Partial Myotomy of the Pectoralis Major in Submuscular Breast Implants

Several authors report that retropectoral or submuscular placing for prostheses reduces the incidence of capsular contracture, preserves the sensitivity of the areola, and gives the breast a more natural look; however, displacement of the prosthesis when contracting the arm, shoulders, and thorax muscles is often observed. In order to prevent this deficiency, partial thickness myotomy was performed in the pectoralis major muscle. Since 1987, our team has carried out 120 subpectoral augmentation mammoplasties by submammary approaches using this procedure. The ages of the patients ranged from 19 to 44 years old. In all cases, physiological saline microtextured prostheses were used. Volumes were between 225 and 275 cc. The results were satisfactory in all cases, with no hematomas, infections or capsular contractures. The main advantage of this technique is that it prevents displacement of the prostheses after movements of the arms or shoulders.     

Fluoride for the Treatment of Postmenopausal Osteoporotic Fractures: A Meta-Analysis

We conducted an efectiveness meta-analysis to determine the efficacy of fluoride therapy on bone loss, vertebral and nonvertebral fractures and side effects in postmenopausal women. A literature search was conducted on MEDLINE, Current Contents and the Cochrane Controlled Trial Registry. Two independent reviewers selected randomized controlled trials which met predetermined inclusion criteria. They independently extracted data using predetermined forms and assessed the methodologic quality of the trials using a validated scale. For dichotomous outcomes, the relative risk (RR) was calculated, and for continuous outcomes, the weighted mean difference (WMD) of percentage change from baseline was calculated. Where heterogeneity existed (determined by a chi-square test) a random effects model was used. Eleven studies (1429 subjects) met the inclusion criteria. The increase in lumbar spine bone mineral density (BMD) was found to be higher in the treatment group than in the control group with a WMD 8.1% (95% CI: 7.15, 9.09) after 2 years of treatment and 16.1% (95% CI: 14.65, 17.5) after 4 years. The RR for new vertebral fractures was not significant at 2 years [0.87 (95% CI: 0.51, 1.46)] or at 4 years [0.9 (95% CI: 0.71, 1.14)]. The RR for new nonvertebral fractures was not significant at 2 years [1.2 (95% CI: 0.68, 2.10)] but was increased at 4 years in the treated group [1.85 (95% CI: 1.36, 2.50)], especially if used at high doses and in a non-slow-release form. The RR for gastrointestinal side effects was not significant at 2 years [2.18 (95% CI: 0.86, 1.21)] but was increased at 4 years in the treated group [2.18 (95% CI: 1.69, 4.57)], especially if fluoride was used at high doses and in a non-slow-release form. The number of withdrawals and dropouts was not different between treated and control groups at 2 and 4 years. Thus, although fluoride has an ability to increase bone mineral density at the lumbar spine, it does not result in a reduction in vertebral fractures. Increasing the dose of fluoride increases the risk of nonvertebral fractures and gastrointestinal side effects without any effect on the vertebral fracture rate. Received: 23 February 2000 / Accepted: 23 February 2000     

A Meta-analysis of Etidronate for the Treatment of Postmenopausal Osteoporosis

The aim of the study was to review the effect of etidronate on bone density and fractures in postmenopausal women. We searched MEDLINE from 1966 to 1998, examined citations of relevant articles, and the proceedings of international osteoporosis meetings. We contacted osteoporosis investigators to identify additional studies, primary authors, and pharmaceutical industry sources for unpublished data. We included 13 trials that randomized women to etidronate or an alternative (placebo or calcium and/or vitamin D) and measured bone density for at least 1 year. For each trial, three independent reviewers assessed the methodologic quality and abstracted data. The data suggested a reduction in vertebral fractures with a pooled relative risk of 0.63 (95% CI 0.44 to 0.92). There was no effect on nonvertebral fractures (relative risk 0.99, (95% CI 0.69 to 1.42). Etidronate, relative to control, increased bone density after 1–3 years of treatment in the lumbar spine by 4.06% (95% CI 3.12 to 5.00), in the femoral neck by 2.35% (95% CI 1.66 to 3.04) and in the total body by 0.97% (95% CI 0.39 to 1.55). Effects were larger at 4 years, though the number of patients followed much smaller. Etidronate increases bone density in the lumbar spine and femoral neck for up to 4 years. The pooled estimates of fracture reduction with etidronate suggest a reduction in vertebral fractures, but no effect on nonvertebral fractures. Received: 25 February 2000 / Accepted: 8 August 2000     

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     

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     

Bone Densitometry: A New, Highly Responsive Region of Interest in the Distal Forearm to Monitor the Effect of Osteoporosis Treatment

The bisphosphonates have been introduced as alternatives to hormone replacement therapy (HRT) for the treatment and prevention of postmenopausal osteoporosis. The expected increasing application in at clinical practice demands cost-effective and easily handled methods to monitor the effect on bone. The weak response at the distal forearm during antiresorptive treatment has restricted the use of bone densitometry at this region. We describe a new model for bone densitometry at the distal forearm, by which the response obtained is comparable to the response in other regions where bone densitometry is much more expensive and technically complicated. By computerized iteration of single X-ray absorptiometry forearm scans we defined a region with 65% trabecular bone. The region was analyzed in randomized, double-masked, placebo- controlled trials: a 2-year trial with alendronate (n= 69), a 1-year trial with ibandronate (n= 141) and a 2-year trial with HRT (n= 121). Bone mineral density (BMD) at the distal forearm revealed a highly statistically significant dose-related response and increased 3–5% per year with 2.5 mg ibandronate, 10 mg alendronate or HRT, whereas the decrease in the placebo groups was 1–3% (p<0.001). The response at the distal forearm was similar to the response at the lumbar spine and hip. In conclusion, trabecular bone at the distal forearm is as responsive to antiresorptive treatment as trabecular bone in other skeletal regions. Bone densitometry at the new region of interest in the distal forearm has comparable performance characteristics to more expensive and technically demanding methods. The method is more accessible clinically and has potential as an alternative for monitoring bone mass changes during antiresorptive treatment. Received: 9 February 1998 / Accepted: 30 July 1998     

The Pain Cycle: Implications for the Diagnosis and Treatment of Pelvic Pain Syndromes

The aim of the study was to report our results of sacral nerve stimulation in patients with pelvic pain after failed conservative treatment. From 1992 to August 1998 we treated 111 patients (40 males, 71 females, ages 46 ± 16 years) with chronic pelvic pain. All patients with causal treatment were excluded from this study. Pelvic floor training, transcutaneous electrical nerve stimulation (TENS) and intrarectal or intravaginal electrostimulation were applied and sacral nerve stimulation was used for therapy-resistant pain. The outcome of conservative treatment and sacral nerve stimulation (VAS <3/10; >50% pain relief) was related to symptoms of voiding dysfunction and dyschezia, and urodynamic proof of dysfunctional voiding, not to the pain localization or treatment modality. Outcome was inversely related to neuropathic pain. When conservative treatment failed, a test stimulation of the S3 root was effective in 16/26 patients, and 11 patients were implanted successfully with a follow-up of 36 ± 8 months. So far no late failures have been seen. A longer test stimulation is needed in patients with pelvic pain because of a higher incidence of initial false positive tests. Our conclusion is that sacral nerve stimulation is effective in the treatment of therapy-resistant pelvic pain syndromes linked to pelvic floor dysfunction.     

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 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     

Treatment with Active Vitamin D Metabolites and Concurrent Treatments in the Prevention of Hip Fractures: A Retrospective Study

The purpose of this study was to determine the effect of treatment with active vitamin D metabolites and other concurrent medication on the prevention of hip fractures in elderly women. We inspected the medical records of the entire female population over 65 years of age on Sado Island, and followed a total of 11377 women for a 3-year period. Of these, 1208 osteoporotic patients were treated with either 1,25-(OH)₂D₃ or 1α-(OH)D₃. The 765 patients who received the minimum effective dosage for more than 6 months made up the ‘treatment group’. Nearly half these patients were also treated with either calcitonin or calcium. The 443 patients who received treatment with active vitamin D metabolites, but at a dosage or for a duration that did not meet the criteria for the treatment group, were deemed the ‘ineffective group’. The remaining 10169 women were the ‘non-treatment group’. Fractures in the non-treatment group occurred at a rate of 39.8 fractures/10000 person-years. The rate in the treatment group was 10.8, which was significantly lower (p= 0.039). Interestingly, the fracture rate after ceasing treatment was 52.1, which was significantly higher (p= 0.002) than the rate in patients receiving treatment. No statistical differences in the fracture rate were found between the ineffective, non-treatment and post-treatment groups. A reduction in the fracture rate was observed only in the treatment subgroup that did not also receive calcitonin (p= 0.042), and not in the subgroup that also received calcitonin therapy (p= 0.333). However, there was no statistical difference in the hip fracture rates between these two subgroups (p= 0.157) and the actual number of fractures was minimal (0 vs 2). Therefore, in this study, the advantage of treatment with active vitamin D alone over combined treatment with calcitonin seems to be marginal. In conclusion: (1) treatment with active vitamin D metabolites and with combined therapy may be marginally effective in preventing hip fractures, and (2) stopping the treatment clearly increases the risk of hip fractures. Received: 26 August 1997 / Accepted: 4 June 1998     

Short-Term Risedronate Treatment in Postmenopausal Women: Effects on Biochemical Markers of Bone Turnover

The development of new biochemical markers has made it possible to assess the effects of therapeutic agents on bone turnover more rapidly and precisely. In this early phase II study, we analyzed the effects of short-term, high-dose treatment with risedronate, a potent pyridinyl bisphosphonate, on markers of bone resorption and formation. Resorption markers included urinary free deoxypyridinoline (D-Pyr) crosslinks, N-terminal telopeptide (NTx) and C-terminal telopeptide (CTx) type I collagen crosslinks. Bone formation markers included osteocalcin (OC), bone-specific alkaline phosphatase (BSAP) and the C-terminal peptide of type I procollagen (PICP). All three resorption markers showed rapid, significant (p<0.05) decreases from baseline following daily administration of 30 mg risedronate for 2 weeks. The mean decreases at 2 weeks were 28% for D-Pyr, 61% for NTx and 73% for CTx, respectively. Over the next 10 weeks after treatment, D-Pyr approached baseline while NTx and CTx remained well below baseline values. The markers of bone formation showed little change during therapy but decreased significantly at 4–10 weeks after therapy – an expected outcome of bisphosphonate therapy. Moreover, there was a significant correlation between the early effects on bone resorption markers and the delayed effects on formation markers. This study demonstrates that the approved dose of risedonate (30 mg/day) for Paget”s disease is effective at decreasing bone turnover after 2 weeks of treatment, as observed by the sensitive response of bone turnover markers. Received: 18 August 1999 / Accepted: 18 January 2000     

Identifying Bone-Mass-Related Risk Factors for Fracture to Guide Bone Densitometry Measurements: A Systematic Review of the Literature

Available evidence suggests that fracture prediction with bone densitometry may improve when used on people at high risk of osteoporotic fractures. The objectives of this literature review were: (1) to identify risk factors for fracture that are associated with the development of a low bone mass for both men and women; (2) to describe and assess the relationship between these factors and the risk of fracture; and (3) to classify them according to the strength of their association with fracture incidence. Studies were identified from MEDLINE (1982-1997), HealthSTAR (1975-1997) and The Cochrane Library (1997) databases. Pre-stated inclusion criteria (original analytic studies assessing risk factors for osteoporotic fractures in men and women) and methodologic quality were assessed by two independent investigators. Information on the study design and analysis, characteristics of participants, exposure (risk factor) and outcome measures (relative risk and odds ratios for fracture incidence), control for potential confounding factors and risk estimates was extracted using a standardized protocol. Qualitative and meta-analytic techniques were used for data synthesis. As a result, risk factors were classified into three groups according to their strength of association with fracture: high risk (RR > or = 2), moderate risk (1 < RR < 2) and no risk or protective (RR < or = 1). Of approximately 80 risk factors identified from 94 cohort and 72 case-control studies, 15% were classified in the high-risk group, including low body weight, loss of weight, physical inactivity, the consumption of corticosteroids or anticonvulsants, primary hyperparathyroidism, diabetes mellitus type 1, anorexia nervosa, gastrectomy, pernicious anemia, and aging (> 70-80 years). Eighteen percent and 8% of risk factors were classified in the moderate and no risk group respectively, whereas 60% showed either a lack of scientific evidence confirming their association with fracture or contradictory results. An efficient strategy for bone densitometry provision may thus be its selective use in those individuals who present with several strong or moderate risk factors for fracture related to bone mass loss.     

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     

Women’s Willingness to Pay Out-of-Pocket for Drug Treatment for Osteoporosis Before and After the Enactment of Regulations Providing Public Funding: Evidence from a Natural Experiment in Israel

This study examines women’s willingness to pay (WTP) for drug treatment for osteoporosis before and after the enactment of regulations approving public funding for the drugs and for a hypothetical more effective but not funded drug. One hundred and nine postmenopausal women recruited sequentially from a large bone metabolism outpatient clinic in central Israel were asked by telephone interview to report their maximum WTP out-of-pocket for a drug that would reduce the risk of hip fracture by 50% in four hypothetical cases varying by the level of risk described. Additionally, after the regulations, responses were elicited also for a hypothetical more effective drug. Information regarding participants’ sociodemographic and health characteristics, as well as their knowledge of osteoporosis, was also collected. Women would pay considerable sums of money (between 85% to 124% of the price of the drugs) for osteoporosis treatment and these sums increase significantly as the risk of suffering a hip fracture increases. After the enactment of the regulations, women were still willing to pay 54% to 100% of the price of the drugs out-of-pocket. Increased WTP after the regulations was associated with increased ability to pay and to lower levels of knowledge of the disease. After the enactment, participants’ WTP for a more effective drug was no different from their WTP for a less effective drug. WTP measures show relative stability over time. The dissemination of information regarding policy or regulatory changes should be encouraged in order to ensure rational decision-making processes. Received: 9 May 2001 / Accepted: 20 August 2001     

Effects of Raloxifene on Fracture Severity in Postmenopausal Women with Osteoporosis: Results from the MORE Study

Raloxifene reduces the risk of new vertebral fractures, but its effect on the severity of these new fractures has not been determined. The MORE (Multiple Outcomes of Raloxifene Evaluation) trial studied the effects of placebo, raloxifene 60 or 120 mg/day in 7705 postmenopausal women with osteoporosis. Radiologists assessed new vertebral fractures from radiographs and graded the fracture severity as normal (no fracture) or mild, moderate or severe. New clinical vertebral fractures were defined as new vertebral fractures associated with symptoms, such as back pain, and confirmed in radiographs. In the total study population, the majority (76.4%) of the women who experienced clinical vertebral fractures were diagnosed with new moderate/severe vertebral fractures. In turn, women with moderate/severe vertebral fractures in the overall population were more likely to experience clinical symptoms suggestive of fracture than were women who had new mild-only vertebral fractures. The incidence of new mild-only and moderate/severe fractures was the same in women without prevalent vertebral fractures, but the incidence of new moderate/severe fractures was 2 to 3 times higher than that for new mild-only fractures in women with prevalent vertebral fractures. Raloxifene 60 mg/day decreased the risk of at least 1 new moderate/severe vertebral fracture by 61% in women without prevalent vertebral fractures [RR 0.39 (95% CI 0.17, 0.69)], and by 37% in women with prevalent vertebral fractures [RR 0.63 (95% CI 0.49, 0.83)] at 3 years. The risk reductions for at least 1 new moderate/severe vertebral fracture were not significantly different between the raloxifene doses, in women with and without prevalent vertebral fractures. The effects of raloxifene on significantly decreasing the risk of new moderate/severe vertebral fractures may explain the risk reduction for new painful clinical vertebral fractures observed with raloxifene, and is particularly important in postmenopausal women with severe osteoporosis who are at higher risk for moderate or severe fractures. Received: 11 April 2002 / Accepted: 19 June 2002 Correspondence and offprint requests to: Ethel Siris, MD, Toni Stabile Osteoporosis Center, Department of Medicine, College of Physicians and Surgeons, Columbia University, 180 Fort Washington Ave, New York, NY 10032, USA. Tel: +1 (212) 305 2529. Fax: +1 (212) 305 6482. e-mail: es27@columbia.edu     

Effects of Different Regimens of Sodium Fluoride Treatment for Osteoporosis on the Structure, Remodeling and Mineralization of Bone

We compared initial and final bone histomorphometric findings in 66 osteoporotic patients treated with sodium fluoride (NaF) according to three regimens, and in 7 osteoporotic patients who did not receive NaF. Fourteen patients received continuous NaF 75 mg/day (high-dose) with calcium 1500 mg/day for a mean of 41 months. Twenty-six patients received continuous NaF 50 mg/day (low-dose) with calcium 2000 mg/day for a mean of 15 months, either with (10 patients) or without (16 patients) vitamin D. Twenty-six patients received cyclical low-dose NaF, alternating with vitamin D, for a mean of 15 months and a total treatment duration of 28 months, of whom 14 were and 12 were not on NaF at the time of the second biopsy. Disregarding differences between regimens, there were significant increases in total and mineralized bone volume and trabecular thickness and nonsignificant decreases in these measurements in the control group. Fluoride-induced bone formation was exclusively appositional with no evidence for the creation of new trabeculae. The effect of low-dose NaF on bone structure was the same when the same total dose was given continuously or intermittently, and when the patient was or was not taking vitamin D. The increases in total and mineralized bone volume but not trabecular thickness were greater with high-dose than with low-dose NaF. Low-dose NaF caused modest but significant increases in all osteoid indices, and modest but significant declines in adjusted apposition rate and osteoid maturation rate and no change in bone formation rate. With high-dose NaF, the increase in BV/TV was greater but all indices of osteoid accumulation were much higher and all indices of impaired osteoblast function and mineralization were much lower, and 12 of 14 patients had some form of osteomalacia. This occurred also in 3 of 30 patients treated with low-dose NaF who were not taking vitamin D; the mean increase in osteoid thickness was significantly greater in these patients than in 22 low-dose patients who were taking vitamin D. We conclude: (1) The inconsistent effect of NaF in increasing bone strength is partly due to failure to restore connectivity in patients with severe bone loss and partly due to substantial osteoid accumulation. (2) Even low-dose NaF causes impaired osteoblast function, but this is much greater with high-dose prolonged therapy. (3) There is an unexplained discrepancy between the increase in bone formation implied by increases in spinal bone mineral and the lack of increase in bone formation measured histomorphometrically. (4) Defective mineralization is more closely related to the total cumulative dose of NaF than to the duration of treatment, and with low-dose treatment may be preventable by vitamin D. (5) Future clinical trials should be carried out with smaller doses of NaF and before there has been substantial loss of horizontal trabeculae in the spine. Received: 31 March 1997 / Accepted: 6 February 1998     

Contribution of Weather to the Seasonality of Distal Forearm Fractures: A Population-Based Study in Rochester, Minnesota

Distal forearm fractures due to falls were more frequent in the winter (p<0.0001) among Rochester men and women 35 years of age or older in 1952–89. The winter excess was partially explained by a greater relative risk of distal forearm fractures on days with freezing rain (1.65; 95% CI 1.28–2.13) or snow (1.42; 95% CI 1.17–1.74) among women under 65 years of age and on days with freezing rain (1.63; 95% CI 1.23–2.17) among older women. The greater seasonality of forearm compared with hip fractures is explained by the fact that more of them occur out-of-doors. However, residual effects of season after adjusting for daily weather conditions suggest that other factors may play a role. Received: 21 April 1998 / Accepted: 17 July 1998     

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     

Defining the Genetics of Osteoporosis: Using the Mouse to Understand Man

Very low bone mineral density (BMD) is now considered as diagnostic of osteoporosis. Moreover, many women who are osteopenic eventually develop osteoporotic fractures. Hence, bone density testing has occupied center stage in the diagnosis and treatment of this disorder. In addition, over the last several years, BMD has been utilized as the phenotype of choice for defining heritable markers for osteoporotic fractures. However, genetic studies in humans have been limited to some degree by the tremendous heterogeneity among populations, as well as multiple genetic, heritable and environmental determinants of the BMD phenotype. Recent advances in technology have afforded investigators the opportunity to study acquisition and maintenance of BMD in small animals. Along with newer knockout and transgenic strategies, quantification of mouse bone mass has advanced our understanding of both the biologic and genetic determinants of bone density. In this review, we will examine the use of the mouse to map the heritable factors that regulate bone acquisition. We will also examine the role of newer technology to decompose the bone density phenotype into components that are amenable to genetic studies. This review will focus on three models: (1) healthy inbred (2) recombinant inbred, and (3) congenic strains of mice. Progress in this area with these strains has been rapid, and a summary of several quantitative trait loci (QTLs) is provided. The future of the mouse as a tool to map the genes that define the osteoporosis syndrome is extremely promising. Received: 23 January 2001 / Accepted: 4 May 2001     

A Prospective Evaluation of the Awareness, Knowledge, Risk Factors and Current Treatment of Osteoporosis in a Cohort of Elderly Subjects

This was a prospective cohort study of 145 seniors attending a senior’s clinic and social day program using a self-administered questionnaire. Its objective was to evaluate the awareness, knowledge, risk factors and current treatment of osteoporosis in our two patient groups. A secondary objective was to determine differences between the two cohorts, and between men and women. Participants included 39 men and 106 women, with an average age of 76 years. Of these, 89% were aware of osteoporosis and 61% gave the correct definition. Awareness and accurate definition were less in men compared with women (p<0.01, and p<0.05) and clinic compared to day program groups (p<0.01). Only 54% of men knew osteoporosis could affect them. Television, newspapers and friends were identified as the main source of information. Physicians ranked as fifth as a source of information. In all, 84% knew diet was important. Prevalence of risk factors other than age were <  20%, except for senescence (38%) and alcohol use (40%). Utilization of specific therapies for osteoporosis was only 18% overall with a rate of 3% in men (p<0.01). In women, 50% and were taking calcium supplements compared with 15% men (p<0.001) and for multivitamins the figures were 57% and 33% respectively (p<0.05). These results show a high level of awareness and correct definition of osteoporosis in this cohort of patients. Specific therapy for prevention or treatment of osteoporosis was inappropriately low in the face of high risk. This study highlights the care gap in osteoporosis in seniors and the need for increased physician involvement in patient education and treatment. Proactive treatment requests from patients need to be encouraged, especially with the future demographic shift. Received: 3 August 2000 / Accepted: 20 December 2000