User login
Vitamin D Assays Flawed, but Improving
MINNEAPOLIS – Some day physicians will be able to order detailed vitamin D assay panels much like the lipid panels used today to assess cholesterol.
We’re just not there yet.
“Where we’re at today with 25-hydroxyvitamin D measurement is where we were at 50 or 60 years ago with lipid measurement ... but I believe vitamin D assay panels are coming,” said Dr. Neil C. Binkley of the Institute on Aging at the University of Wisconsin, Madison.
Part of the problem with 25-hydroxyvitamin D [25(OH)D] measurement is that it has not yet been standardized, and there is no agreement on which cut points should be used by laboratories and assay manufacturers.
In its 2011 report that set for the first time Recommended Dietary Allowances for calcium and vitamin D, the Institute of Medicine declared an “urgent clinical and public health need” to reassess laboratory ranges for 25(OH)D to avoid problems of overtreatment and undertreatment.
The IOM committee concluded that the prevalence of vitamin D deficiency in North Americans has been overestimated by some because of the use of “inappropriate cut points” that greatly exceed levels identified in the report (J. Clin. Endocrinol. Metab. 2011;96:53-8).
Substantial progress has been made in the past decade, thanks in large part to the work of Dr. Graham Carter and DEQAS, the Vitamin D External Quality Assessment Scheme, Dr. Binkley said at the annual meeting of the American Society for Bone and Mineral Research. DEQAS provides serum samples on a quarterly basis to laboratories that wish to check the accuracy of their assays, and statistically trims the data to produce an all-laboratory trimmed mean (ALTM), standard deviation, and coefficient of variation for all major methodologies. Recent DEQAS data show, however, that ALTMs can vary substantially, even among groups striving to improve the quality of their program, he said.
In 2010, the National Institutes of Health Office of Dietary Supplements also launched the international vitamin D standardization program dedicated to standardizing 25(OH)D measurement to the National Institute of Standards and Technology (NIST) reference procedures. The program recently began quantitating DEQAS materials with real values assigned by NIST, and is also working on standardizing measurements for 25(OH)D2 and D3, the C-3 epimer of 25(OH)D2 and D3, and 24,25(OH)2D, he said.
“This, I think, is a substantial positive development; however, despite these efforts some scatter is going to persist in 25(OH)D measurement,” Dr. Binkley said.
The reason for this is that analyses will pick up components of a sample other than the analyte – a phenomenon known as the matrix effect. Given the number of vitamin D metabolites that exist, it’s not surprising that assays have trouble identifying one analyte from other similar analytes, he explained.
One of those confounders is the C-3 epimer (3-epi) of 25(OH)D3, which was previously thought to exist in infants only and, as such, wasn’t of much concern, but is now known to be present at variable, albeit low, levels in virtually all human serum (J. Clin. Endocrinol. Metab. 2012;97:163-8). Since 3-epi has the same molecular structure and molecular weight as 25(OH)D, it’s not surprising that it can add “noise” to your 25(OH)D result, Dr. Binkley said.
Another confounder is 24,25(OH)2D3, which has historically been considered as simply an inactivating step in the 25(OH)D degradation pathway on the way to calcitroic acid. As such, many feel it isn’t worth measuring, he said. Recent studies, however, have found that 24,25(OH)2D3 possesses physiologic effects on cartilage and bone, and that once again, it is present at variable levels in adults up to about 10% of the 25(OH)D level.
“Three of our current immunoassays that I know of have 100% cross-reactivity with 24,25-dihydroxyvitamin D3, so when you’re measuring 25-hydroxyvitamin D, you are also measuring 24,25-dihydroxyvitamin D3,” he said.
A more recent study reports that patients with high levels of serum 24,25-dihydroxyvitamin D3 may have a less robust response to vitamin D3 (J. Steroid. Biochem. Mol. Biol. 2011;126:72-7).
Finally, two additional studies find that vitamin D3 is more potent at increasing 25(OH)D than is vitamin D2, but what may be more important is whether current assays can measure the two equally, Dr. Binkley said. Indeed, unpublished data he presented clearly show that a newer immunoassay was not up to the task.
“By prescribing ergocalciferol, we clinicians are needlessly making life more difficult for our laboratory colleagues” and unnecessarily confounding assay methodologies, he said.
Dr. Binkley reported that he had no relevant financial disclosures.
MINNEAPOLIS – Some day physicians will be able to order detailed vitamin D assay panels much like the lipid panels used today to assess cholesterol.
We’re just not there yet.
“Where we’re at today with 25-hydroxyvitamin D measurement is where we were at 50 or 60 years ago with lipid measurement ... but I believe vitamin D assay panels are coming,” said Dr. Neil C. Binkley of the Institute on Aging at the University of Wisconsin, Madison.
Part of the problem with 25-hydroxyvitamin D [25(OH)D] measurement is that it has not yet been standardized, and there is no agreement on which cut points should be used by laboratories and assay manufacturers.
In its 2011 report that set for the first time Recommended Dietary Allowances for calcium and vitamin D, the Institute of Medicine declared an “urgent clinical and public health need” to reassess laboratory ranges for 25(OH)D to avoid problems of overtreatment and undertreatment.
The IOM committee concluded that the prevalence of vitamin D deficiency in North Americans has been overestimated by some because of the use of “inappropriate cut points” that greatly exceed levels identified in the report (J. Clin. Endocrinol. Metab. 2011;96:53-8).
Substantial progress has been made in the past decade, thanks in large part to the work of Dr. Graham Carter and DEQAS, the Vitamin D External Quality Assessment Scheme, Dr. Binkley said at the annual meeting of the American Society for Bone and Mineral Research. DEQAS provides serum samples on a quarterly basis to laboratories that wish to check the accuracy of their assays, and statistically trims the data to produce an all-laboratory trimmed mean (ALTM), standard deviation, and coefficient of variation for all major methodologies. Recent DEQAS data show, however, that ALTMs can vary substantially, even among groups striving to improve the quality of their program, he said.
In 2010, the National Institutes of Health Office of Dietary Supplements also launched the international vitamin D standardization program dedicated to standardizing 25(OH)D measurement to the National Institute of Standards and Technology (NIST) reference procedures. The program recently began quantitating DEQAS materials with real values assigned by NIST, and is also working on standardizing measurements for 25(OH)D2 and D3, the C-3 epimer of 25(OH)D2 and D3, and 24,25(OH)2D, he said.
“This, I think, is a substantial positive development; however, despite these efforts some scatter is going to persist in 25(OH)D measurement,” Dr. Binkley said.
The reason for this is that analyses will pick up components of a sample other than the analyte – a phenomenon known as the matrix effect. Given the number of vitamin D metabolites that exist, it’s not surprising that assays have trouble identifying one analyte from other similar analytes, he explained.
One of those confounders is the C-3 epimer (3-epi) of 25(OH)D3, which was previously thought to exist in infants only and, as such, wasn’t of much concern, but is now known to be present at variable, albeit low, levels in virtually all human serum (J. Clin. Endocrinol. Metab. 2012;97:163-8). Since 3-epi has the same molecular structure and molecular weight as 25(OH)D, it’s not surprising that it can add “noise” to your 25(OH)D result, Dr. Binkley said.
Another confounder is 24,25(OH)2D3, which has historically been considered as simply an inactivating step in the 25(OH)D degradation pathway on the way to calcitroic acid. As such, many feel it isn’t worth measuring, he said. Recent studies, however, have found that 24,25(OH)2D3 possesses physiologic effects on cartilage and bone, and that once again, it is present at variable levels in adults up to about 10% of the 25(OH)D level.
“Three of our current immunoassays that I know of have 100% cross-reactivity with 24,25-dihydroxyvitamin D3, so when you’re measuring 25-hydroxyvitamin D, you are also measuring 24,25-dihydroxyvitamin D3,” he said.
A more recent study reports that patients with high levels of serum 24,25-dihydroxyvitamin D3 may have a less robust response to vitamin D3 (J. Steroid. Biochem. Mol. Biol. 2011;126:72-7).
Finally, two additional studies find that vitamin D3 is more potent at increasing 25(OH)D than is vitamin D2, but what may be more important is whether current assays can measure the two equally, Dr. Binkley said. Indeed, unpublished data he presented clearly show that a newer immunoassay was not up to the task.
“By prescribing ergocalciferol, we clinicians are needlessly making life more difficult for our laboratory colleagues” and unnecessarily confounding assay methodologies, he said.
Dr. Binkley reported that he had no relevant financial disclosures.
MINNEAPOLIS – Some day physicians will be able to order detailed vitamin D assay panels much like the lipid panels used today to assess cholesterol.
We’re just not there yet.
“Where we’re at today with 25-hydroxyvitamin D measurement is where we were at 50 or 60 years ago with lipid measurement ... but I believe vitamin D assay panels are coming,” said Dr. Neil C. Binkley of the Institute on Aging at the University of Wisconsin, Madison.
Part of the problem with 25-hydroxyvitamin D [25(OH)D] measurement is that it has not yet been standardized, and there is no agreement on which cut points should be used by laboratories and assay manufacturers.
In its 2011 report that set for the first time Recommended Dietary Allowances for calcium and vitamin D, the Institute of Medicine declared an “urgent clinical and public health need” to reassess laboratory ranges for 25(OH)D to avoid problems of overtreatment and undertreatment.
The IOM committee concluded that the prevalence of vitamin D deficiency in North Americans has been overestimated by some because of the use of “inappropriate cut points” that greatly exceed levels identified in the report (J. Clin. Endocrinol. Metab. 2011;96:53-8).
Substantial progress has been made in the past decade, thanks in large part to the work of Dr. Graham Carter and DEQAS, the Vitamin D External Quality Assessment Scheme, Dr. Binkley said at the annual meeting of the American Society for Bone and Mineral Research. DEQAS provides serum samples on a quarterly basis to laboratories that wish to check the accuracy of their assays, and statistically trims the data to produce an all-laboratory trimmed mean (ALTM), standard deviation, and coefficient of variation for all major methodologies. Recent DEQAS data show, however, that ALTMs can vary substantially, even among groups striving to improve the quality of their program, he said.
In 2010, the National Institutes of Health Office of Dietary Supplements also launched the international vitamin D standardization program dedicated to standardizing 25(OH)D measurement to the National Institute of Standards and Technology (NIST) reference procedures. The program recently began quantitating DEQAS materials with real values assigned by NIST, and is also working on standardizing measurements for 25(OH)D2 and D3, the C-3 epimer of 25(OH)D2 and D3, and 24,25(OH)2D, he said.
“This, I think, is a substantial positive development; however, despite these efforts some scatter is going to persist in 25(OH)D measurement,” Dr. Binkley said.
The reason for this is that analyses will pick up components of a sample other than the analyte – a phenomenon known as the matrix effect. Given the number of vitamin D metabolites that exist, it’s not surprising that assays have trouble identifying one analyte from other similar analytes, he explained.
One of those confounders is the C-3 epimer (3-epi) of 25(OH)D3, which was previously thought to exist in infants only and, as such, wasn’t of much concern, but is now known to be present at variable, albeit low, levels in virtually all human serum (J. Clin. Endocrinol. Metab. 2012;97:163-8). Since 3-epi has the same molecular structure and molecular weight as 25(OH)D, it’s not surprising that it can add “noise” to your 25(OH)D result, Dr. Binkley said.
Another confounder is 24,25(OH)2D3, which has historically been considered as simply an inactivating step in the 25(OH)D degradation pathway on the way to calcitroic acid. As such, many feel it isn’t worth measuring, he said. Recent studies, however, have found that 24,25(OH)2D3 possesses physiologic effects on cartilage and bone, and that once again, it is present at variable levels in adults up to about 10% of the 25(OH)D level.
“Three of our current immunoassays that I know of have 100% cross-reactivity with 24,25-dihydroxyvitamin D3, so when you’re measuring 25-hydroxyvitamin D, you are also measuring 24,25-dihydroxyvitamin D3,” he said.
A more recent study reports that patients with high levels of serum 24,25-dihydroxyvitamin D3 may have a less robust response to vitamin D3 (J. Steroid. Biochem. Mol. Biol. 2011;126:72-7).
Finally, two additional studies find that vitamin D3 is more potent at increasing 25(OH)D than is vitamin D2, but what may be more important is whether current assays can measure the two equally, Dr. Binkley said. Indeed, unpublished data he presented clearly show that a newer immunoassay was not up to the task.
“By prescribing ergocalciferol, we clinicians are needlessly making life more difficult for our laboratory colleagues” and unnecessarily confounding assay methodologies, he said.
Dr. Binkley reported that he had no relevant financial disclosures.
EXPERT ANALYSIS FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH
New Assay Simultaneously Measures Vitamin D Metabolites
MINNEAPOLIS – A new automated assay can measure concentrations of both 24,25-dihydroxyvitamin D2 and D3 in human serum.
Current assays based on competitive binding experiments can differentiate between 24,25-dihydroxyvitamin D3 and D2, but are time consuming and not easily automated. Also, immunoassays fail to differentiate between 25-hydroxyvitamin D and 24,25-dihydrxoxyvitamin D.
The new, high-throughput mass spectrometry–based assay – developed by researchers at the Mayo Clinic – is able to quantify both analytes.
Knowledge of the serum concentrations of both 24,25(OH)2D and 25(OH)D3 is particularly important in establishing reduced activity of the primary vitamin D degradation enzyme CYP24A1 in patients with mutations in the CYP24A1 (cytochrome P450 24-hydroxylase A1) gene.
"A lot of physicians want this metabolite to be measured just in case a person might be a candidate for more extensive genotyping studies ... They also want to know the reference range in normal individuals," lead author and research fellow Hemamalini Ketha, Ph.D., said in an interview.
Researchers at the Roswell Park Cancer Institute in Buffalo, N.Y., recently reported that single nucleotide polymorphisms in CYP24A1 may be related to the higher prevalence of estrogen receptor–negative breast cancer in African American women – a group known to have lower levels of vitamin D (Breast Cancer Res. 2012;14:R58).
Dr. Ketha and her colleagues at the Mayo Clinic in Rochester, Minn., used a liquid chromatography tandem mass spectrometry method to measure serum 24,25(OH)2D concentrations in 92 serum samples from men and women with a wide range of 25(OH)D concentrations.
The limit of detection for 24,25(OH)2D3 was 0.08 ng/mL; the limit for 24,25(OH)2D2 was 0.5 ng/mL, Dr. Ketha reported in a poster at the annual meeting of the American Society for Bone and Mineral Research.
The mean concentration of 25(OH)D in the serum samples was 29.36 ng/mL and was 2.59 ng/mL for 24,25(OH)2D3.
Serum 24,25(OH)2D concentrations were linearly correlated with serum 25(OH)D concentrations (R2 = 0.75), she said.
No correlation was observed, however, between 24,25(OH)2D3 and 1,25(OH)2D3 (R2 = 0.0005).
"For diagnostic purposes, the interpretation of concentrations of serum 24,25(OH)2D3 should therefore take the concomitant 25(OH)D3 concentrations into account," the authors concluded.
Dr. Ketha said the assay is rapid and reproducible, and that the Mayo Clinic is planning to make it commercially available through its endocrinology clinical laboratory.
He said he had no relevant financial disclosures. The research was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Ketha said she had no relevant financial disclosures.
"I think there is a major need for assays such as this to get into the clinical world, certainly the research world, so we can have additional insight into what is really going on with the relationship of falling vitamin D status today and all of the [associated] outcomes such as falls and fractures," osteoporosis expert Dr. Neil Binkley said in an interview.
"By just measuring 25-hydroxy D, we’re not seeing the whole picture; just like when we measure total cholesterol, we aren’t seeing the whole picture."
Dr. Binkley is associate director of the Institute on Aging at the University of Wisconsin, Madison. He said he had no relevant financial disclosures.
"I think there is a major need for assays such as this to get into the clinical world, certainly the research world, so we can have additional insight into what is really going on with the relationship of falling vitamin D status today and all of the [associated] outcomes such as falls and fractures," osteoporosis expert Dr. Neil Binkley said in an interview.
"By just measuring 25-hydroxy D, we’re not seeing the whole picture; just like when we measure total cholesterol, we aren’t seeing the whole picture."
Dr. Binkley is associate director of the Institute on Aging at the University of Wisconsin, Madison. He said he had no relevant financial disclosures.
"I think there is a major need for assays such as this to get into the clinical world, certainly the research world, so we can have additional insight into what is really going on with the relationship of falling vitamin D status today and all of the [associated] outcomes such as falls and fractures," osteoporosis expert Dr. Neil Binkley said in an interview.
"By just measuring 25-hydroxy D, we’re not seeing the whole picture; just like when we measure total cholesterol, we aren’t seeing the whole picture."
Dr. Binkley is associate director of the Institute on Aging at the University of Wisconsin, Madison. He said he had no relevant financial disclosures.
MINNEAPOLIS – A new automated assay can measure concentrations of both 24,25-dihydroxyvitamin D2 and D3 in human serum.
Current assays based on competitive binding experiments can differentiate between 24,25-dihydroxyvitamin D3 and D2, but are time consuming and not easily automated. Also, immunoassays fail to differentiate between 25-hydroxyvitamin D and 24,25-dihydrxoxyvitamin D.
The new, high-throughput mass spectrometry–based assay – developed by researchers at the Mayo Clinic – is able to quantify both analytes.
Knowledge of the serum concentrations of both 24,25(OH)2D and 25(OH)D3 is particularly important in establishing reduced activity of the primary vitamin D degradation enzyme CYP24A1 in patients with mutations in the CYP24A1 (cytochrome P450 24-hydroxylase A1) gene.
"A lot of physicians want this metabolite to be measured just in case a person might be a candidate for more extensive genotyping studies ... They also want to know the reference range in normal individuals," lead author and research fellow Hemamalini Ketha, Ph.D., said in an interview.
Researchers at the Roswell Park Cancer Institute in Buffalo, N.Y., recently reported that single nucleotide polymorphisms in CYP24A1 may be related to the higher prevalence of estrogen receptor–negative breast cancer in African American women – a group known to have lower levels of vitamin D (Breast Cancer Res. 2012;14:R58).
Dr. Ketha and her colleagues at the Mayo Clinic in Rochester, Minn., used a liquid chromatography tandem mass spectrometry method to measure serum 24,25(OH)2D concentrations in 92 serum samples from men and women with a wide range of 25(OH)D concentrations.
The limit of detection for 24,25(OH)2D3 was 0.08 ng/mL; the limit for 24,25(OH)2D2 was 0.5 ng/mL, Dr. Ketha reported in a poster at the annual meeting of the American Society for Bone and Mineral Research.
The mean concentration of 25(OH)D in the serum samples was 29.36 ng/mL and was 2.59 ng/mL for 24,25(OH)2D3.
Serum 24,25(OH)2D concentrations were linearly correlated with serum 25(OH)D concentrations (R2 = 0.75), she said.
No correlation was observed, however, between 24,25(OH)2D3 and 1,25(OH)2D3 (R2 = 0.0005).
"For diagnostic purposes, the interpretation of concentrations of serum 24,25(OH)2D3 should therefore take the concomitant 25(OH)D3 concentrations into account," the authors concluded.
Dr. Ketha said the assay is rapid and reproducible, and that the Mayo Clinic is planning to make it commercially available through its endocrinology clinical laboratory.
He said he had no relevant financial disclosures. The research was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Ketha said she had no relevant financial disclosures.
MINNEAPOLIS – A new automated assay can measure concentrations of both 24,25-dihydroxyvitamin D2 and D3 in human serum.
Current assays based on competitive binding experiments can differentiate between 24,25-dihydroxyvitamin D3 and D2, but are time consuming and not easily automated. Also, immunoassays fail to differentiate between 25-hydroxyvitamin D and 24,25-dihydrxoxyvitamin D.
The new, high-throughput mass spectrometry–based assay – developed by researchers at the Mayo Clinic – is able to quantify both analytes.
Knowledge of the serum concentrations of both 24,25(OH)2D and 25(OH)D3 is particularly important in establishing reduced activity of the primary vitamin D degradation enzyme CYP24A1 in patients with mutations in the CYP24A1 (cytochrome P450 24-hydroxylase A1) gene.
"A lot of physicians want this metabolite to be measured just in case a person might be a candidate for more extensive genotyping studies ... They also want to know the reference range in normal individuals," lead author and research fellow Hemamalini Ketha, Ph.D., said in an interview.
Researchers at the Roswell Park Cancer Institute in Buffalo, N.Y., recently reported that single nucleotide polymorphisms in CYP24A1 may be related to the higher prevalence of estrogen receptor–negative breast cancer in African American women – a group known to have lower levels of vitamin D (Breast Cancer Res. 2012;14:R58).
Dr. Ketha and her colleagues at the Mayo Clinic in Rochester, Minn., used a liquid chromatography tandem mass spectrometry method to measure serum 24,25(OH)2D concentrations in 92 serum samples from men and women with a wide range of 25(OH)D concentrations.
The limit of detection for 24,25(OH)2D3 was 0.08 ng/mL; the limit for 24,25(OH)2D2 was 0.5 ng/mL, Dr. Ketha reported in a poster at the annual meeting of the American Society for Bone and Mineral Research.
The mean concentration of 25(OH)D in the serum samples was 29.36 ng/mL and was 2.59 ng/mL for 24,25(OH)2D3.
Serum 24,25(OH)2D concentrations were linearly correlated with serum 25(OH)D concentrations (R2 = 0.75), she said.
No correlation was observed, however, between 24,25(OH)2D3 and 1,25(OH)2D3 (R2 = 0.0005).
"For diagnostic purposes, the interpretation of concentrations of serum 24,25(OH)2D3 should therefore take the concomitant 25(OH)D3 concentrations into account," the authors concluded.
Dr. Ketha said the assay is rapid and reproducible, and that the Mayo Clinic is planning to make it commercially available through its endocrinology clinical laboratory.
He said he had no relevant financial disclosures. The research was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Ketha said she had no relevant financial disclosures.
AT THE ANNUAL MEETING OF THE AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH
Major Finding: The limit of detection in the assay for 24,25(OH)2D3 was 0.08 ng/mL; the limit for 24,25(OH)2D2 was 0.5 ng/mL.
Data Source: Data are from an analysis of 92 serum samples in which a liquid chromatography tandem mass spectrometry assay was used.
Disclosures: The research was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Ketha reported no relevant financial disclosures.
Odanacatib Adds Bone in Alendronate-Pretreated Osteoporosis
MINNEAPOLIS – Odanacatib added bone density in postmenopausal women with osteoporosis previously treated with alendronate, according to results from a study presented at the annual meeting of the American Society for Bone and Mineral Research.
In a phase II trial involving 243 patients, the investigational oral cathepsin K inhibitor began to distinguish itself from placebo at 12 months. At 2 years, the change from baseline in femoral neck bone mineral density (BMD) was significantly increased by 1.73%, compared with a loss of 0.94% for placebo (P less than .001).
BMD changes in the treatment group at 2 years were also significantly different from placebo at the trochanter (1.83% vs. –1.35%) and for the total hip (0.83% vs. –1.87%, both P less than .001).
All of the women studied had received alendronate (Fosamax) for at least 3 years. Patients could have been off the bisphosphonate for up to 3 months prior to enrollment, but many switched directly over to odanacatib, said study coauthor Dr. Albert Leung, executive director of clinical research at Merck Research Laboratories.
"This drug has the potential to give additional benefits when [patients] have been treated with alendronate for a number of years and the treatment effect has reached a plateau and they may need a different treatment," he said in an interview.
In July 2012, a pivotal 16,731-patient, phase III trial of odanacatib was stopped early after an interim analysis showed a "favorable benefit-risk profile" for fracture risk reduction in postmenopausal women with previously untreated osteoporosis.
"It could be quite a population that may benefit from this drug," Dr. Leung remarked.
The study’s data monitoring committee, however, flagged safety concerns in "certain selected areas" for further follow-up. Those safety risks have not been identified as the trial is still closing, but will be monitored along with efficacy in a double-blind, placebo-controlled, extension trial going out to 5 years of treatment, he said.
Merck, which plans to submit regulatory applications for odanacatib in the United States and Europe in the first half of 2013, has high hopes for odanacatib despite competition from generic drugs because of its novel mechanism of action.
Odanacatib inhibits cathepsin K, the primary protease in osteoclasts that breaks down bone collagen during bone resorption. Unlike traditional antiresorptive drugs like bisphosphonates, however, odanacatib does not interfere with the function of the entire osteoclast or reduce the number of osteoclasts. This characteristic is important, as osteoclasts secrete signaling factors to stimulate osteoblasts, the cells responsible for bone formation. As a result, there is greater bone formation with odanacatib, Dr. Leung explained.
The phase II trial enrolled women at least 60 years of age (mean 71 years) with a BMD T score of –2.5 to more than –3.5 at any hip site without a prior fragility fracture or those with a history of fragility fracture (except hip fracture), and a BMD T score of –1.5 and more than –3.5 at any hip site. The women were randomly assigned to odanacatib 50 mg once weekly or placebo for 24 months, as well as 5,600 IU of vitamin D3 per week and calcium at dosages up to 1,200 mg/day. The study was not powered to assess fractures.
At 24 months, the change in BMD at the lumbar spine was significant at 2.28% for odanacatib vs. a loss of 0.30% with placebo (P less than .001).
BMD change was not significant at the distal forearm, with losses of 0.92% vs. 1.14%, respectively.
As expected, urinary collagen type I cross-linked N-telopeptide, a biomarker of bone resorption, increased with placebo, compared with a significant 47% decrease with odanacatib.
The bone formation marker, serum type I procollagen, rose inexplicably with placebo, but this increase was surpassed by a significant gain of 31.2% with odanacatib.
Most unexpected, however, was an increase in the resorption marker collagen type I cross-linked C-telopeptide (sCTx) with once-weekly odanacatib. Dr. Leung said the finding appears to correlate with the bone density changes because sCTx levels remained relatively stable during the first 12 months of treatment before rising in the second year of the study.
Finally, adverse events were similar in both groups. The most common adverse events in the odanacatib and placebo arms were urinary tract infection (11.5% vs. 16.5%, respectively), back pain (11.5% vs. 9.9%), arthralgia (9% vs. 9.9%), and fractures (4.9% vs. 13.2%). Treatment discontinuation rates due to adverse events were 9% vs. 3.3%, he said.
Dr. Leung and several of his coauthors are employees of Merck, the trial sponsor.
MINNEAPOLIS – Odanacatib added bone density in postmenopausal women with osteoporosis previously treated with alendronate, according to results from a study presented at the annual meeting of the American Society for Bone and Mineral Research.
In a phase II trial involving 243 patients, the investigational oral cathepsin K inhibitor began to distinguish itself from placebo at 12 months. At 2 years, the change from baseline in femoral neck bone mineral density (BMD) was significantly increased by 1.73%, compared with a loss of 0.94% for placebo (P less than .001).
BMD changes in the treatment group at 2 years were also significantly different from placebo at the trochanter (1.83% vs. –1.35%) and for the total hip (0.83% vs. –1.87%, both P less than .001).
All of the women studied had received alendronate (Fosamax) for at least 3 years. Patients could have been off the bisphosphonate for up to 3 months prior to enrollment, but many switched directly over to odanacatib, said study coauthor Dr. Albert Leung, executive director of clinical research at Merck Research Laboratories.
"This drug has the potential to give additional benefits when [patients] have been treated with alendronate for a number of years and the treatment effect has reached a plateau and they may need a different treatment," he said in an interview.
In July 2012, a pivotal 16,731-patient, phase III trial of odanacatib was stopped early after an interim analysis showed a "favorable benefit-risk profile" for fracture risk reduction in postmenopausal women with previously untreated osteoporosis.
"It could be quite a population that may benefit from this drug," Dr. Leung remarked.
The study’s data monitoring committee, however, flagged safety concerns in "certain selected areas" for further follow-up. Those safety risks have not been identified as the trial is still closing, but will be monitored along with efficacy in a double-blind, placebo-controlled, extension trial going out to 5 years of treatment, he said.
Merck, which plans to submit regulatory applications for odanacatib in the United States and Europe in the first half of 2013, has high hopes for odanacatib despite competition from generic drugs because of its novel mechanism of action.
Odanacatib inhibits cathepsin K, the primary protease in osteoclasts that breaks down bone collagen during bone resorption. Unlike traditional antiresorptive drugs like bisphosphonates, however, odanacatib does not interfere with the function of the entire osteoclast or reduce the number of osteoclasts. This characteristic is important, as osteoclasts secrete signaling factors to stimulate osteoblasts, the cells responsible for bone formation. As a result, there is greater bone formation with odanacatib, Dr. Leung explained.
The phase II trial enrolled women at least 60 years of age (mean 71 years) with a BMD T score of –2.5 to more than –3.5 at any hip site without a prior fragility fracture or those with a history of fragility fracture (except hip fracture), and a BMD T score of –1.5 and more than –3.5 at any hip site. The women were randomly assigned to odanacatib 50 mg once weekly or placebo for 24 months, as well as 5,600 IU of vitamin D3 per week and calcium at dosages up to 1,200 mg/day. The study was not powered to assess fractures.
At 24 months, the change in BMD at the lumbar spine was significant at 2.28% for odanacatib vs. a loss of 0.30% with placebo (P less than .001).
BMD change was not significant at the distal forearm, with losses of 0.92% vs. 1.14%, respectively.
As expected, urinary collagen type I cross-linked N-telopeptide, a biomarker of bone resorption, increased with placebo, compared with a significant 47% decrease with odanacatib.
The bone formation marker, serum type I procollagen, rose inexplicably with placebo, but this increase was surpassed by a significant gain of 31.2% with odanacatib.
Most unexpected, however, was an increase in the resorption marker collagen type I cross-linked C-telopeptide (sCTx) with once-weekly odanacatib. Dr. Leung said the finding appears to correlate with the bone density changes because sCTx levels remained relatively stable during the first 12 months of treatment before rising in the second year of the study.
Finally, adverse events were similar in both groups. The most common adverse events in the odanacatib and placebo arms were urinary tract infection (11.5% vs. 16.5%, respectively), back pain (11.5% vs. 9.9%), arthralgia (9% vs. 9.9%), and fractures (4.9% vs. 13.2%). Treatment discontinuation rates due to adverse events were 9% vs. 3.3%, he said.
Dr. Leung and several of his coauthors are employees of Merck, the trial sponsor.
MINNEAPOLIS – Odanacatib added bone density in postmenopausal women with osteoporosis previously treated with alendronate, according to results from a study presented at the annual meeting of the American Society for Bone and Mineral Research.
In a phase II trial involving 243 patients, the investigational oral cathepsin K inhibitor began to distinguish itself from placebo at 12 months. At 2 years, the change from baseline in femoral neck bone mineral density (BMD) was significantly increased by 1.73%, compared with a loss of 0.94% for placebo (P less than .001).
BMD changes in the treatment group at 2 years were also significantly different from placebo at the trochanter (1.83% vs. –1.35%) and for the total hip (0.83% vs. –1.87%, both P less than .001).
All of the women studied had received alendronate (Fosamax) for at least 3 years. Patients could have been off the bisphosphonate for up to 3 months prior to enrollment, but many switched directly over to odanacatib, said study coauthor Dr. Albert Leung, executive director of clinical research at Merck Research Laboratories.
"This drug has the potential to give additional benefits when [patients] have been treated with alendronate for a number of years and the treatment effect has reached a plateau and they may need a different treatment," he said in an interview.
In July 2012, a pivotal 16,731-patient, phase III trial of odanacatib was stopped early after an interim analysis showed a "favorable benefit-risk profile" for fracture risk reduction in postmenopausal women with previously untreated osteoporosis.
"It could be quite a population that may benefit from this drug," Dr. Leung remarked.
The study’s data monitoring committee, however, flagged safety concerns in "certain selected areas" for further follow-up. Those safety risks have not been identified as the trial is still closing, but will be monitored along with efficacy in a double-blind, placebo-controlled, extension trial going out to 5 years of treatment, he said.
Merck, which plans to submit regulatory applications for odanacatib in the United States and Europe in the first half of 2013, has high hopes for odanacatib despite competition from generic drugs because of its novel mechanism of action.
Odanacatib inhibits cathepsin K, the primary protease in osteoclasts that breaks down bone collagen during bone resorption. Unlike traditional antiresorptive drugs like bisphosphonates, however, odanacatib does not interfere with the function of the entire osteoclast or reduce the number of osteoclasts. This characteristic is important, as osteoclasts secrete signaling factors to stimulate osteoblasts, the cells responsible for bone formation. As a result, there is greater bone formation with odanacatib, Dr. Leung explained.
The phase II trial enrolled women at least 60 years of age (mean 71 years) with a BMD T score of –2.5 to more than –3.5 at any hip site without a prior fragility fracture or those with a history of fragility fracture (except hip fracture), and a BMD T score of –1.5 and more than –3.5 at any hip site. The women were randomly assigned to odanacatib 50 mg once weekly or placebo for 24 months, as well as 5,600 IU of vitamin D3 per week and calcium at dosages up to 1,200 mg/day. The study was not powered to assess fractures.
At 24 months, the change in BMD at the lumbar spine was significant at 2.28% for odanacatib vs. a loss of 0.30% with placebo (P less than .001).
BMD change was not significant at the distal forearm, with losses of 0.92% vs. 1.14%, respectively.
As expected, urinary collagen type I cross-linked N-telopeptide, a biomarker of bone resorption, increased with placebo, compared with a significant 47% decrease with odanacatib.
The bone formation marker, serum type I procollagen, rose inexplicably with placebo, but this increase was surpassed by a significant gain of 31.2% with odanacatib.
Most unexpected, however, was an increase in the resorption marker collagen type I cross-linked C-telopeptide (sCTx) with once-weekly odanacatib. Dr. Leung said the finding appears to correlate with the bone density changes because sCTx levels remained relatively stable during the first 12 months of treatment before rising in the second year of the study.
Finally, adverse events were similar in both groups. The most common adverse events in the odanacatib and placebo arms were urinary tract infection (11.5% vs. 16.5%, respectively), back pain (11.5% vs. 9.9%), arthralgia (9% vs. 9.9%), and fractures (4.9% vs. 13.2%). Treatment discontinuation rates due to adverse events were 9% vs. 3.3%, he said.
Dr. Leung and several of his coauthors are employees of Merck, the trial sponsor.
AT THE ANNUAL MEETING OF THE AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH
Major Finding: The change from baseline in femoral neck bone mineral density at 2 years was +1.73% with odanacatib vs. –0.94% for placebo (P less than .001).
Data Source: This study was a phase II trial in 243 women with postmenopausal osteoporosis previously treated with alendronate.
Disclosures: Dr. Leung and several of his coauthors are employees of Merck, the trial sponsor.
Hip Fracture Risk Rises as Elderly Start Antihypertensives
MINNEAPOLIS – The risk of hip fracture among elderly patients spikes shortly after starting antihypertensive medications, judging from the findings of a large self-controlled, case series analysis.
Overall, elderly community-dwelling patients had a 43% increased risk of hip fracture within 45 days of initiating an antihypertensive therapy (incidence rate ratio, 1.41; 95% confidence interval, 1.19-1.72).
The risk was significantly higher only for two of the five classes of commonly used antihypertensive drugs: ACE inhibitors and beta-blockers.
The risk of early fracture rose by 53% for patients started on an ACE inhibitor (IRR, 1.53; 95% CI, 1.12-2.10) and by 58% for those on beta-blockers (IRR, 1.58; 95% CI, 1.01-2.48), Dr. Debra Butt reported at the annual meeting of the American Society of Bone and Mineral Research.
This is the first large population-based study to report such an association, and the evidence is conflicting regarding the association between antihypertensives and fracture risk. The majority of studies evaluate long exposure periods, where the underlying mechanism is thought to be related to bone mass.
On the other hand, there are studies of immediate increased risk of falls in the elderly started on antihypertensive drugs, where orthostatic hypotension is thought to be the underlying mechanism. One recently updated analysis reported that the effect on falls in the elderly was strongest in the first 3 weeks of a thiazide diuretic prescription (IRR, 2.80), after taking into account confounding factors (Pharmacoepidemiol. Drug Saf. 2011;20:879-84).
The current analysis used six health care administrative databases to identify 301,591 newly treated hypertensive patients at least 66 years of age living in Ontario and link them with hip fractures occurring from April 1, 2000, to March 31, 2009. The risk period was the first 45 days following initiation of monotherapy antihypertensive therapy, with control periods before and after treatment in a 450-day observation period.
The study excluded long-term care residents and patients with conditions other than hypertension for which an antihypertensive drug may have been prescribed such as diabetes, myocardial infarction, heart failure, angina, cardiomyopathy and transient ischemic attack.
At baseline, only 3% of patients had had a fall in the past year requiring hospital care and 6% had a history of past hip fracture. The majority of patients were female (81%) and the median age was 80.8 years.
Antihypertensive drugs included thiazide diuretics (23%), ACE inhibitors (30%), angiotensin receptor blockers (4%), calcium channel blockers (17%) and beta blockers (26%).
During the observation period, 1,463 hip fractures were identified, according to Dr. Butt of the department of family and community medicine, University of Toronto.
A sensitivity analysis that excluded use of other potential fall-causing drugs and psychotropic drugs that can trigger falls, confirmed the initial association between antihypertensive drug initiation and early hip fracture with a nearly identical incidence ratio of 1.42.
"Based on this finding, caution is advised when initiating antihypertensive drugs in the elderly," she said.
During a discussion of the study, however, concerns were raised about what to advise patients without knowing the absolute risk of falling and the risk of hip fracture while on antihypertensive medications vs. the benefits of treating hypertension.
One audience member said the study alerts clinicians to the risk but that it’s hard to draw any practical, clinical recommendations without more information such as when the falls occurred, whether the patient was standing or sitting down at the time of the fracture, or the magnitude of the hypertension decrease from baseline.
"In order to develop clinical recommendations, you have to start by demonstrating an association and that’s what our study does," Dr. Butt responded. "It’s a start, in an area where we have few studies that exist."
The government of Ontario funded the study. Dr. Butt reported no relevant conflicts of interest.
MINNEAPOLIS – The risk of hip fracture among elderly patients spikes shortly after starting antihypertensive medications, judging from the findings of a large self-controlled, case series analysis.
Overall, elderly community-dwelling patients had a 43% increased risk of hip fracture within 45 days of initiating an antihypertensive therapy (incidence rate ratio, 1.41; 95% confidence interval, 1.19-1.72).
The risk was significantly higher only for two of the five classes of commonly used antihypertensive drugs: ACE inhibitors and beta-blockers.
The risk of early fracture rose by 53% for patients started on an ACE inhibitor (IRR, 1.53; 95% CI, 1.12-2.10) and by 58% for those on beta-blockers (IRR, 1.58; 95% CI, 1.01-2.48), Dr. Debra Butt reported at the annual meeting of the American Society of Bone and Mineral Research.
This is the first large population-based study to report such an association, and the evidence is conflicting regarding the association between antihypertensives and fracture risk. The majority of studies evaluate long exposure periods, where the underlying mechanism is thought to be related to bone mass.
On the other hand, there are studies of immediate increased risk of falls in the elderly started on antihypertensive drugs, where orthostatic hypotension is thought to be the underlying mechanism. One recently updated analysis reported that the effect on falls in the elderly was strongest in the first 3 weeks of a thiazide diuretic prescription (IRR, 2.80), after taking into account confounding factors (Pharmacoepidemiol. Drug Saf. 2011;20:879-84).
The current analysis used six health care administrative databases to identify 301,591 newly treated hypertensive patients at least 66 years of age living in Ontario and link them with hip fractures occurring from April 1, 2000, to March 31, 2009. The risk period was the first 45 days following initiation of monotherapy antihypertensive therapy, with control periods before and after treatment in a 450-day observation period.
The study excluded long-term care residents and patients with conditions other than hypertension for which an antihypertensive drug may have been prescribed such as diabetes, myocardial infarction, heart failure, angina, cardiomyopathy and transient ischemic attack.
At baseline, only 3% of patients had had a fall in the past year requiring hospital care and 6% had a history of past hip fracture. The majority of patients were female (81%) and the median age was 80.8 years.
Antihypertensive drugs included thiazide diuretics (23%), ACE inhibitors (30%), angiotensin receptor blockers (4%), calcium channel blockers (17%) and beta blockers (26%).
During the observation period, 1,463 hip fractures were identified, according to Dr. Butt of the department of family and community medicine, University of Toronto.
A sensitivity analysis that excluded use of other potential fall-causing drugs and psychotropic drugs that can trigger falls, confirmed the initial association between antihypertensive drug initiation and early hip fracture with a nearly identical incidence ratio of 1.42.
"Based on this finding, caution is advised when initiating antihypertensive drugs in the elderly," she said.
During a discussion of the study, however, concerns were raised about what to advise patients without knowing the absolute risk of falling and the risk of hip fracture while on antihypertensive medications vs. the benefits of treating hypertension.
One audience member said the study alerts clinicians to the risk but that it’s hard to draw any practical, clinical recommendations without more information such as when the falls occurred, whether the patient was standing or sitting down at the time of the fracture, or the magnitude of the hypertension decrease from baseline.
"In order to develop clinical recommendations, you have to start by demonstrating an association and that’s what our study does," Dr. Butt responded. "It’s a start, in an area where we have few studies that exist."
The government of Ontario funded the study. Dr. Butt reported no relevant conflicts of interest.
MINNEAPOLIS – The risk of hip fracture among elderly patients spikes shortly after starting antihypertensive medications, judging from the findings of a large self-controlled, case series analysis.
Overall, elderly community-dwelling patients had a 43% increased risk of hip fracture within 45 days of initiating an antihypertensive therapy (incidence rate ratio, 1.41; 95% confidence interval, 1.19-1.72).
The risk was significantly higher only for two of the five classes of commonly used antihypertensive drugs: ACE inhibitors and beta-blockers.
The risk of early fracture rose by 53% for patients started on an ACE inhibitor (IRR, 1.53; 95% CI, 1.12-2.10) and by 58% for those on beta-blockers (IRR, 1.58; 95% CI, 1.01-2.48), Dr. Debra Butt reported at the annual meeting of the American Society of Bone and Mineral Research.
This is the first large population-based study to report such an association, and the evidence is conflicting regarding the association between antihypertensives and fracture risk. The majority of studies evaluate long exposure periods, where the underlying mechanism is thought to be related to bone mass.
On the other hand, there are studies of immediate increased risk of falls in the elderly started on antihypertensive drugs, where orthostatic hypotension is thought to be the underlying mechanism. One recently updated analysis reported that the effect on falls in the elderly was strongest in the first 3 weeks of a thiazide diuretic prescription (IRR, 2.80), after taking into account confounding factors (Pharmacoepidemiol. Drug Saf. 2011;20:879-84).
The current analysis used six health care administrative databases to identify 301,591 newly treated hypertensive patients at least 66 years of age living in Ontario and link them with hip fractures occurring from April 1, 2000, to March 31, 2009. The risk period was the first 45 days following initiation of monotherapy antihypertensive therapy, with control periods before and after treatment in a 450-day observation period.
The study excluded long-term care residents and patients with conditions other than hypertension for which an antihypertensive drug may have been prescribed such as diabetes, myocardial infarction, heart failure, angina, cardiomyopathy and transient ischemic attack.
At baseline, only 3% of patients had had a fall in the past year requiring hospital care and 6% had a history of past hip fracture. The majority of patients were female (81%) and the median age was 80.8 years.
Antihypertensive drugs included thiazide diuretics (23%), ACE inhibitors (30%), angiotensin receptor blockers (4%), calcium channel blockers (17%) and beta blockers (26%).
During the observation period, 1,463 hip fractures were identified, according to Dr. Butt of the department of family and community medicine, University of Toronto.
A sensitivity analysis that excluded use of other potential fall-causing drugs and psychotropic drugs that can trigger falls, confirmed the initial association between antihypertensive drug initiation and early hip fracture with a nearly identical incidence ratio of 1.42.
"Based on this finding, caution is advised when initiating antihypertensive drugs in the elderly," she said.
During a discussion of the study, however, concerns were raised about what to advise patients without knowing the absolute risk of falling and the risk of hip fracture while on antihypertensive medications vs. the benefits of treating hypertension.
One audience member said the study alerts clinicians to the risk but that it’s hard to draw any practical, clinical recommendations without more information such as when the falls occurred, whether the patient was standing or sitting down at the time of the fracture, or the magnitude of the hypertension decrease from baseline.
"In order to develop clinical recommendations, you have to start by demonstrating an association and that’s what our study does," Dr. Butt responded. "It’s a start, in an area where we have few studies that exist."
The government of Ontario funded the study. Dr. Butt reported no relevant conflicts of interest.
AT THE ANNUAL AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH MEETING
Major Finding: The risk of hip fracture within 45 days of starting an antihypertensive drug increased by 43% in elderly patients (incidence rate ratio, 1.43; 95% CI, 1.19-1.72).
Data Source: This finding comes from a self-controlled, case series analysis of 301,591 newly treated hypertensive elderly patients.
Disclosures: The study was funded by the Government of Ontario. Dr. Butt reported no relevant conflicts of interest.
Denosumab/Teriparatide Combo Bests Single-Agent Bone Therapy
MINNEAPOLIS – Combining the antiresorptive denosumab with the anabolic agent teriparatide increased bone mineral density more than either drug alone in postmenopausal women at high fracture risk in the ongoing DATA study.
At 12 months, the combination of denosumab (Prolia) and teriparatide (Forteo) significantly increased bone mineral density (BMD) by 8.9% at the spine, 4.5% at the femoral neck, and 4.9% at the total hip.
The increases in BMD observed in the combination group are larger than those seen in prior combination anabolic and antiresorptive trials, Dr. Benjamin Z. Leder reported at the annual meeting of the American Society for Bone and Mineral Research.
The DATA (Denosumab, Teriparatide or Both for the Treatment of Postmenopausal Osteoporosis) trial is the first to study denosumab in combination with an anabolic agent. Prior trials combining teriparatide and bisphosphonates have shown inconsistent effects on BMD or, in some cases, a blunting effect of the anabolic agent.
The mechanisms underlying the additive effects of denosumab and teriparatide are unclear, but they may be related to the ability of denosumab to fully block teriparatide’s pro-resorptive effects while still allowing for continued modeling-based bone formation and, perhaps, an expansion of the anabolic window, said Dr. Leder, an endocrinologist with Massachusetts General Hospital in Boston.
"If these results persist in the second year of therapy and are confirmed in larger studies, the combination of these two agents may eventually prove to be a beneficial treatment in patients who are at particularly high risk of fracture," he said.
The trial randomized 100 women aged 45 years or older who were at least 3 years post menopause to daily teriparatide 20 mcg subcutaneous or denosumab 60 mg subcutaneous every 6 months or both. All patients received calcium 1,200 mg and vitamin D 400 IU.
Enrollment criteria were a BMD T-score of –2.5 or less at any anatomic site or a T-score of –2 or less with one risk factor (fracture or parental hip fracture after age 50, prior hyperthyroidism, inability to rise from a chair with arms elevated, or current smoker) or a T-score of –1 or less with a history of fragility fracture.
Patients were excluded if they had received oral bisphosphonates in the past 6 months; glucocorticoids for more than 14 days in the past 6 months; and any prior use of teriparatide, strontium, or parenteral bisphosphonates.
Patients were stratified by age and spine BMD. The 94 evaluable patients had an average age of 66 years.
At 12 months, the average increase in total hip BMD was 0.7% with teriparatide, 2.5% with denosumab, and 4.9% with combination therapy. Femoral neck BMD increased 0.8%, 2.1%, and 4.5% and spine BMD increased 6.2%, 5.5%, and 8.9%, respectively.
At the distal one-third of the radius, there was a decrease in BMD of 1.8% with teriparatide, an increase of 1.7% with denosumab, and a gain of 2.5% with the combination, Dr. Leder said. The difference in BMD was significant between the combination and teriparatide groups (P less than .001) but not between the combination and denosumab groups.
Changes in bone density were not significantly different between bisphosphonate-naive patients and those with prior bisphosphonate exposure.
Bone formation biomarker analysis showed significant suppression of osteocalcium with denosumab monotherapy at 3 months that continued through the 12-month study, while there was no change at 3 months and a more modest suppression thereafter in the combination group, he said.
Denosumab monotherapy significantly inhibited procollagen type I N-terminal propeptide at 3 and 6 months, but both groups were similar at 12 months.
The data on bone turnover marker C-telopeptide of type I collagen were distinct, with suppression identical in the denosumab alone and combination groups, Dr. Leder observed.
During a discussion of the study, Dr. Leder said bone biopsies were not available but that data at the distal radius and tibia that have not yet been analyzed "may provide some additional idea of what is going on, specifically in the trabecular and cortical compartments."
Session comoderator Dr. Aliya Khan, director of the calcium disorders clinic at St. Joseph’s Healthcare, McMaster University in Hamilton, Ont., said in an interview that the results shouldn’t be universally applied, but "if someone has a fracture, we can certainly consider this approach."
She went on to say that "combination therapy may be a way to improve bone strength, and it may actually enable us to avoid conditions such as atypical femoral fractures, which appear to be associated with oversuppression of bone remodeling."
Eli Lilly and Amgen sponsored the trial. Dr. Leder reported consulting for Amgen and Merck. Dr. Khan reported no disclosures.
MINNEAPOLIS – Combining the antiresorptive denosumab with the anabolic agent teriparatide increased bone mineral density more than either drug alone in postmenopausal women at high fracture risk in the ongoing DATA study.
At 12 months, the combination of denosumab (Prolia) and teriparatide (Forteo) significantly increased bone mineral density (BMD) by 8.9% at the spine, 4.5% at the femoral neck, and 4.9% at the total hip.
The increases in BMD observed in the combination group are larger than those seen in prior combination anabolic and antiresorptive trials, Dr. Benjamin Z. Leder reported at the annual meeting of the American Society for Bone and Mineral Research.
The DATA (Denosumab, Teriparatide or Both for the Treatment of Postmenopausal Osteoporosis) trial is the first to study denosumab in combination with an anabolic agent. Prior trials combining teriparatide and bisphosphonates have shown inconsistent effects on BMD or, in some cases, a blunting effect of the anabolic agent.
The mechanisms underlying the additive effects of denosumab and teriparatide are unclear, but they may be related to the ability of denosumab to fully block teriparatide’s pro-resorptive effects while still allowing for continued modeling-based bone formation and, perhaps, an expansion of the anabolic window, said Dr. Leder, an endocrinologist with Massachusetts General Hospital in Boston.
"If these results persist in the second year of therapy and are confirmed in larger studies, the combination of these two agents may eventually prove to be a beneficial treatment in patients who are at particularly high risk of fracture," he said.
The trial randomized 100 women aged 45 years or older who were at least 3 years post menopause to daily teriparatide 20 mcg subcutaneous or denosumab 60 mg subcutaneous every 6 months or both. All patients received calcium 1,200 mg and vitamin D 400 IU.
Enrollment criteria were a BMD T-score of –2.5 or less at any anatomic site or a T-score of –2 or less with one risk factor (fracture or parental hip fracture after age 50, prior hyperthyroidism, inability to rise from a chair with arms elevated, or current smoker) or a T-score of –1 or less with a history of fragility fracture.
Patients were excluded if they had received oral bisphosphonates in the past 6 months; glucocorticoids for more than 14 days in the past 6 months; and any prior use of teriparatide, strontium, or parenteral bisphosphonates.
Patients were stratified by age and spine BMD. The 94 evaluable patients had an average age of 66 years.
At 12 months, the average increase in total hip BMD was 0.7% with teriparatide, 2.5% with denosumab, and 4.9% with combination therapy. Femoral neck BMD increased 0.8%, 2.1%, and 4.5% and spine BMD increased 6.2%, 5.5%, and 8.9%, respectively.
At the distal one-third of the radius, there was a decrease in BMD of 1.8% with teriparatide, an increase of 1.7% with denosumab, and a gain of 2.5% with the combination, Dr. Leder said. The difference in BMD was significant between the combination and teriparatide groups (P less than .001) but not between the combination and denosumab groups.
Changes in bone density were not significantly different between bisphosphonate-naive patients and those with prior bisphosphonate exposure.
Bone formation biomarker analysis showed significant suppression of osteocalcium with denosumab monotherapy at 3 months that continued through the 12-month study, while there was no change at 3 months and a more modest suppression thereafter in the combination group, he said.
Denosumab monotherapy significantly inhibited procollagen type I N-terminal propeptide at 3 and 6 months, but both groups were similar at 12 months.
The data on bone turnover marker C-telopeptide of type I collagen were distinct, with suppression identical in the denosumab alone and combination groups, Dr. Leder observed.
During a discussion of the study, Dr. Leder said bone biopsies were not available but that data at the distal radius and tibia that have not yet been analyzed "may provide some additional idea of what is going on, specifically in the trabecular and cortical compartments."
Session comoderator Dr. Aliya Khan, director of the calcium disorders clinic at St. Joseph’s Healthcare, McMaster University in Hamilton, Ont., said in an interview that the results shouldn’t be universally applied, but "if someone has a fracture, we can certainly consider this approach."
She went on to say that "combination therapy may be a way to improve bone strength, and it may actually enable us to avoid conditions such as atypical femoral fractures, which appear to be associated with oversuppression of bone remodeling."
Eli Lilly and Amgen sponsored the trial. Dr. Leder reported consulting for Amgen and Merck. Dr. Khan reported no disclosures.
MINNEAPOLIS – Combining the antiresorptive denosumab with the anabolic agent teriparatide increased bone mineral density more than either drug alone in postmenopausal women at high fracture risk in the ongoing DATA study.
At 12 months, the combination of denosumab (Prolia) and teriparatide (Forteo) significantly increased bone mineral density (BMD) by 8.9% at the spine, 4.5% at the femoral neck, and 4.9% at the total hip.
The increases in BMD observed in the combination group are larger than those seen in prior combination anabolic and antiresorptive trials, Dr. Benjamin Z. Leder reported at the annual meeting of the American Society for Bone and Mineral Research.
The DATA (Denosumab, Teriparatide or Both for the Treatment of Postmenopausal Osteoporosis) trial is the first to study denosumab in combination with an anabolic agent. Prior trials combining teriparatide and bisphosphonates have shown inconsistent effects on BMD or, in some cases, a blunting effect of the anabolic agent.
The mechanisms underlying the additive effects of denosumab and teriparatide are unclear, but they may be related to the ability of denosumab to fully block teriparatide’s pro-resorptive effects while still allowing for continued modeling-based bone formation and, perhaps, an expansion of the anabolic window, said Dr. Leder, an endocrinologist with Massachusetts General Hospital in Boston.
"If these results persist in the second year of therapy and are confirmed in larger studies, the combination of these two agents may eventually prove to be a beneficial treatment in patients who are at particularly high risk of fracture," he said.
The trial randomized 100 women aged 45 years or older who were at least 3 years post menopause to daily teriparatide 20 mcg subcutaneous or denosumab 60 mg subcutaneous every 6 months or both. All patients received calcium 1,200 mg and vitamin D 400 IU.
Enrollment criteria were a BMD T-score of –2.5 or less at any anatomic site or a T-score of –2 or less with one risk factor (fracture or parental hip fracture after age 50, prior hyperthyroidism, inability to rise from a chair with arms elevated, or current smoker) or a T-score of –1 or less with a history of fragility fracture.
Patients were excluded if they had received oral bisphosphonates in the past 6 months; glucocorticoids for more than 14 days in the past 6 months; and any prior use of teriparatide, strontium, or parenteral bisphosphonates.
Patients were stratified by age and spine BMD. The 94 evaluable patients had an average age of 66 years.
At 12 months, the average increase in total hip BMD was 0.7% with teriparatide, 2.5% with denosumab, and 4.9% with combination therapy. Femoral neck BMD increased 0.8%, 2.1%, and 4.5% and spine BMD increased 6.2%, 5.5%, and 8.9%, respectively.
At the distal one-third of the radius, there was a decrease in BMD of 1.8% with teriparatide, an increase of 1.7% with denosumab, and a gain of 2.5% with the combination, Dr. Leder said. The difference in BMD was significant between the combination and teriparatide groups (P less than .001) but not between the combination and denosumab groups.
Changes in bone density were not significantly different between bisphosphonate-naive patients and those with prior bisphosphonate exposure.
Bone formation biomarker analysis showed significant suppression of osteocalcium with denosumab monotherapy at 3 months that continued through the 12-month study, while there was no change at 3 months and a more modest suppression thereafter in the combination group, he said.
Denosumab monotherapy significantly inhibited procollagen type I N-terminal propeptide at 3 and 6 months, but both groups were similar at 12 months.
The data on bone turnover marker C-telopeptide of type I collagen were distinct, with suppression identical in the denosumab alone and combination groups, Dr. Leder observed.
During a discussion of the study, Dr. Leder said bone biopsies were not available but that data at the distal radius and tibia that have not yet been analyzed "may provide some additional idea of what is going on, specifically in the trabecular and cortical compartments."
Session comoderator Dr. Aliya Khan, director of the calcium disorders clinic at St. Joseph’s Healthcare, McMaster University in Hamilton, Ont., said in an interview that the results shouldn’t be universally applied, but "if someone has a fracture, we can certainly consider this approach."
She went on to say that "combination therapy may be a way to improve bone strength, and it may actually enable us to avoid conditions such as atypical femoral fractures, which appear to be associated with oversuppression of bone remodeling."
Eli Lilly and Amgen sponsored the trial. Dr. Leder reported consulting for Amgen and Merck. Dr. Khan reported no disclosures.
AT THE ANNUAL MEETING OF THE AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH
Major Finding: The combination of denosumab and teriparatide significantly increased bone mineral density by 8.9% at the spine, 4.5% at the femoral neck, and 4.9% at the total hip at the end of 12 months of therapy.
Data Source: These findings come from an open-label, randomized controlled trial in 94 postmenopausal women at high fracture risk.
Disclosures: Amgen and Eli Lilly sponsored the study. Dr. Leder reported consulting for Amgen and Merck. Dr. Khan reported no disclosures.
Antisclerostin Therapy AMG 785 Scores Big in Osteoporosis Arena*
MINNEAPOLIS – The investigational antisclerostin antibody AMG 785 produced rapid increases in bone mineral density roughly 50% to 60% higher than standard drugs in postmenopausal women with low bone mineral density in a phase II trial.
At 1 year, the increase in spine bone mineral density (BMD) was 4% with alendronate (Fosamax), 7% with teriparatide (Forteo), and 11.3% with AMG 785 given in a subcutaneous dose of 210 mg/mo.
Increases in BMD followed a similar, but slightly less dramatic pattern, at the total hip (2% vs. 1.5% vs. 4.1%) and femoral neck (1% vs. 1% vs. 3.7%), Dr. Michael McClung reported at the annual meeting of the American Society for Bone and Mineral Research (ASMBR) The differences in BMD at all three sites significantly favored AMG 785 over either active comparator.
AMG 785 is thought to increase bone formation on quiescent surfaces by inhibiting sclerostin, a protein encoded by the SOST gene in osteocytes that downregulates osteoblast-mediated bone formation.
The phase II results are the first longer-term response data presented for an antisclerostin antibody and build on preclinical work, suggesting that these bone-building drugs increase bone formation without the increase in bone resorption seen with some osteoanabolic agents. Data were also presented at the meeting from two phase I studies of Eli Lilly’s antisclerostin antibody, blosozumab.
The drug will be useful for that small proportion of patients who have had substantial bone loss and destruction of the architecture and strength of their bone over time, Dr. McClung said in an interview.
"There are some patients who are truly in need of skeletal reconstruction, and this would be the strategy to do that," he said. "None of our other drugs have that potential.
"The idea of being able to rebuild the skeletal architecture, the skeletal mass, and the skeletal strength back toward, or even to, normal is a really exciting prospect."
The phase II trial randomly assigned 419 postmenopausal women with low bone mineral density to one of five doses of subcutaneous AMG 785 (70 mg monthly, 140 mg monthly, 210 mg monthly, 140 mg every 3 months, or 210 mg every 3 months) or placebo, and one of two open-label active comparators: 70 mg weekly oral alendronate or 20 mcg daily subcutaneous teriparatide.
The women had average lumbar spine, total hip, and femoral neck T scores of –2.3, -1.5, and –1.9, respectively, but did not have severe osteoporosis. Their average age was 67 years.
At 1 year, all doses of AMG 785 significantly increased BMD at the hip, spine, and femoral neck compared with placebo (P less than .005). A clear dose-response relationship was observed, both in terms of the total dose and dosing interval favoring the higher and monthly doses, said Dr. McClung, director of the Oregon Osteoporosis Center in Portland.
Serum bone turnover marker analyses revealed that all doses of AMG 785 increased PINP (procollagen type I N-terminal propeptide) and reduced CTX (C-telopeptide of type I collagen) from baseline by week 1. As expected, researchers observed decreases in both markers with alendronate and increases in both markers with teriparatide.
Although some have characterized antisclerostin antibodies as a game-changer in osteoporosis, Dr. McClung cautioned that the results are just the first step and said the study produced some surprises in that the very dramatic changes in bone makers occurred within a week of beginning therapy, but the effects on stimulating bone formation were transient and the values returned to baseline between 6 and 12 months, despite patients continuing on therapy.
"There’s lots we need to learn about this," he said, noting that the blunting of the bone response has not been observed in animals. "It seems unlikely that we’ll simply identify patients in need of skeletal restoration and add a sclerostin therapy and treat them until they don’t have osteoporosis anymore.
"Likely we’ll use sclerostin therapy for a relatively short time – 6 months, 12 months – followed by probably another drug, like an antiresorptive drug, and then attempt to take advantage of that first burst of anabolic activity again."
Still, it was hard to miss the buzz over this new therapeutic target, with 20 or so sclerostin abstracts at the meeting and the AMG 785 study winning the 2012 ASBMR Most Outstanding Clinical Abstract Award.
Early positive signals from the phase II trial also prompted Amgen to initiate a phase III randomized, alendronate-controlled trial in more than 5,000 postmenopausal women with osteoporosis to determine whether AMG 785 can prevent fractures, the Holy Grail in osteoporosis management.
The most common adverse event with AMG 785 in the phase II trial was injection site reaction (9.8%). No fatal adverse events were reported. The maximum tolerated dose has not been identified, with the monthly 210-mg dose to be carried forward into subsequent phase III trials, Dr. McClung said.
The trial was funded by Amgen and UCB Pharma. Dr. McClung reported financial relationships with Amgen, Lilly, Merck, Novartis, and Warner Chilcott.
CORRECTION 10/19/12: The headline for this story misstated the name of the investigational drug. The headline should read "Antisclerostin Therapy AMG 785 Scores Big in Osteoporosis Arena."
MINNEAPOLIS – The investigational antisclerostin antibody AMG 785 produced rapid increases in bone mineral density roughly 50% to 60% higher than standard drugs in postmenopausal women with low bone mineral density in a phase II trial.
At 1 year, the increase in spine bone mineral density (BMD) was 4% with alendronate (Fosamax), 7% with teriparatide (Forteo), and 11.3% with AMG 785 given in a subcutaneous dose of 210 mg/mo.
Increases in BMD followed a similar, but slightly less dramatic pattern, at the total hip (2% vs. 1.5% vs. 4.1%) and femoral neck (1% vs. 1% vs. 3.7%), Dr. Michael McClung reported at the annual meeting of the American Society for Bone and Mineral Research (ASMBR) The differences in BMD at all three sites significantly favored AMG 785 over either active comparator.
AMG 785 is thought to increase bone formation on quiescent surfaces by inhibiting sclerostin, a protein encoded by the SOST gene in osteocytes that downregulates osteoblast-mediated bone formation.
The phase II results are the first longer-term response data presented for an antisclerostin antibody and build on preclinical work, suggesting that these bone-building drugs increase bone formation without the increase in bone resorption seen with some osteoanabolic agents. Data were also presented at the meeting from two phase I studies of Eli Lilly’s antisclerostin antibody, blosozumab.
The drug will be useful for that small proportion of patients who have had substantial bone loss and destruction of the architecture and strength of their bone over time, Dr. McClung said in an interview.
"There are some patients who are truly in need of skeletal reconstruction, and this would be the strategy to do that," he said. "None of our other drugs have that potential.
"The idea of being able to rebuild the skeletal architecture, the skeletal mass, and the skeletal strength back toward, or even to, normal is a really exciting prospect."
The phase II trial randomly assigned 419 postmenopausal women with low bone mineral density to one of five doses of subcutaneous AMG 785 (70 mg monthly, 140 mg monthly, 210 mg monthly, 140 mg every 3 months, or 210 mg every 3 months) or placebo, and one of two open-label active comparators: 70 mg weekly oral alendronate or 20 mcg daily subcutaneous teriparatide.
The women had average lumbar spine, total hip, and femoral neck T scores of –2.3, -1.5, and –1.9, respectively, but did not have severe osteoporosis. Their average age was 67 years.
At 1 year, all doses of AMG 785 significantly increased BMD at the hip, spine, and femoral neck compared with placebo (P less than .005). A clear dose-response relationship was observed, both in terms of the total dose and dosing interval favoring the higher and monthly doses, said Dr. McClung, director of the Oregon Osteoporosis Center in Portland.
Serum bone turnover marker analyses revealed that all doses of AMG 785 increased PINP (procollagen type I N-terminal propeptide) and reduced CTX (C-telopeptide of type I collagen) from baseline by week 1. As expected, researchers observed decreases in both markers with alendronate and increases in both markers with teriparatide.
Although some have characterized antisclerostin antibodies as a game-changer in osteoporosis, Dr. McClung cautioned that the results are just the first step and said the study produced some surprises in that the very dramatic changes in bone makers occurred within a week of beginning therapy, but the effects on stimulating bone formation were transient and the values returned to baseline between 6 and 12 months, despite patients continuing on therapy.
"There’s lots we need to learn about this," he said, noting that the blunting of the bone response has not been observed in animals. "It seems unlikely that we’ll simply identify patients in need of skeletal restoration and add a sclerostin therapy and treat them until they don’t have osteoporosis anymore.
"Likely we’ll use sclerostin therapy for a relatively short time – 6 months, 12 months – followed by probably another drug, like an antiresorptive drug, and then attempt to take advantage of that first burst of anabolic activity again."
Still, it was hard to miss the buzz over this new therapeutic target, with 20 or so sclerostin abstracts at the meeting and the AMG 785 study winning the 2012 ASBMR Most Outstanding Clinical Abstract Award.
Early positive signals from the phase II trial also prompted Amgen to initiate a phase III randomized, alendronate-controlled trial in more than 5,000 postmenopausal women with osteoporosis to determine whether AMG 785 can prevent fractures, the Holy Grail in osteoporosis management.
The most common adverse event with AMG 785 in the phase II trial was injection site reaction (9.8%). No fatal adverse events were reported. The maximum tolerated dose has not been identified, with the monthly 210-mg dose to be carried forward into subsequent phase III trials, Dr. McClung said.
The trial was funded by Amgen and UCB Pharma. Dr. McClung reported financial relationships with Amgen, Lilly, Merck, Novartis, and Warner Chilcott.
CORRECTION 10/19/12: The headline for this story misstated the name of the investigational drug. The headline should read "Antisclerostin Therapy AMG 785 Scores Big in Osteoporosis Arena."
MINNEAPOLIS – The investigational antisclerostin antibody AMG 785 produced rapid increases in bone mineral density roughly 50% to 60% higher than standard drugs in postmenopausal women with low bone mineral density in a phase II trial.
At 1 year, the increase in spine bone mineral density (BMD) was 4% with alendronate (Fosamax), 7% with teriparatide (Forteo), and 11.3% with AMG 785 given in a subcutaneous dose of 210 mg/mo.
Increases in BMD followed a similar, but slightly less dramatic pattern, at the total hip (2% vs. 1.5% vs. 4.1%) and femoral neck (1% vs. 1% vs. 3.7%), Dr. Michael McClung reported at the annual meeting of the American Society for Bone and Mineral Research (ASMBR) The differences in BMD at all three sites significantly favored AMG 785 over either active comparator.
AMG 785 is thought to increase bone formation on quiescent surfaces by inhibiting sclerostin, a protein encoded by the SOST gene in osteocytes that downregulates osteoblast-mediated bone formation.
The phase II results are the first longer-term response data presented for an antisclerostin antibody and build on preclinical work, suggesting that these bone-building drugs increase bone formation without the increase in bone resorption seen with some osteoanabolic agents. Data were also presented at the meeting from two phase I studies of Eli Lilly’s antisclerostin antibody, blosozumab.
The drug will be useful for that small proportion of patients who have had substantial bone loss and destruction of the architecture and strength of their bone over time, Dr. McClung said in an interview.
"There are some patients who are truly in need of skeletal reconstruction, and this would be the strategy to do that," he said. "None of our other drugs have that potential.
"The idea of being able to rebuild the skeletal architecture, the skeletal mass, and the skeletal strength back toward, or even to, normal is a really exciting prospect."
The phase II trial randomly assigned 419 postmenopausal women with low bone mineral density to one of five doses of subcutaneous AMG 785 (70 mg monthly, 140 mg monthly, 210 mg monthly, 140 mg every 3 months, or 210 mg every 3 months) or placebo, and one of two open-label active comparators: 70 mg weekly oral alendronate or 20 mcg daily subcutaneous teriparatide.
The women had average lumbar spine, total hip, and femoral neck T scores of –2.3, -1.5, and –1.9, respectively, but did not have severe osteoporosis. Their average age was 67 years.
At 1 year, all doses of AMG 785 significantly increased BMD at the hip, spine, and femoral neck compared with placebo (P less than .005). A clear dose-response relationship was observed, both in terms of the total dose and dosing interval favoring the higher and monthly doses, said Dr. McClung, director of the Oregon Osteoporosis Center in Portland.
Serum bone turnover marker analyses revealed that all doses of AMG 785 increased PINP (procollagen type I N-terminal propeptide) and reduced CTX (C-telopeptide of type I collagen) from baseline by week 1. As expected, researchers observed decreases in both markers with alendronate and increases in both markers with teriparatide.
Although some have characterized antisclerostin antibodies as a game-changer in osteoporosis, Dr. McClung cautioned that the results are just the first step and said the study produced some surprises in that the very dramatic changes in bone makers occurred within a week of beginning therapy, but the effects on stimulating bone formation were transient and the values returned to baseline between 6 and 12 months, despite patients continuing on therapy.
"There’s lots we need to learn about this," he said, noting that the blunting of the bone response has not been observed in animals. "It seems unlikely that we’ll simply identify patients in need of skeletal restoration and add a sclerostin therapy and treat them until they don’t have osteoporosis anymore.
"Likely we’ll use sclerostin therapy for a relatively short time – 6 months, 12 months – followed by probably another drug, like an antiresorptive drug, and then attempt to take advantage of that first burst of anabolic activity again."
Still, it was hard to miss the buzz over this new therapeutic target, with 20 or so sclerostin abstracts at the meeting and the AMG 785 study winning the 2012 ASBMR Most Outstanding Clinical Abstract Award.
Early positive signals from the phase II trial also prompted Amgen to initiate a phase III randomized, alendronate-controlled trial in more than 5,000 postmenopausal women with osteoporosis to determine whether AMG 785 can prevent fractures, the Holy Grail in osteoporosis management.
The most common adverse event with AMG 785 in the phase II trial was injection site reaction (9.8%). No fatal adverse events were reported. The maximum tolerated dose has not been identified, with the monthly 210-mg dose to be carried forward into subsequent phase III trials, Dr. McClung said.
The trial was funded by Amgen and UCB Pharma. Dr. McClung reported financial relationships with Amgen, Lilly, Merck, Novartis, and Warner Chilcott.
CORRECTION 10/19/12: The headline for this story misstated the name of the investigational drug. The headline should read "Antisclerostin Therapy AMG 785 Scores Big in Osteoporosis Arena."
AT THE ANNUAL MEETING OF THE AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH
Major Finding: At 1 year, the increase in spine bone mineral density was 4% with alendronate, 7% with teriparatide, and 11.3% with AMG 785.
Data Source: The data come from a phase II trial involving 419 women with low bone mineral density.
Disclosures: The study was funded by Amgen and UCB Pharma. Dr. McClung reported financial relationships with Amgen, Lilly, Merck, Novartis, and Warner-Chilcott.
