year, compared with women receiving no treatment, a significant finding. Trabecular spine volumetric BMD assessed with quantitative CT increased 3.8% in women in the treatment group, compared with those in the control group, though this result was not significant, Dr. Black said. There also were trends toward increases in trabecular number and cortical thickness, though these were not statistically significant.

In the PTH Once Weekly Research (POWR) study, 50 women were randomized evenly to treatment with PTH (1–84) at a dosage of 100 mcg daily for 1 month followed by 11 months of once weekly PTH (also 100 mcg) or no treatment. All women also received 500 mg calcium and 400 IU vitamin D per day, reported Dr. Black, professor of epidemiology and biostatistics at the University of California, San Francisco. Women had to be postmenopausal and aged between 45 and 70 years, with minimal previous use of bisphosphonates. They also had to have a femoral neck BMD T score between −1 and −2 and a spine BMD T score greater than −2.5.

The primary end point was spine BMD measured by dual-energy x-ray absorptiometry (DXA). Secondary end points included BMD at the hip, trabecular, and cortical bone measured by quantitative CT at the spine and hip and bone biomarkers. Based on injection diaries, 94% of the women were found to have at least an 80% compliance with the injection regimen, he said.

Bone formation during daily treatment with PTH, as measured by procollagen type 1 N-propeptide (P1NP) levels, increased roughly 100% compared with untreated women. However, levels slowly decreased during weekly injections, remaining 15% greater than for untreated women at 12 months. There were no significant changes in resorption markers in either group.

He compared the results of this pilot study with those for daily PTH treatment at 12 months from the Parathyroid Hormone and Alendronate (PaTH) study (N. Engl. J. Med. 2005;353:555–65).

Once-weekly PTH following daily PTH for 1 month significantly increased spine BMD. However, compared with daily PTH in the PaTh study, “there was no significant increase in trabecular BMD, a small increase in DXA spine BMD, a smaller increase in bone formation markers, and generally a smaller anabolic response,” he said.

Once weekly PTH may not be frequent enough. A longer loading period may be necessary, he noted. In terms of adverse events, there was one case of chest pain in the placebo group, and there were four mild cases of hypercalcemia in the PTH group.

Dr. Black disclosed that he has significant financial relationships with Novartis, Merck & Co., Hoffmann-La Roche Inc., and GlaxoSmithKline.

PHILADELPHIA — Weekly parathyroid hormone increases bone mineral density and bone formation biomarkers, but only slightly, Dennis M. Black, Ph.D., reported at the annual meeting of the American Society for Bone and Mineral Research.

Spine bone mineral density (BMD) increased 2.1% in women on parathyroid hormone (PTH) at the end of 1 year, compared with women receiving no treatment, a significant finding. Trabecular spine volumetric BMD assessed with quantitative CT increased 3.8% in women in the treatment group, compared with those in the control group, though this result was not significant, Dr. Black said. There also were trends toward increases in trabecular number and cortical thickness, though these were not statistically significant.

In the PTH Once Weekly Research (POWR) study, 50 women were randomized evenly to treatment with PTH (1–84) at a dosage of 100 mcg daily for 1 month followed by 11 months of once weekly PTH (also 100 mcg) or no treatment. All women also received 500 mg calcium and 400 IU vitamin D per day, reported Dr. Black, professor of epidemiology and biostatistics at the University of California, San Francisco. Women had to be postmenopausal and aged between 45 and 70 years, with minimal previous use of bisphosphonates. They also had to have a femoral neck BMD T score between −1 and −2 and a spine BMD T score greater than −2.5.

The primary end point was spine BMD measured by dual-energy x-ray absorptiometry (DXA). Secondary end points included BMD at the hip, trabecular, and cortical bone measured by quantitative CT at the spine and hip and bone biomarkers. Based on injection diaries, 94% of the women were found to have at least an 80% compliance with the injection regimen, he said.

Bone formation during daily treatment with PTH, as measured by procollagen type 1 N-propeptide (P1NP) levels, increased roughly 100% compared with untreated women. However, levels slowly decreased during weekly injections, remaining 15% greater than for untreated women at 12 months. There were no significant changes in resorption markers in either group.

He compared the results of this pilot study with those for daily PTH treatment at 12 months from the Parathyroid Hormone and Alendronate (PaTH) study (N. Engl. J. Med. 2005;353:555–65).

Once-weekly PTH following daily PTH for 1 month significantly increased spine BMD. However, compared with daily PTH in the PaTh study, “there was no significant increase in trabecular BMD, a small increase in DXA spine BMD, a smaller increase in bone formation markers, and generally a smaller anabolic response,” he said.

Once weekly PTH may not be frequent enough. A longer loading period may be necessary, he noted. In terms of adverse events, there was one case of chest pain in the placebo group, and there were four mild cases of hypercalcemia in the PTH group.

Dr. Black disclosed that he has significant financial relationships with Novartis, Merck & Co., Hoffmann-La Roche Inc., and GlaxoSmithKline.

PHILADELPHIA — The investigative osteoporosis therapy denosumab appears to improve several measures of bone geometry, which are factors in bone strength, according to data presented at the annual meeting of the American Society for Bone and Mineral Research.

In a post hoc analysis of phase II trial data, researchers found that denosumab therapy was associated with increased bone cross-sectional areas, cortical thickness, and measures of bending strength and stability against high compressive stresses. “These positive changes in structural geometry support the likelihood that treatment improves the mechanical strength of the proximal femur,” said Dr. Thomas J. Beck, professor of radiology at Johns Hopkins University, Baltimore.

Denosumab is a fully human monoclonal antibody that binds to the receptor activator of nuclear factor kappa B ligand, the primary mediator of osteoclast differentiation, activation, and survival. Denosumab binds to this protein, inhibiting osteoclast differentiation, activation, and survival.

In the phase II study, denosumab therapy was shown to increase bone mineral density (N. Engl. J. Med. 2006;354:821–31) and presumably bone mechanical strength as well.

Bone strength can be altered by changes in bone geometry—the amount and distribution of bone—or by changes in the composition of bone tissue.

The trial data included 39 patients on 60 mg of denosumab every 6 months, 39 subjects on placebo, and 38 patients on open-label alendronate (70 mg once weekly).

The study was funded in part by Amgen Inc. Dr. Beck disclosed that he has significant financial relationships with Merck & Co. Inc., Amgen Inc., and Hologic Inc.

The researchers used hip structural analysis to calculate bone cross-sectional area, section modulus (an indicator of bending strength), estimated cortical thickness, and buckling ratio (an estimate of cortical stability in buckling or against high compressive stresses) from dual-energy x-ray absorptiometry hip scans at baseline and at 12 and 24 months.

Hip structural analysis is an investigational technique used to assess bone geometry in cross-sections of three regions of the proximal femur: across the femoral neck at its narrowest point, in the intertrochanteric region (along the bisector of the neck-shaft angle), and across the shaft (2 cm distal to the midpoint of the lesser trochanter).

For the femoral neck at 24 months, the percent change in bone mineral density (BMD) from baseline was significantly greater for denosumab than for placebo. The percent change in cross-sectional area was similar for denosumab and alendronate, according to Dr. Beck.

The percent changes in section modulus and estimated cortical thickness were significantly greater for denosumab than for placebo, and the percent change in buckling ratio was significantly lower for denosumab than for placebo (a positive result, indicating increased strength).

Dr. Beck added that for the inter-trochanteric region at 24 months, the percent change in BMD from baseline was significantly greater among patients receiving denosumab therapy than for those given placebo. The percent change in cross-sectional area was significantly greater for denosumab than for alendronate, he reported.

The percent change in section modulus was significantly greater for denosumab than for placebo. The percent change in estimated cortical thickness was significantly greater for denosumab than for placebo, and the percent change in buckling ratio was significantly lower for denosumab than for placebo.

For the shaft at 24 months, the percent change in BMD from baseline was significantly greater for denosumab than for placebo. The percent change in cross-sectional area was significantly greater for denosumab than for alendronate, according to Dr. Beck.

The percent changes in section modulus and estimated cortical thickness were significantly greater for denosumab than for alendronate, and the percent change in buckling ratio was significantly lower for denosumab than for alendronate.

PHILADELPHIA — The investigative osteoporosis therapy denosumab appears to improve several measures of bone geometry, which are factors in bone strength, according to data presented at the annual meeting of the American Society for Bone and Mineral Research.

In a post hoc analysis of phase II trial data, researchers found that denosumab therapy was associated with increased bone cross-sectional areas, cortical thickness, and measures of bending strength and stability against high compressive stresses. “These positive changes in structural geometry support the likelihood that treatment improves the mechanical strength of the proximal femur,” said Dr. Thomas J. Beck, professor of radiology at Johns Hopkins University, Baltimore.

Denosumab is a fully human monoclonal antibody that binds to the receptor activator of nuclear factor kappa B ligand, the primary mediator of osteoclast differentiation, activation, and survival. Denosumab binds to this protein, inhibiting osteoclast differentiation, activation, and survival.

In the phase II study, denosumab therapy was shown to increase bone mineral density (N. Engl. J. Med. 2006;354:821–31) and presumably bone mechanical strength as well.

Bone strength can be altered by changes in bone geometry—the amount and distribution of bone—or by changes in the composition of bone tissue.

The trial data included 39 patients on 60 mg of denosumab every 6 months, 39 subjects on placebo, and 38 patients on open-label alendronate (70 mg once weekly).

The study was funded in part by Amgen Inc. Dr. Beck disclosed that he has significant financial relationships with Merck & Co. Inc., Amgen Inc., and Hologic Inc.

The researchers used hip structural analysis to calculate bone cross-sectional area, section modulus (an indicator of bending strength), estimated cortical thickness, and buckling ratio (an estimate of cortical stability in buckling or against high compressive stresses) from dual-energy x-ray absorptiometry hip scans at baseline and at 12 and 24 months.

Hip structural analysis is an investigational technique used to assess bone geometry in cross-sections of three regions of the proximal femur: across the femoral neck at its narrowest point, in the intertrochanteric region (along the bisector of the neck-shaft angle), and across the shaft (2 cm distal to the midpoint of the lesser trochanter).

For the femoral neck at 24 months, the percent change in bone mineral density (BMD) from baseline was significantly greater for denosumab than for placebo. The percent change in cross-sectional area was similar for denosumab and alendronate, according to Dr. Beck.

The percent changes in section modulus and estimated cortical thickness were significantly greater for denosumab than for placebo, and the percent change in buckling ratio was significantly lower for denosumab than for placebo (a positive result, indicating increased strength).

Dr. Beck added that for the inter-trochanteric region at 24 months, the percent change in BMD from baseline was significantly greater among patients receiving denosumab therapy than for those given placebo. The percent change in cross-sectional area was significantly greater for denosumab than for alendronate, he reported.

The percent change in section modulus was significantly greater for denosumab than for placebo. The percent change in estimated cortical thickness was significantly greater for denosumab than for placebo, and the percent change in buckling ratio was significantly lower for denosumab than for placebo.

For the shaft at 24 months, the percent change in BMD from baseline was significantly greater for denosumab than for placebo. The percent change in cross-sectional area was significantly greater for denosumab than for alendronate, according to Dr. Beck.

The percent changes in section modulus and estimated cortical thickness were significantly greater for denosumab than for alendronate, and the percent change in buckling ratio was significantly lower for denosumab than for alendronate.

PHILADELPHIA — The investigative osteoporosis therapy denosumab appears to improve several measures of bone geometry, which are factors in bone strength, according to data presented at the annual meeting of the American Society for Bone and Mineral Research.

In a post hoc analysis of phase II trial data, researchers found that denosumab therapy was associated with increased bone cross-sectional areas, cortical thickness, and measures of bending strength and stability against high compressive stresses. “These positive changes in structural geometry support the likelihood that treatment improves the mechanical strength of the proximal femur,” said Dr. Thomas J. Beck, professor of radiology at Johns Hopkins University, Baltimore.

Denosumab is a fully human monoclonal antibody that binds to the receptor activator of nuclear factor kappa B ligand, the primary mediator of osteoclast differentiation, activation, and survival. Denosumab binds to this protein, inhibiting osteoclast differentiation, activation, and survival.

In the phase II study, denosumab therapy was shown to increase bone mineral density (N. Engl. J. Med. 2006;354:821–31) and presumably bone mechanical strength as well.

Bone strength can be altered by changes in bone geometry—the amount and distribution of bone—or by changes in the composition of bone tissue.

The trial data included 39 patients on 60 mg of denosumab every 6 months, 39 subjects on placebo, and 38 patients on open-label alendronate (70 mg once weekly).

The study was funded in part by Amgen Inc. Dr. Beck disclosed that he has significant financial relationships with Merck & Co. Inc., Amgen Inc., and Hologic Inc.

The researchers used hip structural analysis to calculate bone cross-sectional area, section modulus (an indicator of bending strength), estimated cortical thickness, and buckling ratio (an estimate of cortical stability in buckling or against high compressive stresses) from dual-energy x-ray absorptiometry hip scans at baseline and at 12 and 24 months.

Hip structural analysis is an investigational technique used to assess bone geometry in cross-sections of three regions of the proximal femur: across the femoral neck at its narrowest point, in the intertrochanteric region (along the bisector of the neck-shaft angle), and across the shaft (2 cm distal to the midpoint of the lesser trochanter).

For the femoral neck at 24 months, the percent change in bone mineral density (BMD) from baseline was significantly greater for denosumab than for placebo. The percent change in cross-sectional area was similar for denosumab and alendronate, according to Dr. Beck.

The percent changes in section modulus and estimated cortical thickness were significantly greater for denosumab than for placebo, and the percent change in buckling ratio was significantly lower for denosumab than for placebo (a positive result, indicating increased strength).

Dr. Beck added that for the inter-trochanteric region at 24 months, the percent change in BMD from baseline was significantly greater among patients receiving denosumab therapy than for those given placebo. The percent change in cross-sectional area was significantly greater for denosumab than for alendronate, he reported.

The percent change in section modulus was significantly greater for denosumab than for placebo. The percent change in estimated cortical thickness was significantly greater for denosumab than for placebo, and the percent change in buckling ratio was significantly lower for denosumab than for placebo.

For the shaft at 24 months, the percent change in BMD from baseline was significantly greater for denosumab than for placebo. The percent change in cross-sectional area was significantly greater for denosumab than for alendronate, according to Dr. Beck.

The percent changes in section modulus and estimated cortical thickness were significantly greater for denosumab than for alendronate, and the percent change in buckling ratio was significantly lower for denosumab than for alendronate.

PHILADELPHIA — More physicians are using bone mineral density measurements and biochemical marker testing to identify and treat osteoporosis, according to data from a national survey.

More than 200,000 postmenopausal, nonosteoporotic women were enrolled in the National Osteoporosis Risk Assessment (NORA) in September 1997. In conjunction with the study, 2,836 referring primary care physicians completed a baseline survey in 1998 that tested their knowledge of osteoporosis screening and treatment. In 2006, 808 of these providers responded to a follow-up survey designed to assess changes in their practice patterns and knowledge of the condition, Dr. Paul D. Miller reported in a poster at the annual meeting of the American Society for Bone and Mineral Research.

The number of physicians who reported frequent use of bone mineral density (BMD) measurements to screen for, diagnose, or monitor osteoporosis more than doubled between 1998 and 2006—from 35% to 87%. More impressively, the number of physicians who reported sometimes or often using biochemical marker testing to screen for, diagnose, or monitor osteoporosis almost tripled—from 19% to 54%, wrote Dr. Miller, medical director of the Colorado Center for Bone Research and a professor at the University of Colorado Health Sciences Center in Denver.

In the same period, the percentage of physicians who knew that a bone mineral density T score of −2.5 or less was the threshold indicating the presence of osteoporosis almost doubled, from 34% to 67%.

However, the percentage of physicians who knew the threshold value requiring pharmacologic intervention (T score of −2.5 or less [according to the World Health Organization] or a T score of −2.0 or less with no risk factors [according to the National Osteoporosis Foundation]) remained the same at 60%.

In terms of changes in treatment, the use of hormone therapy dropped sixfold (67% vs. 11%) from 1998 to 2006. In contrast, bisphosphonate use jumped from 15% to 59%.

Dr. Miller reported that he has received funding and consulting fees from F. Hoffmann-La Roche Ltd. and GlaxoSmithKline.

In a separate analysis of data from NORA, Dr. Ethel S. Siris and her colleagues found that most of the women in the study had a repeat BMD measurement within 6 years of baseline.

As part of NORA, the women had their BMD measured at the heel, forearm, or finger at baseline. At 1, 3, and 6 years, the women were asked about repeat measurements.

Within 3 years of baseline, 29% of the women had a repeat BMD, while 58% had one within 6 years, Dr. Siris of the Toni Stabile Osteoporosis Center at Columbia University Medical Center in New York wrote in a poster.

Women were more likely to have repeat BMD measurements within 6 years of baseline if they were taking an osteoporosis medication (odds ratio 3.22), had talked with their physician about their baseline BMD results (OR 1.41), were taking corticosteroids (OR 1.25), were taking thyroid medication (OR 1.16), or weighed less than 127 pounds (OR 1.14) following multivariate adjustment.

Interestingly, women with a baseline T score of −2.5 or lower were less likely to have a repeat BMD (adjusted OR 0.86), while women with a baseline T score between −1.0 and −2.49 were slightly more likely (adjusted OR 1.12).

This study received funding from Merck & Co. Dr. Siris reported receiving consulting fees from Merck & Co., Procter & Gamble, Eli Lilly and Company, and Pfizer Inc.

PHILADELPHIA — More physicians are using bone mineral density measurements and biochemical marker testing to identify and treat osteoporosis, according to data from a national survey.

More than 200,000 postmenopausal, nonosteoporotic women were enrolled in the National Osteoporosis Risk Assessment (NORA) in September 1997. In conjunction with the study, 2,836 referring primary care physicians completed a baseline survey in 1998 that tested their knowledge of osteoporosis screening and treatment. In 2006, 808 of these providers responded to a follow-up survey designed to assess changes in their practice patterns and knowledge of the condition, Dr. Paul D. Miller reported in a poster at the annual meeting of the American Society for Bone and Mineral Research.

The number of physicians who reported frequent use of bone mineral density (BMD) measurements to screen for, diagnose, or monitor osteoporosis more than doubled between 1998 and 2006—from 35% to 87%. More impressively, the number of physicians who reported sometimes or often using biochemical marker testing to screen for, diagnose, or monitor osteoporosis almost tripled—from 19% to 54%, wrote Dr. Miller, medical director of the Colorado Center for Bone Research and a professor at the University of Colorado Health Sciences Center in Denver.

In the same period, the percentage of physicians who knew that a bone mineral density T score of −2.5 or less was the threshold indicating the presence of osteoporosis almost doubled, from 34% to 67%.

However, the percentage of physicians who knew the threshold value requiring pharmacologic intervention (T score of −2.5 or less [according to the World Health Organization] or a T score of −2.0 or less with no risk factors [according to the National Osteoporosis Foundation]) remained the same at 60%.

In terms of changes in treatment, the use of hormone therapy dropped sixfold (67% vs. 11%) from 1998 to 2006. In contrast, bisphosphonate use jumped from 15% to 59%.

Dr. Miller reported that he has received funding and consulting fees from F. Hoffmann-La Roche Ltd. and GlaxoSmithKline.

In a separate analysis of data from NORA, Dr. Ethel S. Siris and her colleagues found that most of the women in the study had a repeat BMD measurement within 6 years of baseline.

As part of NORA, the women had their BMD measured at the heel, forearm, or finger at baseline. At 1, 3, and 6 years, the women were asked about repeat measurements.

Within 3 years of baseline, 29% of the women had a repeat BMD, while 58% had one within 6 years, Dr. Siris of the Toni Stabile Osteoporosis Center at Columbia University Medical Center in New York wrote in a poster.

Women were more likely to have repeat BMD measurements within 6 years of baseline if they were taking an osteoporosis medication (odds ratio 3.22), had talked with their physician about their baseline BMD results (OR 1.41), were taking corticosteroids (OR 1.25), were taking thyroid medication (OR 1.16), or weighed less than 127 pounds (OR 1.14) following multivariate adjustment.

Interestingly, women with a baseline T score of −2.5 or lower were less likely to have a repeat BMD (adjusted OR 0.86), while women with a baseline T score between −1.0 and −2.49 were slightly more likely (adjusted OR 1.12).

This study received funding from Merck & Co. Dr. Siris reported receiving consulting fees from Merck & Co., Procter & Gamble, Eli Lilly and Company, and Pfizer Inc.

PHILADELPHIA — More physicians are using bone mineral density measurements and biochemical marker testing to identify and treat osteoporosis, according to data from a national survey.

More than 200,000 postmenopausal, nonosteoporotic women were enrolled in the National Osteoporosis Risk Assessment (NORA) in September 1997. In conjunction with the study, 2,836 referring primary care physicians completed a baseline survey in 1998 that tested their knowledge of osteoporosis screening and treatment. In 2006, 808 of these providers responded to a follow-up survey designed to assess changes in their practice patterns and knowledge of the condition, Dr. Paul D. Miller reported in a poster at the annual meeting of the American Society for Bone and Mineral Research.

The number of physicians who reported frequent use of bone mineral density (BMD) measurements to screen for, diagnose, or monitor osteoporosis more than doubled between 1998 and 2006—from 35% to 87%. More impressively, the number of physicians who reported sometimes or often using biochemical marker testing to screen for, diagnose, or monitor osteoporosis almost tripled—from 19% to 54%, wrote Dr. Miller, medical director of the Colorado Center for Bone Research and a professor at the University of Colorado Health Sciences Center in Denver.

In the same period, the percentage of physicians who knew that a bone mineral density T score of −2.5 or less was the threshold indicating the presence of osteoporosis almost doubled, from 34% to 67%.

However, the percentage of physicians who knew the threshold value requiring pharmacologic intervention (T score of −2.5 or less [according to the World Health Organization] or a T score of −2.0 or less with no risk factors [according to the National Osteoporosis Foundation]) remained the same at 60%.

In terms of changes in treatment, the use of hormone therapy dropped sixfold (67% vs. 11%) from 1998 to 2006. In contrast, bisphosphonate use jumped from 15% to 59%.

Dr. Miller reported that he has received funding and consulting fees from F. Hoffmann-La Roche Ltd. and GlaxoSmithKline.

In a separate analysis of data from NORA, Dr. Ethel S. Siris and her colleagues found that most of the women in the study had a repeat BMD measurement within 6 years of baseline.

As part of NORA, the women had their BMD measured at the heel, forearm, or finger at baseline. At 1, 3, and 6 years, the women were asked about repeat measurements.

Within 3 years of baseline, 29% of the women had a repeat BMD, while 58% had one within 6 years, Dr. Siris of the Toni Stabile Osteoporosis Center at Columbia University Medical Center in New York wrote in a poster.

Women were more likely to have repeat BMD measurements within 6 years of baseline if they were taking an osteoporosis medication (odds ratio 3.22), had talked with their physician about their baseline BMD results (OR 1.41), were taking corticosteroids (OR 1.25), were taking thyroid medication (OR 1.16), or weighed less than 127 pounds (OR 1.14) following multivariate adjustment.

Interestingly, women with a baseline T score of −2.5 or lower were less likely to have a repeat BMD (adjusted OR 0.86), while women with a baseline T score between −1.0 and −2.49 were slightly more likely (adjusted OR 1.12).

This study received funding from Merck & Co. Dr. Siris reported receiving consulting fees from Merck & Co., Procter & Gamble, Eli Lilly and Company, and Pfizer Inc.

BALTIMORE — The investigational drug desmoteplase combined with imaging to identify appropriate patients could push the treatment opening beyond 3 hours for some patients with acute ischemic stroke, according to Dr. Anthony Furlan, section head of stroke and neurologic intensive care at Cleveland Clinic.

“Even though intravenous tissue plasminogen activator has been an enormous breakthrough in stroke therapy, 95% of patients don't get treated with it,” Dr. Furlan said at the annual neurocritical care and stroke conference sponsored by Cleveland Clinic. “[W]e're not going to be treating lots of patients if we're confined to a 3-hour drug. An estimated 80% of stroke patients don't get to the hospital within the first 3 hours after onset.”

Animal trials have shown that desmoteplase—a plasminogen activator derived from vampire bat saliva—may be a better treatment option for acute stroke than is tissue plasminogen activator (TPA) for several reasons. Desmoteplase is not neurotoxic, and it does not activate β-amyloid, unlike TPA. In addition, desmoteplase has a long half-life, which allows for bolus injection. “That's useful for dosing control,” said Dr. Furlan. In animal models, desmoteplase also has been associated with fewer hemorrhages than has TPA.

The Desmoteplase in Acute Ischemic Stroke (DIAS) and the Dose Escalation Study of Desmoteplase in Acute Ischemic Stroke (DEDAS) trials were the first acute stroke thrombolytic trials to select patients for treatment after 3 hours based on perfusion imaging. Dr. Furlan was the principal investigator for the DEDAS trial. Desmoteplase is being jointly developed by Forest Laboratories Inc. and Paion AG.

Enrollment in the DIAS and DEDAS trials was limited to patients who had stroke onset within 3–8 hours and had a 20% perfusion-diffusion mismatch on baseline MRI. Reperfusion was defined as a 30% or better improvement in mean transit time on perfusion MRI or an improvement of two thrombolysis in myocardial infarction (TIMI) flow grades.

In an unpublished pooled analysis of both trials, none of the 35 patients who received placebo or the 30 patients who received 125 mcg/kg desmoteplase (as bolus) had symptomatic intracranial hemorrhage. Only 1 of the 29 patients (3.4%) who received 90 mcg/kg desmoteplase (as bolus) had symptomatic intracranial hemorrhage.

Mortality was 5.7% for the placebo group, 6.9% for the 90 mcg/kg desmoteplase group, and 3.3% for the 125 mcg/kg desmoteplase group. In addition, perfusion at 4–8 hours (based on MRI) was closely linked with clinical outcome at 90 days, with patients in the 125 mcg/kg group having the best results.

Based on a Rankin scale shift analysis of pooled data from the two trials, “at the 125-mcg dose—with a very small number of patients—we had a statistically significant clinical benefit, defined by improvement in Barthel [index], modified Rankin [scale], and NIH [stroke scale],” said Dr. Furlan.

For the 125-mcg dose, at 3 months there was a “statistically significant Rankin shift, meaning that we saw a positive benefit across the whole spectrum of the modified Rankin scale,” said Dr. Furlan.

“Is the drug alone sufficient? Well, my thinking is no. We have to combine the drug with proper patient selection,” he said. Imaging appears to be key to identifying patients who will benefit.

In the Diffusion-Weighted Imaging/Perfusion-Weighted Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) pilot study, researchers attempted to determine if baseline MR images can identify stroke patients who have a good clinical response when treated 3–6 hours after symptom onset.

MRI was performed before and 3–6 hours after treatment with intravenous TPA, administered 3–6 hours after symptom onset. Baseline MRI profiles were used to categorize patients into subgroups, and clinical responses were compared based on whether early reperfusion was achieved.

The researchers identified a specific type of mismatch—malignant mismatch—that was associated with severe intracranial hemorrhage and poor outcome after reperfusion. Malignant mismatch was defined as a defusion lesion greater than 100 cc in volume and/or a perfusion lesion greater than 100 cc in volume.

For patients with target mismatches—all mismatches other than malignant mismatches—with early reperfusion, there was an almost statistically significant clinical benefit, compared with all other mismatch patients. In addition, those with target mismatch and early reperfusion were more likely to achieve a favorable clinical response than were those with target mismatch but no early reperfusion (Ann. Neurol. 2006;60:508–17).

Dr. Furlan disclosed that his research has been supported by Forest Laboratories, Paion, and Abbott and that he has received speaking honoraria from Bristol-Myers Squibb/Sanofi and Genentech.

Right middle cerebral artery occlusion is on baseline magnetic resonance angiogram (top): the defect resolved 28 hours after IV desmoteplase (bottom). Courtesy Dr. Anthony Furlan

BALTIMORE — The investigational drug desmoteplase combined with imaging to identify appropriate patients could push the treatment opening beyond 3 hours for some patients with acute ischemic stroke, according to Dr. Anthony Furlan, section head of stroke and neurologic intensive care at Cleveland Clinic.

“Even though intravenous tissue plasminogen activator has been an enormous breakthrough in stroke therapy, 95% of patients don't get treated with it,” Dr. Furlan said at the annual neurocritical care and stroke conference sponsored by Cleveland Clinic. “[W]e're not going to be treating lots of patients if we're confined to a 3-hour drug. An estimated 80% of stroke patients don't get to the hospital within the first 3 hours after onset.”

Animal trials have shown that desmoteplase—a plasminogen activator derived from vampire bat saliva—may be a better treatment option for acute stroke than is tissue plasminogen activator (TPA) for several reasons. Desmoteplase is not neurotoxic, and it does not activate β-amyloid, unlike TPA. In addition, desmoteplase has a long half-life, which allows for bolus injection. “That's useful for dosing control,” said Dr. Furlan. In animal models, desmoteplase also has been associated with fewer hemorrhages than has TPA.

The Desmoteplase in Acute Ischemic Stroke (DIAS) and the Dose Escalation Study of Desmoteplase in Acute Ischemic Stroke (DEDAS) trials were the first acute stroke thrombolytic trials to select patients for treatment after 3 hours based on perfusion imaging. Dr. Furlan was the principal investigator for the DEDAS trial. Desmoteplase is being jointly developed by Forest Laboratories Inc. and Paion AG.

Enrollment in the DIAS and DEDAS trials was limited to patients who had stroke onset within 3–8 hours and had a 20% perfusion-diffusion mismatch on baseline MRI. Reperfusion was defined as a 30% or better improvement in mean transit time on perfusion MRI or an improvement of two thrombolysis in myocardial infarction (TIMI) flow grades.

In an unpublished pooled analysis of both trials, none of the 35 patients who received placebo or the 30 patients who received 125 mcg/kg desmoteplase (as bolus) had symptomatic intracranial hemorrhage. Only 1 of the 29 patients (3.4%) who received 90 mcg/kg desmoteplase (as bolus) had symptomatic intracranial hemorrhage.

Mortality was 5.7% for the placebo group, 6.9% for the 90 mcg/kg desmoteplase group, and 3.3% for the 125 mcg/kg desmoteplase group. In addition, perfusion at 4–8 hours (based on MRI) was closely linked with clinical outcome at 90 days, with patients in the 125 mcg/kg group having the best results.

Based on a Rankin scale shift analysis of pooled data from the two trials, “at the 125-mcg dose—with a very small number of patients—we had a statistically significant clinical benefit, defined by improvement in Barthel [index], modified Rankin [scale], and NIH [stroke scale],” said Dr. Furlan.

For the 125-mcg dose, at 3 months there was a “statistically significant Rankin shift, meaning that we saw a positive benefit across the whole spectrum of the modified Rankin scale,” said Dr. Furlan.

“Is the drug alone sufficient? Well, my thinking is no. We have to combine the drug with proper patient selection,” he said. Imaging appears to be key to identifying patients who will benefit.

In the Diffusion-Weighted Imaging/Perfusion-Weighted Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) pilot study, researchers attempted to determine if baseline MR images can identify stroke patients who have a good clinical response when treated 3–6 hours after symptom onset.

MRI was performed before and 3–6 hours after treatment with intravenous TPA, administered 3–6 hours after symptom onset. Baseline MRI profiles were used to categorize patients into subgroups, and clinical responses were compared based on whether early reperfusion was achieved.

The researchers identified a specific type of mismatch—malignant mismatch—that was associated with severe intracranial hemorrhage and poor outcome after reperfusion. Malignant mismatch was defined as a defusion lesion greater than 100 cc in volume and/or a perfusion lesion greater than 100 cc in volume.

For patients with target mismatches—all mismatches other than malignant mismatches—with early reperfusion, there was an almost statistically significant clinical benefit, compared with all other mismatch patients. In addition, those with target mismatch and early reperfusion were more likely to achieve a favorable clinical response than were those with target mismatch but no early reperfusion (Ann. Neurol. 2006;60:508–17).

Dr. Furlan disclosed that his research has been supported by Forest Laboratories, Paion, and Abbott and that he has received speaking honoraria from Bristol-Myers Squibb/Sanofi and Genentech.

Right middle cerebral artery occlusion is on baseline magnetic resonance angiogram (top): the defect resolved 28 hours after IV desmoteplase (bottom). Courtesy Dr. Anthony Furlan

BALTIMORE — The investigational drug desmoteplase combined with imaging to identify appropriate patients could push the treatment opening beyond 3 hours for some patients with acute ischemic stroke, according to Dr. Anthony Furlan, section head of stroke and neurologic intensive care at Cleveland Clinic.

“Even though intravenous tissue plasminogen activator has been an enormous breakthrough in stroke therapy, 95% of patients don't get treated with it,” Dr. Furlan said at the annual neurocritical care and stroke conference sponsored by Cleveland Clinic. “[W]e're not going to be treating lots of patients if we're confined to a 3-hour drug. An estimated 80% of stroke patients don't get to the hospital within the first 3 hours after onset.”

Animal trials have shown that desmoteplase—a plasminogen activator derived from vampire bat saliva—may be a better treatment option for acute stroke than is tissue plasminogen activator (TPA) for several reasons. Desmoteplase is not neurotoxic, and it does not activate β-amyloid, unlike TPA. In addition, desmoteplase has a long half-life, which allows for bolus injection. “That's useful for dosing control,” said Dr. Furlan. In animal models, desmoteplase also has been associated with fewer hemorrhages than has TPA.

The Desmoteplase in Acute Ischemic Stroke (DIAS) and the Dose Escalation Study of Desmoteplase in Acute Ischemic Stroke (DEDAS) trials were the first acute stroke thrombolytic trials to select patients for treatment after 3 hours based on perfusion imaging. Dr. Furlan was the principal investigator for the DEDAS trial. Desmoteplase is being jointly developed by Forest Laboratories Inc. and Paion AG.

Enrollment in the DIAS and DEDAS trials was limited to patients who had stroke onset within 3–8 hours and had a 20% perfusion-diffusion mismatch on baseline MRI. Reperfusion was defined as a 30% or better improvement in mean transit time on perfusion MRI or an improvement of two thrombolysis in myocardial infarction (TIMI) flow grades.

In an unpublished pooled analysis of both trials, none of the 35 patients who received placebo or the 30 patients who received 125 mcg/kg desmoteplase (as bolus) had symptomatic intracranial hemorrhage. Only 1 of the 29 patients (3.4%) who received 90 mcg/kg desmoteplase (as bolus) had symptomatic intracranial hemorrhage.

Mortality was 5.7% for the placebo group, 6.9% for the 90 mcg/kg desmoteplase group, and 3.3% for the 125 mcg/kg desmoteplase group. In addition, perfusion at 4–8 hours (based on MRI) was closely linked with clinical outcome at 90 days, with patients in the 125 mcg/kg group having the best results.

Based on a Rankin scale shift analysis of pooled data from the two trials, “at the 125-mcg dose—with a very small number of patients—we had a statistically significant clinical benefit, defined by improvement in Barthel [index], modified Rankin [scale], and NIH [stroke scale],” said Dr. Furlan.

For the 125-mcg dose, at 3 months there was a “statistically significant Rankin shift, meaning that we saw a positive benefit across the whole spectrum of the modified Rankin scale,” said Dr. Furlan.

“Is the drug alone sufficient? Well, my thinking is no. We have to combine the drug with proper patient selection,” he said. Imaging appears to be key to identifying patients who will benefit.

In the Diffusion-Weighted Imaging/Perfusion-Weighted Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) pilot study, researchers attempted to determine if baseline MR images can identify stroke patients who have a good clinical response when treated 3–6 hours after symptom onset.

MRI was performed before and 3–6 hours after treatment with intravenous TPA, administered 3–6 hours after symptom onset. Baseline MRI profiles were used to categorize patients into subgroups, and clinical responses were compared based on whether early reperfusion was achieved.

The researchers identified a specific type of mismatch—malignant mismatch—that was associated with severe intracranial hemorrhage and poor outcome after reperfusion. Malignant mismatch was defined as a defusion lesion greater than 100 cc in volume and/or a perfusion lesion greater than 100 cc in volume.

For patients with target mismatches—all mismatches other than malignant mismatches—with early reperfusion, there was an almost statistically significant clinical benefit, compared with all other mismatch patients. In addition, those with target mismatch and early reperfusion were more likely to achieve a favorable clinical response than were those with target mismatch but no early reperfusion (Ann. Neurol. 2006;60:508–17).

Dr. Furlan disclosed that his research has been supported by Forest Laboratories, Paion, and Abbott and that he has received speaking honoraria from Bristol-Myers Squibb/Sanofi and Genentech.

Right middle cerebral artery occlusion is on baseline magnetic resonance angiogram (top): the defect resolved 28 hours after IV desmoteplase (bottom). Courtesy Dr. Anthony Furlan

WILLIAMSBURG, VA. — Creating the perfect lip may mean telling a patient to step away from the fillers, Dr. Stephen H. Mandy said at a meeting sponsored by Skin Disease Education Foundation.

Following a procedure to increase lip fullness, most patients will want more filler injected. Dr. Mandy tells his patients that if they think they need more, they can come back to him but if he thinks they've had enough, he won't do any additional lip injections. "I just don't want duck lips walking around with my signature on them," he said.

He offered several other tips to create the perfect lip. First, it's important to recognize that there are significant differences in lip shape and size between the races. Even within a racial group, there can be substantial variation. "Look at the patient's lip before you start," said Dr. Mandy, professor of dermatology at the University of Miami.

Be sure to show patients their natural lip asymmetries, if they have any. "If they don't get shown it before hand, they're going to blame it on you," he said.

Sharp definition of the lip margin is critical, so avoid injecting hyaluronic acid there since it blunts or rounds the lip margin. Instead, use collagen injection such as Zyplast or CosmoPlast.

Dr. Mandy uses hyaluronic acid to add fullness to the body of the lip. "If you look at the lip, there is fullness in the lateral portions of the upper lip on each side," he said. These two sites, along with the central tubercle of the top lip and the two medial lower lip protuberances, make up the five sites for hyaluronic acid injection.

Dr. Mandy uses a 0.4-cc syringe. For the lateral portions of the upper lip he injects 0.05 cc on each side. At the central tubercle and at both medial lower lip protuberances, he injects 0.1 cc. Inject along the wet/dry line of the lips in the submucosa to get "a much more natural-looking lip," he said.

In the aging lip, dermatologists may also have to contend with rhytids, volume reduction, elastosis, excess facial hair, and dyspigmentation. For rhytids, he uses botulinum toxin type A in 4–6 injections (1 U total) across the upper lip and about 2 U on the bottom lip. He also uses CosmoDerm to fill rhytids around the lips. He often uses resurfacing as well.

Dr. Mandy disclosed that he has received funding and is a consultant for Surgical Specialties Corp. and Sanofi-Aventis. SDEF and this news organization are wholly owned subsidiaries of Elsevier.

WILLIAMSBURG, VA. — Creating the perfect lip may mean telling a patient to step away from the fillers, Dr. Stephen H. Mandy said at a meeting sponsored by Skin Disease Education Foundation.

Following a procedure to increase lip fullness, most patients will want more filler injected. Dr. Mandy tells his patients that if they think they need more, they can come back to him but if he thinks they've had enough, he won't do any additional lip injections. "I just don't want duck lips walking around with my signature on them," he said.

He offered several other tips to create the perfect lip. First, it's important to recognize that there are significant differences in lip shape and size between the races. Even within a racial group, there can be substantial variation. "Look at the patient's lip before you start," said Dr. Mandy, professor of dermatology at the University of Miami.

Be sure to show patients their natural lip asymmetries, if they have any. "If they don't get shown it before hand, they're going to blame it on you," he said.

Sharp definition of the lip margin is critical, so avoid injecting hyaluronic acid there since it blunts or rounds the lip margin. Instead, use collagen injection such as Zyplast or CosmoPlast.

Dr. Mandy uses hyaluronic acid to add fullness to the body of the lip. "If you look at the lip, there is fullness in the lateral portions of the upper lip on each side," he said. These two sites, along with the central tubercle of the top lip and the two medial lower lip protuberances, make up the five sites for hyaluronic acid injection.

Dr. Mandy uses a 0.4-cc syringe. For the lateral portions of the upper lip he injects 0.05 cc on each side. At the central tubercle and at both medial lower lip protuberances, he injects 0.1 cc. Inject along the wet/dry line of the lips in the submucosa to get "a much more natural-looking lip," he said.

In the aging lip, dermatologists may also have to contend with rhytids, volume reduction, elastosis, excess facial hair, and dyspigmentation. For rhytids, he uses botulinum toxin type A in 4–6 injections (1 U total) across the upper lip and about 2 U on the bottom lip. He also uses CosmoDerm to fill rhytids around the lips. He often uses resurfacing as well.

Dr. Mandy disclosed that he has received funding and is a consultant for Surgical Specialties Corp. and Sanofi-Aventis. SDEF and this news organization are wholly owned subsidiaries of Elsevier.

WILLIAMSBURG, VA. — Creating the perfect lip may mean telling a patient to step away from the fillers, Dr. Stephen H. Mandy said at a meeting sponsored by Skin Disease Education Foundation.

Following a procedure to increase lip fullness, most patients will want more filler injected. Dr. Mandy tells his patients that if they think they need more, they can come back to him but if he thinks they've had enough, he won't do any additional lip injections. "I just don't want duck lips walking around with my signature on them," he said.

He offered several other tips to create the perfect lip. First, it's important to recognize that there are significant differences in lip shape and size between the races. Even within a racial group, there can be substantial variation. "Look at the patient's lip before you start," said Dr. Mandy, professor of dermatology at the University of Miami.

Be sure to show patients their natural lip asymmetries, if they have any. "If they don't get shown it before hand, they're going to blame it on you," he said.

Sharp definition of the lip margin is critical, so avoid injecting hyaluronic acid there since it blunts or rounds the lip margin. Instead, use collagen injection such as Zyplast or CosmoPlast.

Dr. Mandy uses hyaluronic acid to add fullness to the body of the lip. "If you look at the lip, there is fullness in the lateral portions of the upper lip on each side," he said. These two sites, along with the central tubercle of the top lip and the two medial lower lip protuberances, make up the five sites for hyaluronic acid injection.

Dr. Mandy uses a 0.4-cc syringe. For the lateral portions of the upper lip he injects 0.05 cc on each side. At the central tubercle and at both medial lower lip protuberances, he injects 0.1 cc. Inject along the wet/dry line of the lips in the submucosa to get "a much more natural-looking lip," he said.

In the aging lip, dermatologists may also have to contend with rhytids, volume reduction, elastosis, excess facial hair, and dyspigmentation. For rhytids, he uses botulinum toxin type A in 4–6 injections (1 U total) across the upper lip and about 2 U on the bottom lip. He also uses CosmoDerm to fill rhytids around the lips. He often uses resurfacing as well.

Dr. Mandy disclosed that he has received funding and is a consultant for Surgical Specialties Corp. and Sanofi-Aventis. SDEF and this news organization are wholly owned subsidiaries of Elsevier.

PHILADELPHIA — Once-yearly therapy with zoledronic acid has resulted in impressive reductions in fracture incidence at the three most common fracture sites in postmenopausal women with osteoporosis, according to phase III findings presented at the annual meeting of the American Society for Bone and Mineral Research.

An annual infusion of 5 mg of zoledronic acid (Reclast) reduced clinical vertebral fractures by 75%, hip fractures by 40%, and nonvertebral fractures by 25% at the end of 3 years, said Dennis Black, Ph.D., a professor of epidemiology at the University of California, San Francisco.

Zoledronic acid is currently FDA approved (under the name Zometa) for the treatment of patients with hypercalcemia of malignancy, multiple myeloma, and documented bone metastases from solid tumors. The company is working with the FDA to gain approval for the treatment of osteoporosis.

The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (Horizon) Pivotal Fracture Trial was a randomized, double-blind, placebo-controlled trial involving 7,736 postmenopausal women with osteoporosis from 27 countries. The trial was funded by Novartis; Dr. Black disclosed a significant financial relationship with Novartis.

In the trial, women randomized to the treatment group received an annual infusion of zoledronic acid (5 mg). All women received calcium (1,000–1,500 mg/day) and vitamin D (400–1,200 IU/day).

Women were included in the trial if they were aged 65–89 years (mean age, 73 years) with either a femoral neck T score of −2.5 or less or prevalent vertebral fracture and a femoral neck T score of −1.5 or less.

Women were recruited into two groups based on their osteoporosis treatment history. A total of 6,084 women were not currently taking an osteoporosis drug and had minimal prior therapy; 1,652 women were currently taking a selective estrogen-receptor modulator, calcitonin, or hormone therapy for osteoporosis at baseline.

Primary end points included new morphologic vertebral fractures in women not currently taking an osteoporosis drug and hip fractures in both those undergoing and those not undergoing treatment at baseline. Secondary end points included nonvertebral fractures, change in bone mineral density (BMD) measured by dual-energy x-ray absorptiometry, changes in biochemical markers of bone metabolism, and changes in bone density and size determined by quantitative CT. Safety end points included evaluation of adverse events, assessment of bone histology by histomorphometry, and postdose monitoring for acute changes in renal laboratory values.

A total of 3,875 women were randomized to zoledronic acid (3,045 in stratum I and 830 in stratum II), while 3,861 were randomized to placebo (3,039 in stratum I and 822 in stratum II). Dr. Black presented data from the trial start-up to March 31, 2006 (the study was scheduled to end in June 2006). Mean follow-up was 2 years and 8 months. Retention was 84%.

Overall, 3.8% of women receiving treatment had morphometric vertebral fractures at 3 years, compared with 12.8% of women on placebo, representing a 70% reduction. During the first 2 years, there was a 71% reduction, and during the first year, there was a 60% reduction.

“There was a 40% reduction in the risk of hip fractures [at 3 years] that was also highly statistically significant,” Dr. Black said. Clinical vertebral fractures were reduced by 75% and nonvertebral fractures were reduced by 25% in treated women, compared with those on placebo. Lumbar spine BMD was increased by 7% and total hip BMD was increased by 6% in treated women, compared with those on placebo.

In addition, bone markers were measured in a subsample of 605 women (300 on zoledronic acid and 305 on placebo). There was a decline in beta C-telopeptide of type 1 collagen (β-CTX), a bone resorption marker, following the first infusion. “The values remain relatively constant over the 36 months of the study,” Dr. Black said.

The mean β-CTX values for women on zoledronic acid remained within the premenopausal reference range. There was no progressive decline in β-CTX levels over 3 years.

Additional sampling was performed just after the third infusion at 24 months to determine in more detail how β-CTX levels responded to zoledronic acid infusion. “There is an immediate decline in β-CTX values within 10 days after the infusion. But then the levels begin to increase fairly linearly over the course of that third year,” Dr. Black said.

Likewise, there was a decline in bone-specific alkaline phosphatase values following the first infusion of zoledronic acid, but the values remained fairly constant with no progressive decline following subsequent infusions. These values were also within the reference range for premenopausal women.

There were no differences between the treatment and placebo groups in terms of any adverse event, serious adverse events, or discontinuations due to adverse events.

Postdose symptoms were defined as any adverse experience occurring up to 3 days after an infusion. The five most common postdose symptoms were pyrexia, myalgia, flu-like symptoms, headache, and arthralgia. There was “a dramatic decline in the rate of postdose symptoms with the second and third infusions, compared with the first,” Dr. Black said.

Short-term renal safety was monitored by measuring serum creatinine levels at days 9–11 in more than 4,000 subjects. There were transient rises in serum creatinine but in only a very small number of patients. All of the rises resolved, and patients were redosed at their next infusion. Based on these results and other measures of renal safety, the researchers concluded that zoledronic acid infusions had no cumulative impact on renal function.

In terms of cardiac safety, atrial fibrillation was more common in the women on zoledronic acid (1.2%) than in the women on placebo (0.4%). In electrocardiogram studies of 559 women at 9–11 days following the third infusion, there were no differences between the two groups.

There were no spontaneous adverse event reports of osteonecrosis of the jaw. The researchers also searched the database for terms related to the condition. Using the definition “exposed bone in the mouth for longer than 6 weeks,” three cases were identified—two subjects on placebo and one subject on zoledronic acid. All three healed with antibiotic treatment.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA — Once-yearly therapy with zoledronic acid has resulted in impressive reductions in fracture incidence at the three most common fracture sites in postmenopausal women with osteoporosis, according to phase III findings presented at the annual meeting of the American Society for Bone and Mineral Research.

An annual infusion of 5 mg of zoledronic acid (Reclast) reduced clinical vertebral fractures by 75%, hip fractures by 40%, and nonvertebral fractures by 25% at the end of 3 years, said Dennis Black, Ph.D., a professor of epidemiology at the University of California, San Francisco.

Zoledronic acid is currently FDA approved (under the name Zometa) for the treatment of patients with hypercalcemia of malignancy, multiple myeloma, and documented bone metastases from solid tumors. The company is working with the FDA to gain approval for the treatment of osteoporosis.

The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (Horizon) Pivotal Fracture Trial was a randomized, double-blind, placebo-controlled trial involving 7,736 postmenopausal women with osteoporosis from 27 countries. The trial was funded by Novartis; Dr. Black disclosed a significant financial relationship with Novartis.

In the trial, women randomized to the treatment group received an annual infusion of zoledronic acid (5 mg). All women received calcium (1,000–1,500 mg/day) and vitamin D (400–1,200 IU/day).

Women were included in the trial if they were aged 65–89 years (mean age, 73 years) with either a femoral neck T score of −2.5 or less or prevalent vertebral fracture and a femoral neck T score of −1.5 or less.

Women were recruited into two groups based on their osteoporosis treatment history. A total of 6,084 women were not currently taking an osteoporosis drug and had minimal prior therapy; 1,652 women were currently taking a selective estrogen-receptor modulator, calcitonin, or hormone therapy for osteoporosis at baseline.

Primary end points included new morphologic vertebral fractures in women not currently taking an osteoporosis drug and hip fractures in both those undergoing and those not undergoing treatment at baseline. Secondary end points included nonvertebral fractures, change in bone mineral density (BMD) measured by dual-energy x-ray absorptiometry, changes in biochemical markers of bone metabolism, and changes in bone density and size determined by quantitative CT. Safety end points included evaluation of adverse events, assessment of bone histology by histomorphometry, and postdose monitoring for acute changes in renal laboratory values.

A total of 3,875 women were randomized to zoledronic acid (3,045 in stratum I and 830 in stratum II), while 3,861 were randomized to placebo (3,039 in stratum I and 822 in stratum II). Dr. Black presented data from the trial start-up to March 31, 2006 (the study was scheduled to end in June 2006). Mean follow-up was 2 years and 8 months. Retention was 84%.

Overall, 3.8% of women receiving treatment had morphometric vertebral fractures at 3 years, compared with 12.8% of women on placebo, representing a 70% reduction. During the first 2 years, there was a 71% reduction, and during the first year, there was a 60% reduction.

“There was a 40% reduction in the risk of hip fractures [at 3 years] that was also highly statistically significant,” Dr. Black said. Clinical vertebral fractures were reduced by 75% and nonvertebral fractures were reduced by 25% in treated women, compared with those on placebo. Lumbar spine BMD was increased by 7% and total hip BMD was increased by 6% in treated women, compared with those on placebo.

In addition, bone markers were measured in a subsample of 605 women (300 on zoledronic acid and 305 on placebo). There was a decline in beta C-telopeptide of type 1 collagen (β-CTX), a bone resorption marker, following the first infusion. “The values remain relatively constant over the 36 months of the study,” Dr. Black said.

The mean β-CTX values for women on zoledronic acid remained within the premenopausal reference range. There was no progressive decline in β-CTX levels over 3 years.

Additional sampling was performed just after the third infusion at 24 months to determine in more detail how β-CTX levels responded to zoledronic acid infusion. “There is an immediate decline in β-CTX values within 10 days after the infusion. But then the levels begin to increase fairly linearly over the course of that third year,” Dr. Black said.

Likewise, there was a decline in bone-specific alkaline phosphatase values following the first infusion of zoledronic acid, but the values remained fairly constant with no progressive decline following subsequent infusions. These values were also within the reference range for premenopausal women.

There were no differences between the treatment and placebo groups in terms of any adverse event, serious adverse events, or discontinuations due to adverse events.

Postdose symptoms were defined as any adverse experience occurring up to 3 days after an infusion. The five most common postdose symptoms were pyrexia, myalgia, flu-like symptoms, headache, and arthralgia. There was “a dramatic decline in the rate of postdose symptoms with the second and third infusions, compared with the first,” Dr. Black said.

Short-term renal safety was monitored by measuring serum creatinine levels at days 9–11 in more than 4,000 subjects. There were transient rises in serum creatinine but in only a very small number of patients. All of the rises resolved, and patients were redosed at their next infusion. Based on these results and other measures of renal safety, the researchers concluded that zoledronic acid infusions had no cumulative impact on renal function.

In terms of cardiac safety, atrial fibrillation was more common in the women on zoledronic acid (1.2%) than in the women on placebo (0.4%). In electrocardiogram studies of 559 women at 9–11 days following the third infusion, there were no differences between the two groups.

There were no spontaneous adverse event reports of osteonecrosis of the jaw. The researchers also searched the database for terms related to the condition. Using the definition “exposed bone in the mouth for longer than 6 weeks,” three cases were identified—two subjects on placebo and one subject on zoledronic acid. All three healed with antibiotic treatment.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA — Once-yearly therapy with zoledronic acid has resulted in impressive reductions in fracture incidence at the three most common fracture sites in postmenopausal women with osteoporosis, according to phase III findings presented at the annual meeting of the American Society for Bone and Mineral Research.

An annual infusion of 5 mg of zoledronic acid (Reclast) reduced clinical vertebral fractures by 75%, hip fractures by 40%, and nonvertebral fractures by 25% at the end of 3 years, said Dennis Black, Ph.D., a professor of epidemiology at the University of California, San Francisco.

Zoledronic acid is currently FDA approved (under the name Zometa) for the treatment of patients with hypercalcemia of malignancy, multiple myeloma, and documented bone metastases from solid tumors. The company is working with the FDA to gain approval for the treatment of osteoporosis.

The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (Horizon) Pivotal Fracture Trial was a randomized, double-blind, placebo-controlled trial involving 7,736 postmenopausal women with osteoporosis from 27 countries. The trial was funded by Novartis; Dr. Black disclosed a significant financial relationship with Novartis.

In the trial, women randomized to the treatment group received an annual infusion of zoledronic acid (5 mg). All women received calcium (1,000–1,500 mg/day) and vitamin D (400–1,200 IU/day).

Women were included in the trial if they were aged 65–89 years (mean age, 73 years) with either a femoral neck T score of −2.5 or less or prevalent vertebral fracture and a femoral neck T score of −1.5 or less.

Women were recruited into two groups based on their osteoporosis treatment history. A total of 6,084 women were not currently taking an osteoporosis drug and had minimal prior therapy; 1,652 women were currently taking a selective estrogen-receptor modulator, calcitonin, or hormone therapy for osteoporosis at baseline.

Primary end points included new morphologic vertebral fractures in women not currently taking an osteoporosis drug and hip fractures in both those undergoing and those not undergoing treatment at baseline. Secondary end points included nonvertebral fractures, change in bone mineral density (BMD) measured by dual-energy x-ray absorptiometry, changes in biochemical markers of bone metabolism, and changes in bone density and size determined by quantitative CT. Safety end points included evaluation of adverse events, assessment of bone histology by histomorphometry, and postdose monitoring for acute changes in renal laboratory values.

A total of 3,875 women were randomized to zoledronic acid (3,045 in stratum I and 830 in stratum II), while 3,861 were randomized to placebo (3,039 in stratum I and 822 in stratum II). Dr. Black presented data from the trial start-up to March 31, 2006 (the study was scheduled to end in June 2006). Mean follow-up was 2 years and 8 months. Retention was 84%.

Overall, 3.8% of women receiving treatment had morphometric vertebral fractures at 3 years, compared with 12.8% of women on placebo, representing a 70% reduction. During the first 2 years, there was a 71% reduction, and during the first year, there was a 60% reduction.

“There was a 40% reduction in the risk of hip fractures [at 3 years] that was also highly statistically significant,” Dr. Black said. Clinical vertebral fractures were reduced by 75% and nonvertebral fractures were reduced by 25% in treated women, compared with those on placebo. Lumbar spine BMD was increased by 7% and total hip BMD was increased by 6% in treated women, compared with those on placebo.

In addition, bone markers were measured in a subsample of 605 women (300 on zoledronic acid and 305 on placebo). There was a decline in beta C-telopeptide of type 1 collagen (β-CTX), a bone resorption marker, following the first infusion. “The values remain relatively constant over the 36 months of the study,” Dr. Black said.

The mean β-CTX values for women on zoledronic acid remained within the premenopausal reference range. There was no progressive decline in β-CTX levels over 3 years.

Additional sampling was performed just after the third infusion at 24 months to determine in more detail how β-CTX levels responded to zoledronic acid infusion. “There is an immediate decline in β-CTX values within 10 days after the infusion. But then the levels begin to increase fairly linearly over the course of that third year,” Dr. Black said.

Likewise, there was a decline in bone-specific alkaline phosphatase values following the first infusion of zoledronic acid, but the values remained fairly constant with no progressive decline following subsequent infusions. These values were also within the reference range for premenopausal women.

There were no differences between the treatment and placebo groups in terms of any adverse event, serious adverse events, or discontinuations due to adverse events.

Postdose symptoms were defined as any adverse experience occurring up to 3 days after an infusion. The five most common postdose symptoms were pyrexia, myalgia, flu-like symptoms, headache, and arthralgia. There was “a dramatic decline in the rate of postdose symptoms with the second and third infusions, compared with the first,” Dr. Black said.

Short-term renal safety was monitored by measuring serum creatinine levels at days 9–11 in more than 4,000 subjects. There were transient rises in serum creatinine but in only a very small number of patients. All of the rises resolved, and patients were redosed at their next infusion. Based on these results and other measures of renal safety, the researchers concluded that zoledronic acid infusions had no cumulative impact on renal function.

In terms of cardiac safety, atrial fibrillation was more common in the women on zoledronic acid (1.2%) than in the women on placebo (0.4%). In electrocardiogram studies of 559 women at 9–11 days following the third infusion, there were no differences between the two groups.

There were no spontaneous adverse event reports of osteonecrosis of the jaw. The researchers also searched the database for terms related to the condition. Using the definition “exposed bone in the mouth for longer than 6 weeks,” three cases were identified—two subjects on placebo and one subject on zoledronic acid. All three healed with antibiotic treatment.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA — Intermittent intravenous injections of ibandronate continue to improve bone mineral density of the spine and hip at 2 years, according to data that were presented at the annual meeting of the American Society for Bone and Mineral Research.

The 2-year results from the Dosing IntraVenous Administration (DIVA) study show that IV ibandronate injections every 2 or 3 months were superior to oral daily ibandronate (Boniva) in terms of increased bone mineral density (BMD) at the lumbar spine. The periodic IV injections were also superior to oral daily ibandronate at 1 and 2 years in terms of increased BMD for the total hip, femoral neck, and trochanter.

“IV ibandronate injections improve BMD at the spine and the hip [and] they produce superior BMD gains to oral dosing,” said Dr. E. Michael Lewiecki, who is both the osteoporosis director of the New Mexico Clinical Research and Osteoporosis Center and also a professor of medicine at the University of New Mexico in Albuquerque.

The study was funded in part by F. Hoffman-La Roche Ltd. as well as by GlaxoSmithKline. Dr. Lewiecki disclosed that he has received research grants from both of those companies.

DIVA was a randomized, double-blind, active-control study involving women aged 55–80 years, who were at least 5 years postmenopausal and who had a lumbar spine T score less than −2.5.

Overall 1,395 women were randomized to receive 2-mg IV ibandronate injections every 2 months (454 women), 3 mg IV ibandronate every 3 months (472 women), or 2.5 mg daily oral ibandronate (469 women).

All of the women also received daily calcium (500 mg) and vitamin D (400 IU) supplements.

The study's primary end point was mean percent change from baseline in lumbar spine BMD at 1 year, and these results were presented at the 2005 annual meeting of the American College of Rheumatology.

The secondary end points of the study included mean percent change from baseline in lumbar spine BMD at 2 years, and mean percent change from baseline in total hip, femoral neck, and trochanter BMD at 1 and 2 years.

In early 2006, the Food and Drug Administration approved the 3-mg trimonthly ibandronate IV injection for the treatment of postmenopausal osteoporosis.

“These data support the use of the every-3-month regimen in clinical practice,” Dr. Lewiecki said.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA — Intermittent intravenous injections of ibandronate continue to improve bone mineral density of the spine and hip at 2 years, according to data that were presented at the annual meeting of the American Society for Bone and Mineral Research.

The 2-year results from the Dosing IntraVenous Administration (DIVA) study show that IV ibandronate injections every 2 or 3 months were superior to oral daily ibandronate (Boniva) in terms of increased bone mineral density (BMD) at the lumbar spine. The periodic IV injections were also superior to oral daily ibandronate at 1 and 2 years in terms of increased BMD for the total hip, femoral neck, and trochanter.

“IV ibandronate injections improve BMD at the spine and the hip [and] they produce superior BMD gains to oral dosing,” said Dr. E. Michael Lewiecki, who is both the osteoporosis director of the New Mexico Clinical Research and Osteoporosis Center and also a professor of medicine at the University of New Mexico in Albuquerque.

The study was funded in part by F. Hoffman-La Roche Ltd. as well as by GlaxoSmithKline. Dr. Lewiecki disclosed that he has received research grants from both of those companies.

DIVA was a randomized, double-blind, active-control study involving women aged 55–80 years, who were at least 5 years postmenopausal and who had a lumbar spine T score less than −2.5.

Overall 1,395 women were randomized to receive 2-mg IV ibandronate injections every 2 months (454 women), 3 mg IV ibandronate every 3 months (472 women), or 2.5 mg daily oral ibandronate (469 women).

All of the women also received daily calcium (500 mg) and vitamin D (400 IU) supplements.

The study's primary end point was mean percent change from baseline in lumbar spine BMD at 1 year, and these results were presented at the 2005 annual meeting of the American College of Rheumatology.

The secondary end points of the study included mean percent change from baseline in lumbar spine BMD at 2 years, and mean percent change from baseline in total hip, femoral neck, and trochanter BMD at 1 and 2 years.

In early 2006, the Food and Drug Administration approved the 3-mg trimonthly ibandronate IV injection for the treatment of postmenopausal osteoporosis.

“These data support the use of the every-3-month regimen in clinical practice,” Dr. Lewiecki said.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA — Intermittent intravenous injections of ibandronate continue to improve bone mineral density of the spine and hip at 2 years, according to data that were presented at the annual meeting of the American Society for Bone and Mineral Research.

The 2-year results from the Dosing IntraVenous Administration (DIVA) study show that IV ibandronate injections every 2 or 3 months were superior to oral daily ibandronate (Boniva) in terms of increased bone mineral density (BMD) at the lumbar spine. The periodic IV injections were also superior to oral daily ibandronate at 1 and 2 years in terms of increased BMD for the total hip, femoral neck, and trochanter.

“IV ibandronate injections improve BMD at the spine and the hip [and] they produce superior BMD gains to oral dosing,” said Dr. E. Michael Lewiecki, who is both the osteoporosis director of the New Mexico Clinical Research and Osteoporosis Center and also a professor of medicine at the University of New Mexico in Albuquerque.

The study was funded in part by F. Hoffman-La Roche Ltd. as well as by GlaxoSmithKline. Dr. Lewiecki disclosed that he has received research grants from both of those companies.

DIVA was a randomized, double-blind, active-control study involving women aged 55–80 years, who were at least 5 years postmenopausal and who had a lumbar spine T score less than −2.5.

Overall 1,395 women were randomized to receive 2-mg IV ibandronate injections every 2 months (454 women), 3 mg IV ibandronate every 3 months (472 women), or 2.5 mg daily oral ibandronate (469 women).

All of the women also received daily calcium (500 mg) and vitamin D (400 IU) supplements.

The study's primary end point was mean percent change from baseline in lumbar spine BMD at 1 year, and these results were presented at the 2005 annual meeting of the American College of Rheumatology.

The secondary end points of the study included mean percent change from baseline in lumbar spine BMD at 2 years, and mean percent change from baseline in total hip, femoral neck, and trochanter BMD at 1 and 2 years.

In early 2006, the Food and Drug Administration approved the 3-mg trimonthly ibandronate IV injection for the treatment of postmenopausal osteoporosis.

“These data support the use of the every-3-month regimen in clinical practice,” Dr. Lewiecki said.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA — Balicatib, an investigational agent that belongs to a new class of osteoporosis drugs, appears comparable to bisphosphonate therapy in increasing bone mineral density in postmenopausal women, according to trial results presented at the annual meeting of the American Society for Bone and Mineral Research.

“Balicatib was able to increase [bone mineral density] at both the spine and hip, with changes very similar to those seen with bisphosphonates,” said Dr. Silvano Adami.

Balicatib inhibits cathepsin K, a cysteine protease that plays an important role in the pathologic process of bone resorption. Cathepsin K is highly and selectively expressed by osteoclasts. Selective cathepsin K inhibitors provide a new method of action for reducing bone resorption and improving BMD.

In this randomized, placebo-controlled trial, 675 postmenopausal women with lumbar spine BMD T scores of less than −2 were randomized to receive 5 mg, 10 mg, 25mg, or 50 mg of daily oral balicatib or placebo, said Dr. Adami, head of gastroenterologic, rheumatologic, and vascular rehabilitation at the University of Verona (Italy). All patients received calcium and vitamin D supplements.

The women were assessed with dual-energy x-ray absorptiometry (DXA) measurements of spine and hip BMD, and levels of bone formation and resorption biomarkers were measured.

At baseline, the average patient age was 62 years. The average lumbar spine and total hip T scores were −2.6 and −1.4, respectively; 87% of the women had no morphometric vertebral fractures.

Following 1 year of treatment with balicatib, “the changes in BMD were quite remarkable,” said Dr. Adami. “With the highest dose [50 mg/day], the change in spine BMD was similar to that which [can be] achieved with bisphosphonate therapy.” Overall there was a dose-related increase in both spine and hip BMD (see table).

In terms of bone resorption, the researchers looked at levels of urinary N-terminal cross-linked telopeptides of type I collagen (normalized with respect to urine creatinine) and serum C-terminal collagen I telopeptide (CTX).

In the first month of treatment, a decrease was observed in serum CTX levels. However, over the next 11 months, there was a trend of rising CTX levels in all patients—even those in the placebo group. “We do not have an explanation,” said Dr. Adami. Overall, there was also a dose-related decrease in serum CTX and urinary NTX levels.

In terms of biomarkers of bone formation, the researchers measured serum osteocalcin and NTX. Serum osteocalcin and NTX decreased somewhat during the early stages but at 12 months, no differences were observed between the treated and placebo patients. Overall, bone resorption markers were decreased, while bone formation markers remained the same.

The numbers of adverse events were very similar between all of the groups. Two patients developed sclerodermic/morphea-like lesions, which improved when the treatment was stopped, Dr. Adami reported.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA — Balicatib, an investigational agent that belongs to a new class of osteoporosis drugs, appears comparable to bisphosphonate therapy in increasing bone mineral density in postmenopausal women, according to trial results presented at the annual meeting of the American Society for Bone and Mineral Research.

“Balicatib was able to increase [bone mineral density] at both the spine and hip, with changes very similar to those seen with bisphosphonates,” said Dr. Silvano Adami.

Balicatib inhibits cathepsin K, a cysteine protease that plays an important role in the pathologic process of bone resorption. Cathepsin K is highly and selectively expressed by osteoclasts. Selective cathepsin K inhibitors provide a new method of action for reducing bone resorption and improving BMD.

In this randomized, placebo-controlled trial, 675 postmenopausal women with lumbar spine BMD T scores of less than −2 were randomized to receive 5 mg, 10 mg, 25mg, or 50 mg of daily oral balicatib or placebo, said Dr. Adami, head of gastroenterologic, rheumatologic, and vascular rehabilitation at the University of Verona (Italy). All patients received calcium and vitamin D supplements.

The women were assessed with dual-energy x-ray absorptiometry (DXA) measurements of spine and hip BMD, and levels of bone formation and resorption biomarkers were measured.

At baseline, the average patient age was 62 years. The average lumbar spine and total hip T scores were −2.6 and −1.4, respectively; 87% of the women had no morphometric vertebral fractures.

Following 1 year of treatment with balicatib, “the changes in BMD were quite remarkable,” said Dr. Adami. “With the highest dose [50 mg/day], the change in spine BMD was similar to that which [can be] achieved with bisphosphonate therapy.” Overall there was a dose-related increase in both spine and hip BMD (see table).

In terms of bone resorption, the researchers looked at levels of urinary N-terminal cross-linked telopeptides of type I collagen (normalized with respect to urine creatinine) and serum C-terminal collagen I telopeptide (CTX).

In the first month of treatment, a decrease was observed in serum CTX levels. However, over the next 11 months, there was a trend of rising CTX levels in all patients—even those in the placebo group. “We do not have an explanation,” said Dr. Adami. Overall, there was also a dose-related decrease in serum CTX and urinary NTX levels.

In terms of biomarkers of bone formation, the researchers measured serum osteocalcin and NTX. Serum osteocalcin and NTX decreased somewhat during the early stages but at 12 months, no differences were observed between the treated and placebo patients. Overall, bone resorption markers were decreased, while bone formation markers remained the same.

The numbers of adverse events were very similar between all of the groups. Two patients developed sclerodermic/morphea-like lesions, which improved when the treatment was stopped, Dr. Adami reported.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA — Balicatib, an investigational agent that belongs to a new class of osteoporosis drugs, appears comparable to bisphosphonate therapy in increasing bone mineral density in postmenopausal women, according to trial results presented at the annual meeting of the American Society for Bone and Mineral Research.

“Balicatib was able to increase [bone mineral density] at both the spine and hip, with changes very similar to those seen with bisphosphonates,” said Dr. Silvano Adami.

Balicatib inhibits cathepsin K, a cysteine protease that plays an important role in the pathologic process of bone resorption. Cathepsin K is highly and selectively expressed by osteoclasts. Selective cathepsin K inhibitors provide a new method of action for reducing bone resorption and improving BMD.

In this randomized, placebo-controlled trial, 675 postmenopausal women with lumbar spine BMD T scores of less than −2 were randomized to receive 5 mg, 10 mg, 25mg, or 50 mg of daily oral balicatib or placebo, said Dr. Adami, head of gastroenterologic, rheumatologic, and vascular rehabilitation at the University of Verona (Italy). All patients received calcium and vitamin D supplements.

The women were assessed with dual-energy x-ray absorptiometry (DXA) measurements of spine and hip BMD, and levels of bone formation and resorption biomarkers were measured.

At baseline, the average patient age was 62 years. The average lumbar spine and total hip T scores were −2.6 and −1.4, respectively; 87% of the women had no morphometric vertebral fractures.

Following 1 year of treatment with balicatib, “the changes in BMD were quite remarkable,” said Dr. Adami. “With the highest dose [50 mg/day], the change in spine BMD was similar to that which [can be] achieved with bisphosphonate therapy.” Overall there was a dose-related increase in both spine and hip BMD (see table).

In terms of bone resorption, the researchers looked at levels of urinary N-terminal cross-linked telopeptides of type I collagen (normalized with respect to urine creatinine) and serum C-terminal collagen I telopeptide (CTX).

In the first month of treatment, a decrease was observed in serum CTX levels. However, over the next 11 months, there was a trend of rising CTX levels in all patients—even those in the placebo group. “We do not have an explanation,” said Dr. Adami. Overall, there was also a dose-related decrease in serum CTX and urinary NTX levels.

In terms of biomarkers of bone formation, the researchers measured serum osteocalcin and NTX. Serum osteocalcin and NTX decreased somewhat during the early stages but at 12 months, no differences were observed between the treated and placebo patients. Overall, bone resorption markers were decreased, while bone formation markers remained the same.

The numbers of adverse events were very similar between all of the groups. Two patients developed sclerodermic/morphea-like lesions, which improved when the treatment was stopped, Dr. Adami reported.

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