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Osteoporosis is an increased porosity of the skeleton resulting from a reduction in bone mass. It affects both sexes but is especially cruel to women. In 1995, it was estimated that total direct medical expenditure in the United States for treatment of osteoporotic fractures in adults older than 45 years was $13.8 billion. Clearly prevention is the key in preventing the horrible consequences of this disease. A number of biochemical markers and sophisticated tests have been used to screen for individuals at risk.


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INCIDENCE 14 million American women over the age of 50
AGE RANGE-MEDIAN 70% of women over age 80
Prevalence in African-American women is half that in Caucasian and Mexican-American

Bone mineral density in elderly men and women: results from the Framingham osteoporosis study.

Hannan MT, Felson DT, Anderson JJ.

Boston University Arthritis Center, Massachusetts.

J Bone Miner Res 1992 May;7(5):547-53 Abstract quote

Our study investigated bone mineral density of the proximal femur and ultradistal and proximal radius in a population of elderly men and women. The Framingham study started in 1948, following a population-based sample for evaluation of cardiovascular risk factors and events.

During the 20th biennial Framingham examination (1988-89) we conducted the Framingham osteoporosis study, measuring bone mineral density in the proximal femur and distal and proximal radius for 1154 study participants. Ages ranged from 68 to 98 years, with a mean age of 76 years. Bone mineral density was measured using Lunar SP2 and DP3 densitometers. This cross-sectional study evaluates mean bone mineral density measurements at each site by 5 year age intervals for men and women, testing for trends in bone density with age. Analyses were repeated adjusting for weight and height. Among the 446 and 708 women, bone mineral density of the femur and bone mineral content of the proximal radius were inversely and significantly related to age in both sexes and were considerably higher in men than women at all sites.

The linear decline with age group in our cross-sectional study remained after multivariate adjustment for height and weight. The ultradistal radius showed no significant correlation with age for either sex.

There were significant correlations between the bone measurements made at different sites for both men and women (range in r = 0.27-0.89). Cross-sectional curves of bone mineral density with age showed no significant differences in slope between males and females.

Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study.

Hannan MT, Felson DT, Dawson-Hughes B, Tucker KL, Cupples LA, Wilson PW, Kiel DP.

Hebrew Rehabilitation Center for Aged, Research and Training Institute, Boston, Massachusetts 02131-1097, USA.

J Bone Miner Res 2000 Apr;15(4):710-20 Abstract quote

Few studies have evaluated risk factors for bone loss in elderly women and men. Thus, we examined risk factors for 4-year longitudinal change in bone mineral density (BMD) at the hip, radius, and spine in elders.

Eight hundred elderly women and men from the population-based Framingham Osteoporosis Study had BMD assessed in 1988-1989 and again in 1992-1993. BMD was measured at femoral neck, trochanter, Ward's area, radial shaft, ultradistal radius, and lumbar spine using Lunar densitometers. We examined the relation of the following factors at baseline to percent BMD loss: age, weight, change in weight, height, smoking, caffeine, alcohol use, physical activity, serum 25-OH vitamin D, calcium intake, and current estrogen replacement in women. Multivariate regression analyses were conducted with simultaneous adjustment for all variables. Mean age at baseline was 74 years +/-4.5 years (range, 67-90 years). Average 4-year BMD loss for women (range, 3.4-4.8%) was greater than the loss for men (range, 0.2-3.6%) at all sites; however, BMD fell with age in both elderly women and elderly men.

For women, lower baseline weight, weight loss in interim, and greater alcohol use were associated with BMD loss. Women who gained weight during the interim gained BMD or had little change in BMD. For women, current estrogen users had less bone loss than nonusers; at the femoral neck, nonusers lost up to 2.7% more BMD.

For men, lower baseline weight and weight loss also were associated with BMD loss. Men who smoked cigarettes at baseline lost more BMD at the trochanter site. Surprisingly, bone loss was not affected by caffeine, physical activity, serum 25-OH vitamin D, or calcium intake.

Risk factors consistently associated with bone loss in elders include female sex, thinness, and weight loss, while weight gain appears to protect against bone loss for both men and women.

This population-based study suggests that current estrogen use may help to maintain bone in women, whereas current smoking was associated with bone loss in men. Even in the elderly years, potentially modifiable risk factors, such as weight, estrogen use, and cigarette smoking are important components of bone health.


Sex difference in the validity of vertebral deformities as an index of prevalent vertebral osteoporotic fractures: a population survey of older men and women.

Leidig-Bruckner G, Limberg B, Felsenberg D, Bruckner T, Holder S, Kather A, Miksch J, Wuster C, Ziegler R, Scheidt-Nave C.

Department of Internal Medicine I, Endocrinology and Metabolism, University of Heidelberg, Germany

Osteoporos Int 2000;11(2):102-19 Abstract quote

Morphometric methods have been developed for standardized assessment of vertebral deformities in clinical and epidemiologic studies of spinal osteoporosis. However, vertebral deformity may be caused by a variety of other conditions.

To examine the validity of morphometrically assessed vertebral deformities as an index of osteoporotic vertebral fractures, we developed an algorithm for radiological differential classification (RDC) based on a combination of quantitative and qualitative assessment of lateral spinal radiographs.

Radiographs were obtained in a population of 50- to 80-year-old German women (n = 283) and men (n = 297) surveyed in the context of the European Vertebral Osteoporosis Study (EVOS). Morphometric methods (Eastell 3 SD and 4 SD criteria, McCloskey) were validated against RDC and against bone mineral density (BMD) at the femur and the lumbar spine. According to RDC 36 persons (6.2%) had at least one osteoporotic vertebral fracture; among 516 (88.9%) nonosteoporotics 154 had severe spondylosis, 132 had other spinal disease and 219 had normal findings; 14 persons (2.4%) could not be unequivocally classified.

The prevalence of morphometrically assessed vertebral deformities ranged from 7.3% to 19.2% in women and from 3.5% to 16.6% in men, depending on the stringency of the morphometric criteria. The agreement between RDC and morphometric methods was poor. In men, 62-86% of cases with vertebral deformities were classified as nonosteoporotic (severe spondylosis or other spinal disease) by RDC, compared with 31-68% in women. Among these, most had wedge deformities of the thoracic spine. On the other hand, up to 80% of osteoporotic vertebral fractures in men and up to 48% in women were missed by morphometry, in particular endplate fractures at the lumbar spine. In the group with osteoporotic vertebral fractures by RDC the proportion of persons with osteoporosis according to the WHO criteria (T-score < -2.5 SD) was 90.0% in women and 86.6% in men, compared with 67.9-85.0% in women and 20.8-50.0% in men with vertebral deformities by various methods.

Although vertebral deformities by most definitions were significantly and inversely related to BMD as a continuous variable in both sexes [OR; 95% CI ranged between (1.70; 1.07-2.70) and (3.69; 1.33-10.25)], a much stronger association existed between BMD and osteoporotic fractures defined by RDC [OR; 95% CI between (4.85; 2.30-10.24) and (15.40; 4.65-51.02)]. In the nonosteoporotic group individuals with severe spondylosis had significantly higher BMD values at the femoral neck (p < 0.01) and lumbar spine (p < 0.0004) compared with the normal group.

On the basis of internal (RDC) and external (BMD) validation, we conclude that assessment of vertebral osteoporotic fracture by quantitative methods alone will result in considerable misclassification, especially in men. Criteria for differential diagnosis as used within RDC can be helpful for a standardized subclassification of vertebral deformities in studies of spinal osteoporosis.


Primary Postmenopausal
Pituitary tumors
Diabetes, type I
Addison disease
Multiple myeloma
Hepatic insufficiency
Vitamin C, D deficiencies
Rheumatologic disease
Osteogenesis imperfecta
Pulmonary disease

Bone mineral density and fracture among prevalent kidney stone cases in the Third National Health and Nutrition Examination Survey.

Lauderdale DS, Thisted RA, Wen M, Favus MJ.

Department of Health Studies, University of Chicago, Illinois 60637, USA.

J Bone Miner Res 2001 Oct;16(10):1893-8 Abstract quote

Concern that people who form kidney stones may have reduced bone mineral density (BMD) and increased fracture risk has motivated clinical and population-based studies, but findings are inconsistent.

In this cross-sectional study, we use the Third National Health and Nutrition Examination Survey (NHANES III) to determine whether a history of kidney stones (n = 793) is associated with lower femoral neck BMD and whether the association is similar for men and women. We further ask whether dietary calcium modifies the association between kidney stone history and BMD and whether there is an association between kidney stone history and prevalent spine or wrist fracture.

We find that men with kidney stone history have lower femoral neck BMD than men without kidney stone history after adjusting for age, body mass index (BMI), race/ethnicity, and other potential confounders. The effect of kidney stone history on BMD is weaker for women. Men with kidney stone history also are more likely to report prevalent wrist and spine fractures. Dietary calcium, represented by usual milk consumption, is associated positively with BMD for both men and women and modifies the effect of kidney stone history on BMD for men.

For men who form kidney stones, milk consumption is associated more strongly with femoral neck BMD than for men without such a history. The effect modification is such that the difference in BMD between men with and without kidney stone history is observed only at lower levels of milk consumption.


Age related changes Osteoblasts have reduced reproductive and biosynthetic potential
Proteins bound to extracellular matrix become less active
Reduced physical activity Increases rate of bone loss
Genetic factors Polymorphism in the vitamin D receptor
Nutritional state Most adolescent girls have insufficient calcium intake
Hormonal influences

After menopause, yearly bone mass reduction may reach 2% of cortical bone and 9% of cancellous bone

Within 30-40 years following menopause, women may lose 35% of cortical bone and 50% of trabecular bone

Largely due to estrogen deficiency-leads to increased IL1, IL6, and TNF-alpha with stimulate osteoclast recruitment and activity

Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes.

Ioannidis JP, Ralston SH, Bennett ST, Brandi ML, Grinberg D, Karassa FB, Langdahl B, van Meurs JB, Mosekilde L, Scollen S, Albagha OM, Bustamante M, Carey AH, Dunning AM, Enjuanes A, van Leeuwen JP, Mavilia C, Masi L, McGuigan FE, Nogues X, Pols HA, Reid DM, Schuit SC, Sherlock RE, Uitterlinden AG; GENOMOS Study.

Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
JAMA. 2004 Nov 3;292(17):2105-14. Abstract quote  

CONTEXT: Both bone mineral density (BMD) and fracture risk have a strong genetic component. Estrogen receptor alpha (ESR1) is a candidate gene for osteoporosis, but previous studies of ESR1 polymorphisms in this field were hampered by small sample size, lack of standardization, and inconclusive results.

OBJECTIVE: To generate large-scale evidence on whether 3 common ESR1 polymorphisms (intron 1 polymorphisms XbaI [dbSNP: rs9340799] and PvuII [dbSNP: rs2234693] and promoter TA repeats microsatellite) and haplotypes thereof are associated with BMD and fractures.

DESIGN AND SETTING: Meta-analysis of individual-level data involving standardized genotyping of 18 917 individuals in 8 European centers.

MAIN OUTCOME MEASURES: BMD of femoral neck and lumbar spine; all fractures and vertebral fractures by genotype.

RESULTS: No between-center heterogeneity was observed for any outcome in any genetic contrast. None of the 3 polymorphisms or haplotypes had any statistically significant effect on BMD in adjusted or unadjusted analyses, and estimated differences between genetic contrasts were 0.01 g/cm2 or less. Conversely, we found significant reductions in fracture risk. In women homozygous for the absence of an XbaI recognition site, the adjusted odds of all fractures were reduced by 19% (odds ratio, 0.81 [95% CI, 0.71-0.93]; P = .002) and vertebral fractures by 35% (odds ratio, 0.65 [95% CI, 0.49-0.87]; P = .003). Effects on fractures were independent of BMD and unaltered in adjusted analyses. No significant effects on fracture risk were seen for PvuII and TA repeats.

CONCLUSIONS: ESR1 is a susceptibility gene for fractures, and XbaI determines fracture risk by mechanisms independent of BMD. Our study demonstrates the value of adequately powered studies with standardized genotyping and clinical outcomes in defining effects of common genetic variants on complex diseases.

A Mutation in the LDL Receptor-Related Protein 5 Gene Results in the Autosomal Dominant High-Bone-Mass Trait.

Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braunschweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, Nogues X, Gong G, Allen KM, Anisowicz A, Morales AJ, Lomedico PT, Recker SM, Van Eerdewegh P, Recker RR, Johnson ML.

Department of Human Genetics, Genome Therapeutics Corporation, Waltham, MA, USA. .

Am J Hum Genet 2002 Jan;70(1):11-19 Abstract quote

Osteoporosis is a complex disease that affects >10 million people in the United States and results in 1.5 million fractures annually. In addition, the high prevalence of osteopenia (low bone mass) in the general population places a large number of people at risk for developing the disease.

In an effort to identify genetic factors influencing bone density, we characterized a family that includes individuals who possess exceptionally dense bones but are otherwise phenotypically normal. This high-bone-mass trait (HBM) was originally localized by linkage analysis to chromosome 11q12-13. We refined the interval by extending the pedigree and genotyping additional markers. A systematic search for mutations that segregated with the HBM phenotype uncovered an amino acid change, in a predicted beta-propeller module of the low-density lipoprotein receptor-related protein 5 (LRP5), that results in the HBM phenotype. During analysis of >1,000 individuals, this mutation was observed only in affected individuals from the HBM kindred. By use of in situ hybridization to rat tibia, expression of LRP5 was detected in areas of bone involved in remodeling.

Our findings suggest that the HBM mutation confers a unique osteogenic activity in bone remodeling, and this understanding may facilitate the development of novel therapies for the treatment of osteoporosis.


Vitamin D receptor gene polymorphisms, bone mass, bone loss and prevalence of vertebral fracture: differences in postmenopausal women and men.

Gomez C, Naves ML, Barrios Y, Diaz JB, Fernandez JL, Salido E, Torres A, Cannata JB.

Bone and Mineral Research Unit, Instituto Reina Sofia de Investigacion, Hospital Central de Asturias, Oviedo

Osteoporos Int 1999;10(3):175-82 Abstract quote

Bone mineral density (BMD), the major determinant of fracture risk, is under strong genetic control. Although polymorphisms of the vitamin D receptor (VDR) gene have been suggested to account for some of the genetic variation in bone mass, the influence of VDR genotypes on osteoporosis remains controversial. Previous published studies have focused mainly on women, but the pattern of response in men has not been determined.

Using the BsmI restriction enzyme, we studied the influence of the different VDR genotypes on bone mass, bone loss and the prevalence of vertebral fractures in a population-based sample of both sexes (n = 326). BMD was measured at the lumbar spine and femoral neck, with a 4-year interval, using dual-energy X-ray absorptiometry. Vertebral fractures were assessed by two lateral radiographs at the beginning and end of the study.

The prevalence of the three possible VDR genotypes was similar to those in other Caucasian populations and no differences were found between men and women. Women with the favorable bb genotype showed significantly higher BMD values at the lumbar spine and femoral neck, and a positive rate of BMD change at the femoral neck compared with women with the BB and Bb genotypes. Moreover, women with the bb genotype showed a trend toward a lower prevalence and incidence of vertebral fractures (p = 0.07). We have not found any differences between VDR genotypes in men.

In conclusion, VDR gene polymorphisms are related to bone mass and bone loss in women; also a trend in the prevalence of vertebral fractures was observed in postmenopausal women but not in men.



Radiographs Cannot be reliably detected until 30-40% of bone mass is lost
CT scan and MRI  

High-Resolution Three-Dimensional Micro-Computed Tomography Detects Bone Loss and Changes in Trabecular Architecture Early: Comparison with DEXA and Bone Histomorphometry in a Rat Model of Disuse Osteoporosis.

Barou O, Valentin D, Vico L, Tirode C, Barbier A, Alexandre C, Lafage-Proust MH.

Laboratoire de Biologie et de Biochimie du Tissu Osseux, Equipe Mixte INSERM 9901, Faculte de Medecine, Saint-Etienne; and Departement de Pharmacologie Generale, SANOFI Recherche, Montpellier, France. Barou O, Valentin D, Vico L, et al.

Invest Radiol 2002 Jan;37(1):40-46 Abstract quote

RATIONALE AND OBJECTIVES: The ability of three-dimensional micro-computed tomography (3D-&mgr;CT) to detect changes in a rat model of disuse osteoporosis was evaluated and compared with two reference techniques: dual x-ray absorptiometry (DEXA) for bone mass, and bone histomorphometry (BHM) for bone mass and trabecular micro-architecture.

METHODS: Forty-two rats were divided into controls or were hindlimb unloaded for 7, 13, and 23 days. DEXA bone mineral density measurements were performed on right tibiae. Then, after plastic embedding, bone volume (BV/TV) and trabecular (Tb)-derived parameters of trabecular bone architecture (Tb Th, thickness; Tb N, number) were measured with BHM. 3D-&mgr;CT measurements of BV/TV, Tb Th, and Tb N were carried out on left tibiae.

RESULTS: Unloaded rats lost bone in a time-dependent manner. DEXA and 3D-&mgr;CT detected bone loss earlier than BHM. The decreases in Tb Th and Tb N were observed at day 13 only with 3D-&mgr;CT (P < 0.05 and P < 0.01, respectively). All bone mass and architectural parameters measured with the three techniques correlated significantly (0.59, 0.89, P < 0.001), except Tb Th.

CONCLUSIONS: 3D-&mgr;CT is a valid technique for bone mass and micro-architecture measurements in this rat model of disuse osteoporosis.

Laboratory Markers

AHRQ Evidence Report/Technology Assessment: Number 28, Osteoporosis in Postmenopausal Women: Diagnosis and Monitoring Summary

"No single marker or cluster of markers accurately identified individuals who had osteoporosis, as determined by the results of densitometry. It is not suprising that agreement between the two tests was poor. Densitometry measures current bone status, whereas markers measure the process of bone turnover.

No marker was associated with increased fracture risk consistently across all studies. One study [in older women] provides evidence that using markers in conjunction with densitometry may increase predictability, but this result has not been otherwise confirmed.

Studies correlating marker results and bone loss indicated no clear trend. Furthermore, the sensitivity and specificity of the markers were too low to be useful for the purpose of selecting patients for treatment.

Some studies found better test accuracy when a combination of two or more markers and/or other risk factors were used to predict bone loss.

There is a small correlation between response to therapy as measured by densitometry and marker results, but no marker is accurate enough to reliably identify those individuals who will fail to respond to treatment.:


Fracture thresholds in osteoporosis: implications for hormone replacement treatment.

Ryan PJ, Blake GM, Fogelman I.

Department of Nuclear Medicine, Guy's Hospital, London, United Kingdom.

Ann Rheum Dis 1992 Sep;51(9):1063-5 Abstract quote

The bone mineral densities of the lumbar spine and femoral neck were determined by dual energy chi ray absorptiometry in 110 women aged 40-82 years (average 65 years) with spinal osteoporosis who had had at least one atraumatic vertebral compression fracture and in 1026 normal women aged 40-79 years (average 52 years).

The women with osteoporosis showed a significant decrease in bone mineral density (BMD) at the lumbar spine and femoral neck compared with age matched normal women (sixth decade of life -26% spine, -23% femoral neck; seventh decade -26% spine, -16% femoral neck). The fracture threshold, defined as the 90th centile of spinal BMD for women with osteoporosis, was 0.81 g/cm2 at the lumbar spine and 0.656 g/cm2 at the femoral neck. Five per cent of normal women aged 40-49 years, 20% aged 50-59 years, and 45% aged 60-69 years had a BMD below this threshold.

To maintain the bones of women above the fracture threshold until the age of 70 years about 50% of postmenopausal women need hormone replacement therapy. However, if the BMD is to be kept above the fracture threshold for a women's lifetime, e.g. until the age of 80-90 years, then most women will need treatment, though for various lengths of time depending on their initial BMD.

Measurements of BMD in postmenopausal women currently help in identifying the risk of osteoporotic fractures but in the lifetime assessment of risk in a single subject they may have a more important role in deciding the duration of hormone replacement therapy.

The Role of Serial Bone Mineral Density Testing for Osteoporosis.

Crandall C.

Department of Medicine, UCLA School of Medicine, Iris Cantor-UCLA Women's Health Center, Los Angeles, California

J Womens Health Gend Based Med 2001;10(9):887-895 Abstract quote

As a whole, groups of women who gain more bone mineral density (BMD) on antiresorptive medications experience greater fracture protection, although the relationship is not clear on the individual level.

A literature search (Medline 1966 to present) for randomized, controlled trials was performed with keywords serial bone density, osteoporosis, dual-energy x-ray absorptiometry, fracture, alendronate, risedronate, calcitonin, estrogen replacement therapy, and raloxifene. Also, reference lists and tables of contents from journals were searched manually for additional relevant randomized controlled trials.

Trials were 2-3 years in duration, and the number of subjects ranged from 670 to 3954. Medications analyzed include alendronate, either 5 mg/day or 5 mg/day, followed by 10 mg/day; raloxifene, 60 or 120 mg/day; and combination hormone replacement therapy (HRT) of four different regimen types. There have been no controlled studies showing that change in treatment based on serial bone density measurement results in improved patient outcomes. Whereas studies have shown changes in BMD during antiresorptive therapy to be predictive of fracture reduction in groups of patients, their utility in individual patients remains inconclusive.

Osteoporotic women who lose BMD in the first year of alendronate or raloxifene use will likely gain BMD in the second year of treatment, illustrating regression to the mean. Effective medication for osteoporosis should not be changed solely because of BMD loss occurring after the first year of treatment. Young, healthy, postmenopausal women taking commonly prescribed doses of estrogen or estrogen/progestin (HRT) rarely lose BMD. Bone loss over the first 12 months of HRT is independent of bone loss in the next 24 months. If bone is not lost in the first 12 months of HRT, there is a significant chance that bone density will be lost later in treatment. Half of placebo-treated women do not lose BMD over 3 years.

Treatment should be continued in patients who initially lose bone density on therapy because most will gain density with continued treatment and end in gaining bone overall. Also, patients who gain large amounts of bone in the first year and lose in the second year are not necessarily failing therapy but rather may be showing that a random error in the earlier bone density change corrects itself later. Loss of BMD with alendronate, raloxifene, or combination conjugated equine estrogen/ medroxyprogesterone acetate is likely to convert to gain in BMD.

More research is needed to confirm that this regression to the mean may apply to all densitometry techniques, antiresorptives, age groups, and genders.

Forearm bone mineral density by age in 7,620 men and women: the Tromso study, a population-based study.

Berntsen GK, Fonnebo V, Tollan A, Sogaard AJ, Magnus JH.

Institute of Community Medicine, University of Tromso, N-9037 Tromso, Norway.

Am J Epidemiol 2001 Mar 1;153(5):465-73 Abstract quote

Population-based studies of adult forearm bone mineral density (BMD) by age are scarce, and standardized reference values are lacking.

In this cross-sectional study, men aged 55-74 years, women aged 50-74 years, and representative 5-10% samples of remaining age groups between 25 and 84 years living in Tromso, Norway, were invited for forearm BMD measurement in 1994-1995. The authors measured 3,062 men and 4,558 women (response rate, 78%) by single x-ray absoptiometry at distal and ultradistal forearm sites. Up to age 50, the mean BMD difference was -0.1% per 1-year age group in both sexes. After age 50, the mean BMD difference per 1-year age group was -0.6% in men and -1.3% (distal) and -1.5% (ultradistal) in women.

The BMD by age curve was linear for men throughout senescence, but women had a slope change to -0.7% (distal) and -0.8% (ultradistal) per 1-year age group from the 65- to 69-year age group. BMD levels and BMD by age association in the general population (n = 7,620) and in the population without bone-threatening diseases or medication (n = 5,179) were similar.

Only longitudinal studies can clarify whether cohort effects or longitudinal BMD development patterns explain these cross-sectional results.


Instant Vertebral Assessment: A Noninvasive Dual X-ray Absorptiometry Technique to Avoid Misclassification and Clinical Mismanagement of Osteoporosis.

Greenspan SL, von Stetten E, Emond SK, Jones L, Parker RA.

University of Pittsburgh Medical Center, Osteoporosis Prevention and Treatment Center, Lilliane S. Kaufmann Medical Building, Suite 1110, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA.

J Clin Densitom 2001 Winter;4(4):373-380 Abstract quote

The presence of a vertebral fracture significantly increases the risk of future fracture, classifies a patient with "clinical" osteoporosis, and usually results in treatment for osteoporosis. However, the majority of vertebral fractures are silent, and lateral X-rays (the standard method for identification) are not routinely obtained. Instant vertebral assessment (IVA), a technology that utilizes dual X-ray absorptiometry (DXA), provides rapid assessment of vertebral fractures and is highly correlated with vertebral fractures, as assessed on standard lateral spine X-rays.

To assess the role of IVA in patient management, we examined standard bone mineral density (BMD) of the spine, total hip, and femoral neck and spine IVA by DXA in 482 participants screened for an osteoporosis study, who had no previous knowledge of vertebral fractures.

Using World Health Organization (WHO) guidelines, subjects were classified using BMD at the spine, total hip, femoral neck, or any combination of these central sites. In addition, we considered subjects as osteoporotic if they had vertebral fractures independent of low bone density. We found that vertebral fractures assessed by IVA were present in 18.3% of asymptomatic postmenopausal women recruited for this study. The sensitivity of BMD alone to diagnose osteoporosis based on either a vertebral fracture or low BMD using WHO criteria ranged from 40 to 74%. This means that between 26 and 60% of osteoporotic individuals could have potentially been missed. Furthermore, 11.0-18.7% of clinically osteoporotic individuals would have been classified as normal by BMD criteria alone.

We conclude that IVA is a useful adjunct in the clinical identification of osteoporosis and may prevent mismanagement of osteoporotic patients.


General Affects entire skeleton but preferentially bones with increased surface area such as the cancellous compartment of vertebral bodies

Semiquantitative evaluation of prevalent vertebral deformities in men and their relationship with osteoporosis: the MINOS study.

Szulc P, Munoz F, Marchand F, Delmas PD.

INSERM Research Unit 403, Lyon, France.

Osteoporos Int 2001;12(4):302-10 Abstract quote

Epidemiologic studies have shown a high prevalence of vertebral deformities in men without a steep increase with aging, suggesting that a substantial number of these deformities are not related to osteoporosis.

To determine which vertebral deformities are likely to be osteoporotic fractures, we compared vertebral deformities and bone mineral density (BMD) in a cohort of 786 men aged 51-85 years (the MINOS study). Normal vertebral height ratios were defined in a group of 120 healthy men aged 21-50 years.

We classified vertebral deformities by using the semiquantitative method described by Genant et al., which was slightly modified at the level of thoracic kyphosis (T6-T9). At that level, grade 1 wedge deformities were defined as a 25-30% decrease in anterior vertebral height and grade 2 by a 30-40% decrease. The same cutoff of 40% was used for grade 3 for all vertebrae from T4 to L4. BMD was measured with a Hologic 1500 device at the lumbar spine, hip and whole body and with an Osteometer DTX 100 device at the forearm. Z-scores were calculated in 10-year age groups.

The prevalence of vertebral deformities increased significantly with age. After adjustment for age and body weight, BMD did not differ between those with and without vertebral deformities. In patients having grade 2 and 3 deformities, BMD was lower than in men having no deformities or only grade 1 deformities when adjusted for age and body weight. Using the age- and body-weight-adjusted test of linear trend for sextiles of BMD, prevalence of grade 2 and 3 vertebral deformities increased with a decrease in BMD at all the sites of measurement. Grade 1 deformities were not correlated with BMD at any site. Among 126 patients who had only grade 1 vertebral deformities, 32 deformities in 30 men were confirmed as vertebral fractures according to their morphology but their BMD did not differ from the nonfractured men. These findings were confirmed when vertebral deformities were measured by the conventional morphometric method in a subgroup of 131 men.

Our data suggest that a cutoff of 30% for wedge deformities from T6 to T9 and of 25% for other deformities has a high specificity and a moderate sensitivity for identifying vertebral deformities related to low BMD in men. Grade 1 deformities are often either false positive or deformities related to nonosteoporotic disease of the spine.


General Thinned trabeculae with loss of interconnections
Senile osteoporosis has thinned cortex secondary to subperiosteal and endosteal resorption and widening of the Haversian systems


PROGNOSIS Fractures are the most common complication leading to lumbar lordosis and kyphoscoliosis
Additional complications include pulmonary embolism and pneumonia
Survival Complications lead to 40-50,000 deaths per year

Femoral bone mineral density, neck-shaft angle and mean femoral neck width as predictors of hip fracture in men and women. Multicenter Project for Research in Osteoporosis.

Alonso CG, Curiel MD, Carranza FH, Cano RP, Perez AD. Servicio de Metabolismo

Oseo y Mineral, Instituto Reivia Sofia de Investigacion, Hospital Central de Asturias, Oviedo, Spain.

Osteoporos Int 2000;11(8):714-20 Abstract quote

The effect of femoral bone mineral density (BMD) and several parameters of femoral neck geometry (hip axis length, neck-shaft angle and mean femoral neck width) on hip fracture risk in a Spanish population was assessed in a cross-sectional study. All parameters were determined by dual-energy X-ray absorptiometry.

There were 411 patients (116 men, 295 women; aged 60-90 years) with hip fractures in whom measurements were taken in the contralateral hip. Controls were 545 persons (235 men, 310 women; aged 60-90 years) who participated in a previous study on BMD in a healthy Spanish population. Femoral neck BMD was significantly lower, and neck-shaft angle and mean femoral neck width significantly higher, in fracture cases than in controls.

The logistic regression analysis adjusted by age, height and weight showed that a decrease of 1 standard deviation (SD) in femoral neck BMD was associated with an odds ratio of hip fracture of 4.52 [95% confidence interval (CI) 2.93 to 6.96] in men and 4.45 (95% CI 3.11 to 6.36) in women; an increase of 1 SD in neck-shaft angle of 2.45 (95% CI 1.73 to 3.45) in men and 3.48 (95% CI 2.61 to 4.65) in women; and an increase of 1 SD in mean femoral neck width of 2.15 (95% CI 1.55 to 2.98) in men and 2.40 (95% CI 1.79 to 3.22) in women.

The use of a combination of femoral BMD and geometric parameters of the femoral neck except for hip axis length may improve hip fracture risk prediction allowing a better therapeutic strategy for hip fracture prevention.

Bone mineral density and bone loss measured at the radius to predict the risk of nonspinal osteoporotic fracture.

Gnudi S, Malavolta N, Lisi L, Ripamonti C.

Internal Medicine, Rizzoli Orthopaedic Institute, Bologna, Italy.

J Bone Miner Res 2001 Jun;16(6):1130-5 Abstract quote

Low bone mineral density (BMD) and, probably, the rate of bone loss (RBL) are associated with the risk of osteoporotic fractures.

To estimate the risk of nonspinal fracture in osteoporotic women, we measured BMD and RBL in a prospective study (average follow-up, 5.38 years) in 656 postmenopausal women. The women were considered in three groups: group A (whole population), group B (women under the age of 65 years) and group C (women over the age of 65 years). At the beginning of the study, BMD was measured at the distal radius (DR) and at the proximal radius (PR) using a single-energy densitometer. BMD measurements made 2 years previously in the same patients were used to calculate RBL. Then patients were checked annually for nonspine fracture due to minor trauma. During follow-up, 121 nonspinal fractures were detected.

Women with fractures were older and had lower BMD. With the Cox regression, age-corrected BMD at both DR and PR predicts fracture risk in groups A and B but not in group C. After correction for potential confounders, DR still predicts fractures in groups A and B whereas PR predicts fractures only in group B. In group C, only the RBL at the PR was predictive of the fracture risk as well as in the other two groups. Specific types of fractures are predictable in the whole population at the wrist.

In conclusion, radial BMD predicts the risk of nonspine fractures except in women over the age of 65 years. The RBL at the PR is an effective predictor of fracture risk also in women over the age of 65 years.


Identification and Fracture Outcomes of Undiagnosed Low Bone Mineral Density in Postmenopausal Women: Results From the National Osteoporosis Risk Assessment.

Siris ES, Miller PD, Barrett-Connor E, Faulkner KG, Wehren LE, Abbott TA, Berger ML, Santora AC, Sherwood LM.

Toni Stabile Osteoporosis Center, Columbia Presbyterian Medical Center, 180 Fort Washington Ave, New York, NY 10032-3784.

JAMA 2001 Dec 12;286(22):2815-2822 Abstract quote

CONTEXT: Large segments of the population at risk for osteoporosis and fracture have not been evaluated, and the usefulness of peripheral measurements for short-term prediction of fracture risk is uncertain.

OBJECTIVES: To describe the occurrence of low bone mineral density (BMD) in postmenopausal women, its risk factors, and fracture incidence during short-term follow-up.

DESIGN: The National Osteoporosis Risk Assessment, a longitudinal observational study initiated September 1997 to March 1999, with approximately 12 months of subsequent follow-up.

SETTING AND PARTICIPANTS: A total of 200 160 ambulatory postmenopausal women aged 50 years or older with no previous osteoporosis diagnosis, derived from 4236 primary care practices in 34 states.

MAIN OUTCOME MEASURES: Baseline BMD T scores, obtained from peripheral bone densitometry performed at the heel, finger, or forearm; risk factors for low BMD, derived from questionnaire responses; and clinical fracture rates at 12-month follow-up.

RESULTS: Using World Health Organization criteria, 39.6% had osteopenia (T score of -1 to -2.49) and 7.2% had osteoporosis (T score

CONCLUSIONS: Almost half of this population had previously undetected low BMD, including 7% with osteoporosis. Peripheral BMD results were highly predictive of fracture risk. Given the economic and social costs of osteoporotic fractures, strategies to identify and manage osteoporosis in the primary care setting need to be established and implemented.


Prediction of osteoporotic fractures by bone densitometry and COLIA1 genotyping: a prospective, population-based study in men and women.

McGuigan FE, Armbrecht G, Smith R, Felsenberg D, Reid DM, Ralston SH.

Department of Medicine and Therapeutics, Foresterhill, Aberdeen, UK.

Osteoporos Int 2001;12(2):91-6 Abstract quote

Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mineral density and increased fracture risk. Although the genetic basis of osteoporosis is incompletely understood, previous studies have identified a polymorphism affecting an Sp1 binding site in the COLIA1 gene that predicts bone mineral density and osteoporotic fractures in several populations.

Here we investigated the role of COLIA1 genotyping and bone densitometry in the prediction of osteoporotic fractures in a prospective, population-based study of men (n = 156) and women (n = 185) who were followed up for a mean (+/- SEM) of 4.88+/-0.03 years.

There was no significant difference in bone density, rate of bone loss, body weight, height, or years since menopause between the genotype groups but women with the 'ss' genotype were significantly older than the other genotype groups (p = 0.03). Thirty-nine individuals sustained 54 fractures during follow-up and these predominantly occurred in women (45 fractures in 30 individuals). Fractures were significantly more common in females who carried the COLIA1 's' allele (p = 0.001), although there was no significant association between COLIA1 genotype and the occurrence of fractures in men.

Logistic regression analysis showed that carriage of the COLIA1 's' allele was an independent predictor of fracture in women with an odds ratio (OR) [95% CI] of 2.59 [1.23-5.45], along with spine bone mineral density (OR = 1.57 [1.04-2.37] per Z-score unit) and body weight (OR = 1.05 [1.01-1.10] per kilogram). Moreover, bone densitometry and COLIA1 genotyping interacted significantly to enhance fracture prediction in women (p = 0.01), such that the incidence of fractures was 45 times higher in those with low BMD who carried the 's' allele (24.3 fractures/100 patient-years) compared with those with high BMD who were 'SS' homozygotes (0.54 fracture/100 patient-years).

We conclude that in our population, COLIA1 genotyping predicts fractures independently of bone mass and interacts with bone densitometry to help identify women who are at high and low risk of sustaining osteoporotic fractures.


Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update.

American College of Rheumatology Ad Hoc Committee on Glucocoritcoid-Induced Osteoporosis.

Arthritis Rheum 2001 Jul;44(7):1496-503 Abstract quote

Glucocorticoid-induced bone loss should be prevented, and if present, should be treated (Table 2). Supplementation with calcium and vitamin D at a dosage of 800 IU/day, or an activated form of vitamin D (e.g., alfacalcidiol at 1 microg/day or calcitriol at 0.5 microg/day), should be offered to all patients receiving glucocorticoids, to restore normal calcium balance. This combination has been shown to maintain bone mass in patients receiving long-term low-to-medium-dose glucocorticoid therapy who have normal levels of gonadal hormones. However, while supplementation with calcium and vitamin D alone generally will not prevent bone loss in patients in whom medium-to-high-dose glucocorticoid therapy is being initiated, supplementation with calcium and an activated form of vitamin D will prevent bone loss.

There are no data available to support any conclusion about the antifracture efficacy of the combination of calcium supplementation plus an activated form of vitamin D. Antiresorptive agents are effective in the treatment of glucocorticoid-induced bone loss. All of these agents either prevent bone loss or modestly increase lumbar spine bone mass and maintain hip bone mass. While there are no randomized controlled trials of prevention of glucocorticoid-induced bone loss or radiographic vertebral fracture outcomes with HRT or testosterone, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered HRT.

The bisphosphonates are effective for both the prevention and the treatment of glucocorticoid-induced bone loss. Large studies have demonstrated that bisphosphonates also reduce the incidence of radiographic vertebral fractures in postmenopausal women with glucocorticoid-induced osteoporosis. Treatment with a bisphosphonate is recommended to prevent bone loss in all men and postmenopausal women in whom long-term glucocorticoid treatment at > or =5 mg/day is being initiated, as well as in men and postmenopausal women receiving long-term glucocorticoids in whom the BMD T-score at either the lumbar spine or the hip is below normal. While there is little information on the prevention or treatment of bone loss in premenopausal women, these women, too, may lose bone mass if they are being treated with glucocorticoids, so prevention of bone loss with antiresorptive agents should be considered. If bisphosphonate therapy is being considered for a premenopausal woman, she must be counseled regarding use of appropriate contraception.

The therapies to prevent or treat glucocorticoid-induced bone loss should be continued as long as the patient is receiving glucocorticoids. Data from large studies of anabolic agents (e.g., PTH) and further studies of combination therapy in patients receiving glucocorticoids are eagerly awaited so additional options will be available for the prevention of this serious complication of glucocorticoid treatment.


Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women: a randomized controlled trial.

Greenspan SL, Resnick NM, Parker RA.

Division of Endocrinology and Metabolism and Division of Geriatric Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pa.

JAMA 2003 May 21;289(19):2525-33 Abstract quote

CONTEXT: Therapy with individual antiresorptive agents has been shown to be effective for prevention and treatment of postmenopausal osteoporosis, but whether combination antiresorptive therapy with hormones and bisphosphonates is safe or efficacious or how these agents compare in elderly women is unknown.

OBJECTIVE: To determine whether hormone replacement and the bisphosphonate alendronate sodium in combination are efficacious and safe, and how they compare with monotherapy in community-dwelling elderly women.

DESIGN: Randomized, double-blind, placebo-controlled, clinical trial.

Setting and PARTICIPANTS: Five hundred seventy-three community-dwelling women age 65 years or older were screened: 485 completed screening and 373 (aged 65 to 90 years) were randomized following a 3-month, open-label, run-in phase with hormone replacement and alendronate placebo. The trial was conducted at a single academic US medical center from January 1996 to May 2001.

INTERVENTIONS: Participants were randomly assigned in a 2 x 2 factorial design to receive hormone replacement (conjugated equine estrogen, 0.625 mg/d, with or without medroxyprogesterone, 2.5 mg/d) and alendronate, 10 mg daily, both agents, or neither. All participants received calcium and vitamin D supplements.

MAIN OUTCOME MEASURES: Annualized change in bone mineral density of the hip and spine and occurrence of adverse events.

RESULTS: Bone mineral density at 3 years was significantly greater at all femoral and vertebral sites in women treated with combination therapy than with monotherapy, with mean (SD) increases of 5.9% (3.8) at the total hip, 10.4% (5.4) at the posteroanterior lumbar spine, and 11.8% (6.8) at the lateral lumbar spine. Mean (SD) increases in bone mass at the hip in women treated with alendronate alone were significantly greater than in those treated with hormone replacement therapy alone (4.2% [3.8] vs 3.0% [4.9]; P<.05, respectively), and alendronate resulted in more responders to therapy. All therapies were well tolerated and participant retention was 90% at 3 years.

CONCLUSIONS: Combination therapy with hormone replacement and alendronate was efficacious and well tolerated in this cohort. Alendronate was superior to hormone replacement, and combination therapy was superior to either therapy alone. Combination therapy may represent an option for women with more severe disease or for those who have failed to achieve an adequate response to monotherapy.

Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group.

Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M.

N Engl J Med 1995 Nov 30;333(22):1437-43 Abstract quote

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.

Prevention of nonvertebral fractures by alendronate. A meta-analysis. Alendronate Osteoporosis Treatment Study Groups.

Karpf DB, Shapiro DR, Seeman E, Ensrud KE, Johnston CC Jr, Adami S, Harris ST, Santora AC 2nd, Hirsch LJ, Oppenheimer L, Thompson D.

Merck Research Laboratories, Rahway, NJ 07065-0900, USA.

JAMA 1997 Apr 9;277(14):1159-64 Abstract quote

OBJECTIVE: To evaluate the effect of treatment with alendronate sodium, a potent aminobisphosphonate, on the incidence of nonvertebral fractures in postmenopausal women with osteoporosis.

DATA SOURCES: Published data and data on file at Merck Research Laboratories.

STUDY SELECTION: All completed prospective, randomized, placebo-controlled alendronate trials of at least 2 years' duration (5 studies).

DATA EXTRACTION: All subjects were women with osteoporosis between the ages of 42 and 85 years, postmenopausal at least 4 years, with lumbar spine bone mineral density (measured using dual-energy x-ray absorptiometry) at least 2.0 SD below the mean for young adult women. All women randomized to treatment with placebo or alendronate at a dose higher than 1 mg per day for at least 2 years were included.

DATA SYNTHESIS: In the placebo group (n=590), 60 women reported nonvertebral fractures during 1347 patient-years at risk (overall rate, 4.45 women with fractures per 100 patient-years at risk). In the alendronate group (n = 1012), 73 women reported nonvertebral fractures during 2240 patient-years-at risk (overall rate, 3.26 women with fractures per 100 patient-years at risk). The estimated cumulative incidence of nonvertebral fractures after 3 years was 12.6% in the placebo group and 9.0% in alendronate group. The relative risk for nonvertebral fracture estimated using the Cox proportional hazards model was 0.71 (95% confidence interval,0.502-0.997) (P=.048). A reduction in risk was consistent across each of the studies and at each major site of osteoporotic fracture, including the hip and wrist.

CONCLUSION: In postmenopausal women with osteoporosis, treatment with alendronate reduces the risk of nonvertebral fractures over at least 3 years.

Cyclical etidronate in the treatment of postmenopausal osteoporosis: efficacy and safety after seven years of treatment.

Miller PD, Watts NB, Licata AA, Harris ST, Genant HK, Wasnich RD, Ross PD, Jackson RD, Hoseyni MS, Schoenfeld SL, Valent DJ, Chesnut CH 3rd.

University of Colorado Health Sciences Center, Denver, USA.

Am J Med 1997 Dec;103(6):468-76 Abstact quote

PURPOSE: To determine the efficacy and safety of cyclical etidronate for up to 7 years in the treatment of postmenopausal osteoporosis and to examine the effects of discontinuing treatment after 2 or 5 years of therapy.

PATIENTS AND METHODS: Patients were randomized at entry into the original study in 1986 to blinded treatment for 2 years with either a calcium (placebo) or an intermittent cyclical etidronate regimen, which most patients continued for a third year. Following this phase of the study, patients were enrolled into an open-label, follow-up study (years 4 and 5), during which all patients received cyclical etidronate treatment. In the present double-blind study (years 6 and 7), patients were rerandomized to receive intermittent cyclical therapy with either etidronate or placebo; all patients received calcium. The treatment regimen consisted of 400 mg/day etidronate or placebo for 14 days, followed by 76 days of elemental calcium (500 mg/day); this cycle was repeated approximately 4 times in each year. Of the 193 patients who continued in years 6 and 7 of the study, 93 were randomized to receive cyclical etidronate and 100 were randomized to receive calcium only. For purposes of efficacy analyses, patients were categorized by their total years of cumulative etidronate treatment (7, 5, 4, or 2 years). There were 51, 46, 42, and 54 patients in the 7-, 5-, 4-, and 2-year groups, respectively. Annual assessments included lumbar spine bone mineral density (BMD), as measured by densitometry, and vertebral radiographs.

RESULTS: The groups receiving cyclical etidronate during this 2-year study period (7- and 4-year groups) had statistically significant mean percent increases in spinal BMD of 1.8% and 2.2%, respectively (P < 0.05) at the week 104 observation time. The 5- and 2-year groups, which did not receive etidronate during this period, had mean values of 1.4% and 0.2%, respectively (not significant) at week 104. In the 7-, 5-, 4-, and 2-year groups, the increases in spinal BMD at the end of 7 years were 7.6%, 8.6%, 8.1%, and 3.9%, respectively; these values were statistically significant for all groups compared with original baseline (year 0) (P < 0.05). BMD of the femur and wrist was maintained throughout the 7-year period. The incidence and rate of vertebral fractures were lowest in patients with the longest exposure to etidronate. Etidronate was well tolerated during the study, with low incidences of gastrointestinal side effects and nonvertebral fractures.

CONCLUSIONS: Long-term cyclical etidronate is a safe, effective, and well-tolerated treatment for postmenopausal osteoporosis. Bone mass is maintained for at least 2 years after treatment with etidronate is stopped; however, further gains in spinal bone mass are seen in patients who continue therapy.

A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis.

Wimalawansa SJ.

Department of Medicine, Royal Postgraduate Medical School, London, England

Am J Med 1998 Mar;104(3):219-26 Abstract quote

PURPOSE: Hormone replacement therapy (HRT) with estrogen and treatment with bisphosphonates have been shown to increase bone mineral density (BMD) in postmenopausal women. This 4-year prospective randomized study was carried out to assess the effectiveness of the combined HRT plus etidronate on BMD in postmenopausal women with established osteoporosis.

PATIENTS AND METHODS: Seventy-two postmenopausal women (mean age 64.9+/-0.5 years) attending metabolic bone disease outpatient clinics with established osteoporosis were randomly allocated into one of four treatment groups and monitored for 4 years. All patients enrolled in this study including the control group (n=18) received 1.0 g elemental calcium and 400 units vitamin D per day. The HRT group (n=18) received cyclical estrogen and progesterone; the etidronate group (n=17) received intermittent cyclical etidronate; and the combined therapy group (n=19) received both HRT and etidronate. BMD was measured in the lumbar spine and the hip before treatment and at 2 and 4 years after treatment. Changes in height were recorded, and the occurrence of new vertebral fractures were documented in comparison with the baseline radiographic evaluation. In 40 patients (10 patients per group), analysis of bone histomorphometry was carried out after 4 years of treatment.

RESULTS: In patients who received the combined therapy, BMD increased in the lumbar spine by 10.4% (P <0.001) and in the hip by 7.0% (P <0.001) at 4 years. For patients treated with ICE, these increases were 7.3% (P <0.001) and 0.9% (P <0.05), and with HRT, the increases were 7.0% (P <0.001) and 4.8% (P <0.01) in the vertebrae and femora, respectively. The group treated with calcium and vitamin D lost 2.5% (P <0.05) and 4.4% (P <0.01) of BMD in the vertebrae and femora, respectively, after 4 years. Patients who received combined therapy had significantly higher BMD in both the vertebrae and in the femora (P <0.05) in comparison with patients who were treated with HRT or etidronate alone after 4 years. In comparison with patients in the control group, there was a trend toward a lower rate of new vertebral fractures in the treatment groups. Height loss was significantly less in all three active treatment groups (HRT [P <0.001], etidronate [P <0.02], and combined therapy group [P <0.0001]), in comparison with the control group. The combined therapy group did not have a significant height loss, in comparison with the HRT (P <0.02) and the etidronate (P <0.001) groups. None of the patients had histomorphometric evidence of osteomalacia.

CONCLUSION: This 4-year randomized study showed an additive effect of etidronate and HRT on hip and spine BMD in postmenopausal women with established osteoporosis.

Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial.

Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ.

Department of Epidemiology and Biostatistics, University of California, San Francisco 94105, USA.

JAMA 1998 Dec 23-30;280(24):2077-82 Abstract quote

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 clinical and vertebral fractures in women who have low bone mineral density (BMD) but no vertebral fractures.

DESIGN: Randomized, blinded, placebo-controlled trial.

SETTING: Eleven community-based clinical research centers.

SUBJECTS: Women aged 54 to 81 years with a femoral neck BMD of 0.68 g/cm2 or less (Hologic Inc, Waltham, Mass) but no vertebral fracture; 4432 were randomized to alendronate or placebo and 4272 (96%) completed outcome measurements at the final visit (an average of 4.2 years later).

INTERVENTION: All participants reporting calcium intakes of 1000 mg/d or less received a supplement containing 500 mg of calcium and 250 IU of cholecalciferol. Subjects were randomly assigned to either placebo or 5 mg/d of alendronate sodium for 2 years followed by 10 mg/d for the remainder of the trial.

MAIN OUTCOME MEASURES: Clinical fractures confirmed by x-ray reports, new vertebral deformities detected by morphometric measurements on radiographs, and BMD measured by dual x-ray absorptiometry.

RESULTS: Alendronate increased BMD at all sites studied (P<.001) and reduced clinical fractures from 312 in the placebo group to 272 in the intervention group, but not significantly so (14% reduction; relative hazard [RH], 0.86; 95% confidence interval [CI], 0.73-1.01). Alendronate reduced clinical fractures by 36% in women with baseline osteoporosis at the femoral neck (>2.5 SDs below the normal young adult mean; RH, 0.64; 95% CI, 0.50-0.82; treatment-control difference, 6.5%; number needed to treat [NNT], 15), but there was no significant reduction among those with higher BMD (RH, 1.08; 95% CI, 0.87-1.35). Alendronate decreased the risk of radiographic vertebral fractures by 44% overall (relative risk, 0.56; 95% CI, 0.39-0.80; treatment-control difference, 1.7%; NNT, 60). Alendronate did not increase the risk of gastrointestinal or other adverse effects.

CONCLUSIONS: In women with low BMD but without vertebral fractures, 4 years of alendronate safely increased BMD and decreased the risk of first vertebral deformity. Alendronate significantly reduced the risk of clinical fractures among women with osteoporosis but not among women with higher BMD.

Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators.

Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Gluer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR.

Division of Research, Kaiser Permanente, Oakland, Calif 94611-5400, USA.

JAMA 1999 Aug 18;282(7):637-45 Abstract quote

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). Women receiving raloxifene had increased risk of venous thromboembolus vs placebo (RR, 3.1; 95% CI, 1.5-6.2). Raloxifene did not cause vaginal bleeding or breast pain and was associated with a lower incidence of breast cancer.

CONCLUSIONS: In postmenopausal women with osteoporosis, raloxifene increases bone mineral density in the spine and femoral neck and reduces risk of vertebral fracture.

Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group.

Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH 3rd, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD.

University of California, San Francisco 94117-3608, USA.

JAMA 1999 Oct 13;282(14):1344-52 Abstract quote

CONTEXT: Risedronate, a potent bisphosphonate, has been shown to be effective in the treatment of Paget disease of bone and other metabolic bone diseases but, to our knowledge, it has not been evaluated in the treatment of established postmenopausal osteoporosis.

OBJECTIVE: To test the efficacy and safety of daily treatment with risedronate to reduce the risk of vertebral and other fractures in postmenopausal women with established osteoporosis.

DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial of 2458 ambulatory postmenopausal women younger than 85 years with at least 1 vertebral fracture at baseline who were enrolled at 1 of 110 centers in North America conducted between December 1993 and January 1998.

INTERVENTIONS: Subjects were randomly assigned to receive oral treatment for 3 years with risedronate (2.5 or 5 mg/d) or placebo. All subjects received calcium, 1000 mg/d. Vitamin D (cholecalciferol, up to 500 IU/d) was provided if baseline levels of 25-hydroxyvitamin D were low.

MAIN OUTCOME MEASURES: Incidence of new vertebral fractures as detected by quantitative and semiquantitative assessments of radiographs; incidence of radiographically confirmed nonvertebral fractures and change from baseline in bone mineral density as determined by dual x-ray absorptiometry.

RESULTS: The 2.5 mg/d of risedronate arm was discontinued after 1 year; in the placebo and 5 mg/d of risedronate arms, 450 and 489 subjects, respectively, completed all 3 years of the trial. Treatment with 5 mg/d of risedronate, compared with placebo, decreased the cumulative incidence of new vertebral fractures by 41 % (95% confidence interval [CI], 18%-58%) over 3 years (11.3 % vs 16.3%; P= .003). A fracture reduction of 65% (95% CI, 38%-81 %) was observed after the first year (2.4% vs 6.4%; P<.001). The cumulative incidence of nonvertebral fractures over 3 years was reduced by 39% (95% CI, 6%-61 %) (5.2 % vs 8.4%; P = .02). Bone mineral density increased significantly compared with placebo at the lumbar spine (5.4% vs 1.1 %), femoral neck (1.6% vs -1.2%), femoral trochanter (3.3% vs -0.7%), and midshaft of the radius (0.2% vs -1.4%). Bone formed during risedronate treatment was histologically normal. The overall safety profile of risedronate, including gastrointestinal safety, was similar to that of placebo.

CONCLUSIONS: These data suggest that risedronate therapy is effective and well tolerated in the treatment of women with established postmenopausal osteoporosis.

Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group.

Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, Lund B, Ethgen D, Pack S, Roumagnac I, Eastell R.

Centre Universitaire d'Investigation du Metabolisme Osseux et du Cartilage Articulaire, University of Liege, Belgium.

Osteoporos Int 2000;11(1):83-91 Abstract quote

The purpose of this randomized, double-masked, placebo-controlled study was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis.

The study was conducted at 80 study centers in Europe and Australia. Postmenopausal women (n = 1226) with two or more prevalent vertebral fractures received risedronate 2.5 or 5 mg/day or placebo; all subjects also received elemental calcium 1000 mg/day, and up to 500 IU/day vitamin D if baseline levels were low. The study duration was 3 years; however, the 2.5 mg group was discontinued by protocol amendment after 2 years. Lateral spinal radiographs were taken annually for assessment of vertebral fractures, and bone mineral density was measured by dual-energy X-ray absorptiometry at 6-month intervals. Risedronate 5 mg reduced the risk of new vertebral fractures by 49% over 3 years compared with control (p<0.001). A significant reduction of 61% was seen within the first year (p = 0.001). The fracture reduction with risedronate 2.5 mg was similar to that in the 5 mg group over 2 years. The risk of nonvertebral fractures was reduced by 33% compared with control over 3 years (p = 0.06). Risedronate significantly increased bone mineral density at the spine and hip within 6 months. The adverse-event profile of risedronate, including gastrointestinal adverse events, was similar to that of control.

Risedronate 5 mg provides effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving bone density in women with established disease.

A comparison of continuous alendronate, cyclical alendronate and cyclical etidronate with calcitriol in the treatment of postmenopausal vertebral osteoporosis: a randomized controlled trial.

Sahota, Fowler I, Blackwell PJ, Lawson N, Cawte SA, San P, Masud T, Hosking DJ.

Ageing and Disability Research Unit (ADRU), University Hospital, Nottingham, UK.

Osteoporos Int 2000;11(11):959-66 Abstract quote

A number of drugs are now available for the treatment of established osteoporosis and have been shown to significantly increase bone mineral density (BMD). There are, however, few comparative treatment studies and, furthermore, adverse events remain a problem with some of the newer agents, particularly in the elderly, in everyday clinical practice.

We report a 12 month, open labeled, randomized controlled, prospective treatment study in 140 postmenopausal women with established vertebral osteoporosis, comparing the effect of continuous alendronate, cyclical alendronate and cyclical etidronate with calcitriol in terms of gain in BMD, reduction in bone turnover markers and adverse event profile. The mean percentage increases in BMD at 12 months, at the spine and hip respectively, were: continuous alendronate 5.7%, 2.6%; cyclical alendronate 4.1%, 1.6%; cyclical etidronate 4.9%, 2.0% (p<0.0 1) and calcitriol 2.0%, 0.4% (NS). In comparison with calcitriol, the mean changes in BMD at the spine and hip respectively were greater in the other groups; continuous alendronate: 3.7% (95% CI 1.4 to 8.3), 2.2% (95% CI 0.7 to 4.0); cyclical alendronate: 2.1% (95% CI 1.2 to 6.4), 1.2% (95% CI -0.3 to 3.0); cyclical etidronate: 2.9% (95% CI 1.9 to 6.5), 1.6% (95% CI 0.9 to 3.1)). The reduction in bone turnover markers was between 26% and 32% in the alendronate and etidronate groups (p<0.01), with a trend toward greater reduction in the continuous alendronate group. Eight patients discontinued the study: 6 in the continuous alendronate group, 1 in the cyclical alendronate group and 1 in the calcitriol group. Two patients in the cyclical etidronate group were unable to tolerate the Cacit component, but continued on substituting Cacit with Calcichew.

In summary, 12 months of treatment with continuous alendronate, cyclical alendronate and cyclical etidronate are effective in terms of the gain in BMD at the anteroposterior spine and total hip in a comparable treatment population. These treatments are more effective than calcitriol and were generally well tolerated. Continuous alendronate showed a trend toward a larger gain in BMD and greater suppression of bone turnover markers than the other treatment groups, but had a higher incidence of adverse events, particularly within the older subgroup. Cyclical alendronate offers a lower adverse event profile and appears to be effective in comparison with continuous treatment, and may possibly be an alternative in the elderly. However, further studies are necessary, but more importantly with fracture end-points.

Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study.

Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderoth DH, Adami S, Eusebio RA, Devogelaer JP.

Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, United Kingdom

J Bone Miner Res 2000 Jun;15(6):1006-13Abstract quote

Long-term use of high-dose corticosteroids often results in bone loss, which may lead to osteoporosis-related fractures. This was a multicenter, double-blind study in which 290 ambulatory men and women receiving high-dose oral corticosteroid therapy (prednisone > or = 7.5 mg/day or equivalent) for 6 or more months were randomized to receive placebo, risedronate 2.5 mg/day, or risedronate 5 mg/day for 12 months.

All patients received calcium 1 g and vitamin D 400 IU daily. The primary endpoint was lumbar spine bone mineral density (BMD) at month 12. Additional measurements included BMD at the femoral neck and trochanter and the incidence of vertebral fractures. Overall, there were statistically significant treatment effects on BMD at 12 months at the lumbar spine (p < 0.001), femoral neck (p = 0.004), and trochanter (p = 0.010). Risedronate 5 mg increased BMD at 12 months by a mean (SEM) of 2.9% (0.49%) at the lumbar spine, 1.8% (0.46%) at the femoral neck, and 2.4% (0.54%) at the trochanter, whereas BMD was maintained only in the control group.

Although not powered to show fracture efficacy, we observed a reduction in the incidence of vertebral fractures of 70% in the combined risedronate treatment groups, relative to placebo (p = 0.042). Risedronate was well tolerated, had a good safety profile, and was not associated with gastrointestinal adverse events.

We conclude that risedronate increases BMD and potentially reduces the incidence of vertebral fractures in patients with corticosteroid-induced osteoporosis.

A meta-analysis of etidronate for the treatment of postmenopausal osteoporosis.

Cranney A, Guyatt G, Krolicki N, Welch V, Griffith L, Adachi JD, Shea B, Tugwell P, Wells G;

Osteoporosis Research Advisory Group (ORAG). Department of Medicine and Clinical Epidemiology, Loeb Research Institute, University of Ottawa, Canada.

Osteoporos Int 2001;12(2):140-51 Abstract quote

The aim of the study was to review the effect of etidronate on bone density and fractures in postmenopausal women.

We searched MEDLINE from 1966 to 1998, examined citations of relevant articles, and the proceedings of international osteoporosis meetings. We contacted osteoporosis investigators to identify additional studies, primary authors, and pharmaceutical industry sources for unpublished data.

We included 13 trials that randomized women to etidronate or an alternative (placebo or calcium and/or vitamin D) and measured bone density for at least 1 year. For each trial, three independent reviewers assessed the methodologic quality and abstracted data.

The data suggested a reduction in vertebral fractures with a pooled relative risk of 0.63 (95% CI 0.44 to 0.92). There was no effect on nonvertebral fractures (relative risk 0.99, (95% CI 0.69 to 1.42). Etidronate, relative to control, increased bone density after 1-3 years of treatment in the lumbar spine by 4.06% (95% CI 3.12 to 5.00), in the femoral neck by 2.35% (95% CI 1.66 to 3.04) and in the total body by 0.97% (95% CI 0.39 to 1.55). Effects were larger at 4 years, though the number of patients followed much smaller. Etidronate increases bone density in the lumbar spine and femoral neck for up to 4 years.

The pooled estimates of fracture reduction with etidronate suggest a reduction in vertebral fractures, but no effect on nonvertebral fractures.


Calcitonin versus etidronate for the treatment of postmenopausal osteoporosis: a meta-analysis of published clinical trials.

Cardona JM, Pastor E.

Centro de Atencion Primaria Valls de Pego, Valenciana, Spain.

Osteoporos Int 1997;7(3):165-74 Abstract quote

This review examines the evidence on the efficacy of calcitonin and etidronate in the prevention of osteoporosis and osteoporotic fractures.

MEDLINE was searched for clinical trials calcitonin or etidronate and reviews of the treatment of postmenopausal osteoporosis. The reference sections of the papers retrieved were again searched for trials on the treatments of interest. Two people independently collected data from the trials that met the inclusion criteria of the study. Weighted means in the change in bone mineral density (BMD) and differences in vertebral fracture rates were computed for calcitonin and etidronate separately. The existence of publication bias was investigated by funnel plots of effect size against sample size.

Eighteen clinical trials and calcitonin and six with etidronate were included in the meta-analysis. The pooled change in vertebral BMD at the end of the studies was 1.97 (95% CI 1.77 to 2.17) with calcitonin and 3.20 (95% CI 2.92 to 3.48) with etidronate. Pooled change in proximal femur BMD was 0.32 (95% CI -0.27 to 0.91) with calcitonin and 2.42 (95% CI 2.16 to 2.68) with etidronate. The aggregated number of vertebral fractures prevented by the treatment was 59.2 per 1000 patient-years (95% CI 55.1 to 63.3) for calcitonin and 28.3 (95% CI 26.2 to 30.4) for etidronate.

With the available evidence we cannot establish the superiority of either of the two drugs for the treatment of postmenopausal osteoporosis. The clinical trials are particularly lacking in data on hip fracture, the most important consequence of osteoporosis. In this situation consideration of the relative costs of the drugs is prominent.


The effect of sodium monofluorophosphate plus calcium on vertebral fracture rate in postmenopausal women with moderate osteoporosis. A randomized, controlled trial.

Reginster JY, Meurmans L, Zegels B, Rovati LC, Minne HW, Giacovelli G, Taquet AN, Setnikar I, Collette J, Gosset C.

University of Liege, Belgium.

Ann Intern Med 1998 Jul 1;129(1):1-8 Abstract quote

BACKGROUND: Fluoride is effective in increasing trabecular bone mineral density (BMD) in the spine, but its efficacy in reducing vertebral fracture rates and its effect on BMD at cortical sites are controversial.

OBJECTIVE: To study the effect of low-dose fluoride (sodium monofluorophosphate [MFP]) plus a calcium supplement over 4 years on vertebral fractures and BMD at the lumbar spine and total hip in postmenopausal women with moderately low BMD of the spine.

DESIGN: Randomized, double-blind, controlled clinical trial.

SETTING: Outpatient clinic for osteoporosis at a university medical center.

PATIENTS: 200 postmenopausal women with osteoporosis (according to the World Health Organization definition) and a T-score less than -2.5 for BMD of the spine.

INTERVENTION: Women were randomly assigned (100 patients per group) to continuous daily treatment for 4 years with 1) oral MFP (20 mg of equivalent fluoride) plus 1000 mg of calcium (as calcium carbonate) or 2) calcium only.

MEASUREMENTS: Lateral spine radiographs were taken at enrollment and at each year of follow-up for detection of new vertebral fractures (defined as a reduction > or =20% and > or =4 mm from baseline in any of the heights of a vertebral body). Nonvertebral fractures were also recorded. All analyses were done with the intention-to-treat approach.

RESULTS: Radiologic follow-up was possible for 164 of 200 patients (82%). The rate of new vertebral fractures during the 4 years of the study was lower in the MFP-plus-calcium group (2 of 84 patients; 2.4% [95% CI, 0.3% to 8.3%]) than in the calcium-only group (8 of 80 patients; 10% [CI, 4.4% to 18.8%]). The difference between the groups was 7.6 percentage points (CI, 0.3 to 15 percentage points) (P = 0.05). A moderate but progressive increase in BMD of the spine (10.0% +/- 1.5% at 4 years) was found for MFP plus calcium compared with calcium only (P < 0.001), whereas the more modest increase in BMD of the total hip seen with MFP plus calcium (1.8% +/- 0.6%) did not differ from the increase seen with calcium only.

CONCLUSIONS: Low-dose fluoride (20 mg/d) given continuously with calcium for prolonged periods can decrease vertebral fracture rates compared with calcium alone in patients with mild to moderate osteoporosis.

Fluoride for the treatment of postmenopausal osteoporotic fractures: a meta-analysis.

Haguenauer D, Welch V, Shea B, Tugwell P, Adachi JD, Wells G.

Clinical Epidemiology Unit, University of Ottawa, Ottawa Hospital, Ottawa, Ontario, Canada

Osteoporos Int 2000;11(9):727-38 Abstract quote

We conducted an effectiveness meta-analysis to determine the efficacy of fluoride therapy on bone loss, vertebral and nonvertebral fractures and side effects in postmenopausal women. A literature search was conducted on MEDLINE, Current Contents and the Cochrane Controlled Trial Registry. Two independent reviewers selected randomized controlled trials which met predetermined inclusion criteria. They independently extracted data using predetermined forms and assessed the methodologic quality of the trials using a validated scale. For dichotomous outcomes, the relative risk (RR) was calculated, and for continuous outcomes, the weighted mean difference (WMD) of percentage change from baseline was calculated. Where heterogeneity existed (determined by a chi-square test) a random effects model was used.

Eleven studies (1429 subjects) met the inclusion criteria. The increase in lumbar spine bone mineral density (BMD) was found to be higher in the treatment group than in the control group with a WMD 8.1% (95% CI: 7.15, 9.09) after 2 years of treatment and 16.1% (95% CI: 14.65, 17.5) after 4 years. The RR for new vertebral fractures was not significant at 2 years [0.87 (95% CI: 0.51, 1.46)] or at 4 years [0.9 (95% CI: 0.71, 1.14)]. The RR for new nonvertebral fractures was not significant at 2 years [1.2 (95% CI: 0.68, 2.10)] but was increased at 4 years in the treated group [1.85 (95% CI: 1.36, 2.50)], especially if used at high doses and in a non-slow-release form. The RR for gastrointestinal side effects was not significant at 2 years [2.18 (95% CI: 0.86, 1.21)] but was increased at 4 years in the treated group [2.18 (95% CI: 1.69, 4.57)], especially if fluoride was used at high doses and in a non-slow-release form. The number of withdrawals and dropouts was not different between treated and control groups at 2 and 4 years.

Thus, although fluoride has an ability to increase bone mineral density at the lumbar spine, it does not result in a reduction in vertebral fractures. Increasing the dose of fluoride increases the risk of nonvertebral fractures and gastrointestinal side effects without any effect on the vertebral fracture rate.

Cyclical etidronate versus sodium fluoride in established postmenopausal osteoporosis: a randomized 3 year trial.

Guanabens N, Farrerons J, Perez-Edo L, Monegal A, Renau A, Carbonell J, Roca M, Torra M, Pavesi M.

Metabolic Bone Diseases Unit, ICAL, Department of Medicine, IDIBAPS Hospital Clinic, University of Barcelona, Spain.

Bone 2000 Jul;27(1):123-8 Abstract quote

To compare the effects of sodium fluoride and etidronate in severe postmenopausal osteoporosis, we conducted a 3 year, prospective, trial in 118 postmenopausal osteoporotic women with at least one vertebral fracture, who were randomly assigned to receive sodium fluoride (25 mg twice daily, as enteric-coated tablets) plus calcium (1000 mg/day) or intermittent etidronate (400 mg/day for 14 days) followed by calcium (1000 mg/day for 76 days).

Lateral spine X-ray films and dual-energy X-ray absorptiometry (DXA) measurements of the lumbar spine and proximal femur were performed at enrollment and yearly. Nonvertebral fractures were recorded every 6 months. Thirty-one women in the fluoride group and 47 in the etidronate group completed the trial.

At 36 months, the mean change from baseline of the lumbar bone density in the fluoride group was 8.5 +/- 2.04% (p = 0.001) and in the etidronate group was of 3.6 +/- 0. 84% (p < 0.001). The changes in the fluoride group were significantly higher than in the etidronate group (p = 0.01). Both groups showed nonsignificant changes in femoral neck bone density. There was no significant difference between groups in the cumulative proportion of women with new vertebral fractures, with an incidence in the fluoride group of 16% vs. 17% in the etidronate group.

However, the number of new vertebral fractures was significantly lower in the fluoride group (6 fractures) than in the etidronate group (19 fractures) (p = 0.05). The number of patients with nonvertebral fractures was similar in both groups. A high incidence of side effects, mainly gastrointestinal symptoms and lower extremity pain syndrome, was observed in the fluoride group. Etidronate was well tolerated.

We conclude that, in women with severe osteoporosis, although sodium fluoride is more favorable than cyclical etidronate for increasing lumbar bone mass, no differences were observed in the incidence of fractures.

Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women.

Banks E, Beral V, Reeves G, Balkwill A, Barnes I; Million Women Study Collaborators.

Cancer Research UK Epidemiology Unit, Radcliffe Infirmary, Oxford, England
JAMA. 2004 May 12;291(18):2212-20. Abstract quote  

CONTEXT: Evidence is limited on the effects of different patterns of use of postmenopausal hormone therapy on fracture incidence and particularly on the effects of ceasing use.

OBJECTIVE: To investigate the effect of different patterns of hormone therapy use on fracture incidence.

DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 138,737 postmenopausal women aged 50 to 69 years recruited from the UK general population in 1996-1998 (the Million Women Study) and followed up for 1.9 to 3.9 years (average, 2.8 years) for fracture incidence.

MAIN OUTCOME MEASURE: Adjusted relative risk (RR) for incident fracture (except fracture of the fingers, toes, and ribs) in hormone therapy users compared with never users at baseline.

RESULTS: A total of 5197 women (3.7%) reported 1 or more fractures, 79% resulting from falls. Current users of hormone therapy at baseline had a significantly reduced incidence of fracture (RR, 0.62; 95% confidence interval [CI], 0.58-0.66; P<.001). This protection was evident soon after hormone therapy began, and the RR decreased with increasing duration of use (P =.001). Among current users at baseline the RR of fracture did not vary significantly according to whether estrogen-only, estrogen-progestin, or other types of hormones were used (RR [95% CI], 0.64 [0.58-0.71], 0.58 [0.53-0.64], and 0.67 [0.56-0.80], respectively; P =.19), nor did it vary significantly according to estrogen dose or estrogen or progestin constituents. The RR associated with current use of hormone therapy did not vary significantly according to 11 personal characteristics of study participants, including their age at menopause, body mass index, and physical activity. Past users of hormone therapy at baseline experienced no significant protection against fractures (RR, 1.07; 95% CI, 0.99-1.15); incidence rates returned to those of never-users within about a year of ceasing use.

CONCLUSIONS: All types of hormone therapy studied confer substantial protection against fracture while they are used. This protection appears rapidly after use commences and wears off rapidly after use ceases. The older women are, the greater is their absolute reduction in fracture incidence while using hormone therapy.

HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial.

Komulainen MH, Kroger H, Tuppurainen MT, Heikkinen AM, Alhava E, Honkanen R, Saarikoski S.

Department of Obstetrics and Gynecology, Kuopio University Hospital, Finland

Maturitas 1998 Nov 30;31(1):45-54 Abstract quote

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.

Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women.

Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH.

Internal Medicine, Helen Hayes Hospital, Rte 9W, West Haverstraw, NY 10993.

JAMA 2002 May 22;287(20):2668-76 Abstract quote

CONTEXT: Lower-than-commonly-prescribed doses of conjugated equine estrogens (CEEs) with medroxyprogesterone acetate (MPA) improve vasomotor symptoms and vaginal atrophy, provide acceptable bleeding and lipid profiles, and afford endometrial protection. This lower-dose therapy's protection against loss of bone mineral density (BMD) associated with menopause has not been thoroughly investigated.

OBJECTIVE: To determine the effects of lower doses of CEEs only or CEEs-MPA on spine and hip BMD, total body bone mineral content (BMC), and biochemical markers of bone turnover in postmenopausal women.

DESIGN AND SETTING: Two-year randomized, double-blind, placebo-controlled substudy of the Women's Health, Osteoporosis, Progestin, Estrogen trial, conducted at 19 US centers between August 1995 and October 2000.

PARTICIPANTS: Eight hundred twenty-two healthy postmenopausal women aged 40 to 65 years who were within 4 years of their last menstrual period.

INTERVENTIONS: Patients were randomly assigned to receive CEEs, 0.625; CEEs, 0.625 and MPA, 2.5; CEEs, 0.45; CEEs, 0.45 and MPA, 2.5; CEEs, 0.45 and MPA, 1.5; CEEs, 0.3; CEEs 0.3 and MPA, 1.5 (all doses in mg/d); or placebo for 2 years. All participants also received elemental calcium at 600 mg/d.

MAIN OUTCOME MEASURES: Changes from baseline in spine and total hip BMD, total body BMC, and biochemical markers of bone turnover (serum osteocalcin and urinary cross-linked N-telopeptides of type I collagen), assessed at 6-month intervals and compared among treatment groups with a modified intention-to-treat approach.

RESULTS: At 24 months, women assigned to all of the active treatment groups had significant gains from baseline (P<.001) in spine and hip BMD and total body BMC (except total body BMC in the group receiving CEEs, 0.3 mg/d). These changes were significantly different from those in the placebo group, in which losses of bone mass in spine and total body were evident over the course of the study (P<.001). The loss in hip BMD from baseline in the placebo group was significant at 18 (P =.02) but not at 24 months (P =.06). Osteocalcin and N-telopeptides of type I collagen were significantly reduced from baseline (P<.001) for all active treatment groups at all time points; no changes were found for the placebo group. For women treated with CEEs alone, the gains in spine BMD for the group taking CEEs, 0.625 mg/d, were significantly higher than those of the group taking CEEs, 0.3 mg/d (P =.02), but not the group treated with CEEs, 0.45 mg/d (P =.48).

CONCLUSIONS: Doses of CEEs or CEEs-MPA lower than 0.625 mg/d effectively increase BMD and BMC in early postmenopausal women.

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