Michael Kleerekoper

The role of three-dimensional trabecular microstructure in the pathogenesis of vertebral compression fractures

SummaryWe compared indices of three-dimensional microstructure of iliac trabecular bone between 26 patients with vertebral compression fractures due to postmenopausal osteoporosis and 24 control subjects without vertebral fracture, who were matched for age, sex, race, menopausal status, and several densitometric and histologic indices of both cortical and trabecular bone mass. The patients with fracture had a significantly lower mean value (1.03±0.15 vs. 1.26±0.26;P<0.005) for indirectly calculated mean trabecular plate density, an index of the number and connectivity of structural elements, and as a necessary corollary, a significantly higher mean value for the mean thickness of structural elements. Plate density was more than one standard deviation below the age-adjusted mean value for normal postmenopausal white females in 19 (73%) of the fracture caes and in only 5 (21%) of the nonfracture cases (P<0.001). We conclude that the biomechanical competence of trabecular bone is dependent not only on the absolute amount of bone present but also on the trabecular microstructure.

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 manufacturers 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.

Clinical Use of Biochemical Markers of Bone Remodeling: Current Status and Future Directions

Abstract: 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.

A Randomized Trial of Sodium Fluoride as a Treatment for Postmenopausal Osteoporosis

The anti-fracture efficacy of sodium fluoride (NaF) was evaluated in 84 postmenopausal white women with spinal osteoporosis. The dose of NaF used was 75 mg/day and all patients in this prospective, randomized, double-blind, placebo-controlled clinical trial received calcium supplements (carbonate salt) 1500 mg/day in addition to participating in a structured physical therapy program. For each of the outcome measures (change in stature, change in cortical bone mass in the forearm and development of new vertebral fractures determined by change in vertebral morphometry and by scintigraphy) there was no significant difference between the fluoride or placebo treated groups. Side effects, predominantly gastrointestinal symptoms and the development of the painful lower extremity syndrome, occurred significantly more frequently in the fluoride group (P<0.05). Peripheral fractures were not more frequent in the fluoride group. We conclude that, in the dose and manner used in this study, NaF is no more effective than placebo in retarding the progression of spinal osteoporosis. There is no role for NaF in the treatment of osteoporosis outside the confines of clinical research.

The accumulation of whole body skeletal mass in third- and fourth-grade children: Effects of age, gender, ethnicity, and body composition

The purpose of this longitudinal study is to describe bone mass and body composition, and the annual changes in these measurements, among third grade students recruited from a suburban school district. Whole body bone mineral content (WBBMC), bone mineral density (WBBMD), fat, and lean mass were measured by dual-energy X-ray absorptiometry. Bone mass in the lumbar spine (LBMC) region of the whole body scan was also utilized. 773 students (38% white, 57% black, 5% other) had baseline visits; 561 had a second measurement a year later. At baseline, black children have significantly higher WBBMC, WBBMD, height, and lean mass than whites. Black males, but not black females, have a greater LBMC. There are no significant gender differences in body size, WBBMC, or WBBMD, although girls have a greater LBMC and fat mass, and boys have a higher lean mass. Most of these differences persist in visit 2. The annual change in bone and lean mass is greater in blacks. Stepwise linear regression analyses of bone mass on body size, gender, and ethnicity and their interactions indicate that log-transformed weight explains most of the variance in both WBBMC and WBBMD (multiple r2 = 0.90 and 0.64, respectively). There are significant black/white differences in intercepts and slopes. Other variables explain only another 1%-2% of the variance. The strongest Pearson correlations are between changes in bone mass and changes in lean mass and log-transformed weight (r ranging from 0.62 to 0.84, p = 0.0001). We conclude that there is a significant black/white, but not male/female difference in whole body bone mass and bone density before puberty. Ethnic and gender differences in bone and body composition suggest that the lean component may contribute to a greater peak bone mass in blacks vs. whites, and perhaps in males vs. females.

Development and Validation of a Discriminative Quality of Life Questionnaire for Osteoporosis (The OPTQoL)

We report the development and validation of an osteoporosis‐targeted quality of life questionnaire to measure the impact of the disease in the general population. From multiple focus groups with women with osteoporosis, healthy women at risk for osteoporosis, spouses and relatives of women with osteoporosis, and health care providers, we identified over 300 potential items related to the disease. A lengthy questionnaire incorporated these items and was administered to a second large study cohort of 222 women with clinical osteoporosis (history of fracture, significant height loss, and/or kyphosis); 101 women with known low bone mineral density levels that would categorize them as osteoporotic but who had not yet shown obvious physical manifestations of the disease; and 142 women with other conditions (such as arthritis, cancer, depression) expected to also have an impact on quality of life. Final items from among the original 300 were chosen for their demonstrated relationship with osteoporosis as measured by clinical manifestations and low bone density and with quality of life measured by a standard generic questionnaire, the SF‐36. The final questionnaire contains 26 scored items in three domains—physical activity, adaptations, and fears—and six nonscored questions relating to osteoporotic changes and diagnosis. This instrument is unique among osteoporosis‐targeted questionnaires in that it attempts to measure the total impact of the disease on quality of life within a population at a single point in time.

SECONDARY OSTEOPOROSIS: A REVIEW OF THE RECENT EVIDENCE

OBJECTIVE To review several causes of secondary osteoporosis as well as screening recommendations for underlying disorders. METHODS We conducted a review of the literature on many of the causes of osteoporosis that have been published during the past 15 years, focusing on those sources available from 2000 through the present. Indeed, more than two-thirds of the articles that we reviewed were printed during the past 6 years. These reports examined secondary osteoporosis in general, as well as many of the specific causes. RESULTS Secondary osteoporosis occurs in almost two-thirds of men, more than half of premenopausal and perimenopausal women, and about one-fifth of postmenopausal women. Its causes are vast, and they include hypogonadism, medications, hyperthyroidism, vitamin D deficiency, primary hyperparathyroidism, solid organ transplantation, gastrointestinal diseases, hematologic diseases, Cushings syndrome, and idiopathic hypercalciuria. These causes have their own pathogenesis, epidemiologic features, and effect on the skeleton. CONCLUSION The causes of secondary osteoporosis are numerous, and an understanding of their characteristics with respect to bone density and potential fracture risk is essential in the management of osteoporosis. A heightened awareness of the possibility of their existence is necessary to provide optimal care.

Identification of women at risk for developing postmenopausal osteoporosis with vertebral fractures: role of history and single photon absorptiometry

Putative risk factors for the development of postmenopausal osteoporosis (PMO) with vertebral fractures were examined in a retrospective study of 663 postmenopausal white females aged 45-75 years (266 women with non-traumatic vertebral compression fractures (VF+), 134 non-fractured women from a general medicine clinic (controls) and 263 non-fractured women who were evaluated when they presented specifically for osteoporosis screening (VF-]. The VF+ women differed from control women in several respects. The VF+ group reported a higher prevalence of a positive family history of osteoporosis, and a higher prevalence of a history of medical or surgical conditions known to be independently associated with metabolic bone disease, had fewer children, were smaller (weight, height) and were slightly older. The two groups, VF+ and controls, did not differ with respect to cigarette smoking, alcohol consumption, exercise habits, menstrual or menopausal history, dietary intake of milk and cheese or in amount taking calcium supplements during pregnancy. The VF+ group also differed in certain respects from the VF- group. The VF+ group were smaller (weight, height) and were older. The VF+ group had lower cortical bone mass (measured by single photon absorptiometry of the non-dominant forearm) than either the control or VF- groups. The latter two groups did not differ from each other with respect to this measurement. These markers demonstrated limited sensitivity and specificity as estimated from a confirmatory data set, particularly for the historical and anthropometric variables. We conclude that an assessment of the risk of developing PMO with vertebral fractures cannot be based on the putative risk factors as measured in our study, but must be based on measurement of bone mass.

Soy isoflavones in the management of postmenopausal osteoporosis.

This is a review article designed to address the effects of soy isoflavones on bone metabolism in postmenopausal women and their place in the prevention and treatment of postmenopausal osteoporosis. Soy isoflavones are natural products that could be used as an alternative to menopausal hormone therapy because they are structurally and functionally related to 17&bgr;-estradiol. In vitro and animal studies have shown that they act in multiple ways to exert their bone-supporting effects. They act on both osteoblasts and osteoclasts through genomic and nongenomic pathways. Epidemiological studies and clinical trials suggest that soy isoflavones have beneficial effects on bone mineral density, bone turnover markers, and bone mechanical strength in postmenopausal women. However, there are conflicting results related to differences in study design, estrogen status of the body, metabolism of isoflavones among individuals, and other dietary factors. The long-term safety of soy isoflavone supplements remains to be demonstrated.

Hypophosphatemic osteomalacia and adult Fanconi syndrome due to light-chain nephropathy. Another form of oncogenous osteomalacia.

Two patients, one with myeloma (Patient 1) and the other with probable chronic lymphocytic leukemia (Patient 2), had reduced renal tubular phosphate reabsorption in the absence of hyperparathyroidism together with other features of the Fanconi syndrome, as consequences of the nephropathy associated with light-chain proteinuria. Both patients had hypophosphatemic osteomalacia, demonstrated for the first time in this condition by iliac bone histomorphometry after in vivo double tetracycline labeling, despite absence of bone pain or Looser zones. Neither patient was vitamin D-depleted, but plasma calcitriol level was normal in Patient 1 and low in Patient 2; only the latter patient had severe muscle weakness. Complete histologic correction of osteomalacia was achieved by treatment in accordance with the biochemical defects--oral phosphate therapy alone in Patient 1 and combined with calcitriol in Patient 2. Both patients are now symptom-free, five and three years after the initial diagnosis of bone disease and hematogenous malignancy. Thirteen previous instances of the same form of osteomalacia were reviewed; in most cases, the Fanconi syndrome developed before its probable cause became apparent. The Fanconi syndrome has also been reported in two cases of osteomalacia due to mesenchymal tumor, but not in osteomalacia associated with prostatic carcinoma. Light-chain nephropathy and consequent renal tubular dysfunction appears to be a third form of oncogenous osteomalacia.