Johnson1989   Johnson BE, Lucasey B, Robinson RG, Lukert BP. Contributing diagnoses in osteoporosis. The value of a complete medical evaluation. Arch-Intern-Med. 1989 May; 149(5): 1069-72

Osteoporosis often occurs as a consequence of, or is accelerated by, many medical diseases, drug exposures, or other conditions. We called these conditions contributing diagnoses. Although technological advances permit the accurate measurement of bone density, identifying osteoporosis without searching for contributing diagnoses may result in remediable diseases being missed or in the initiation of inadvisable therapy. The value of comprehensive medical evaluation in conjunction with appropriate diagnostic studies was demonstrated in an osteoporosis referral center. We studied 300 consecutive persons who presented to an osteoporosis clinic. Using strict criteria, 180 patients (60%) had osteoporosis. Of these 180 patients, 83 (46%) had one or more contributing diagnosis, ie, a condition thought to accelerate bone loss. The largest single group was composed of persons with past or present exposure to glucocorticoids; the second largest group consisted of women who had undergone premature menopause. In all, 27 different contributing diagnoses were identified. Additionally, in 19 (11%) of the 180 patients with osteoporosis, a contributing diagnosis new to those patients was made. The evaluation of osteoporosis does not only entail measurement of bone density but must also take into consideration a patient’s entire medical milieu.

Hui1988a   Hui SL, Slemenda CW, Johnston CC Jr. Age and bone mass as predictors of fracture in a prospective study. J-Clin-Invest. 1988 Jun; 81(6): 1804-9

To study the effect of bone mass on the risk of fracture, we followed 521 Caucasian women over an average of 6.5 yr and took repeated bone mass measurements at the radius. We observed 138 nonspinal fractures in 3,388 person-yr. The person-years of follow-up and the incident fractures were cross-classified by age and bone mass. The incidence of fracture was then fitted to a log-linear model in age and bone mass. It was found that incidence of fracture increased with both increasing age and decreasing radius bone mass. When subsets of fractures were examined it was found that age was a stronger predictor of hip fractures, whereas midshaft radius bone mass was a stronger predictor of fractures at the distal forearm. We concluded that bone mass is a useful predictor of fractures but that other age-related factors associated with fractures need to be identified.  

Consensus2002  Osteoporose. Tweede herziene richtlijn. Kwaliteitsinstituut voor de Gezondheidszorg CBO. Van Zuiden Communications, Alphen a/d Rijn

Pols2002  Pols HAP, Wittenberg J. CBO-richtlijn Osteoporose (tweede herziening). Ned Tijdschr Geneesk 2002;146:1359-63

- Risicofactoren voor een osteoporotische fractuur die bruik­baar zijn bij opsporing: een wervelfractuur. een fractuur na het 50^e levensjaar, een positieve familieanamnese voor osteoporo­tische fracturen, laag lichaamsgewicht, ernstige immobiliteit en het gebruik van corticosterotden.

- Een botmineraaldichtheids(BMD)meting wordt alleen gead­viseerd voor opsporing en niet voor screening van de popula­tie.

- Een BMD-meting is te overwegen bij vrouwen ≥50 jaar met een fractuur, een wervelfractuur ongeacht de leeftijd,. bij vrouwen ≥ 6o jaar met 3 van de navolgende risicofactoren en bij vrouwen ≥ 70 jaar met 2 van de navolgende risicofactoren:

positieve famiheanamnese, laag lichaamsgewicht en ernstige immobiliteit.

- Personen die minder dan 1000-1 200 mg calcium per dag via de voeding innemen en corticosteroiden gebruiken, personen met osteoporotische fracturen en personen die medicamenteus behandeld worden voor osteoporose komen in aanmerking voor calciumsuppletie.

- Suppletie van vitamine D wordt aanbevolen bij personen zonder blootstelling aan zonlicht

- Voor medicamenteuze behandeling van osteoporose in de eerste jaren na de menopauze kunnen oestrogenen, tibolon en raloxifen worden gebruikt.

- Het verdient aanbeveling om postmenopauzale vrouwen met een of meer osteoporotische wervelfracturen of een verhoogd risico en een T-score onder -2.5 te behandelen met een bis­fosfonaat.

- Bij patiënten die naar verwachting langer dan 3 maanden behandeld gaan worden met > 15 mg prednisolonequivalent per dag en bij postmenopauzale vrouwen en oudere mannen (≥ 70 jaar) die behandeld gaan worden met ≥7,5 mg predniso­lonequivalent per dag dient zo snel mogelijk gestart te worden met een bisfosfonaat.

- Overige patiënten die behandeld gaan worden met ≥7,5 mg prednisolonequivalent per dag komen in aanmerking voor een bisfosfonaat bij een T-score onder -1 of een T-score onder -2.5.

Gezondheidsraad1998a  Gezondheidsraad: Commissie Osteoporose. Preventie van aan osteoporose gerelateerde fracturen. Rijswijk: Gezondheidsraad 1998; publicatie nr 1998/05. 

ACOG2002  ACOG Committee on Gynecologic Practice. Bone density screening for osteoporosis. Obstet Gynecol 2002;99:523-5

Bone mineral density (BMD) testing is an effective approach for the early detection of osteopenia and osteoporosis. The American College of Obstetricians and Gynecologists Committee on Gynecologic Practice recommends BMD testing for all postmenopausal women aged 65 years or older and for all postmenopausal women who present with fractures. The Committee also concludes that BMD testing may be recommended to postmenopausal women younger than 65 years who have one or more risk factors for osteoporosis. Bone mineral density testing also may be useful for premenopausal and postmenopausal women who present with certain diseases or medical conditions and those who take certain drugs associated with an increased risk of osteoporosis

Gezondheidsraad1998b  Gezondheidsraad: Commissie Osteoporose. Preventie van aan osteoporose gerelateerde fracturen. Rijswijk: Gezondheidsraad 1998; publicatie nr 1998/05. 

Hui1989a   Hui SL, Slemenda CW, Johnston CC Jr. Baseline measurement of bone mass predicts fracture in white women. Ann-Intern-Med. 1989 Sep 1; 111(5): 355-61

STUDY OBJECTIVE: To determine if a single bone mass measurement of the radius is predictive of future fractures at any site. DESIGN: Observational study of a cohort of free-living subjects and a cohort of retirement-home residents with an average follow-up of 6.7 years and 5.5 years, respectively (range, 1 to 15 years for both cohorts). SETTING: General community and a retirement home. SUBJECTS: Volunteer sample of white women (386 free-living and 135 living in a retirement home) who were free of disease and were not receiving medication known to affect bone metabolism. In terms of physical condition subjects ranged from the totally independent to the wheelchair-bound. MEASUREMENTS AND MAIN RE-SULTS: A radial bone mass measurement was done at the initial visit. Subsequent non-spine fractures were reported by the subjects at follow-up visits, which were less than a year apart in most cases, and verified with medical records. Cox regression was used to model time to first fracture as a function of age and bone mass. These analyses showed that for every 0.1 g/cm decrement in bone mass, the relative risk of fracture was 2.2 (CI, 1.7 to 2.8) for the free-living and 1.5 (CI, 1.2 to 1.9) for the retirement-home residents. Baseline age did not predict the risk of fracture in either cohort, and controlling for baseline age did not reduce the relative-risk estimates of bone mass. Similar analyses also showed that bone mass was a statistically significant predictor for first hip fractures (n = 30) among the nursing-home residents (relative risk, 1.9; CI, 1.4 to 2.7) and first forearm fractures (n = 10) among the free living (relative risk, 3.6; CI, 1.9 to 6.8). For both cohorts, the 8-year probability of any nonspine fracture was about 80% for subjects with initial bone mass less than 0.6 g/cm and was less than 10% for subjects with initial bone mass greater than 0.8 g/cm. Similarly, those in the retirement home with bone mass below 0.6 g/cm had a 6-year probability of hip fracture of 43%, compared with a 17% risk for those with greater bone mass. CONCLUSION: A single bone mass measurement of the radius is predictive of future nonspine fractures at all sites, and at both the forearm and the hip. Baseline age was not a significant predictor of fracture within either cohort. Relative-risk estimates were not dissimilar across fracture sites.

Black1992   Black DM, Cummings SR, Genant HK, Nevitt MC, Palermo L, Browner W. Axial and appendicular bone density predict fractures in older women. J-Bone-Miner-Res. 1992 Jun; 7(6): 633-8

To determine whether measurement of hip and spine bone mass by dual-energy x-ray absorptiometry (DEXA) predicts fractures in women and to compare the predictive value of DEXA with that of single-photon absorptiometry (SPA) of appendicular sites, we prospectively studied 8134 nonblack women age 65 years and older who had both DEXA and SPA measurements of bone mass. A total of 208 nonspine fractures, including 37 wrist fractures, occurred during the follow-up period, which averaged 0.7 years. The risk of fracture was inversely related to bone density at all measurement sites. After adjusting for age, the relative risks per decrease of 1 standard deviation in bone density for the occurrence of any fracture was 1.40 for measurement at the proximal femur (95% confidence interval 1.20-1.63) and 1.35 (1.15-1.58) for measurement at the spine. Results were similar for all regions of the proximal femur as well as SPA measurements at the calcaneus, distal radius, and proximal radius. None of these measurements was a significantly better predictor of fractures than the others. Furthermore, measurement of the distal radius was not a better predictor of wrist fracture (relative risk 1.64: 95% CI 1.13-2.37) than other sites, such as the lumbar spine (RR 1.56; CI 1.07-2.26), the femoral neck (RR 1.65; CI 1.12-2.41), or the calcaneus (RR 1.83;, CI 1.26-2.64). We conclude that the inverse relationship between bone mass and risk of fracture in older women is similar for absorptiometric measurements made at the hip, spine, and appendicular sites.

Cummings1993   Cummings SR, Black DM, Nevitt MC, Browner W, Cauley J, Ensrud K, Genant HK, Palermo L, Scott J, Vogt TM. Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group. Lancet. 1993 Jan 9; 341(8837): 72-5

Women with low bone density in the radius or calcaneus are at increased risk of hip fracture. To see whe-ther bone density of the hip measured by dual X-ray absorptiometry is a better predictor of hip fracture than measurements of other bones, we assessed bone density at several sites in 8134 women aged 65 ye-ars or more. 65 women had hip fractures during a mean follow-up of 1.8 years. Each SD decrease in femo-ral neck bone density increased the age-adjusted risk of hip fracture 2.6 times (95% CL 1.9, 3.6). Women with bone density in the lowest quartile had an 8.5-fold greater risk of hip fracture than those in the hig-hest quartile. Bone density of the femoral neck was a better predictor than measurements of the spine (p  0.0001), radius (p  0.002), and moderately better than the calcaneus (p = 0.10). Low hip bone density is a stronger predictor of hip fracture than bone density at other sites. Efforts to prevent hip fractures should focus on women with low hip bone density.

Gardsell1993a   Gardsell P, Johnell O, Nilsson BE, Gullberg B. Predicting various fragility fractures in women by forearm bone densitometry: a follow-up study. Calcif-Tissue-Int. 1993 May; 52(5): 348-53

This is a follow-up of a previous study on the predictive power of bone mineral measurements; two more observation years have been added. A group of women (n = 1076) had their forearm bone mineral content (BMC) measured from 1970-1976. All fractures that occurred in 1975-1987 (13 years) were recorded. Four hundred sixty-nine fragility fractures occurred during the collection period. Again, it was found that BMC at the distal end of the forearm is a good predictor of future fracture before the age of 70. The measurement at the proximal site (forearm shafts), however, in contrast to our previous study, has a capacity of predicting fracture also in the age group 70-80. BMC measurements were good predictors of vertebral crush fractures and trochanteric hip fracture but lesser predictors of fractures of the distal end of the fore-arm. In age groups 40-70, BMC was a stronger predictor of fracture than age, and the risk associated with a 1 SD decrease of BMC 6 was 3.2 for a hip fracture as compared with those without any fragility fracture, even when adjusted for age. In addition to BMC, low body weight was a fracture predictor. Body weight kg below age-adjusted mean increased the risk of a trochanteric hip fracture by 30%. The data are used in hypothetical calculations of the effects of screening.

Hui1989b   Hui SL, Slemenda CW, Johnston CC Jr. Baseline measurement of bone mass predicts fracture in white women. Ann-Intern-Med. 1989 Sep 1; 111(5): 355-61

STUDY OBJECTIVE: To determine if a single bone mass measurement of the radius is predictive of future fractures at any site. DESIGN: Observational study of a cohort of free-living subjects and a cohort of retirement-home residents with an average follow-up of 6.7 years and 5.5 years, respectively (range, 1 to 15 years for both cohorts). SETTING: General community and a retirement home. SUBJECTS: Volunteer sample of white women (386 free-living and 135 living in a retirement home) who were free of disease and were not receiving medication known to affect bone metabolism. In terms of physical condition subjects ranged from the totally independent to the wheelchair-bound. MEASUREMENTS AND MAIN RE-SULTS: A radial bone mass measurement was done at the initial visit. Subsequent non-spine fractures were reported by the subjects at follow-up visits, which were less than a year apart in most cases, and verified with medical records. Cox regression was used to model time to first fracture as a function of age and bone mass. These analyses showed that for every 0.1 g/cm decrement in bone mass, the relative risk of fracture was 2.2 (CI, 1.7 to 2.8) for the free-living and 1.5 (CI, 1.2 to 1.9) for the retirement-home residents. Baseline age did not predict the risk of fracture in either cohort, and controlling for baseline age did not reduce the relative-risk estimates of bone mass. Similar analyses also showed that bone mass was a statistically significant predictor for first hip fractures (n = 30) among the nursing-home residents (relative risk, 1.9; CI, 1.4 to 2.7) and first forearm fractures (n = 10) among the free living (relative risk, 3.6; CI, 1.9 to 6.8). For both cohorts, the 8-year probability of any nonspine fracture was about 80% for subjects with initial bone mass less than 0.6 g/cm and was less than 10% for subjects with initial bone mass greater than 0.8 g/cm. Similarly, those in the retirement home with bone mass below 0.6 g/cm had a 6-year probability of hip fracture of 43%, compared with a 17% risk for those with greater bone mass. CONCLUSION: A single bone mass measurement of the radius is predictive of future nonspine fractures at all sites, and at both the forearm and the hip. Baseline age was not a significant predictor of fracture within either cohort. Relative-risk estimates were not dissimilar across fracture sites.

Hui1988b   Hui SL, Slemenda CW, Johnston CC Jr. Age and bone mass as predictors of fracture in a prospective study. J-Clin-Invest. 1988 Jun; 81(6): 1804-9

To study the effect of bone mass on the risk of fracture, we followed 521 Caucasian women over an average of 6.5 yr and took repeated bone mass measurements at the radius. We observed 138 nonspinal fractures in 3,388 person-yr. The person-years of follow-up and the incident fractures were cross-classified by age and bone mass. The incidence of fracture was then fitted to a log-linear model in age and bone mass. It was found that incidence of fracture increased with both increasing age and decreasing radius bone mass. When subsets of fractures were examined it was found that age was a stronger predictor of hip fractures, whereas midshaft radius bone mass was a stronger predictor of fractures at the distal forearm. We concluded that bone mass is a useful predictor of fractures but that other age-related factors associated with fractures need to be identified.

Consensus2002b  Osteoporose. Tweede herziene richtlijn. Kwaliteitsinstituut voor de Gezondheidszorg CBO. Van Zuiden Communications, Alphen a/d Rijn

Gezondheidsraad1998c Gezondheidsraad: Commissie Osteoporose. Preventie van aan osteoporose gerelateerde fracturen. Rijswijk: Gezondheidsraad 1998; publicatie nr 1998/05.  

Davies1990   Davies MC, Hall ML, Jacobs HS. Bone mineral loss in young women with amenorrhoea. BMJ. 1990 Oct 6; 301(6755): 790-3

OBJECTIVE-To examine the impact of amenorrhoea on bone mineral density in women of reproductive age. DESIGN-Cross sectional study of 200 amenorrhoeic women compared with normally menstruating controls. SETTING-Teaching hospital outpatient clinic specialising in reproductive medicine. SUBJECTS-200 Women aged 16-40 with a past or current history of amenorrhoea from various causes and of a median duration of three years, and a control group of 57 age matched normal volunteers with no history of menstrual disorder. MAIN OUTCOME MEASURE-Bone mineral density in the lumbar spine (L1-L4) as measured by dual energy x ray absorptiometry. RESULTS-The amenorrhoeic group showed a mean reduction in bone mineral density of 15% (95% confidence interval 12% to 18%) as compared with controls (mean bone mineral density 0.89 (SD 0.12) g/cm2 v 1.05 (0.09) g/cm2 in controls). Bone loss was related to the duration of amenorrhoea and the severity of oestrogen deficiency rather than to the underlying diagnosis. Patients with a history of fracture had significantly lower bone density than those without a history of fracture. Ten patients had suffered an apparently atraumatic fracture. CONCLUSIONS-Amenorrhoea in young women should be investigated and treated to prevent bone mineral loss. Menopausal women with a past history of amenorrhoea should be considered to be at high risk of osteoporosis.

Prior1990   Prior JC, Vigna YM, Schechter MT, Burgess AE. Spinal bone loss and ovulatory disturbances. NEJM 1990;323:1221-7

BACKGROUND. Osteoporosis develops in women with estrogen deficiency and amenorrhea who lose bone at an accelerated rate. It is not known to what extent bone loss differs between ovulatory women with regular menstrual cycles who are training intensely and those who are sedentary. METHODS. We measured the density of cancellous spinal bone from the 12th thoracic vertebra to the 3rd lumbar vertebra by quantitative computed tomography on two occasions one year apart in 66 premenopausal women 21 to 42 years of age. All the women had two consecutive ovulatory cycles immediately before entering the study. Twenty-one women were training for a marathon, 22 ran regularly but less intensively, and 23 had normal levels of activity. The lengths of the women’s menstrual cycles and luteal phases, diet, exercise levels, and hormonal levels were also determined. We defined ovulatory disturbances as anovulatory cycles and cycles with short luteal phases. RESULTS. The mean ( SD) spinal bone density in the 66 women decreased 3.0 4.8 mg per cubic centimeter per year (2.0 percent per year) (P less than 0.001). Amenorrhea did not develop in any woman during the year of observation (only 2.7 percent of the cycles were greater than 36 days long). Ovulatory disturbances occurred in 29 percent of all cycles, however. Bone loss was strongly associated with these disturbances (r = 0.54, 24 percent of the variance). The 13 women who had anovulatory cycles lost bone mineral at a rate of 6.4 3.8 mg per cubic centimeter per year (4.2 percent per year). The women training for a marathon had menstrual cycles similar to those of the women in the other two groups. CONCLUSION. Decreases in spinal bone density among women with differing exercise habits correlated with asymptomatic disturbances of ovulation (without amenorrhea) and not with physical activity.

Prior1994   Prior JC, Vigna YM, Barr SI, Rexworthy C, Lentle BC. Cyclic medroxyprogesterone treatment increases bone density: a controlled trial in active women with menstrual cycle disturbances. Am J Med 1994;96:521-30

OBJECTIVE: Bone loss occurs in young women who experience amenorrhea or ovulatory disturbances. The purpose of this study was to determine whether bone loss could be prevented by simulating a more normal hormonal pattern, using treatment with cyclic medroxyprogesterone, with or without calcium supplementation, in physically active women with disturbed menstruation. DESIGN: This study was a 1-year randomized, double-blind, placebo-controlled trial. Women who were stratified by menstrual cycle disturbance were randomized into four groups. The outcome variable was the change in spinal bone density measured by dual energy techniques. SETTING: A large metropolitan area. PARTICIPANTS: Sixty-one healthy, normal-weight physically active premenopausal women aged 21 to 45 years who experienced amenorrhea, oligomenorrhea, anovulation, or short luteal phase cycles completed the study. INTERVENTION: Therapies were cyclic medroxyprogesterone (10 mg/day for 10 days per month) and calcium carbonate (1,000 mg/day of calcium) in four groups: (A) (n = 16) cyclic medroxyprogesterone plus calcium carbonate; (B) (n = 16) cyclic medroxyprogesterone with calcium placebo; (C) (n = 15) placebo medroxyprogesterone with active calcium; or (D) (n = 14) both medroxyprogesterone and calcium placebos. RESULTS: The initial bone density (mean = 1.12 g/cm2) did not differ by group (P = 0.85). The 1-year bone density change was strongly related to treatment with medroxyprogesterone (P = 0.0001) and weakly to calcium (P = 0.072) treatment. Bone density increased significantly (+1.7% +/- 0.5%, +/- SEM, P = 0.004) in the medroxyprogesterone-treated groups (A and B), did not change in the calcium-treated group (C) (-0.7% +/- 0.6%, P = 0.28), and decreased on both placebos (D) (-2.0% +/- 0.6%, P = 0.005). CONCLUSIONS: Cyclic medroxyprogesterone increased spinal bone density in physically active women experiencing amenorrhea or ovulatory disturbances. POTENTIAL CLINICAL SIGNIFICANCE: Amenorrhea, oligomenorrhea, anovulation, and short luteal phase cycles are common in premenopausal women and associated with spinal bone loss occurring at a stage of life when bone density would normally be stable or increasing. This controlled trial shows a significant gain in bone in women in the cyclic medroxyprogesterone intervention group, whereas those subjects in the placebo group lost bone. Calcium supplementation appeared to be helpful but did not reach statistical significance. The implications of these findings for the prevention of osteoporosis warrant further investigation.

Consensus2002d Osteoporose. Tweede herziene richtlijn. Kwaliteitsinstituut voor de Gezondheidszorg CBO. Van Zuiden Communications, Alphen a/d Rijn

WHO1994   WHO study group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO Technical report series 843. Geneva 1994.

Gezondheidsraad1998   Gezondheidsraad: Commissie Osteoporose. Preventie van aan osteoporose gerelateerde fracturen. Rijswijk: Gezondheidsraad 1998; publicatie nr 1998/05.  

Osteoporosis1998   Osteoporosis: review of the evidence for prevention, diagnosis and treatment and cost-effectiveness analysis. Osteoporosis International 1998;8:Suppl.4.

GuidelineDevelopmentGroup1998   Guideline Development Group. Osteoporosis. Clinical guidelines for prevention and treatment. Royal College of Physicians of London 1998.  

Elders1999   Elders P, Van Keimpema JC, Petri H et al. NHG-Standaard Osteoporose. Huisarts Wet 1999;42:115-28.  

Consensus2002c  Osteoporose. Tweede herziene richtlijn. Kwaliteitsinstituut voor de Gezondheidszorg CBO. Van Zuiden Communications, Alphen a/d Rijn

ACOG2002b  ACOG Committee on Gynecologic Practice. Bone density screening for osteoporosis. Obstet Gynecol 2002;99:523-5

Bone mineral density (BMD) testing is an effective approach for the early detection of osteopenia and osteoporosis. The American College of Obstetricians and Gynecologists Committee on Gynecologic Practice recommends BMD testing for all postmenopausal women aged 65 years or older and for all postmenopausal women who present with fractures. The Committee also concludes that BMD testing may be recommended to postmenopausal women younger than 65 years who have one or more risk factors for osteoporosis. Bone mineral density testing also may be useful for premenopausal and postmenopausal women who present with certain diseases or medical conditions and those who take certain

Oursler1993   Oursler MJ, Landers JP, Riggs BL, Spelsberg TC. Oestrogen effects on osteoblasts and osteoclasts. Ann Med 1993;25:361-371.

Although it has been recognized for many years that oestrogen is a key component in the maintenance of normal bone balance, the mechanisms by which oestrogen exerts its influence have remained unresolved. Recent identification of oestrogen receptors in both bone-forming osteoblasts and bone-resorbing osteoclasts has opened up exciting new areas of research on the direct effects of oestrogen on both osteoblasts and osteoclasts. This review presents an updated model for the molecular mechanisms involved in oestrogen action, the mechanism of anti-oestrogen action, and outlines recent advances in knowledge of oestrogen effects on osteoblasts, osteoclasts, and the coupling of bone resorption and bone formation.

Horowitz1993   Horowitz MC. Cytokines and estrogen in bone: anti-osteoporotic effects. Science 1993;260:626-627.

Cummings1998   Cummings SR, Browner WS, Bauer D et al. Endogenous hormones and the risk of hip and vertebral fractures among older women. NEJM 1998;339:733-8.

BACKGROUND AND METHODS: In postmenopausal women, the serum concentrations of endogenous sex hormones and vitamin D might influence the risk of hip and vertebral fractures. In a study of a cohort of women 65 years of age or older, we compared the serum hormone concentrations at base line in 133 women who subsequently had hip fractures and 138 women who subsequently had vertebral fractures with those in randomly selected control women from the same cohort. Women who were taking estrogen were excluded. The results were adjusted for age and weight. RESULTS: The women with undetectable serum estradiol concentrations ( 5 pg per milliliter 18 pmol per liter ) had a relative risk of 2.5 for subsequent hip fracture (95 percent confidence interval, 1.4 to 4.6) and subsequent vertebral fracture (95 percent confidence interval, 1.4 to 4.2), as compared with the women with detectable serum estradiol concentrations. Serum concentrations of sex hormone-binding globulin that were 1.0 microg per deciliter (34.7 nmol per liter) or higher were associated with a relative risk of 2.0 for hip fracture (95 percent confidence interval, 1.1 to 3.9) and 2.3 for vertebral fracture (95 percent confidence interval, 1.2 to 4.4). Women with both undetectable serum estradiol concentrations and serum sex hormone-binding globulin concentrations of 1 microg per deciliter or more had a relative risk of 6.9 for hip fracture (95 percent confidence interval, 1.5 to 32.0) and 7.9 for vertebral fracture (95 percent confidence interval, 2.2 to 28.0). For those with low serum 1,25-dihydroxyvitamin D concentrations ( or =23 pg per milliliter 55 pmol per liter ), the risk of hip fracture increased by a factor of 2.1 (95 percent confidence interval, 1.2 to 3.5). CONCLUSIONS: Postmenopausal women with undetectable serum estradiol concentrations and high serum concentrations of sex hormone-binding globulin have an increased risk of hip and vertebral fracture.

Ettinger1998   Ettinger B, Pressman A, Sklarin P, Bauer DC, Cauley JA, Cummings SR. Associations between low levels of serum estradiol, bone density and fractures among elderly women: the study of osteoporotic fractures. J Clin Endocrinol Metab 1998;83:2239-43.

To evaluate the skeletal effects of endogenous serum estradiol, we measured bone mineral density (BMD) at the calcaneus and radius (single photon absorptiometry) and at the hip and spine (dual x-ray absorptiometry) in 274 women aged 65 yr or more who participated in the Study of Osteoporotic Fractures. Lateral radiographs of the thoracic and lumbar spine were also taken, and serum was assayed for estradiol. Those who had estradiol levels from 10-25 pg/mL had 4.9%, 9.6%, 7.3%, and 6.8% greater BMD at total hip, calcaneus, proximal radius, and spine than those with levels below 5 pg/mL. After multiple adjustments, BMD differences remained statistically significant and corresponded to about 0.4 SD. Vertebral deformities were less prevalent among women whose estradiol level exceeded 5 pg/mL; the multiple adjusted odds ratio was 0.4 (95% confidence interval, 0.2-0.8). We conclude that physiologically low estradiol has a salutary effect on the skeleton in elderly women, possibly by reducing skeletal remodeling.

Stone1998   Stone K, Bauer DC, Black DM et al. Hormonal predictors of bone loss in elderly women: a prospective study. J Bone Miner Res 1998;13:1167-74.

To test the hypotheses that baseline concentrations of sex steroids, sex hormone binding globulin (SHBG), and calciotropic hormones predict rates of bone loss in elderly women, sera were stored at -190 degrees, and calcaneal bone mineral density (BMD) was measured in 9704 community-dwelling white women aged 65 and over (1986-1988). Hip BMD was measured 2 years later (1900). Repeat measurements of a calcaneal and hip BMD were obtained in 1993-1994, after 5.7 and 3.5 years of follow-up, respectively. In 1994, sera were assayed for circulating hormone levels in random subcohorts of 231 and 218 women who did not report current use of hormone replacement therapy at baseline. Lower levels of endogenous estrogens and higher SHBG concentrations were associated with more rapid subsequent bone loss from both the calcaneus and hip. After adjusting for age and weight, women with high SHBG levels (highest quartile  or = 2.3 micrograms/dI) experienced an average of 2.2% (95% confidence interval = 1.6%, 2.9%) calcaneal bone loss per year compared with 1.2% (0.7%, 1.2%) among women with low SHBG concentrations (lowest quartile  1.1 micrograms/dI; p  0.01). This association was independent of concentrations of other sex hormones. Women with estradiol levels  or = 10 pg/ml averaged only 0.1% (-0.7%, 0.5%) annual hip bone loss while women with levels below 5 pg/ml averaged 0.8% (0.3, 1.2) hip bone loss per year. Lower 25-hydroxyvitamin D levels were associated with increased hip but not calcaneal bone loss. Levels of parathyroid hormone, 1,25-dihydroxyvitamin D, and Calcium were not significantly associated with bone loss from the calcaneus or hip.

Kanis1992   Kanis JA, Johnell O, Gullberg B, Allander E, Dilsen G, Gennari C, Lopes Vaz AA, Lyritis GP, Mazzuoli G, Miravet L, et al. Evidence for efficacy of drugs affecting bone metabolism in preventing hipfracture BMJ. 1992;305: 1124-8.

OBJECTIVE-To examine the effects of taking drugs affecting bone metabolism on the risk of hip fracture in women aged over 50 years. DESIGN-Retrospective, population based, case-control study by questionnaire. SETTING-14 centres in six countries in southern Europe. SUBJECTS-2086 women with hip fracture and 3532 control women matched for age. MAIN OUTCOME MEASURES-Number of drugs affecting bone metabolism taken and length taken for. RESULTS-Women taking drugs affecting bone metabolism had a significantly decreased risk of hip fracture. After adjustment for differences in other risk factors, the relative risk of hip fractures was 0.55 (95% confidence interval 0.31 to 0.85) in women taking oestrogens, 0.75 (0.60 to 0.94) in those taking calcium, and 0.69 (0.51 to 0.92) in those taking calcitonin. The fall in risk was not significant for anabolic steroids (0.6 (0.29 to 1.22)). Neither vitamin D nor fluorides were associated with a significant decrease in the risk of hip fracture. The effect on hip fracture risk increased significantly with increasing duration of exposure (risk ratio 0.8 (0.61 to 1.05) for less than median exposure v 0.66 (0.5 to 0.88) for greater than median exposure). Drugs were equally effective in older and younger women, with the exception of oestrogen. CONCLUSIONS-Oestrogen, calcium, and calcitonins significantly decrease the risk of hip fracture. Short term intervention late in the natural course of osteoporosis may have significant effects on the incidence of hip fracture.

Henry1998   Henry D, Robertson J, O’Connell D, Gillespie W. A systemic review of the skeletal effects of estrogen therapy in postmenopausal women. I. An assessment of the quality of randomized trials published between 1977 and 1995. Climacteric 1998;1:92-111.

Purpose To examine the quality of published randomized controlled trials of the effects of estrogen treatment on fracture risk and measures of bone mass. Data sources Articles on estrogen treatment for osteoporosis published between 1977 and 1995 were identified by searching Medline and Excerpta Medica databases and bibliographies of original papers and published reviews. Study selection Studies selected were randomized controlled trials of the efficacy of estrogens in preventing loss of bone mass or fractures in postmenopausal women. Data extraction Data extraction and quality assessment were performed in duplicate, with assistance of a manual. Raters were blinded as to authors and their affiliations and the publication details. Results Of 99 eligible randomized controlled trials published between 1977 and 1995, eight included no extractable data, and 23 contained results that were published in duplicate. Total quality scores increased over time, but this was accounted for by improvements only in the measurement technologies used to estimate bone mineral content or density. There was no improvement in the quality of randomization methods, the extent to which withdrawals were accounted for, or in the baseline comparability of treated and control patients. Neither sample sizes nor durations of follow-up increased over time. Conclusions This body of literature falls to address whether estrogen therapy reduces fracture rates, and does not allow for comparison of the effects of different active therapies on change in bone density. Although there were improvements in the techniques for estimating bone mass and delivering estrogen treatment, the studies published in the 1990s were no more informative for making clinical or policy decisions than those published in the 1970s.

OConnell1998   O’Connell D, Robertson J, Henry D, Gillespie W. A systematic review of the skeletal effects of estogen therapy in postmenopausal women. II. An assessment of treatment effects. Climacteric 198; 1: 112-23.

Purpose To combine the results of randomized controlled trials to provide overall estimates of the effect of estrogen treatment on fracture rates and measures of bone mass. Data sources Articles on estrogen treatment for osteoporosis published between 1977 and 1995 were identified. Study selection Studies selected were randomized controlled trials of the efficacy of estrogens in preventing loss of bone mass or fractures in postmenopausal women. Data extraction Data extraction and quality assessment were performed in duplicate, with assistance of a manual. Raters were blinded as to authors and their affiliations and the publication details. With estimates of bone mass, the treatment effect size was defined as the difference in the mean annual change in bone mass between the treatment and control groups divided by the pooled standard deviation for change. In the case of fractures, efficacy was measured as the reduction in the numbers of individuals experiencing new fractures with treatment. Effect sizes were pooled using the random effects model. Results Thirty-seven studies met the criteria for inclusion in the systematic review. Only one small secondary prevention trial contained evaluable data on vertebral fractures. This study found a fracture relative risk of 0.63 (95% confidence interval, CI 0.28-1.43) with estrogen treatment. There was more information on the effects of treatment on bone mass. Overall effect sizes ranged between 0.5 and 2.5 standard deviation (SD) units for change. A dose-response relationship was apparent but high doses of estrogens were not associated with effect sizes greater than those observed with recommended doses. There was no significant difference in efficacy between transdermal and oral administration of estrogens. Pooling of paired data from secondary prevention studies indicated that treatment effect sizes were smaller at the hip (0.92, 95% CI 0.3-1.5 SD units) than at the spine (2.1, 95% CI 0.9-3.3 SD units). No significant effects of co-intervention with calcium, progestogens or androgens were seen, although an additive effect of higher doses of calcium could not be ruled out.

Macedo1998   Macedo JMS, Macedo CRB, Elkis H, De Oliveira IR. Meta-analysis about efficacy of anti-resorptive drugs in postmenopausal osteoporosis. J Clin Pharm Ther 1998;23:345-352.

OBJECTIVE: The purpose of this study was to compare the effect of three groups of anti-resorptive drugs in post-menopausal osteoporosis. DATA SOURCES: We collected data covering the period between 1983 and 1995, by first using MEDLINE. References retrieved were scanned further to identify additional papers. STUDY SELECTION: Only randomized studies evaluating bone mass by means of dual-photon or dual energy densitometry over a period of 1 year were accepted. DATA EXTRACTION: Studies were arranged into three drug groups. We used densitometry results after 1 year in all treatment or control groups. Factors which might interfere with the results were recorded for subsequent separate analysis. DATA SYNTHESIS: The MEDLINE search identified almost 25,000 studies. On reading the abstracts, 275 trials appeared to be controlled trials and original copies were retrieved for detailed analysis. A total of 31 articles which satisfied the inclusion criteria were identified. The first meta-analysis included studies which compared oestrogens and placebo, and the global effect-size was 0.54 (95% CI 0.34, 0.73). The second meta-analysis compared calcitonins with placebo and produced an effect-size of 0.41 (95% CI 0.21, 0.61) The third analysis compared bisphosphonates and placebo and showed an effect-size of 0.87 (95% CI 0.68, 1.07). Only oestrogen dose affected the results found. CONCLUSIONS: Bisphosphonates had the greatest effect on bone mass in post-menopausal osteoporosis.

Henry1998b   Henry D, Robertson J, O’Connell D, Gillespie W. A systemic review of the skeletal effects of estrogen therapy in postmenopausal women. I. An assessment of the quality of randomized trials published between 1977 and 1995. Climacteric 1998;1:92-111.

Purpose To examine the quality of published randomized controlled trials of the effects of estrogen treatment on fracture risk and measures of bone mass. Data sources Articles on estrogen treatment for osteoporosis published between 1977 and 1995 were identified by searching Medline and Excerpta Medica databases and bibliographies of original papers and published reviews. Study selection Studies selected were randomized controlled trials of the efficacy of estrogens in preventing loss of bone mass or fractures in postmenopausal women. Data extraction Data extraction and quality assessment were performed in duplicate, with assistance of a manual. Raters were blinded as to authors and their affiliations and the publication details. Results Of 99 eligible randomized controlled trials published between 1977 and 1995, eight included no extractable data, and 23 contained results that were published in duplicate. Total quality scores increased over time, but this was accounted for by improvements only in the measurement technologies used to estimate bone mineral content or density. There was no improvement in the quality of randomization methods, the extent to which withdrawals were accounted for, or in the baseline comparability of treated and control patients. Neither sample sizes nor durations of follow-up increased over time. Conclusions This body of literature falls to address whether estrogen therapy reduces fracture rates, and does not allow for comparison of the effects of different active therapies on change in bone density. Although there were improvements in the techniques for estimating bone mass and delivering estrogen treatment, the studies published in the 1990s were no more informative for making clinical or policy decisions than those published in the 1970s.

OConnell1998a   O’Connell D, Robertson J, Henry D, Gillespie W. A systematic review of the skeletal effects of estogen therapy in postmenopausal women. II. An assessment of treatment effects. Climacteric 198; 1: 112-23.

Purpose To combine the results of randomized controlled trials to provide overall estimates of the effect of estrogen treatment on fracture rates and measures of bone mass. Data sources Articles on estrogen treatment for osteoporosis published between 1977 and 1995 were identified. Study selection Studies selected were randomized controlled trials of the efficacy of estrogens in preventing loss of bone mass or fractures in postmenopausal women. Data extraction Data extraction and quality assessment were performed in duplicate, with assistance of a manual. Raters were blinded as to authors and their affiliations and the publication details. With estimates of bone mass, the treatment effect size was defined as the difference in the mean annual change in bone mass between the treatment and control groups divided by the pooled standard deviation for change. In the case of fractures, efficacy was measured as the reduction in the numbers of individuals experiencing new fractures with treatment. Effect sizes were pooled using the random effects model. Results Thirty-seven studies met the criteria for inclusion in the systematic review. Only one small secondary prevention trial contained evaluable data on vertebral fractures. This study found a fracture relative risk of 0.63 (95% confidence interval, CI 0.28-1.43) with estrogen treatment. There was more information on the effects of treatment on bone mass. Overall effect sizes ranged between 0.5 and 2.5 standard deviation (SD) units for change. A dose-response relationship was apparent but high doses of estrogens were not associated with effect sizes greater than those observed with recommended doses. There was no significant difference in efficacy between transdermal and oral administration of estrogens. Pooling of paired data from secondary prevention studies indicated that treatment effect sizes were smaller at the hip (0.92, 95% CI 0.3-1.5 SD units) than at the spine (2.1, 95% CI 0.9-3.3 SD units). No significant effects of co-intervention with calcium, progestogens or androgens were seen, although an additive effect of higher doses of calcium could not be ruled out.

Macedo1998a   Macedo JMS, Macedo CRB, Elkis H, De Oliveira IR. Meta-analysis about efficacy of anti-resorptive drugs in postmenopausal osteoporosis. J Clin Pharm Ther 1998;23:345-352.

OBJECTIVE: The purpose of this study was to compare the effect of three groups of anti-resorptive drugs in post-menopausal osteoporosis. DATA SOURCES: We collected data covering the period between 1983 and 1995, by first using MEDLINE. References retrieved were scanned further to identify additional papers. STUDY SELECTION: Only randomized studies evaluating bone mass by means of dual-photon or dual energy densitometry over a period of 1 year were accepted. DATA EXTRACTION: Studies were arranged into three drug groups. We used densitometry results after 1 year in all treatment or control groups. Factors which might interfere with the results were recorded for subsequent separate analysis. DATA SYNTHESIS: The MEDLINE search identified almost 25,000 studies. On reading the abstracts, 275 trials appeared to be controlled trials and original copies were retrieved for detailed analysis. A total of 31 articles which satisfied the inclusion criteria were identified. The first meta-analysis included studies which compared oestrogens and placebo, and the global effect-size was 0.54 (95% CI 0.34, 0.73). The second meta-analysis compared calcitonins with placebo and produced an effect-size of 0.41 (95% CI 0.21, 0.61) The third analysis compared bisphosphonates and placebo and showed an effect-size of 0.87 (95% CI 0.68, 1.07). Only oestrogen dose affected the results found. CONCLUSIONS: Bisphosphonates had the greatest effect on bone mass in post-menopausal osteoporosis.

Hillard1994   Hillard TC, Whitcroft S, Ellerington MC et al. Long-term effects of transdermal and oral hormone replacement therapy on postmenopausal bone loss. Osteoporosis Int 1994;4:341-8.

Transdermal hormone replacement therapy (HRT) is now an accepted form of treatment, but the long-term skeletal effects have not been assessed. Sixty-six early postmenopausal women were randomized to receive either transdermal HRT (continuous 17 beta-oestradiol 0.05 mg/day, with 0.25 mg/day of norethisterone acetate added for 14 days of each 28-day cycle) or oral HRT (continuous conjugated equine oestrogens 0.625 mg/day, with 0.15 mg/day dl-norgestrel added for 12 days of each 28-day cycle). Treatment was given for 3 years and 30 matched untreated women were studied concurrently as a control group. Bone density was measured in the lumbar spine and proximal femur by dual-photon absorptiometry at 6-monthly intervals. Bone turnover was assessed by measurement of biochemical markers. At 3 years bone density had declined by 4% in the lumbar spine and by more than 5% in the femoral neck in the untreated group. By comparison bone density increased in both treatment groups at both sites (p  0.001 vs. untreated) and biochemical measurements indicated a significant reduction in bone turnover. There were no significant differences between the treatment groups. Twelve per cent of women on transdermal or oral treatments lost a significant amount of bone from the femoral neck by 3 years despite adequate compliance. Women taking therapy primarily for hip fracture prevention may require a follow-up bone density measurement to establish the efficacy of treatment.

Castelo-Branco1999   Castelo-Branco C, Figueras F, Sanjuan A et al. Long-term compliance with estrogen replacement therapy in surgical postmenopausal women: benefits to bone and analysis of factors associated with discontinuation. Menopause 1999;6:307-11.

OBJECTIVE: To evaluate prospectively the effects of long-term estrogen replacement therapy (ERT) on bone density in surgical postmenopausal women treated for 5 years with two different modalities and to determine the factors associated with discontinuation of ERT. DESIGN: We included in the present study 165 women (mean age, 46.8 4.6 years) who had undergone surgical menopause. ERT was prescribed immediately after surgery, and bone mineral density was measured at the lumbar spine before the women entered the study and at 12, 24, 36, 48, and 60 months after being included. Treated patients were assigned at random to one of two groups. The first group received conjugated equine estrogens 0.625 mg/day continuously, and the second group received transdermal 17beta-estradiol 50 mg/day continuously. Treated groups were compared with a nontreated control group. RESULTS: Our data showed that although ERT clearly protected against bone loss in women who had experienced surgical menopause, only one third of the treated patients continued ERT at the end of follow-up. The main reason for discontinuation was fear of cancer (36.1 % of cases). In addition, no differences were observed between oral and transdermal groups of treatment. CONCLUSIONS: Long-term ERT may have a protective effect against bone loss in surgically postmenopausal women; however, two thirds of treated patients discontinued therapy after 5 years and 43% of them presented a negative balance on bone mass in one or more bone density assessments. For this reason, enhancing compliance and monitoring treatment are mandatory.

Nachtigall1979   Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM. Estrogen replacement therapy I: a 10-year prospective study in the relationship to osteoporosis. Obstet Gynecol 1979;53:277-81.

Lindsay1980   Lindsay R, Hart DM, Forrest C, Baird C. Prevention of osteoporosis in oophorectomised women. Lancet 1980;ii:1151-4.

100 women who had taken part in a prospective controlled trial of oestrogen therapy for prevention of post-oophorectomy bone loss were reviewed after a median follow-up period of nine years. A significant reduction in height occurred among the placebo-treated group, but not in the group treated with mestranol (mean 23 x 3 micrograms/day). The placebo-treated group had a higher spine score, lower central vertebral height, and larger wedge-angle than the oestrogen group. Within each group none of these spinal morphometric changes correlated with changes in mineral content of metacarpal or radial bones as measured by photon absorptiometry or X-ray densitometry, although both peripheral and central measurements showed highly significant differences between groups. Oestrogen treatment, therefore, prevents against central, as well as peripheral, bone loss, and reduces the incidence of vertebral compression.

Lufkin1992   Lufkin EG, Wahner HW, O’Fallon WM et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 1992;117:1-9.

OBJECTIVE: To evaluate the tolerance and effectiveness of transdermal estrogen for women with established postmenopausal osteoporosis and vertebral fractures. DESIGN: Double-blind, randomized, placebo-controlled clinical trial lasting 1 year. SETTING: Referral-based outpatient clinic. PATIENTS: Seventy-five postmenopausal women, 47 to 75 years of age, with one or more vertebral fractures due to osteoporosis. INTERVENTIONS: Thirty-nine women received dermal patches delivering 0.1 mg of 17 beta-estradiol for days 1 to 21 and oral medroxyprogesterone acetate for days 11 to 21 of a 28-day cycle. Another 39 women received placebo. MEASUREMENTS: Bone turnover assessed by biochemical markers and iliac bone histomorphometry; bone loss assessed by serial measurement of bone density; and vertebral fracture rate. RESULTS: Compared with the placebo group, the median annual percentage change in bone mineral density in the estrogen group reflected increased or steady-state bone mineral density at the lumbar spine (5.3 compared with 0.2; P = 0.007), femoral trochanter (7.6 compared with 2.1; P = 0.03), and midradius (1.0 compared with -2.6, P less than 0.001) but showed no significant difference at the femoral neck (2.6 compared with 1.4; P = 0.17). Estrogen treatment uniformly decreased bone turnover as assessed by several methods including serum osteocalcin concentration (median change, -0.35 compared with 0.02 nmol/L; P less than 0.001). Histomorphometric evaluation of iliac biopsy samples confirmed the effect of estrogen on bone formation rate per bone volume (median change, -12.9 compared with -6.2% per year; P = 0.004). Also, 8 new fractures occurred in 7 women in the estrogen group, whereas 20 occurred in 12 women in the placebo group, yielding a lower vertebral fracture rate in the estrogen group (relative risk, 0.39; 95% CI, 0.16 to 0.95). CONCLUSIONS: Transdermal estradiol treatment is effective in postmenopausal women with established osteoporosis.

Komulainen1998   Komulainen MH, Kröger H, Tuppurainen MT et al. HRT and Vitamin D in prevention of non-vertebral fractures in postmenopausal women. Maturitas 1998;31::45-54.

OBJECTIVES: We investigated the incidence of new non-vertebral fractures during HRT or low-dose vitamin (Vit) D3 supplementation in a 5-year prospective trial. METHODS: A total of 464 early postmenopausal women, (a subgroup of the Kuopio Osteoporosis Study, n = 13,100) were randomized to four groups: (1) HRT, a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate; (2) Vit D (300 IU/day and 100 IU/day during the fifth years); (3) HRT + Vit D; and (4) placebo. Lumbar (L2-4) and femoral neck bone mineral densities (BMD) were determined by dual X-ray absorptiometry (DXA) at baseline, after 2.5 and 5 years of treatment. All new symptomatic non-vertebral, radiographically defined fractures were recorded. RESULTS: Altogether, 368 women (79%) completed the 5 year treatment. In all, 32 women had 39 non-vertebral fractures during a mean of 4.3 year follow-up (HRT 4, Vit D 10, HRT + Vit D 8 and placebo 17). The reduction in the incidence of new non-vertebral fractures was significant in women with HRT alone (P = 0.032) when adjusted by baseline BMD and previous fractures; observed also with the intention-to-treat principle (P = 0.048). When the HRT groups were pooled, HRT showed a significantly lower incidence of new non-vertebral fractures (P = 0.042) than women receiving placebo and also after adjusting as above (P = 0.016); both in valid-case and in the intention-to-treat analysis. In the Vit D group, the fracture incidence was non-significantly decreased (P = 0.229) in comparison with the placebo group. The estimated risk of new non-vertebral fractures among women treated with HRT alone was 0.29 (95% CI, 0.10-0.90) and with Vit D 0.47 (95% CI, 0.20-1.14) and with HRT + Vit D 0.44 (95% CI, 0.17-1.15), in comparison with the placebo group (adjusted by femoral BMD and previous fractures). CONCLUSIONS: This study is the first prospective trial confirming the beneficial effect of HRT on prevention of peripheral fractures in non-osteoporotic postmenopausal women. The effect of low-dose Vit D remains to be proved.

Grady1992   Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016-37.

PURPOSE: To critically review the risks and benefits of hormone therapy for asymptomatic postmenopausal women who are considering long-term hormone therapy to prevent disease or to prolong life. DATA SOURCES: Review of the English-language literature since 1970 on the effect of estrogen therapy and estrogen plus progestin therapy on endometrial cancer, breast cancer, coronary heart disease, osteoporosis, and stroke. We used standard meta-analytic statistical methods to pool estimates from studies to determine summary relative risks for these diseases in hormone users and modified lifetable methods to estimate changes in lifetime probability and life expectancy due to use of hormone regimens. RESULTS: There is evidence that estrogen therapy decreases risk for coronary heart disease and for hip fracture, but long-term estrogen therapy increases risk for endometrial cancer and may be associated with a small increase in risk for breast cancer. The increase in endometrial cancer risk can probably be avoided by adding a progestin to the estrogen regimen for women who have a uterus, but the effects of combination hormones on risk for other diseases has not been adequately studied. We present estimates for changes in lifetime probabilities of disease and life expectancy due to hormone therapy in women who have had a hysterectomy; with coronary heart disease; and at increased risk for coronary heart disease, hip fracture, and breast cancer. CONCLUSIONS: Hormone therapy should probably be recommended for women who have had a hysterectomy and for those with coronary heart disease or at high risk for coronary heart disease. For other women, the best course of action is unclear.

Ettinger1994   Ettinger B, Grady D. Maximizing the Benefit of Estrogen Therapy for Prevention of Osteoporosis. Menopause 1994;1:19-24.

Postmenopausal hormone therapy to prevent osteoporosis is commonly started during menopause and often discontinued within 5-10 years. This approach may preserve bone density during use, but there is evidence that it does not preserve bone density or protect against osteoporotic fractures that occur late in life. We used data on the effects of hormone therapy on bone density and the association of bone density and fracture risk to estimate and compare the expected benefits of beginning therapy at menopause and continuing for the remainder of life, beginning therapy at menopause and stopping at age 65, and beginning hormone therapy at age 65 and continuing for the remainder of life. Compared to never users, women who use estrogen continuously beginning at menopause are predicted to have about 22% higher mean bone density between ages 75 and 85 and to reduce their risk of fracture about 73%. In contrast, women who begin therapy at menopause but stop at age 65 are predicted to have only about 8% higher mean bone density and to reduce their risk of fractures about 23% compared to never users. Those who start using estrogen at age 65 are predicted to have 14-19% higher mean bone density than never users and to reduce fracture risk 57-69%. Beginning hormone therapy later in life may provide almost as much protection against osteoporotic fractures as starting at menopause and would halve the period of hormone exposure, reducing the potential risks of very long-term estrogen therapy. Key Words: Estrogen-Fracture-Bone density-Osteoporosis.

Ettinger1999   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.

CONTEXT: Raloxifene hydrochloride, a selective estrogen receptor modulator, prevents bone loss in postmenopausal women, but whether it reduces fracture risk in these women is not known. OBJECTIVE: To determine the effect of raloxifene therapy on risk of vertebral and nonvertebral fractures. DESIGN: The Multiple Outcomes of Raloxifene Evaluation (MORE) study, a multicenter, randomized, blinded, placebo-controlled trial. SETTING AND PARTICIPANTS: A total of 7705 women aged 31 to 80 years in 25 countries who had been postmenopausal for at least 2 years and who met World Health Organization criteria for having osteoporosis. The study began in 1994 and had up to 36 months of follow-up for primary efficacy measurements and nonserious adverse events and up to 40 months of follow-up for serious adverse events. INTERVENTIONS: Participants were randomized to 60 mg/d or 120 mg/d of raloxifene or to identically appearing placebo pills; in addition, all women received supplemental calcium and cholecalciferol. MAIN OUTCOME MEASURES: Incident vertebral fracture was determined radiographically at baseline and at scheduled 24- and 36-month visits. Nonvertebral fracture was ascertained by interview at 6-month-interim visits. Bone mineral density was determined annually by dual-energy x-ray absorptiometry. RESULTS: At 36 months of the evaluable radiographs in 6828 women, 503 (7.4%) had at least 1 new vertebral fracture, including 10.1% of women receiving placebo, 6.6% of those receiving 60 mg/d of raloxifene, and 5.4% of those receiving 120 mg/d of raloxifene. Risk of vertebral fracture was reduced in both study groups receiving raloxifene (for 60-mg/d group: relative risk RR , 0.7; 95% confidence interval CI , 0.5-0.8; for 120-mg/d group: RR, 0.5; 95% CI, 0.4-0.7). Frequency of vertebral fracture was reduced both in women who did and did not have prevalent fracture. Risk of nonvertebral fracture for raloxifene vs placebo did not differ significantly (RR, 0.9; 95% CI, 0.8-1.1 for both raloxifene groups combined). Compared with placebo, raloxifene increased bone mineral density in the femoral neck by 2.1 % (60 mg) and 2.4% (120 mg) and in the spine by 2.6% (60 mg) and 2.7% (120 mg) P 0.001 for all comparisons). (abbreviated)

Ettinger1999b   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.

CONTEXT: Raloxifene hydrochloride, a selective estrogen receptor modulator, prevents bone loss in postmenopausal women, but whether it reduces fracture risk in these women is not known. OBJECTIVE: To determine the effect of raloxifene therapy on risk of vertebral and nonvertebral fractures. DESIGN: The Multiple Outcomes of Raloxifene Evaluation (MORE) study, a multicenter, randomized, blinded, placebo-controlled trial. SETTING AND PARTICIPANTS: A total of 7705 women aged 31 to 80 years in 25 countries who had been postmenopausal for at least 2 years and who met World Health Organization criteria for having osteoporosis. The study began in 1994 and had up to 36 months of follow-up for primary efficacy measurements and nonserious adverse events and up to 40 months of follow-up for serious adverse events. INTERVENTIONS: Participants were randomized to 60 mg/d or 120 mg/d of raloxifene or to identically appearing placebo pills; in addition, all women received supplemental calcium and cholecalciferol. MAIN OUTCOME MEASURES: Incident vertebral fracture was determined radiographically at baseline and at scheduled 24- and 36-month visits. Nonvertebral fracture was ascertained by interview at 6-month-interim visits. Bone mineral density was determined annually by dual-energy x-ray absorptiometry. RESULTS: At 36 months of the evaluable radiographs in 6828 women, 503 (7.4%) had at least 1 new vertebral fracture, including 10.1% of women receiving placebo, 6.6% of those receiving 60 mg/d of raloxifene, and 5.4% of those receiving 120 mg/d of raloxifene. Risk of vertebral fracture was reduced in both study groups receiving raloxifene (for 60-mg/d group: relative risk RR , 0.7; 95% confidence interval CI , 0.5-0.8; for 120-mg/d group: RR, 0.5; 95% CI, 0.4-0.7). Frequency of vertebral fracture was reduced both in women who did and did not have prevalent fracture. Risk of nonvertebral fracture for raloxifene vs placebo did not differ significantly (RR, 0.9; 95% CI, 0.8-1.1 for both raloxifene groups combined). Compared with placebo, raloxifene increased bone mineral density in the femoral neck by 2.1 % (60 mg) and 2.4% (120 mg) and in the spine by 2.6% (60 mg) and 2.7% (120 mg) P 0.001 for all comparisons). (abbreviated)

Berning1996   Berning B, Kuijk CV, Kuiper JW, Coelingh Bennink HJT, Kicovic PM, Fauser BCJM. Effects of two doses of tibolone on trabecular and cortical bone loss in early postmenopausal women: a two-year randomized placebo-controlled study. Bone 1996;19:395-9.

The present randomized, double-blind, placebo-controlled, 2-year study is the first to evaluate the effect of 1.25 and 2.5 mg tibolone daily oral administration on trabecular and cortical bone loss in early postmenopausal women. Ninety-four healthy, normal weight, nonsmoking women participated 1-3 years following spontaneous menopause. Twenty-three subjects were randomized to the placebo group, 36 to the 1.25 mg/day tibolone group, and 35 to the 2.5 mg/day tibolone group. Bone density was assessed at 6 month intervals. Spinal trabecular bone density (BD) was measured with quantitative computed tomography. Phalangeal cortical BD was measured by radiographic absorptiometry. The 2-year change vs. baseline in the placebo group for trabecular BD was -6.4% (95% confidence interval -8.1 to -4.7). Cortical BD did not change significantly. At 24 months both tibolone groups showed a statistically significantly higher trabecular 9.4% (6.6-12.2) for the 1.25 mg group and 14.7% (11.8-17.5%) for the 2.5 mg group and phalangeal BD 4.4% (1.5-7.4) for the 1.25 mg group and 6.8% (3.8-9.8) for the 2.5 mg group as compared to the placebo group. After 2 years of tibolone in both regimes, trabecular and phalangeal BD was significantly higher as compared to pretreatment values. At 24 months the 2.5 mg group showed a significantly higher trabecular (p  0.001) but not phalangeal (p = 0.064) BD compared to the 1.25 mg group. Tibolone prevents early postmenopausal bone loss by inducing an increase in trabecular and phalangeal BD.

Bjarnason1996   Bjarnason NH, Bjarnason K, Haarbo J, Rosenquist C, Christiansen C. Tibolone: prevention of bone loss in late postmenopausal women. J Clin Endocrinol Metab 1996;81:2419-22.

The aim of the study was to assess the effects of 2 yr of treatment with two dose levels of tibolone on bone mineral density and bio-chemical markers of bone metabolism in late postmenopause. Ninety-one healthy women, more than 10 yr after menopause, entered a 2-yr double blind, randomized, placebo-controlled study of treatment with either 1.25 mg/day (n = 36) or 2.5 mg/day (n = 35) Tibolone or placebo (n = 20). Densitometry and determinations of biochemical markers of bone metabolism in serum and urine were performed before randomization and every 3 months during the study. The results revealed a steady and equal increase in bone mineral density in both tibolone groups at the bone sites studied. Gains in BMD spine of 5.9 0.9% in the 1.25 mg group, 5.1 0.9% in the 2.5 mg group, and 0.4 1.1% in the placebo group were found. In the forearm, increases of 2.2 0.7% in the 1.25 mg group and 1.9 1.1% in the 2.5 mg group were detected, whereas the placebo group lost 2.1 1.0%. This was fully supported by changes in biochemical markers of bone resorption (urinary excretion of fragments from the osteoclastic degradation of the alpha 1-chain of the C telopeptides of type 1 collagen and hydroxyproline) and bone formation (serum osteocalcin), respectively. In conclusion, within 2 yr of treatment, tibolone increases bone mass in the spine and prevents bone loss in the forearm in late postmenopausal women determined by densitometry and several biochemical parameters of bone turnover. Tibolone at two doses (1.25 and 2.5 mg/day) had similar effects, indicating that even lower doses may be efficacious.

Studd1998   Studd J, Arnala I, Kkicovic PM, Kröger H, Holland N. A randomized study of tibolone on bone mineral density in osteoporotic postmenopausal women with previous fractures. Obstet Gynecol 1998;92:574-9.

OBJECTIVE: To investigate the effects of tibolone on trabecular and cortical bone mineral density and on indices of calcium metabolism in postmenopausal women with previous fractures. METHODS: In a 2-year, randomized, double-blind, placebo-controlled, bicenter study, 45 women were treated with tibolone and 43 with placebo. All subjects received 800 mg of calcium daily. Trabecular bone mineral density of lumbar spine (L1 to L4) and cortical bone mass at the femoral neck were assessed by dual energy x-ray absorptiometry at baseline and at 6-month intervals. Serum and urinary bone biochemistry variables were also assessed. RESULTS: After 2 years, subjects in the tibolone group gained 6.9% bone mass at lumbar spine and 4.5% at femoral neck, and respective increases from baseline in the placebo group were 2.7% and 1.4%. Tibolone-treated patients gained statistically significantly more bone mass than placebo-treated patients in the spine and femur. Urinary calcium: creatinine and hydroxyproline:creatinine ratios, as well as serum alkaline phosphatase and phosphate levels, were significantly reduced with tibolone compared with placebo. CONCLUSION: Tibolone induced a significant increase in trabecular (lumbar spine) and cortical (femoral neck) bone mass in postmenopausal osteoporotic women compared to placebo, suggesting its potential to treat postmenopausal osteoporosis.

Gallagher2001 Gallagher JC, Baylink DJ, Freeman R, McClung M.Prevention of bone loss with tibolone in postmenopausal women: results of two randomized, double-blind, placebo-controlled, dose-finding studies. J Clin Endocrinol Metab 2001;86:4717-26

Tibolone, a novel compound with tissue-specific effects, has been found to have antiresorptive properties in bone. To confirm the efficacy of tibolone and determine its minimum effective dose for prevention of bone loss in early postmenopausal women, two randomized, double-blind, placebo-controlled, dose-finding studies were performed. Seven hundred seventy healthy women postmenopausal within 1-4 yr, with normal bone density for their age, were treated for 2 yr with 0.3, 0.625, 1.25, or 2.5 mg tibolone daily or placebo. All subjects took supplemental calcium carbonate (500 mg daily). Bone mineral density (BMD) of the lumbar spine and right proximal femur was measured by dual-energy x-ray absorptiometry for up to 2 yr. At each dose level, except the lowest (0.3 mg), tibolone produced a progressive increase in lumbar spine and total hip BMD over the 2-yr treatment period; at 0.3 mg, total hip density was maintained. However, only the doses 1.25 mg and 2.5 mg produced a progressive increase in femoral neck BMD. The differences in mean percent change from baseline in spine and total hip density were significant (P < 0.05) for all tibolone dose groups compared with placebo at all time points. Tibolone was well tolerated, with a similar overall incidence of adverse events compared with placebo. Tibolone 1.25 mg per day is recommended because it shows a positive and statistically significant change in BMD of spine and femoral neck.

Watts1990   Watts NB, Harris ST, Genant HK et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 1990;323:73-9.

BACKGROUND. To determine the effects of etidronate (a bisphosphonate that inhibits osteoclast-mediated bone resorption) in the treatment of postmenopausal osteoporosis, we conducted a prospective, two-year, double-blind, placebo-controlled, multicenter study in 429 women who had one to four vertebral compression fractures plus radiographic evidence of osteopenia. METHODS. The patients were randomly assigned to treatment with phosphate (1.0 g) or placebo twice daily on days 1 through 3, etidronate (400 mg) or placebo daily on days 4 through 17, and supplemental calcium (500 mg) daily on days 18 through 91 (group 1, placebo and placebo; group 2, phosphate and placebo; group 3, placebo and etidronate; and group 4, phosphate and etidronate). The treatment cycles were repeated eight times. The bone density of the spine was measured by dual-photon absorptiometry, and the rates of new vertebral fractures were determined from sequential radiographs. RESULTS. After two years, the patients receiving etidronate (groups 3 and 4) had significant increases in their mean ( SE) spinal bone density (4.2 0.8 percent and 5.2 0.7 percent, respectively; P less than 0.017). The rate of new vertebral fractures was reduced by half in the etidronate-treated patients (groups 3 and 4 combined) as compared with the patients who did not receive etidronate (groups 1 and 2 combined) (29.5 vs. 62.9 fractures per 1000 patient-years; P = 0.043); the effect of treatment was most striking in the subgroup of patients with the lowest spinal bone mineral density at base line, in whom fracture rates were reduced by two thirds (42.3 vs. 132.7 fractures per 1000 patient-years; P = 0.004). The addition of phosphate provided no apparent benefit. There were no significant adverse effects of treatment. CONCLUSIONS. Intermittent cyclical therapy with etidronate for two years significantly increases spinal bone mass and reduces the incidence of new vertebral fractures in women with postmenopausal osteoporosis.

Storm1990   Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 1990;322:1265-71.

Progressive bone loss in osteoporosis results from bone resorption in excess of bone formation. We conducted a double-blind study in 66 women with postmenopausal osteoporosis of therapy with etidronate, a diphosphonate compound that reduces bone resorption by inhibiting osteoclastic activity. The patients were randomly assigned in equal numbers to receive oral etidronate (400 mg per day) or placebo for 2 weeks, followed by a 13-week period in which no drugs were given. This sequence was repeated 10 times, for a total of 150 weeks. Daily oral supplementation with calcium and vitamin D was given throughout the study to both groups. Vertebral bone mineral content was measured by dual-photon absorptiometry; spinal radiographs were assessed to identify new vertebral fractures. Vertebral bone mineral content increased significantly (P less than 0.01) after 150 weeks of etidronate therapy (5.3 percent; 95 percent confidence interval, 2.0 to 8.6; n = 20) but decreased with placebo (-2.7 percent; 95 percent confidence interval, -7.3 to 1.9; n = 20). The difference between groups was 8.0 percentage points (P less than 0.01; 95 percent confidence interval, 2.4 to 13.6). The rates of fracture were significantly different for the period from week 60 to week 150 between the etidronate and placebo groups (6 vs. 54 fractures per 100 patient-years; P = 0.023). No adverse clinical, biochemical, or bone histomorphometric effects of treatment were observed. We conclude that at the end of nearly three years, etidronate therapy for postmenopausal osteoporosis results in significant increases in vertebral bone mineral content and, after approximately one year of treatment, a significant decrease in the rate of new vertebral fractures.

Liberman1995   Liberman UA, Weiss SR, Broll J et al. Effect of oral alendronate on bone mineral density and the incidece of fractures in postmneopausal osteoporosis. N Egl J Med 1995;333:1437-43.

BACKGROUND. Postmenopausal osteoporosis is a serious health problem, and additional treatments are needed. METHODS. We studied the effects of oral alendronate, an aminobisphosphonate, on bone mineral density and the incidence of fractures and height loss in 994 women with postmenopausal osteoporosis. The women were treated with placebo or alendronate (5 or 10 mg daily for three years, or 20 mg for two years followed by 5 mg for one year); all the women received 500 mg of calcium daily. Bone mineral density was measured by dual-energy x-ray absorptiometry. The occurrence of new vertebral fractures and the progression of vertebral deformities were determined by an analysis of digitized radiographs, and loss of height was determined by sequential height measurements. RESULTS. The women receiving alendronate had significant, progressive increases in bone mineral density at all skeletal sites, whereas those receiving placebo had decreases in bone mineral density. At three years, the mean ( SE) differences in bone mineral density between the women receiving 10 mg of alendronate daily and those receiving placebo were 8.8 0.4 percent in the spine, 5.9 0.5 percent in the femoral neck, 7.8 0.6 percent in the trochanter, and 2.5 0.3 percent in the total body (P  0.001 for all comparisons). The 5-mg dose was less effective than the 10-mg dose, and the regimen of 20 mg followed by 5 mg was similar in efficacy to the 10-mg dose. Overall, treatment with alendronate was associated with a 48 percent reduction in the proportion of women with new vertebral fractures (3.2 percent, vs. 6.2 percent in the placebo group; P = 0.03), a decreased progression of vertebral deformities (33 percent, vs. 41 percent in the placebo group; P = 0.028), and a reduced loss of height (P = 0.005) and was well tolerated. CONCLUSIONS. Daily treatment with alendronate progressively increases the bone mass in the spine, hip, and total body and reduces the incidence of vertebral fractures, the progression of vertebral deformities, and height loss in postmenopausal women with osteoporosis.

Ensrud1997   Ensrud KE, Black DM, Palermo L et al. Treatment with alendronate prevents fractures in women at highest risk. Results from the Fracture Intervention Trial. Arch Intern Med 1997;157:2617-24.

BACKGROUND: The efficacy of antiresorptive therapy in preventing fractures in women at highest fracture risk, such as very elderly women or those with severe osteoporosis, is uncertain. PARTICIPANTS AND METHODS: Using data from a double-blind, randomized, placebo-controlled clinical trial that enrolled 2027 postmenopausal women aged 55 to 81 years with low femoral neck bone mineral density (BMD) and existing vertebral fractures, we examined the consistency of the effect of treatment with alendronate sodium in preventing fractures within a priori-specified risk subgroups defined at baseline by age, bone density, number of preexisting vertebral fractures, and history of postmenopausal fracture. The women were randomized to oral administration of alendronate or placebo and followed up for an average of 2.9 years. The initial dose of alendronate sodium was 5 mg/d; the dosage was increased from 5 to 10 mg/d at 24 months. New vertebral fractures, the primary end point of this arm of the trial, were defined by morphometry as a decrease of 20% and at least 4 mm in any vertebral height between baseline and a follow-up radiograph at 36 months. Incident clinical fractures, the secondary end point, included nonspine and clinical (symptomatic) vertebral fractures. All clinical fractures were confirmed with x-ray film reports or, in the case of clinical vertebral fractures, x-ray films. RESULTS: Overall, there was a 47% significant reduction in risk of new vertebral fractures in the alendronate group compared with the placebo group. The reduction in risk of new vertebral fracture was consistent across fracture risk categories including age (relative risk RR , 0.49 in women  75 years compared with 0.62 in those  or = 75 years), BMD (RR, 0.54 in women with a femoral neck BMD  0.59 g/cm2 median compared with 0.53 in those with a BMD  or = 0.59 g/cm2), and number of preexisting vertebral fractures (RR, 0.58 in women with 1 vertebral fracture compared with 0.52 in those with  or = 2). The overall significant 28% reduction in risk of incident clinical fractures in the alendronate group compared with the placebo group was also observed within these subgroups. Compared with the number of lower-risk women, a similar or smaller number of high-risk women needed to be treated to prevent 1 fracture. For example, 8 women aged 75 years or older compared with 9 women younger than 75 years, or 4 women with 2 or more existing vertebral fractures compared with 16 women with 1 existing vertebral fracture, needed to be treated with alendronate for 5 years to prevent 1 new vertebral fracture. (abbreviated)

Cummings1998a   Cummings SR, Black DM, Thompson DE et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280:2077-82.

CONTEXT: Alendronate sodium reduces fracture risk in postmenopausal women who have vertebral fractures, but its effects on fracture risk have not been studied for women without vertebral fractures. OBJECTIVE: To test the hypothesis that 4 years of alendronate would decrease the risk of cli