Evidence of taxonomy for Developmental Topographical Disorientation: Developmental Landmark Agnosia Case 1.

We report Developmental Landmark Agnosia (DLA) in a 6-year-old boy (L.G.) who was referred to us for congenital prosopagnosia (see Pizzamiglio et al., 2017 , in which both testing and rehabilitation of Congenital Prosopagnosia are reported). We investigated his performance using a neuropsychological battery and eye movement recordings. The assessment showed the presence of deficits in recognizing familiar places (along with Congenital Prosopagnosia), but not common objects. Eye movement recordings confirmed his problems in recognizing familiar landmarks and misrecognition of unfamiliar places. L.G. is the first evidence of a DLA, suggesting identification of taxonomy of navigational disorders in Developmental Topographical Disorientation is possible, as in the Acquired Topographical Disorientation.

Congenital prosopagnosia in a child: Neuropsychological assessment, eye movement recordings and training.

Here we report the assessment and treatment of a 6-year-old boy (L.G.) who was referred to us for congenital prosopagnosia (CP). We investigated his performance using a test battery and eye movement recordings pre- and post-training. L.G. showed deficits in recognising relatives and learning new faces, and misrecognition of unfamiliar people. Eye movement recordings showed that L.G. focused on the lower part of stimuli in naming tasks based on familiar or unfamiliar incomplete or complete faces. The training focused on improving his ability to explore internal features of faces, to discriminate specific facial features of familiar and unfamiliar faces, and to provide his family with strategies to use in the future. At the end of the training programme L.G. no longer failed to recognise close and distant relatives and classmates and did not falsely recognise unknown people.

In Vivo Efficacy of Measles Virus Fusion Protein-Derived Peptides Is Modulated by the Properties of Self-Assembly and Membrane Residence.

Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV hemagglutinin (H) and fusion (F) envelope glycoproteins; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad repeat (HR) regions of F can inhibit MV infection at the entry stage. In previous work, we have generated potent MV fusion inhibitors by dimerizing the F-derived peptides and conjugating them to cholesterol. We have shown that prophylactic intranasal administration of our lead fusion inhibitor efficiently protects from MV infection in vivo We show here that peptides tagged with lipophilic moieties self-assemble into nanoparticles until they reach the target cells, where they are integrated into cell membranes. The self-assembly feature enhances biodistribution and the half-life of the peptides, while integration into the target cell membrane increases fusion inhibitor potency. These factors together modulate in vivo efficacy. The results suggest a new framework for developing effective fusion inhibitory peptides. IMPORTANCE: Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS) and severe neurological disease. No specific treatment is available. We have shown that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. We show here that specific biophysical properties regulate the in vivo efficacy of MV F-derived peptides.

Age effect in generating mental images of buildings but not common objects.

Imagining a familiar environment is different from imagining an environmental map and clinical evidence demonstrated the existence of double dissociations in brain-damaged patients due to the contents of mental images. Here, we assessed a large sample of young and old participants by considering their ability to generate different kinds of mental images, namely, buildings or common objects. As buildings are environmental stimuli that have an important role in human navigation, we expected that elderly participants would have greater difficulty in generating images of buildings than common objects. We found that young and older participants differed in generating both buildings and common objects. For young participants there were no differences between buildings and common objects, but older participants found easier to generate common objects than buildings. Buildings are a special type of visual stimuli because in urban environments they are commonly used as landmarks for navigational purposes. Considering that topographical orientation is one of the abilities mostly affected in normal and pathological aging, the present data throw some light on the impaired processes underlying human navigation.

Peculiar body representation alterations in hemineglect: a case report.

We report the case of FP affected by personal and extrapersonal neglect and a body representation deficit characterized by delusional ideas. When FP performed the human figure, he placed body parts to the left, despite his extrapersonal neglect. Differently, when he performed the car figure, he placed all parts to the right, in line with his deficit. Comparing FP with a small patient group with the same clinical features without delusional ideas about body emerged that he was the only one to suffer from a specific body representation deficit characterized by a lack of body ownership sense.

One's own country and familiar places in the mind's eye: different topological representations for navigational and non-navigational contents.

Visual mental imagery is a process that draws on different cognitive abilities and is affected by the contents of mental images. Several studies have demonstrated that different brain areas subtend the mental imagery of navigational and non-navigational contents. Here, we set out to determine whether there are distinct representations for navigational and geographical images. Specifically, we used a Spatial Compatibility Task (SCT) to assess the mental representation of a familiar navigational space (the campus), a familiar geographical space (the map of Italy) and familiar objects (the clock). Twenty-one participants judged whether the vertical or the horizontal arrangement of items was correct. We found that distinct representational strategies were preferred to solve different categories on the SCT, namely, the horizontal perspective for the campus and the vertical perspective for the clock and the map of Italy. Furthermore, we found significant effects due to individual differences in the vividness of mental images and in preferences for verbal versus visual strategies, which selectively affect the contents of mental images. Our results suggest that imagining a familiar navigational space is somewhat different from imagining a familiar geographical space.

A selective egocentric topographical working memory deficit in the early stages of Alzheimer's disease: a preliminary study.

The aim of this study was to determine whether an egocentric topographical working memory (WM) deficit is present in the early stages of Alzheimer's disease (AD) with respect to other forms of visuospatial WM. Further, we would investigate whether this deficit could be present in patients having AD without topographical disorientation (TD) signs in everyday life assessed through an informal interview to caregivers. Seven patients with AD and 20 healthy participants performed the Walking Corsi Test and the Corsi Block-Tapping Test. The former test requires memorizing a sequence of places by following a path and the latter is a well-known visuospatial memory task. Patients with AD also performed a verbal WM test to exclude the presence of general WM impairments. Preliminary results suggest that egocentric topographical WM is selectively impaired, with respect to visuospatial and verbal WM, even without TD suggesting an important role of this memory in the early stages of AD.

What analytic method should clinicians use to derive spine T-scores and predict incident fractures in men? Results from the MrOS study.

UNLABELLED: In this study, the area under the curve was highest when using the lowest vertebral body T-score to diagnose osteoporosis. In men for whom hip imaging is not possible, the lowest vertebral body T-score improves the ability to diagnose osteoporosis in men who are likely to have an incident fragility fracture. INTRODUCTION: Spine T-scores have limited ability to predict fragility fracture. We hypothesized that using lowest vertebral body T-score to diagnose osteoporosis would better predict fracture. METHODS: Among men enrolled in the Osteoporotic Fractures in Men Study, we identified cases with incident clinical fracture (n = 484) and controls without fracture (n = 1,516). We analyzed the lumbar spine bone mineral density (BMD) in cases and controls (n = 2,000) to record the L1-L4 (referent), the lowest vertebral body, and International Society for Clinical Densitometry (ISCD)-determined T-scores using a male normative database and the L1-L4 T-score using a female normative database. We compared the ability of method to diagnose osteoporosis and, therefore, to predict incident clinical fragility fracture, using area under the receiver operator curves (AUCs) and the net reclassification index (NCI) as measures of diagnostic accuracy. ISCD-determined T-scores were determined in only 60 % of participants (n = 1,205). RESULTS: Among 1,205 men, the AUC to predict incident clinical fracture was 0.546 for L1-L4 male, 0.542 for the L1-L4 female, 0.585 for lowest vertebral body, and 0.559 for ISCD-determined T-score. The lowest vertebral body AUC was the only method significantly different from the referent method (p = 0.002). Likewise, a diagnosis of osteoporosis based on the lowest vertebral body T-score demonstrated a significantly better net reclassification index (NRI) than the referent method (net NRI +0.077, p = 0.005). By contrast, the net NRI for other methods of analysis did not differ from the referent method. CONCLUSION: Our study suggests that in men, the lowest vertebral body T-score is an acceptable method by which to estimate fracture risk.

The Walking Corsi Test (WalCT): a normative study of topographical working memory in a sample of 4- to 11-year-olds.

We report normative data on topographical working memory collected through the Walking Corsi Test (WalCT; Piccardi et al., 2008 ) for developing a standard administration procedure to be used in clinical and educational practice. A total of 268 typically developing Italian children aged 4-11 years performed both WalCT and Corsi Block-Tapping Test (CBT; Corsi, 1972 ) a well-known visuo-spatial memory test. WalCT has already been validated in adults, demonstrating sensitivity in detecting topographical memory deficits even in individuals who have no other memory impairments. Our results showed that age, but not sex, affected performances. Both girls and boys had a larger span on the CBT than the WalCT. The youngest group did not differ in performing WalCT and CBT, but from 5.6 years of age children performed better on CBT than WalCT, suggesting that memory in reaching space develops before topographical memory. Only after 5 years of age do children learn to process specifically topographical stimuli, suggesting that this happens when their environmental knowledge becomes operational and they increase environmental independence. We also discuss the importance to introduce WalCT in the clinical assessment.

Postmenopausal women treated with combination parathyroid hormone (1-84) and ibandronate demonstrate different microstructural changes at the radius vs. tibia: the PTH and Ibandronate Combination Study (PICS).

SUMMARY: In postmenopausal women receiving combination parathyroid hormone (PTH) (1-84) therapy and ibandronate, we evaluated bone microarchitecture and biomechanics using high-resolution peripheral quantitative computed tomography (HR-pQCT). Cortical and trabecular changes were different at the nonweight-bearing radius vs. the weight-bearing tibia, with more favorable overall changes at the tibia. INTRODUCTION: PTH therapy and bisphosphonates decrease fracture risk in postmenopausal osteoporosis, but their effects on bone microstructure and strength have not been fully characterized, particularly during combination therapy. PTH increases trabecular bone mineral density (BMD) substantially but may decrease cortical BMD, possibly by stimulating intracortical remodeling. We evaluated bone microarchitecture and biomechanics with HR-pQCT at the radius (a nonweight-bearing site) and tibia (weight bearing) in women receiving combination PTH(1-84) and ibandronate. METHODS: Postmenopausal women with low bone mass (n = 43) were treated with 6 months of PTH(1-84) (100 µg/day), either as one 6- or two 3-month courses, in combination with ibandronate (150 mg/month) over 2 years. HR-pQCT was performed before and after therapy. RESULTS: Because changes in HR-pQCT parameters did not differ between treatment arms, groups were pooled into one cohort for analysis. Trabecular BMD increased at both radius and tibia (p < 0.01 for each). Cortical thickness and BMD decreased at the radius (p < 0.01), consistent with changes in dual-energy X-ray absorptiometry, while these parameters did not change at the tibia (p ≤ 0.02 for difference between radius and tibia). In contrast, cortical porosity increased at the tibia (p < 0.01) but not radius. Stiffness and failure load decreased at the radius (p < 0.0001) but did not change at the tibia. CONCLUSIONS: Cortical and trabecular changes in response to the PTH/ibandronate treatment combinations utilized in this study were different at the nonweight-bearing radius vs. the weight-bearing tibia, with more favorable overall changes at the tibia. Our findings support the possibility that weight bearing may optimize the effects of osteoporosis therapy.

The Walking Corsi Test (WalCT): standardization of the topographical memory test in an Italian population.

Selective visuo-spatial memory deficits can seriously affect many aspects of daily life; for example, an individual may not remember where he put an object or which path he took to reach his destination. In general, visuo-spatial memory is assessed through pen-and-paper tests that mainly assess memory components in peripersonal space. Recent studies (Piccardi et al. in Exp Brain Res 206:171-177, 2010; Piccardi et al. in Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 18:362-384, 2011) have shown that brain-damaged patients selectively fail on navigation memory tasks but not on other tests of visuo-spatial memory ability. These findings underline the need for a standardized test that measures memory in navigation separately from other types of visuo-spatial memory. Here, we report the validation of the Walking Corsi Test (WalCT: Piccardi et al. in Neurosci Lett 432:127-131, 2008) on 289 individuals aged 15-86 years. The WalCT is a new instrument that assesses topographical memory in real environments and reproduces on a large-scale version the Corsi Block-Tapping Test (CBT: Corsi in Unpublished doctoral dissertation, McGill University, Montreal, 1972). The WalCT has been used in clinical practice and has proven sensitive in detecting navigational memory deficits even in individuals who have no other memory impairments (Piccardi et al. in Exp Brain Res 206:171-177, 2010; Piccardi et al. in Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 18:362-384, 2011; Bianchini et al. in Neuropsychologia 48:1563-1573, 2010 ).

MRI and CT findings of metastatic pulmonary calcification.

Metastatic pulmonary calcification is a consequence of calcium deposition in the normal pulmonary parenchyma, secondary to abnormal calcium metabolism. The most characteristic radiological manifestation is poorly defined nodular opacities that are mainly seen in the upper lung zone. The aim of this report is to describe the CT and MRI findings observed in two patients with metastatic pulmonary calcification. The disease may present in CT as consolidations with calcification, and with a high lesion/muscle signal intensity ratio on T(1) weighted imaging without contrast in MRI. The high signal on T(1) weighted imaging probably occurs because the low calcium concentration of the lesion changes the surface effects of diamagnetic calcium particles, causing T(1) shortening of water protons. MRI is a good option for characterising calcium accumulation caused by a metabolic disorder.

Predictors of new and severe vertebral fractures: results from the HORIZON Pivotal Fracture Trial.

UNLABELLED: We examined prevalent and recent vertebral fractures in 1 year as predictors of new vertebral fractures over subsequent 2 years using data from RCT placebo patients. We found that prevalent and recent vertebral fractures strongly and independently predicted subsequent vertebral fractures including those which were severe. INTRODUCTION: While several studies have shown that prevalent vertebral fractures (pVFx) increase the risk of new vertebral fractures (VFx), the impact of recent vertebral fractures on future fractures is less studied. METHODS: Data from the placebo arm of the HORIZON Pivotal Fracture Trial, an international trial of zoledronic acid in postmenopausal, osteoporotic women between 65 and 85 years, were used. We included the subset of 2677 women with annual spinal radiographs to study the impact of vertebral fractures in year 1 (Y1 VF) on those occurring in years 2 and 3 using morphometric and semiquantitative (SQ) criteria. In addition, a subset of severe VFx was defined using SQ criteria. Logistic regression examined the impact of pVFx and Y1 VF on all incident VFx and on severe incident VFx. RESULTS: Two hundred fourty-five (9.1%) women sustained a new VFx in years 2-3. VFx risk in years 2-3 was 3.9% in those without pVFx or VFy1 and 29.8% in those with both risk factors. Both pVF and VFy1 remained independent predictors for future VF when they were both entered into a logistic regression model (odds ratio (OR) = 3.3; 95% confidence interval (CI), 2.3-4.7; OR = 3.7, 95% CI, 2.3, 5.8, respectively). ORs were similar after adjustment. Of the total number of women, 4.1% had severe VFx. PVFx and Y1 VF were also significant predictors of severe VFx; however, Y1 VF appeared more strongly predictive of severe VFx. CONCLUSIONS: Prevalent and incident vertebral fractures are highly predictive of subsequent new and severe vertebral fractures. Women with both of these risk factors are likely to benefit from anti-osteoporosis treatment.

Developmental topographical disorientation in a healthy subject.

We present the case of F.G., a healthy, normally developed 22-year-old male subject affected by a pervasive disorder in environmental orientation and navigation who presents no history of neurological or psychiatric disease. A neuro-radiological examination showed no evidence of anatomical or structural alterations to the brain. We submitted the subject for a comprehensive neuropsychological assessment of the different cognitive processes involved in topographical orientation to evaluate his ability to navigate the spatial environment. The results confirmed a severe developmental topographical disorder and deficits in a number of specific cognitive processes directly or indirectly involved in navigation. The results are discussed with reference to the sole previously described case of developmental topographical disorientation (Pt1; Iaria et al., 2009). F.G. differs from the former case due to the following: the greater severity of his disorder, his complete lack of navigational skills, the failure to develop compensatory strategies, and the presence of a specific deficit in processing the spatial relationships between the parts of a whole. The present case not only confirms the existence of developmental topographical-skill disorders, but also sheds light on the architecture of topographical processes and their development in human beings.

The prevalence of radiographic vertebral fractures in Mexican men.

SUMMARY: The prevalence of radiographically ascertained vertebral fractures in a random sample of 413 in Mexican men is 9.7% (95% CI 6.85-12.55). Increase of vertebral fracture rises with age from 2.0% in the youngest group (50-59 years) to 21.4% in the oldest group (80 years and over). INTRODUCTION: This is the first population-based study of vertebral fractures in Mexican men using a standardized methodology reported in other studies. METHODS: The presence of radiographic vertebral fractures increases with age. This same pattern was found in Mexican women with steady age increments, but the higher prevalence of fractures in women starts at age 70, whereas in men, the higher prevalence starts a decade later (80 years and over). RESULTS: The standardized prevalence per 1,000 men 50 years and over in the Mexican population for the year 2005 is 65.8 (95% CI 29.9-105.5), and it is 68.6 (95% CI 32.2-108.7) in the US population for the year 2000.

The prevalence of radiographic vertebral fractures in Latin American countries: the Latin American Vertebral Osteoporosis Study (LAVOS).

UNLABELLED: In the first population-based study of vertebral fractures in Latin America, we found a 11.18 (95% CI 9.23-13.4) prevalence of radiographically ascertained vertebral fractures in a random sample of 1,922 women from cities within five different countries. These figures are similar to findings from studies in Beijing, China, some regions of Europe, and slightly lower than those found in the USA using the same standardized methodology. INTRODUCTION: We report the first study of radiographic vertebral fractures in Latin America. METHODS: An age-stratified random sample of 1,922 women aged 50 years and older from Argentina, Brazil, Colombia, Mexico, and Puerto Rico were included. In all cases a standardized questionnaire and lateral X-rays of the lumbar and thoracic spine were obtained after informed consent. RESULTS: A standardized prevalence of 11.18 (95% CI 9.23-13.4) was found. The prevalence was similar in all five countries, increasing from 6.9% (95% CI 4.6-9.1) in women aged 50-59 years to 27.8% (95% CI 23.1-32.4) in those 80 years and older (p for trend < 0.001). Among different risk factors, self-reported height loss OR = 1.63 (95% CI: 1.18-2.25), and previous history of fracture OR = 1.52 (95% CI: 1.14-2.03) were significantly (p < 0.003 and p < 0.04 respectably) associated with the presence of radiographic vertebral fractures in the multivariate analysis. In the bivariate analyses HRT was associated with a 35% lower risk OR = 0.65 (95% CI: 0.46-0.93) and physical activity with a 27% lower risk of having a vertebral fracture OR = 0.73 (95% CI: 0.55-0.98), but were not statistically significant in multivariate analyses CONCLUSION: We conclude that radiographically ascertained vertebral fractures are common in Latin America. Health authorities in the region should be aware and consider implementing measures to prevent vertebral fractures.

Vitamin D insufficiency does not affect response of bone mineral density to alendronate.

SUMMARY: We investigated whether osteoporosis therapy with alendronate in postmenopausal patients is equally effective in patients who are vitamin D insufficient as in those who are vitamin D sufficient. We found that vitamin D insufficiency is common among patients with low bone density but that vitamin D insufficiency did not impair response to alendronate. INTRODUCTION: Treatment of vitamin D deficiency leads to significant improvements in bone mineral density (BMD); however, whether insufficiency affects BMD's response to bisphosphonate therapy is unknown. METHODS: To determine whether vitamin D insufficiency at initiation of alendronate therapy for low BMD affects treatment efficacy, we used data from 1,000 postmenopausal women randomly selected from the vertebral fracture arm (n = 2,027) of the placebo-controlled Fracture Intervention Trial of alendronate. Participants were randomly assigned to placebo (50%) or alendronate therapy and most (83%) to calcium (500 mg/day) and cholecalciferol (250 IU/day). We measured serum 25-hydroxy vitamin D (25OHD) at enrollment, then categorized baseline vitamin D status according to 25OHD concentration (10 but 30 ng/ml = sufficient) and used linear regression to compare the effects of alendronate treatment among these categories. RESULTS AND CONCLUSION: At baseline, participants were vitamin D sufficient (14%), insufficient (83%), and deficient (2%). We found that BMD response to therapy at total hip or spine did not vary by vitamin D status at baseline (p for heterogeneity = 0.6). We determined that vitamin D insufficiency is common among participants with low BMD. However, vitamin D status at initiation of therapy does not affect BMD's response to alendronate, when it is coadministered with cholecalciferol and calcium.

Hetereogeneity in skeletal response to full-length parathyroid hormone in the treatment of osteoporosis.

UNLABELLED: In the PaTH trial, among the 119 women randomized to parathyroid hormone PTH(1-84) and 60 to alendronate, we found much greater variation in BMD and markers in response to PTH(1-84) compared to alendronate. No baseline participant characteristic consistently predicted increased bone density response to PTH(1-84), although women with larger changes in 1,25 dihydroxyvitamin D during therapy had larger increases in BMD. INTRODUCTION: We examined variability in BMD and markers of bone turnover in response to treatment with PTH(1-84) or alendronate in the PaTH trial. METHODS: Differences in SD were examined using Levine's test for homogeneity of variance. Change in BMD across quartiles of participant characteristics was examined using ANOVA. RESULTS: We found much greater variation in response to PTH(1-84) compared to alendronate. The SD for change in cancellous spine BMD (by QCT) was 32% on PTH(1-84) compared to 13% on alendronate (p < 0.0001). The higher variability in the PTH(1-84) group was due to substantial numbers of women with large increases in BMD on PTH(1-84). Similarly, the SD of changes in markers of formation and resorption were significantly higher on PTH(1-84) than on ALN. No baseline participant characteristics predicted increased bone density response to PTH(1-84) therapy. However, change in 1,25-OH(2)D explained 16% of the variance in BMD response to PTH(1-84). CONCLUSION: There is significant variability in the skeletal response to PTH(1-84), which exceeds that observed with alendronate. Changes in 1,25-OH(2)D were related to larger gains in BMD. This finding may have implications for elucidating either the pathway by which PTH affects the skeleton or traits that result in particular responsiveness to PTH therapy.

Short-term changes in bone turnover markers and bone mineral density response to parathyroid hormone in postmenopausal women with osteoporosis.

CONTEXT: Treatment of osteoporotic women with PTH increases biochemical markers of bone turnover, increases axial bone mineral density (BMD), and reduces fracture risk. OBJECTIVE: Our objective was to determine the relationship between levels of baseline turnover before PTH therapy and short-term changes in turnover during PTH therapy and subsequent changes in areal and volumetric BMD. DESIGN AND SETTING: We conducted a randomized, placebo-controlled trial at four academic centers. PATIENTS: Patients included 238 postmenopausal women with low hip or spine BMD. INTERVENTION: Subjects were randomized to sc PTH (1-84), 100 mug/d (119 women), for 1 yr. MAIN OUTCOME MEASURE: Bone turnover markers were measured in fasting blood samples collected before therapy and after 1 and 3 months. Areal and volumetric BMD at the spine and hip were assessed by dual-energy x-ray absorptiometry and quantitative computed tomography (QCT) after 1 yr of therapy. RESULTS: Among women treated with PTH alone, the relationships between baseline turnover and 1-yr changes in dual-energy x-ray absorptiometry and QCT BMD were inconsistent. Greater 1- and 3-month increases in turnover, particularly the formation marker N-propeptide of type I collagen, were associated with greater increases in areal BMD. When volumetric hip and spine BMD were assessed by QCT, greater short-term increases in turnover were even more positively associated with 1-yr increases in BMD. Each sd increase in the 3-month change of N-propeptide of type I collagen was associated with an a 21% greater increase in QCT spine trabecular BMD. CONCLUSIONS: Greater short-term changes in turnover with PTH therapy are associated with greater 1-yr increases in spine and hip BMD among postmenopausal osteoporotic women.

Risk of fracture among women who lose bone density during treatment with alendronate. The Fracture Intervention Trial.

It is commonly believed that the response to treatment in patients on alendronate is proportional to the increase in bone mineral density (BMD), and that those who lose BMD during treatment might not respond to treatment. In the Fracture Intervention Trial 6,459 women were randomly assigned to treatment with alendronate or placebo; BMD was measured annually, and new spine fractures were assessed by lateral spine films, taken at baseline and end of follow-up. Among subjects who took at least 70% of the study drug (5,220 women), we compared reductions in risk of spine fractures at end of follow-up (3 or 4 years) within various levels of change in total hip and spine BMD after 1 and 2 years of treatment, after adjustment for differences in characteristics between the treatment and control groups. Women "losing" BMD at the lumbar spine (0% to 4%) while on alendronate had a reduction of 60% in vertebral fracture risk [OR = 0.40 (0.16, 0.99)] compared to their counterparts in the placebo group. The few women that lost more than 4% did not have a significant benefit [OR = 0.15 (0.02, 1.29)]. Those who "gained" BMD (0% to 4%) during treatment had a reduction in risk of 51% [OR = 0.49 (0.30, 0.78)]. Similarly, women who "lost" total hip BMD (0% to 4%) during the first year on alendronate had a 53% decreased risk of vertebral fracture compared to their controls taking placebo [OR = 0.47 (0.27, 0.81)], whereas those "gaining" BMD (0% to 4%) had a comparable risk reduction [OR = 0.49 (0.34, 0.71)]. This was not observed for the few women who lost more than 4% [OR = 0.61 (0.11, 3.45)]. Patients who lost BMD at both the hip and spine were not protected by alendronate. Among patients who adhere to treatment with alendronate, even those who lose BMD benefit from a substantial reduction in risk of vertebral fracture. So, the reduction in bone turnover induced by alendronate might be more important than BMD changes. The few women who lose the most BMD (more than 4% per year) might not benefit from the treatment.