Agonist activity of the 3-hydroxy metabolites of tibolone through the oestrogen receptor in the mouse N20.1 oligodendrocyte cell line and normal human astrocytes.

17beta-oestradiol (E(2)) may have a beneficial impact on the development of age-related diseases, in part through alpha and beta oestrogen receptors (ER) in glia. Tibolone, a synthetic steroid, could influence glial-mediated neuroprotection if agonist oestrogenic activity is demonstrable. We used the N20.1 mouse oligodendrocyte cell line as a glial cell model to evaluate the response of ERalpha and ERbeta through oestrogen-response element (ERE) and AP-1-driven reporters to E(2), 4-hydroxytamoxifen (4OHT) and to two tibolone metabolites, 3alpha-hydroxytibolone (3alpha-OH-Tib) and 3beta-hydroxytibolone (3beta-OH-Tib). In addition, we tested the activity of these same ligands through the endogenous ERalpha in human normal astrocytes. Because endogenous ER was not detected in the N20.1 cells, we tested the ability of exogenous ER to activate transcription in response to ligands (100 nM) using a transient cotransfection assay with an ERalpha expression vector. To test the antagonist activity of 3alpha-OH-Tib and 3beta-OH-Tib, we used them in combination with E(2) (10(-8) M), at concentrations of 10(-7) M and 10(-6) M. The human normal astrocytes were treated similarly, with the exception that no ER-encoding DNA was used. Specific ER ligand mediated activity was shown using the E(2) antagonist ICI 182 780 and the pSG5 empty vector. E(2), 3alpha-OH-Tib, and 3beta-OH-Tib stimulated ERalpha on an ERE-promoter at each concentration (P < 0.001) but not at an AP-1-driven promoter. 4OHT was an effective antagonist, but did not exhibit agonist activity on the ERE-driven promoter. 4OHT was an effective agonist through ERalpha on an AP-1-driven promoter. 3alpha-OH-Tib and 3beta-OH-Tib were not effective antagonists of E(2). Both metabolites acted through the ER because the addition of an E(2) antagonist blocked their activity. These results show that 3alpha-OH-Tib and 3beta-OH-Tib exert agonist activity, yet lack antagonist or additive activity, through the ERalpha and ERbeta on an ERE-driven but not on an AP-1-driven promoter in a glial cell model and in normal human astrocytes. This contrasts with the effects of 4OHT, which exerted little or no agonist activity, but reduced E(2)-stimulated activity through ERalpha on the ERE, in the same cells.

Osteoporosis prevention and therapy: preserving and building strength through bone quality.

While bone mineral density measurements play a central role in osteoporosis management, the degree to which increases in this parameter contribute to bone fragility, fracture risk, and the therapeutic efficacy of osteoporosis agents is controversial. Indeed, bone strength is also significantly dependent upon bone turnover and bone quality, including microarchitecture, mineralization, and geometry. Given the critical role of these factors, it is essential to understand how they are affected by therapeutic agents. Even though a number of technological advances, such as microcomputed tomography, magnetic resonance imaging, and computerized analysis of radiographic patterns, help to provide critical information toward a more comprehensive assessment of bone turnover and bone quality, clinical trials addressing these factors are scarce. This article provides a review of studies relating to how osteoporosis therapies impact parameters of bone strength and quality.

Importance of precision in bone density measurements.

Bone densitometry, regardless of the specific technique, is not perfectly reproducible even when consistently performed in exact accordance with the manufacturer's recommendations. Precision must be quantified at each densitometry facility in precision studies of the various skeletal sites used for monitoring. The precision, as the root-mean-square standard deviation or root-mean-square coefficient of variation, is then used to determine the change in bone density that constitutes the least significant change and the minimum interval between follow-up measurements. Until precision studies are performed, the least significant change cannot be determined for any level of statistical confidence, making the interpretation of serial studies impossible.

Excretion of sweat and urine pyridinoline crosslinks in healthy controls and subjects with established metabolic bone disease.

Convenient techniques for measuring rates of bone turnover have been developed in recent years with the advent of biochemical markers of bone metabolism. One recent of these techniques is a collection method and quantitative enzyme immunoassay for free pyridinoline crosslinks in human sweat. The concentrations of pyridinoline crosslinks in 5-day sweat collections and first morning void and 24-hour urine collections from healthy subjects and subjects with established metabolic bone disorders were determined. T-scores were higher in the sweat system than in the urine system by up to 10-fold in postmenopausal subjects, women with hyperparathyroidism, and subjects with postmenopausal osteoporosis. For subjects with postmenopausal osteoporosis, receiver-operating characteristic curve analysis yielded areas under the curve of 0.699, 0.629, and 0.520 for sweat pyridinoline, first morning void urine pyridinoline, and 24 hour urine pyridinoline respectively. The areas under the curve of the sweat and first morning void urine measurements were significantly greater (p<0.05) than the 24-hour pyridinoline measurements. Healthy postmenopausal subjects and subjects with postmenopausal osteoporosis were monitored before and during estrogen replacement therapy or alendronate therapy. Sweat pyridinoline values declined by 49.0 +/- 12.4% and 19.4 +/- 19.9% for estrogen and alendronate subjects respectively. We conclude that this non-invasive technique is a sensitive and specific measure of bone resorption and is appropriate as an adjunct to techniques such as bone density and may also be useful in monitoring of response to anti-resorptive therapies.

Comparative safety of bone remodeling agents with a focus on osteoporosis therapies.

This article reviews the different treatments currently available for osteoporosis and examines the benefits and adverse events that are associated with each. While emphasizing safety considerations, this review summarizes the following treatments for osteoporosis: calcium supplements, fluoride, hormone replacement therapy, raloxifene, bisphosphonates, salmon calcitonin, and calcitriol. Before prescribing any of these agents, the clinician should review the risk/benefit profile of each drug in the context of the individual patient's history, concomitant diseases, concurrent medications, and general physical condition.

Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-36 health survey.

BACKGROUND: The treatment of patients with asymptomatic primary hyperparathyroidism remains controversial despite a National Institutes of Health consensus statement. This statement also recommended a randomized clinical trial because none exists to address this issue. METHODS: Informed consent was obtained from 53 asymptomatic patients with confirmed asymptomatic primary hyperparathyroidism who participated in this randomized trial of parathyroidectomy versus observation. Patients completed the SF-36 Health Survey, an instrument that measures wellness, every 6 months for 2 years. Average annual changes were compared. RESULTS: Fifty-three patients (42 female, 11 male) with asymptomatic, mild (serum calcium level, 10.1-11.5 mg/dL) asymptomatic primary hyperparathyroidism who agreed to participate were randomized into either a surgical group or an observation group. The mean calcium level was 10.31 mg/dL. The only demographic difference between groups was age, with the operative group being older (66.7 vs 62.6 years; P <.03). The scores on 2 of the 9 domains of the SF-36 were significantly different (P <.007 and <.012, respectively); both favored the operative group. CONCLUSIONS: Improved function is seen after parathyroidectomy when compared with patients who did not undergo operation. This study supports surgical management of mild primary hyperparathyroidism at the time of diagnosis because many patients have reversible nonclassic symptoms of the disease.

Clinical use of biochemical markers of bone remodeling: current status and future directions.

Biochemical markers of bone turnover provide a means of evaluating skeletal dynamics that complements static measurements of bone mineral density (BMD). This review evaluates the use of commercially available bone turnover markers as aids in diagnosis and monitoring response to treatment in patients with osteoporosis. High within-person variability complicates but does not preclude their use. Elevated bone resorption markers appear to be associated with increased fracture risk in elderly women, but there is less evidence of a relationship between bone formation markers and fracture risk. The critical question of predicting fracture efficacy with treatment has not been answered. Changes in bone markers as currently determined do not predict BMD response to either bisphosphonates or hormone replacement therapy. Single measurements of markers do not predict BMD cross-sectionally (except possibly in the very elderly), or change in BMD in individual patients, either treated or untreated. On the other hand, research applications of bone turnover markers are of value in investigating the pathogenesis and treatment of bone diseases. Markers have potential in the clinical management of osteoporosis, but their use in this regard is not established. Additional studies with fracture endpoints and information on negative and positive predictive value are needed to evaluate fully the utility of bone turnover markers in individual patients.

Bone density distribution and gender dominate femoral neck fracture risk predictors.

OBJECTIVE: To determine whether regional characteristics of the proximal femur could discriminate between a group of patients who had just sustained a first low-trauma femoral neck fracture (n=50) from a group of healthy volunteers (n=123). DESIGN: The application of an integral bone measurement (dual-energy X-ray absorptiometry) in conjunction with a volumetric cancellous bone density measurement (quantitative computed tomography) to the proximal femur in vivo provided an estimate of the contribution of the spatial distribution of bone density to hip fracture risk prediction. RESULTS: The primary finding of this study was a significant difference between male and female hip fracture risk predictor variables. In men with femoral neck fracture, a significant decrease in bone density throughout the proximal femur was observed. In women with femoral neck fracture, a combination of local bone deficits (significant decrease in cancellous bone at the site of fracture, and a decrease in cortical bone at the site of impact) and significantly larger proximal femur dimensions (femoral neck and head widths) was evident. CONCLUSIONS: These results imply that effective hip fracture prevention strategies may require separate approaches for men and women. Screening programs for diminished bone density at the proximal femur have proved effective in previous studies. An approach which includes examining these local bone characteristics may further improve our ability to accurately determine hip fracture risk in vivo.

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.

The epidemiology of osteoporosis. Practical implications for patient care.

The new definition of osteoporosis moves this disorder from a disease of fractures to a disease of fracture risks. Like blood lipids and blood pressure, bone mineral density is now viewed as a predictor of possible problems. Through careful history taking and physical examination, primary care physicians can identify patients in whom intervention is likely to prevent the anguish of broken bones and lost mobility. In this article, Drs Goddard and Kleerekoper discuss the new diagnostic criteria and what they mean for your patients.

The role of fluoride in the prevention of osteoporosis.

Osteoporosis defined as low bone mass and increased susceptibility to fracture is a reflection of the sum of peak bone mass and any bone that has been lost once peak mass has been attained. Several strategies have been applied to optimize peak bone mass and to prevent bone loss. Fluoride has greatest potential as a therapy for osteoporosis once bone has been lost. It has been demonstrated both experimentally and clinically to stimulate bone formation directly and to increase bone mass in patients who already have osteoporosis. Several bone formation/stimulation therapies are under development, and some of these have reached the stage of clinical trial. None of these therapies has been as extensively studied as fluoride, and none is sufficiently advanced in development to be clinically available in the next 3 to 5 years. Fluoride therapy for osteoporosis is already performed in many countries, and approval for use in osteoporosis in the United States is pending. The first clinical trials of NaF therapy for osteoporosis were reported by Rich and Ensinck in 1961. Since then, hundreds of reports on the successes and failures of fluoride therapy have appeared in the literature. At first glance, it seems disappointing and inexplicable that, after 40 years of research, fluoride is still considered an experimental drug in the United States. One plausible explanation is that much of the early research on this drug was suboptimal, including the author's contributions. Fluoride as a naturally occurring element is difficult to patent, and this has kept major pharmaceutical companies from investing heavily in fluoride therapy despite its obvious potential. As a result, pharmacologic and pharmacokinetics studies of fluoride are limited in scope, as are phase I and phase II human toxicology and dose-finding studies. Most early studies of large doses of plain NaF were unable to demonstrate a consistent effect on fracture rate despite a consistent and dramatic effect on bone density. Once this became obvious and as new technologies for measuring bone density became available, it became equally clear that future clinical trials would have to be performed using different formulations of fluoride and lower doses. This approach has not resulted in uniformly positive clinical trials, and one must look elsewhere for answers. The most compelling explanation is that the trials have included patients with different severity of disease, suggesting that there is point in the bone loss spectrum at which even a potent bone-stimulating agent such as fluoride is ineffective. This possibility should provoke a reappraisal of the earlier negative studies: was the failure a result of the drug or of patient selection? The answer to this question is crucial, because these failures have cast a long shadow over the safety of fluoride and are contributing more to the absence of this drug from the pharmacopoeia than any other factor.

Peripheral bone densitometry: an old friend revisited.

The earliest assessments of bone "mass" involved metacarpal morphometry that provided insight into age-related changes, the effects of low habitual dietary calcium intake, and the effects of estrogen deficiency and replacement. Single photon absorptiometry (SPA) made quantitative mass measurement possible but this was intellectually unsatisfactory since osteoporotic fractures are more of a concern at the spine and hip than at the wrist. Necessity forced the development of axial bone mass measurement (dual photon absorptiometry--DPA, dual energy xray absorptiometry--DXA, quantitative computed tomography--QCT). Hip measurements provide a better prediction of hip fracture risk than measurements at any other skeletal site. For every standard deviation decrement of bone mass at the hip, relative risk of fracture is 3.0. At non-hip sites the relative risk is only 2.0 for each standard deviation decrement in bone mass. However measurement at non-hip sites provide a fracture risk prediction that is at least the equal of blood pressure measurement for predicting risk of CVA, and substantially better than the risk assessment of acute MI afforded by cholesterol measurement. An important caveat of the superiority of hip measurement is that the data are derived from short-term studies in older women (> 70 years). The relative risk data from phalangeal, forearm, and heel measurements have all been obtained from longer-term studies in younger women. From a community health perspective, bone density measurements, no matter how accurate, precise, and meaningful, have limited value if access to the technology is limited. Peripheral measurements can be obtained on existing radiographic equipment (phalanges), or small, portable, inexpensive dedicated equipment (forearm, heel). This technology is more likely to make it to the office of the primary care physician than the larger, more expensive, dedicated equipment needed for hip measurements. The peripheral measurement technology is also suitable for high traffic areas, just as blood pressure and cholesterol measurements are widely available. This presentation reviewed the scientific validity of peripheral bone mass measurement and explored the potential for making this technology available at non-traditional facilities such as pharmacies, shopping malls, health clubs, etc.