Assessment of methods for estimating autonomic nervous control of the heart in patients with diabetes mellitus.

A comparison of the cardiac responses to a variety of maneuvers that modify cardiac vagal tone was made in nondiabetic and diabetic subjects. We concluded that assessment of heart rate variability by reference to standard deviation of R-R intervals is unhelpful; that a single deep breath is a more potent stimulus for heart rate change than repeated deep breaths in diabetic subjects; and that measurement of this response together with the bradycardia evoked by the Valsalva maneuver obviate the need to perform invasive investigations, such as the estimation of baroreflex sensitivity, or tedious procedures, such as apneic face immersion. In a small number of subjects, heart responses to lower body, negative pressure provided information not forthcoming from other tests.

Osteoporosis therapy: an example of putting evidence-based medicine into clinical practice.

A major aim of evidence-based medicine is to assist clinical decision-making by providing the most current and reliable medical information. Systematic reviews and meta-analyses are important tools in this process. Systematic reviews identify and compile relevant evidence, while meta-analyses summarize and quantify the results of such reviews. Results from meta-analyses are, at present, the main source of summary evidence for the efficacy of treatments for a specific condition. They are important tools for helping to choose among treatment options, although they cannot be used to directly compare the magnitude of the effect of various therapies. However, the methods used and the consequent clinical value of the results, may be poorly understood by clinicians, who may therefore not take full advantage of the evidence. Recently, a panel of experts in osteoporosis and evidence-based medicine applied rigorous, validated, scientific standards to produce a systematic review and meta-analysis of randomized controlled trials of anti-resorptive agents used to treat osteoporosis. They found that, although several agents reduced the risk of vertebral fracture, only two, alendronate and risedronate, demonstrated convincing evidence for both non-vertebral and vertebral fracture risk reductions. The clinical implication of these results is that there are important differences in anti-fracture efficacy among currently available agents. In the absence of evidence from head-to-head clinical trials and because of the systematic nature and methodological rigor of the analyses, these data provide important information for clinical decision-making.

Cardiovascular responses to lower body negative pressure in normal subjects and in patients with diabetes mellitus.

The cardiovascular responses of non-diabetic and diabetic subjects to lower body negative pressure at 1.3, 2.7, and 5.3 kPa (10, 20, and 40 mmHg) were measured. The diabetics fell into two groups--those showing little change in systolic blood pressure with lower body negative pressure at 5.3 kPa (40 mmHg) and those showing falls greater than 2.7 kPa (20 mmHg). The patterns of response in the former group of diabetics and in the non-diabetics were similar. The diabetics who showed a fall in systolic blood pressure with lower body negative pressure nonetheless responded with a forearm vasoconstriction indicating that the vasomotor dysfunction was localised to some other vascular bed. In one subject forearm vasodilatation occurred with lower body negative pressure at 5.3 kPa (40 mmHg) although his response to milder levels of lower body negative pressure appeared normal. It is suggested that the integrity of vasomotor reflexes is most reliably tested by exposure to stepped increases in lower body negative pressure.

Cardiovascular reflex responses to apnoeic face immersion and mental stress in diabetic subjects.

The cardiovascular reflex responses to apnoea accompanied by immersion of the face in water and to mental stress, have been investigated in 21 diabetic subjects. Apnoeic face immersion caused bradycardia and forearm vasoconstriction (in seven subjects), bradycardia and forearm vasodilation (three subjects), tachycardia and forearm vasoconstriction (three subjects), or tachycardia and forearm vasodilatation (eight subjects). Mental stress evoked a tachycardia and forearm vasodilatation in all subjects. The abnormalities in the responses to apnoeic face immersion are most readily accounted for by loss of vagal and/or vasoconstrictor function.

Determinants of remission of Paget's disease of bone.

Bisphosphonates are a safe and effective treatment for Paget's disease of bone, but little information is available about the factors influencing the duration of remission so obtained. We assessed 60 patients with Paget's disease treated with disodium pamidronate (APD). The mean duration of remission was 9.5 months (range 3-25). The major influences were the initial pretreatment alkaline phosphatase (ALP; r = -4.6, p < 0.0001), minimum posttreatment ALP (r = -0.51, p < 0.0001), and the rate of response of bone turnover to the first dose of APD (r = 0.61, p < 0.0001). Multiple linear regression showed that the initial response to treatment was the most significant influence. Also, despite a minimum ALP within the normal range, the duration of remission varied considerably (4-25 months). This may be due to the difficulties in applying a population-based normal range to individuals.

Cross-sectional analysis of renal transplantation osteoporosis.

We report a cross-sectional study of 54 adult female renal transplant recipients. We measured bone mineral density (BMD) of the lumbar spine, femoral neck, total hip, and mid- and total radius, and 38 patients underwent transiliac crest bone biopsy. Osteopenia was widespread with 31/54 (57%) of patients osteoporotic at one or more sites. Seventeen out of 54 (32%) of the patients had a prevalent low-trauma fracture. There was a clear trend in BMD reduction across spine, hip and midradius, with the predominantly cortical midradial site showing the greatest loss. We found no relationship between BMD and body mass index, parathyroid hormone (PTH), dose of immunosuppressant, years since transplantation, age at menopause, or years since menopause. Histologically, abnormal biopsies could be classified into three categories: hyperparathyroid (n = 20), adynamic (n = 14), and osteomalacic (n = 2). Mean PTH was lower (p = NS) and mean cumulative prednisolone dose was higher (p = 0.04) in the adynamic group compared with the hyperparathyroid group, but because of overlap between groups neither was an effective discriminator of histology. We suggest that bone biopsy is indicated in these patients to direct appropriate treatment. At the cellular level, there were significant negative correlations between osteoclast function (eroded surface, r = 0.47, p = 0.003) and osteoblast numbers (osteoblast surface, r = -0.40, p = 0.01) and cumulative exposure to prednisolone. We postulate that suppression of osteoblast function by prednisolone with unopposed bone resorption may result in relative hypercalcaemia and low PTH. This progressive reduction in bone turnover may promote or prolong the adynamic state.

Treatment of Paget's disease with intermittent low-dose infusions of disodium pamidronate (APD).

Disodium pamidronate (APD) is a potent inhibitor of bone resorption, with less risk of defective mineralization than earlier bisphosphonates. We assessed the response to six spaced low-dose intravenous infusions of APD given at intervals of approximately 6 weeks followed by weekly infusions if bone turnover remained abnormal. Three groups of 10 patients were studied, each group receiving infusions of 15, 30, or 45 mg. Hydroxyproline excretion fell by 62% and alkaline phosphatase was reduced by 72%, with no difference between the dose levels. A total of 21 patients (70%) achieved normal levels of bone turnover, indicating that low-dose infusions of APD are a safe and effective treatment for Paget's disease.

Bisphosphonate space measurement in Paget's disease of bone treated with APD.

The bisphosphonate space (BPS) is a quantitative measurement of skeletal uptake of 99mTc-HMDP. We measured BPS in 36 patients with Paget's disease of bone, both before and 6 months after treatment with intravenous APD (disodium pamidronate) infusions. BPS fell after treatment, but proportionally less than serum alkaline phosphatase (ALP) and fasting urinary hydroxyproline/creatinine (HYPRO). There was no dose-response relationship between the dose of APD given and the percentage reduction in ALP and HYPRO at 6 months. Log dose of APD/pretreatment BPS, however, predicted the percentage reduction in ALP and HYPRO very well, and from the respective regression equations it was possible to predict the dose of APD needed to achieve normal values of ALP and HYPRO. In the 10 patients who achieved a normal ALP and 9 patients a normal HYPRO after more than 6 months treatment with APD (range 7-18 months), the predicted dose of APD agreed closely with the actual dose. In conclusion, our data support the idea that log dose APD/pretreatment BPS is a valid predictor of biochemical response in Paget's disease.

Abnormalities in osteoclast precursors and marrow accessory cells in Paget's disease.

Paget's disease of bone is characterized by increased numbers of abnormal osteoclasts. To determine if osteoclast precursors were increased or abnormal in this disease, we examined CFU-GM, the committed granulocyte-macrophage progenitor and the most likely precursor for osteoclasts. In cultures of unfractionated marrow mononuclear cells, CFU-GM colony formation was significantly increased in Paget's marrow cultures compared to that in normal cells (356 +/- 44 vs. 271 +/- 15/10(5) cells; P < 0.05). However, when we enriched hematopoietic precursors from Paget's and normal marrow samples using an antibody that recognizes the CD34 antigen present on most hematopoietic precursors, we found that similar numbers of CFU-GM colonies were formed (87 +/- 13/10(4) cells plated vs. 83 +/- 13). Coculture experiments with highly purified hematopoietic precursors (CD34+ cells) and nonhematopoietic marrow accessory cells (CD34- cells) revealed that the growth of Paget's precursors was significantly enhanced above expected levels by normal or Pagetic CD34- cells (P < 0.05). CFU-GM colony formation was also significantly enhanced when normal CD34+ cells were cocultured with Pagetic, but not with normal, CD34- cells. In addition, CFU-GM colony-derived cells from Paget's patients were hyperresponsive to 1,25-dihydroxyvitamin D3 and could form osteoclast-like multinucleated cells with 1,25-dihydroxyvitamin D3 concentrations one tenth of that required for normal multinucleated formation (10(-11) vs. 10(-10) M). These data suggest that osteoclast precursors may be abnormal in Paget's disease, and other cells in the Pagetic marrow microenvironment may further enhance the growth and differentiation of these abnormal precursors.

Alendronate in the treatment of primary hyperparathyroid-related osteoporosis: a 2-year study.

We investigated the effect of alendronate on calcium, PTH, and bone mineral density in 27 female and 5 male patients with primary hyperparathyroidism. The treatment group [n = 14; T score < or = -2.5 SD at the femoral neck (FN) or T < or = -1.0 SD plus previous nonvertebral fracture] was given alendronate 10 mg/d for 24 months. The second group (n = 18; T score > -2.5 SD at the FN) was untreated. Biochemistry was repeated at 1.5, 3, 6, 12, 18, and 24 months, and dual-energy x-ray absorptiometry at 12 and 24 months. There were no significant between-group baseline differences in calcium, creatinine, or PTH. Alendronate-treated patients gained bone at all sites [lumbar spine (LS), 1 yr gain, +7.3 +/- 1.7%; P < 0.001; 2 yr, +7.3 +/- 3.1%; P = 0.04). Untreated patients gained bone at the LS over 2 yr (+4.0 +/- 1.8%; P = 0.03) but lost bone elsewhere. Calcium fell nonsignificantly in the alendronate group between baseline (2.84 +/- 0.12 mmol/liter) and 6 wk (2.76 +/- 0.09 mmol/liter), with a nonsignificant rise in PTH (baseline, 103.5 +/- 14.6 ng/liter; 6 wk, 116.7 +/- 15.6 ng/liter). By 3 months, values had reverted to baseline. In primary hyperparathyroidism, alendronate is well tolerated and significantly improves bone mineral density at the LS (with lesser gains at FN and radius), especially within the first year of treatment. Short-term changes in calcium and PTH resolve by 3 months.

Acute changes in calcium homeostasis during treatment of primary hyperparathyroidism with risedronate.

We administered risedronate, a potent oral bisphosphonate, to patients with mild primary hyperparathyroidism in order to 1) determine if we could normalize the serum calcium concentration in the short term, and 2) analyze changes in the homeostatic mechanisms responsible for maintaining hypercalcemia in this patient population. When administered for 7 days, risedronate reduced fasting serum calcium concentrations without significant toxicity in patients with primary hyperparathyroidism. The decrease in serum calcium was accompanied by evidence of inhibition of bone resorption, as assessed by measurement of urinary hydroxyproline, increased serum immunoreactive PTH concentrations, enhanced renal tubular reabsorption of calcium, and a progressive decrease in serum alkaline phosphatase. Serum PTH was partially suppressed by an oral calcium load in untreated patients as well as in patients treated with risedronate. Although patients treated with risedronate had normal fasting serum calcium levels, serum calcium values in these normocalcemic patients were labile after oral ingestion of calcium. After daily calcium intake of 2 g, serum calcium levels in risedronate-treated patients were similar to those in untreated patients with primary hyperparathyroidism, suggesting that there are likely to be fluctuations in serum calcium in risedronate-treated patients with normal fasting serum calcium during postprandial periods. These studies show that risedronate lowers fasting serum calcium during short term treatment. However, further studies are required to determine whether the lability in serum calcium in these patients after an oral calcium load has clinical significance, and whether longer term treatment would maintain serum calcium in the normal range.

A multicenter study of the influence of fat and lean mass on bone mineral content: evidence for differences in their relative influence at major fracture sites. Early Postmenopausal Intervention Cohort (EPIC) Study Group.

We examined the relative influence of fat and lean mass on bone mineral content (BMC) among 1600 early postmenopausal women aged 45-59 y from four geographical locations (Nottingham, United Kingdom; Portland, OR; Honolulu; and Copenhagen). Bone sites investigated included the major fracture sites: hip, spine, and radius. Body weight had strong associations at all skeletal sites examined [BMC differences of 4-6% per interquartile range (IQR) of weight]. Associations with the fat and lean components of weight were more variable. The BMC differences per IQR of lean mass were 5-7% at the hip sites, 3% at the spine, and 2% at the radial sites. The greater differences for lean mass at the hip may reflect the high physical mobility and muscular activity of this site. The BMC differences per IQR of fat mass were 4-6% at the hip sites, 4% at the spine, and 5% at the ultradistal radius. These results suggest that low fat mass or low lean mass, particularly at the extremes, may adversely affect the major fracture sites. The bone sites with the greatest differences for fat mass were the most highly trabecular sites. With only a few exceptions, the associations of BMC with fat mass and lean mass were similar in direction and comparable in magnitude across the four geographic locations. We conclude that both fat and lean mass have independent influences on bone mass, but that their relative influence may vary by bone site depending on the trabecular content, physical mobility, and muscularity of the site.

Prediction and assessment of the response of Paget's disease to bisphosphonate treatment.

The rate of change of bone turnover either in response to treatment or its withdrawal taken in conjunction with fixed points in the disease cycle allows planning of treatment on an individual basis. This, in turn, helps to define the optimum scheduling of clinical visits to assess symptom response and to monitor disease activity.

Fluoride pharmacokinetics and changes in lumbar spine and hip bone mineral density.

Debate about the use of fluoride for the treatment of vertebral osteoporosis has centered not only on whether fluoride treatment decreases vertebral fractures, but also the interindividual vertebral bone mineral density (BMD) response, the potential for nonvertebral fractures, as well as side effects and tolerability. These effects may be dose dependent and, in this study, we examine the pharmacokinetics of sodium monofluorophosphate (MFP) in osteoporotic patients and relate this to changes in BMD. Plasma fluoride absorption curves were measured from 0 to 6 h after ingestion of MFP at baseline and during long-term dosing in 21 patients with vertebral osteoporosis (T scores < or = 2). BMD was measured at baseline and at 12 months at the lumbar spine (LS), femoral neck (FN), trochanter, and Ward's triangle. We found that fluoride elimination was inversely related to creatinine clearance. LS BMD increased from a median of 0.77 g/cm2 (range 0.69 to 0.99) at baseline to 0.88 g/cm2 (0.75 to 1.13) (p < 0.001) after 12 months. This equates to a median increase of 12% (range -1.2 to 37). Median femoral neck BMD decreased from 0.75 g/cm2 (0.62 to 0.94) at baseline to 0.69 g/cm2 (0.62 to 0.92) (p = 0.13) after 12 months. This equates to a decrease of -2% (-19 to 10). BMD at the other hip sites also decreased slightly. Changes in LS and FN BMD were not significantly related (r = 0.28, p = 0.29). The various pharmacokinetic parameters measured were not related to changes in LS BMD; however, there was an inverse relationship between trough fluoride concentration during long-term dosing and change in FN BMD. Further studies are required to see if this relationship can be used to monitor osteoporotic patients treated with fluoride and prevent significant decreases in FN BMD and possibly fractures at this site.

Biochemical response to combination of disodium etidronate with calcitonin in Paget's disease.

The biochemical responses to salmon calcitonin (SCT: 100 MRC units thrice weekly) and disodium etidronate (EHDP: 400 mg daily) alone and in combination for 6 months were compared in 72 patients with symptomatic Paget's disease of bone unresponsive to simple analgesic agents. SCT produced a 53% reduction in alkaline phosphatase (AP) and a 38% reduction in 24 h urinary hydroxyproline excretion (HYPRO). The response to EHDP was not significantly different--56% reduction in AP and 48% reduction in HYPRO. Their use in combination produced a significantly greater reduction of 71% in AP (P less than 0.002) and 69% reduction in HYPRO (P less than 0.0001). In those that remained symptomatic with increased disease activity treatment for longer than 6 months had a unpredictable effect and normal bone turnover was rarely achieved. Once therapy was withdrawn AP and HYPRO increased rapidly in those given SCT alone, returning to initial levels within 6 months. More sustained control of disease activity was achieved in those given EHDP either alone or with SCT but the combination retained the advantage obtained during treatment. Combinations of SCT + EHDP may find a place in the treatment of very active Paget's disease.

Paget's disease of bone: reduction of disease activity with oral risedronate.

Risedronate monosodium [1-hydroxy-2-(3-pyridinyl)ethylidene bisphosphonic acid monosodium salt] is a pyridinyl bisphosphonate drug under development as a treatment for Paget's disease of bone and other metabolic bone disorders. An open-label, single-center study was conducted to determine the efficacy and safety of oral resedronate in patients with severe Paget's disease [mean baseline serum alkaline phosphatase (ALP) about six times the upper limit of normal]. 20 patients (12 men, 8 women; mean age 74 years) were treated with 30 mg/day of oral risedronate for 84 days, followed by 112 days without treatment. This 196 day period was repeated once in 19 patients in whom ALP did not reach the midpoint of the normal range or increased by > or = 25% from the nadir value by the end of the first 196 day period. At the end of the first 196 day period, the mean percentage decrease from baseline in excess ALP and excess urinary hydroxyproline/creatinine (OHP/Cr) was 79.5% and 85.5%, respectively (excess defined as difference between the patient's ALP or OHP/Cr and midpoint of the normal range). At the end of the second period, the decreases were 86.3% and 101.3%, respectively. The decreases in excess ALP and OHP/Cr were significant (p < 0.0001). In 13 patients (65%), ALP normalized: 8 during the first treatment period and 5 during the second. There was a progressive decline and elimination of pagetic bone pain: 70% (14 of 20) of patients reported pagetic bone pain at baseline, 25% (5 of 20) reported pain after the first 196 day period; and 0% at retreatment day 56 (p = 0.003). Thereafter, all patients remained pain-free until the end of the study. No patients withdrew from the study due to adverse events, and no adverse events were judged related to the study drug. In summary, 30 mg/day of oral risedronate given in 3 month course significantly reduced the biochemical indices of disease activity, showing normalization of ALP in the majority of patients with severe Paget's disease, and was associated with a significant reduction in pagetic bone pain. Risedronate was well-tolerated and demonstrated a good safety profile.

Comparison of methods of assessing response of Paget's disease to bisphosphonate therapy.

Bisphosphonates have been shown to be effective in suppressing the elevated bone turnover found in Paget's disease of bone. In theory, the major determinants of post-treatment bone turnover are the initial disease activity and the rate of decline in bone turnover with therapy. In the present study, we examined the rate of decrease of alkaline phosphatase and hydroxyproline (expressed as a half-life) and showed this to be superior to percentage changes in bone turnover as a marker of response. The combination of pre-treatment alkaline phosphatase and the alkaline phosphatase half-life and pre-treatment hydroxyproline and the hydroxyproline half-life were the best models to predict post-treatment bone turnover (multiple r = 0.75, r2 = 0.56, p < 0.0001; and r = 0.71, r2 = 0.51, p < 0.0001, respectively). In addition, measurement of the half-lives of these markers of bone turnover may allow prospective changes to be made during treatment so that maximal disease suppression can be achieved.

The relationship between vitamin D and parathyroid hormone: calcium homeostasis, bone turnover, and bone mineral density in postmenopausal women with established osteoporosis.

It is evident from several studies that not all patients with hypovitaminosis D develop secondary hyperparathyroidism. What this means for bone biochemistry and bone mineral density (BMD) remains unclear. The aim of this study was to investigate the effects of hypovitaminosis D (defined as a 25OHD < or = 30 nmol/l) and patients with a blunted PTH response (defined arbitrarily as a PTH within the standard laboratory reference range in the presence of a 25OHD < or = 30 nmol/l) in comparison to patients with hypovitaminosis D and secondary hyperparathyroidism (defined arbitrarily as a PTH above the standard laboratory reference range in the presence of a 25OHD < or = 30 nmol/l) and vitamin D-replete subjects (25OHD > 30 nmol/l). Four hundred twenty-one postmenopausal women (mean age: 71.2 years) with established vertebral osteoporosis were evaluated by assessing mean serum calcium, 25OHD, 1,25(OH)2D, bone turnover markers, and BMD. The prevalence of hypovitaminosis D was 39%. Secondary hyperparathyroidism was found in only one-third of these patients who maintained calcium homeostasis at the expense of increased bone turnover relative to the vitamin D-replete subjects (bone ALP mean difference: 43.9 IU/l [95% CI: 24.8, 59.1], osteocalcin: 1.3 ng/ml [95% CI: 1.1, 2.5], free deoxypyridinoline mean difference: 2.6 nmol/nmol creatinine [95% CI: 2.5, 4.8]) and bone loss (total hip BMD mean difference: 0.11 g/cm2 [95% CI: 0.09, 0.12]). Patients with hypovitaminosis D and a blunted PTH response were characterized by a lower serum calcium (mean difference: 0.07 mmol/l [95% CI: 0.08, 0.2]), a reduction in bone turnover (bone ALP mean difference: 42.4 IU/l [95% CI: 27.8, 61.9], osteocalcin: 1.6 ng/ml [95% CI: 0.3, 3.1], free-deoxypyridinoline mean difference: 3.0 nmol/nmol creatinine [95% CI: 1.9, 5.9]), but protection in bone density (total hip BMD mean difference: 0.10 g/cm2, [95% CI: 0.08, 0.11]) as compared to those with hypovitaminosis D and secondary hyperparathyroidism. This study identifies a distinct group of patients with hypovitaminosis D and a blunted PTH response who show a disruption in calcium homeostasis but protected against PTH-mediated bone loss. This has clinical implications with respect to disease definition and may be important in deciding the optimal replacement therapy in patients with hypovitaminosis D but a blunted PTH response.

Association between a family history of fractures and bone mineral density in early postmenopausal women.

The aim of this analysis was to measure the strength of the association between a family history of fractures and bone mineral density (BMD), and to determine what definition of family fracture history best predicts BMD. Five hundred and eighty postmenopausal women aged 45-59 at recruitment completed a risk factor questionnaire. Women were asked to recall details of fractures sustained by any female relative. BMD measurements taken at five sites were used. The data were analysed using linear regression, adjusting for age. Two hundred and ninety-seven (52.8%) women reported a family history of fractures, and they had a significantly lower BMD at two of the sites measured (p < 0.05). The associations with BMD were most significant when only counting fractures that occurred in the subject's mother or a sister as a result of low trauma, with no restrictions made on age at the time of fracture and site of fracture (p < 0.01 at three sites; 0.01 < p < 0.05 at two sites). Women with a family history according to this definition had a 4.6% reduction in BMD at the femoral neck. When T scores were used to categorize women as either osteopenic/osteoporotic (T < -1) or normal at the femoral neck, the sensitivity of using this definition was 39% and the specificity was 74%. The small group of women that reported a low-trauma hip fracture in a mother or sister (n = 23) had a mean femoral neck BMD which was 8.9% lower than that of the remainder of the sample, although this difference was less statistically significant than when low trauma fractures at any site were counted. Of these 23 women, 70% were osteopenic or osteoporotic, compared with 57% of those reporting a low-trauma fracture at any site and 47% of the sample as a whole. The sensitivity of this definition, however, was low (6%). From these analyses it can be concluded that the definition of family fracture history that best predicts BMD in postmenopausal women is a fracture at any age in a mother or sister resulting from low trauma, although the sensitivity and specificity of using a family history of fractures by itself to screen for low BMD were poor.

Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience.

Limited placebo-controlled data are available to assess the long-term fracture efficacy of bisphosphonates. In order to determine the effects of 5 years of risedronate treatment, we extended a 3-year, placebo-controlled vertebral fracture study in osteoporotic women for an additional 2 years; women who entered the extension study continued to receive 5 mg risedronate or placebo according to the original randomization, with maintenance of blinding. End points included vertebral and nonvertebral fracture assessments, bone mineral density measurements, and changes in biochemical markers of bone turnover. A total of 265 women (placebo, 130; 5 mg risedronate, 135) entered the study extension and 220 (83%) completed the additional 2 years. Fracture results observed in the study extension were consistent with those observed in the first 3 years. The risk of new vertebral fractures was significantly reduced with risedronate treatment in years 4 and 5 by 59% (95% confidence interval, 19 to 79%, P = 0.01) compared with a 49% reduction in the first 3 years. Rapid and significant decreases in markers of bone turnover observed in the first 3 years were similarly maintained in the next 2 years of treatment. Increases in spine and hip bone mineral density that occurred in the risedronate group during the first 3 years were maintained or increased with a further 2 years of treatment. The mean increase from baseline in lumbar spine BMD over 5 years was 9.3% (P < 0.001). This study demonstrates that the effects of risedronate over 3 years on vertebral fracture and BMD are maintained with a further 2 years of treatment.