2. Osteoporosis:
Speaker’s Notes
Heightened patient & physician awareness of osteoporosis
Establishment of low BMD as fracture predictor
More precise and available diagnostic techniques
Clearer diagnostic and therapeutic guidelines
Advances in pharmacological and nonpharmacological management
Speaker’s Notes
Heightened patient & physician awareness of osteoporosis
Establishment of low BMD as fracture predictor
More precise and available diagnostic techniques
Clearer diagnostic and therapeutic guidelines
Advances in pharmacological and nonpharmacological management
3. slide 3
Postmenopausal women bear the major share of the osteoporosis burden. At menopause, diminished estrogen levels lead to excessive bone resorption without a compensatory increase in bone formation, resulting in reduced bone mass and osteoporosis.
In the United States, 4 to 6 million women age 50 or older (13% to 18%) have osteoporosis, and 13 to 17 million (37% to 50%) have low bone mass. Forty percent of women over age 50 will suffer fractures in their lifetime: 5.6% will experience a vertebral fracture, 17.5% a hip fracture, and 16% a forearm fracture.
The risk of osteoporosis, low bone mass, and fracture is highest in Caucasian and Asian women. This risk is lower but still significant in Hispanic and African American women.
Melton LJ 3rd, Chrischilles EA, Cooper C, et al. How many women have osteoporosis? J Bone Miner Res 1992;7:1005-10.
Looker AC, Orwoll ES, Johnston CC Jr, et al. Prevalence of low femoral bone density in US adults from NHANES III. J Bone Miner Res 1997;12:1761-8.
Postmenopausal women bear the major share of the osteoporosis burden. At menopause, diminished estrogen levels lead to excessive bone resorption without a compensatory increase in bone formation, resulting in reduced bone mass and osteoporosis.
In the United States, 4 to 6 million women age 50 or older (13% to 18%) have osteoporosis, and 13 to 17 million (37% to 50%) have low bone mass. Forty percent of women over age 50 will suffer fractures in their lifetime: 5.6% will experience a vertebral fracture, 17.5% a hip fracture, and 16% a forearm fracture.
The risk of osteoporosis, low bone mass, and fracture is highest in Caucasian and Asian women. This risk is lower but still significant in Hispanic and African American women.
Melton LJ 3rd, Chrischilles EA, Cooper C, et al. How many women have osteoporosis? J Bone Miner Res 1992;7:1005-10.
Looker AC, Orwoll ES, Johnston CC Jr, et al. Prevalence of low femoral bone density in US adults from NHANES III. J Bone Miner Res 1997;12:1761-8.
4. Osteoporosis:
The burden of osteoporosis in the United States will become an even larger economic and social burden as the proportion of the elderly increases with the aging of baby boomers. Widespread use of effective prevention and new treatment options could reduce these future costs.
Ray NF, Chan JK, Thamer M, et al. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res 1997;12:25-35
National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Bell Mead, NJ: Excerpta Medica, Inc; 1998. Washington, DC: National Osteoporosis Foundation;1998. Available at www.nof.org/physguide/inside_cover.htm.
The burden of osteoporosis in the United States will become an even larger economic and social burden as the proportion of the elderly increases with the aging of baby boomers. Widespread use of effective prevention and new treatment options could reduce these future costs.
Ray NF, Chan JK, Thamer M, et al. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res 1997;12:25-35
National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Bell Mead, NJ: Excerpta Medica, Inc; 1998. Washington, DC: National Osteoporosis Foundation;1998. Available at www.nof.org/physguide/inside_cover.htm.
5. Human Costs of Osteoporosis
The first sign of a clinical vertebral fracture is usually the sudden onset of back pain with little or no trauma, leaving all the chronic manifestations of spine fracture (loss of height, spinal deformity/dowager’s hump, protuberant abdomen).
Osteoporotic fractures lead to decreased activity, which perpetuates bone loss. Pulmonary disorders are also a major complication of vertebral fractures. One thoracic vertebral compression fracture causes a 9% loss of forced vital capacity, and lumbar fractures have also been linked to impairment of pulmonary function. The beginning of a vertebral kyphosis predisposes to other fractures, resulting in an almost 12-fold increased risk for new vertebral fractures with 2 or more previous fractures.
Ross PD et al, Davis JW, Epstein RS, et al. Pre-existing fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med 1991;114;919-23.
Silverman SL. The clinical consequences of vertebral compression fracture. Bone 1992;13 (suppl 2):S27-S31.
Cooper C, Atkinson EJ, Jacobsen SJ, et al. Population-based study of survival after osteoporotic fractures. Am J Epidem 1993;137:1001-5.
Lyles KW, Gold DT, Shipp KM, et al. Association of osteoporotic vertebral compression fractures with impaired functional status. Am J Med 1993;94:595-601.
Schlaich C, Minne HW, Bruckner T, et al. Reduced pulmonary function in patients with spinal osteoporotic fractures. Osteoporosis Int 1998;8:261-7.
The first sign of a clinical vertebral fracture is usually the sudden onset of back pain with little or no trauma, leaving all the chronic manifestations of spine fracture (loss of height, spinal deformity/dowager’s hump, protuberant abdomen).
Osteoporotic fractures lead to decreased activity, which perpetuates bone loss. Pulmonary disorders are also a major complication of vertebral fractures. One thoracic vertebral compression fracture causes a 9% loss of forced vital capacity, and lumbar fractures have also been linked to impairment of pulmonary function. The beginning of a vertebral kyphosis predisposes to other fractures, resulting in an almost 12-fold increased risk for new vertebral fractures with 2 or more previous fractures.
Ross PD et al, Davis JW, Epstein RS, et al. Pre-existing fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med 1991;114;919-23.
Silverman SL. The clinical consequences of vertebral compression fracture. Bone 1992;13 (suppl 2):S27-S31.
Cooper C, Atkinson EJ, Jacobsen SJ, et al. Population-based study of survival after osteoporotic fractures. Am J Epidem 1993;137:1001-5.
Lyles KW, Gold DT, Shipp KM, et al. Association of osteoporotic vertebral compression fractures with impaired functional status. Am J Med 1993;94:595-601.
Schlaich C, Minne HW, Bruckner T, et al. Reduced pulmonary function in patients with spinal osteoporotic fractures. Osteoporosis Int 1998;8:261-7.
7. Incidence of Osteoporosis and Osteopenia
Looker et al used dual-energy X-ray absorptiometry measurements of femoral bone mineral density (BMD) from the third National Health and Nutrition Examination Survey (NHANES III) to estimate the overall scope of osteoporosis and osteopenia in the older US population.
WHO criteria were used to define the presence of osteopenia and osteoporosis.
Women:
4-6 million with osteoporosis
13-17 million with osteopenia
Men (based on female cutoffs):
.25-1 million with osteoporosis
4-9 million with osteopenia
Looker AC, Orwoll ES, Johnston CC jr, et al. Prevalence of low femoral bone density in older U.S. adults from NHANES III. J Bone Miner Res 1997;12:1761-8.
Looker et al used dual-energy X-ray absorptiometry measurements of femoral bone mineral density (BMD) from the third National Health and Nutrition Examination Survey (NHANES III) to estimate the overall scope of osteoporosis and osteopenia in the older US population.
WHO criteria were used to define the presence of osteopenia and osteoporosis.
Women:
4-6 million with osteoporosis
13-17 million with osteopenia
Men (based on female cutoffs):
.25-1 million with osteoporosis
4-9 million with osteopenia
Looker AC, Orwoll ES, Johnston CC jr, et al. Prevalence of low femoral bone density in older U.S. adults from NHANES III. J Bone Miner Res 1997;12:1761-8.
9. Osteoporosis: Identifying the Problem
Osteoporosis is the most common disease of bone in humans. It is a systemic skeletal disease, characterized by low bone mass and by microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.
Dempster DW, Shane E, Horbert W, et al. A simple method for correlative light and scanning electron microscopy in human iliac crest bone biopsies: qualitative observations in normal and osteoporotic subjects. J Bone Miner Res 1986;1:15-21.
Consensus Development Conference. Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 1993;94:646-50.
.
Osteoporosis is the most common disease of bone in humans. It is a systemic skeletal disease, characterized by low bone mass and by microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.
Dempster DW, Shane E, Horbert W, et al. A simple method for correlative light and scanning electron microscopy in human iliac crest bone biopsies: qualitative observations in normal and osteoporotic subjects. J Bone Miner Res 1986;1:15-21.
Consensus Development Conference. Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 1993;94:646-50.
.
13. Relationship Between BMD and
ANIMATED SLIDE
In untreated individuals, each 1 SD reduction is BMD is associated with a 2-fold increase in risk of fracture.
If the reverse were true in response to treatment, a 1 SD increase in BMD would result in a 50% decrease in fracture risk.
The next slide shows that this is not the case.
ANIMATED SLIDE
In untreated individuals, each 1 SD reduction is BMD is associated with a 2-fold increase in risk of fracture.
If the reverse were true in response to treatment, a 1 SD increase in BMD would result in a 50% decrease in fracture risk.
The next slide shows that this is not the case.
17. Relationship Between BMD and
ANIMATED SLIDE
In untreated individuals, each 1 SD reduction is BMD is associated with a 2-fold increase in risk of fracture.
If the reverse were true in response to treatment, a 1 SD increase in BMD would result in a 50% decrease in fracture risk.
The next slide shows that this is not the case.
ANIMATED SLIDE
In untreated individuals, each 1 SD reduction is BMD is associated with a 2-fold increase in risk of fracture.
If the reverse were true in response to treatment, a 1 SD increase in BMD would result in a 50% decrease in fracture risk.
The next slide shows that this is not the case.
18. How to deal with the patient whose bone density is in
the osteopenic range (AACE Guidelines)
Within 1 minute, a patient’s risk and need for treatment can be assessed by reviewing his or her T-scores. A T-score above -1.5 indicates the patient is at low risk and should be checked again within 1 to 2 years. A T-score between
-1.5 to -2.0 indicates that the patient is at moderate risk and should be treated if he or she has other risk factors. A T-score below -2.0 is an indication of high risk, and the patient should be treated.
National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC;1998.
Within 1 minute, a patient’s risk and need for treatment can be assessed by reviewing his or her T-scores. A T-score above -1.5 indicates the patient is at low risk and should be checked again within 1 to 2 years. A T-score between
-1.5 to -2.0 indicates that the patient is at moderate risk and should be treated if he or she has other risk factors. A T-score below -2.0 is an indication of high risk, and the patient should be treated.
National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC;1998.
19. Design
Longitudinal, observational study of postmenopausal women in the U.S.
Objectives
To describe the occurrence of low bone mineral density (BMD) in postmenopausal women, its risk factors, and fracture incidence during short-term follow-up
Study Participants
200,160 postmenopausal women aged 50 and older not previously assessed, or diagnosed with “osteoporosis”
Participation Criteria
Primary care physicians:
Practices with a large population of female patients 50 years of age and older
No in-office densitometry
Postmenopausal women:
50 years of age and older
No previous diagnosis of osteoporosis
No BMD test in the previous 12 months
No osteoporosis specific medications
HRT, calcium and vitamin D not excluded
Data Collection
Baseline
Peripheral BMD Test (heel, forearm, finger)
Core patient questionnaire
Records information on background, demographic data, and osteoporosis risk factors
Patients also randomly received 4 of 8 supplemental questionnaires
Assessments included osteoporosis awareness, health insurance, calcium and vitamin D use, reproductive and medical history, general health status, and mood
Fractures
self-reported at 12 months follow-up
Definition of Low BMD
The World Health Organization criteria for low BMD
T-score Interpretation
0 Equivalent to the mean peak BMD of healthy pre-menopausal women aged 20-29 years
-1 to -2.5 "Osteopenia"
-2.5 "Osteoporosis"
Each SD decline in T-score results in a doubling in relative risk of fracture.
Participation Criteria
Primary care physicians:
Practices with a large population of female patients 50 years of age and older
No in-office densitometry
Postmenopausal women:
50 years of age and older
No previous diagnosis of osteoporosis
No BMD test in the previous 12 months
No osteoporosis specific medications
HRT, calcium and vitamin D not excluded
Data Collection
Baseline
Peripheral BMD Test (heel, forearm, finger)
Core patient questionnaire
Records information on background, demographic data, and osteoporosis risk factors
Patients also randomly received 4 of 8 supplemental questionnaires
Assessments included osteoporosis awareness, health insurance, calcium and vitamin D use, reproductive and medical history, general health status, and mood
Fractures
self-reported at 12 months follow-up
Definition of Low BMD
The World Health Organization criteria for low BMD
T-score Interpretation
0 Equivalent to the mean peak BMD of healthy pre-menopausal women aged 20-29 years
-1 to -2.5 "Osteopenia"
-2.5 "Osteoporosis"
Each SD decline in T-score results in a doubling in relative risk of fracture.
20. Fracture Rate Ratio Within
Relative Risk for Fracture Within One Year
by T-score from peripheral devices
Patients with osteoporosis had a 4 times higher rate of osteoporotic fracture and almost 9 times higher rate of hip fracture, compared with patients with a normal T-score.
Likewise, osteopenic patients had a 1.8 times higher rate of osteoporotic fracture compared with patients with normal BMD. Patients with low bone mass ("osteopenia") had almost 3 times higher rate of hip fracture.
Siris E, Miller P, Barrett-Connor E, et al. Identification and Fracture Outcomes of Undiagnosed Low Bone Mineral Density in Postmenopausal Women. JAMA. 2001;286:2815-2822.
Relative Risk for Fracture Within One Year
by T-score from peripheral devices
Patients with osteoporosis had a 4 times higher rate of osteoporotic fracture and almost 9 times higher rate of hip fracture, compared with patients with a normal T-score.
Likewise, osteopenic patients had a 1.8 times higher rate of osteoporotic fracture compared with patients with normal BMD. Patients with low bone mass ("osteopenia") had almost 3 times higher rate of hip fracture.
Siris E, Miller P, Barrett-Connor E, et al. Identification and Fracture Outcomes of Undiagnosed Low Bone Mineral Density in Postmenopausal Women. JAMA. 2001;286:2815-2822.
21. 1-Year-Risk of New Fracture by T-score Category: all Caucasian NORA women
As shown here, the overall risk of fracture for women increases as the T-score decreases.
More fractures occur in women with T-score between -2.5 and -1.0 than in each of the other T-score categories.
2% of the women in this category fractured
Whereas 4.3% of the women with T-score <-2.5 fractured
The goal of this analysis was to determine the women with T-scores between -2.5 and -1.0 who have a similar risk for fracture as women with T-scores below -2.5
As shown here, the overall risk of fracture for women increases as the T-score decreases.
More fractures occur in women with T-score between -2.5 and -1.0 than in each of the other T-score categories.
2% of the women in this category fractured
Whereas 4.3% of the women with T-score <-2.5 fractured
The goal of this analysis was to determine the women with T-scores between -2.5 and -1.0 who have a similar risk for fracture as women with T-scores below -2.5
22. Fracture Rates, Population T-Score Distribution and
39% of the NORA women were osteopenic and had 50% of the fractures
In the NORA data set, most of the people fell as not osteoporotic, but had higher bone mass.
Most fractures occurred in the group that had higher bone mass because there were more people in that group.
The T-scores were derived using peripheral technology.
39% of the NORA women were osteopenic and had 50% of the fractures
In the NORA data set, most of the people fell as not osteoporotic, but had higher bone mass.
Most fractures occurred in the group that had higher bone mass because there were more people in that group.
The T-scores were derived using peripheral technology.
23. How to deal with the patient whose bone density is in
the osteopenic range (AACE Guidelines)
Within 1 minute, a patient’s risk and need for treatment can be assessed by reviewing his or her T-scores. A T-score above -1.5 indicates the patient is at low risk and should be checked again within 1 to 2 years. A T-score between
-1.5 to -2.0 indicates that the patient is at moderate risk and should be treated if he or she has other risk factors. A T-score below -2.0 is an indication of high risk, and the patient should be treated.
National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC;1998.
Within 1 minute, a patient’s risk and need for treatment can be assessed by reviewing his or her T-scores. A T-score above -1.5 indicates the patient is at low risk and should be checked again within 1 to 2 years. A T-score between
-1.5 to -2.0 indicates that the patient is at moderate risk and should be treated if he or she has other risk factors. A T-score below -2.0 is an indication of high risk, and the patient should be treated.
National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC;1998.
24. How to deal with the patient whose bone density is in
the osteopenic range (AACE Guidelines)
Within 1 minute, a patient’s risk and need for treatment can be assessed by reviewing his or her T-scores. A T-score above -1.5 indicates the patient is at low risk and should be checked again within 1 to 2 years. A T-score between
-1.5 to -2.0 indicates that the patient is at moderate risk and should be treated if he or she has other risk factors. A T-score below -2.0 is an indication of high risk, and the patient should be treated.
National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC;1998.
Within 1 minute, a patient’s risk and need for treatment can be assessed by reviewing his or her T-scores. A T-score above -1.5 indicates the patient is at low risk and should be checked again within 1 to 2 years. A T-score between
-1.5 to -2.0 indicates that the patient is at moderate risk and should be treated if he or she has other risk factors. A T-score below -2.0 is an indication of high risk, and the patient should be treated.
National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC;1998.
26. 160
Hui SL, Slemenda CW, Johnston CC Jr. Age and bone mass as predicators of fracture in a prospective study. J Clin Invest. 1988;81(6):1804-1809.
Hui SL, Slemenda CW, Johnston CC Jr. Age and bone mass as predicators of fracture in a prospective study. J Clin Invest. 1988;81(6):1804-1809.
28. The Importance of One Vertebral Fracture
A number of large prospective and retrospective studies of fracture risk in mostly postmenopausal women have revealed that a baseline vertebral fracture increases the risk of subsequent hip and/or vertebral fracture. The risk of a new vertebral fracture increased as much as 12-fold when there were two or more fractures at baseline.
Ross PD, Davis JW, Epstein RS, Wasnich RD. Pre-existing fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med 1991;114:919-23.
Kotowicz MA, Melton JL III, Cooper C, et al. Risk of hip fracture in women with vertebral fracture. J Bone Miner Res 1994:9:599-605.
Black DM, Arden NK, Palermo L, et al. Prevalent vertebral deformities predict hip fractures and new vertebral deformities but no wrist fractures. J Bone Miner Res 1999;14:821-8.
Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA 2001;285:320-3.
A number of large prospective and retrospective studies of fracture risk in mostly postmenopausal women have revealed that a baseline vertebral fracture increases the risk of subsequent hip and/or vertebral fracture. The risk of a new vertebral fracture increased as much as 12-fold when there were two or more fractures at baseline.
Ross PD, Davis JW, Epstein RS, Wasnich RD. Pre-existing fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med 1991;114:919-23.
Kotowicz MA, Melton JL III, Cooper C, et al. Risk of hip fracture in women with vertebral fracture. J Bone Miner Res 1994:9:599-605.
Black DM, Arden NK, Palermo L, et al. Prevalent vertebral deformities predict hip fractures and new vertebral deformities but no wrist fractures. J Bone Miner Res 1999;14:821-8.
Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA 2001;285:320-3.
29. The Osteoporotic Fracture Does Not Often
Despite evidence that fractures beget fractures, many postmenopausal women with an existing fracture are neither diagnosed nor treated for osteoporosis. A retrospective cohort study of a large claims database, including more than 3 million patients in 30 states from 1994 to 1997 demonstrated the magnitude of the problem.
Among these patients were 1162 postmenopausal women who had sustained a distal radial fracture—a strong predictor of future hip fracture. Only 266 (22.9%) of the women with distal radial fractures were treated with one or more medications approved for treatment of osteoporosis. Only 33 women (2.8%) underwent a bone density scan, 20 of whom received therapy. In total, only 279 (24.0%) of the 1162 women were either evaluated or treated.
Freedman KB, Kaplan, FS, Bilker WB, et al. Treatment of osteoporosis: are physicians missing an opportunity? J Bone Joint Surg 2000;82-A:1063-70.
Mallmin H, Ljunghall S, Persson L, et al. Fracture of the distal forearm as a forecaster of subsequent hip fracture: a population-based cohort study with 24 years of follow-up. Calcif Tissue Int 1993;52:269-72.
Despite evidence that fractures beget fractures, many postmenopausal women with an existing fracture are neither diagnosed nor treated for osteoporosis. A retrospective cohort study of a large claims database, including more than 3 million patients in 30 states from 1994 to 1997 demonstrated the magnitude of the problem.
Among these patients were 1162 postmenopausal women who had sustained a distal radial fracture—a strong predictor of future hip fracture. Only 266 (22.9%) of the women with distal radial fractures were treated with one or more medications approved for treatment of osteoporosis. Only 33 women (2.8%) underwent a bone density scan, 20 of whom received therapy. In total, only 279 (24.0%) of the 1162 women were either evaluated or treated.
Freedman KB, Kaplan, FS, Bilker WB, et al. Treatment of osteoporosis: are physicians missing an opportunity? J Bone Joint Surg 2000;82-A:1063-70.
Mallmin H, Ljunghall S, Persson L, et al. Fracture of the distal forearm as a forecaster of subsequent hip fracture: a population-based cohort study with 24 years of follow-up. Calcif Tissue Int 1993;52:269-72.
30. Osteoporosis Treatment Rate after Fracture Decreases with Age as Fracture Incidence Rises
The rate of treatment for osteoporosis decreases significantly with increased patient age. Freedman’s study shows that while 36% of women aged 55 to 59 with fracture were treated for osteoporosis, only 25.7% of those aged 80 to 84 were treated. For women aged 85 to 89 with fracture, only 9.1% received treatment. Of those over 90 years old, only 4.5% were treated.
While treatment rates decline with increasing age, fracture incidence rises.
Melton LJ 3rd, Atkinson EJ Cooper C, et al. Vertebral fractures predict subsequent fractures. Osteoporos Int 1999;10:214-21.
Freedman KB, Kaplan FS, Bilker WB, et al. Treatment of osteoporosis: are physicians missing an opportunity? J Bone Joint Surg 2000;82:1063-70.
The rate of treatment for osteoporosis decreases significantly with increased patient age. Freedman’s study shows that while 36% of women aged 55 to 59 with fracture were treated for osteoporosis, only 25.7% of those aged 80 to 84 were treated. For women aged 85 to 89 with fracture, only 9.1% received treatment. Of those over 90 years old, only 4.5% were treated.
While treatment rates decline with increasing age, fracture incidence rises.
Melton LJ 3rd, Atkinson EJ Cooper C, et al. Vertebral fractures predict subsequent fractures. Osteoporos Int 1999;10:214-21.
Freedman KB, Kaplan FS, Bilker WB, et al. Treatment of osteoporosis: are physicians missing an opportunity? J Bone Joint Surg 2000;82:1063-70.
33. Is this post-menopausal osteoporosis?
Postmenopausal and age related bone loss are, by far, the most common causes of osteoporosis in women, but other diseases can also present as low bone density or fractures. (Table 5).
Postmenopausal and age related bone loss are, by far, the most common causes of osteoporosis in women, but other diseases can also present as low bone density or fractures. (Table 5).
37. Low BMD and Other Factors Multiply Risk
Although the effect of a single risk factor may be moderate, compounded risk factors have substantial effects. Women with more than one risk factor and low BMD are at especially high risk for fracture.
Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1995;332:767-73.
Although the effect of a single risk factor may be moderate, compounded risk factors have substantial effects. Women with more than one risk factor and low BMD are at especially high risk for fracture.
Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1995;332:767-73.
39. Osteoporotic Women with New Diagnoses
% of osteoporosis women on thyroid replacement were on excessive dose.
% of osteoporosis women on thyroid replacement were on excessive dose.
42. Evaluation of the Patient
In uncomplicated postmenopausal osteoporosis, all lab studies should be normal.
Look carefully at these test results. If they are abnormal , additional studies should be pursued. See KP-16 for a guide to what you should think about if any of these tests are abnormal.
Although 24 hour urine may be onerous to some patients, without it, 32% of the new diagnoses would have been missed if just did PTH, sCa, 25VitD, performed. (Tannenbaum C, et al)
In uncomplicated postmenopausal osteoporosis, all lab studies should be normal.
Look carefully at these test results. If they are abnormal , additional studies should be pursued. See KP-16 for a guide to what you should think about if any of these tests are abnormal.
Although 24 hour urine may be onerous to some patients, without it, 32% of the new diagnoses would have been missed if just did PTH, sCa, 25VitD, performed. (Tannenbaum C, et al)
44. Correction of Vitamin D Deficiency
Up to 150 days to reach new steady state
Up to 5000IU/day probably safe
Up to 150 days to reach new steady state
Up to 5000IU/day probably safe
54. Estrogen Therapy….
Estrogen has been available to women for a long time to treat a variety of disorders. In general, there are several good reasons for ERT after menopause, as listed above.
Although its cardioprotective effects in secondary prevention settings have recently been called into question and the possibility that it prevents Alzheimer’s disease is uncertain, many physicians continue to prescribe estrogen for several of the reasons listed here, usually in combination with other therapies.
Estrogen has been available to women for a long time to treat a variety of disorders. In general, there are several good reasons for ERT after menopause, as listed above.
Although its cardioprotective effects in secondary prevention settings have recently been called into question and the possibility that it prevents Alzheimer’s disease is uncertain, many physicians continue to prescribe estrogen for several of the reasons listed here, usually in combination with other therapies.
62. How to deal with the patient whose bone density is in
the osteopenic range (AACE Guidelines)
Within 1 minute, a patient’s risk and need for treatment can be assessed by reviewing his or her T-scores. A T-score above -1.5 indicates the patient is at low risk and should be checked again within 1 to 2 years. A T-score between
-1.5 to -2.0 indicates that the patient is at moderate risk and should be treated if he or she has other risk factors. A T-score below -2.0 is an indication of high risk, and the patient should be treated.
National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC;1998.
Within 1 minute, a patient’s risk and need for treatment can be assessed by reviewing his or her T-scores. A T-score above -1.5 indicates the patient is at low risk and should be checked again within 1 to 2 years. A T-score between
-1.5 to -2.0 indicates that the patient is at moderate risk and should be treated if he or she has other risk factors. A T-score below -2.0 is an indication of high risk, and the patient should be treated.
National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC;1998.
64. Effects of Raloxifene on New Vertebral
After 36 months, raloxifene significantly reduced the incidence of new vertebral fractures in women with or without previous fractures. There was no difference in the rate of vertebral fracture incidence between the 60- and 120-mg-treated groups.
At the end of the 1-year extension (ie, 48 months), raloxifene continued to show a significant reduction in the risk of new vertebral fractures in women regardless of whether they had existing fractures at the beginning of the study. The relative risks for new vertebral fractures were similar between years 3 and 4.
Eastell R, Adachi J, Harper K, et al. J Bone Miner Res 2000:15(suppl 1):S229.
Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:634-45.
After 36 months, raloxifene significantly reduced the incidence of new vertebral fractures in women with or without previous fractures. There was no difference in the rate of vertebral fracture incidence between the 60- and 120-mg-treated groups.
At the end of the 1-year extension (ie, 48 months), raloxifene continued to show a significant reduction in the risk of new vertebral fractures in women regardless of whether they had existing fractures at the beginning of the study. The relative risks for new vertebral fractures were similar between years 3 and 4.
Eastell R, Adachi J, Harper K, et al. J Bone Miner Res 2000:15(suppl 1):S229.
Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:634-45.
65. Effects of Raloxifene on Nonvertebral
The MORE study was unable to show any benefit of raloxifene therapy on nonvertebral fractures (ie, hip, wrist or ankle). There was a statistically significant decrease in ankle fractures observed at 36 months. However, this benefit was no longer achieved at 48 months. The MORE study was not powered to show a change in nonvertebral fracture risk. In fact, based on the rate of fractures in the placebo group, the authors indicate that the study had 80%, 38% and 12% power to detect a 20% reduction in total nonvertebral, wrist and hip fractures, respectively, for pooled raloxifene groups.
Eastell R, Adachi J, Harper K, et al. J Bone Miner Res 2000:15(suppl 1):S229.
Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:634-45.
The MORE study was unable to show any benefit of raloxifene therapy on nonvertebral fractures (ie, hip, wrist or ankle). There was a statistically significant decrease in ankle fractures observed at 36 months. However, this benefit was no longer achieved at 48 months. The MORE study was not powered to show a change in nonvertebral fracture risk. In fact, based on the rate of fractures in the placebo group, the authors indicate that the study had 80%, 38% and 12% power to detect a 20% reduction in total nonvertebral, wrist and hip fractures, respectively, for pooled raloxifene groups.
Eastell R, Adachi J, Harper K, et al. J Bone Miner Res 2000:15(suppl 1):S229.
Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:634-45.
66. Effects of Raloxifene on BMD:
After 36 months, BMD increased by 2.6% and 2.1% at the spine and femoral neck in the group treated with 60 mg raloxifene and by 2.7% and 2.4% at the spine and femoral neck in the 120 mg raloxfene group, respectively ( P<0.001).
In the raloxifene-treated groups, BMD of the spine remained constant between years 2 and 3, while hip BMD peaked at 24 months.
Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:637-45.
After 36 months, BMD increased by 2.6% and 2.1% at the spine and femoral neck in the group treated with 60 mg raloxifene and by 2.7% and 2.4% at the spine and femoral neck in the 120 mg raloxfene group, respectively ( P<0.001).
In the raloxifene-treated groups, BMD of the spine remained constant between years 2 and 3, while hip BMD peaked at 24 months.
Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:637-45.
67. Impact of Raloxifene on Bone Markers:
Baseline measurements of markers for bone turnover were assessed. Median serum osteocalcin (bone formation) concentration was 24.1 ?g/L and urinary C-telopeptide (bone resorption) was 248 ?g/mmol of creatinine.
After 36 months, serum osteocalcin was decreased by 26.3% and 31.1% in those treated with raloxifene 60 mg and 120 mg, respectively. Urinary C-telopeptide was decreased by 34% and 31.5% in the 60-mg and 120-mg groups of raloxifene-treated patients. The P-value of <0.001 was repeated for each raloxifene dose vs placebo.
Delmas PD, Ensrud KE, Harper K, et al. Effects of raloxifene on bone mineral density and biochemcial markers of bone turnover in postmenopausal women with osteoporosis: 4-year results from the MORE Trial. J Bone Miner Res 2000;Suppl1:M423.
Baseline measurements of markers for bone turnover were assessed. Median serum osteocalcin (bone formation) concentration was 24.1 ?g/L and urinary C-telopeptide (bone resorption) was 248 ?g/mmol of creatinine.
After 36 months, serum osteocalcin was decreased by 26.3% and 31.1% in those treated with raloxifene 60 mg and 120 mg, respectively. Urinary C-telopeptide was decreased by 34% and 31.5% in the 60-mg and 120-mg groups of raloxifene-treated patients. The P-value of <0.001 was repeated for each raloxifene dose vs placebo.
Delmas PD, Ensrud KE, Harper K, et al. Effects of raloxifene on bone mineral density and biochemcial markers of bone turnover in postmenopausal women with osteoporosis: 4-year results from the MORE Trial. J Bone Miner Res 2000;Suppl1:M423.
68. Effect of Raloxifene on the Risk of Invasive Breast Cancer: The MORE Trial–48 Months
The MORE Trial also showed an 84% reduction in the annual rate of estrogen-receptor (ER)-positive breast cancer compared with placebo. There was no difference in the rate of ER-negative breast cancers. This was expected because of the structural similarity to tamoxifen, which also had no effect on ER-negative breast cancer rates.
It is not clear if the women participating in the MORE trial were at greater or lesser risk of getting breast cancer to begin with.
Seven women whose ER status was unknown were included in the evaluation of the cumulative incidence of all confirmed breast cancer among participants in all three study groups. The total of 61 cases adjudicated to be invasive breast cancer resulted in a 72% reduction in relative risk for those treated with raloxifene.
Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Breast Canc Res Treat 2001;65:125-34.
The MORE Trial also showed an 84% reduction in the annual rate of estrogen-receptor (ER)-positive breast cancer compared with placebo. There was no difference in the rate of ER-negative breast cancers. This was expected because of the structural similarity to tamoxifen, which also had no effect on ER-negative breast cancer rates.
It is not clear if the women participating in the MORE trial were at greater or lesser risk of getting breast cancer to begin with.
Seven women whose ER status was unknown were included in the evaluation of the cumulative incidence of all confirmed breast cancer among participants in all three study groups. The total of 61 cases adjudicated to be invasive breast cancer resulted in a 72% reduction in relative risk for those treated with raloxifene.
Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Breast Canc Res Treat 2001;65:125-34.
69. Raloxifene Summary
Based on clinical trial data to date, the benefits of raloxifene therapy appear to outweigh its risks.
The increased incidence of thromboembolic events seen with raloxifene use is similar to that observed with estrogen.
Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE Trial. Breast Canc Res Treat 2001;65:125-34.
Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:637-45.
Based on clinical trial data to date, the benefits of raloxifene therapy appear to outweigh its risks.
The increased incidence of thromboembolic events seen with raloxifene use is similar to that observed with estrogen.
Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE Trial. Breast Canc Res Treat 2001;65:125-34.
Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:637-45.
80. Antifracture Efficacy of Antiresorptive Agents
Standard therapies currently in use for treatment or prevention of osteoporosis, including those under investigation, have demonstrated both bone-mass sparing and bone-mass enhancing effects. Both antiresorptive and anabolic agents are associated with increases in BMD, reflecting an improvement in bone quantity.
Their effects on bone turnover (measured by serum and urinary bone markers) are opposing, ie, antiresorptive agents decrease bone markers while anabolic agents increase them.
An increase in bone markers is considered to reflect an improvement in bone quality. Therapy that combines the use of agents with these differing mechanisms of action and effects may be expected to improve both bone quantity and quality in an additive, if not synergistic, manner.
Standard therapies currently in use for treatment or prevention of osteoporosis, including those under investigation, have demonstrated both bone-mass sparing and bone-mass enhancing effects. Both antiresorptive and anabolic agents are associated with increases in BMD, reflecting an improvement in bone quantity.
Their effects on bone turnover (measured by serum and urinary bone markers) are opposing, ie, antiresorptive agents decrease bone markers while anabolic agents increase them.
An increase in bone markers is considered to reflect an improvement in bone quality. Therapy that combines the use of agents with these differing mechanisms of action and effects may be expected to improve both bone quantity and quality in an additive, if not synergistic, manner.
92. Change in BMD and Reduction in Fracture
Please note: These data are not derived from head-to-head comparisons.
A similar analysis of the data from these studies was reported in an editorial by Kenneth Faulkner in: J Bone Miner Res. 2000.
Please note: These data are not derived from head-to-head comparisons.
A similar analysis of the data from these studies was reported in an editorial by Kenneth Faulkner in: J Bone Miner Res. 2000.
94. Relationship Between Change in Femoral Neck BMD and Vertebral Fracture Risk
This figure displays the risk of new vertebral fractures at 3 years as a function of the percentage change in FN BMD at 3 years for the RLX group and for the placebo group with 95% CIs indicated.
For every change in BMD (shown on the X axis) the risk curve for RLX was below the risk curve for the placebo, showing that the risk for vertebral fracture was lower for patients treated with RLX than for patients treated with placebo irrespective of the changes in FN BMD.
Since the regression curves for both groups were parallel, any percentage change in FN BMD corresponded to a similar vertebral fracture risk reduction in the raloxifene group compared to the placebo group.
Even patients with an apparent decrease of FN BMD still had a reduction in fracture risk.
Due to the shallow slope of –0.04 of the regression curves, the 3-year percentage changes in FN BMD were poorly predictive of the anti-fracture efficacy and, in fact, only accounted for about 5% of the total vertebral fracture risk reduction with RLX.
This figure displays the risk of new vertebral fractures at 3 years as a function of the percentage change in FN BMD at 3 years for the RLX group and for the placebo group with 95% CIs indicated.
For every change in BMD (shown on the X axis) the risk curve for RLX was below the risk curve for the placebo, showing that the risk for vertebral fracture was lower for patients treated with RLX than for patients treated with placebo irrespective of the changes in FN BMD.
Since the regression curves for both groups were parallel, any percentage change in FN BMD corresponded to a similar vertebral fracture risk reduction in the raloxifene group compared to the placebo group.
Even patients with an apparent decrease of FN BMD still had a reduction in fracture risk.
Due to the shallow slope of –0.04 of the regression curves, the 3-year percentage changes in FN BMD were poorly predictive of the anti-fracture efficacy and, in fact, only accounted for about 5% of the total vertebral fracture risk reduction with RLX.
98. Bone turnover is an independent risk factor for fracture
High bone turnover, evidenced by serum markers, predicts fracture risk independently of BMD. Slowing bone turnover may reduce the number of remodeling sites and may also reduce trabecular perforation. Slowing bone turnover may also permit increased mineralization time, contributing to increased strength. A theoretical negative aspect of decreasing bone turnover may be an accumulation of microdamage or microfracture because, although resorption is slowed, so is formation.
Garnero P, Hausherr E, Chapuy MC, et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS prospective study. J Bone Miner Res 1996;11:1531-8.
High bone turnover, evidenced by serum markers, predicts fracture risk independently of BMD. Slowing bone turnover may reduce the number of remodeling sites and may also reduce trabecular perforation. Slowing bone turnover may also permit increased mineralization time, contributing to increased strength. A theoretical negative aspect of decreasing bone turnover may be an accumulation of microdamage or microfracture because, although resorption is slowed, so is formation.
Garnero P, Hausherr E, Chapuy MC, et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS prospective study. J Bone Miner Res 1996;11:1531-8.
105. Microcracks in Dogs Treated with High Doses of Bisphosphonates
Burr’s group showed in dogs when dosed daily for a year with a high dose of alendronate or risedronate microcracks did appear in the bone.
In normal bone micorcracks probably occur regularly simply because of everyday living. However, they are thought to quickly be repaired via normal bone turnover. Shutting down turnover too much may allow them to accumulate.
Burr’s group showed in dogs when dosed daily for a year with a high dose of alendronate or risedronate microcracks did appear in the bone.
In normal bone micorcracks probably occur regularly simply because of everyday living. However, they are thought to quickly be repaired via normal bone turnover. Shutting down turnover too much may allow them to accumulate.
112. Microanalysis of Bone Architecture From
In a Phase II study in early postmenopausal women (Mortensen, JCE&M 1998) iliac crest biopsies were collected at baseline and after 1 year of treatment. The study included a placebo group (n=36) and a risedronate 5m/day group (n=37).
Background on study: the average age of the patients at baseline was 51-52 years. Average calcium intake from the diet was about 900-1,000 mg per day (note, the patients did not receive supplemental calcium during the study). As these patients were 2-3 years after menopause, they had normal to mildly osteopenic LS BMD at baseline. However, they had relatively high bone turnover at baseline, as evidenced histologically by MS/BS ratio of 8.6%.
The primary endpoint of the trial was LS BMD. After 1 year, the placebo patients lost 2.8% LS BMD versus baseline. This loss was prevented by risedronate (+1.3% LS BMD versus baseline).
………………………………….
The mean LS BMD T-scores for subjects in the biopsy cohort showed that they were normal to mildly osteopenic at baseline (placebo –1.32, risedronate –1.02). The average changes in LS BMD at 1 year for subjects in the biopsy cohort were similar to the changes seen in the overall population in this study: the placebo patients in the biopsy cohort lost 3.3% (p = 0.002 vs baseline), and the risedronate patients in the biopsy cohort gained +2.02% (p = 0.009 vs baseline).
In a Phase II study in early postmenopausal women (Mortensen, JCE&M 1998) iliac crest biopsies were collected at baseline and after 1 year of treatment. The study included a placebo group (n=36) and a risedronate 5m/day group (n=37).
Background on study: the average age of the patients at baseline was 51-52 years. Average calcium intake from the diet was about 900-1,000 mg per day (note, the patients did not receive supplemental calcium during the study). As these patients were 2-3 years after menopause, they had normal to mildly osteopenic LS BMD at baseline. However, they had relatively high bone turnover at baseline, as evidenced histologically by MS/BS ratio of 8.6%.
The primary endpoint of the trial was LS BMD. After 1 year, the placebo patients lost 2.8% LS BMD versus baseline. This loss was prevented by risedronate (+1.3% LS BMD versus baseline).
………………………………….
The mean LS BMD T-scores for subjects in the biopsy cohort showed that they were normal to mildly osteopenic at baseline (placebo –1.32, risedronate –1.02). The average changes in LS BMD at 1 year for subjects in the biopsy cohort were similar to the changes seen in the overall population in this study: the placebo patients in the biopsy cohort lost 3.3% (p = 0.002 vs baseline), and the risedronate patients in the biopsy cohort gained +2.02% (p = 0.009 vs baseline).
113. Risedronate Preserves Bone Microarchitecture
Click on pictures to make bone segment rotate. (can do in any order)
Click on pictures to make bone segment rotate. (can do in any order)
115. Alendronate Increases Bone Mineralization
This slide shows the results of work of Boivin et al (from Pierre Meuniers’s group) to evaluate the long-term effect of alendronate on the degree of mineralization of bone. Boivin studied iliac crest biopsy samples from a Phase III study of alendronate in patients with postmenopausal osteoporosis (Liberman study).
The curves in the graph illustrate the distribution of degree of mineralization in cancellous bone from subjects treated with placebo (blue line) or alendronate 10mg (green line) after 2 and 3 years.
The horizontal axis represent degree of mineralization of bone (gm mineral/cm3).
The vertical axis represents the percent of the bone measurements with specific degrees of mineralization.
After 2 years there was a small but significant increase in bone mineralization in the alendronate 10 mg group compared to the placebo group (+ 7.3%).
After 3 years there was a larger (11.4%) increase in bone mineralization with alendronate 10 mg compared to placebo.
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The degree of bone mineralization was measured by micro x-ray methods on 100micrometer sections of cancellous bone. Quantitative evaluation of mineral content was based on a reference system made of aluminum with know absorption exposed on the same microradiographs. At 2 years Boivin studied biopsies from 15 placebo and 9 Aln subjects. At 3 years he studied biopsies from 13 placebo and 16 Aln subjects.
This slide shows the results of work of Boivin et al (from Pierre Meuniers’s group) to evaluate the long-term effect of alendronate on the degree of mineralization of bone. Boivin studied iliac crest biopsy samples from a Phase III study of alendronate in patients with postmenopausal osteoporosis (Liberman study).
The curves in the graph illustrate the distribution of degree of mineralization in cancellous bone from subjects treated with placebo (blue line) or alendronate 10mg (green line) after 2 and 3 years.
The horizontal axis represent degree of mineralization of bone (gm mineral/cm3).
The vertical axis represents the percent of the bone measurements with specific degrees of mineralization.
After 2 years there was a small but significant increase in bone mineralization in the alendronate 10 mg group compared to the placebo group (+ 7.3%).
After 3 years there was a larger (11.4%) increase in bone mineralization with alendronate 10 mg compared to placebo.
………………………………..
The degree of bone mineralization was measured by micro x-ray methods on 100micrometer sections of cancellous bone. Quantitative evaluation of mineral content was based on a reference system made of aluminum with know absorption exposed on the same microradiographs. At 2 years Boivin studied biopsies from 15 placebo and 9 Aln subjects. At 3 years he studied biopsies from 13 placebo and 16 Aln subjects.
116. Change in Degree of Bone Mineralization
This slide shows the quantitative change in degree of mineralization from baseline to end of three years measured in paired biopsies for the placebo and risedronate 5mg groups.
The horizontal axis represent the gray levels, or the degree of attenuation of x-ray signal throughout the bone biopsy specimens. An increase in the degree of attenuation of x-ray signal is associated with an increase in the degree of mineralization.
The vertical axis represents the frequency of appearance (or the % of bone volume) with specific levels of x-ray attenuation.
In placebo group, there was a small shift in peak mineral density after 3 years (red line) compared to baseline values (blue line). This was a 2.06% increase in mineralization (not significant). For reference, in this biopsy cohort of subjects the mean increase in LS BMD over 3 years was small (0.84%). If asked how this compared to 3 year LS BMD response for ITT population: it was +1.1% for ITT placebo group (note, very similar to 0.84%). Recall, placebo subjects were all taking 1,000 mg calcium/day.
In the risedronate group, there was a larger shift to the right from baseline (blue line) to end of 3 years (red line). This was a 5.1% increase in mineralization that was significant. For reference, in this biopsy cohort the mean increase in LS BMD over three years was 7.85%. If asked how this compared to the LS BMD response for ITT population: it was +5.4% for ITT risedronate group (fairly similar to 7.85% for the biopsy cohort).
…………………………………………
If asked about how this compares to alendronate: 3 years alendronate 10mg increased mineralization by 11.4%, and increased LS BMD by 9.6% (Boivin et al, 2000).
This slide shows the quantitative change in degree of mineralization from baseline to end of three years measured in paired biopsies for the placebo and risedronate 5mg groups.
The horizontal axis represent the gray levels, or the degree of attenuation of x-ray signal throughout the bone biopsy specimens. An increase in the degree of attenuation of x-ray signal is associated with an increase in the degree of mineralization.
The vertical axis represents the frequency of appearance (or the % of bone volume) with specific levels of x-ray attenuation.
In placebo group, there was a small shift in peak mineral density after 3 years (red line) compared to baseline values (blue line). This was a 2.06% increase in mineralization (not significant). For reference, in this biopsy cohort of subjects the mean increase in LS BMD over 3 years was small (0.84%). If asked how this compared to 3 year LS BMD response for ITT population: it was +1.1% for ITT placebo group (note, very similar to 0.84%). Recall, placebo subjects were all taking 1,000 mg calcium/day.
In the risedronate group, there was a larger shift to the right from baseline (blue line) to end of 3 years (red line). This was a 5.1% increase in mineralization that was significant. For reference, in this biopsy cohort the mean increase in LS BMD over three years was 7.85%. If asked how this compared to the LS BMD response for ITT population: it was +5.4% for ITT risedronate group (fairly similar to 7.85% for the biopsy cohort).
…………………………………………
If asked about how this compares to alendronate: 3 years alendronate 10mg increased mineralization by 11.4%, and increased LS BMD by 9.6% (Boivin et al, 2000).
117. Visualization of Trabecular Remodeling Areas
This slide shows a rotating image of the same biopsy pair from the placebo subject (see last slide) in the VERT-NA study at baseline (left image) and after 3 years (right image).
The color for low mineralized bone is depicted as yellow in this rotating image. The white background color represents areas of high mineralized bone.
This rotating image enables a unique look into the trabecular surfaces of cancellous bone. The synchrotron micro-CT analysis method allows us to visualize and to quantitate the degree of bone remodeling in subjects with osteoporosis as evidenced by the areas of low mineralized bone (colored yellow).
Key Point: There was no marked change in the relative area of low mineralized bone (yellow areas) from baseline to the end of 3 years.
This slide shows a rotating image of the same biopsy pair from the placebo subject (see last slide) in the VERT-NA study at baseline (left image) and after 3 years (right image).
The color for low mineralized bone is depicted as yellow in this rotating image. The white background color represents areas of high mineralized bone.
This rotating image enables a unique look into the trabecular surfaces of cancellous bone. The synchrotron micro-CT analysis method allows us to visualize and to quantitate the degree of bone remodeling in subjects with osteoporosis as evidenced by the areas of low mineralized bone (colored yellow).
Key Point: There was no marked change in the relative area of low mineralized bone (yellow areas) from baseline to the end of 3 years.
118. Visualization of Trabecular Remodeling Areas
This slide shows a rotating image of the same biopsy sample from the risedronate subject in the VERT-NA study at baseline (left image) and after 3 years (right image).
The color for low mineralized bone is depicted as yellow in this rotating image. The white background color represents high mineralized bone.
The rotating image helps us to visualize the relative decrease in bone turnover (yellow areas) that was associated with 3 years of 5mg risedronate. However, it also allows us to see evidence of continued bone remodeling on trabecular surfaces with continued risedronate treatment.
This slide shows a rotating image of the same biopsy sample from the risedronate subject in the VERT-NA study at baseline (left image) and after 3 years (right image).
The color for low mineralized bone is depicted as yellow in this rotating image. The white background color represents high mineralized bone.
The rotating image helps us to visualize the relative decrease in bone turnover (yellow areas) that was associated with 3 years of 5mg risedronate. However, it also allows us to see evidence of continued bone remodeling on trabecular surfaces with continued risedronate treatment.
127. PTH Mode of Administration, Timing and Dose Determine whether PTH is anabolic or catabolic in the rat skeleton
A study of male rats compared an intermittent dosing regimen of 1 hour of PTH per day in contrast to a continuous dosing regimen. Several bone perimeters were measured. Shown here are trabecular bone perimeter measurements.
The intermittent dosing regimen in rats had a selective effect on the osteoblast but not much of an effect on the osteoclast, whereas there were opposite effects with the continuous regimen.
Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology 1997;138:4607-12.
A study of male rats compared an intermittent dosing regimen of 1 hour of PTH per day in contrast to a continuous dosing regimen. Several bone perimeters were measured. Shown here are trabecular bone perimeter measurements.
The intermittent dosing regimen in rats had a selective effect on the osteoblast but not much of an effect on the osteoclast, whereas there were opposite effects with the continuous regimen.
Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology 1997;138:4607-12.
129. PTH and Dose Determine Effect on Bone
The dual actions of PTH as a function of dosing and amount were teased apart, which led to the idea that continuous high-dose PTH is catabolic primarily for cortical bone, whereas the daily low dose was associated with anabolic effects.
Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology 1997;138:4607-12.
The dual actions of PTH as a function of dosing and amount were teased apart, which led to the idea that continuous high-dose PTH is catabolic primarily for cortical bone, whereas the daily low dose was associated with anabolic effects.
Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology 1997;138:4607-12.
131. PTH (1-34) in Postmenopausal Women
In this large, prospective, randomized, double-blind trial, the effects of placebo versus low-dose rhPTH (1-34) at 20 or 40 micrograms, were compared in 1637 postmenopausal women (1239 completed the study).
Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41.
In this large, prospective, randomized, double-blind trial, the effects of placebo versus low-dose rhPTH (1-34) at 20 or 40 micrograms, were compared in 1637 postmenopausal women (1239 completed the study).
Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41.
132. rhPTH (1-34) Increases Lumbar Spine and
Lumbar spine BMD increased by 13.7 ? 9.7% (PTH 40 µg), 9.7 ? 7.4% (PTH 20 µg) and 1.1 ? 5.5% (placebo).
Total hip BMD increased by 3.6 ? 5.4% (PTH 40 µg), 2.6 ? 4.9% (PTH 20 µg) and -1.0 [? 4.3% (placebo). Changes in the PTH-treated groups were statistically significant from placebo (p<0.001).
Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41.
Lumbar spine BMD increased by 13.7 ? 9.7% (PTH 40 µg), 9.7 ? 7.4% (PTH 20 µg) and 1.1 ? 5.5% (placebo).
Total hip BMD increased by 3.6 ? 5.4% (PTH 40 µg), 2.6 ? 4.9% (PTH 20 µg) and -1.0 [? 4.3% (placebo). Changes in the PTH-treated groups were statistically significant from placebo (p<0.001).
Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41.
136. Glucocorticoid-Induced Osteoporosis
Lumbar spine BMD increased by 11.8% after 12 months of human parathyroid hormone (1-34) [hPTH(1-34)] treatment, and was maintained at 11.9% above baseline at 24 months (which included 12 months off hPTH(1-34)) (P<0.001). There were no significant changes in the HRT group.
Femoral neck BMD increase of 5.2% was significantly changed from baseline in the hPTH(1-34) group, but there were no significant differences between groups.
Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. J Clin Invest. 1998;102:1627-1633.
Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Bone mass continues to increase at the hip after parathyroid hormone treatment is discontinued in glucocorticoid-induced osteoporosis: Results of a randomized controlled clinical trial. J Bone Miner Res. 2000;15:944-951.
Lumbar spine BMD increased by 11.8% after 12 months of human parathyroid hormone (1-34) [hPTH(1-34)] treatment, and was maintained at 11.9% above baseline at 24 months (which included 12 months off hPTH(1-34)) (P<0.001). There were no significant changes in the HRT group.
Femoral neck BMD increase of 5.2% was significantly changed from baseline in the hPTH(1-34) group, but there were no significant differences between groups.
Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. J Clin Invest. 1998;102:1627-1633.
Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Bone mass continues to increase at the hip after parathyroid hormone treatment is discontinued in glucocorticoid-induced osteoporosis: Results of a randomized controlled clinical trial. J Bone Miner Res. 2000;15:944-951.
137. Fracture-Associated Height Loss
[Keywords] 699, Stock, advisory board, 02/10/2002, Miami, FL, osteoporosis, erectile dysfunction, PTH, future, John Stock, Alisa Lask, Lilly, Tania Miller, Matt Persman, teriparatide###
[Keywords] 699, Stock, advisory board, 02/10/2002, Miami, FL, osteoporosis, erectile dysfunction, PTH, future, John Stock, Alisa Lask, Lilly, Tania Miller, Matt Persman, teriparatide###
138. hPTH (1-34) Trial in Men With
This prospective, randomized, double-blind trial compared placebo with 400 IU of PTH (close to 20 microgram dose) in 23 men. The 18-month protocol with a 12-month extension was designed to evaluate the impact of therapy on BMD in bone markers. Study groups were well-matched in terms of age, BMI, smoking history, physical activity level and use of prior medication.
Kurland ES, Cosman F, McMahon DJ, et al. Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J Clin Endocrinol Metab 2000;85:3069-76.
This prospective, randomized, double-blind trial compared placebo with 400 IU of PTH (close to 20 microgram dose) in 23 men. The 18-month protocol with a 12-month extension was designed to evaluate the impact of therapy on BMD in bone markers. Study groups were well-matched in terms of age, BMI, smoking history, physical activity level and use of prior medication.
Kurland ES, Cosman F, McMahon DJ, et al. Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J Clin Endocrinol Metab 2000;85:3069-76.
141. Differences in Kinetics of Bone Formation
Markers of bone formation changed in a way that is very different from what is observed with the anti-resorptive agents.
Bone-specific alkaline phosphatase (BSAP) and osteocalcin (bone formation markers) both rose remarkably during the first 12 months of therapy, but tended to return toward baseline.
Bone resorption markers peaked at 9 months (PYD) and at 12 months (NTX).
Kurland ES, Cosman F, McMahon DJ, et al. Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J Clin Endocrinol Metab 2000;85:3069-76.
Markers of bone formation changed in a way that is very different from what is observed with the anti-resorptive agents.
Bone-specific alkaline phosphatase (BSAP) and osteocalcin (bone formation markers) both rose remarkably during the first 12 months of therapy, but tended to return toward baseline.
Bone resorption markers peaked at 9 months (PYD) and at 12 months (NTX).
Kurland ES, Cosman F, McMahon DJ, et al. Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J Clin Endocrinol Metab 2000;85:3069-76.
145. Antifracture Efficacy of
Standard therapies currently in use for treatment or prevention of osteoporosis, including those under investigation, have demonstrated both bone-mass sparing and bone-mass enhancing effects. Both antiresorptive and anabolic agents are associated with increases in BMD, reflecting an improvement in bone quantity.
Their effects on bone turnover (measured by serum and urinary bone markers) are opposing, ie, antiresorptive agents decrease bone markers while anabolic agents increase them.
An increase in bone markers is considered to reflect an improvement in bone quality. Therapy that combines the use of agents with these differing mechanisms of action and effects may be expected to improve both bone quantity and quality in an additive, if not synergistic, manner.
Standard therapies currently in use for treatment or prevention of osteoporosis, including those under investigation, have demonstrated both bone-mass sparing and bone-mass enhancing effects. Both antiresorptive and anabolic agents are associated with increases in BMD, reflecting an improvement in bone quantity.
Their effects on bone turnover (measured by serum and urinary bone markers) are opposing, ie, antiresorptive agents decrease bone markers while anabolic agents increase them.
An increase in bone markers is considered to reflect an improvement in bone quality. Therapy that combines the use of agents with these differing mechanisms of action and effects may be expected to improve both bone quantity and quality in an additive, if not synergistic, manner.
146. Cellular Mechanisms
However, the results from the marker studies have led to the hypothesis that PTH treatment increases bone mass rapidly by directly stimulating bone formation, i.e., bone formation without prior resorption.
However, the results from the marker studies have led to the hypothesis that PTH treatment increases bone mass rapidly by directly stimulating bone formation, i.e., bone formation without prior resorption.
148. hPTH(1-34) Treatment Markedly Increases Bone Forming Surfaces
These photos show tetracycline labels on iliac crest bone biopsies obtained from patients treated with hPTH(1-34).
Tetracycline double labels allow measurement of how rapidly lacunae are being filled in. Patients are administered tetracycline twice, approximately 11-14 days apart. The tetracycline binds to newly formed, unmineralized bone, where it fluoresces.
The fluorescent green lining the lacunae in this hPTH(1-34)-treated bone is in two distinct lines (left panel). The large amount of space between the two lines represents a rapid rate of bone formation. In biopsies of bone with slower formation rates, it is common for the two labels to appear as one (for this reason, it is common for two different types of tetracycline each showing a different color, to be used).
The photograph on the right panel shows the presence of two tetracycline labels given 12 months apart. hPTH(1-34) increased the trabecular thickness.
Reeve J, Meunier PJ, Parsons JA, Bernat M, Bijvoet OLM, Courpron P, Edouard C, KlenermanL, Neer RM, Renier JC, Slovik D, Vismans JFJE, Potts JT Jr. Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial. BMJ 1980;280:1340-1344.
These photos show tetracycline labels on iliac crest bone biopsies obtained from patients treated with hPTH(1-34).
Tetracycline double labels allow measurement of how rapidly lacunae are being filled in. Patients are administered tetracycline twice, approximately 11-14 days apart. The tetracycline binds to newly formed, unmineralized bone, where it fluoresces.
The fluorescent green lining the lacunae in this hPTH(1-34)-treated bone is in two distinct lines (left panel). The large amount of space between the two lines represents a rapid rate of bone formation. In biopsies of bone with slower formation rates, it is common for the two labels to appear as one (for this reason, it is common for two different types of tetracycline each showing a different color, to be used).
The photograph on the right panel shows the presence of two tetracycline labels given 12 months apart. hPTH(1-34) increased the trabecular thickness.
Reeve J, Meunier PJ, Parsons JA, Bernat M, Bijvoet OLM, Courpron P, Edouard C, KlenermanL, Neer RM, Renier JC, Slovik D, Vismans JFJE, Potts JT Jr. Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial. BMJ 1980;280:1340-1344.
153. Effect of Teriparatide on Trabecular Connectivity
The connectivity density describes how well trabecular are connected. I a two-component system bone and marrow it si derived from the Euler number (E) 1-e/TV E is a measure of the maximum number of branches which can be removed before the structure is divided into multiple pieces, was determined in the micro Ct.
The connectivity density describes how well trabecular are connected. I a two-component system bone and marrow it si derived from the Euler number (E) 1-e/TV E is a measure of the maximum number of branches which can be removed before the structure is divided into multiple pieces, was determined in the micro Ct.
155. Jiang et al, J Bone Miner Res. 2003
These are microCT images of iliac crest bone biopsies, obtained at baseline and after 21 months of treatment with FORTEO, from a 65 year-old postmenopausal woman (patient 1124) who had a BMD response that is representative of the treatment group. The lumbar spine BMD increased by 7.4% (group mean was 9.7 ? 7.4%) and total hip increased 5.2% (group mean was 2.6 ? 4.9%).
Jiang Y, Zhao J, Eriksen EF, Wang O, Genant HK, Mitlak BH. Improved 3-dimensional microstructure of cancellous and cortical bone in a multicenter, double-blind, randomized and placebo controlled study of teriparatide [rhPTH(1-34)]. J Bone Miner Res 2002;17(suppl 1):S135
These are microCT images of iliac crest bone biopsies, obtained at baseline and after 21 months of treatment with FORTEO, from a 65 year-old postmenopausal woman (patient 1124) who had a BMD response that is representative of the treatment group. The lumbar spine BMD increased by 7.4% (group mean was 9.7 ? 7.4%) and total hip increased 5.2% (group mean was 2.6 ? 4.9%).
Jiang Y, Zhao J, Eriksen EF, Wang O, Genant HK, Mitlak BH. Improved 3-dimensional microstructure of cancellous and cortical bone in a multicenter, double-blind, randomized and placebo controlled study of teriparatide [rhPTH(1-34)]. J Bone Miner Res 2002;17(suppl 1):S135
156. Improved Trabecular Connectivity
This slide shows paired biopsies from a 64 year old woman. The sample on the left was taken before treatment, the one on the right was taken from the contralateral side after treatment. In this patient, cortical thickness increased from 0.32 to 0.42 mm , and connectivity density increased from 2.9 to 4.6 / mm cubed.
This slide shows paired biopsies from a 64 year old woman. The sample on the left was taken before treatment, the one on the right was taken from the contralateral side after treatment. In this patient, cortical thickness increased from 0.32 to 0.42 mm , and connectivity density increased from 2.9 to 4.6 / mm cubed.