SPECIAL ARTICLE Seven questions about osteopenia 233 284 Joseph A. Riancho, Joseph L.

Hernández and Jesús González-Macías Department of Internal Medicine. Hospital Universitario Marqués de Valdecilla. U niversity of Cantabria. RETICEF. Santander. Cantabria. Spain. The availability of densitometers and awareness of society towards osteoporosis have increased in recent years. This makes doctors of different specialties (int ernists, rheumatologists, endocrinologists, gynecologists, chiropractors, family physicians, and others) often attend patients reporting densitometric with the result of "osteopenia" and seeking treatment for that diagnosis. However, just a s the treatment of osteoporosis received wide attention in the medical literatur e, osteopenia is rarely considered. So we thought it useful to try to answer som e of the questions that normally arise in this situation the clinician. What is osteopenia? Bone mass increases during the growth period to reach a peak around the third decade of life. Then held constant for some years and then begins to d ecline. In women this bone loss accelerates dramatically in the 5-10 years follo wing menopause. In practice, densitometry is the usual procedure for measuring b one mass. Densitometers using an X-ray source are the most commonly used (densit ometry Dual energy X-ray [DXA]) and the usual places of measurement are the lumb ar spine and the 'hip' (actually, the proximal femur). Hip measurements are usua lly performed in the femoral neck and total region ('total hip'), which includes , besides the neck, intertrochanteric area, and Ward's triangle. You can also de termine bone mass in other locations (forearm, calcaneus, phalanges, etc..) By D XA, CT or ultrasound. However, these peripheral measurement sites are less stand ardized and are more variable than the measurements 'thrust', so that measures b one mineral density (BMD) by DXA of spine and hip is now considered the most rel iable. The measurement results of BMD can be expressed in absolute terms (g/cm2) , but often expressed in relation to the values found in young people (index T o r T-score). Thus, the index T is the value of standardized BMD values according to the young people of the same sex, that is, the index T indicates the number o f standard deviations the BMD of the individual studied is separated from the BM D of young people of the same sex. T BMD (g/cm2) 0 -1 -2.5 Osteopenia Osteoporosis 20 50 Age (years) 60 Fig 1. Schematic representation of the evolution of bone mineral density (BMD) w ith age, and diagnostic thresholds for osteoporosis and osteopenia. An expert group established in 1994 cut points of the BMD values depending on th e index T. Decided to consider "normal" BMD values equivalent to a T greater tha n -1, osteopenia values between -1 and -2.5 T, and osteoporosis below -2.5 when T1. Although these cut points were established mainly to epidemiological effects , have been widely distributed and are often used today with the intention diagn ostic or therapeutic, although this was not the target that were established and therefore its employment for this purpose is problematic. In any case, osteopen ia is defined as a BMD value located between 1 and 2.5 standard deviations below the BMD of young subjects, ie a T between -1 and -2.5 (Fig. 1 .) On the other h and, we must bear in mind that these cut points that define thresholds establish

ed osteopenia and osteoporosis for postmenopausal women. Its use in men and prem enopausal women is questionable. Sometimes the term osteopenia is used to descri be the findings of a radiograph in which the bones are less dense. However, it s hould be noted that plain radiography is not an appropriate procedure to assess BMD, because the apparent density of bone on radiographs depends much on the phy sical characteristics of the patient (eg., Degree of obesity) and technical char acteristics exploration. In fact, numerous studies have shown the limited predic tive value of radiography to determine BMD, compared with DXA2. What is the freq uency of osteopenia? By definition, we expect that 15% of women between 20 and 3 0 have osteopenia, since that is the proportion of cases that are normally distr ibuted between -1 and -2.5 standard deviations.€BMD decrease Correspondence: Dr. J.A. Riancho. Department of Internal Medicine. Hospital Univ ersitario Marqués de Valdecilla. Avda Valdecilla s / n. 39008 Santander. Cantabr ia. Spain. Email: rianchoj@unican.es Received 29/11/2007, accepted for publicati on 01/02/2008. 136 Med Clin (Barc). 2008, 131 (4) :136-40 Riancho JA ET AL. SEVEN QUESTIONS OSTEOPENIA e with age. Although the rate of bone loss varies among individuals, it is a uni versal phenomenon. Consequently, the proportion of women with BMD in the range o f "osteopenia" increases progressively with advancing age. Thus, in a study in o ur country found that the prevalence of osteopenia in the lumbar spine was aroun d 40% in women 50-60 years was 50% in 60-70 years (Table 1) 3. Other countries h ave published similar figures. Does osteopenia increase the risk of fracture? It is estimated that approximately one in every three women aged 50 years presente d a fragility fracture, ie "osteoporotic" throughout his life. There is an inver se exponential relationship between BMD and fracture risk, so that for every sta ndard deviation decrease in BMD increases fracture risk approximately twofold (r elative risk between 1.4 and 2.9, depending on sex, age, measurement site and th e type of fracture seen) 4. Thus, women with osteopenia have a lower risk of ost eoporotic fracture, but greater than those with a normal DXA. For example, a stu dy reciente5 the frequency of vertebral fractures over 2 years of follow-up was 2.3% in women with a T of -2 (osteopenia), and 3.8% in those with a T -3 (osteop orosis). In many other studies have found similar results. Canadian postmenopaus al women found that the rate of hip fractures was 0.7 per 100 women-years among those with a normal BMD and rose to 1.6 per 100 women per year in the osteopenic and 4 / 100 women per year in osteoporóticas6. Thus, lower BMD, higher individu al risk of presenting a fragility fracture. However, since in the general popula tion, more women with osteopenia than osteoporosis, much of fragility fractures that occur in the population are women with BMD values in the range typical of o steopenia. Thus, in the Canadian study mentioned above, between 35 and 45% of al l fractures occurred in women with osteopenia, the 30-35% in women with osteopor osis, and the rest in women with BMD values above - 1 T6. Something similar was found in a study of postmenopausal Australian women 60-94 years, followed for a median of 5.6 years: 27% of fractures occurred in women with osteoporosis, 56% i n women with osteopenia and 17 % in women with DXA normal7. What other factors i nfluence the risk of fracture? The above data suggest that other factors influen ce the risk of fracture independently of BMD. Indeed, several studies have ident ified some clinical and epidemiological factors that influence this risk. One is age: the older, higher risk of fracture, even though the results are adjusted f or BMD. That is, for a given index value T, the risk of fracture is higher the g reater the age of mujer8. On the other hand, have filed a fragility fracture (eg ., A vertebral fracture, wrist, humerus or hip without significant trauma after age 50) increases to approximately twice the risk of having a new fracture, in s ame or other localizaciones9. Kanis et al8 have estimated that in women with a h

istory of vertebral fracture relative risk of wrist fracture is 1.8; TABLE 1 Prevalence of osteopenia and osteoporosis in Spanish women. The numbers indicate the percentages of each group of age.3 Age L2-L4 femoral neck 50-59 years Normal Normal Osteopenia Osteoporosis Osteoporosis Osteopenia Osteoporosis Osteo penia Normal 49 9 42 26 50 24 21 39 40 60 39 1 43 51 5 18 58 24 60-69 70-80 years the hip fracture, 2.3, and of new vertebral fracture of 4.4. Similarly, those wh o filed a hip fracture have relative risks of 3.3, 1.7, and 1.9 for wrist fractu res, spine and hip, respectively. This increased risk is largely independent of age and BMD. However, it must be remembered that the diagnosis of osteoporosis i s established by the existence of a BMD below -2.5 T, or filing a fragility frac ture irrespective of BMD. That is, women with BMD between -1 and -2,5 T with a f racture should be diagnosed with osteoporosis, not osteopenia. In addition to ad vanced age and previous fractures, other factors identified as predictors of an increased risk of fracture (regardless of BMD) are: family history of hip fractu re, low weight (eg., Body mass index <20 kg/m2), smoking, rheumatoid arthritis a nd treatment with glucocorticoids. In a multinational study, these factors incre ased the risk of hip fracture between 1.7 and 2.3 times in the univariate analys is, and between 1.4 and 2.3 times after adjustment for BMD (Table 2) 8. Some res earchers have evaluated the influence of clinical factors in fracture risk speci fically considering the group of postmenopausal women with osteopenia, and the r esults are largely similar to those obtained in the general population. Miller e t al10, who studied a large cohort of American women with osteopenia in peripher al densitometry, found that the frequency of fractures during 2 years of follow up was only 1% among those without additional risk factors, but increased to 2 % among those with a fragile general condition, impaired mobility or a T-score be low -1.8. For its part, in the subgroup who had previously suffered a fracture, the rate of new fractures increased to 4%. On the other hand, in a study of Fren ch women with osteopenia also identified previous fractures and BMD TABLE 2 Risk factors for fracture independent of bone mineral density, identified in a study multinacional8 Factor RR 95% CI Low weight (BMI 20 kg/m2) Previous fracture after 50 years with hip fracture Par ents Alcohol Smoking (> 20 g / day) 1.6 2.3 2.3 1.6 1.7 1,3-2,0 1,5-3,5 1,5-3,5 1,3-2,0 1,2-1,4 CI: confidence interval, BMI: body mass index, RR: relative risk. Med Clin (Barc). 2008, 131 (4) :136-40 137 Riancho JA ET AL. SEVEN QUESTIONS OSTEOPENIA

very low (T <-2) as predictors of an increased risk of fracture. Also in this st udy the elevation of markers of remodeling, and in particular the increase in al kaline phosphatase, was also associated with an increased risk of fractura11. Ho w effective are the anti-osteoporotic drugs on osteopenia? Obviously, the clinic al significance of osteoporosis and osteopenia is determined by the increased ri sk of fracture condition. Similarly, although several treatments have shown that they are able to increase BMD in different groups of patients, what is really i mportant is to reduce the incidence of fractures. Fortunately, today there is a set of drugs, antiresorptive and osteoformadores, which have clearly demonstrate d their ability to reduce the risk of peripheral and vertebral fractures in wome n with osteoporosis12. However, little study has evaluated the effect of drugs i n women with osteopenia. However, there have been secondary analysis of large cl inical trials of antiresorptive drugs that provide some data on its effects on s ubgroups of women with DXA in the range of osteopenia. Thus, to reanalyze the da ta from the MORE study found that raloxifene decreased the incidence of vertebra l fractures in women with osteopenia of the hip without previous vertebral fract ures. The risk reduction was 69% (confidence interval [CI] 95%, 29-94%). However , in this group the mean spine T-score was -2.2, with a standard deviation of 1. 0, ie were included many women with spinal osteoporosis. In fact, to classify wo men according to DXA of the spine, not hip, not found a significant protective e ffect of raloxifeno13. The drug did not reduce non-vertebral fractures. For its part, Quandt et al14 analyzed data from women with osteopenia included in the FI T study and found that alendronate significantly reduced the incidence of verteb ral fractures in those who had previous fractures (reduced risk of clinical frac tures was 66% CI 95%, 16-88%). However, although a similar trend was observed in women with osteopenia without previous fractures, the effect did not reach stat istical significance (risk reduction 54%, 95%, from -17 to 84%). Siris et al15 r eanalyzed the results of several clinical trials with risedronate and find a ben eficial effect in the subgroup of women with osteopenia of the hip, with a reduc tion in vertebral fracture risk of 56% (95% from 89% -78 p = 0.25) and total fra ctures by 73% (95% CI, 17-91%, p = 0.02). It is noteworthy that these women had no previous vertebral fractures,€but 18% had peripheral fractures presented earl ier. On the other hand, by excluding women who had "column osteoporosis (T <-2.5 ) showed a trend towards lower incidence of total fractures in those treated wit h risedronate than in those who received placebo, but without reaching the stati stical significance (risk reduction 78%, 95% from 97% -202, p = 0.18). Seeman et al16 have recently reanalyzed the data from the SOTI and TROPOS studies focusin g on the subgroup of women with osteopenia in the spine. In them, treatment with strontium ranelate reduced the risk of vertebral fractures by 41% compared with the group 138 Med Clin (Barc). 2008, 131 (4) :136-40 placebo or not they had previous fractures. However, among women with osteopenia column densitometric values were some of osteoporosis in the hip. In the subgro up of women with osteopenia in both the spine and hip, treatment also significan tly reduced the risk of new vertebral fractures by 52% (95% CI, 4-76%), while on ly 265 were in that category and, moreover, about half of them had had previous fragility fractures (ie, should be considered osteoporotic). The authors do not discuss the results in the subgroup of women who truly can be classified as oste openic: those with an index between -1 and -2.5 T in one location, in any of the regions the rate is lower than T -2 5 and have not submitted prior fragility fr actures. Therefore, in the light of our findings, it is doubtful that antiresorp tive drugs reduce the risk of vertebral fractures in women with osteopenia true (ie without previous fractures), and there is no evidence that reduce peripheral fractures. However, available data do not provide clarity if this is because dr ugs are less effective in women than in osteopenic or osteoporotic, however, is simply the power of studies to detect effect is lower in the group with osteopen ia by their lower frequency of fractures. Are the drugs that inhibit efficient i n osteopenia? Some authors have published studies of cost-benefit and cost-effec

tiveness of antiresorptive in women with osteopenia. These studies assume that t hese drugs have a protective effect against fractures similar to that shown in w omen with osteoporosis (fancy that, while unproven, may be considered possible.) Still, the results have clearly shown that the treatments are efficient. Schous boe et al17 estimated that, for women with osteopenia without previous fractures or other additional risk factors, treatment with alendronate would cost between $ 70,000 and $ 332,000 per year of quality-adjusted life (QALY) win. For his pa rt, Meadows et al18 estimated that the treatment of osteopenic women with raloxi fene would cost between $ 50,000 and $ 100,000, depending on age, per QALY gaine d. In addition, much of the benefit in quality of life should be to reduce the r isk of breast cancer, not decreasing fractures. In our country, where the incide nce of hip fracture is approximately half that of EE.UU.19, costs per QALY gaine d would be greater efficiency and therefore lower. Can you identify decisions ac cording to the characteristics of the patients? As mentioned, we believe that th e available studies provide no data supporting the treatment of women with osteo penia systematically. The same conclusion also reached by other authors with ext ensive experience in the treatment of metabolic diseases óseas20-22. However, it is a specific task of identifying clínicosl medical treatment decisions using t he data available based on the characteristics of each patient. And the approach of patients with osteopenia is not an exception. Ultimately, as noted McClung, "the aim of the administration of antiRiancho JA ET AL. SEVEN QUESTIONS OSTEOPENIA teoporóticos is to prevent fractures. This can only be achieved by treating pati ents likely to experience a fracture, not just trying indices T '20. For the ide ntification of attitude can be useful some scales that help to establish, even w ith limited accuracy, the risk of fracture (http://courses.washington.edu/boneph ys/FxRiskCalculator.html). Between them, one of the most widespread is the scale Fracture23, which was developed in the U.S. with the SOF study data and validat ed later in France. The following two clinical cases will clarify its applicatio n. A.P.M.€is a woman of 61 years you perform a DXA after suffering a broken ster num in a traffic accident. No other fractures had previously or have a history o f other diseases of concern. She had menopause at age 50. In your family has no history of osteoporotic fractures. It weighs 68 kg. DXA T shows an index of -1.6 at the spine and -1.5 at the hip. Fracture the scale we can estimate that over the next five years the risk of vertebral fracture is 1.2% and of hip fracture, 0.4%. Table 3 provides an analysis of the clinical efficiency of treatment. It c an be seen that the present treatment is more cost-effective low from the social point of view (even considering a larger efficacy with reduced fracture rate of 50% and a high incidence of osteoporotic fractures, as the U.S. .). J.S.L. is a woman of 74 who have recently suffered a wrist fracture after an accidental fal l in the bathtub. No relevant previous diseases, but his mother had a hip fractu re. It weighs 49 kg. DXA T shows an index of -1.6 in -1.5 in spine and hip. Frac ture the scale is estimated that the risk of vertebral fracture is 7.1% over the next five years and hip fracture, 3.9%. The expected benefits with treatment, a s outlined in Table 3, are clearly superior to those achieved in earlier clinica l stage. In conclusion From the information currently available, one can identif y the following conclusions for the clinical approach of postmenopausal women de nsitometric values in the range of osteopenia: TABLE 3 Impact of treatment of osteopenia in patients with different clinical de nsitometry * Patient A.P.M. Patient J.S.L. Baseline risk of vertebral fracture at baseline risk of hip fracture risk of ver tebral fracture with treatment of hip fracture risk in vertebral fracture NNT NN T treatment of hip fractures prevented fracture treating 100 women for five year s cost of treating 100 patients for 5 years ( )

1.2 0.4 0.6 0.2 167 500 <1 vertebral and <1 240 000 hip 7.1 3.9 3.5 2 29 50 3-4 vertebral and hip 2 240 000 * It is considered the risk of fracture over 5 years on fracture rates U.S. (In Spain the incidence of hip fracture is about 50% of these figures.) It is assumed that treatment reduced by 50% the risk of vertebral and hip fractures , and is not considered the possible residual effect later. As the cost of treat ment included only the cost (retail price) an average of antiresorptive, prescri bed for 5 years. NNT: number of patients needed to treat to prevent one fracture . 1. There is an inverse relationship between BMD and fractures, so that women wit h osteopenia have an intermediate risk of fracture among those with osteoporosis and those with a normal DXA. 2. Osteopenia is very common and is present in alm ost half of women over 60, so a high proportion of fragility fractures occur in women with densitometric values between -1 and -2.5 T (osteopenia) . 3. Besides BMD, other factors influence the risk of fracture, particularly the elderly, per sonal and family history of osteoporotic fractures, smoking, glucocorticoids and low body weight. 4. It is shown that antiresorptive therapy is effective in wom en with osteopenia who have no other additional risk factors or history of fract ure, particularly with regard to prevention of new peripheral fractures. 5. Acco rdingly, since the risk of fracture in this population is relatively low, is not recommended " ment with drugs that inhibit systematic in women with osteopenia. However, they are indicated in these general measures that favor the maintenance of bone mass (leaving the snuff, avoid excessive alcohol intake, ensure adequate nutrition wi th a sufficient intake of calcium and vitamin D) and reducing the risk of falls (maintenance of balance and muscle strength, avoid risk and improve environmenta l conditions in the home). 6. However, antiresorptive therapy may be considered in women with osteopenia and fracture risk factors. In particular, treatment is indicated in postmenopausal women who are to receive prolonged treatment with gl ucocorticoids, regardless of their baseline BMD. We also recommend treatment in premenopausal women receiving glucocorticoids and have a BMD below -1.5 T24.€The band of values is very wide and osteopenia in some studies have shown an increa sed risk of fractures in women with T levels less than -2. Therefore, some women in that group with BMD between -2 and -2.5 T could be considered the introducti on of treatment with fewer clinical risk factors than in those who had higher le vels of BMD. 7. It is also particularly suitable treatment for women who, having osteopenia on DXA, have already submitted some fragility fractures. In fact, th ese women should not be diagnosed with osteopenia, but osteoporosis. Addendum Af ter sending this work has been made available on the Internet a new tool for pre dicting fracture risk, based on data from reference 8 and emphasizes the outcome s for different countries, including Spain (www.shef.ac.uk / FRAX). REFERENCES 1. Kanis JA, WHO study group. Assessment of Fracture Risk and Its app lication to screening for postmenopausal osteoporosis: synopsis of a WHO report. Osteoporos Int 1994, 4:368-81. Med Clin (Barc). 2008, 131 (4) :136-40 139 Riancho JA ET AL. SEVEN QUESTIONS OSTEOPENIA 2. Masud T, Mootoosamy I, McCloskey EV, O'Sullivan MP, Whitby EP, King D, et al. Assessment of osteopenia from spine radiographs using two Different methods: th e Chingford study. Br J Radiol. 1996; 69:451-6. 3. Diaz Curiel M, García JJ, Car rasco JL, Honorato J, Pérez Cano R, Rapado A, et al. Prevalence of osteoporosis determined by densitometry in the Spanish female population. Med Clin (Barc). 20

01, 116: 86-8. 4. Johnell O, Kanis JA, Oden A, Johansson H, De Laet C, Delmas P, et al. Predictive value of BMD for hip and Other fractures. J Bone Miner Res 20 05, 20:1185-94. 5. Siris ES, Genant HK, Laster AJ, Chen P, Misurski DA, JH Krege r. Enhanced prediction of fracture Risk Combining BMD and vertebral fracture sta tus. Osteoporos Int 2007, 18:761-70. 6. Cranney A, Jamal SA, Tsang JF, Josse RG, Leslie WD. Low bone mineral density in postmenopausal and fracture burden Women . Can Med Ass J. 2007, 177:575-80. 7. Pasco JA, Seeman E, Henry MJ, Merriman EN, Nicholson GC, Kotowicz MA. The Population burden of fractures in Women with ost eopenia originals, NOT osteoporosis. Osteoporos Int 2006; 17:1404-9. 8. Kanis JA , Borgstrom F, De Laet C, Johansson H, Johnell O, Jonsson B, et al. Risk Assessm ent of fracture. Osteoporos Int 2005; 16:581-9. 9. Kanis JA, Johnell O, De Laet C, Johansson H, Oden A, Delmas P, et al. A meta-analysis of previous fracture an d subsequent fracture Risk. Bone. 2004; 35:375-82. 10. Miller PD, Barlas S, Bren neman SK, Abbott TA, Chen YT, Barrett-Connor E, et al. An Approach to Identifyin g osteopenic Increaser Women at Risk of short-term fracture. Arch Intern Med 200 4, 164:1113-20. 11. Sornay-Rendu E, Munoz F, Garnero P, Duboeuf F, Delmas PD. Id entification of osteopenic Women at High Risk of fracture: the OFELY study. J Bo ne Miner Res 2005, 20:1813-9. 12. Sambrook P, Cooper C. Osteoporosis. Lancet. 20 06, 367:2010-8. 13. Kanis JA, Johnell O, Black DM, Downs RW Jr, Sarkar S, Fuerst T, et al. Effect of raloxifene on the Risk of new vertebral fracture in postmen opau14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. Women salt with osteopenia or osteoporosis: a reanalysis of the Multiple Outcome s of Raloxifene Evaluation trial. Bone. 2003, 33:293-300. Quandt SA, Thompson DE , Schneider DL, Nevitt MC, Black DM. Effect of alendronate on vertebral fracture Risk in Women with bone mineral density T scores of -1.6 to -2.5 at the femoral neck: the Fracture Intervention Trial. Mayo Clin Proc. 2005; 80:343-9. Siris ES , Simon JA, Barton IP, McClung MR, Grauer A. Effects of risedronate on Fracture Risk in Women with postmenopausal osteopenia. Osteoporos Int 2008; 19:681-6. See man E, Devogelaer J, Lorenc R, Spector T, Brixen K, Balogh A, et al. Strontium r anelate you reduce the Risk of Vertebral Fractures in Patients with osteopenia. J Bone Miner Res 2008; 23:433-8. Schousboe JT, Nyman JA, Kane RL, Ensrud KE. Cos t-effectiveness of alendronate therapy for osteopenic postmenopausal Women. Ann Intern Med 2005, 142:734-41. Meadows ES, Klein R, Rousculp MD Smolen L, Ohsfeldt RL, Johnston JA. Cost-effectiveness of Preventative therapies for postmenopausa l Women with osteopenia. BMC Women's Health. 2007, 7:6. Kanis JA, Johnell O, De Laet C, Jonsson B, Oden A, Ogelsby AK. International Variations in hip fracture probabilities: Implications for Risk Assessment. J Bone Miner Res 2002, 17:123744. McClung MR. Osteopenia: to treat or not to treat? Ann Intern Med 2005, 142:7 96-7. Cummings SR. A 55-year-old woman with osteopenia. JAMA. 2006, 296: 2601-10 . Khosla S, Melton LJ III. Clinical practice. Osteopenia. N Engl J Med 2007, 356 :2293-300. Black DM, Steinbuch M, Palermo L, Dargent-Molina P, Lindsay R, Hoseyn i MS, et al. An assessment tool for Predicting Risk fracture in postmenopausal W omen. Osteoporos Int 2001; 12:519-28.€Sosa M, Working Group of the SEMI osteopor osis. Guide to prevention and treatment of glucocorticoid-induced osteoporosis. Madrid: Medical Marketing & Communications, 2007. 140 Med Clin (Barc). 2008, 131 (4) :136-40