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     

Is Distal Forearm Fracture in Men due to Osteoporosis?

Although widely regarded as a disease of women, osteoporosis does cause considerable morbidity and mortality in men. The lifetime risk of an osteoporortic fracture for a man is 1 in 12 and 30% of all hip fractures occur in men. In women, low-trauma distal forearm fracture is widely regarded as a typical early manifestation of postmenopausal osteoporosis. Traditionally, this has not been thought to be the case for men. We present a case–control study of 147 men with distal forearm fracture compared with 198 age-matched controls. The controls were selected from a pre-existing database of dual-energy X-ray absorptiometry scans of healthy volunteers. Both groups were sent questionnaires regarding basic demographics, fracture history and risk factors for osteoporosis, and the fracture group was asked to attend for bone densitometry. There were 103 responses from the fracture group (70%), of whom 67 (47%) underwent densitometry. There were 165 (83%) responses from the control group. Secondary causes of osteoporosis could be identified in 51% of the fracture group and 37% of the control group. The fracture group had significantly lower bone mineral density at all sites measured compared with the controls (0.75 g/cm² vs 0.85 g/cm² at the femoral neck, p<0.0001; 0.95 g/cm² vs 1.03 g/cm² at the total femur, p= 0.001; and 0.99 g/cm² vs 1.06 g/cm² at the lumbar spine, p= 0.001). These differences remained after adjusting for age and body mass index (p<0.0005 at all sites). Overall, 41.8% of the fracture group were osteoporotic in at least one site (T-score <−2.5 SD below the mean for young men) compared with only 10.3% of controls. This study is the first to demonstrate that men with distal forearm fractures have lower bone mineral density than their peers and a higher risk of osteoporosis. Received: 28 November 2001 / Accepted: 19 February 2002     

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     

Evaluation of Osteoporosis Treatment in Seniors after Hip Fracture

A retrospective chart review was carried out on all consecutive patients over 65 years of age admitted to a tertiary care teaching hospital with a diagnosis of a new hip fracture. A further chart review occurred after discharge from post-surgery rehabilitation. The primary objective was to evaluate the prevalence of osteoporosis diagnosis and treatment in both phases of the study. Secondary objectives included evaluation of the mortality rates, length of stay, prevalence of osteoporosis investigation, and prevalence of osteoporosis diagnosis based on the clinical subspecialty involved. There were 311 patients evaluated in the initial phase, and 226 after rehabilitation. The mortality rate was 5.8% (10% for men, 4% for women; p<0.005) in the acute care hospital and 9.3% (8% men, 10% women) during rehabilitation. Previous hip fracture occurred in 17.4%, and 1.5% were readmitted during the study period with fracture of the opposite hip. Osteoporosis was diagnosed in the acute care hospital on admission in 11.9% and on discharge in 15.4%. In the rehabilitation hospital it was diagnosed in 9.7% on admission and 11.2% on discharge (p = NS). Osteoporosis treatment (including calcium or vitamin D therapy) was instituted in 13% on admission to acute care and in 9.7% at the time of discharge. For the rehabilitation hospital, treatment occurred in 12.8% on admission and 10.2% on discharge. The diagnosis of osteoporosis significantly increased the prevalence of treatment (p<0.001). Use of specific agents (hormone replacement therapy, bisphosphonates or calcitonin) occurred in <6% of all patients. Osteoporosis is under-diagnosed and under-treated in this group of elderly hip fracture patients. It is associated with significant mortality and morbidity and every effort should be made to prevent future fractures. Physicians in the “front line” of hip fracture treatment are missing this key aspect of management in their patients. Education of these physicians, as well as the public, may be the key to addressing this care gap. Received: 12 March 2001 / Accepted: 23 July 2001     

Bone Histomorphometric Evaluation of Pamidronate Treatment in Clinically Manifest Osteoporosis

The effect of pamidronate therapy on bone histology was studied in patients with osteoporosis with at least one vertebral fracture in a randomized, double-masked, placebo-controlled, multi-center trial. Patients received pamidronate 150 mg/day or placebo in addition to calcium 500 mg/day and vitamin D₃ 400 IU/day. Transiliac bone biopsies were obtained before and after 1 or 2 years of treatment. Of these, 23 pairs of biopsies obtained from 14 women and 9 men (mean age t SD, 61.5 t 10 years) were of sufficient quality for histomorphometry. Histomorphometry was performed on sections stained with Goldner’s trichrome, using a drawing tube and a digitizer. Urinary hydroxyproline excretion decreased significantly (p<0.005) following pamidronate treatment, indicating a decrease in bone resorption. Osteoid volume and osteoid surface also decreased significantly in the pamidronate group (p<0.004 and p<0.003 respectively), consistent with a secondary decrease in bone formation. Osteoid variables did not change in the placebo-treated patients. Cortical thickness, trabecular bone volume and trabecular thickness did not change after pamidronate or placebo treatment. Wall thickness, however, showed a borderline increase following pamidronate treatment. After pamidronate, eroded surface and mineral apposition rate did not change significantly in the placebo and pamidronate groups. Mineralizing surface and activation frequency showed a borderline decrease in the placebo and pamidronate groups. The decrease in mineralization lag time was of borderline significance in the pamidronate group, corroborating the absence of any negative effect on mineralization. In conclusion, pamidronate treatment led to a decrease in bone turnover and did not interfere with bone mineralization. Received: 2 February 1998 / Accepted: 19 October 1998     

Vertebral Fracture and Cortical Bone Changes in Corticosteroid-Induced Osteoporosis

Despite an intriguing understanding of trabecular bone dynamics, little is known about corticosteroid-induced cortical bone loss and fractures. Recently, we verified a steroid-induced decrease in cortical bone volume and density using peripheral quantitative computed tomography (pQCT) in adult asthmatic patients given oral corticosteroids. Subsequently, the pQCT parameters and presence of vertebral fractures were investigated to further clarify the role of cortical bone quality in fractures in 86 postmenopausal (>5 years after menopause) asthmatic patients on high-dose oral steroid (>10 g cumulative oral prednisolone) (steroid group) and 194 age-matched controls (control group). Cortical and trabecular bone was subjected to measurement of various parameters using pQCT (Stratec XCT960). Relative Cortical Volume (RCV) was calculated by dividing the cortical area by the total bone area. Strength Strain Index (SSI) was determined in the radius based on the density distribution around the axis. Spinal fracture was assessed on lateral radiographs. Patients treated with high doses of oral steroid (>10 g cumulative oral prednisolone) were found to have an increased risk of fracture compared with control women receiving no steroid medication (odds ratio, 8.85; 95% CI, 4.21–18.60) after adjustment was made for years since menopause, body mass index and RCV. In both groups, the diagnostic and predictive ability of the pQCT parameters for vertebral fracture was assessed by the areas under their receiver operating characteristic (ROC) curves. All parameters were found to be significant predictors (p<0.0001) in the control group. In the steroid group, however, the cortical bone mineral density (BMD) (p= 0.001), RCV (p<0.0001) and SSI (p= 0.001) were found to be significant predictors, but not trabecular BMD (p= 0.176). For comparison between the two groups, thresholds of all parameters for vertebral fracture were also calculated by the point of coincidence of sensitivity with specificity in ROC testing and the 90th percentile value. Although a rise in fracture threshold in the steroid group was suggested, considerable difference in the values obtained by the two methods of calculation precluded any conclusion. High-dose oral steroid administration was associated with an increased risk of fracture. Cortical bone parameters obtained by pQCT could play a role as good predictors of future corticosteroid-induced vertebral fractures. Received: 30 November 2001 / Accepted: 28 February 2002     

The Decision to Accept Treatment for Osteoporosis Following Hip Fracture: Exploring the Woman’s Perspective Using a Stage-of-Change Model

Despite the availability of medications that reduce fracture risk, most women who sustain a hip fracture are not evaluated or treated for osteoporosis. While a number of studies have attributed this to a lack of physician awareness, no studies have evaluated this problem from the patient’s perspective. To explore the process a woman negotiates when deciding to accept pharmacologic treatment for osteoporosis after hip fracture, we used a stage-of-change model to characterize a consecutive series of 70 postmenopausal women (mean age 85 years) admitted to a tertiary care hospital with an acute low-impact hip fracture between May 2000 and August 2000. We measured stage-of-change using a modified form of the Weinstein Precaution Adoption Process Model (PAPM). The majority of patients (65%) were ineligible because of dementia or delirium; only 29 were eligible and 21 were enrolled. Most women (62%) were in stages 1 or 2 of the PAPM, indicating that they were unaware of osteoporosis or had never considered pharmacologic treatment for it. The only factors associated with a more advanced PAPM stage (indicating active consideration or currently taking treatment) were a previous bone mineral density (BMD) evaluation (p= 0.007) and a diagnosis of osteoporosis (p= 0.001). Although 48% of women had a previous fragility fracture and osteoporosis knowledge was poor overall (mean score 52% correct), neither was associated with a more advanced PAPM stage in this sample. In conclusion, women evaluated after hip fracture were not ready to accept pharmacologic treatment for osteoporosis; they were unaware that they had osteoporosis or had never considered treatment for it. For a woman to advance through the behavior change process, she must first be made aware of the problem that requires a change in behavior. Physicians play a crucial role in promoting awareness of the diagnosis of osteoporosis after fracture, which in turn is associated with patient advancement through the behavior change process and the decision to accept pharmacologic intervention. The large number of cognitively impaired patients in this population, however, will certainly make efforts to improve osteoporosis awareness, diagnosis and intervention more challenging. Received: 20 August 2001 / Accepted: 12 December 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     

An Osteoporosis Clinical Pathway for the Medical Management of Patients with Low-Trauma Fracture

Patients with an osteoporotic fracture have at least a 2-fold risk for additional fracture and should benefit from targeted diagnostic and treatment procedures for osteoporosis. To address this issue, we set up an osteoporosis clinical pathway (OCP) for the medical management of patients with low-trauma fracture. Following acute management of the fracture by the orthopedic team, patients are enrolled in the pathway, which is based on an interaction between the OCP multidisciplinary team, orthopedic surgeons and/or primary care physicians. After collection of patient data, suggestions for additional diagnostic examinations with their interpretation, and treatment proposals are made. Patients and their families are also invited to attend a multidisciplinary interactive educational program on physical therapy, lifestyle habits and nutrition. During a 36-month period, 385 patients (311 women, 74 men; mean age ± SD: 73.0 ± 13.5 years; hip fracture 45%, ankle/tibia 24%, proximal humerus 8.6%, spine 5.5%, pelvis 3.9%, distal forearm 3.6%, other sites 17.4%) were enrolled in the OCP. An osteoporosis awareness questionnaire administered within 10 days of fracture showed that 73% of patients believed that their fracture was not related to the disease. Dual-energy X-ray absorptiometry, performed in 63% of patients, showed that 86% had low bone mass or osteoporosis. Specific antiosteoporotic therapy was proposed for 33% of patients in addition to calcium and vitamin D supplements, the latter suggested for 93%. A survey performed in 216 patients 6 months later, indicated that 63% of the suggested treatments had been prescribed and that 67% of this group were continuing treatment. Such a clinical pathway for the medical management of low-trauma fracture can help to identify patients with osteoporosis in a high-risk population, provide support to the orthopedic surgeon and/or the primary care physician for diagnostic and treatment procedures, and should significantly contribute to increase awareness of the disease in patients and their families. Received: 25 June 2001 / Accepted: 23 November 2001     

Response to Alendronate in Osteoporosis after Previous Treatment with Etidronate

Bisphosphonates such as etidronate and alendronate are widely accepted as effective agents for the treatment of osteoporosis. However, some physicians find the choice of which one to use in different patients, and the comparative magnitude of response, unclear. Fifty postmenopausal women with osteoporosis [group 1: 27 women who had received 3 years of previous cyclical etidronate treatment, mean age 70.5 years, bone mineral density (BMD) mean T-score lumbar spine (LS) −3.58 and femoral neck (FN) −2.51; group 2: 23 women who had not previously received cyclical etidronate treatment, mean age 73.7 years, BMD mean T-score LS −3.65 and FN −2.96] were treated with 10 mg alendronate daily, to determine whether pretreatment with etidronate affected the response to alendronate, and whether patients who did not respond to etidronate, responded to alendronate. There was a significant increase in LS BMD after 2 years of treatment with alendronate compared with baseline (group 1: 7.84%, p<0.001; group 2: 6.69%, p<0.001), but there was no statistical difference between the groups. In the group 1 patients there was a significant difference between the initial response (at the LS BMD) to 2 years of cyclical etidronate (1.86%) and later response to 2 years of alendronate (7.84%) (p<0.0001). The 10 patients who did not respond at the LS to etidronate alone, showed a significantly better response (mean BMD change +6.3%) when subsequently treated with alendronate (a net difference of 9.3%, p = 0.002). In 15 patients who did not respond at the FN to etidronate alone, the mean response to alendronate was +0.96% (a difference of 7%, p = 0.004). This study shows that pretreatment with 3 years of cyclical etidronate is not detrimental to the subsequent LS BMD response to alendronate. There is evidence that alendronate produced a greater bone density response than etidronate, and patients who did not respond to etidronate with an increase in LS bone density, subsequently did so following alendronate. Received: 22 June 1999 / Accepted: 18 January 2000     

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     

Importance of Preclinical Studies in the Development of Drugs for Treatment of Osteoporosis: A Review Related to the 1998 WHO Guidelines

Osteoporosis, which is defined as a disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk, is a major health issue worldwide. Among the various strategies to prevent and cure this devastating ailment, an important objective is the development of new efficacious and safe drugs. This situation prompted the World Health Organization (WHO) to provide a comprehensive statement of guiding principles for the design, implementation and interpretation of both preclinical testing and clinical trials in osteoporosis. These guidelines, which are now available, underline the crucial importance of the preclinical evaluation, particularly for assessing the effect of an intervention on bone strength. This concept is heightened by the lack of a validated technique for noninvasively evaluating bone strength in humans and the multiple difficulties and heavy burden inherent in the evaluation of fracture rate in clinical trials. The WHO guidelines emphasize that a comprehensive and adequate preclinical program is expected to provide key information on the relationship between bone mass and strength and thus attenuate the burden of clinical studies. The present report provides a review of experimental evidence in support of the preclinical program as proposed in the WHO guidelines. This program is based on the recent development and refinement of animal models of osteoporosis that mimic the human condition according to the conceptual definition of the disease. Many preclinical studies carried out in appropriate animal models with agents that exert either antiresorbing or anabolic effects on bone indicate that they have been highly predictive of the drug action in humans in terms of both bone mass and remodeling, as well as of bone strength whenever fracture rate has been documented in clinical trials. Based on this evidence the WHO guidelines propose strategies according to which the results of preclinical evaluation will determine the end-points required in the different phases of the clinical development of the drug. Such a distribution of task assignment between preclinical and clinical programs should optimize the progress of research available to patients already suffering from or at risk of osteoporosis. Received: 3 January 1998 / Accepted: 6 October 1998     

The Mechanical Properties of Fluoride-Treated Bone in the Ovariectomized Rat

The effect of fluoride therapy on the osteopenic bone of the ovariectomized rat was studied by comparing the densitometric and biomechanical data. Forty retired breeder female Sprague-Dawley rats aged 10 months were randomly divided into five groups. One group (Group A) was killed at the beginning of the study and was used as a baseline. Three groups were ovariectomized and one was sham-operated (Group B) and observed for the same period as a sham-aged group. A group of ovariectomized rats was used as a sham therapy control (Group C) and received only deionized drinking water; the other two groups (F1 and F2) received L-glutamine monofluorophosphate and calcium at a rate of 1:30 F/Ca at different doses by gavage (0.57 mg F/17 mg Ca per kg/day-Group F1; 0.21 mg F/6.30 mg Ca per kg/day-Group F2). Densitometric and biomechanical (compression and three-point bending test) assays, X-ray diffraction, and Fourier transformed infrared spectroscopy were performed on femoral specimens. Biomechanical data showed that the femoral heads of Group F2 required a significantly greater energy-to-failure than Group C (P < 0.05) as well as treated femoral diaphysis when compared with the others (P < 0.01). Significant increases in the elastic modules were observed in fluoride-treated groups (P < 0.001) when compared with other groups. Diffractometric and spectroscopic data showed the presence of fluorine-apatite in both treated groups with a high component of carbonates. Also, fluoride therapy causes an increase of bone stiffness due to the presence of fluoroapatite. It seems to produce two opposed properties in the osteopenic rat bone: a higher resistance to compression loading and a greater frailty to flexion loading. Received: 18 November 1997 / Accepted: 28 January 1999     

Unbalanced Diet to Lower Serum Cholesterol Level is a Risk Factor for Postmenopausal Osteoporosis and Distal Forearm Fracture

The purpose of this study was to assess whether dietary changes aimed at reducing serum cholesterol can increase the risk of osteoporosis (OP) and fracture. The study group consisted of 311 postmenopausal women with high serum cholesterol levels and following a diet low in dairy products (calcium intake estimated at less than 300 mg/day) for 27.3 ± 29.1 months. This sample was compared with a case–control group of 622 healthy postmenopausal women paired for age and age at menopause and with a calcium intake estimated at more than 1 g/day. Bone mineral density was measured at the lumbar spine by dual-energy X-ray absorptiometry. Prevalence of OP was significantly higher in women with a low dairy calcium intake (42.1% vs 22.3%; p<0.0001), as was the number of Colles” fractures occurring after menopause (4.5% vs 1.6%; p = 0.008). Multiple logistic regression analyses demonstrated that a diet low in dairy calcium was a risk factor for OP (OR = 2.52, 95% CI 1.84–3.45) and Colles” fracture (OR = 2.72, 95% CI 1.18–6.26). In the low dairy calcium group, diet duration significantly influenced the risk of OP (OR = 1.13, 95% CI 1.01–1.25 for 1 year of diet). No differences in further risk factors for coronary heart disease were found between the groups, but the proportion of women physically active was lower in the women with high serum cholesterol levels. A diet that severely limits calcium intake from dairy products in an attempt to correct raised serum cholesterol levels is a risk factor for postmenopausal OP and Colles” fracture. Dietary intervention methods to lower serum cholesterol in postmenopausal women should maintain an adequate calcium intake by providing calcium from low-fat dairy products or calcium supplements. Received: 16 May 2000 / Accepted: 18 November 2000     

Effects of Alendronate on Bone Density in Men with Primary and Secondary Osteoporosis

Alendronate has been reported to increase bone mineral density (BMD) and reduce fracture risk in women with osteoporosis. As there are no proven safe and effective treatments available for men with osteoporosis, we compared the effects of alendronate (10 mg/day) on BMD, measured using dual-energy X-ray absorptiometry, in a 12-month prospective, controlled, open label study involving (i) men with primary (n= 23) or secondary osteoporosis (n= 18), (ii) postmenopausal women with primary (n= 18) or secondary (n= 21) osteoporosis, and (iii) 29 male and 14 female untreated controls matched by age, height and weight. The patients had one or more vertebral fractures and ranged in age from 34.6 to 85.1 years. BMD was detectably increased relative to baseline by 6 months, and increased by comparable amounts in males and females with primary or secondary osteoporosis. At 12 months, lumbar spine BMD was 5.4%± 1.1% to 7.0%± 2.2% higher in the treated groups compared with baseline and controls (p<0.05 to 0.0001). Trochanteric BMD increased by 2.6%± 1.5% and 3.7%± 1.7% in treated men with primary and secondary osteoporosis, respectively (p = 0.06 to 0.08), and by 3.9%± 1.3% in treated women with primary osteoporosis (p<0.01) after 12 months. No significant changes were detected at the femoral neck or Ward’s triangle. BMD remained unchanged in controls. We infer that alendronate has comparable incremental effects on BMD in men and women with primary and secondary osteoporosis within 12 months of treatment. The changes are in the order of 0.5 SD – effects associated with a clinically worthwhile reduction in fracture risk. The data provide room for optimism regarding the role of alendronate in the treatment of osteoporosis in men. Randomized, double-masked and placebo-controlled trials are needed to confirm these preliminary findings and demonstrate antifracture efficacy using vertebral and nonvertebral fracture rates as the primary endpoint. Received: 23 February 1999 / Accepted: 2 June 1999     

Changes in Bone Mass and Bone Turnover Following Distal Forearm Fracture

Bone loss occurs close to a fracture and is associated with increased bone turnover. Fracture healing itself results in increased markers of bone turnover. 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 distal forearm fracture. Twenty women (mean age 63 years) were recruited following fracture of the distal radius and ulna. Bone mineral density (BMD) of the hand and forearm were measured by dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) of the fingers was measured 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), free deoxypyridinoline (iFDpd), N-telopeptides of type I collagen (NTx). We used the nonfractured limb to calculate values for baseline BMD and amplitude-dependent speed of sound (AD-SoS). There was a decrease in BMD at the hand and in AD-SoS of the fingers after forearm fracture (p<0.001). This bone loss was maximal for BMD by 6 weeks at 9% (p<0.001) and remained decreased at 52 weeks. AD-SoS decreased at 12 weeks by 3% (p<0.01) and recovered completely by 52 weeks. Bone formation markers increased between 2 and 4 weeks by 13–52% (p<0.001), and were still elevated at 52 weeks. Bone resorption markers increased between 2 and 6 weeks by 18–35% and returned to baseline at 52 weeks (TRAcP remained elevated). We conclude that BMD decreased distal and immediately proximal to the fracture line when measured with DXA and QUS. Bone loss after distal forearm fracture did not recover by 52 weeks and most bone turnover markers did not return to baseline. Received: 27 January 1999 / Accepted: 19 April 1999     

Predicting Subsequent Bone Density Response to Intermittent Cyclical Therapy with Etidronate from Initial Density Response in Patients with Osteoporosis

We investigated whether an increase in lumbar spine bone mineral density (LS BMD) at 6 months or at 12 months could predict the response to intermittent cyclical therapy (ICT) with etidronate, defined in one of two ways: (i) an increase in LS BMD at 24 months (improvement) or (ii) an increase in LS BMD ≥0.028 g/cm² (significant improvement). The latter is a precision term calculated from test–retest values for LS BMD in osteoporotic patients. Two hundred and forty-seven patients (32 men; 5 premenopausal and 210 postmenopausal women) were followed for 24 months by dual-energy X-ray absorptiometry (DXA) and were not taking estrogen, calcitonin or fluoride during treatment with ICT-etidronate. One hundred and fifty patients had a LS BMD measurement after 6 months of treatment with ICT-etidronate and 205 patients had one at 12 months. Baseline characteristics (mean;SD) were as follows: age, 66;11 years; years since menopause, 21;10; number of vertebral fractures at baseline, 0.87;1.26; LS BMD T-score, −2.8;1.2. After 24 months of treatment with ICT-etidronate, 81% of the patients had an improvement, and 55% had a significant improvement at the LS. Only 6% significantly lost bone (loss of 0.028 g/cm² or more). The mean percent change from baseline in LS BMD was 5.1% (95% confidence interval 4.2% to 6.0%). The results for men and postmenopausal women were similar to those for the entire group. Accuracy and sensitivity were marginally, but not significantly, higher when response was predicted using 12 month versus 6 month LS BMD measurements. The positive predictive values of improvement at 6 or 12 months were 89% and 90% respectively for improvement at 24 months, and 66% and 68% for significant improvement at 24 months. Identification of nonresponders was less successful and similar at 6 months and 12 months. Forty percent and 39% of the patients, who had no improvement at 6 or 12 months respectively, also had no improvement at 24 months, i.e., were true negatives, while 77% and 71% had no significant improvement at 24 months. The results may reflect slow response in a small subgroup of patients rather than nonresponse; however, no response at 1 year might identify patients whose rate of response is sufficiently slow that alternative therapy is justified. These data demonstrate a good response rate to ICT-etidronate and may help reduce the need for follow-up BMD measurements in those who show an early improvement. Received: 12 November 1999 / Accepted: 3 January 2000     

Intermittent Cyclic Tiludronate in the Treatment of Osteoporosis

The objective of the study was to determine the efficacy and safety of tiludronate in the treatment of postmenopausal osteoporosis. Two placebo-controlled, randomized, double-masked, multicenter, cyclical, intermittent, dose-ranging studies including 1805 women with low vertebral bone mineral density and prevalent vertebral fractures and 488 women with low bone mineral density and no prevalent fracture were conducted. Patients were randomized to either tiludronate 50 mg/day, tiludronate 200 mg/day or placebo, given orally for the first 7 days of each month. A supplement of 500 mg elemental calcium was provided daily from day 8 to the end of the month. Both studies demonstrated no statistically or clinically relevant trends in the incidence of adverse effects accross the three treatment groups. However, tiludronate administered at these two doses in a cyclic intermittent regimen was not effective in reducing the incidence of vertebral fractures or increasing spinal bone mineral density. Thus, tiludronate, administered at these doses in a cyclic intermittent regimen, cannot be considered an appropriate treatment of postmenopausal osteoporosis, notwithstanding a high safety profile. Received: 6 July 2000 / Accepted: 25 September 2000     

The New Selective Estrogen Receptor Modulator MDL 103,323 Increases Bone Mineral Density and Bone Strength in Adult Ovariectomized Rats

Selective estrogen receptor modulators (SERMs) can prevent the bone loss induced by ovariectomy (OVX), but it is not established whether they can increase bone mass and strength in a curative protocol in ovariectomized osteopenic animals. We investigated the influence of a SERM of the new generation, MDL 103,323, on areal bone mineral density (BMD), as measured by dual-energy X-ray absorptiometry, bone strength and remodeling in OVX osteopenic rats. Nine weeks after OVX, 8-month-old rats were divided into six groups of 10 animals. MDL 103,323 was given by gavage at doses of 0.01, 0.1 or 0.6 mg/kg body weight, 5 days a week. The effect of MDL 103,323 was compared with that of the bisphosphonate pamidronate (APD), which was injected subcutaneously at a dose of 1.6 mmol/kg body weight for 5 days every 4 weeks. Lumbar spine (LS), femoral neck (FN), proximal tibia (PT) and midshaft tibia (MT) BMD, bone strength, and proximal tibia histomorphometry, serum osteocalcin, urinary total deoxypyridinoline and serum insulin-like growth factor I (IGF-I) were measured. After 16 weeks of treatment, BMD changes (means ± SEM) were −11.4 ± 2.2, +4.0 ± 2.1 and +6.4 ± 1.0% respectively in OVX controls, in rats treated with 0.1 mg/kg MDL 103,323 (p<0.05) and in APD-treated rats (p<0.02) at the level of LS; −0.4 ± 1.1, +6.7 ± 1.4, +7.2 ± 1.8% (p<0.01 and NS) at the level of FN; and −2.6 ± 1.2%, +5.8 ± 1.2, +6.9 ± 1.4% (p<0.03 and 0.01) at the level of PT. MDL 103,323-treated animals had a higher trabecular bone volume, a higher number of trabeculae and smaller intertrabecular spaces compared with OVX controls. Vertebral body ultimate strength was 186 ± 13, 292 ± 16, 249 ± 23 N (p<0.05) in OVX controls, MDL 103,323-treated rats and APD-treated rats, respectively. The administration of 0.6 mg/kg of MDL 103,323 did not further increase BMD or bone strength, indicating a bell-shaped dose–response curve. MDL 103,323 lowered plasma osteocalcin concentration and urinary deoxypyridinoline excretion. In rats treated with 0.1 mg/kg MDL 103,323, plasma IGF-I was increased as compared with OVX controls (664 ± 36 ng/ml vs 527 ± 39 ng/ml, p<0.05). In conclusion, these results indicate that this new SERM positively influences BMD and lumbar spine bone strength in estrogen-deficient rats. Received: 30 October 1998 / Accepted: 12 April 1999