Menopause: The Journal of The North American Menopause Society Vol. 22, No. 6, pp. 581/583 DOI: 10.1097/gme.0000000000000477 * 2015 by The North American Menopause Society
EDITORIAL Bone mineral density measurements: how often should bone mineral density be measured in postmenopausal women? Results from the Women_s Health Initiative study he article by Gourlay et al1 in this issue of Menopause addresses the incidence of hip and clinical spine fractures among postmenopausal women in the Women_s Health Initiative, the relationship of fractures with bone mineral density (BMD) measurements, and the frequency of BMD rescreening for predicting future fracture. In the Women_s Health Initiative 4,068 postmenopausal women were recruited into the BMD study. These women were participants either in clinical trial studies (hormone therapy, calcium/vitamin D, and diet modification) or in observational studies. In clinical trial studies, approximately half of the women were on placebo. BMD measures were collected for 11.2 years, and fracture data were collected for 18.6 years. They used a competing risk model, which allows for other events (such as treatment or death during follow-up) that can affect fracture incidence data and provides a more accurate measure of fracture rates. For example, researchers might project a hip fracture rate for 15 years; however, if 20% of participants were to die or if 20% of participants were to be given treatment during follow-up, then the true incident fracture rate would in fact be lower. This cohort of 4,068 women (age groups of 50-54, 55-59, and 60-64 y) were followed for approximately 12 years. They used as endpoint the time it took for 1% of the group to develop a clinical spine or hip fracture and for 3% of the group to develop an osteoporotic fracture before starting treatment, after adjusting for risk factors and competing risks. One should point out here that the outcome only applied to severe osteoporosis. The primary outcome of 1% fracture events (adjusted) was met after 12.8 years in the youngest age group of 50 to 54 years, compared with 7.6 years in the older age group of 60 to 64 years and 3 years in those who had osteoporosis (T score G j2.5) at baseline. Their conclusion was that women aged 50 to 64 years without osteoporosis on the first BMD test were not likely to benefit from frequent rescreening. At baseline, they used World Health Organization guidelines for diagnosis of osteoporosis.2 BMD classification was based on T score groups (Gj1.5; j1.5 to 2.49; Gj2.5). However, the National Osteoporosis Risk Assessment (NORA) study showed that T scores lower than j1.8 are associated with increased fracture3 and that only 18% of osteoporotic fractures and 26% of hip fractures had osteoporotic T scores lower
T
than j2.5, suggesting that a T score lower than j2.5 is too high for a diagnosis of osteoporosis. Many of these are fractures associated with nonosteoporotic BMD caused by impaired bone quality. Analysis with different T score categories might give a better cutoff point for BMD values associated with increased fracture risk and a better definition of those who do not benefit from rescreening. However, in this study, the numbers are relatively small. About one third of women in all age groups with T scores of between j1.5 and j2.49 initiated bone active therapy during the study (Bcompeting risk[), and treatment as competing risk was the first event in 16% of the group. Treatment would be expected to increase time interval to the first fracture, as was seen in Table 2. In the age group of 50 to 54 years, it took 12.8 years before they developed a hip or clinical spine fracture. In the age group of 55 to 59 years, it took them 11.7 years, whereas in the age group of 60 to 64 years, time to fracture was approximately 7.6 years. Because the risk was too low, they suggested that there was little benefit from frequent rescreening of BMD in the younger age group. For those with osteoporosis at baseline (T score G j2.5), time to fracture was much shorter at 3 years. Risk factors increased the chance of a fracture. The incidence of hip and clinical vertebral fractures was very low at age younger than 60 years (1.6%) and increased to 2.4% in the age group of 60 to 64 years; however, the incidence was lower in part because of competing risks. Bone active treatment was given to approximately 36% of younger women with T scores from j1.5 to higher than j2.5 and to approximately 26% of women in the age group older than 60 years. In the group with osteoporosis, treatment was given to increasing numbers of women with age (50-54 y, 20%; 55-59 y, 42%; 60-64 y, 80%). Based on clinical trials, treatment reduces fracture incidence by at least 50%. Death also was a competing risk in 7% to 13%. In addition, hip fracture incidence increases exponentially after age 80 years; in this analysis, the numbers in this older group are small. In comparison with the same age groups that had osteoporotic T scores, the clinical fracture rate was higher at approximately 7.5%. As expected, risk factors played a role in osteoporotic fracture cases, history of previous fractures, parental history of hip fracture, low body mass index, white race, smoking, alcohol, and several other conditions. As a reminder, Menopause, Vol. 22, No. 6, 2015
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
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EDITORIAL
diagnosis of osteoporosis is often made among individuals who develop an osteoporotic fracture with a nonosteoporotic BMD; thus, rescreening will not detect these cases. Another factor that was not considered in this analysis is the incidence of peripheral fractures, which usually outnumber hip and spine fractures and are not included in fracture outcome data. About 16% of women with osteoporosis had a fracture compared with 4.7% of women without osteoporosis at baseline. The incidence of spinal fractures is probably an underestimate. In clinical trials, one of the main efficacy endpoints is Bmorphometric[ spine fracture, which is usually asymptomatic. A morphometric fracture is, by definition, one where there has been a painless decrease in vertebral height of 20% measured on lateral radiographs. These are three times more common than clinical spine fractures,4 which are usually painful and are the only type collected in this study. Although this article indicates that BMD need not be repeated more than once every 10 years among those with T scores of j1.5 to j2.49, clinicians have to identify those who do not fit into the group. All of these women had BMD measured after menopause; thus, menopause effect is built on that baseline BMD test. Menopause effect on bone reduces BMD by almost 1 SD or approximately 13%.5 However, in clinical practice, women in the age group of 50 to 60 years who might have had early menopause 5 to 10 years previously have BMD lower than expected for age; this is a risk factor.6 Based on serial bone loss measurements, approximately 20% of women are Brapid losers[ of bone7; if the next BMD measurement is not performed in 10 years, these cases will be missed. The only way to identify this group is by repeated dualenergy x-ray absorptiometry (DXA), preferably of the spine. Bone markers in a clinical setting are not useful. With today_s Affordable Care Act, a DXA can cost less than US$75; thus, DXA is now a cost-effective measure. However, a single measure will not be able to predict rapid losers of bone, nor can it identify individuals with normal BMD who develop fractures because of a change in bone quality. Use of FRAX scores based on femoral neck or total hip BMD is helpful because it incorporates risk factors but fails to identify women who lose bone rapidly from the spine. Thus, repeated spine BMD is essential for women in the first 10 years after menopause but loses some of its value among women in their 60s because of the impact of osteoarthritis, which artifactually increases BMD. As Gourlay et al1 correctly pointed out, women with other osteoporotic risk factors had increased risk of severe osteoporotic fractures. The abstract indicates that BMD screening should be used infrequently in women with normal BMD (Gj1.5 to j2.49). However, that is based on the development of hip and clinical spine factures and is not the whole point of this article. Gourlay et al1 made it clear that women with risk factors or previous fractures are not included in the general recommendations despite their BMD values and that increased surveillance of these women is necessary. In other words, this group is excluded from guidelines on routine screening.
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Menopause, Vol. 22, No. 6, 2015
My own view is that clinicians can make a case for screening all women in menopause. The test is no longer expensive. As Gourlay et al1 suggested, if BMD is lower than j1.5, then waiting 10 years is reasonable. Regarding follow-up, it is more difficult to decide for the group with T scores between j1.5 to j2.49. In this study, although the fracture rate for women aged between 50 and 69 years was low, the total number (620) was small (about 30% of women were on bone active therapy and 10% died) and 63 of these women had risk factors associated with BMD values between j1.5 and j2.49; thus, women who had normal values and were untreated numbered about 320Vmaybe not a large-enough population! Results from the Nordic Research on Aging study with 150,000 women showed that a T score lower than j1.8 was associated with increased fractures. Thus, the 1994 World Health Organization guidelines used in this study may not be the gold standard now that more data relating fractures to T scores have become available. A well-meaning recommendation from the National Physicians Alliance in 2011 stated that DXA should not be used in women younger than 65 years because it was not cost-effective.8 That recommendation is already outdated because the cost of DXA is less than that of a complete chemistry profile. My other concern is that waiting for that first fracture may be too late. Fractures are usually caused by a 25% to 30% loss of bone mass. By that time, the structure has already been severely damaged. Should clinicians wait for this to happen or should clinicians be more proactive? This is the conflict between an epidemiologist and a clinician sitting across the desk from an individual. Personal medicine comes into play when a 52-year-old woman undergoes DXA and the T score is j1.8. According to the group data (j1.5 to j2.49) in Table A1, her BMD value predicts that her risk of hip or clinical spine fracture is 0.9% for 12 years. Then she tells her physician that she had early menopause, has a family history of osteoporosis and a history of fracture, has high caffeine intake, is a smoker, and takes antidepressants for vasomotor symptoms. Should the physician refer to the table or use clinical judgment and initiate bone active therapy? This is an interesting study that puts fracture risk in perspective in tabular form but is not able to fully take into account the number of risk factors and the individual case. What was heartening in this study was to see the large proportion of women, particularly older women, who were actually treated with bone active therapy. This group, however, was probably a better-than-average well-informed group, having been in the study for more than 10 years. I think it is fair to say that for individuals with BMD scores lower than j1.5, repeating BMD screening more than once every 10 years is not effective, but I am not ready to wait for 12 years for women with T scores lower than j1.8. If a scan were to be repeated, it would be of the spine because it is the site of rapid bone loss, as first noted by Albright et al9 in 1941, and because spine fractures are probably underestimated in this study. * 2015 The North American Menopause Society
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
EDITORIAL Financial disclosure/conflicts of interest: None reported.
J. Christopher Gallagher, MD Department of Endocrinology Creighton University Omaha, Nebraska
REFERENCES 1. Gourlay ML, Overman RA, Fine JP, et al; Women_s Health Initiative Investigators. Baseline age and time to major fracture in younger postmenopausal women. Menopause 2015;22:589-597. 2. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser 1994;843:1-129.
3. Siris ES, Chen YT, Abbott TA, et al. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 2004;164:1108Y1112. 4. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab 2000;85:4118Y4124. 5. Greendale GA, Sowers M, Han W, et al. Bone mineral density loss in relation to the final menstrual period in a multiethnic cohort: results from the Study of Women_s Health Across the Nation (SWAN). J Bone Miner Res 2012;27:111Y118. 6. Gallagher JC. Effect of early menopause on bone mineral density and fractures. Menopause 2007;14:567-571. 7. Riis BJ, RLdbro P, Christiansen C. The role of serum concentrations of sex steroids and bone turnover in the development and occurrence of postmenopausal osteoporosis. Calcif Tissue Int 1986;38:318-322. 8. Good Stewardship Working Group. The Btop 5[ lists in primary care: meeting the responsibility of professionalism. Arch Intern Med 2011;171: 1385-1390. 9. Albright F, Smith PH, Richardson AM. Postmenopausal osteoporosis. JAMA 1941;116:2465Y2474.
Menopause, Vol. 22, No. 6, 2015
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
583
EDITORIAL Bone mineral density measurements: how often should bone mineral density be measured in postmenopausal women? Results from the Women_s Health Initiative study he article by Gourlay et al1 in this issue of Menopause addresses the incidence of hip and clinical spine fractures among postmenopausal women in the Women_s Health Initiative, the relationship of fractures with bone mineral density (BMD) measurements, and the frequency of BMD rescreening for predicting future fracture. In the Women_s Health Initiative 4,068 postmenopausal women were recruited into the BMD study. These women were participants either in clinical trial studies (hormone therapy, calcium/vitamin D, and diet modification) or in observational studies. In clinical trial studies, approximately half of the women were on placebo. BMD measures were collected for 11.2 years, and fracture data were collected for 18.6 years. They used a competing risk model, which allows for other events (such as treatment or death during follow-up) that can affect fracture incidence data and provides a more accurate measure of fracture rates. For example, researchers might project a hip fracture rate for 15 years; however, if 20% of participants were to die or if 20% of participants were to be given treatment during follow-up, then the true incident fracture rate would in fact be lower. This cohort of 4,068 women (age groups of 50-54, 55-59, and 60-64 y) were followed for approximately 12 years. They used as endpoint the time it took for 1% of the group to develop a clinical spine or hip fracture and for 3% of the group to develop an osteoporotic fracture before starting treatment, after adjusting for risk factors and competing risks. One should point out here that the outcome only applied to severe osteoporosis. The primary outcome of 1% fracture events (adjusted) was met after 12.8 years in the youngest age group of 50 to 54 years, compared with 7.6 years in the older age group of 60 to 64 years and 3 years in those who had osteoporosis (T score G j2.5) at baseline. Their conclusion was that women aged 50 to 64 years without osteoporosis on the first BMD test were not likely to benefit from frequent rescreening. At baseline, they used World Health Organization guidelines for diagnosis of osteoporosis.2 BMD classification was based on T score groups (Gj1.5; j1.5 to 2.49; Gj2.5). However, the National Osteoporosis Risk Assessment (NORA) study showed that T scores lower than j1.8 are associated with increased fracture3 and that only 18% of osteoporotic fractures and 26% of hip fractures had osteoporotic T scores lower
T
than j2.5, suggesting that a T score lower than j2.5 is too high for a diagnosis of osteoporosis. Many of these are fractures associated with nonosteoporotic BMD caused by impaired bone quality. Analysis with different T score categories might give a better cutoff point for BMD values associated with increased fracture risk and a better definition of those who do not benefit from rescreening. However, in this study, the numbers are relatively small. About one third of women in all age groups with T scores of between j1.5 and j2.49 initiated bone active therapy during the study (Bcompeting risk[), and treatment as competing risk was the first event in 16% of the group. Treatment would be expected to increase time interval to the first fracture, as was seen in Table 2. In the age group of 50 to 54 years, it took 12.8 years before they developed a hip or clinical spine fracture. In the age group of 55 to 59 years, it took them 11.7 years, whereas in the age group of 60 to 64 years, time to fracture was approximately 7.6 years. Because the risk was too low, they suggested that there was little benefit from frequent rescreening of BMD in the younger age group. For those with osteoporosis at baseline (T score G j2.5), time to fracture was much shorter at 3 years. Risk factors increased the chance of a fracture. The incidence of hip and clinical vertebral fractures was very low at age younger than 60 years (1.6%) and increased to 2.4% in the age group of 60 to 64 years; however, the incidence was lower in part because of competing risks. Bone active treatment was given to approximately 36% of younger women with T scores from j1.5 to higher than j2.5 and to approximately 26% of women in the age group older than 60 years. In the group with osteoporosis, treatment was given to increasing numbers of women with age (50-54 y, 20%; 55-59 y, 42%; 60-64 y, 80%). Based on clinical trials, treatment reduces fracture incidence by at least 50%. Death also was a competing risk in 7% to 13%. In addition, hip fracture incidence increases exponentially after age 80 years; in this analysis, the numbers in this older group are small. In comparison with the same age groups that had osteoporotic T scores, the clinical fracture rate was higher at approximately 7.5%. As expected, risk factors played a role in osteoporotic fracture cases, history of previous fractures, parental history of hip fracture, low body mass index, white race, smoking, alcohol, and several other conditions. As a reminder, Menopause, Vol. 22, No. 6, 2015
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
581
EDITORIAL
diagnosis of osteoporosis is often made among individuals who develop an osteoporotic fracture with a nonosteoporotic BMD; thus, rescreening will not detect these cases. Another factor that was not considered in this analysis is the incidence of peripheral fractures, which usually outnumber hip and spine fractures and are not included in fracture outcome data. About 16% of women with osteoporosis had a fracture compared with 4.7% of women without osteoporosis at baseline. The incidence of spinal fractures is probably an underestimate. In clinical trials, one of the main efficacy endpoints is Bmorphometric[ spine fracture, which is usually asymptomatic. A morphometric fracture is, by definition, one where there has been a painless decrease in vertebral height of 20% measured on lateral radiographs. These are three times more common than clinical spine fractures,4 which are usually painful and are the only type collected in this study. Although this article indicates that BMD need not be repeated more than once every 10 years among those with T scores of j1.5 to j2.49, clinicians have to identify those who do not fit into the group. All of these women had BMD measured after menopause; thus, menopause effect is built on that baseline BMD test. Menopause effect on bone reduces BMD by almost 1 SD or approximately 13%.5 However, in clinical practice, women in the age group of 50 to 60 years who might have had early menopause 5 to 10 years previously have BMD lower than expected for age; this is a risk factor.6 Based on serial bone loss measurements, approximately 20% of women are Brapid losers[ of bone7; if the next BMD measurement is not performed in 10 years, these cases will be missed. The only way to identify this group is by repeated dualenergy x-ray absorptiometry (DXA), preferably of the spine. Bone markers in a clinical setting are not useful. With today_s Affordable Care Act, a DXA can cost less than US$75; thus, DXA is now a cost-effective measure. However, a single measure will not be able to predict rapid losers of bone, nor can it identify individuals with normal BMD who develop fractures because of a change in bone quality. Use of FRAX scores based on femoral neck or total hip BMD is helpful because it incorporates risk factors but fails to identify women who lose bone rapidly from the spine. Thus, repeated spine BMD is essential for women in the first 10 years after menopause but loses some of its value among women in their 60s because of the impact of osteoarthritis, which artifactually increases BMD. As Gourlay et al1 correctly pointed out, women with other osteoporotic risk factors had increased risk of severe osteoporotic fractures. The abstract indicates that BMD screening should be used infrequently in women with normal BMD (Gj1.5 to j2.49). However, that is based on the development of hip and clinical spine factures and is not the whole point of this article. Gourlay et al1 made it clear that women with risk factors or previous fractures are not included in the general recommendations despite their BMD values and that increased surveillance of these women is necessary. In other words, this group is excluded from guidelines on routine screening.
582
Menopause, Vol. 22, No. 6, 2015
My own view is that clinicians can make a case for screening all women in menopause. The test is no longer expensive. As Gourlay et al1 suggested, if BMD is lower than j1.5, then waiting 10 years is reasonable. Regarding follow-up, it is more difficult to decide for the group with T scores between j1.5 to j2.49. In this study, although the fracture rate for women aged between 50 and 69 years was low, the total number (620) was small (about 30% of women were on bone active therapy and 10% died) and 63 of these women had risk factors associated with BMD values between j1.5 and j2.49; thus, women who had normal values and were untreated numbered about 320Vmaybe not a large-enough population! Results from the Nordic Research on Aging study with 150,000 women showed that a T score lower than j1.8 was associated with increased fractures. Thus, the 1994 World Health Organization guidelines used in this study may not be the gold standard now that more data relating fractures to T scores have become available. A well-meaning recommendation from the National Physicians Alliance in 2011 stated that DXA should not be used in women younger than 65 years because it was not cost-effective.8 That recommendation is already outdated because the cost of DXA is less than that of a complete chemistry profile. My other concern is that waiting for that first fracture may be too late. Fractures are usually caused by a 25% to 30% loss of bone mass. By that time, the structure has already been severely damaged. Should clinicians wait for this to happen or should clinicians be more proactive? This is the conflict between an epidemiologist and a clinician sitting across the desk from an individual. Personal medicine comes into play when a 52-year-old woman undergoes DXA and the T score is j1.8. According to the group data (j1.5 to j2.49) in Table A1, her BMD value predicts that her risk of hip or clinical spine fracture is 0.9% for 12 years. Then she tells her physician that she had early menopause, has a family history of osteoporosis and a history of fracture, has high caffeine intake, is a smoker, and takes antidepressants for vasomotor symptoms. Should the physician refer to the table or use clinical judgment and initiate bone active therapy? This is an interesting study that puts fracture risk in perspective in tabular form but is not able to fully take into account the number of risk factors and the individual case. What was heartening in this study was to see the large proportion of women, particularly older women, who were actually treated with bone active therapy. This group, however, was probably a better-than-average well-informed group, having been in the study for more than 10 years. I think it is fair to say that for individuals with BMD scores lower than j1.5, repeating BMD screening more than once every 10 years is not effective, but I am not ready to wait for 12 years for women with T scores lower than j1.8. If a scan were to be repeated, it would be of the spine because it is the site of rapid bone loss, as first noted by Albright et al9 in 1941, and because spine fractures are probably underestimated in this study. * 2015 The North American Menopause Society
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
EDITORIAL Financial disclosure/conflicts of interest: None reported.
J. Christopher Gallagher, MD Department of Endocrinology Creighton University Omaha, Nebraska
REFERENCES 1. Gourlay ML, Overman RA, Fine JP, et al; Women_s Health Initiative Investigators. Baseline age and time to major fracture in younger postmenopausal women. Menopause 2015;22:589-597. 2. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser 1994;843:1-129.
3. Siris ES, Chen YT, Abbott TA, et al. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 2004;164:1108Y1112. 4. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab 2000;85:4118Y4124. 5. Greendale GA, Sowers M, Han W, et al. Bone mineral density loss in relation to the final menstrual period in a multiethnic cohort: results from the Study of Women_s Health Across the Nation (SWAN). J Bone Miner Res 2012;27:111Y118. 6. Gallagher JC. Effect of early menopause on bone mineral density and fractures. Menopause 2007;14:567-571. 7. Riis BJ, RLdbro P, Christiansen C. The role of serum concentrations of sex steroids and bone turnover in the development and occurrence of postmenopausal osteoporosis. Calcif Tissue Int 1986;38:318-322. 8. Good Stewardship Working Group. The Btop 5[ lists in primary care: meeting the responsibility of professionalism. Arch Intern Med 2011;171: 1385-1390. 9. Albright F, Smith PH, Richardson AM. Postmenopausal osteoporosis. JAMA 1941;116:2465Y2474.
Menopause, Vol. 22, No. 6, 2015
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
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