Do Markers of Bone Resorption Add to Bone Mineral Density and Ultrasonographic Heel Measurement for the Prediction of Hip Fracture in Elderly Women? The EPIDOS Prospective Study

We have previously shown that hip bone mineral density (BMD), heel broadband ultrasound attenuation (BUA) and bone resorption markers are independent predictors of hip fracture in elderly women. We investigated whether a combination of these three parameters could improve the predictive value of a single test in a nested case–control analysis (75 hip fractures and 228 age-matched controls) of the EPIDOS prospective study comprising 7598 healthy women 75 years of age and older followed prospectively for a mean 22 months. At baseline, prior fracture, femoral neck BMD by dual-energy X-ray absorptiometry (DXA), heel BUA and urinary type I collagen C-telopeptide breakdown products (CTX) were assessed. The area under the receiver operating characteristic curve was significant for the three diagnostic tests, heel BUA being the best single predictor. The added value of urinary CTX to either BMD or BUA depends on the cutoff point chosen to define patients at risk and on the therapeutic strategy that is considered. Defining patients at risk as those with low BMD (or low BUA) or high CTX resulted in a significant increase in the sensitivity compared with BMD or BUA alone – a strategy that could be applied when a broad treatment is considered. However, this increased sensitivity was also obtained simply by increasing the BMD and BUA cutoffs, suggesting that a combination of CTX with BMD/BUA is not useful for that type of treatment strategy. Conversely, defining patients at risk as those with both low BMD and high CTX increases the specificity (88% vs 78%) with a similar number of hip fracture patients being identified (30% vs 32%) – a combination that could be useful when the strategy is to target treatment to a subset of high-risk patients. This strategy appears to be more cost-effective than bone mass measurement alone as indicated by the 37% fewer patients who need to be treated to avoid one fracture per year. If DXA or ultrasound is not available, the combination of a bone resorption marker with a history of any type of fracture after the age of 50 years gave a predictive value similar to that obtained with femoral neck BMD or heel BUA alone, for both types of treatment strategy. We conclude that the combination of urinary CTX with hip BMD could be useful for the identification of elderly women at high risk for hip fracture, resulting in higher specificity for a given sensitivity threshold than BMD measurement alone. If DXA is not available, the combination of history of fracture and urinary CTX performs as well as hip BMD to assess hip fracture risk in elderly women. Received: 24 November 1997 / Revised: 3 March 1998     

A Comparison of Continuous Alendronate, Cyclical Alendronate and Cyclical Etidronate with Calcitriol in the Treatment of Postmenopausal Vertebral Osteoporosis: A Randomized Controlled Trial

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<0.01) 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. Received: 6 April 1999 / Accepted: 8 June 2000     

Six and Twelve Month Changes in Bone Turnover are Related to Reduction in Vertebral Fracture Risk During 3 Years of Raloxifene Treatment in Postmenopausal Osteoporosis

We studied the relationship between change in bone turnover and vertebral fracture risk during raloxifene therapy using 3-year data from the MORE trial, where 2622 of the 7705 randomized women had measurement of bone markers at baseline and after 6 and 12 months participation. Change in bone turnover was significantely related to future risk of vertebral fracture, also after adjusting for baseline vertebral fracture status and BMD. Thus, for a decrease of 9.3 mg/l in serum osteocalcin after 1 year’s raloxifene therapy, the odds ratio (OR) for a new vertebral fracture during 3 years was 0.69 (0.54–0.88), p= 0.003. Similarly, for a decrease of 5.91 mg/l in serum bone alkaline phosphatase, OR was 0.75 (0.62–0.92), p= 0.005. The change in BMD over 12 and 24 months was not related to fracture risk in any of the analyses. The strongest predictor for vertebral fracture was prevalent vertebral fracture – even during therapy. The predictive value of baseline BMD was in the same order of magnitude as bone turnover change during raloxifene treatment. In conclusion, the change in bone turnover is related to fracture risk during raloxifene therapy. In contrast the change in BMD is not related to fracture risk. The strongest predictor for vertebral fracture is prevalent vertebral fracture. Received: 2 January 2001 / Accepted: 30 May 2001     

Serum Bone Alkaline Phosphatase and Calcaneus Bone Density Predict Fractures: A Prospective Study

The aim of this study was to assess the ability of serum bone-specific alkaline phosphatase (bone ALP), creatinine-corrected urinary collagen crosslinks (CTx) and calcaneus bone mineral density (BMD) to identify postmenopausal women who have an increased risk of osteoporotic fractures. Calcaneus BMD and biochemical markers of bone turnover (serum bone ALP and urinary CTx) were measured in 512 community-dwelling postmenopausal women (mean age at baseline 69 years) participating in the Hawaii Osteoporosis Study. New spine and nonspine fractures subsequent to the BMD and biochemical bone markers measurements were recorded over an average of 2.7 years. Lateral spinal radiographs were used to identify spine fractures. Nonspine fractures were identified by self-report at the time of each examination. During the 2.7-year follow-up, at least one osteoporotic fracture occurred in 55 (10.7%) of the 512 women. Mean baseline serum bone ALP and urinary CTx were significantly higher among women who experienced an osteoporotic fracture compared with those women who did not fracture. In separate age-adjusted logistic regression models, serum bone ALP, urinary CTx and calcaneus BMD were each significantly associated with new fractures (odds ratios of 1.53, 1.54 and 1.61 per SD, respectively). Multiple variable logistic regression analysis identified BMD and serum bone ALP as significant predictors of fracture (p = 0.002 and 0.017, respectively). The results from this investigation indicate that increased bone turnover is significantly associated with an increased risk of osteoporotic fracture in postmenopausal women. This association is similar in magnitude and independent of that observed for BMD. Received: 18 June 1999 / Accepted: 21 June 1999     

Performance of COLIA1 Polymorphism and Bone Turnover Markers to Identify Postmenopausal Women with Prevalent Vertebral Fractures

Some studies have suggested that bone turnover markers (BTM) and collagen type I alpha 1 gene (COLIA1) may be useful in the prediction of rates of future bone loss, and may therefore provide information about fracture risk. Our study aimed to examine the association of the COLIA1 genotype with the risk of vertebral fracture and to investigate the predictive value of this genetic factor in comparison with bone mineral density (BMD) and BTM, in ambulatory postmenopausal Spanish women. We determined the COLIA1 polymorphism by polymerase chain reaction, BMD by dual-energy X-ray absorptiometry and BTM in 43 postmenopausal women with prevalent vertebral fracture and a control group of 101 postmenopausal women without fracture. There was a significant overrepresentation of the ‘T’ allele in fractured women (p= 0.029). BTM exhibited no differences between women with or without fractures or COLIA1 genotype groups. After adjusting for all other variables, the osteoporosis densitometric criteria variable was the most strongly associated with fracture (OR = 5 [1.8–13.3]) followed by COLIA1 (OR = 2.1 [1–4.3] per copy of the ‘T’ allele). Our study shows that COLIA1 is associated with prevalent vertebral fracture independently of bone mass, and the performance of this genetic factor to assess prevalent vertebral fracture is better than bone turnover markers. Received: 29 June 2001 / Accepted: 11 December 2001     

An Assessment Tool for Predicting Fracture Risk in Postmenopausal Women

Due to the magnitude of the morbidity and mortality associated with untreated osteoporosis, it is essential that high-risk individuals be identified so that they can receive appropriate evaluation and treatment. The objective of this investigation was to develop a simple clinical assessment tool based on a small number of risk factors that could be used by women or their clinicians to assess their risk of fractures. Using data from the Study of Osteoporotic Fractures (SOF), a total of 7782 women age 65 years and older with bone mineral density (BMD) measurements and baseline risk factors were included in the analysis. A model with and without BMD T-scores was developed by identifying variables that could be easily assessed in either clinical practice or by self-administration. The assessment tool, called the FRACTURE Index, is comprised of a set of seven variables that include age, BMD T-score, fracture after age 50 years, maternal hip fracture after age 50, weight less than or equal to 125 pounds (57 kg), smoking status, and use of arms to stand up from a chair. The FRACTURE Index was shown to be predictive of hip fracture, as well as vertebral and nonvertebral fractures. In addition, this index was validated using the EPIDOS fracture study. The FRACTURE Index can be used either with or without BMD testing by older postmenopausal women or their clinicians to assess the 5-year risk of hip and other osteoporotic fractures, and could be useful in helping to determine the need for further evaluation and treatment of these women. Received: 7 November 2000 / Accepted: 23 May 2001     

Does the Combination of Quantitative Ultrasound and Dual-Energy X-Ray Absorptiometry Improve Fracture Discrimination?

The widespread availability of quantitative ultrasound (QUS) and X-ray absorptiometry densitometers raises the question of whether a combination of QUS and bone mineral density (BMD) measurements could provide a clinically useful method of enhancing the prediction of fracture risk. The aim of this study was to examine whether a combination of axial BMD and calcaneal QUS measurements can enhance fracture discrimination compared with either method alone. The study population consisted of 154 postmenopausal women with a history of atraumatic fracture at the spine, hip or forearm and 221 healthy postmenopausal women with no clinical risk factors for osteoporosis. Subjects had dual-energy X-ray absorptiometry (DXA) measurements of the lumbar spine (LS), femoral neck (FN) and total hip (THIP) and calcaneal broadband ultrasound attenuation (BUA) and speed of sound (SOS) measurements on the Hologic Sahara (SAH) and Osteometer DTUone (DTU). Z-scores were calculated using the mean and SD obtained from the healthy postmenopausal group. Logistic regression analysis yielded odds ratios for BMD measurements at the LS, FN and THIP of 2.2, 2.2 and 2.3, respectively. The odds ratios obtained for QUS measurements ranged from 2.5 for DTU BUA to 3.3 for SAH SOS. While these odds ratios for QUS measurements were higher than those obtained for BMD measurements, the differences were not statistically significant. When the odds ratios for QUS were adjusted for BMD at the spine and hip, the odds ratios remained significant in all cases indicating that QUS and BMD variables contribute independently to fracture discrimination. When the BMD-adjusted odds ratios were compared with those for QUS alone, they were slightly lower but not significantly so. When the QUS measurements were adjusted for THIP BMD, the odds ratios for QUS tended to be lower than when adjusted for LS and FN BMD. The Z-scores for each of the QUS measurement variables were combined with spine or hip Z-scores. Logistic regression analysis of the QUS and BMD combined Z-scores yielded slightly higher odds ratios of approximately 3.1 (compared with 2.9 obtained for QUS alone) and increases in the area under the curve of approximately 2%. However, these increases were not clinically significant. In conclusion, the combination of axial BMD and calcaneal QUS measurements did not significantly improve fracture discrimination compared with either method alone. Received: 29 June 2000 / Accepted: 18 December 2000     

Bisphosphonates in the Treatment of Thalassemia-Induced Osteoporosis

The aim of our randomized, placebo-controlled study was to investigate the effects of 2 years’ daily oral administration of alendronate or intramuscular administration of clodronate every 10 days, on bone remodeling parameters and bone mineral density (BMD), safety and tolerability in a group of osteoporotic thalassemic patients. Twenty-five young patients (mean age 26.6 ± 7.1 years) with beta-thalassemia major were randomly divided to receive placebo or 100 mg of clodronate intramuscularly every 10 days or 10 mg of alendronate per os daily. All patients took 500 mg of elemental calcium and 400 IU cholecalciferol in the evening at meal time. After 2 years, pyridinium crosslinks, which are bone resorption markers, did not differ significantly from baseline values in the placebo group, whereas they had decreased significantly in the clodronate and alendronate groups. Osteocalcin, a bone formation marker, did not change significantly in the placebo group, whereas it decreased slightly, but not significantly, in the clodronate and alendronate groups after 12 and 24 months. At the end of the study, the lumbar spine BMD had decreased significantly in the placebo group; it did not change significantly in the clodronate group; in the alendronate group it had increased but not significantly, whereas the increase was significant with respect to the placebo group. Femoral neck BMD decreased significantly in the placebo group; it did not change significantly in the clodronate group, but increased significantly in the alendronate group. No relevant side effects were recorded during our study. In conclusion, in patients with thalassemia-induced osteoporosis, the daily administration of alendronate significantly increases BMD, the most important predictor of the risk of fracture at several sites. Clodronate treatment at our dosage is ineffective in this pathology in spite of the good compliance of patients. Received: 13 August 2001 / Accepted: 19 February 2002     

Prevention of Corticosteroid-Induced Osteoporosis with Alendronate in Sarcoid Patients

Prolonged corticosteroid administration, as often required in the treatment of sarcoidosis, increases the risk of osteoporosis and fracture. The aim of the present study was to evaluate the usefulness of alendronate, a third generation bisphosphonate, in preventing corticosteroid-induced osteoporosis. Forty-three consecutive, previously untreated, sarcoid patients (17 men and 26 premenopausal women) were included in the study: 13 needed no treatment and served as controls (Group 1) and 30 needed glucocorticoids (prednisone) and were randomly selected to also receive either placebo (n = 15, Group 2) or alendronate 5 mg/day (n = 15, Group 3). Bone mineral density (BMD) at the ultradistal radius by dual photon absorptiometry (Osteograph 1000, NIM, Verona, Italy) and biochemical markers of bone turnover were measured at baseline and after 6 and 12 months of glucocorticoid therapy. No significant difference was found between Groups 2 and 3 in the mean cumulative dose of prednisone (4945 ± 1956 mg and 5110 ± 2013 mg, respectively). At the end of the study period, BMD increased by 0.8% in the alendronate-treated group; in the placebo-treated group, BMD decreased by 4.5%. The difference between groups was significant (P < 0.01, ANOVA). A significant decrease in markers of bone formation was found in all patients treated with prednisone (Groups 2 and 3), independently of alendronate. Alendronate, however, counteracted the increase in markers of bone resorption induced by glucocorticoid therapy. Our data suggest that alendronate is effective in preventing glucocorticoid-induced bone loss in sarcoid patients. Further studies on alendronate use in steroid-induced osteoporosis are needed. Received: 30 September 1996 / Accepted: 30 April 1997     

A Simple Tool to Identify Asian Women at Increased Risk of Osteoporosis

Patients with low bone mineral density (BMD) have a high risk of future fractures, and should be actively considered for treatment to reduce their risk. However, BMD measurements are not widely available in some communities, because of cost and lack of equipment. Simple questionnaires have been designed to help target high-risk women for BMD measurements, thereby avoiding the cost of measuring women at low risk. However, such tools have previously focused on evaluation of non-Asian women. We collected information about numerous risk factors from postmenopausal Asian women in eight countries in Asia using questionnaires, and evaluated the ability of these risk factors to identify women with osteoporosis as defined by femoral neck BMD T-scores < or =-2.5. Multiple variable regression analysis and item reduction yielded a final tool based on only age and body weight. This risk index had a sensitivity of 91% and specificity of 45%, with an area under the curve of 0.79. Previously published risk indices based on larger numbers of variables performed similarly well in this Asian population. Large differences in risk were identified using our index to create three categories: 61% of the high-risk women had osteoporosis, compared with only 15% and 3% of the intermediate- and low-risk women, respectively. The low-risk group represented 40% of all women, for whom BMD measurements are probably not needed unless important risk factors, such as prior nonviolent fracture or corticosteroid use, are present. An existing population-based sample of postmenopausal Japanese women was used to validate our index. In this sample of Japanese women the sensitivity was 98% and specificity was 29%; the low-risk category, for whom BMD is probably unnecessary, represented 25% of all women. We conclude that our index performed well for classifying the risk of osteoporosis among postmenopausal Asian women and applying it would result in more prudent use of BMD technology.     

A Comparison of the Effect of Risedronate and Etidronate on Lumbar Bone Mineral Density in Japanese Patients with Osteoporosis: A Randomized Controlled Trial

To demonstrate the clinical benefit of 2.5 mg daily risedronate in the treatment of involutional osteoporosis, the effect of risedronate on bone mineral density (BMD) of the lumbar spine was compared with that of etidronate, selected as a representative of the bisphosphonates currently marketed in Japan. In this multicenter, randomized, double-masked, active (etidronate) controlled comparative study, a total of 235 Japanese patients with involutional osteoporosis were randomized to receive either treatment with 2.5 mg/day of risedronate for 48 weeks or intermittent treatment with etidronate (4 cycles of 2 weeks of treatment with 200 mg/day followed by 10-week medication-free periods). All patients received 200 mg of calcium supplement daily in the form of the calcium lactate. Bone mineral density of the lumbar spine (L2–L4 BMD) was determined at 12, 24, 36 and 48 weeks by dual-energy X-ray absorptiometry. The primary endpoint was the percent change in L2–L4 BMD from baseline to the time of final evaluation. Changes in biochemical markers of bone turnover and safety profiles were also compared. A significant increase in L2–L4 BMD was observed at 12 weeks after initiation of therapy in both the risedronate (2.8%) and etidronate (1.8%) groups. The increase in L2–L4 BMD at the time of final evaluation in the risedronate group (4.9%) was significantly greater (p = 0.002) than that in the etidronate group (3.1%). The changes in bone resorption markers (urinary total deoxypyridinoline and N-terminal telopeptide of type I collagen) from baseline to 48 weeks were −37.6% and −41.3% for risedronate and −22.5% and −26.6% for etidronate, respectively. New vertebral fractures or deterioration of existing fractures were observed in 2.8% (3/106) of the patients in the etidronate group, while no such cases (0/101) were observed in the risedronate group. No significant difference in the incidence of adverse events was found between two treatments. Daily oral risedronate (2.5 mg) exhibited efficacy superior to that of intermittent cyclical etidronate (200 mg) in increasing L2–L4 BMD, and was well tolerated by Japanese patients with involutional osteoporosis. Received: 7 February 2002 / Accepted: 18 July 2002     

Changes in Bone Mass and Bone Turnover Following Ankle Fracture

Bone loss and increased bone turnover are recognized local changes after a fracture, but the exact patterns of these changes after different fractures are unclear. We aimed to investigate the changes in bone density and biochemical markers following ankle fracture. Fourteen subjects (7 postmenopausal women and 7 men, mean age 63 years) were recruited following fracture of the distal tibia and fibula. Bone mineral density (BMD) of the ankle and proximal femur were measured by dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) of the calcaneus at 0, 6, 12, 26 and 52 weeks after fracture. Serum and urine samples were collected at 0, 3 and 7 days and at 2, 4, 6, 12, 26 and 52 weeks after fracture to measure markers of bone turnover. For bone formation we measured: bone alkaline phosphatase (iBAP), osteocalcin (Oc), procollagen type I N-terminal propeptide (PINP); and for bone resorption: tartrate-resistant acid phosphatase (TRAcP), deoxypyridinoline (iFDpd), N-telopeptides of type I collagen (NTx). We used the nonfractured limb to calculate values for baseline BMD and QUS. There was a significant decrease in BMD at the ultradistal ankle (p<0.001), the trochanteric region of the hip (p<0.01) and QUS of the heel after ankle fracture. This bone loss was maximal for ultradistal ankle BMD by 6 weeks at 13% (p<0.001) and for the trochanter by 26 weeks at 3% (p<0.01). The ankle BMD returned to baseline at 52 weeks but the trochanter BMD did not. Velocity of sound (VOS) decreased at 6 weeks by 2% (p<0.01) and broadband ultrasound attenuation (BUA) by 15% (p<0.01). VOS recovered completely by 52 weeks, but BUA did not return to baseline. Bone formation markers increased significantly between 1 and 4 weeks by 11–78% (p<0.01), and iBAP returned to baseline at 52 weeks but PINP and Oc remained elevated. Bone resorption markers did not increase and NTx was decreased at 52 weeks. We conclude that BMD decreased distal and immediately proximal to the fracture line when measured with DXA and QUS. Ankle BMD and heel VOS recovered at 52 weeks (trochanteric BMD and heel BUA did not) and the bone turnover markers returned toward baseline. Received: 27 January 1999 / Accepted: 19 April 1999     

Digital X-ray Radiogrammetry Predicts Hip,Wrist and Vertebral Fracture Risk in Elderly Women: A Prospective Analysis from the Study of Osteoporotic Fractures

Digital X-ray radiogrammetry (DXR) is a technique that uses automated image analysis of standard hand radiographs to estimate bone mineral density (DXR-BMD). Previous studies have shown that DXR-BMD measurements have high precision, are strongly correlated with forearm BMD and are lower in individuals with prevalent fractures. To determine whether DXR-BMD measurements predict wrist, hip and vertebral fracture risk we conducted a case–cohort study within a prospective study of 9704 community-dwelling elderly women (the Study of Osteoporotic Fractures). We compared DXR-BMD, and BMD of the radius (proximal and distal), calcaneus, femoral neck and posteroanterior lumbar spine in women who subsequently suffered a wrist (n= 192), hip (n= 195), or vertebral fracture (n= 193) with randomly selected controls from the same cohort (n= 392–398). DXR-BMD was estimated from hand radiographs acquired at the baseline visit. The radiographs were digitized and the Pronosco X-posure System was used to compute DXR-BMD from the second through fourth metacarpals. Wrist fractures were confirmed by radiographic reports and hip fractures were confirmed by radiographs. Vertebral fractures were defined using morphometric analysis of lateral spine radiographs acquired at baseline and an average of 3.7 years later. Age-adjusted odds ratio (OR, vertebral fracture) or relative hazard (RH, wrist and hip fracture) for a 1 SD decrease in BMD were computed. All BMD measurements were similar for prediction of wrist (RH = 1.5–2.1) and vertebral fracture (OR = 1.8–2.5). Femoral neck BMD best predicted hip fracture (RH = 3.0), while the relative hazards for all other BMD measurements were similar (RH = 1.5–1.9). These prospective data indicate that DXR-BMD performs as well as other peripheral BMD measurements for prediction of wrist, hip and vertebral fractures. Therefore, DXR-BMD may be useful for prediction of fracture risk in clinical settings where hip BMD is not available. Received: 27 April 2001 / Accepted: 10 October 2001     

Identification of Metabolic Bone Disease in Patients with Endogenous Hyperthyroidism: Role of Biological Markers of Bone Turnover

Active hyperthyroidism is associated with reduced bone mass. Nevertheless, not all patients show the same risk for developing osteoporosis. Our aim was to analyze some clinical and biochemical potential predictors of low bone mass in hyperthyroid patients. We studied 127 consecutive hyperthyroid patients (110 females, 17 males; aged 42 ± 16 years). Bone mineral density (BMD) was measured by dual X-ray absorptiometry (DXA) at lumbar spine (LS; L₂–L₄) and femoral neck (FN). Data were expressed as g/cm² and T-score. Patients were placed into two groups based on recent WHO criteria: Group A, no osteoporosis (n = 98); and group B, lumbar or femoral osteoporosis (n = 29). Study protocol included evaluation of osteoporosis risk factors, anthropometrical variables, thyroid function, and bone turnover markers. Receiver-operating characteristic (ROC) plots for the precision of bone markers and multivariate analysis for the prediction of BMD and osteoporosis were performed. Group B showed greater age and proportion of menopausal females; lower weight, height, and calcium intake; longer duration of menopause; and greater levels of total and bone alkaline phosphatase and of urine hydroxyproline. No differences in thyroid function, osteocalcin, tartrate-resistant acid phosphatase, and type I collagen C-telopeptide (ICTP) were found. The best predictive model accounted for 46% and 62% of the variability of lumbar and femoral BMD respectively and correctly classified 89% of the osteoporotic hyperthyroid patients. No significant difference in ROC plots was observed. It is concluded that hyperthyroid patients with lumbar or femoral osteoporosis show a typical clinical and biochemical profile illustrating that the relationship between BMD and bone markers is better in high turnover states. Classical bone turnover markers show high performance in the evaluation of hyperthyroid bone disease. Received: 5 May 1997 / Accepted: 5 June 1997     

Quantitative Ultrasound of Bone in Male Osteoporosis

Quantitative ultrasound (QUS) measurement, a different approach to bone fragility assessment, has already been attempted in women with osteoporosis but rarely in men. In order to test its value and ability to identify osteoporotic men, a case–control prospective study was conducted using the Lunar Achilles, a device that measures attenuation and velocity parameters. Broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI), a composite parameter, were assessed through the heel of 66 osteoporotic patients, and compared with the results in 35 controls. Patients had sustained a low-trauma fracture and/or had a lumbar and/or femoral bone mineral density (BMD) more than 2.5 SD below the young male reference value. As expected, all QUS parameters were statistically lower in patients, as were the dual-energy X-ray absorptiometry (DXA) measurements at the hip and lumbar spine. The two methods were compared for their ability to predict the risk of osteoporotic fractures. The odds ratios (ORs), with their 95% confidence limits, for fractures per 1 SD decrease were significant, especially for SOS and SI (OR = 2.3 [1.4–3.6] and 2.1 [1.3-3.3] respectively) and to a lesser extent for BUA (1.6 [1.0–2.4]). Our study suggests that QUS is associated with a history of low-trauma fracture in men; sensitivity is, however, less than when results are compared with BMD measurements (OR = 2.8 [1.6–5.0] and 3.4 [1.6–7.0] for lumbar spine and hip, respectively). Prospective studies are required before QUS can be recommended for clinical use in male osteoporosis. Received: 11 June 2001 / Accepted: 16 November 2001     

Treatment of Postmenopausal Women with Osteoporosis or Low Bone Density with Raloxifene

Raloxifene, a selective estrogen receptor modulator (SERM), has been shown to improved bone mineral density (BMD) and serum lipid profiles in healthy postmenopausal women. The objective of this study was to examine the effects of raloxifene on BMD, biochemical markers of bone metabolism and serum lipids in postmenopausal women with low bone density or osteoporosis. This Phase II, multicenter, 24-month, double-masked study assessed the efficacy and safety of raloxifene in 129 postmenopausal women (mean age ± SD: 60.2 ± 6.7 years) with osteoporosis or low bone density (baseline mean lumbar spine BMD T-score: −2.8). Women were randomly assigned to one of three treatment groups: placebo, 60 mg/day raloxifene-HCl (RLX 60) or 150 mg/day raloxifene-HCl (RLX 150) and concomitantly received 1000 mg/day calcium and 300 U/day vitamin D₃. At 24 months, BMD was significantly increased in the lumbar spine (+3.2%), femoral neck (+2.1%), trochanter (+2.7%) and total hip (+1.6%) in the RLX 60 group compared with the placebo group (p<0.05). The RLX 150 group had increases in BMD similar to those observed with RLX 60. A greater percentage of raloxifene-treated patients, compared with those receiving placebo, had increased BMD (p<0.05). Serum bone-specific alkaline phosphatase activity, serum osteocalcin, and urinary type I collagen:creatinine ratio were significantly decreased in the RLX-treated groups, compared with the placebo group (p<0.01). RLX 60 treatment significantly decreased serum levels of triglycerides, and total- and LDL-cholesterol levels (p<0.01). The rates of patient discontinuation and adverse events were not significantly different among groups. In this study, raloxifene increased bone density, decreased bone turnover, and improved the serum lipid profile with minimal adverse events, and may be a safe and effective treatment for postmenopausal women with osteoporosis or low bone density. Received: 26 December 1998 / Accepted: 31 March 1999     

Separate and Combined Value of Bone Mass and Gait Speed Measurements in Screening for Hip Fracture Risk: Results from the EPIDOS Study

Based on data from the EPIDOS prospective study, we have shown that femoral bone mineral density (BMD), calcaneal ultrasound measurements and fall-related factors are significant predictors of the risk of hip fracture. The goal of the present investigation, in the same cohort of elderly women, was (1) to assess and compare the value of femoral BMD, calcaneal broadband ultrasound attenuation (BUA), gait speed and age for identifying elderly women at high risk of hip fracture and (2) to determine whether combining two or more of these measurements would improve predictive ability over single measures. A total of 5895 elderly women had baseline measurements of femoral neck BMD by dual-energy X-ray absorptiometry, calcaneal BUA and gait speed. During an average of 33 months of follow-up, 170 women suffered a hip fracture. We compared the sensitivity and specificity of single and combined measures for three specific cutoff levels to define high risk, i.e., the median, the top quartile and the top decile of risk. We found that femoral BMD, calcaneal BUA, gait speed and age have approximatively the same discriminant value to identify women at high risk of hip fracture even though certain measures and combinations of measures have a significantly higher sensitivity for certain cutoff levels. The sensitivity of the available screening tools is low, even when they are combined: to obtain a sensitivity of about 80%, approximately 50% of the population must be considered to be at high risk. Received: 13 April 1998 / Accepted: 23 May 1998     

Bone turnover markers: understanding their value in clinical trials and clinical practice

While bone mineral density (BMD) by dual-energy X-ray absorptiometry is the primary method of determining fracture risk, assessing bone turnover may add valuable information for the management of patients with low bone mass. Bone turnover markers (BTMs) are used in clinical trials where they can provide essential information on the biological efficacy of osteoporosis treatments. In such population-based studies, BTMs can predict fracture risk independent of BMD. When combined with BMD, they improve the fracture risk estimate above and beyond BMD alone in postmenopausal osteoporotic women. Since changes in bone turnover after the initiation of therapy with bone resorption inhibitors occur much more rapidly than changes in BMD, treatment efficacy could, in theory, be determined within weeks of using BTMs. However, such predictive value is limited by the large biological variability of these biochemical markers, even though newer automated methods have reduced their analytical variability. Consequently, widespread adoption as a means of predicting treatment efficacy in fracture prevention for individual patients cannot yet be recommended. BTMs may be useful for monitoring adherence to antiresorptive therapy and may aid in identifying patients for whom antiresorptive therapy is most appropriate. Thus, although BTMs are currently confined to clinical research applications, further improvement in assay precision may extend their diagnostic value in clinical settings.     

Fall Characterictics, Functional Mobility and Bone Mineral Density as Risk Factors of Hip Fracture in the Community-Dwelling Ambulatory Elderly

Hip fracture is the most serious consequence of osteoporosis, frequently occurring in the elderly; however, no research has been performed to identify the fall characteristics, functional mobility and bone mineral density (BMD) concurrently as risk factors. We investigated the risk factors of hip fractures using a multifactorial approach for a further preventive strategy. This age- and sex-matched case-control study was conducted in a community-based general hospital. A total of 252 consecutive community-dwelling ambulatory elderly, aged between 65 and 85 years, were studied: 127 patients (faller with hip fracture) and 125 controls (faller without hip fracture). Body mass index (BMI), predisposing medical conditions, fall characteristics, functional mobility and BMD of the hip were evaluated by direct interview and clinical examination. In the final model of multivariate regression analysis, risk factors for hip fracture were direct hip impact (adjusted odds ratio (OR), 4.9; 95% confidence interval (CI), 2.7–8.8), previous stroke (adjusted OR, 2.9; 95% CI, 1.3–6.3), sideways fall (adjusted OR, 2.5; 95% CI, 1.6–3.9), functional mobility (a decrease of 1 SD; adjusted OR, 2.0; 95% CI, 1.1–3.5), BMI (a decrease of 1 SD; adjusted OR, 1.8; 95% CI, 1.1–2.8) and femoral neck BMD (a decrease of 1 SD; adjusted OR, 1.7; 95% CI, 1.0–2.8). The effect of risk factors remained the same in different analysis sets, and adding or removing femoral neck BMD did not change other risk factors, though BMD was significantly correlated with functional mobility and BMI. Importantly, both sideways fall and direct hip impact are independent predictors of hip fracture. From these results, we suggest a preventive strategy of hip fracture in the elderly: besides the maintenance of BMD, keeping an appropriate body weight and maintaining a physically active lifestyle might be crucial. Received: 11 January 2001 / Accepted: 6 July 2001     

Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk.

The change in BMD is a poor predictor of vertebral fracture risk after raloxifene treatment. One-year percent change in bone turnover and BMD was used to predict vertebral fracture risk. The percent change in osteocalcin was determined to be a better predictor of vertebral fracture risk than BMD. INTRODUCTION: The association between baseline BMD and fracture risk is well understood. However, the relationship between changes in BMD and fracture risk is not well defined. It has previously been demonstrated that BMD change was a poor predictor of vertebral fracture risk in raloxifene-treated women, whereas bone turnover markers were significantly associated with fracture risk. In the current analysis, we explore the prediction of vertebral fracture risk using changes in both BMD and bone turnover. MATERIALS AND METHODS: The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a randomized, placebo-controlled trial of 7705 women with osteoporosis treated with raloxifene 60 or 120 mg/day for 3 years. Markers of bone turnover were measured in one-third of the study population (n = 2503), and the present analyses include these women. Logistic regression models were constructed using one-year percent changes in BMD and bone turnover and relevant baseline demographics to predict the risk of vertebral fracture with pooled raloxifene therapy at 3 years. All covariates were standardized before modeling to facilitate direct comparisons between changes in BMD and bone turnover. RESULTS AND CONCLUSION: Prevalent vertebral fracture status (p < 0.0001), baseline lumbar spine BMD (p < 0.0001), and number of years postmenopausal (p = 0.0005) were independent predictors of fracture risk in raloxifene-treated patients. Therapy-by-change in femoral neck BMD (p = 0.02) and therapy-by-change in osteocalcin (OC; p = 0.01) were also significant for all treatment groups, indicating that changes in BMD and OC have different effects on fracture risk for the placebo and pooled raloxifene groups. The final model included significant baseline variables and change in OC (p = 0.01), whereas change in femoral neck BMD was not significant. After adjustment of each significant baseline variable, the percent change in OC was better able to predict the reduction in vertebral fracture risk than the percent change in femoral neck BMD in patients treated with raloxifene.