Intravenous Pamidronate as Treatment for Osteoporosis after Heart Transplantation: A Prospective Study

Fractures due to osteoporosis are one of the major complications after heart transplantation, occurring mostly during the first 6 months after the graft, with an incidence ranging from 18% to 50% for vertebral fractures. Bone mineral density (BMD) decreases dramatically following the graft, at trabecular sites as well as cortical sites. This is explained by the relatively high doses of glucocorticoids used during the months following the graft, and by a long-term increase of bone turnover which is probably due to cyclosporine. There is some evidence for a beneficial effect on BMD of antiresorptive treatments after heart transplantation. The aim of this study was to assess prospectively the effect on BMD of a 3-year treatment of quarterly infusions of 60 mg of pamidronate, combined with 1 g calcium and 1000 U vitamin D per day, in osteoporotic heart transplant recipients, and that of a treatment with calcium and vitamin D in heart transplant recipients with no osteoporosis. BMD of the lumbar spine and the femoral neck was measured by dual-energy X-ray absorptiometry in all patients every 6 months for 2 years and after 3 years. Seventeen patients, (1 woman, 16 men) aged 46 ± 4 years (mean ± SEM) received only calcium and vitamin D. A significant decrease in BMD was observed after 6 months following the graft, at the lumbar spine (−6.6%) as well as at the femoral neck (−7.8%). After 2 years, BMD tended to recover at the lumbar spine, whereas the loss persisted after 3 years at the femoral neck. Eleven patients (1 woman and 10 men) aged 46 ± 4 years (mean ± SEM) started treatment with pamidronate on average 6 months after the graft, because they had osteoporosis of the lumbar spine and/or femoral neck (BMD T-score below −2.5 SD). Over the whole treatment period, a continuous increase in BMD at the lumbar spine was noticed, reaching 18.3% after 3 years (14.3% compared with the BMD at the time of the graft). BMD at the femoral neck was lowered in the first year by −3.4%, but recovered totally after 3 years of treatment. In conclusion, a 3-year study of treatment with pamidronate given every 3 months to patients with existing osteoporosis led to a significant increase in lumbar spine BMD and prevented loss at the femoral neck. However, since some of these patients were treated up to 14 months after the transplant, they may already have passed through the phase of most rapid bone loss. In patients who were not osteoporotic at baseline, treatment with calcium and vitamin D alone was not able to prevent the rapid bone loss that occurs immediately after transplantation. Received: 31 June 2000 / Accepted: 23 August 2000     

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     

Bone Mineral Density and Vertebral Fractures in Men

In women, many studies indicate that the risk of vertebral fragility fractures increases as bone mineral density (BMD) declines. In contrast, few studies are available for BMD and vertebral fractures in men. It is uncertain that the strength of the relationship between BMD and fractures is similar in magnitude in middle-aged men and in postmenopausal women. In the present study, 200 men (mean age 54.7 years) with lumbar osteopenia (T-score <−1.5) were recruited to examine the relationships between spine BMD and hip BMD and the associations of BMD with vertebral fractures. Lumbar BMD was assessed from L2 to L4, in the anteroposterior view, using dual-energy X-ray densitometry. At the upper left femur, hip BMD was measured at five regions of interest: femoral neck, trochanter, intertrochanter, Ward’s triangle and total hip. Spinal radiographs were analyzed independently by two trained investigators and vertebral fracture was defined as a reduction of at least 20% in the anterior, middle or posterior vertebral height. Spinal radiographs evidenced at least one vertebral crush fracture in 119 patients (59.5%). The results of logistic regression showed that age, femoral and spine BMDs were significant predictors of the presence of a vertebral fracture. Odds ratios for a decrease of 1 standard deviation ranged from 1.8 (1.3–2.8) for spine BMD to 2.3 (1.5–3.6) for total hip BMD. For multiple fractures odds ratios ranged from 1.7 (1.1–2.5) for spine BMD to 2.6 (1.7–4.3) for total hip BMD. In all models, odds ratios were higher for hip BMD than for spine BMD, particularly in younger men, under 50 years. A T-score <−2.5 in the femur (total femoral site) was associated with a 2.7-fold increase in the risk of vertebral fracture while a T-score <−2.5 in the spine was associated with only a 2-fold increase in risk. This study confirms the strong association of age and BMD with vertebral fractures in middle-aged men, shows that the femoral area is the best site of BMD measurement and suggests that a low femoral BMD could be considered as an index of severity in young men with lumbar osteopenia. Received: 27 October 1998 / Accepted: 22 February 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     

Cut-off Values Determined for Vertebral Fracture by Peripheral Quantitative Computed Tomography in Japanese Women

In spite of the benefits of bone mass measurement by dual-energy X-ray absorptiometry (DXA), the use of DXA has limitations. It is unable to assess a true bone density, and cannot discriminate between the trabecular and cortical bone compartments. Ultradistal radius bone density was measured using peripheral quantitative computed tomography (pQCT) to determine reference values for total bone density (BD), trabecular bone density (TBD), polar strength strain index (pSSI), total bone mineral content (BC), trabecular bone mineral content (TBC), cortical bone density (CBD), cortical bone mineral content (CBC) and polar cross-sectional moment of inertia (pCSMI) in the Japanese female population, and to ascertain the cut-off values of the measured indicators that could most efficiently discriminate osteoporotic subjects with vertebral fractures. A total of 5266 healthy Japanese women aged 20–89 years were included in this study to determine Japanese reference values. Additionally, 621 who had undergone radiographic examination of the thoracic and lumbar spine at the time of pQCT measurement were selected to determine the cut-off values of BD, TBD, pSSI and other indicators for vertebral fractures. All the healthy subjects were divided into 5 year age groups. The BD showed nonsignificant changes from the 20–24 year age group to the 45–49 year age group, and fell significantly thereafter. The TBD maintained a plateau until the 40–44 year group, which corresponds to the young adult mean (YAM) values of the lumbar spine, femoral neck and radius BMDs measured using DXA. The TBD decreased significantly thereafter. The pSSI did not change significantly from the 20–24 year age group to the 45–49 year age group, and decreased slightly in the 50–54 year age group and markedly after 55–59 years. The cut-off values for the discrimination of vertebral fractures were obtained by the calculation of sensitivities, specificities and the area under the curves obtained using age-adjusted receiver operating characteristics (ROC) analysis. Odds ratios and 95% confidence limits (CL) were calculated using age-adjusted logistic analysis. The cut-off values for vertebral fractures, the area under the ROC curves (AUC) and odds ratios were 270.1 mg/cm³ (−2.2 SD, 66.6% of YAM), 0.689 ± 0.025, 2.10 (1.63, 2.70) for BD, 104.8 mg/cm³ (−2.2 SD, 53.5% of YAM), 0.699 ± 0.023, 2.17 (1.69, 2.77) for TBD and 192.8 mm³ (−1.9 SD, 59.8% of YAM), 0.631 ± 0.028, 1.72 (1.34, 2.21) for pSSI, respectively. These findings suggest that ultradistal radius BMD measured using pQCT can be used to discriminate women with vertebral fractures. Received: 3 August 2000 / Accepted: 5 March 2001     

Multisite Quantitative Ultrasound: Colles’ Fracture Discrimination in Postmenopausal Women

Distal forearm fractures are the most common perimenopausal fracture and are generally associated with osteoporosis. The aim of this study was to evaluate the capability of speed of sound (SOS) measurements in cortical bone at the phalanx, radius, tibia and metatarsal to discriminate Colles’ fracture cases from controls in postmenopausal women and to compare this with bone mineral density (BMD) measurements obtained by dual-energy X-ray absorptiometry (DXA). Sixty-three postmenpausal Colles’ fracture cases and 191 postmenopausal controls had SOS measurements of the radius, tibia, phalanx and metatarsal using a semi-reflection ultrasound technique and BMD measurements of the lumbar spine and proximal femur using DXA. The age-adjusted odds ratios (ORs) for fracture for the SOS measurement sites were 1.50 [95% CI 1.07–2.10] for the radius, 1.23 [0.86-1.76] for the tibia, 1.85 [1.06–3.23] for the phalanx and 1.74 [1.12–2.71] for the metatarsal site. For the BMD measurements the ORs were 1.95 [1.34–2.85] for the lumbar spine, 2.21 [1.43–3.40] for the femoral neck and 2.62 [1.69–4.08] for the total hip. The benefits of combining sites either by taking their average Z-score or by using the manufacturer’s ORI algorithm were evaluated. The two methods yielded similar results and the ORs for the combination of the radius and phalanx were 2.00 [1.21–3.33], for the radius and metatarsal 1.67 [1.05–2.67], for the phalanx and metatarsal 1.86 [1.11–3.08] and for the radius, phalanx and metatarsal 1.81 [1.07–3.06]. Combinations of DXA sites gave 2.22 [1.44–3.41] for the lumbar spine and femoral neck and 2.41 [1.57–3.70] for the lumbar spine and total hip. In conclusion, semi-reflection ultrasound measurements at the radius, phalanx or metatarsal demonstrated an ability to discriminate fracture cases from controls in postmenopausal Colles’ fracture patients, although the odds ratios were lower than with spine and femur BMD. Received: 6 July 2001 / Accepted: 11 December 2001     

A Randomized Trial of Sodium Fluoride (60 mg) ± Estrogen in Postmenopausal Osteoporotic Vertebral Fractures: Increased Vertebral Fractures and Peripheral Bone Loss with Sodium Fluoride; Concurrent Estrogen Prevents Peripheral Loss, But Not Vertebral Fractures

Postmenopausal Caucasian women aged less than 80 years (n= 99) with one or more atraumatic vertebral fracture and no hip fractures, were treated by cyclical administration of enteric coated sodium fluoride (NaF) or no NaF for 27 months, with precautions to prevent excessive stimulation of bone turnover. In the first study 65 women, unexposed to estrogen (–E study), age 70.8 ± 0.8 years (mean ± SEM) were all treated with calcium (Ca) 1.0–1.2 g daily and ergocalciferol (D) 0.25 mg per 25 kg once weekly and were randomly assigned to cyclical NaF (6 months on, 3 months off, initial dose 60 mg/day; group F CaD, n= 34) or no NaF (group CaD, n= 31). In the second study 34 patients, age 65.5 ± 1.2 years, on hormone replacement therapy (E) at baseline, had this standardized, and were all treated with Ca and D and similarly randomized (FE CaD, n= 17; E CaD, n= 17) (+E study). The patients were stratified according to E status and subsequently assigned randomly to ± NaF. Seventy-five patients completed the trial. Both groups treated with NaF showed an increase in lumbar spinal density (by DXA) above baseline by 27 months: FE CaD + 16.2% and F CaD +9.3% (both p= 0.0001). In neither group CaD nor E CaD did lumbar spinal density increase. Peripheral bone loss occurred at most sites in the F CaD group at 27 months: tibia/fibula shaft –7.3% (p= 0.005); femoral shaft –7.1% (p= 0.004); distal forearm –4.0% (p = 0.004); total hip –4.1% (p = 0.003); and femoral neck –3.5% (p= 0.006). No significant loss occurred in group FE CaD. Differences between the two NaF groups were greatest at the total hip at 27 months but were not significant [p<0.05; in view of the multiple bone mineral density (BMD) sites, an alpha of 0.01 was employed to denote significance in BMD changes throughout this paper]. Using Cox’s proportional hazards model, in the –E study there were significantly more patients with first fresh vertebral fractures in those treated with NaF than in those not so treated (RR = 24.2, p= 0.008, 95% CI 2.3–255). Patients developing first fresh fractures in the first 9 months were markedly different between groups: –23% of F CaD, 0 of CaD, 29% of FE CaD and 0 of E CaD. The incidence of incomplete (stress) fractures was similar in the two NaF-treated groups. Complete nonvertebral fractures did not occur in the two +E groups; there were no differences between groups F CaD and CaD. Baseline BMD (spine and femoral neck) was related to incident vertebral fractures in the control groups (no NaF), but not in the two NaF groups. Our results and a literature review indicate that fluoride salts, if used, should be at low dosage, with pretreatment and co-treatment with a bone resorption inhibitor. Received: 22 August 2000 / Accepted: 23 July 2001     

Osteoporosis and Apolipoprotein E Genotype in Older Adults: The Rancho Bernardo Study

Recent studies reported an association between apolipoprotein E (ApoE) 4 and osteoporosis. We examined the association of ApoE 4 genotype with bone mineral density (BMD), bone loss and fracture risk in 596 men and 332 community-dwelling women aged 45–95 years. Women were postmenopausal and not using estrogen. At the baseline visit, BMD was measured at the ultradistal and midshaft radius using single photon densitometry, and at the hip and lumbar spine using dual-energy X-ray absorptiometry. Hip and lumbar spine BMD levels were remeasured 4 years later. Self-reported fractures were confirmed by radiology reports in 95% of cases. ApoE allele distribution did not vary by age; 25% of men and 20% of women had one ApoE 4 allele. There were no differences in BMD at the lumbar spine, total hip, ultradistal or midshaft radius in men or women with the ApoE 4 allele compared with men or women without the ApoE 4 allele. After an average 4 year interval, there were also no differences in the annualized percent change in BMD at the hip or lumbar spine in men or women with or without an ApoE 4 allele. One or more clinical fractures were reported by 55 men and 109 women. Fewer, not more, clinical fractures were reported in men and women with an ApoE 4 allele; these differences were not statistically significant (p= 0.21 and p= 0.62, respectively). These data do not support the hypotheses that there is an association between ApoE genotype and BMD, bone loss or osteoporotic fractures in older community-dwelling men or women. Received: 26 July 2000 / Accepted: 13 October 2000     

Sex Difference in the Validity of Vertebral Deformities as an Index of Prevalent Vertebral Osteoporotic Fractures: A Population Survey of Older Men and Women

Morphometric methods have been developed for standardized assessment of vertebral deformities in clinical and epidemiologic studies of spinal osteoporosis. However, vertebral deformity may be caused by a variety of other conditions. To examine the validity of morphometrically assessed vertebral deformities as an index of osteoporotic vertebral fractures, we developed an algorithm for radiological differential classification (RDC) based on a combination of quantitative and qualitative assessment of lateral spinal radiographs. Radiographs were obtained in a population of 50- to 80-year-old German women (n= 283) and men (n = 297) surveyed in the context of the European Vertebral Osteoporosis Study (EVOS). Morphometric methods (Eastell 3 SD and 4 SD criteria, McCloskey) were validated against RDC and against bone mineral density (BMD) at the femur and the lumbar spine. According to RDC 36 persons (6.2%) had at least one osteoporotic vertebral fracture; among 516 (88.9%) nonosteoporotics 154 had severe spondylosis, 132 had other spinal disease and 219 had normal findings; 14 persons (2.4%) could not be unequivocally classified. The prevalence of morphometrically assessed vertebral deformities ranged from 7.3% to 19.2% in women and from 3.5% to 16.6% in men, depending on the stringency of the morphometric criteria. The agreement between RDC and morphometric methods was poor. In men, 62–86% of cases with vertebral deformities were classified as nonosteoporotic (severe spondylosis or other spinal disease) by RDC, compared with 31–68% in women. Among these, most had wedge deformities of the thoracic spine. On the other hand, up to 80% of osteoporotic vertebral fractures in men and up to 48% in women were missed by morphometry, in particular endplate fractures at the lumbar spine. In the group with osteoporotic vertebral fractures by RDC the proportion of persons with osteoporosis according to the WHO criteria (T-score <−2.5 SD) was 90.0% in women and 86.6% in men, compared with 67.9–85.0% in women and 20.8–50.0% in men with vertebral deformities by various methods. Although vertebral deformities by most definitions were significantly and inversely related to BMD as a continuous variable in both sexes [OR; 95% CI ranged between (1.70; 1.07–2.70) and (3.69; 1.33–10.25)], a much stronger association existed between BMD and osteoporotic fractures defined by RDC [OR; 95% CI between (4.85; 2.30–10.24) and (15.40; 4.65–51.02)]. In the nonosteoporotic group individuals with severe spondylosis had significantly higher BMD values at the femoral neck (p <0.01) and lumbar spine (p <0.0004) compared with the normal group. On the basis of internal (RDC) and external (BMD) validation, we conclude that assessment of vertebral osteoporotic fracture by quantitative methods alone will result in considerable misclassification, especially in men. Criteria for differential diagnosis as used within RDC can be helpful for a standardized subclassification of vertebral deformities in studies of spinal osteoporosis. Received: 5 February 1999 / Accepted: 24 June 1999     

Effect of Ovariectomy, Malnutrition and Glucocorticoid Application on Bone Properties in Sheep: A Pilot Study

The demographic changes in the human population continue to lead to an increasing incidence of osteoporosis. The main clinical symptom of osteoporosis is fracture. Fracture fixation in osteoporosis is frequently complicated by failure of fixation. There is a great need for a large-animal model of osteoporosis for controlled studies, which allows the investigation of fracture healing and fracture treatment in weak bone. Eight swiss mountain sheep, 7–9 years old, were divided into four treatment groups of two animals each. Group 1 was ovariectomized and fed a calcium/vitamin D-restricted diet (O+D). Group 2 was ovariectomized and given a daily intramuscular injection of 25 mg methylprednisolone (O+S). Group 3 was ovariectomized, fed a calcium/vitamin D-restricted diet and injected with 25 mg intramuscular methylprednisolone per day (O+D+S). Group 4 was used as an untreated, not sham operated control group. At the beginning of the study and every 2 months for 6 months the bone mineral density (BMD) was determined using quantitative computed tomography (pQCT) at the distal radius. Biopsies were taken after 6 months from vertebral bodies and femoral heads and the bone structure, i.e. trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), bone surface fraction (BS/BV) and bone volume fraction (BV/TV), was determined by micro-CT. In vitro compression testing of the biopsies was performed to determine failure load and stiffness. The control group showed no changes in BMD. The greatest decrease in BMD was seen in group 3 (O+D+S), which had a decline of 58% in cancellous bone and 22% in cortical bone. In the vertebral body biopsies a prominent change in structural parameters was observed (Tb.N, –53%; Tb.Th, –63%, Tb.Sp, +150%). The changes were less pronounced in the femoral head biopsies. In the compression test the vertebral body biopsies of group 3 (O+D+S) had stiffness values 40% lower failure load 70% lower compared with the control group. The most effective method of inducing osteoporosis in sheep was found to be the combined treatment. These results need to be confirmed in a larger number of animals. Received: 4 May 2001 / Accepted: 13 December 2001     

Effect of raloxifene combined with monofluorophosphate as compared with monofluorophosphate alone in postmenopausal women with low bone mass: a randomized,controlled trial

Raloxifene effectively reduces the incidence of vertebral fractures in patients with postmenopausal osteoporosis. Recent data suggest that low-dose monofluorophosphate (MFP) plus calcium reduces the vertebral fracture rate in postmenopausal women with moderate osteoporosis. The objective of this study was to evaluate the combination of raloxifene and MFP in the treatment of postmenopausal women with osteopenia, osteoporosis and severe osteoporosis. A total of 596 postmenopausal women with osteopenia, osteoporosis and severe osteoporosis (mean femoral neck T-score of –2.87 SD) were randomized to treatment with 60 mg/day raloxifene HCl and 20 mg/day fluoride ions (as MFP) or 20 mg/day fluoride and placebo for 18 months. All patients received calcium (1000 mg/day) and vitamin D (500 IU/day) supplements. Changes in bone mineral density (BMD), as primary endpoint, and the rate of osteoporotic fractures and biochemical markers, as secondary endpoints, were assessed. As compared with MFP, raloxifene plus MFP was associated with significantly greater mean increases in the BMD of the femoral neck (1.37% versus 0.33%; P=0.004), total hip (0.89% versus –0.42%; P<0.001) and lumbar spine (8.80% versus 5.47% P<0.001). In the raloxifene plus MFP group, 16 patients sustained 17 osteoporotic fractures, as compared with 22 patients sustaining 34 incident osteoporotic fractures in the MFP group (P=0.313). One patient in the raloxifene plus MFP group sustained multiple osteoporotic fractures, as compared with eight patients in the MFP group (P=0.020). MFP alone significantly increased the serum bone alkaline phosphatase (bone ALP) and the urinary C-terminal crosslinking telopeptide of type I collagene (U-CTX). The addition of raloxifene in the combination arm blunted the rise in bone ALP, which remained nevertheless significant, and abolished the increase in U-CTX. The combination of raloxifene with MFP was generally well tolerated. This study demonstrates that, in postmenopausal women with osteopenia, osteoporosis and severe osteoporosis, the combination therapy of raloxifene plus MFP favorably influences the BMD and the bone formation and resorption balance, and may reduce the risk of multiple osteoporotic fractures compared to MFP alone.     

Serum Albumin and Bone Mineral Density in Healthy Older Men and Women: The Rancho Bernardo Study

Serum albumin has been found to be positively correlated with bone mass in small studies of ambulatory men or women with diagnosed osteoporosis. In this study the relation between serum albumin and bone mineral density (BMD) was examined in 1593 white, community-dwelling men and women aged 50–95 years. BMD was determined using single-photon absorptiometry (SPA) at the ultradistal radius and the midshaft radius, and using dual-energy X-ray absorptiometry (DXA) at the hip and spine. Albumin was measured from a fasting blood sample using the Technicon SMA 12 autoanalyzer. Mean albumin levels in both men and women decreased significantly with increasing age. All but four values were within the normal range (3.5–5.0 g/dl). BMD decreased with increasing age at all sites. In both sexes there was weak positive correlation between serum albumin and BMD in the unadjusted model (Pearson's rvalues <0.3, p values <0.005). After age adjustment, however, the relationship was no longer significant (Pearson's r values <0.05, p values >0.18). Men and women were divided into three sex-specific categories – osteoporotic, osteopenic and normal – based on World Health Organization criteria in relation to young adult means (normal, BMD > –1 SD; osteopenia, BMD between –1 SD and –2.5 SD; osteoporosis, BMD <–2.5 SD). Mean albumin values did not differ significantly across the three BMD categories in men or women. BMD levels stratified for albumin levels and calcium supplement status (a marker for osteoporosis awareness) also did not differ. Albumin levels were also not associated with a history of low-trauma fractures. In summary, there was no age-independent association between serum albumin within the normal range and low BMD or fractures in community-dwelling healthy older adults. We conclude that previously reported associations most likely reflect inadequate adjustment for the age-related decrease in albumin levels and the selection of very frail osteoporotic subjects. Received: 7 October 1997 / Revised: 21 January 1998     

Multisite Quantitative Ultrasound: Precision, Age- and Menopause-Related Changes, Fracture Discrimination, and T-score Equivalence with Dual-Energy X-ray Absorptiometry

This study evaluated the clinical utility of a new multisite ultrasound device capable of measuring speed of sound (SOS) at the phalanx, radius, tibia and metatarsal. The in vitro and in vivo short- and long-term precision were evaluated, reference data were collected for 409 healthy white women (236 premenopausal and 173 postmenopausal), and age and menopause related changes were calculated using linear regression. Fracture discrimination was evaluated using 109 women with vertebral fractures and the age-adjusted odds ratios calculated for each standard deviation decrease in SOS measurement. Correlations between SOS measurements and spine and femur bone mineral density (BMD) were calculated. T-score equivalence with BMD was also investigated together with the prevalence of osteoporosis as defined by the WHO criteria. The in vivo short-term precision standardized in T-score units ranged from 0.14 to 0.33 and long-term standardized precision was 0.35–0.65. Postmenopausal age-related bone loss expressed as the annual change in T-score ranged from 0.040 to 0.089 for SOS and 0.053 to 0.066 for BMD, whilst menopause-related annual loss ranged from 0.036 to 0.094 for SOS and 0.050 to 0.074 for BMD. Correlations between the different SOS sites ranged from r= 0.24 to 0.55, and between SOS and BMD from r= 0.12 to 0.47. The odds ratio (and 95% confidence intervals) for fracture per 1 SD decrease in SOS were 2.0 (1.22 to 3.23) for the phalanx; 1.5 (1.01 to 2.24) for the metatarsal; 1.4 (1.03 to 1.99) for the radius and 1.2 (0.87 to 1.66) for the tibia. Odds ratios for BMD in the same population ranged from 2.6 to 4.8 (1.70 to 8.29). The prevalence of osteoporosis as defined by T= <–2.5 in the age range 60–69 ranged from 7.1% to 20.6% for SOS and 6.4% to 12.1% for BMD. In conclusion, this study demonstrated that multisite ultrasound has adequate precision for investigating skeletal status, is capable of differentiating between pre- and postmenopausal women and women with vertebral fractures, has a T-score equivalence similar to that of dual-energy X-ray absorptiometry (DXA), and appears to be a promising new technique for evaluating skeletal status at clinically relevant sites. Received: 11 August 2000 / Accepted: 14 December 2000     

Treatment of Reduced Bone Mineral Density in Athletic Amenorrhea: A Pilot Study

There is considerable concern about the adverse effects on the skeleton of loss of menstrual function as a result of athletic activity, as well as uncertainty as to how it should be managed clinically. In a pilot intervention study 34 elite middle and long-distance runners, aged 18–35 years, with menstrual irregularity due to their athletic activity were randomized to three groups: (A) to receive hormone replacement therapy (HRT) and 1000 mg calcium per day (n= 10), (B) to receive 1000 mg calcium per day (n = 14), (C) a control group who received no treatment (n= 10). Bone mineral density (BMD) was measured in the left hip and lumbar spine (L2–4) using dual-energy X-ray absorptiometry. Results were first analyzed according to whether menstruation returned, either naturally or secondary to HRT (EU), and compared with those from subjects who remained amenorrheic (AM). During the first year BMD increased in the EU group in Ward’s triangle (3.8%) and the lumbar spine (4.1%; both P<0.05). BMD fell in the AM group in all regions and the between-group differences were 5.6% (p<0.02) in Ward’s triangle, 5.8% (p<0.02) in L2–4 and 3.9% in the trochanter (p<0.05). An ‘intention to treat’ analysis was then performed. It was found that the mean relative improvement at 1 year in spinal BMD was only 1.5%, due to return of menses in some of the controls and withdrawals from treatment in the treatment group. In consequence, a trial designed to show, with 80% power and 5% significance, a measurable benefit in lumbar spine BMD resulting from allocation to HRT treatment would require about 1150 athletes with amenorrhea or oligomenorrhea. These numbers could be reduced substantially to 380 subjects by confining the trial to completely amenorrheic athletes, who in this study were less likely to regain menses. For these and other logistical reasons, an HRT trial in amenorrheic athletes could only be successfully organized through international collaboration. This study illustrates the major effects of treatment withdrawals and instability of menstrual status on the design of longitudinal studies on the bony effects of menstrual dysfunction prior to menopause. Received: 5 August 1998 / Accepted: 11 March 1999     

Bone loss after cardiac transplantation: Effects of calcium,calcidiol and monofluorophosphate

Of 203 patients who underwent cardiac transplantation and were given long-term treatment with cyclosporine and 0.3 mg/kg per day prednisone, 123 were studied prospectively for at least 6 months and 46 for up to 2 years to evaluate the effects on lumbar bone mineral density (BMD) and calcium metabolism of a combined therapy with calcium, calcidiol and disodium monofluorophosphate (MFP). The population was arbitrarily assigned to one of two groups. Group I consisted of patients who had a lumbar spine BMDZ score above –1.5 SD as compared with an age-and sex-matched population and no vertebral fractures. They received daily 1 g elemental calcium and 25 µg (1000 IU) calcidiol. Group II consisted of patients who received daily the same doses of calcium and calcidiol combined with 200 mg MFP, and was divided into two subgroups: (a) osteopenic subjects who had a lumbar spine BMD Z score below –1.5 SD without vertebral fractures and (b) osteoporotic subjects with vertebral fractures. If serum creatinine was higher than 140 µmol/l the daily dose of MFP was tapered to 100 mg. Fifty-four and 27 patients from group I and 38 and 19 patients from group II were followed respectively for 12 and 24 months. In both groups serum parathyroid hormone levels were significantly reduced from the twelfth month in parallel with a significant increase in serum 25-OHD levels. No decline in lumbar BMD occurred in non-osteopenic and non-osteoporotic patients (group I) who received the calcium and calcidiol supplement. In group II, where MFP was added, a significant and linear increase in lumbar BMD was observed. The average increase reached 12.5% after 12 months and 29.5% after 24 months (p<0.0001). The magnitude of the response was similar to the response previously reported in patients suffering from vertebral fractures due to postmenopausal osteoporosis and treated with the same daily dose of MFP. Because osteoporosis and fractures are not rare in patients after cardiac transplantation, these pilot results may be useful for further prevention and treatment trials of bone loss in this condition.     

Vertebral Deformities and Low Bone Mineral Density in Adults with Cystic Fibrosis: A Cross-sectional Study

Patients with cystic fibrosis (CF) have low bone mineral density (BMD). The clinical relevance of this is not clearly established. The aim of this study was to determine the prevalence of low BMD and vertebral deformities in CF adults with varied disease severity. One hundred and seven patients (58 men) aged 18–60 years underwent dual-energy X-ray absorptiometry scanning of the lumbar spine and hip, radiology of the spine and biochemical studies. Thirty-eight percent had a Z-score of <−1, with 13% having Z-scores <−2. Seventeen percent had evidence of vertebral deformity on radiography, mostly in the thoracic spine. Thirty-five percent reported past fractures, of which 9% were rib fractures. Percent predicted forced expiratory volume in 1 second (FEV1) and the amount of daily physical activity were positively related to BMD. The number of intravenous antibiotic courses in the previous 5 years was negatively related to BMD. Patients with a history of rib fracture and CF-related diabetes had significantly lower femoral neck BMD (p<0.02). The median serum 25-hydroxyvitamin D was 28 nmol/l, with 36% of patients having levels below 25 nmol/l despite vitamin D supplementation. Forty-four percent had raised levels of urinary pyridinium crosslinks (NTx). In conclusion, fragility fractures and hypovitaminosis D occur commonly in adult patients with CF. Low BMD occurs in patients with more severe disease and significantly relates to FEV₁, infective exacerbations and daily energy expended in physical activity. Received: 27 June 2000 / Accepted: 1 December 2000     

Effects of Risedronate Treatment on Bone Density and Vertebral Fracture in Patients on Corticosteroid Therapy

Men and women (n = 518) receiving moderate-to-high doses of corticosteroids were enrolled in two studies with similar protocols and randomly assigned to receive either placebo or risedronate (2.5 or 5 mg) for 1 year. All patients received daily calcium supplementation (500–1000 mg), and most also received supplemental vitamin D (400 IU). The primary endpoint was the difference between the placebo and active groups in lumbar spine bone mineral density (BMD) at 1 year; changes in BMD at other sites, biochemical markers of bone turnover, and the incidence of vertebral fractures were also assessed. In the overall population, the mean (SE) lumbar spine BMD increased 1.9 ± 0.38% from baseline in the risedronate 5 mg group (P < 0.001) and decreased 1.0 ± 0.4% in the placebo group (P= 0.005). BMD at the femoral neck, trochanter, and distal radius increased or was maintained with risedronate 5 mg treatment, but decreased in the placebo group. Midshaft radius BMD did not change significantly in either treatment group. The difference in BMD between the risedronate 5 mg and placebo groups was significant at all skeletal sites (P < 0.05) except the midshaft radius at 1 year. The 2.5 mg dose also had a positive effect on BMD, although of a lesser magnitude than that seen with risedronate 5 mg. A significant reduction of 70% in vertebral fracture risk was observed in the risedronate 5 mg group compared with the placebo group (P= 0.01). Risedronate was efficacious in both men and women, irrespective of underlying disease and duration of corticosteroid therapy, and had a favorable safety profile, with a similar incidence of upper gastrointestinal adverse events in the placebo and active treatment groups. Daily treatment with risedronate 5 mg significantly increases BMD and decreases vertebral fracture risk in patients receiving moderate-to-high doses of corticosteroid therapy. Received: 11 October 1999 / Accepted: 1 May 2000 / Online publication: 27 July 2000     

Bone Changes due to Glucocorticoid Application in an Ovariectomized Animal Model for Fracture Treatment in Osteoporosis

In a pilot experiment comparing four different modalities for inducing osteoporosis in the sheep, a combination of ovariectomy, calcium/vitamin D-restricted diet and steroid administration was found to generate the highest decrease in bone mineral density (BMD). The aim of the present study was to quantify the outcome of this triple treatment in an animal model of osteoporosis in terms of alteration in bone mass, bone structure and bone mechanics. A total of 32 sheep were divided into two equal groups. Group 1 (age 3–5 years) was used as a normal control. Group 2 (age 7–9 years) was ovariectomized, fed a calcium/vitamin D-restricted diet and injected with methylprednisolone (MP) over 7 months (22 weeks MP solution, 6 weeks MP suspension). The BMD at the distal radius and tibia was determined preoperatively and at repeated intervals bilaterally using quantitative computed tomography. Steroid blood levels were determined 4 and 24 h after selected injections. BMD was measured at L3 and L4 after 7 months. Biopsies were taken from iliac crests, vertebral bodies and femoral heads, and bone structure parameters investigated by three-dimensional micro-CT. Compressive mechanical properties of cancellous bone were determined from biopsies of vertebral bodies and femoral heads. After 7 months of osteoporosis induction the BMD of cancellous bone decreased 36 ± 3% in the radius and 39 ± 4% in the tibia. Steroid blood levels 24 h after injection of MP suspension were significantly higher than after injection of MP solution. Changes in structural parameters of cancellous bone from the iliac crest, lumbar spine and femoral head in group 2 indicated osteoporosis-associated changes. In group 2 there was a significant reduction in BMD of the lumbar spine and a significant reduction in stiffness and failure load in compression testing of biopsies of lumbar vertebrae. In sheep, changes in the structural parameters of bone such as trabecular number and separation during osteoporosis induction are comparable to the human situation. The sheep model presented seems to meet the criteria for an osteoporosis model for fracture treatment with respect to mechanical and morphometric bone properties. Received: 4 May 2001 / Accepted: 6 December 2001     

Risedronate Reduces the Risk of First Vertebral Fracture in Osteoporotic Women

Risedronate treatment reduces the risk of vertebral fracture in women with existing vertebral fractures, but its efficacy in prevention of the first vertebral fracture in women with osteoporosis but without vertebral fractures has not been determined. We examined the risk of first vertebral fracture in postmenopausal women who were enrolled in four placebo-controlled clinical trials of risedronate and who had low lumbar spine bone mineral density (BMD) (mean T-score =–3.3) and no vertebral fractures at baseline. Subjects received risedronate 5 mg (n= 328) or placebo (n= 312) daily for up to 3 years; all subjects were given calcium (1000 mg daily), as well as vitamin D supplementation (up to 500 IU daily) if baseline serum 25-hydroxyvitamin D levels were low. The incidence of first vertebral fracture was 9.4% in the women treated with placebo and 2.6% in those treated with risedronate 5 mg (risk reduction of 75%, 95% confidence interval 37% to 90%; P= 0.002). The number of patients who would need to be treated to prevent one new vertebral fracture is 15. When subjects were stratified by age, similar significant reductions were observed in patients with a mean age of 64 years (risk reduction of 70%, 95% CI 8% to 90%; P= 0.030) and in those with a mean age of 76 years (risk reduction of 80%, 95% CI 7% to 96%; P= 0.024). Risedronate treatment therefore significantly reduces the risk of first vertebral fracture in postmenopausal women with osteoporosis, with a similar magnitude of effect early and late after the menopause. Received: 12 September 2001 / Accepted: 11 December 2001     

Intermittent Oral Disodium Pamidronate in Established Osteoporosis: A 2 Year Double-Masked Placebo-Controlled Study of Efficacy and Safety

The effect of oral pamidronate on bone mineral density and its adverse effect profile was investigated by a double-masked placebo-controlled study of 122 patients aged 55–75 years with established vertebral osteoporosis. Patients on active therapy received disodium pamidronate 300 mg/day (group A) for 4 weeks every 16 weeks, 150 mg/day (group B) for 4 weeks every 8 weeks or placebo (group C). All patients additionally received 500 mg of calcium and 400 IU vitamin D daily. Dual-energy X-ray absorptiometry measurements of the spine, hip, forearm and total body were performed at baseline and 6-monthly for 2 years using a Hologic QDR 1000 device at two sites. Serum osteocalcin and urinary deoxypyridinoline were measured at the above visits and at 3 months. The percentage change (SEM) in spine bone mineral density (BMD) at 2 years based on intention-to-treat analysis was 4.64 (1.01) in group A, 6.10 (0.87) in group B and 1.13 (1.32) in group C. Analysis of variance showed significant increases in group A and B compared with placebo (p<0.01). There were also significant rises in femoral neck BMD for group A (p = 0.005), trochanter BMD for groups A and B (p<0.01) and total-body BMD for groups A and B (p<0.001). There was a significant reduction in serum osteocalcin and urinary deoxypyridinoline for groups A and B (p<0.01). There was an excess of gastrointestinal side-effects in the treated groups, particularly group A. We conclude that intermittent pamidronate therapy can prevent bone loss at both the lumbar spine and femoral neck in patients with established vertebral osteoporosis, although due to gastrointestinal side-effects the 300 mg dose in particular does not appear suitable for clinical usage. Received: 12 January 1999 / Accepted: 30 August 1999