- Email: [email protected]
Pitfalls in the hunt for osteoporosis
EDITORIALS
Pitfalls in the Hunt for Osteoporosis Laura K. Bachrach, MD, E. Kirk Neely, MD
F
or 40 years, physicians have recognized potential threats to bone health in patients with Turner syndrome (1). Despite extensive research, the causes of low bone mass and its reversibility with treatment remain controversial. Recent investigations have cast doubt on earlier conclusions that bone fragility is increased substantially in Turner syndrome, which alludes to the limitations of dual-energy X-ray absorptiometry (DEXA) in assessing key elements of bone integrity. Reduced bone mass in Turner syndrome was first observed on bone radiographs and later confirmed using photon absorptiometry or DEXA (1). Most investigators attributed these deficits to estrogen deficiency from the ovarian failure found in 95% of patients with Turner syndrome. Women with Turner syndrome who experienced spontaneous menses achieved normal bone mass (2). Those with ovarian failure, however, reached adulthood with a low peak bone mass despite estrogen replacement (1,3). This observation spawned speculation of an intrinsic skeletal defect in Turner syndrome that limited bone mineral accrual and caused slow bone growth, cubitus valgus, and Madelung deformity (1,3). Some studies of biochemical bone markers have suggested an imbalance in bone remodeling with resorption exceeding formation (3). If there were an intrinsic skeletal defect, women with Turner syndrome might experience bone fragility despite adequate estrogen replacement. How common is low bone mass in Turner syndrome and does it matter clinically? Do women with the syndrome have clinical evidence of bone fragility as predicted by their low bone density? These questions reflect the myriad challenges in interpreting bone densitometry in children and young adults. Of the noninvasive techniques for assessing bone mass, DEXA is used most commonly because it is precise and rapid, and delivers a minimal dose of ionizing radiation. Unfortunately, DEXA is an imperfect yardstick for evaluating bone health (4). It reports bone mass in terms of bone mineral content (grams) and areal bone mineral density or bone mineral density (BMD) (gm/cm2). To complicate matters, these two measurements are influenced by bone size, skeletal Am J Med. 2003;115:322–323. From the Division of Pediatric Endocrinology, Stanford University School of Medicine, Stanford, California. Requests for reprints should be addressed to Laura K. Bachrach, MD, Division of Pediatric Endocrinology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305-5208, or [email protected]. 322
© 2003 by Excerpta Medica Inc. All rights reserved.
maturation, and body composition. Although BMD corrects for bone height and width, the measure does not adjust for the thickness of bone. Without this correction, BMD underestimates the true (volumetric) bone density in smaller persons. Failure to consider bone size can lead to the misdiagnosis of low bone mass, not only in patients with Turner syndrome but in any small person. Several models of volumetric bone density have been developed to reduce the influence of bone size on DEXA measurements (4,5). Although these estimates of volumetric bone density have been shown to correlate with direct measurements using quantitative computed tomography or with in vitro bone strength (5), their value in predicting bone fractures has not been established. In this issue of The American Journal of Medicine, Bakalov et al examined the skeletal health of 40 adult women with Turner syndrome who had been given adequate estrogen replacement from mid-adolescence (6). DEXA studies of spine and hip as well as fracture rates were used as measures of bone fragility. Spine and femoral neck BMD was significantly lower in subjects with Turner syndrome compared with 43 healthy agematched (but not size-matched) controls. Twenty percent of those with Turner syndrome had BMD values more than 2.5 SD below the mean for healthy young adults. However, when BMD was adjusted for estimated bone volume or body surface area, the magnitude of difference between subjects and controls was reduced and remained significant only at the femoral neck. Additionally, fracture prevalence was not different between the two cohorts. The authors concluded that size-adjusted bone mass is not reduced in most women with Turner syndrome and that there is no increased risk of clinical bone fragility. Can we dismiss all worries about bone health in women with Turner syndrome who are given estrogen therapy? Several prior studies have concluded that the low bone mass in adolescents or adults with Turner syndrome was an artifact of small bone size or delayed bone maturity (1,7,8). Others found that small deficits in bone mineral persisted even after correcting for bone or body size (2). These differences likely reflect small cohort sizes, variability in the models used to adjust BMD for body size, and differences in reference data used. Even within the Bakalov paper, the percentage difference between the cohorts varied by skeletal site and by the method used to adjust for bone volume or body surface area. Of greater concern are the reports by other investigators showing 0002-9343/03/$–see front matter doi:10.1016/S0002-9343(03)00401-7
Pitfalls in the Hunt for Osteoporosis/Bachrach and Neely
that fractures are more common among adolescents and adults with Turner syndrome than expected by age (1,8 – 10). In one study, increased fractures occurred after the age of 45 years, suggesting the need for long-term systematic follow-up of these women to define the risk adequately (9). A second study based on Danish patient registry data documented a two- to 22-fold increase in fracture risk at different skeletal sites (10); unfortunately, there were no data on the adequacy of estrogen replacement therapy for these women. In short, the jury is still out as to whether increased bone fragility develops more often in women with Turner syndrome despite estrogen replacement therapy. Historically, the replacement deemed “adequate” in the past may not have been begun early enough in adolescence to optimize bone mineral accrual. The optimal time to initiate sex steroid therapy, the most effective dose and route, and strategies to ensure compliance are worthy of further investigation. The study by Bakalov et al raises fundamental questions about bone mass measurement to predict bone fragility in children, adolescents, and premenopausal women. In elderly women, assessment of BMD by DEXA is a robust predictor of bone fragility. The relation between low bone mass and fractures is sufficiently strong to allow a low T-score to serve as a proxy for the disease. By World Health Organization criteria, a diagnosis of osteoporosis can be established in postmenopausal women with T-scores below –2.5. This criterion cannot be applied in the same way to adolescents or premenopausal women because the “fracture threshold” has not been set for these younger persons. Even in older adults, the likelihood of fracture for a given T-score is affected markedly by age, and the fracture rates for those under age 50 years have not been determined (11). T-scores should not even be calculated for those under age 18 years, who have not yet attained the bone mass for young adults; instead, their bone mass should be compared with age-matched controls to generate a Z-score. As evidenced by the Bakalov study, T-scores are also misleading in small persons because of the effect of bone size on BMD. Furthermore, vulnerability to fracture is a function not only of bone mass but of bone size, geometry, and quality (4,5). Given two bones of identical material properties (mass), the larger one is more resistant to fracture than the smaller one. Bone must be large enough to support the soft tissue surrounding it. Recent studies using peripheral quantitative computed tomography have suggested that cortical thickness in patients with Turner syndrome may not be adequate for their body mass (12). Additionally, the elusive factor of bone quality affects bone strength. Distribution of bone around the long axis of bone influences resistance to breakage with bending. Finally, factors unrelated to bone also play a role in the risk equation. Increased clumsiness and falls in subjects
with Turner syndrome may contribute to fractures in the absence of low bone mass (8). The caveats raised by this study apply to the use of bone density data in general. Interpretation of DEXA results requires attention to more than the T-score generated by the software. Age, bone size, and bone geometry are but a few of the clinical variables worthy of consideration. Models that correct for these variables must be proven worthy against the “gold standard” of predicting fragility fractures. More work is needed to determine if quantitative computed tomography or other techniques will prove to be superior to DEXA in identifying those at greatest risk of bone fractures. The increased attention to skeletal health risks in younger patients is gratifying, since earlier recognition may allow for greater efforts at prevention. At the same time, failure to appreciate the limitations of DEXA may cause unwarranted concern and inappropriate intervention.
REFERENCES 1. Salvesen Sykes K, Neely EK. Long-term outcome of height, bone density and body composition in Turner syndrome. Curr Opin Endocrinol Diabet. 1997;4:100 –107. 2. Carrascosa A, Gussinye M, Terradas P, Yeste D, Audi L, VicensCalvet E. Spontaneous, but not induced, puberty permits adequate bone mass acquisition in adolescent Turner syndrome patients. J Bone Miner Res. 2000;15:2005–2010. 3. Gravholt CH, Lauridsen AL, Brixen K, Mosekilde L, Heickendorff L, Christiansen JS. Marked disproportionality in bone size and mineral, and distinct abnormalities in bone markers and calcitropic hormones in adult Turner syndrome: a cross-sectional study. J Clin Endocrinol Metab. 2002;87:2798 –2808. 4. Seeman E. From density to structure: growing up and growing old on the surfaces of bone. J Bone Miner Res. 1997;12:509 –521. 5. Tabensky AD, Williams J, Deluca V, Briganti E, Seeman E. Bone mass, areal, and volumetric bone density are equally accurate, sensitive, and specific surrogates of the breaking strength of the vertebral body: an in vitro study. J Bone Miner Res. 1996;11:1981–1988. 6. Bakalov VK, Chen ML, Baron J, et al. Bone mineral density and fractures in Turner syndrome. Am J Med. 2003;115:259 –264. 7. Bertelloni S, Cinquanta L, Baroncelli GI, Simi P, Rossi S, Saggese G. Volumetric bone mineral density in young women with Turner’s syndrome treated with estrogens or estrogens plus growth hormone. Horm Res. 2000;53:72–76. 8. Ross JL, Long LM, Feuillan P, Cassorla F, Cutler GBJ. Normal bone density of the wrist and spine and increased wrist fractures in girls with Turner’s syndrome. J Clin Endocrinol Metab. 1991;73:355–359. 9. Landin-Wilhelmsen K, Bryman I, Windh M, Wilhelmsen L. Osteoporosis and fractures in Turner syndrome—importance of growth promoting and oestrogen therapy. Clin Endocrinol. 1999;51:497– 502. 10. Gravholt CH, Juul S, Naeraa RW, Hansen J. Morbidity in Turner syndrome. J Clin Epidemiol. 1998;51:147–158. 11. Kanis JA, Oden A, Johnell O, Jonsson B, de Laet C, Dawson A. The burden of osteoporotic fractures: a method for setting intervention thresholds. Osteoporosis Int. 2001;12:417–427. 12. Bechtold S, Rauch F, Noelle V, et al. Musculoskeletal analyses of the forearm in young women with Turner syndrome: a study using peripheral quantitative computed tomography. J Clin Endocrinol Metab. 2001;86:5819 –5823.
September 2003
THE AMERICAN JOURNAL OF MEDICINE威
Volume 115 323
Pitfalls in the Hunt for Osteoporosis Laura K. Bachrach, MD, E. Kirk Neely, MD
F
or 40 years, physicians have recognized potential threats to bone health in patients with Turner syndrome (1). Despite extensive research, the causes of low bone mass and its reversibility with treatment remain controversial. Recent investigations have cast doubt on earlier conclusions that bone fragility is increased substantially in Turner syndrome, which alludes to the limitations of dual-energy X-ray absorptiometry (DEXA) in assessing key elements of bone integrity. Reduced bone mass in Turner syndrome was first observed on bone radiographs and later confirmed using photon absorptiometry or DEXA (1). Most investigators attributed these deficits to estrogen deficiency from the ovarian failure found in 95% of patients with Turner syndrome. Women with Turner syndrome who experienced spontaneous menses achieved normal bone mass (2). Those with ovarian failure, however, reached adulthood with a low peak bone mass despite estrogen replacement (1,3). This observation spawned speculation of an intrinsic skeletal defect in Turner syndrome that limited bone mineral accrual and caused slow bone growth, cubitus valgus, and Madelung deformity (1,3). Some studies of biochemical bone markers have suggested an imbalance in bone remodeling with resorption exceeding formation (3). If there were an intrinsic skeletal defect, women with Turner syndrome might experience bone fragility despite adequate estrogen replacement. How common is low bone mass in Turner syndrome and does it matter clinically? Do women with the syndrome have clinical evidence of bone fragility as predicted by their low bone density? These questions reflect the myriad challenges in interpreting bone densitometry in children and young adults. Of the noninvasive techniques for assessing bone mass, DEXA is used most commonly because it is precise and rapid, and delivers a minimal dose of ionizing radiation. Unfortunately, DEXA is an imperfect yardstick for evaluating bone health (4). It reports bone mass in terms of bone mineral content (grams) and areal bone mineral density or bone mineral density (BMD) (gm/cm2). To complicate matters, these two measurements are influenced by bone size, skeletal Am J Med. 2003;115:322–323. From the Division of Pediatric Endocrinology, Stanford University School of Medicine, Stanford, California. Requests for reprints should be addressed to Laura K. Bachrach, MD, Division of Pediatric Endocrinology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305-5208, or [email protected]. 322
© 2003 by Excerpta Medica Inc. All rights reserved.
maturation, and body composition. Although BMD corrects for bone height and width, the measure does not adjust for the thickness of bone. Without this correction, BMD underestimates the true (volumetric) bone density in smaller persons. Failure to consider bone size can lead to the misdiagnosis of low bone mass, not only in patients with Turner syndrome but in any small person. Several models of volumetric bone density have been developed to reduce the influence of bone size on DEXA measurements (4,5). Although these estimates of volumetric bone density have been shown to correlate with direct measurements using quantitative computed tomography or with in vitro bone strength (5), their value in predicting bone fractures has not been established. In this issue of The American Journal of Medicine, Bakalov et al examined the skeletal health of 40 adult women with Turner syndrome who had been given adequate estrogen replacement from mid-adolescence (6). DEXA studies of spine and hip as well as fracture rates were used as measures of bone fragility. Spine and femoral neck BMD was significantly lower in subjects with Turner syndrome compared with 43 healthy agematched (but not size-matched) controls. Twenty percent of those with Turner syndrome had BMD values more than 2.5 SD below the mean for healthy young adults. However, when BMD was adjusted for estimated bone volume or body surface area, the magnitude of difference between subjects and controls was reduced and remained significant only at the femoral neck. Additionally, fracture prevalence was not different between the two cohorts. The authors concluded that size-adjusted bone mass is not reduced in most women with Turner syndrome and that there is no increased risk of clinical bone fragility. Can we dismiss all worries about bone health in women with Turner syndrome who are given estrogen therapy? Several prior studies have concluded that the low bone mass in adolescents or adults with Turner syndrome was an artifact of small bone size or delayed bone maturity (1,7,8). Others found that small deficits in bone mineral persisted even after correcting for bone or body size (2). These differences likely reflect small cohort sizes, variability in the models used to adjust BMD for body size, and differences in reference data used. Even within the Bakalov paper, the percentage difference between the cohorts varied by skeletal site and by the method used to adjust for bone volume or body surface area. Of greater concern are the reports by other investigators showing 0002-9343/03/$–see front matter doi:10.1016/S0002-9343(03)00401-7
Pitfalls in the Hunt for Osteoporosis/Bachrach and Neely
that fractures are more common among adolescents and adults with Turner syndrome than expected by age (1,8 – 10). In one study, increased fractures occurred after the age of 45 years, suggesting the need for long-term systematic follow-up of these women to define the risk adequately (9). A second study based on Danish patient registry data documented a two- to 22-fold increase in fracture risk at different skeletal sites (10); unfortunately, there were no data on the adequacy of estrogen replacement therapy for these women. In short, the jury is still out as to whether increased bone fragility develops more often in women with Turner syndrome despite estrogen replacement therapy. Historically, the replacement deemed “adequate” in the past may not have been begun early enough in adolescence to optimize bone mineral accrual. The optimal time to initiate sex steroid therapy, the most effective dose and route, and strategies to ensure compliance are worthy of further investigation. The study by Bakalov et al raises fundamental questions about bone mass measurement to predict bone fragility in children, adolescents, and premenopausal women. In elderly women, assessment of BMD by DEXA is a robust predictor of bone fragility. The relation between low bone mass and fractures is sufficiently strong to allow a low T-score to serve as a proxy for the disease. By World Health Organization criteria, a diagnosis of osteoporosis can be established in postmenopausal women with T-scores below –2.5. This criterion cannot be applied in the same way to adolescents or premenopausal women because the “fracture threshold” has not been set for these younger persons. Even in older adults, the likelihood of fracture for a given T-score is affected markedly by age, and the fracture rates for those under age 50 years have not been determined (11). T-scores should not even be calculated for those under age 18 years, who have not yet attained the bone mass for young adults; instead, their bone mass should be compared with age-matched controls to generate a Z-score. As evidenced by the Bakalov study, T-scores are also misleading in small persons because of the effect of bone size on BMD. Furthermore, vulnerability to fracture is a function not only of bone mass but of bone size, geometry, and quality (4,5). Given two bones of identical material properties (mass), the larger one is more resistant to fracture than the smaller one. Bone must be large enough to support the soft tissue surrounding it. Recent studies using peripheral quantitative computed tomography have suggested that cortical thickness in patients with Turner syndrome may not be adequate for their body mass (12). Additionally, the elusive factor of bone quality affects bone strength. Distribution of bone around the long axis of bone influences resistance to breakage with bending. Finally, factors unrelated to bone also play a role in the risk equation. Increased clumsiness and falls in subjects
with Turner syndrome may contribute to fractures in the absence of low bone mass (8). The caveats raised by this study apply to the use of bone density data in general. Interpretation of DEXA results requires attention to more than the T-score generated by the software. Age, bone size, and bone geometry are but a few of the clinical variables worthy of consideration. Models that correct for these variables must be proven worthy against the “gold standard” of predicting fragility fractures. More work is needed to determine if quantitative computed tomography or other techniques will prove to be superior to DEXA in identifying those at greatest risk of bone fractures. The increased attention to skeletal health risks in younger patients is gratifying, since earlier recognition may allow for greater efforts at prevention. At the same time, failure to appreciate the limitations of DEXA may cause unwarranted concern and inappropriate intervention.
REFERENCES 1. Salvesen Sykes K, Neely EK. Long-term outcome of height, bone density and body composition in Turner syndrome. Curr Opin Endocrinol Diabet. 1997;4:100 –107. 2. Carrascosa A, Gussinye M, Terradas P, Yeste D, Audi L, VicensCalvet E. Spontaneous, but not induced, puberty permits adequate bone mass acquisition in adolescent Turner syndrome patients. J Bone Miner Res. 2000;15:2005–2010. 3. Gravholt CH, Lauridsen AL, Brixen K, Mosekilde L, Heickendorff L, Christiansen JS. Marked disproportionality in bone size and mineral, and distinct abnormalities in bone markers and calcitropic hormones in adult Turner syndrome: a cross-sectional study. J Clin Endocrinol Metab. 2002;87:2798 –2808. 4. Seeman E. From density to structure: growing up and growing old on the surfaces of bone. J Bone Miner Res. 1997;12:509 –521. 5. Tabensky AD, Williams J, Deluca V, Briganti E, Seeman E. Bone mass, areal, and volumetric bone density are equally accurate, sensitive, and specific surrogates of the breaking strength of the vertebral body: an in vitro study. J Bone Miner Res. 1996;11:1981–1988. 6. Bakalov VK, Chen ML, Baron J, et al. Bone mineral density and fractures in Turner syndrome. Am J Med. 2003;115:259 –264. 7. Bertelloni S, Cinquanta L, Baroncelli GI, Simi P, Rossi S, Saggese G. Volumetric bone mineral density in young women with Turner’s syndrome treated with estrogens or estrogens plus growth hormone. Horm Res. 2000;53:72–76. 8. Ross JL, Long LM, Feuillan P, Cassorla F, Cutler GBJ. Normal bone density of the wrist and spine and increased wrist fractures in girls with Turner’s syndrome. J Clin Endocrinol Metab. 1991;73:355–359. 9. Landin-Wilhelmsen K, Bryman I, Windh M, Wilhelmsen L. Osteoporosis and fractures in Turner syndrome—importance of growth promoting and oestrogen therapy. Clin Endocrinol. 1999;51:497– 502. 10. Gravholt CH, Juul S, Naeraa RW, Hansen J. Morbidity in Turner syndrome. J Clin Epidemiol. 1998;51:147–158. 11. Kanis JA, Oden A, Johnell O, Jonsson B, de Laet C, Dawson A. The burden of osteoporotic fractures: a method for setting intervention thresholds. Osteoporosis Int. 2001;12:417–427. 12. Bechtold S, Rauch F, Noelle V, et al. Musculoskeletal analyses of the forearm in young women with Turner syndrome: a study using peripheral quantitative computed tomography. J Clin Endocrinol Metab. 2001;86:5819 –5823.
September 2003
THE AMERICAN JOURNAL OF MEDICINE威
Volume 115 323