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Biomedical subjects

Philip D Ross

Publications and source records attributed to Philip D Ross.

At least 19 recordsLinked to original sources
PubMed2006

A thermally induced phase transition in a viral capsid transforms the hexamers, leaving the pentamers unchanged.

Scanning calorimetry combined with cryo-electron microscopy affords a powerful approach to investigating hierarchical interactions in multi-protein complexes. Calorimetry can detect the temperatures at which certain interactions are disrupted and cryo-EM can reveal the accompanying structural changes. The procapsid of bacteriophage HK97 (Prohead I) is a 450A-diameter shell composed of 60 hexamers and 12 pentamers of gp5, organized with icosahedral symmetry. Gp5 consists of the N-terminal Delta-domain (11kDa) and gp5* (31 kDa): gp5* forms the contiguous shell from which clusters of Delta-domains extend inwards. At neutral pH, Prohead I exhibits an endothermic transition at 53 degrees C with an enthalpy change of 14 kcal/mole (of gp5 monomer). We show that this transition is reversible. To capture its structural expression, we incubated Prohead I at 60 degrees C followed by rapid freezing and, by cryo-EM, observed a capsid species 10% larger than Prohead I. At 11A resolution, visible changes are confined to the gp5 hexamers. Their Delta-domain clusters have disappeared and are presumably disordered, either by unfolding or dispersal. The gp5* hexamer rings are thinned and flattened as they assume the conformation observed in Expansion Intermediate I, a transition state of the normal, proteolysis-induced, maturation pathway. We infer that, at ambient temperatures, the hexamer Delta-domains restrain their gp5* rings from switching to a lower free energy, EI-I-like, state; above 53 degrees, this restraint is overcome. Pentamers, on the other hand, are more stably anchored and resist this thermal perturbation.

Bacteriophages↗
PubMed2006

A free energy cascade with locks drives assembly and maturation of bacteriophage HK97 capsid.

We investigated the thermodynamic basis of HK97 assembly by scanning calorimetry and cryo-electron microscopy. This pathway involves self-assembly of hexamers and pentamers of the precursor capsid protein gp5 into procapsids; proteolysis of their N-terminal Delta-domains; expansion, a major conformational change; and covalent crosslinking. The thermal denaturation parameters convey the changes in stability at successive steps in assembly, and afford estimates of the corresponding changes in free energy. The procapsid represents a kinetically accessible local minimum of free energy. In maturation, it progresses to lower minima in a cascade punctuated by irreversible processes ("locks"), i.e. proteolysis and crosslinking, that lower kinetic barriers and prevent regression. We infer that Delta-domains not only guide assembly but also restrain the procapsid from premature expansion; their removal by proteolysis is conducive to initiating expansion and to its proceeding to completion. We also analyzed the mutant E219K, whose capsomers reassemble in vitro into procapsids with vacant vertices called "whiffleballs". E219K assemblies all have markedly reduced stability compared to wild-type gp5 (DeltaT(p) approximately -7 degrees C to -10 degrees C; where T(p) is the denaturation temperature). As the mutated residue is buried in the core of gp5, we attribute the observed reduction in stability to steric and electrostatic perturbations of the packing of side-chains in the subunit interior. To explain the whiffleball phenotype, we suggest that these effects propagate to the capsomer periphery in such a way as to differentially affect the stability or solubility of dissociated pentamers, leaving only hexamers to reassemble.

Bacteriophages↗
PubMed2005

Crosslinking renders bacteriophage HK97 capsid maturation irreversible and effects an essential stabilization.

In HK97 capsid maturation, structural change ('expansion') is accompanied by formation of covalent crosslinks, connecting residue K169 in the 'E-loop' of each subunit with N356 on another subunit. We show by complementation experiments with the K169Y mutant, which cannot crosslink, that crosslinking is an essential function. The precursor Prohead-II passes through three expansion intermediate (EI) states en route to the end state, Head-II. We investigated the effects of expansion and crosslinking on stability by differential scanning calorimetry of wild-type and K169Y capsids. After expansion, the denaturation temperature (Tp) of K169Y capsids is slightly reduced, indicating that their thermal stability is not enhanced, but crosslinking effects a major stabilization (deltaTp, +11 degrees C). EI-II is the earliest capsid to form crosslinks. Cryo-electron microscopy shows that for both wild-type and K169Y EI-II, most E-loops are in the 'up' position, 30 A from the nearest N356: thus, crosslinking in EI-II represents capture of mobile E-loops in 'down' positions. At pH 4, most K169Y capsids remain as EI-II, whereas wild-type capsids proceed to EI-III, suggesting that crosslink formation drives maturation by a Brownian ratchet mechanism.

Bacteriophages↗
PubMed2005

Effect of alendronate on the age-specific incidence of symptomatic osteoporotic fractures.

UNLABELLED: Analyses of data from 3658 postmenopausal women with osteoporosis enrolled in the Fracture Intervention Trial showed that alendronate is effective in reducing the risk of symptomatic osteoporotic fractures across a spectrum of ages. INTRODUCTION: Most osteoporosis studies examine the relative risk of fracture based on the entire duration of treatment. Because older patients tend to be at higher risk for osteoporosis-related fractures, this analysis examined the effect of alendronate treatment on the relative risk of fracture in terms of the age that patients attained during the study. MATERIALS AND METHODS: We studied 3658 postmenopausal women with osteoporosis 55-80 years of age at baseline enrolled in the Fracture Intervention Trial, a large randomized, double-blind, placebo-controlled study. Patients were treated with placebo or with alendronate at a daily dose of 5 mg for 2 years followed by 10 mg for an additional 1-2.5 years, and monitored for clinical fractures. Age, rather than study time, was the dynamic variable in our analysis. RESULTS: The relative risk reductions for hip, clinical spine, and wrist fractures were constant across age groups, without evidence of a decline at older ages. Specifically, alendronate reduced the risk of clinical fracture by 53% at the hip (relative risk [RR] = 0.47; 95% CI = 0.27-0.81; p < 0.01), 45% at the spine (RR = 0.55; 95% CI = 0.37-0.83; p < 0.01), and 31% at the wrist (RR = 0.69; 95% CI = 0.50-0.98; p = 0.038). In addition, alendronate produced a significant risk reduction of 40% (RR = 0.60; 95% CI = 0.47-0.77; p < 0.01) for the composite event of clinical hip, spine, and wrist fractures. As a consequence of the constant relative risk model, the absolute risk reduction with alendronate treatment increased with age because of the age-related increase in fracture risk in the placebo group. The absolute risk reduction for the composite event (hip, spine, and wrist fractures together) for alendronate treatment versus placebo was 65, 80, 111, and 161 women with fractures per 10,000 PYR for the 55 to <65, 65 to <70, 70 to <75, and 75-85 year age groups, respectively. CONCLUSIONS: These data show that alendronate is effective in reducing the risk of symptomatic osteoporotic fractures across a spectrum of ages. The effectiveness is somewhat greater in patients with femoral neck T score < or = -2.5 than in those with a T score < or = -2.0.

Age Factors↗
PubMed2005

A risk assessment tool (OsteoRisk) for identifying Latin American women with osteoporosis.

OBJECTIVE: To develop a simple and easy-to-use tool for identifying osteoporotic women (femoral neck bone mineral density [BMD] T-scores or=50 in Latin America who had femoral neck BMD measurements. MEASUREMENTS AND MAIN RESULTS: A risk index was developed from 1,547 patients based on least square regression using age, weight, history of fractures, and other variables as predictors for BMD T-score. The final model was simplified by reducing the number of predictors; sensitivity and specificity were evaluated before and after reducing the number of predictors to assess performance of the index. The final model included age, weight, country, estrogen use, and history of fractures as significant predictors for T-score. The resulting scoring index achieved 91% sensitivity and 47% specificity. Simplifying the index by using only age and weight yielded similar performance (sensitivity, 92%; specificity, 45%). Three risk categories were identified based on OsteoRisk, the index using only age and body weight: high-risk patients (index <=-2; 65.6% were osteoporotic), moderate-risk patients (-2< index <=1; 26.7% were osteoporotic), and low-risk patients (index>1; 8% were osteoporotic). Similar results were seen in a validation sample of 279 women in Brazil. CONCLUSION: Age and weight alone performed well for predicting the risk of osteoporosis among postmenopausal women. The OsteoRisk is an easy-to-use tool that effectively targets the vast majority of osteoporotic patients in Latin America for evaluation with BMD.

Aged↗
PubMed2005

How useful are measures of BMD and bone turnover?

Measurements of bone mineral density (BMD) and biochemical markers of bone turnover are useful in the diagnosis and management of osteoporosis, as well as in research relating to the pathogenesis and treatment of the disease. Recent challenges to the utility of these measures have resulted in some confusion among both researchers and clinicians. BMD accounts for the great majority of bone strength and is the current gold standard for the diagnosis of osteoporosis, as well as for prediction of fracture risk. Although bone turnover increases sharply after menopause, biochemical markers of bone turnover have limited usefulness in fracture risk prediction. Persistently elevated bone turnover throughout the menopause is associated with structural decrements, cannot be measured routinely and non-invasively. In research applications, both BMD and markers of bone turnover are used to identify candidate agents in preclinical and clinical studies. In addition, head-to-head comparisons of treatments utilize these measures, because fracture endpoint trials would need to be extraordinarily large and complex. Analyses that have suggested that change in BMD or bone turnover 'explains' little of change in fracture risk with treatment appear to be flawed. Although neither can perfectly predict fracture, they are our current best alternatives.

Bone Density↗
PubMed2004

Development of a clinical assessment tool in identifying Asian men with low bone mineral density and comparison of its usefulness to quantitative bone ultrasound.

Osteoporosis in men is a largely neglected condition in Asia (and elsewhere), despite the fact that one-third of hip fractures occur in men. Moreover, access to bone mineral density (BMD) measurements is limited in many areas of Asia, and inexpensive methods of targeting high risk patients for BMD measurements would be valuable. We have developed a simple clinical assessment tool to identify high risk Asian men for BMD measurements. Information on risk factors was collected from 420 community-dwelling adult Chinese men aged 50 years and above using a structured questionnaire, and the ability of these risk factors to identify subjects with femoral neck BMD T score < or = -2.5 was assessed. Multiple regression analysis and item reduction yielded a final clinical risk assessment tool based on only age and weight, similar to the Osteoporosis Self-assessment Tool for Asians (OSTA), described previously for Asian women. The OSTA values of < or = -1 had a sensitivity of 81% and specificity of 66%, and the area under the receiver operating characteristics curve was 0.83. The index was validated in another sample of 356 men with a sensitivity of 82% and specificity of 67 %, and an AUC of 0.85. The usefulness of OSTA was further compared to calcaneal quantitative bone ultrasound (QUS) in the validation sample of 356 men. The optimal cutoff T score of -1.2 for QUS yielded sensitivity and specificity values of 75 and 67%, respectively. The AUC for QUS was 0.79. Combining OSTA and QUI gave a sensitivity of 88% and specificity of 66% to identify men with low BMD at the femoral neck, and an AUC of 0.86 which was statistically not different from either OSTA or QUI alone. We conclude that OSTA is a simple and effective clinical risk assessment tool for identifying not only female but also male subjects at increased risk of osteoporosis, and its use could facilitate the appropriate and more cost-effective use of bone densitometry in developing countries.

Absorptiometry, Photon↗
PubMed2004

The carboxy-terminal portion of TnsC activates the Tn7 transposase through a specific interaction with TnsA.

Tn7 transposition requires the assembly of a nucleoprotein complex containing four self-encoded proteins, transposon ends, and target DNA. Within this complex, TnsC, the molecular switch that regulates transposition, and TnsA, one part of the transposase, interact directly. Here, we demonstrate that residues 504-555 of TnsC are responsible for TnsA/TnsC interaction. The crystal structure of the TnsA/TnsC(504-555) complex, resolved to 1.85 A, illustrates the burial of a large hydrophobic patch on the surface of TnsA. One consequence of sequestering this patch is a marked increase in the thermal stability of TnsA as shown by differential scanning calorimetry. A model based on the complex structure suggested that TnsA and a slightly longer version of the cocrystallized TnsC fragment (residues 495-555) might cooperate to bind DNA, a prediction confirmed using gel mobility shift assays. Donor DNA binding by the TnsA/TnsC(495-555) complex is correlated with the activation of the TnsAB transposase, as measured by double-stranded DNA cleavage assays, demonstrating the importance of the TnsA/TnsC interaction in affecting Tn7 transposition.

Amino Acid Sequence↗
PubMed2004

The N-terminal prion domain of Ure2p converts from an unfolded to a thermally resistant conformation upon filament formation.

According to the "amyloid backbone" model of Ure2p prionogenesis, the N-terminal domain of Ure2p polymerizes to form an amyloid filament backbone surrounded by the C-terminal domains. The latter domains retain their native glutathione-S-transferase (GST)-like fold but are sterically inactivated from their regulatory role in nitrogen catabolism. We have tested this model by differential scanning calorimetry of soluble and filamentous Ure2p and of soluble C-terminal domains, combined with electron microscopy. As predicted, the C-terminal domains respond to thermal perturbation identically in all three states, exhibiting a single endotherm at 76 degrees C. In contrast, no thermal signal was associated with the N-terminal domains: in the soluble state of Ure2p, because they are unfolded; in the filamentous state, because their robust amyloid conformation resists heating to 100 degrees C.

Calorimetry, Differential Scanning↗
PubMed2004

Prevention of postmenopausal bone loss: six-year results from the Early Postmenopausal Intervention Cohort Study.

We report the effect of continuous treatment with alendronate for 6 yr vs. placebo in the Early Postmenopausal Intervention Cohort study. A total of 1609 healthy, early postmenopausal women were recruited; we describe results for the 585 women who received continuous placebo or alendronate (2.5 or 5 mg) daily for 6 yr. Bone mineral density (BMD) was evaluated at the lumbar spine, hip, forearm, and total body at baseline and annually thereafter. Bone turnover markers were measured every 6 months from baseline to yr 2 and annually thereafter. Adverse experiences, including upper gastrointestinal events and fractures, were recorded throughout the study. Women receiving placebo experienced progressive decreases in BMD at all skeletal sites. Patients receiving alendronate experienced significant gains in spine and hip BMD that were maintained through yr 6. Significantly greater, dose-related decreases in bone turnover markers in the alendronate groups vs. placebo occurred within the first year and were sustained through yr 6. Women receiving alendronate had adverse experience incidences similar to those receiving placebo. Fractures occurred in 11.5, 10.3, and 8.9% of women taking placebo, 2.5 mg alendronate, or 5 mg alendronate daily, respectively. Therapy with alendronate is an effective and promising strategy for the prevention of postmenopausal osteoporosis.

Alendronate↗
PubMed2003

Comparison of a simple clinical risk index and quantitative bone ultrasound for identifying women at increased risk of osteoporosis.

Osteoporosis is a growing problem in Asia, and early identification of at risk subjects for preventive measures is likely the most cost-effective method for managing this disease in developing countries. Patients with low bone mineral density (BMD) have a high risk of future fracture. However, access to BMD measurements is limited in many areas of Asia, and inexpensive methods of targeting high-risk patients for BMD measurements would be valuable. We compared two methods, a simple clinical risk assessment tool, the Osteoporosis Self-assessment Tool for Asians (OSTA), and quantitative bone ultrasound (QUS) in identifying subjects with low BMD by DXA in 722 southern Chinese postmenopausal women recruited from the community in Hong Kong. Using the published cutoff value of -1 (versus 0 or higher) for OSTA to identify subjects with femoral neck BMD T-score < or =-2.5, basing on our local population peak young mean value, the sensitivity and specificity was 88% and 54% respectively. The optimal cutoff T-score of -2.35 for QUS yielded sensitivity and specificity values of 81% and 65%, respectively. The AUC for QUS was 0.78, which was not significantly different from that of 0.80 for OSTA. Both OSTA and QUS correlated significantly with BMD at the femoral neck (0.62 and 0.36, respectively, P both <0.001). When these cut-off values were used to identify subjects with either lumbar spine or femoral neck BMD T-score < or =-2.5, the sensitivity and specificity was 79% and 60%, respectively, for OSTA, and 69% and 70%, respectively, for QUS. Combining QUS with OSTA improved the sensitivity to 91%, but the specificity was reduced to 44%. We conclude that the simple clinical risk assessment tool OSTA is a free and effective method for identifying subjects at increased risk of osteoporosis, and its use could facilitate the appropriate and more cost-effective use of bone densitometry in developing countries.

Absorptiometry, Photon↗
PubMed2003

The thermodynamic contribution of the 5-methyl group of thymine in the two- and three-stranded complexes formed by poly(dU) and poly(dT) with poly(dA).

To assess the thermodynamic contribution of the 5-methyl group of thymine, we have studied the two-stranded helical complexes poly(dA).poly(dU) and poly(dA).poly(dT) and the three-stranded complexes--poly(dA).2poly(dU), poly(dA).poly(dT).poly(dU) and poly(dA).2poly(dT)--by differential scanning calorimetry, and uv optical melting experiments. The thermodynamic quantities associated with the 3 --> 2, 2 --> 1, and 3 --> 1 melting transitions are found to vary with salt concentration and temperature in a more complex manner than commonly believed. The transition temperatures, T(m), are generally not linear in the logarithm of concentration or activity of NaCl. The change in enthalpy and in entropy upon melting varies with salt concentration and temperature, and a change in heat capacity accompanies each transition. The poly(dA).2poly(dU) triple helix is markedly different from poly(dA).2poly(dT) in both its CD spectrum and thermodynamic behavior, while the poly(dA).poly(dT).poly(dU) triple helix resembles poly(dA).2poly(dT) in these properties. In comparing poly(dA).2poly(dT) with either the poly(dA).poly(dT).poly(dU) or the poly(dA).2poly(dU) triplexes, the substitution of thymine for uracil in the third strand results in an enhancement of stability against the 3 --> 2 dissociation of deltadeltaG degrees = -135 +/- 85 cal (mol A)(-1) at 37 degrees C. This represents a doubling of the absolute stability toward dissociation compared to the triplexes with poly(dU) as the third strand. The poly (dA).poly (dT) duplex is more stable than poly(dA).poly(dU) by deltadeltaG degrees = -350 +/- 60 cal (mol base pair)(-1) at 37 degrees C. Poly(dA).poly(dT) has 50% greater stability than poly(dA).poly(dU) as a result of the dT for dU substitution in the duplex.

Adenine↗
PubMed2003

Biochemical markers for prediction of 4-year response in bone mass during bisphosphonate treatment for prevention of postmenopausal osteoporosis.

Short-term changes in biochemical markers of bone turnover (bone markers) have been suggested as predictors of long-term response in bone mass during antiresorptive treatment. In the Danish cohort (n = 306) of the Early Postmenopausal Intervention Cohort (EPIC) Study (n = 1609) of oral alendronate (ALN) for prevention of postmenopausal osteoporosis, bone markers (urine C-telopeptides of type I collagen (uCTX), urine N-telopeptide cross-links of type I collagen (uNTX), serum total osteocalcin measured by ELISA [total OC (ELISA)], and serum total osteocalcin measured by RIA [total OC (RIA)]) were measured at 6-month intervals. The correlation between 6-month change in uCTX and 4-year change in spine and hip bone mineral density (BMD) was r = -0.41 and r = -0.42, respectively (P < 0.001). The corresponding values for the other bone markers were r = -0.53 and r = -0.42 (uNTX), r = -0.46 and r = -0.47 [total OC (ELISA)], and r = -0.43 and r = -0.41 [total OC (RIA)], all P < 0.001. ROC curves were used to analyse the ability of the bone markers to predict a change in spine BMD greater than 0%. The best performance [defined as the maximum value of (sensitivity plus specificity)] was found at the cut-off values of a -29% change from baseline in uCTX, a -45% change from baseline in uNTX, a -13% change from baseline in total OC (ELISA), and a -15% change from baseline in total OC (RIA). At these values the corresponding sensitivity was 66% (uCTX), 76% (uNTX), 70% [total OC (ELISA)], and 83% [total OC (RIA)]. The specificity was 80% (uCTX), 75% (uNTX), 71% [total OC (ELISA)], and 55% [total OC (RIA)]. The positive predictive value (PPV) was 82% (uCTX), 80% (uNTX), 77% [total OC (ELISA)], and 71% [total OC (RIA)]. The negative predictive value (NPV) was 64% (uCTX), 70% (uNTX), 64% [total OC (ELISA)], and 71% [total OC (RIA)]. In conclusion, the bone markers predicted a change in spine BMD greater than 0% with a high PPV and specificity. There was a trend toward better performance in this respect for the bone resorption markers.

Alendronate↗
PubMed2003

Korean experience with the OSTA risk index for osteoporosis: a validation study.

The Osteoporosis Self-assessment Tool for Asians (OSTA) was developed to help physicians focus their efforts on patients at increased risk, and encourage appropriate use of bone mineral density (BMD) measurements. Previously, OSTA performed well in a sample of women from eight countries in Asia, and in a validation group of Japanese women. In this study, we evaluate the performance of OSTA using a sample of 1101 postmenopausal women from a clinic in Korea who had femoral neck BMD measurements by dual-energy X-ray absorptiometry (DXA). The OSTA had a high sensitivity (87%), and good specificity (67%) for identifying osteoporosis (BMD T-scores -1) to 64% among those classified as high risk (OSTA < -4); these results were almost identical to those reported earlier for a sample of women from eight Asian countries. We conclude that the OSTA risk tool performed well in this sample of postmenopausal Korean women, similar to previous results in other Asian women. The OSTA tool is free and very easy to use; risk can be tabulated by age and weight, so that calculations are not necessary. Using OSTA could encourage patients and clinicians to actively assess osteoporosis, and measure BMD when appropriate, before fractures occur.

Aged↗
PubMed2002

Appendicular bone mass and knee and hand osteoarthritis in Japanese women: a cross-sectional study.

BACKGROUND: It has been reported that there is an inverse association between osteoarthritis (OA) and osteoporosis. However, the relationship of bone mass to OA in a Japanese population whose rates of OA are different from Caucasians remains uncertain. METHODS: We studied the association of appendicular bone mineral density (second metacarpal; mBMD) and quantitative bone ultrasound (calcaneus; stiffness index) with knee and hand OA among 567 Japanese community-dwelling women. Knee and hand radiographs were scored for OA using Kellgren-Lawrence (K/L) scales. In addition, we evaluated the presence of osteophytes and of joint space narrowing. The hand joints were examined at the distal and proximal interphalangeal (DIP, PIP) and first metacarpophalangeal/carpometacarpal (MCP/CMC) joints. RESULTS: After adjusting for age and body mass index (BMI), stiffness index was significantly higher in women with K/L scale, grade 3 at CMC/MCP joint compared with those with no OA. Adjusted means of stiffness index and mBMD were significantly higher in women with definite osteophytes at the CMC/MCP joint compared to those without osteophytes, whereas there were no significant differences for knee, DIP and PIP joints. Stiffness index, but not mBMD, was higher in women with definite joint space narrowing at the CMC/MCP joint compared with those with no joint space narrowing. CONCLUSIONS: Appendicular bone mass was increased with OA at the CMC/MCP joint, especially among women with osteophytes. Our findings suggest that the association of peripheral bone mass with OA for knee, DIP or PIP may be less clearcut in Japanese women than in other populations.

Journal Article↗
PubMed2002

Association of body mass index with joint pain among community-dwelling women in Japan.

BACKGROUND AND AIMS: To investigate the impact of obesity on joint pain, we examined the association of body mass index (BMI) with joint pain. METHODS: 351 community-dwelling Japanese women aged 40-85 years were asked about joint pain at specific joints, and height and weight were measured. Logistic regression analysis was used to evaluate BMI and other potential predictors of joint pain. RESULTS: BMI was positively associated with knee pain, but not with pain at other specific joints, after adjusting for age. The association of BMI with knee pain remained significant after adjustment for an additional covariate (physical activity). We also examined the associations of age, BMI, and regular physical activity with joint pain at any site, in the arm, in the leg, or in the back. Independently of age and regular physical activity, BMI was positively associated with joint pain in the leg, but not with pain at any site, in the arm or in the back. No significant association of physical activity with joint pain at any site, in the arm, in the leg or in the back was found. CONCLUSIONS: Knee pain was associated with greater BMI. This finding supports previous longitudinal studies, suggesting that some knee pain could be prevented by avoidance of excess weight, if the association is causative. However, the association was not very strong; thus, it is likely that many cases of knee pain cannot be avoided by weight reduction only, and may require other interventions.

Aged↗
PubMed2002

Alendronate reduces the risk of multiple symptomatic fractures: results from the fracture intervention trial.

OBJECTIVES: To evaluate the effect of alendronate on the occurrence rate of multiple svmptomatic fractures and on the risk of multiple symptomatic fractures (likelihood of having more than one fracture diagnosed because of the symptoms the fractures caused over the study period) among women with osteoporosis. DESIGN: Primary analysis of data from a randomized, placebo-controlled, double-blind trial. SETTING: Eleven community-based clinical research centers. PARTICIPANTS: Subset of women enrolled in the Fracture Intervention Trial: aged 55 to 81 and having at least one morphometric vertebral fracture at baseline (n=2,027) or having no vertebral fracture but meeting prevailing World Health Organization bone mineral density criteria for osteoporosis (T-score < or =2.5 at the femoral neck)(n = 1,631). INTERVENTION: All participants reporting calcium intake of 1,000 mg/day or less received a supplement of 500 mg calcium and 250 IU cholecalciferol. Participants were randomly assigned to placebo or alendronate sodium (5 mg/day for 2 years and 10 mg/day for the remainder of the study). Average total follow-up was 4.3 years. MEASUREMENTS: Symptomatic fractures were diagnosed by personal physicians and confirmed by review of radiological data by an expert committee blinded to treatment assignments. RESULTS: Eighty-six of 1,817 women receiving placebo experienced multiple symptomatic fractures during the follow-up period, compared with 51 of 1,841 receiving alendronate. Reduction of risk for multiple symptomatic fractures combined was 42% (relative risk (RR) = 0.58, 95% confidence interval (CI) = 0.41, 0.81) and for multiple symptomatic vertebral fractures was 84% (RR = 0.16,95% Cl = 0.05, 0.42). Cumulative incidence curves showed divergence after as little as 3 months of treatment, with a statistically significant (P = .044) reduction at 6 months for multiple symptomatic vertebral fractures. When all fractures over the follow-up period were included, the occurrence rates of all symptomatic fractures and symptomatic vertebral fractures were 34% and 63% lower, respectively, with alendronate than with placebo. These reductions were sustained during the follow-up period. All reductions in risk were consistent across predefined subgroups: age (<75 vs > or =75), morphometric vertebral fracture(present vs absent), prior clinical fracture since age 45 (yes vs no), and whether the subject had fallen in the 12 months before randomization. CONCLUSIONS: These data demonstrate that treatment with alendronate reduces the risk of multiple symptomatic fractures during a treatment period averaging 4.3 years. The reductions were consistent across prespecified sub-groups. This effect is evident early in treatment and is sustained.

Aged↗