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Cancer treatment-induced bone loss in patients with breast or prostate cancer.

PURPOSE/OBJECTIVES: To review the prevalence, consequences, pathophysiology, diagnosis, and treatment of cancer treatment-induced bone loss (CTIBL) in patients with breast or prostate cancer. DATA SOURCES: Published articles, abstracts, book chapters, electronic resources, and manufacturer information. DATA SYNTHESIS: CTIBL is a long-term complication associated with cancer therapies that cause hypogonadism in patients with breast or prostate cancer. Early diagnosis and treatment of CTIBL is essential to prevent bone fractures. CTIBL treatment includes modification of lifestyles that increase the risk of developing bone loss and fractures and includes the use of bone loss therapies (e.g., bisphosphonates, selective estrogen receptor modifiers, calcitonin). CONCLUSIONS: CTIBL is becoming more common as patients with breast or prostate cancer survive longer. Identifying and treating CTIBL early are important because once bone is lost, damaged bone becomes more difficult to repair; early diagnosis and treatment also may prevent fractures. IMPLICATIONS FOR NURSING: Nurses must be knowledgeable about CTIBL to identify high-risk patients and educate patients and their families about CTIBL, bone loss therapies, and lifestyle modifications.

Bone Resorption↗

Esthesioneuroblastoma. A report of seven cases.

The biologic behavior of esthesioneuroblastoma in seven patients, treated from 1978 to 1989, is reviewed. The patients were initially treated with surgical resection (2 cases), radiation alone (1 case) or a combination of radiation and surgery (4 cases). The radiation dose ranged from 30 to 62 Gy. Operations were performed via a transmaxillary approach (2 cases), lateral rhinotomy approach (3 cases) and craniofacial approach (1 case). Four of the seven patients experienced local recurrence, occurring after disease-free intervals as long as 6 years. The other three patients died of distant metastasis within one year after initial treatment. The effectiveness of radiation therapy varied, and in some patients a dose of 60 Gy was not enough to control microscopic disease. One patient developed bone marrow metastases which was fatal due to the ensuing pancytopenia. One patient developed a brain metastasis. Hyams' histopathologic staging of the tumor appeared to be related to prognosis.

Adolescent↗

Bone matrix deposition of T1, a homologue of interleukin 1 receptors.

The mouse T1 glycoprotein is a secreted molecule of the immunoglobulin superfamily with significant homology to interleukin 1 receptors. It is expressed during bone development, and the extracellular diffusible gene product is found associated with newly formed bone but not cartilage matrix. During osteogenic differentiation of mandibular condyles of newborn mice in vitro, T1 gene expression is induced shortly after cultivation and is observed throughout the differentiation process. The temporal expression pattern of the gene is an mandibular condyles indicates that T1 expression is an early marker of osteogenic differentiation. This view is substantiated by the analysis of T1 gene regulation in continuous osteogenic cell lines. Both in differentiating osteoblast-like KM-1K cells derived from mandibular condyles and in MC3T3 cells, T1 gene activity is preferentially associated with early differentiation stages. In mandibular condyles, the secreted extracellular T1 protein is deposited into newly formed osteoid but not into cartilage matrix. This novel bone matrix protein may locally modulate the availability of its ligand.

Animals↗

Bone metastases in childhood renal tumours.

Analysis of data from 1434 children with primary renal tumours revealed 57 who developed bone metastases. Of these, 54 were initially recorded as nephroblastoma. Fifty-two of the 57 cases were reviewed histologically, and only 18 were found to be Wilms' tumours. Twenty-three were classified as "Bone-Metastasizing Renal Tumour of Childhood" (BMRTC), and a high male incidence was found for these tumours (M:F=6.7:1). Differences in the pattern of metastasis and the one-year survival between BMRTC and nephroblastoma are discussed. The rarity of bone metastases from true Wilms' tumours is emphasized.

Adolescent↗

The murine stanniocalcin 1 gene is not essential for growth and development.

The stanniocalcin 1 (STC1) gene is expressed in a wide variety of tissues, including the kidney, prostate, thyroid, bone, and ovary. STC1 protein is considered to have roles in many physiological processes, including bone development, reproduction, wound healing, angiogenesis, and modulation of inflammatory response. In fish, STC1 is a hormone that is secreted by the corpuscles of Stannius and is involved in calcium and phosphate homeostasis. To determine the role of STC1 in mammals, we generated Stc1-null mice by gene targeting. The number of Stc1-/- mice obtained was in accordance with Mendelian ratios, and both males and females produced offspring normally. No anatomical or histological abnormalities were detected in any tissues. Our results demonstrated that Stc1 function is not essential for growth or reproduction in the mouse.

Animals↗

Human immunodeficiency virus infection of bone marrow endothelium reduces induction of stromal hematopoietic growth factors.

The majority of human immunodeficiency virus (HIV)-seropositive patients develop bone marrow abnormalities associated with hematopoietic malfunction during the progression of disease. One important manifestation of HIV-associated hematopoietic dysfunction is that after myelosuppression, bone marrow recovery, a process known to be mediated in part by the production of stromal cell-derived hematopoietic growth factors, is impaired. We sought to test the hypothesis that bone marrow stromal cells are infected by HIV-1 in vivo and that production of certain stromal cell-derived hematopoietic growth factors is deficient as a consequence. In this report, we demonstrate that bone marrow microvascular endothelial cells (MVEC), a key element of the stroma, are the predominant cells infected by HIV (5% to 20%) in bone marrow stromal cultures obtained from 11 consecutive HIV-seropositive patients. Although HIV-infected stromal cultures enriched for MVEC constitutively express normal levels of interleukin (IL)-4, IL-6, granulocyte (G)-colony-stimulating factor (CSF), granulocyte-macrophage (GM)-CSF, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, and Steel factor, IL-1 alpha-induced release of IL-6 and G-CSF is significantly reduced in these cultures. These observations suggest that HIV infection of bone marrow MVEC reduces the capacity of hematopoietic stroma to respond to regulatory signals that normally augment blood cell production during periods of increased demand.

Adult↗

Immunohistochemical localization of osteonectin in developing human and calf bone using monoclonal antibodies.

Osteonectin was immunolocalized in human fetal and calf neonatal developing bone using newly developed monoclonal antibodies. The protein was localized to the cytoplasm of osteoblasts and young osteocytes. In bone matrix, strong reactivity was found in newly laid down osteoid. Bone matrix immunoreactivity was enhanced by pretreatment of sections with proteases, possibly because of an unmasking of epitopes engaged in protein-protein interactions. Osteonectin immunoreactivity was also found in preosteoblasts in all types of human fetal osteogenesis (membranous, endochondral, subperiosteal, and mantellar (Meckel's cartilage) ossification), and in some chondrocytes of metaphyseal growth plate, possibly modulating towards an osteoblastic phenotype.

Alkaline Phosphatase↗

Proto-oncogene c-fos expression in growth regions of fetal bone and mesodermal web tissue.

The phylogenic conservation of the proto-oncogene c-fos suggests that this gene product is required for normal metabolic processes. Investigations into the transcription pattern of c-fos in normal tissues and cells have revealed expression during development, differentiation and growth which is dependent to a large extent on external signals transferred by growth factors. The complex pattern of stage and tissue-specific expression has raised the hypothesis that the c-fos gene product might function in the control of either proliferation or differentiation. However, no detailed analysis is yet available concerning the normal expression of c-fos during embryonic and fetal development. Interestingly, recent data derived from studies in transgenic mice reveal that the biological effect of overexpression of exogenous fos is restricted to the developing bone tissue and T-cell development of the mice, perhaps signifying that these cells represent a physiological target tissue of the proto-oncogene fos. Thus, to gain deeper insight into the functional role of the c-fos gene product during physiological processes, it is a requirement to carry out a detailed analysis of the localization and cell-type specificity of c-fos expression in normal mouse embryos. Using the technique of in situ hybridization, we demonstrate here that stage-specific expression of the proto-oncogene c-fos in mouse embryos is restricted to the perichondrial growth regions of the cartilaginous skeleton. Moreover, we found strong c-fos transcription in web-forming mesodermal cells, which are also characterized by a stage-specific high growth capacity. Our results suggest a tissue-specific regulatory role of c-fos during differentiation-dependent growth processes of fetal bone and mesodermal web tissue.

Animals↗

The prenatal development of the normal human skeleton: a combined ultrasonographic and post-mortem radiographic study.

Post-mortem radiography of fetuses with skeletal dysplasia is essential for diagnostic classification. Interpretation of the radiographs should be based on the knowledge of morphology and dimensions of the normal skeleton in all stages of development. A retrospective post-mortem radiographic study is presented with measurements of the lengths of the long bones and thoracic and lumbar spine. The study included 69 fetuses and neonates with a normal skeleton, whose gestational age ranged from 13-42 weeks and who died perinatally or lived for less than one week. The measurements of the long bones were plotted on growth curves obtained from a prospective longitudinal ultrasonographic investigation of another group of 63 normal fetuses from 12-40 weeks of gestation. Thoracic and lumbar spine measurements by ultrasonography were not available. The radiographic data of thoracic and lumbar spine were, therefore, compared to radiographic studies from the literature. No disagreement with these studies was found. It can be concluded that measurements of bones from standardized post-mortem radiographs in cases of questionable gestational age or defects of bone development can be compared with ultrasonographic measurements. To illustrate the usefulness of the graphs, 13 fetuses with various types of skeletal dysplasia were evaluated retrospectively.

Bone Diseases, Developmental↗

Variability of embryonic development among three inbred strains of mice.

We examined the relationships between litter size, embryonic growth, days of gestation, onset and duration of morphological stages and development of the first arch skeleton in three inbred strains of mice--C57BL/6, CBA/J and C3H/He. Detailed embryonic staging was based on craniofacial development between 11 and 18 days of gestation. Considerable intra- and interlitter variation of morphological stages of embryonic development exists in all three inbred strains. The relationship of morphological stages to days of gestation reveals that each stage has a different duration, being shortest at Theiler's stage 18 and longest at stage 21 in all three inbred strains. Embryos of CBA/J mice tend to reach each stage later than do embryos of the other two strains, i.e., morphological development is slowest in CBA/J. The greatest length, a measurement of embryonic growth, increases at a constant rate during gestation in all three strains. In C57BL/6 and CBA/J, more embryos tend to be implanted in the right horn of the uterus than in the left, whereas in C3H/He an even number of embryos tends to be implanted in both horns. Timing of the development of Meckel's cartilage differs between the three inbred strains: both condensation and onset of matrix deposition begin one stage earlier in C57BL/6 than in CBA/J and C3H/He. On the other hand, alkaline phosphatase, one of the earliest markers for bone development, is expressed at the same time in all three inbred strains. Differences in timing of skeletal development between the strains may be attributed in part to the genealogical closeness OF CBA/J and C3H/He mice.

Animals↗

Evidence of a role for RANKL in the development of myeloma bone disease.

Multiple myeloma is associated with the development of a devastating bone disease mediated by increased osteoclastic activity. The ligand for receptor activator of nuclear factor-kappaB (RANKL) plays a critical role in normal osteoclast biology and is abnormally regulated in myeloma. Targeting this system with recombinant decoy receptor, osteoprotegerin, or soluble forms of the receptor activator of nuclear factor-kappaB is able to prevent myeloma bone disease in pre-clinical models. Intriguingly, inhibiting osteoclast formation and bone resorption, and altering the bone marrow microenvironment, results in an indirect anti-myeloma effect.

Animals↗

Effects of ionizing irradiation on formation and resorbing activity of osteoclasts in vitro.

The effects of ionizing irradiation on the differentiation and activity of the osteoclast were investigated. Embryonic mouse metatarsal bones of different ages (14, 15, 16, 17 days) in which no osteoclasts had as yet been formed were irradiated with various x-ray doses and cultured until a marrow cavity became visible in the nonirradiated paired control bones. Bone growth and calcification were followed microscopically during culture. Irradiation caused a dose-dependent stunting of the longitudinal growth. Calcification was inhibited by high radiation doses (10 to 20 Gray (Gy), whereas a dose of 2.5 Gy stimulated the process in the early stages of long bone development. Histologic examination revealed complete inhibition of osteoclast formation in the 14- and 15-day-old bones after irradiation with 2.5 Gy or more. The number of osteoclasts in cultured older bones (16 days) was significantly reduced by irradiation, but osteoclast formation could not be completely prevented even by high dosages. Irradiation of explanted bone rudiments which were in a stage 1 day prior to the appearance of osteoclasts in vivo (17 days) did not significantly influence the formation of osteoclasts. Autoradiographic experiments using young bones showed that differentiation of osteoclast precursors into multinucleated osteoclasts is preceded by one or more divisions of the precursors in the periosteum. Furthermore, it was established from continuous 3H-thymidine-labeling experiments that in older bones (16 days) a part of the osteoclast nuclei originated from postmitotic osteoclast precursors. Irradiation mainly inhibited the appearance of labeled osteoclast nuclei in these bones. The results indicate that the osteoclast precursor, already present in the periosteum at an early stage of embryonic development, first proliferates and then differentiates into a mononuclear postmitotic preosteoclast. The proliferation is probably highly radiosensitive. Subsequently, the preosteoclasts fuse into multinucleated osteoclasts and invade the calcified hypertrophic cartilage zone. The resorbing activity of the osteoclast is less radiosensitive but can be inhibited by 5.0 Gy or more, as was established by morphometric and biochemical methods.

Age Factors↗

Bone mineral density in the cortical and trabecular distal forearm in healthy children and adolescents.

Bone mineral density in cortical (BMDd) and trabecular parts (BMDud) of the distal forearm was studied in 494 healthy subjects ranging from 8 to 17 years with single photon absorptiometry. Mean BMDd was 6.8% higher (p < 0.0001) in boys than in girls in the < 11 years age group (n = 163). Mean BMDud was 8.2% higher (p < 0.0001) in boys than in girls in the adolescent age group (> or = 11 years, n = 331). While BMDd increased from 11 years of age in girls and was delayed by 2 years in boys, BMDud increased from 10 years of age in boys and was delayed by 1 year in girls. By multiple regression analysis, age, weight and height were variably related to bone density depending on measuring site, sex and age. At 14 years of age, postmenarcheal girls had obtained BMDud values similar to those of an adult premenopausal group. Cortical bone density in girls was very close to corresponding BMDd values of the adult premenopausal group at 16 years of age. In conclusion, this cross-sectional study indicates sex and age variability in forearm bone mineralization at trabecular and cortical sites. The substantial mineralization taking place between 11 and 16 years of age, with achievement of adult premenopausal bone density values, makes this 5-year period crucial for bone development.

Absorptiometry, Photon↗

Testosterone prevents orchidectomy-induced bone loss in estrogen receptor-alpha knockout mice.

To examine the role of the estrogen receptor-alpha (ERalpha) during male skeletal development, bone density and structure of aged ERalphaKO mice and wild-type (WT) littermates were analyzed and skeletal changes in response to sex steroid deficiency and replacement were also studied. In comparison to WT, ERalphaKO mice had smaller and thinner bones, arguing for a direct role of ERalpha to obtain full skeletal size in male mice. However, male ERalphaKO mice had significantly more trabecular bone as assessed both by pQCT and histomorphometry, indicating that ERalpha is not essential to maintain cancellous bone mass. Six weeks following orchidectomy (ORX), both WT and ERalphaKO mice showed high-turnover osteoporosis as revealed by increases in serum osteocalcin and decreases in trabecular (-38% and -58% in WT and ERalphaKO, respectively) and cortical bone density (-5% and -4% in WT and ERalphaKO, respectively). Administration of testosterone propionate (T, 5 mg/kg/day) completely prevented bone loss both in ERalphaKO and in WT mice. As expected, estradiol (E2, 60 microg/kg/day) replacement did not prevent cancellous bone loss in ORX ERalphaKO mice. However, E2 stimulated bone formation at the endocortical surface in ORX ERalphaKO, suggesting that osteoblasts may respond to nonERalpha-mediated estrogen action. In conclusion, although functional ERalpha may play a significant role during male skeletal development, this receptor does not seem essential for androgen-mediated skeletal maintenance in older male mice.

Animals↗

A middle stone age worked bone industry from Katanda, Upper Semliki Valley, Zaire.

Three archaeological sites at Katanda on the Upper Semliki River in the Western Rift Valley of Zaire have provided evidence for a well-developed bone industry in a Middle Stone Age context. Artifacts include both barbed and unbarbed points as well as a daggerlike object. Dating by both direct and indirect means indicate an age of approximately 90,000 years or older. Together with abundant fish (primarily catfish) remains, the bone technology indicates that a complex subsistence specialization had developed in Africa by this time. The level of behavioral competence required is consistent with that of upper Paleolithic Homo sapiens sapiens. These data support an African origin of behaviorally as well as biologically modern humans.

Animals↗

An experimental study of intraspecific variation, developmental timing, and heterochrony in fishes.

Heterochrony is widely regarded as an important evolutionary mechanism, one that may underlie most, if not all, morphological evolution, yet relatively few studies have examined variation in the sequence of development. Even fewer studies have been designed so that intraspecific variation in the relative sequence of developmental events can be assessed, although this variation must be the basis for evolutionary change. Intraspecific variation in developmental ossification sequences was documented from the zebrafish (Danio rerio) by Cubbage and Mabee (1996) and from the Siamese fighting fish (Betta splendens) by Mabee and Trendler (1996), but a quantitative analysis of the patterns within this variation was not made. Here, we quantify the effect of rearing temperature on the sequence of ossification and characterize the levels and patterns of intraspecific variation in these fishes. For Danio, there were no temperature effects on the sequence of bone development across the cranium, cranial region development, cartilage versus dermal bones, or lateral line bone versus nonassociated bones. Likewise the level of variation in relative sequence (position) of ossification was low, about two ranks, across temperatures. At higher temperatures, we found higher levels of variation in iterated cranial bones and less in bones forming early in the sequence. No temperature effects on variation were found among regions, between lateral line-associated bones and nonassociated bones, between median and paired bones, or across the entire sequence, indicating concordant variability among the three temperatures. Individual bones with the highest levels of variability were not consistent among temperatures. Baseline patterns of intraspecific variation in Danio were compared to those of Betta. For both species, the level of intraspecific variation in sequence position was low and the variability of cranial bones was concordant. Individual bones with the highest levels of variability were not consistent between species. In both species, variation was widespread (distributed evenly across the sequence). We used comparisons (among regions, between dermal and cartilage bones, between lateral line-associated and other bones, between median and paired bones, between iterated and noniterated bones, between feeding-associated bones and others) to see which subsets were most variable and thus potentially useful in predicting high levels of evolutionary change. The only subset of bones that was significantly more variable than others was cartilage bones. If interspecific patterns are parallel to these intraspecific differences, cartilage bones would be expected to show higher levels of heterochrony. Although concordance across the cranial ossification sequence and among regions in Danio, Betta, and two other teleosts, Oryzias and Barbus, suggests an evolutionarily conserved pattern of ossification, identity in sequence position across taxa was not observed for any bone. Thus, variation existed in sequence position across temperatures and species. Intraspecific variation of this sort may influence the morphological outcome and evolutionary trajectories of species.

Animals↗

A histological and radiological investigation of the nasal bone in fetuses with Down syndrome.

OBJECTIVES: Previous studies of nasal bone development in Down syndrome have used radiographs or ultrasound for the detection of nasal bone length or nasal bone absence. The aim of this study was to investigate the presence and size of the nasal bones in postmortem Down syndrome fetuses by means of radiographs and histological examination. METHODS: Thirty-three aborted human fetuses (gestational age 14-25 weeks) with Down syndrome were included. A mid-sagittal tissue block was excised from the skull base to the foramen magnum and along the lateral aspect of the spine. Radiographs of the tissue block were taken in lateral, frontal and axial projections. The length of the nasal bone was measured. The tissue blocks were cut in serial sections and stained. The crown-rump length (CRL), foot length (FL) and number of ossified bones in the hand and foot (CNO) were recorded. RESULTS: A total of 8/33 fetuses had bilateral nasal bone absence and two had unilateral absence. In fetuses with radiographically diagnosed nasal bone absence, no nasal bone could be found histologically. The majority of the Down syndrome fetuses had CRL, FL and CNO values within the range of those for normal age-matched fetuses. Nasal bone length was normal or reduced. CONCLUSIONS: Absence of the nasal bone was registered by postmortem examination in one-third of fetuses with Down syndrome. In some fetuses this could be a result of delayed maturation associated with Down syndrome. The phenotypic differences in nasal bone appearance may reflect genotypic differences in the Down syndrome group.

Autopsy↗

Calcium acquisition rates do not support age-appropriate gains in total body bone mineral content in prepuberty and late puberty in girls with cystic fibrosis.

Few longitudinal data are available characterizing bone development in adolescents with cystic fibrosis (CF) although this is a critical time for bone mineralization. Dual energy X-ray absorptiometry (DXA) scans were obtained at 1- to 4-year intervals in 18 prepubertal and pubertal girls (age 7-18 years) with CF to determine calcium (Ca) accretion rates and changes (Delta) in total body bone mineral content (TBBMC) and lumbar spine bone mineral density (LS BMD) Z-scores. Daily Ca acquisition rates were calculated assuming TBBMC was composed of 32.2% Ca. Bone Ca accretion averaged 82 mg/day (2.05 mmol/day) [(range:-38 to +197 mg/day (-0.95 to 4.9 mmol/day)] on approximately 1,200 mg/day (30 mmol/day) Ca intakes. Estimated mean peak Ca accretion was 160 mg/day (4 mmol/day) at age 13 years; losses of bone Ca occurred in late puberty. Gains in insulin-like growth factor 1 (IGF-1) predicted Ca accretion (p<0.06). Body mass index (BMI) Z-score predicted LS BMD and TBBMC Z-score cross-sectionally but did not predict DeltaTBBMC Z-score. Changes in TBBMC Z-score paralleled Ca accretion rates with age. Bone Ca accretion in girls with CF fell below rates in healthy girls during prepuberty and late puberty despite Ca intakes approaching recommendations. IGF-1 and BMI Z-scores may identify children with CF at risk of compromised bone accretion, and more data are required to elucidate roles of lung function and glucocorticoid use in compromised bone health.

Absorptiometry, Photon↗