Citations

Abstract To assess the influence of bone turnover on bone density and fracture risk, we measured serum levels of osteocalcin (OC), bone alkaline phosphatase (BAP), and carboxy-terminal propeptide of type I procollagen (PICP), as well as 24-h urine levels of cross-linked N-telopeptides of type I collagen (NTx) and the free pyridinium cross-links, pyridinoline (Pyd) and deoxypyridinoline (Dpd), among 351 subjects recruited from an age-stratified random sample of Rochester, Minnesota women. PICP, NTx, and Dpd were negatively associated with age among the 138 premenopausal women. All of the biochemical markers were positively associated with age among the 213 postmenopausal women, and the prevalence of elevated turnover (>1 standard deviation [SD] above the premenopausal mean) varied from 9% (PICP) to 42% (Pyd). After adjusting for age, most of the markers were negatively correlated with bone mineral density (BMD) of the hip, spine, or forearm as measured by dual-energy X-ray absorptiometry, and women with osteoporosis were more likely to have high bone turnover. A history of osteoporotic fractures of the hip, spine, or distal forearm was associated with reduced hip BMD and with elevated Pyd. After adjusting for lower BMD and increased bone resorption, reduced bone formation as assessed by OC was also associated with prior osteoporotic fractures. These data indicate that a substantial subset of elderly women has elevated bone turnover, which appears to adversely influence BMD and fracture risk. Combined biochemical and BMD screening may provide better prediction of future fracture risk than BMD alone.

Abstract Osteoporotic fractures are a significant public health problem, resulting in substantial morbidity and mortality. Previous estimates of the economic burden of osteoporosis, however, have not fully accounted for the costs associated with treatment of nonhip fractures, minority populations, or men. Accordingly, the 1995 total direct medical expenditures for the treatment of osteoporotic fractures were estimated for all persons aged 45 years or older in the United States by age group, sex, race, type of fracture, and site of service (inpatient hospital, nursing home, and outpatient). Osteoporosis attribution probabilities were used to estimate the proportion of health service utilization and expenditures for fractures that resulted from osteoporosis. Health care expenditures attributable to osteoporotic fractures in 1995 were estimated at $13.8 billion, of which $10.3 billion (75.1%) was for the treatment of white women, $2.5 billion (18.4%) for white men, $0.7 billion (5.3%) for nonwhite women, and $0.2 billion (1.3%) for nonwhite men. Although the majority of U.S. health care expenditures for the treatment of osteoporotic fractures were for white women, one-fourth of the total was borne by other population subgroups. By site-of-service, $8.6 billion (62.4%) was spent for inpatient care, $3.9 billion (28.2%) for nursing home care, and $1.3 billion (9.4%) for outpatient services. Importantly, fractures at skeletal sites other than the hip accounted for 36.9% of the total attributed health care expenditures nationally. The contribution of nonhip fractures to the substantial morbidity and expenditures associated with osteoporosis has been underestimated by previous researchers.

Abstract To assess the cost-effectiveness of interventions to prevent osteoporosis, it is necessary to estimate total health care expenditures for the treatment of osteoporotic fractures. Resources utilized for the treatment of many diseases can be estimated from secondary databases using relevant diagnosis codes, but such codes do not indicate which fractures are osteoporotic in nature. Therefore, a panel of experts was convened to make judgments about the probabilities that fractures of different types might be related to osteoporosis according to patient age, gender, and race. A three-round Delphi process was applied to estimate the proportion of fractures related to osteoporosis (i.e., the osteoporosis attribution probabilities) in 72 categories comprised of four specific fracture types (hip, spine, forearm, all other sites combined) stratified by three age groups (45–64 years, 65–84 years, 85 years and older), three racial groups (white, black, all others), and both genders (female, male). It was estimated that at least 90% of all hip and spine fractures among elderly white women should be attributed to osteoporosis. Much smaller proportions of the other fractures were attributed to osteoporosis. Regardless of fracture type, attribution probabilities were less for men than women and generally less for non-whites than whites. These probabilities will be used to estimate the total direct medical costs associated with osteoporosis-related fractures in the United States.

Abstract IGF-I and their binding proteins are important in bone health. Examination of BMD, osteoblast proliferation, and markers of bone resorption in transgenic mice that constitutively overexpress IGFBP-3 indicates that overexpression of IGFBP-3 increases osteoclast number and bone resorption, impairs osteoblast proliferation, and has a significant negative effect on bone formation. Introduction: Low serum insulin-like growth factor I (IGF-I) levels correlate with an increased risk of osteoporotic fractures. Serum IGF-I is largely bound to IGF-binding protein-3 (IGFBP-3), which can inhibit IGF-I action and enhance delivery of IGF-I to tissues. Its role in bone biology is unclear. Methods: Bone mineral density (BMD), osteoblast proliferation, and markers of bone resorption were examined in transgenic (Tg) mice that constitutively overexpressed human IGFBP-3 cDNA driven by either the cytomegalovirus (CMV) or phosphoglycerate kinase (PGK) promoter. Results: Cultured calvarial osteoblasts from Tg mice expressed the transgene and grew more slowly than cells from wild-type (Wt) mice, and the mitogenic response to IGF-I was attenuated in osteoblasts from Tg mice. Total volumetric BMD and cortical BMD, measured in the femur using peripheral quantitative computed tomography (pQCT) were significantly reduced in both Tg mouse strains compared with Wt mice. PGKBP-3 Tg mice showed the most marked reduction in bone density. Osteocalcin levels were similar in Wt and CMVBP-3 Tg mice but were significantly reduced in PGKBP-3 Tg mice. Urinary deoxypyridinoline and osteoclast perimeter, markers of bone resorption, were significantly increased in both Tg mouse strains compared with Wt mice. Using double labeling with tetracycline, we demonstrated that pericortical and endocortical mineral apposition rate was significantly reduced in PGKBP-3 Tg mice compared with Wt mice. Conclusions: These data show that overexpression of IGFBP-3 increases osteoclast number and bone resorption, impairs osteoblast proliferation, and has a significant negative effect on bone formation.

Abstract To meet expectations for the participation of minority populations in research, we committed to enroll 140 minority subjects in addition to a random sample of Olmsted County, Minnesota residents (90% white) for a study of risk factors for age-related bone loss and fractures. We successfully enrolled 597 additional minority subjects but encountered specific problems with respect to identification of potential subjects, recruitment, obtaining informed consent, transportation to the study site, and collecting study data. These problems were resolved by observing the tenets of outreach to a diverse study population, namely (1) understand the target population; (2) establish explicit recruitment goals; (3) agree on research plans between study staff and minority communities; (4) continuously evaluate the recruitment process; and (5) maintain lines of communication. Success depended especially on the recruitment of cultural advisors from the different ethnic groups. These special efforts increased the recruitment cost substantially; the total expense of $122,000 for recruiting 550 Asian, Hispanic, and Somali subjects was almost 5-fold higher than the $26,000 required to recruit 699 mostly white study subjects from the population who were contacted by mail. Although it is not impossible to recruit minority subjects, investigators (and grant reviewers) should recognize that significant resources are required to gain access to ethnic communities for research. These results should contribute to more realistic budgets for recruiting minority subjects into clinical research studies.

Abstract Oncogenic osteomalacia (OOM) is associated with primitive mesenchymal tumors that secrete phosphaturic factors resulting in low serum concentrations of phosphate and calcitriol, phosphaturia, and defective bone mineralization. To identify overexpressed genes in these tumors, we compared gene expression profiles of tumors resected from patients with OOM and histologically similar control tumors using serial analysis of gene expression (SAGE). Three hundred and sixty-four genes were expressed at least twofold greater in OOM tumors compared with control tumors. A subset of 67 highly expressed genes underwent validation with an extended set of OOM and control tumors using array analysis or reverse-transcription polymerase chain reaction (RT-PCR). Ten of these validated genes were consistently overexpressed in all OOM tumors relative to control tumors. Strikingly, genes with roles in bone matrix formation, mineral ion transport, and bone mineralization were highly expressed in the OOM tumors.

Abstract Fibrous dysplasia (FD) of bone is characterized by focal replacement of normal bone and marrow with abnormal bone and fibrous tissue. It arises from postzygotic activating mutations of the GNAS1 gene. Hypophosphatemia due to renal phosphate wasting has been reported in association with FD as a part of the McCune-Albright Syndrome (MAS), which is characterized by FD, skin hyperpigmentation, and precocious puberty. To date, the prevalence and mechanism of phosphate wasting has not been well studied. We evaluated 42 patients with FD/MAS. Serum and urine samples were tested for indices of mineral metabolism, amino acid handling, and markers of bone metabolism. Twenty (48%) patients had some degree of renal phosphate wasting. Nephrogenous cyclic adenosine monophosphate (cAMP) was normal in FD patients, suggesting that the underlying cause of phosphate wasting is not the presence of activating GNAS1 mutations in the kidney. In addition, there was evidence of a more generalized renal tubulopathy as represented by the presence of abnormal vitamin D metabolism, proteinuria in 36 (86%) patients, and aminoaciduria in 39 (94%) patients. Renal phosphate wasting significantly correlated with the degree of bone involvement, as assessed by serum and urine markers of bone metabolism, suggesting that a circulating factor produced by FD bone and impacting on the kidney may be the mechanism. These data show that phosphaturia as part of a generalized renal tubulopathy represents the most common extraskeletal manifestation of FD and that the observed tubulopathy is similar to that seen in tumor-induced osteomalacia (TIO).

Abstract Measures of musculoskeletal rehabilitation play an integral part in the management of patients with increased fracture risk because of osteoporosis or extraskeletal risk factors. This article delineates current scientific evidence concerning nonpharmacologic approaches that are used in conjunction with pharmacotherapy for prevention and management of osteoporosis. Fractures caused by osteoporotic fragility may be prevented with multidisciplinary intervention programs, including education, environmental modifications, aids, and implementation of individually tailored exercise programs, which are proved to reduce falls and fall-related injuries. In addition, strengthening of the paraspinal muscles may not only maintain BMD but also reduce the risk of vertebral fractures. Given the strong interaction between osteoporosis and falls, selection of patients for prevention of fracture should be based on bone-related factors and on risk factors for falls. Rehabilitation after vertebral fracture includes proprioceptive dynamic posture training, which decreases kyphotic posturing through recruitment of back extensors and thus reduces pain, improves mobility, and leads to a better quality of life. A newly developed orthosis increases back extensor strength and decreases body sway as a risk factor for falls and fall-related fractures. Hip fractures may be prevented by hip protectors, and exercise programs can improve strength and mobility in patients with hip fracture. So far, there is no conclusive evidence that coordinated multidisciplinary inpatient rehabilitation is more effective than conventional hospital care with no rehabilitation professionals involved for older patients with hip fracture. Further studies are needed to evaluate the effect of combined bone- and fall-directed strategies in patients with osteoporosis and an increased propensity to falls.

Abstract The role of the IGFs and IGFBPs on age-related changes in BMD in adult men and women is not well understood. Studying an age-stratified community based sample of 344 men and 276 women, we found higher IGFBP-2 levels to be associated with lower BMD. IGFBP-2, which increases with age in both men and women, was the strongest, most consistent predictor of BMD among the IGF/IGFBPs studied. Introduction: Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are important regulators of tissue growth and metabolism, but their association with BMD in adult men and women is controversial. Materials and Methods: In an age-stratified, random sample of the community population, we examined the role of serum levels of IGF-I, IGF-II, and IGFBP-1, −2, and −3 on BMD of the proximal femur (total hip), lateral spine, midshaft, and ultradistal radius as measured by DXA. We explored the association before and after adjustment for potential confounders, including age, bioavailable estradiol and testosterone, sex hormone binding globulin (SHBG), and measures of total fat and skeletal muscle mass. Results: We studied 344 men (age, 23-90 years) and 276 women (age, 21-93 years; 166 postmenopausal) not on hormone replacement or oral contraceptives. In both men and women, IGF-I and IGFBP-3 levels fell with advancing age, whereas IGFBP-2 levels tended to rise with age. There was an inverse association of IGFBP-2 with BMD at most skeletal sites in men and both premenopausal and postmenopausal women, whereas lower IGF-I and IGFBP-3 were associated with lower BMD in men and postmenopausal women only. Lower IGF-II was associated with lower BMD in men only. There were no associations between IGFBP-1 and BMD in either sex. After adjustment for age, in most cases, we found no further associations between IGF-I, IGF-II, or IGFBP-3 and BMD. In contrast, after age adjustment, higher IGFBP-2 remained a predictor of lower BMD in men and postmenopausal women at all sites except for the lateral spine (for men: r = −0.21, −0.20, and −0.19, all p < 0.001; and for postmenopausal women: r = −0.34, −0.24, and −0.25, all p < 0.01, for the total hip, midshaft, and ultradistal radius, respectively). IGFBP-2 remained an independent negative predictor of BMD in men, postmenopausal women, and all women combined after additional adjustment for bioavailable sex steroids, but not at all sites after adjustment for SHBG and muscle mass. In premenopausal women, IGFBP-2 had similar associations as seen in postmenopausal women, but they were weaker and not statistically robust. Conclusions: Among the IGF/IGFBPs in our study, IGFBP-2 was a key negative predictor of BMD among men and women, particularly postmenopausal women. Our findings suggest a potential role of the IGF/IGFBP system in regulating bone loss in aging men and women and identify a previously under-recognized, potentially deleterious role for IGFBP-2, a known inhibitor of IGF action that increases with age in both sexes. Whether the action of the IGF/IGFBP system on bone metabolism is mediated partly through its effects on muscle mass or SHBG deserves further study.

Abstract While androgens clearly have significant skeletal effects, the paracrine mediators of androgen action on bone are at present unclear. Interleukin-6 (IL-6) is a candidate cytokine that is produced by osteoblastic lineage cells and promotes osteoclastogenesis and bone resorption. Here, we assessed constitutive as well as IL-1β– and tumor necrosis factor-α (TNF-α)–stimulated IL-6 mRNA expression by Northern analysis and protein secretion by immunoassay in a human androgen-responsive osteoblastic cell line (hFOB/AR-6) which contains ∼4000 androgen receptors (ARs)/nucleus. Treatment with 5α-dihydrotestosterone (DHT) dose-dependently inhibited constitutive and TNF-α/IL-1β–stimulated IL-6 mRNA steady-state levels in hFOB/AR-6 cells by 70–80% at 10−7 M. In addition, testosterone also suppressed TNF-α/IL-1β–stimulated IL-6 mRNA levels by 57%, while the adrenal androgen dehydroepiandrosterone had no effect. Of note, the specific AR antagonist, hydroxyflutamide, also inhibited IL-6 mRNA levels by 70%. Consistent with the Northern analyses, treatment with 5α-DHT, testosterone, and hydroxyflutamide also inhibited IL-6 protein production by 79%, 62%, and 71%, respectively (p < 0.001), while these agents had no effect on IL-6 soluble receptor levels. Finally, we demonstrated that hydroxyflutamide treatment of hFOB/AR-6 cells markedly inhibited the activation and binding of NF-κB (a known stimulator of IL-6 gene transcription) to its response element, thus providing a potential mechanism for its effect on IL-6 production by osteoblasts. These data are consistent with the hypothesis that suppression of osteoblast IL-6 production by androgens may mediate, at least in part, the antiresorptive effects of androgens on bone. Moreover, our findings also indicate that hydroxyflutamide, which is a known AR antagonist in most tissues, may function as a selective AR modulator for effects on IL-6 production by osteoblasts.