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Biomedical subjects

L Mosekilde

Publications and source records attributed to L Mosekilde.

At least 91 records · Page 5Linked to original sources
PubMed2000

Fracture risk in patients treated for hyperthyroidism.

AIM: To study fracture risk and risk factors for fractures in patients with hyperthyroidism. DESIGN: Historical follow-up. MATERIAL AND METHODS: A total of 864 patients with diffuse toxic goiter (ICD 10: E05.0) or toxic nodular goiter (E05.2) were contacted through a self-administered questionnaire. Each respondent was compared to an age: (+/- 5 years) and gender-matched control from a random sample of the background population who responded to the same questionnaire. RESULTS: Among the patients 621 (72%) responded and of these 617 could be analyzed. Within the first 5 years before the diagnosis, the patients had the same fracture risk as the controls (RR = 1.2, 95% CI; 0.7-2.0). After the diagnosis, fracture risk was elevated among the patients (RR = 1.7, 95% CI: 1.2-2.3), especially in the age group 50 years or older (RR = 2.2, 95% CI: 1.5-3.3). Fracture risk was elevated for fractures of the spine (RR = 8.9, 95% CI: 1.6-48.4), and the forearms (RR = 3.1, 95% CI: 1.6-6.2), but not at other skeletal sites. Treatment with radioactive iodine alone was associated with an increased fracture risk (OR = 2.7, 95% CI: 1.2-6.0), a risk that was not present in patients who, in addition to radioactive iodine, also had received methimazole (RR = 1.5, 95% CI: 0.7-3.2). CONCLUSIONS: Our study demonstrated an increased fracture risk in hyperthyroidism, a fracture risk that was present with radioactive iodine treatment alone, but not in subjects that had received both radioactive iodine and methimazole or other types of antithyroid therapy.

Adult↗
PubMed2000

Fracture risk is increased in Crohn's disease, but not in ulcerative colitis.

AIMS: To study fracture rates and risk factors for fractures in patients with Crohn's disease and ulcerative colitis. METHODS: 998 self administered questionnaires were issued to members of the Danish Colitis/Crohn Association, and 1000 questionnaires were issued to randomly selected control subjects. 845 patients (84.5%) and 645 controls (65.4%) returned the questionnaire (p<0.01). 817 patients and 635 controls could be analysed. RESULTS: Analysis was performed on 383 patients with Crohn's disease (median age 39, range 8-82 years; median age at diagnosis 26, range 1-75 years), 434 patients with ulcerative colitis (median age 39, range 11-86 years; median age at diagnosis 29, range 10-78 years), and 635 controls (median age 43, range 19-93 years, p<0.01). The fracture risk was increased in female patients with Crohn's disease (relative risk (RR) = 2.5, 95% confidence interval (CI) 1.7-3.6), but not in male patients with Crohn's disease (RR = 0.6, 95% CI 0.3-1.3) or in patients with ulcerative colitis (RR = 1.1, 95% CI 0.8-1.6). An increased proportion of low energy fractures was observed in patients with Crohn's disease (15.7% versus 1.4 % in controls, 2p<0. 01), but not in patients with ulcerative colitis (5.4%, 2p=0.30). The increased fracture frequency in Crohn's disease was present for fractures of the spine, feet, and toes and fractures of the ribs and pelvis. Fracture risk increased with increasing duration of systemic corticosteroid use in Crohn's disease (2p=0.028), but not in ulcerative colitis (2p=0.50). CONCLUSIONS: An increased risk of low energy fractures was observed in female patients with Crohn's disease, but not in male patients with Crohn's disease or in patients with ulcerative colitis.

Adolescent↗
PubMed2000

Growth hormone treatment in adults with adult-onset growth hormone deficiency increases iliac crest trabecular bone turnover: a 1-year, double-blind, randomized, placebo-controlled study.

The effects of growth hormone (GH) substitution on bone metabolism were evaluated by dynamic histomorphometry on iliac crest bone biopsies. Twenty-nine patients, aged 21-61 years (mean 45.5 years), with adult-onset GH deficiency (GHD) were randomized to receive subcutaneous injections with GH (2 IU/m2/day = 0.67 mg/m2/day) or placebo for 12 months. Serum insulin-like growth factor I (IGF-I) levels increased 263 +/- 98% (mean +/- SD) during GH treatment (p < 0.0001). In the GH group, osteoid surface increased during treatment from 11% (3-15%) (median [25-75 percentiles]) to 21% (10-27%) (p = 0.01) and mineralizing surface from 4% (1-8%) to 11%(7-16%) (p = 0.04). Moreover, erosion surface tended to increase in the GH group from 2% (1-3%) to 4% (3-5%) (p = 0.07). The quiescent surface decreased in the GH group from 87% (83-96%) to 74% (68-87%) (p = 0.01). The adjusted appositional rate, mineral apposition rate, bone formation rate, bone erosion rate, mineralization lag time, and osteoid thickness remained unchanged during treatment. Erosion depth showed a trend toward increase in the GH group (p = 0.09), whereas wall thickness was unchanged. Bone balance at the remodeling unit level and activation frequency were unchanged. At the tissue level, bone erosion rate increased significantly from 26% (17-36%)/year to 39% (23-72%)/year (p = 0.03). Similarly, the bone formation rate at the tissue level tended to increase, from 24% (15-31%)/year to 36% (17%-63%)%/year (p = 0.06). Finally, bone balance at the tissue level decreased significantly from 1% (-2-2%)/year to -5% (-13-1%)/year (p = 0.01). No significant difference in change was seen in the cancellous bone volume. We conclude that 12 months of GH substitution therapy increases trabecular bone turnover. Moreover, our data suggest that bone balance at the bone multicellular unit level is not changed to positive.

Adult↗
PubMed2000

Premenopausal smoking and bone density in 2015 perimenopausal women.

The importance of cigarette smoking in relation to bone mass remains uncertain, especially in younger women. In a recent meta-analysis including 10 studies in premenopausal women no effect was seen in this age group. We used baseline data from a large national cohort study (Danish Osteoporosis Prevention Study [DOPS]) to study the cumulated effect of pre- and perimenopausal smoking on bone mineral density (BMD) measured shortly after the cessation of cyclic bleedings. Baseline observations on 2015 recently menopausal women were available. Eight hundred thirty-two women were current smokers and 285 were exsmokers. Significant negative associations of cigarette smoking coded as current, ex-, or never smoking were seen on bone mass in the lumbar spine (P = 0.012), femoral neck (P<0.001), and total body (P<0.001). Quantitatively, the differences between current smokers and never smokers were limited to 1.6, 2.9, and 1.9%, respectively. A statistical interaction was found between smoking and fat mass, indicating that women in the highest tertile of fat mass were unaffected by cigarette smoking. Serum vitamin D levels and osteocalcin were inversely related to the number of cigarettes smoked per day (r = 0.11 and P<0.001; r = 0.17 and P = 0.04), respectively. Bone alkaline phosphatase (BALP) and urinary hydroxyproline (U-OHP) were unaffected by current smoking. The average cumulated effect of premenopausal smoking on bone is small but biologically significant. Reduced body mass in smokers explains part of the negative effect on the skeleton and a complex interaction between smoking and fat mass on the skeleton is indicated. Serum levels of 25-hydroxyvitamin D (25-OHD) and osteocalcin are lower in smokers, which may effect rate of bone loss.

Alkaline Phosphatase↗
PubMed2000

Artifact in bone mineral measurements during a very low calorie diet: short-term effects of growth hormone.

Short-term effects of growth hormone on bone metabolism and soft tissue collagen metabolism during weight loss in obese subjects on a very low calorie diet were investigated in a double-blind, placebo-controlled design. Twenty healthy obese women (BMI between 33 and 45 kg/m(2)) aged 21-48 yr were followed for 8 wk: half received growth hormone. A 740-kcal diet was administered the first 4 wk, followed by a 1200-kcal diet. Lumbar spine BMC, total-body fat mass, total-body lean body mass, total-body BMC, and total-body bone area were measured by dual-energy X-ray absorptiometry along with biochemical markers of bone turnover. Body weight decreased by 5.5% and fat mass by 11.4%. There were no changes in biochemical bone markers in the placebo group despite a marked decrease in BMC (3.1%). Projected total bone area decreased proportional to BMC (r = 0.89) during the weight loss. Growth hormone treatment did not modulate the decrease in lean body mass, body weight, fat mass, or BMC, but increased bone turnover markers. Growth hormone did not change the results concerning BMC, projected bone area, BMD, lean body mass or fat mass. Since 89% of the observed change in BMC could be explained by alterations in projected bone area without changes in biochemical bone markers, it is concluded that a large part of the observed decrease in BMC during weight loss may be due to scanner artifact.

Absorptiometry, Photon↗
PubMed2000

Long-term excessive magnesium supplementation is deleterious whereas suboptimal supply is beneficial for bones in rats.

The long-term effects of a suboptimal magnesium supply inducing a marginal or moderate deficiency or of an excessive magnesium supplementation corresponding to a basal diet with a high pharmacological intake were investigated in 36 growing Sprague-Dawley female rats. The rats were randomly divided in three groups and received a purified diet with 7 g calcium, 5 g phosphorus and either 0.2, 0.5 or 2 g magnesium per kg diet for 7 months. At the end of the trial, plasma and erythrocyte total magnesium concentrations were significantly lower in the magnesium-deficient group than in the respective control group. Serum concentrations of 1,25-dihydroxyvitamin D, PTH and IGF-I and the length of the right humeri were not affected by the dietary treatment. The volumes corrected for body weight, the medio-lateral diameters and the ratios dry weight/length of the right humeri, and the dry weight corrected for body weight of the left tibiae and of the right humeri were significantly smaller in the magnesium-supplemented group than in the two other groups. The magnesium contents of the left tibiae and of the first lumbar vertebrae were significantly lower in the magnesium-deficient group than in the two other groups. In the right femora, dual energy X-ray absorptiometry revealed significantly smaller areas in the proximal part and significantly smaller mineral contents in the second proximal quarter in the magnesium-supplemented group compared with the two other groups. Peripheral quantitative computer tomography of the right humeri revealed in the cortex significantly larger values for the relative area, mineral content, mineral density and thickness in the magnesium-deficient group compared with the control group. The maximum point of the load-deformation curve was significantly reduced in the fifth lumbar vertebrae and in the proximal femoral metaphyses of the magnesium-supplemented group. These results indicate that the long-term suboptimal magnesium supply improved some of the parameters indicators of bone health whereas the long-term supplementation was deleterious.

Animals↗
PubMed2000

Trabecular bone structure and strength - remodelling and repair.

The strength of the spinal trabecular bone declines by a factor of 4-5 from the age of 20 to 80 years. At the same time, the volumetric (apparent) density declines by a factor of only 2. This discrepancy can be explained by the known power relationship between density and strength; this power relationship is based on the fact that trabecular bone is a porous material. To date, it has not been possible to determine or quantify the influence other factors may have in determining the strength of a loadbearing trabecular network. However, it is known that with age: 1) There is a loss of connectivity through osteoclastic perforations of horizontal struts. 2) There is an increase in anisotropy - again due to loss of horizontal struts, and perhaps also due to micro-modelling drift or to thickening of some vertical trabeculae. 3) The changes in the network can lead to the slenderness ratio between vertical and horizontal struts reaching a certain magnitude and thereby inducing buckling under compression. 4) Microdamage and microfractures will occur - mainly in these very loaded vertical struts. The microfractures will be repaired by microcallus formation, and these calluses will later be removed by the remodelling process. 5) Bone material quality will slightly change, leading to a decrease in collagen content and a relative increase in the degree of mineralisation. But, it is not known how these factors will influence the power relationship between density and strength. Nor is it known how different treatment regimens will affect the 'natural' power relationship: will the same curve be followed, but in the opposite direction? Or will the curve be less or more steep? Will the gain in bone strength be larger if treatment is started early - on the steep part of the curve? Furthermore, as trabecular bone can never be isolated in vivo, other factors need to be investigated: The interplay between the cortical shell and the trabecular network; transmission of load; the interplay between soft tissues (cartilage, connective tissue, muscle) and bone; the shock absorbing capacity of the discs; and the hydraulic effect of the bone marrow. In order to answer these questions, more in vitro and in vivo studies on human bone in relation to aging, to immobilisation, to exercise and in relation to different treatment regimens are needed.

Journal Article↗
PubMed2000

PTH and interactions with bisphosphonates.

We report that a therapeutic dose of the antiresorptive bisphosphonate alendronate administered to skeletally mature rats for the duration of 16 weeks significantly blunted the anabolic response to a high dose SDZ PTS 893 in the tibia and femur but not in lumbar vertebra. Effects were seen at the level of bone mass (DEXA, pQCT) as well as in biomechanical tests. In one arm of this study, rats were switched to vehicle injections after 8 weeks on alendronate for another 8 weeks before being challenged with the anabolic stimulus (washout). This recovery period was insufficient for full recovery and the response to SDZ PTS 893 was still greatly reduced after this procedure. Serial pQCT-measurements suggest that part of the interaction happened during the first two weeks of PTH treatment when bone-lining cells are activated by the anabolic drug. In addition bisphosphonate pretreated rats failed to catch up with the vehicle control at all time points suggesting a second level of drug interaction. The failure of the 'washout' period to restore the normal response to PTH is suggestive of a physico-chemical interaction on the level of the matrix embedded bisphosphonate with the overlaying bone lining cells, rather than of direct effects of the drug on osteoblasts or their precursor cells. Overall the data raises the possibility, that bisphosphonate treated patients respond to PTH and SDZ PTS 893 with a delay which could affect the shorter bone mass measurements carried out at 6 months to 1 year. Additionally, bisphosphonate pre-treated rats did not develop the full anabolic response over time. Clinical investigators studying anabolic drugs such as PTH should be aware of potential long-term interactions of bisphosphonates when assessing the outcome of their experiments. However, the beneficial effect of bisphosphonates like alendronate on PTH-induced bone remodeling, as well as its potent action in the protection of bone loss after cessation of anabolic therapy might outweigh the worries about a small delay in the bone response to parathyroid hormone.

Journal Article↗
PubMed1999

[Biological action mechanisms and effects of calcitriol].

Vitamin D is an important regulator of calcium homeostasis in the body and it plays an essential role in bone metabolism. 1,25(OH)2D (calcitriol), the active metabolite of vitamin D stimulates intestinal calcium and phosphate absorption, thereby maintaining sufficient concentrations of these ions in the extracellular fluids, necessary for normal mineralization of bone matrix. Furthermore, calcitriol exerts a number of important functions in regulating bone metabolism. Similar to other classical steroid hormones, calcitriol regulates the transcription of a large number of target genes. A large number of recent studies of the mechanisms of genomic actions of calcitriol have been published. The aim of this review is to give a summary of these recent findings. The interaction between calcitriol and the vitamin D receptor as well as receptor structure and function in relation to transcriptional regulation are discussed.

Animals↗
PubMed1999

[Costs of different intervention strategies to prevent hip fractures].

The cost of primary prevention and the number of hip fractures prevented was compared in different scenarios. Primary prevention with hormonal replacement therapy (HRT) in women over the age of 50 years, secondary prevention with HRT in women over 50 years with low bone mineral on screening, use of external hip protectors in nursing home residents, use of calcium and vitamin D in nursing home residents and tertiary prevention with bisphosphonates (alendronate) or external hip protectors in subjects with a previous hip fracture were evaluated. External hip protectors or calcium plus vitamin D were cheap in nursing home residents. The economic cost of bisphosphonate treatment was high even in tertiary prevention in the high risk group with previous hip fracture. It was doubtful whether potential savings in prevention would out-weigh the cost in younger individuals even in high-risk groups.

Adult↗
PubMed1999

The Danish Osteoporosis Prevention Study (DOPS): project design and inclusion of 2000 normal perimenopausal women.

OBJECTIVE: In 1990 we initiated a 20 year, partly randomised study (Danish Osteoporosis Prevention Study, DOPS) in order to (a) evaluate clinical, biochemical and osteodensitometric variables as predictors of low bone mass and future osteoporotic fractures, and (b) test the hypothesis, that hormone replacement therapy (HRT) initiated shortly after menopause reduces the risk of later osteoporotic fractures. This report describes study design and baseline characteristics of the DOPS-cohort. METHODS: The study design is pragmatic, attempting to mimic the normal clinical situation. Several HRT alternatives are available according to clinical need. It was considered futile, impractical and unethical to use placebo for 20 years. Instead the study focus on hard endpoints (fractures) confirmed by independent persons (peripheral fractures) or by methods which allow investigator blinding (spinal X-rays). Statistical evaluation will focus on intention to treat analyses evaluating the decision of HRT and it's feasibility. With a compliance of 60% we will have sufficient statistical power (88%) to detect a fracture reduction of 40% in the treatments group. Clinical risk factors, current daily intakes of macronutrients, vitamins and minerals, anthropometric variables, biochemical variables (including bone markers and 25-hydroxyvitamin D), regional bone mineral density (BMD) and total body composition were assessed in all participants at entry and at various follow up intervals. RESULTS: 2016 study participants were recruited by direct mailing to a random sample of 45-58 years old women. In the randomised arm 501 were allocated to HRT and 505 to no treatment. In the non-randomised arm 219 preferred HRT and 791 preferred no treatment. Post-randomisation analysis revealed a slight but significant difference in age (50.01 versus 50.44 years) but no difference in menopausal age, prevalence of hysterectomy, educational level, BMI, serum bone alkaline phosphatase, serum osteocalcin, urine hydroxyproline or serum 25-hydroxyvitamin D. In the non-randomised arm women preferring HRT were closer to menopause, had a higher prevalence of hysterectomy, were better educated, were leaner, and had lower bone turnover than the women, who refused HRT. CONCLUSION: It is possible to include a sufficient number of perimenopausal women in a randomised 20 year study on the antifracture effect of HRT.

Body Composition↗
PubMed1999

Age-related changes in the biochemical properties of human cancellous bone collagen: relationship to bone strength.

The metabolism of bone collagen has received little attention in relation to age-related loss of bone mass and strength. The aim of the present study was to analyze bone collagen content and metabolism in human bone with respect to age. The material consisted of iliac crest bone biopsies from 94 individuals: 46 women (ages 18-96, mean age 60.8 years) and 48 men (ages 23-92, mean age 59.5 years). Excluded from the study were all individuals with known osteoporotic lumbar vertebral fractures and renal, hepatic, or malignant diseases. Prior to collagen analysis the biopsies were scanned in a pQCT scanner for density assessment and then tested biomechanically. The results showed a decline in apparent bone density with age (P < 0.0001), a decline in maximum stress, Young's modulus, and energy absorption with age (P < 0.001). Concomittantly, there was an age-related decline in the intrinsic collagen content with age (P < 0.001). However, there were no biochemical modifications of the bone collagen during aging. There were no significant differences between women and men in the slopes of the regressions-curves. When multiple regression analyses were performed, only apparent bone density came out as a significant contributor in the correlation to biomechanical properties. Nevertheless, the decrease in bone collagen content with age might indicate an increase in the mineralization degree (probably due to decreased bone turnover) and thereby a change in material properties of bone. In conclusion, the present study has shown that loss of bone mass plays the major role in loss of bone strength. However, there is also a change in bone composition during normal aging, leading to a decrease in collagen content and an increase in the degree of mineralization. At this skeletal site, in a normal population there was no change in the biochemical properties of bone collagen.

Adolescent↗
PubMed1999

Additive effect of voluntary exercise and growth hormone treatment on bone strength assessed at four different skeletal sites in an aged rat model.

The aim of the study was to assess the effect of growth hormone (GH), voluntary exercise (Ex), and the combination of GH and Ex on bone strength, mass, and dimensions in aged, intact female rats. In addition, the effect of food restriction (FR) was studied. Fourteen-month-old virgin F-344 rats were divided into 6 groups with 13 animals in each: (1) baseline (BSL); (2) control + solvent vehicle (CTRL); (3) GH 2.5 mg/kg/day (GH); (4) exercise, voluntary: 0.6-0.7 km/day (Ex); (5) GH treatment and voluntary exercise (GH + Ex); and (6) FR. Group 1 was killed at the beginning of the study and served as baseline. All the other groups were killed after 18 weeks' treatment. The effects of aging and treatment regimes were measured at four different skeletal sites: lumbar vertebrae, femoral cortical bone, femoral neck, and the distal femoral metaphysis. Aging in itself induced a decline in vertebral body strength and ash density. At the appendicular skeletal sites, bone mass and strength were unchanged or increased. Treatment with GH alone induced a significant increase in the biomechanical parameters at the vertebral body and the femoral diaphysis, but not at the femoral neck or the distal femoral metaphysis. Voluntary exercise on its own increased load values significantly over CTRL at the vertebral body site, but not at any of the appendicular skeletal sites. The combination of GH and voluntary exercise resulted in an additive effect at the vertebral site and at the femoral diaphysis, and a synergistic (potentiating) effect at the two femoral metaphyses. FR, on the other hand, had a negative effect on cortical bone area and strength at the femoral diaphysis, but no significant effect on the other sites tested. We conclude that GH treatment and voluntary exercise both have skeletal anabolic effects; however, these effects are exerted to differing degrees at different sites. Importantly, when dosed together, GH and Ex have either an additive or synergistic anabolic effect on all sites (axial and appendicular).

Aging↗
PubMed1999

Primary hyperparathyroidism: short-term changes in bone remodeling and bone mineral density following parathyroidectomy.

Changes in bone remodeling and bone mineral density were observed during a period of 6 months after surgery in 24 patients with primary hyperparathyroidism (20 women and 4 men; age 54+/-12 years, range 26-69 years). All bone markers declined significantly within the 6 month follow-up period, but the time course for changes in renal N-terminal telopeptide of type 1 collagen (NTx) excretion differed from those of the other markers by a steep and significant reduction (p < 0.05) after less than 1 month. During the 6 month period, bone mineral density (BMD) increased significantly at all sites measured (p < 0.05) apart from the femoral neck and the proximal and midforearm. The greatest increase of 4.2% was observed in the trochanteric region (p < 0.001). The increase in BMD in spine, trochanteric, and intertrochanteric regions of the hip correlated inversely with baseline forearm BMD values (p < 0.05). Baseline bone markers (serum alkaline phosphatase [AP], serum bone AP, serum pyridinoline crosslinked telopeptide of type 1 collagen, urinary hydroxyproline, urinary osteocalcin), as well as baseline histomorphometric indices of bone turnover (eroded and labeled surface, bone formation rate, activation frequency, and cortical porosity) were positively correlated with changes in spinal BMD over 6 months (p < 0.05). It was concluded that, within 6 months after parathyroidectomy, patients with primary hyperparathyroidism obtain normalization of bone remodeling and a substantial increase in bone mineral density in regions rich in cancellous bone but no significant changes in regions with predominantly cortical bone.

Aged↗
PubMed1999

Effect of treatment for 6 months with human parathyroid hormone (1-34) peptide in ovariectomized cynomolgus monkeys (Macaca fascicularis).

A potential negative side effect of intermittent parathyroid hormone (PTH) therapy to treat osteoporosis is the loss of cortical bone concomitant with increased cancellous bone mass. We addressed this issue by studying the effects of PTH on whole-body, axial, and appendicular bone mass in an animal model with haversian cortical bone remodeling. Ovariectomized, young adult female cynomolgus monkeys were assigned to placebo (n = 9) or PTH groups (n = 10). The PTH group received 10 microg/kg synthetic human PTH(1-34) peptide by subcutaneous injection, 3 days/week for 6 months, and the placebo group received vehicle. Multiple endpoints of bone mass, strength, and turnover in the axial and appendicular skeleton were assessed, including dual-energy X-ray absorptiometry (DEXA), quantitative computed tomography (qCT), analysis of serum (calcium, phosphorus, alkaline phosphatase, osteocalcin, and tartrate-resistant acid phosphatase) and urinary (calcium and creatinine) biomarkers, histomorphometry, and biomechanical testing. Compared with placebo-treated animals, PTH-treated monkeys had no change in whole-body bone mass, but a 6.7% increase in spinal areal bone mineral density (aBMD) was observed. Cortical bone mass measured by qCT at appendicular sites was not affected by PTH treatment, but there were significant increases in cancellous bone mass in the proximal tibia, and a similar trend in the distal radius. Small, transient increases in serum and urinary calcium were observed, but there were no treatment-related effects on other biochemical endpoints. Increased bone formation rate (BFR/BV) in the midradius and midfemur was accompanied by a nonsignificant increase in midfemur porosity. Increased vertebral cancellous bone volume (BV/TV) was associated with greater trabecular and interstitial thickness with no effect on wall thickness. Increases in bone strength were observed in both axial (vertebral maximum stress and load at fracture) and appendicular (femoral neck fracture load) skeleton. Together, these results indicate that PTH therapy in the cynomolgus monkey results in a net gain of spinal and appendicular cancellous bone mass with no adverse effect on cortical bone.

Absorptiometry, Photon↗
PubMed1999

Missing observations in bone histomorphometry on osteoporosis: implications and suggestions for an approach.

Crucial bone histomorphometric indices, i.e., turnover-related indices, are based on tetracycline double labeling. However, these indices are particularly exposed to loss of information because of missing readings on double labels. If the failure to make the observation is related to its magnitude, then selection bias may invalidate the conclusions. Therefore, ignoring missing double labels may lead to a selection of high-turnover patients. The aim of this study was to analyze the dimension and the impact of excluding iliac crest bone biopsies with missing readings in women with spinal crush fracture osteoporosis (n = 158, median 68 years, range 49-80 years). Furthermore, two different lower limits of the mineral apposition rate (MAR) were examined to explore their usefulness as a biological minimum that can be used for cases with missing readings, i.e., recoding of missing values. The average MAR (calculated as the mean of all interlabel widths measured in each individual) shows a lower limit of 0.3 microm/day, suggesting an apparent minimum for the interlabel width (Ir.L.Wi) of 3-4 microm. Identifying the smallest interlabel width measured in each individual and calculating the minimal MAR shows that 77% of the minimal MAR values are below 0.3 microm/day and reach a minimum of 0.1 microm/day, corresponding to an interlabel width of about 1 microm. Therefore, the minimal MAR presents a biological minimum of 0.1 microm/day. This value is used for our recoding: if no labels are sampled (2% of our population), Ir.L.Wi is assigned the value 0; if none or an insufficient number of double labels are sampled (29% of our population), then Ir.L.Wi is assigned the value 1 microm. Excluding cases with missing readings on any dependent variable increases the mineralizing surface (MS/BS) by 60% (2p < 0.01); other indices show no significant change. The suggested recoding decreases the average MAR by 4% (2p < 0.01), prolongs the remodeling period by 19% (2p < 0.01), and tends to decrease the activation frequency (2p = 0.09). Furthermore, the number of excluded biopsies tends to be larger among the older (2p = 0.09) and more severely osteopenic individuals (2p = 0.09). We conclude that ignoring missing double labels leads to selection bias; therefore, specific measures such as recoding procedures are needed to allow proper representation of low turnover patients. There is also a risk of bias caused by the exclusion of the older, osteopenic patients in bone histomorphometric osteoporosis trials.

Aged↗
PubMed1999

Analysis of the effects of growth hormone, voluntary exercise, and food restriction on diaphyseal bone in female F344 rats.

The aim of this study is to examine the effects of growth hormone, exercise, and weight loss due to food restriction on tibial diaphyseal bone and on tibial muscle mass. Thirteen-month-old female F344 rats were divided into six groups: group 1, baseline controls (B); group 2, age-matched controls (C); group 3, GH treated (GH); group 4, voluntary wheel running exercise (EX); group 5, GH + EX; and group 6, food restricted (FR). The dose of GH was 2.5 mg recombinant human (rh) GH/kg body weight/day, 5 days per week, given in two divided doses of 1.25 mg at 9-10 A.M. and 4-5 P.M. Food-restricted rats were fed 60% of the mean food intake of the age-matched controls. All animals except the baseline controls were killed after 4.5 months. The baseline controls were killed at the beginning of the study. Growth hormone increased the body weight and tibial muscle mass of the rats markedly, while EX caused only a slight decrease in body weight and partially inhibited the increase caused by GH in the GH + EX group. Food restriction greatly decreased body weight below that of age-matched controls, but neither FR nor EX had a significant effect on the mass of the muscles around the tibia. Growth hormone and EX independently increased tibial diaphyseal cortical bone area (p < 0.0001, p < 0.0001), cortical thickness (p < 0.0001, p < 0.0001), cortical bone mineral content (p < 0.0001, p < 0.0001), periosteal perimeter (p < 0.0001, p < 0.0001), and bone strength-strain index (SSI) (p < 0.0001, p < 0.0001). The effects of GH were more marked and resulted in a greater increase in the weight of the mid tibial diaphysis (p < 0.0001). The combination of GH and EX produced additive effects on many of the tibial diaphyseal parameters, including bone SSI. GH + EX, but not GH or EX alone, caused a significant increase in endocortical perimeter (p < 0.0001). In the FR rats, cortical bone area and cortical mineral content increased above the baseline level (p < 0.001, p < 0.0001) but were below the levels for age-matched controls (p < 0.0001, p < 0.0001). In addition, marrow area, endocortical perimeter, and endocortical bone formation rate increased significantly in the FR rats (p < 0.01, p < 0.0001, p < 0.0001). Three-point bending test of right tibial diaphysis resulted in maximum force (Fmax) values that reflected the group differences in indices of tibial diaphyseal bone mass, except that GH + EX did not produce additive effect on Fmax. The latter showed good correlation with left tibial diaphyseal SSI (r = 0.857, p < 0.0001), and both indices of bone strength correlated well with tibial muscle mass (r = 0.771, Fmax; r = 0.700, SSI; p < 0.0001). GH increased serum IGF-I (p < 0.0001), and the increase was partially reduced by EX. Serum osteocalcin was increased by GH with or without EX (p < 0.01, p < 0.01), and FR or EX alone did not alter serum IGF-I and osteocalcin levels. The bone anabolic effects of GH with or without EX may relate, in part, to increased load on bone from tibial muscles and body weight, which were increased by the hormone. The osteogenic effect of EX with or without GH may relate, in part, to increased frequency of muscle load on bone as EX decreased body weight (p < 0.05), but had no significant effect on tibial muscle mass. The enhanced loss of endocortical bone by FR may relate, in part, to decreased load on bone due to low body weight (p < 0.0001), as FR did not cause a significant decrease in tibial muscle mass (p = 0.357). The roles of humoral and local factors in the bone changes observed remain to be established.

Animals↗