Gait speed and one-leg standing time each add to the predictive ability of FRAX.

Gait speed or one-leg standing time (OLST) as additional predictors in FRAX. Population 351 elderly women followed 10 years. Both could improve predictions. The area under curve (AUC) for FRAX is 0.59, OLST is 0.69 and gait speed is 0.71. The net reclassification index (NRI) for classification to highest risk quartile or lowest three quartiles was 0.24 for gait speed and non-significant for OLST. INTRODUCTION: The risk of falls and bone strength are two main determinants of hip fracture risk. The fracture risk assessment tool FRAX, however, lacks direct measures of fall risk1. A short OLST and a slow gait speed are both fall-related risk factors for hip fractures. The aim of this study was to investigate whether the addition to FRAX of either gait speed or OLST could improve the predictive ability for hip fractures, compared to FRAX alone. METHODS: A population-based sample of 351 women aged between 69 and 79 years were tested for one-leg standing time with eyes open and mean gait speed over a 15 + 15-m walk. Fracture and mortality data were obtained from health care registers. RESULTS: The AUC for the receiver operating characteristic (ROC) increased from 0.61 to 0.71 when gait speed was added to FRAX. The AUC was 0.69 for OLST added to FRAX. The highest quartile of hip fracture risks according to FRAX had an absolute 10-year risk of ≥15%. The population was divided into one group with a hip fracture risk of ≥15% and one group with a fracture risk of <15%. NRI for addition of gait speed to FRAX was 0.24 (p = 0.023), while NRI was 0.08 (p = 0.544) for addition of OLST to FRAX. CONCLUSION: Gait speed tended to improve the predictive ability of FRAX more than OLST, but they both added value to FRAX.

The impact of vitamin D on the innate immune response to uropathogenic Escherichia coli during pregnancy.

Urinary tract infections are highly common during pregnancy, and can cause serious complications for the mother and baby. Vitamin D, predominantly obtained from the sunlight, is known to have an effect on the urothelium, with immunomodulatory capacity against Escherichia coli infection. However, its influence at this site remains to be further explored. This study therefore investigated its impact during pregnancy in a population of women who have the possibility of adequate year-round sun exposure. Serum from pregnant Ugandan women (n = 32) in each trimester of pregnancy, from women after delivery (n = 29) and from never-pregnant controls (n = 25) was collected. 25-Hydroxyvitamin D (25-OHD), cathelicidin LL-37, human ß-defensin 2, interleukin (IL)-8 and soluble CD14 serum concentrations were measured by chemiluminescence immunoassay or ELISA. The ability of serum to inhibit E. coli growth was tested. The immunomodulatory capacities of these serum samples and 1,25-dihydroxyvitamin D3 were investigated in urothelial cells. Increases in 25-OHD and LL-37 levels were observed as pregnancy progressed, peaking in the third trimester. Serum 25-OHD levels were higher in multigravidae than in primigravidae, and correlated positively with maternal age. IL-8 levels were lower in the third trimester than in the first trimester, increased after delivery, but remained below those of never-pregnant women. Similarly, soluble CD14 concentrations increased after delivery. As gestation advanced, serum had an increased capacity to inhibit E. coli growth. In vitro, it modulated the IL-8 response to infection in a vitamin D concentration-dependent manner. Our findings demonstrate that increasing vitamin D levels as pregnancy advances modulate the innate immune system towards a protective response to infection.

One-leg standing time and hip-fracture prediction.

UNLABELLED: A hip fracture results in a lower quality of life and a cost of £30,000. In this study, one-leg standing time (OLST) had a negative linear relationship to the risk of a hip fracture. OLST could be a useful tool to assess the need for fracture-preventive interventions. INTRODUCTION: A hip fracture immobilizes, restricts autonomy, shortens life expectancy, and results in a cost of £30,000 in the UK health care system. However, effective preventive treatments can be offered to high-risk individuals. Impaired postural balance is an important risk factor for hip fractures, and the aim of this study was to evaluate whether OLST can predict hip fractures in elderly women. FRAX is the most established fracture risk assessment tool worldwide and a secondary aim was to relate the predictive ability of OLST to that of FRAX in this population. METHODS: Three hundred fifty-one women aged between 69 and 79 years were timed standing on one leg up to 30 s with eyes open and assessed with FRAX. Fracture data was obtained from registers. RESULTS: The main outcome, a hip fracture, occurred in 40 of the 351 participants (11.4%). The age-adjusted risk of a hip fracture was 5% lower with 1 s longer OLST (Hazard ratio 0.95, 95% CI 0.927-0.978). The relation between OLST and hip fracture risk was linear. Harrell's c was 0.60 for FRAX and 0.68 for OLST adjusted for age. CONCLUSION: With 1 s longer OLST, the risk of a hip fracture decreased significantly by 5%. This risk reduction was not explained by differences in the classic fracture risk factors included in FRAX. OLST had a predictive ability similar to FRAX. OLST is an easily performed balance test which may prove to be valuable in the assessment of hip fracture risk.

Health related quality of life, reoperation rate and function in patients with diabetes mellitus and hip fracture--a 2 year follow-up study.

INTRODUCTION: Diabetes mellitus confers an increased risk of hip fractures. There is a limited knowledge of how the outcome after a hip fracture in patients with diabetes affect Health Related Quality of Life (HRQoL). The primary aim of this study was to evaluate HRQoL. Secondary aims were reoperation rate, complications and functions in patients with diabetes followed for 2 years after a hip fracture. MATERIALS AND METHODS: Out of 2133 patients diabetes was present in 234 patients (11%). Main outcome measurements were HRQoL evaluated with EuroQoL 5-Dindex score, reoperation rate, surgical and medical complications, function as walking ability, daily activities, living condition and pain. RESULTS: Preoperatively, patients with diabetes mellitus had more pain (p=0.044), co-morbidities, reduced health status (p=0.001) and more often used a walking frame (p=0.014) than patients without diabetes, whereas Katz ADL index, cognition and body mass index did not differ. There was no difference in fracture type, surgical method or reoperation between the two groups or between patients with insulin treated or oral treated diabetes. The EQ-5Dindex score decreased from 0.64 at admission to 0.45 at 4 months, 0.49 at 12 months and 0.51 at 24 months with similar results for patients with and without diabetes. During the first postoperative year there was not more medical complications among patients with diabetes, however cardiac (p=0.023) and renal failure (p=0.032) were more frequent in patients with diabetes at 24 months. Patients with diabetes more often had severe hip pain at 4 months (p=0.031). At 12 months more diabetic patients were living independently (p=0.034). There was no difference in walking ability, ADL and living condition between the groups at 24 months. CONCLUSION: The findings of this study indicate that patients with diabetes mellitus had more pain, co-morbidities, reduced health status preoperatively than patients without diabetes. Hip fracture patients with diabetes mellitus have more hip pain at 4 months. Cardiac and renal failure was more frequent in patients with diabetes at 24 months but otherwise we found a comparable re-operation rate, function and deterioration of Health Related Quality of Life as patients without diabetes within 2 years after a hip fracture.

Mini nutritional assessment and 10-year mortality in free-living elderly women: a prospective cohort study with 10-year follow-up.

BACKGROUND/OBJECTIVES: Mini nutritional assessment (MNA) is the most frequently used screening test for malnutrition in elderly populations in continental Europe and Asia. Most studies on MNA's ability to predict mortality have only included persons admitted to hospital, living in nursing homes or at home with professional help with activities of daily living. The aim of this cohort study was to examine if MNA can predict 10-year mortality in the general elderly female population. SUBJECTS/METHODS: Of the 584 free-living elderly women invited, 351 agreed to participate and were tested with MNA between 1999 and 2000. A 10-year follow-up was conducted in 2010 with dates of death obtained from the Swedish death register. RESULTS: Participants whose MNA score was ≤ 23.5 points at inclusion had a significantly higher age-adjusted 10-year mortality risk than participants with a MNA score of >23.5 points. The hazard ratio was 2.36 (95% confidence interval 1.25-4.46), P <0.01. CONCLUSIONS: Participants with a MNA score, indicating an increased risk for malnutrition, were more than twice as likely to die during the 10-year follow-up as participants whose MNA score indicated normal nutritional status. Hence, MNA can predict mortality in a general, free-living, elderly female population.

Risk of hip fracture in Addison's disease: a population-based cohort study.

OBJECTIVES: The results of studies of bone mineral density in Addison's disease (AD) are inconsistent. There are no published data on hip fracture risk in patients with AD. In this study, we compare hip fracture risk in adults with and without AD. DESIGN: A population-based cohort study. METHODS: Through the Swedish National Patient Register and the Total Population Register, we identified 3219 patients without prior hip fracture who were diagnosed with AD at the age of ≥30 years during the period 1964-2006 and 31 557 age- and sex-matched controls. Time to hip fracture was measured. RESULTS: We observed 221 hip fractures (6.9%) in patients with AD and 846 (2.7%) in the controls. Patients with AD had a higher risk of hip fracture [hazard ratio (HR) = 1.8; 95% confidence interval (CI), 1.6-2.1; P < 0.001]. This risk increase was independent of sex and age at or calendar period of diagnosis. Risk estimates did not change with adjustment for type 1 diabetes, autoimmune thyroid disease, rheumatoid arthritis or coeliac disease. Women diagnosed with AD ≤50 years old had the highest risk of hip fracture (HR = 2.7; 95 % CI, 1.6-4.5). We found a positive association between hip fracture and undiagnosed AD [odds ratio (OR) = 2.4; 95 % CI, 2.1-3.0] with the highest risk estimates in the last year before AD diagnosis (OR = 2.8; 95 % CI, 1.8-4.2). CONCLUSION: Both clinically undiagnosed and diagnosed AD was associated with hip fractures, with the highest relative risk seen in women diagnosed with AD ≤50 years of age.

Amino acid profiles in adults with growth hormone (GH) deficiency before and during GH replacement therapy.

OBJECTIVE: GH replacement to growth hormone deficient (GHD) adults improves body composition. In a subset however, lean body mass (LBM) fails to increase despite normalization of IGF-I and amino acid availability could be of importance. We analyzed amino acid (AA) profiles in plasma and erythrocytes (RBC) and associations with LBM, serum IGF-I and IGFBP-1 before and during GH replacement. DESIGN AND METHODS: Examinations were performed in 15 GHD patients (six women), aged 34-61 yrs before and after 12 months of GH therapy and in a control group of 20 healthy males aged 31-68 yrs. LBM was measured by dual energy X-ray absorptiometry (DXA), free AAs in plasma and RBC by high performance liquid chromatography and serum IGF-I and IGFBP-1 by in-house RIAs. SETTING: Tertiary care referral centre. RESULTS: At baseline, female GHD patients tended to have lower concentrations of the essential branched - chain AAs isoleucine and leucine, total essential AAs, and of the non-essential AA glutamine than the male patients. Male GHD patients tended to have higher plasma and RBC glutamate than controls. At 12 months, IGF-I had normalized in all but one patient and mean LBM gain was 1.9+/-0.4 kg. AA levels were unchanged. The change in LBM at 12 months was positively correlated to the ratio between the sum of isoleucine, leucine and valine and baseline LBM kg/m(2) (r=0.76, p=0.001, n=15). CONCLUSION: Our results suggest that the essential branched-chain amino acids in plasma are important for the LBM response to GH substitution. Our finding has to be confirmed in larger groups of GHD adults before making a proper selection of AAs to be measured in plasma and added as dietary supplement during GH therapy. GH administration did not change AA levels and measurements are not useful for monitoring of GH therapy at the time being.

The role of IGF-I and IGFBP-1 status and secondary hyperparathyroidism in relation to osteoporosis in elderly Swedish women.

UNLABELLED: IGFBP-1 showed a strong inverse relation to the BMD values. The IGF-I values had a significant positive relation to the BMD values at all sites with the exception of the lumbar spine. The use of loop diuretics was a more important cause of secondary hyperparathyroidism than vitamin D status. INTRODUCTION: Our aim was to investigate among elderly women the relationship to osteoporosis of calcium-regulating hormones and insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-1 (IGFBP-1). METHODS: A population-based cross-sectional study of 350 elderly women (mean age 73 years). Measurements of bone mineral density (BMD) of the left hip, lumbar spine and heel and risk markers for osteoporosis were studied. RESULTS: The BMD values showed significant inverse relationship with the values of IGFBP-1 at all sites of measurement and significant positive relationship with the values of IGF-I at all sites with the exception of the lumbar spine. There was no significant association between the values of BMD and the values of 25-hydroxy vitamin D (25(OH)D). The use of loop diuretics was strongly and significantly associated with elevated levels of PTH >65 pg/ml (OR 4.4, P < 0.001). CONCLUSIONS: The anabolic growth factor IGF-I and its modulating binding protein IGFBP-1 showed a stronger association with the BMD values than the calcium regulating hormones 25(OH)D and PTH. In this study the use of loop diuretics was a more important cause of secondary hyperparathyroidism than vitamin D status.

Osteoblast dysfunction in male idiopathic osteoporosis.

The etiology of primary osteoporosis in young and middle-aged men is unknown. We have studied osteoblast function in cells derived from men with idiopathic osteoporosis and in control cells from age-matched men with osteoarthrosis. Osteoblasts were isolated from transiliac bone biopsies. Osteoblast function was measured as vitamin D-stimulated osteocalcin production and production of cytokines and factors involved in osteoclast activation and bone formation. Cell proliferation was measured as (3)H-thymidine incorporation. Parathyroid hormone-related peptide (PTHrP) mRNA was measured using reverse-transcriptase polymerase chain reaction. In osteoporotic men, bone mineral density at the femoral neck was correlated to in vitro production of osteocalcin. Osteoblasts from osteoporotic men produced significantly less osteocalcin after vitamin D stimulation but had increased production of macrophage colony-stimulating factor (M-CSF) compared to controls. The osteocalcin response was negatively correlated to production of M-CSF, interleukin-6, and C-terminal propeptide of type I collagen. Basal (3)H-thymidine incorporation was similar in cells from osteoporotic patients and controls. PTHrP (10(-9 )M) significantly increased cell proliferation in control cells but not in osteoporotic cells. Basal PTHrP mRNA levels were significantly higher in osteoporotic cells than in cells from controls. The results are in agreement with previous histomorphologic studies indicating that men with idiopathic osteoporosis have an osteoblast dysfunction with decreased osteocalcin production and increased production of factors stimulating osteoclast activation. This indicates a catabolic cellular metabolic balance leading to negative bone turnover, resulting in osteoporosis. The cause of such cellular dysfunction needs further evaluation.

Nutritional status, as determined by the Mini-Nutritional Assessment, and osteoporosis: a cross-sectional study of an elderly female population.

OBJECTIVE: To investigate the relationship between osteoporosis and nutritional status as determined by the Mini-Nutritional Assessment (MNA). DESIGN: A cross-sectional study. SETTING: Stockholm, Sweden. SUBJECTS: A total of 351 elderly free-living women (mean age 73+/-2.3 years). METHODS: MNA (range 0-30 points; <17 indicates malnutrition, 17.5-23.5 risk of malnutrition and >or=24 well nourished), measurements of bone mineral density of the left hip and lumbar spine using Hologic QDR 4500, and of the heel using Calscan DEXA-T. RESULTS: The median MNA score was 27 (range 12.5-30). One woman was classified as malnourished and 7.4% were at risk of malnutrition. Osteoporosis of the femoral neck was observed in 22% and a fracture after the age of 50 was reported by 31% of the participants. The following items in the MNA questionnaire exhibited an increased risk of having osteoporosis in the femoral neck and/or total hip: an MNA score of <27 (odds ratio (OR)=2.09; CI=1.14-3.83); a mid-arm circumference of less than 28 cm (OR=2.97; CI=1.29-6.81); and regular use of more than 3 drugs each day (OR=2.12; CI=1.00-4.50). A body weight of more than 70 kg exhibited a decreased risk of having osteoporosis (OR=0.31; CI=0.14-0.70). CONCLUSIONS: In general, the nutritional status was good in this population of free-living elderly women. Nevertheless, half of the women who displayed an MNA score <27 points had a twofold increased risk of having osteoporosis. SPONSORSHIP: Karolinska Institutet, Stockholm County Council.

Bone mineral density measurement in the calcaneus with DXL: comparison with hip and spine measurements in a cross-sectional study of an elderly female population.

We investigated the relationship between calcaneal and axial bone mineral density in an elderly female population. We also investigated the influence of changing the reference populations on T-score values. Bone mineral density (BMD) was determined in 388 women (mean age 73 years) participating in a cross-sectional study. BMD values were determined at the left hip and the lumbar spine, L1-L4, using Hologic QDR 4500 equipment for dual X-ray absorptiometry (DXA). The calcaneal measurements were made with DEXA-T, a device using a dual X-ray and laser (DXL) technique that combines DXA measurement with measurement of the heel thickness using a laser reflection technique. DEXA-T is an older version of the Calscan DXL device now commercially available. T-score values were calculated for hip measurements with both the original reference population of the Hologic device and the NHANES III reference population. T scores for heel measurements were calculated with the original reference population of the peripheral device and the Calscan database, a new calcaneal reference population. Changing the reference populations had a great influence on both the heel and the hip T scores, especially those of the femoral neck where the percentage of subjects identified as osteoporotic decreased from 53% to 23%. We conclude that, with the NHANES III and the larger Calscan database, using the cut-off point of -2.5 SD, the heel measurements had optimal accuracy for detecting osteoporosis at either the combination of the lumbar spine and the femoral neck or the combination of the lumbar spine, the femoral neck, the total hip and the trochanter. BMD measurements of the calcaneus with DXL correlated fairly well with measurements at axial sites at the group level, while in individual subjects large deviations were observed between all the measured sites. We also conclude that the influence of the reference populations on the T scores is substantial when different DXA methods are being compared; the total number of subjects classified as osteoporotic varied from 7% to 53% between the sites and with different reference populations.

Skeletal changes in type-2 diabetic Goto-Kakizaki rats.

We characterized appendicular and axial bones in rats with type-2 diabetes in five female Goto-Kakizaki (GK) rats, a strain developed from the Wistar rat showing spontaneous type-2 diabetes, and five age- and sex-matched non-diabetic Wistar rats. The humerus, tibia, metatarsals and vertebral bodies were analysed by peripheral quantitative computerized tomography (pQCT). In diabetic rats, the height of the vertebral bodies and length of the humerus were decreased while the length of the metatarsals was increased. A decreased cross-sectional area was found in the vertebral end-plate region and the tibial metaphysis. Notably, the diaphysis in all long bones showed expansion of periosteal and endosteal circumference. In tibia this resulted in increased cortical thickness, whereas in humerus and metatarsal it was unchanged. Areal moment of inertia was increased in all diaphyses suggesting greater bending strength. The most conspicuous finding in diabetic rats pertained to trabecular osteopenia. Thus, trabecular bone mineral density was significantly reduced in all bones examined, by 33-53%. Our pQCT study of axial and appendicular bones suggests that the typical feature of diabetic osteopathy in the GK rat is loss of trabecular bone and expansion of the diaphysis. The loss of metaphyseal trabecular bone if also present in diabetic patients may prove to underlie the susceptibility to periarticular fracture and Charcot arthropathy. The findings suggest that the risk of fracture in diabetes varies according to the specific sub-regions of a bone. The approach described may prove to be useful in the early detection of osteopathy in diabetic patients who may be amenable to preventive treatment.

Seasonal variations in serum levels of 25-hydroxyvitamin D and parathyroid hormone but no detectable change in femoral neck bone density in an older population with regular outdoor exposure.

OBJECTIVES: To investigate the influence of season and outdoor daylight exposure on serum levels of 25-hydroxyvitamin D (25OHD), intact parathyroid hormone (PTH), ionized calcium, and femoral neck bone mineral density (BMD). DESIGN: A 12-month, longitudinal, prospective study on a consecutively selected sample of healthy independent older people. SETTING: Men and women living in their own homes in the inner city of Stockholm (latitude 59.2 degrees N). PARTICIPANTS: Sixty-four healthy men (n = 13) and women (n = 51), age 79 to 96 (mean age 83.7) were requested to spend at least 3 hours per week outdoors during April through September. Fifteen of these, who failed to comply with the required time outdoors, constituted a separate group. Subjects with serious diseases and subjects with medication that could interfere with vitamin D metabolism or bone mineralization were excluded from the study. MEASUREMENTS: Daily dietary intakes of calcium and vitamin D were recorded on the basis of the subjects' recall. The participants kept a diary recording the time spent in sunlight and the area of skin exposed. Fasting blood samples were collected and analyzed on four occasions for 25OHD, intact PTH, and ionized calcium. BMD was determined at 6-month intervals in the femoral neck, using dual energy x-ray absorptiometry. RESULTS: At study start in the spring, 6% of the subjects had 25OHD levels below 10 ng/ml and 78% had levels below 31 ng/ml. Forty-seven percent had intact PTH levels above the upper limit of the reference range (8-51 ng/L). Seasonal variations in the serum levels of 25OHD (P <.001), intact PTH (P <.001) and ionized calcium (P <.001) were observed only in the group with > or =3 hours of weekly outdoor daylight exposure. The 25OHD levels in autumn were positively correlated with the number of hours spent outdoors during the preceding summer (r = 0.63, P <.001). In the whole group and in the group with weekly outdoor exposure of > or =3 hours, there were no significant changes detectable in mean values of femoral neck BMD during the study year. Femoral neck BMD, expressed as Z-score, was significantly and positively correlated with serum 25OHD (r = 0.38, P =.003 after summer; r = 0.37, P =.003 after winter). CONCLUSION: The seasonal changes in serum levels of 25OHD, PTH, and ionized calcium and the positive correlation between femoral neck BMD and 25OHD indicate that regular outdoor daylight exposure during the summer could enhance calcium homeostasis and possibly bone health, even among very old people living at northerly latitudes.

[The value of bone density measurement--a follow-up of the conclusions in the earlier SBU report]. / Värdet av bentäthetsmätningar--en uppföljning av slutsatserna i den tidigare SBU-rapporten.

Osteoporotic fractures are common primarily among elderly Swedish women. Vertebral compression fractures can occur spontaneously without trauma, while wrist and hip fractures are nearly always the result of trauma. The risk of fracture increases in skeletal wasting. If bone density measurement can demonstrate osteoporosis already before fractures occur, then preventive measures could be set in. The present study, which is a systematic review of articles published from 1994 to the spring of 1998, confirms the conclusions of the 1995 report "Bone Density Measurement" from SBU, the Swedish Council on Technology Assessment in Health Care, that the relative risk of fracture can be predicted utilizing bone density measurement. The best risk assessment is achieved by taking into account both clinical risk factors and bone density.

Vitamin D status, parathyroid function and femoral bone density in an elderly Swedish population living at home.

The aim of this study was to determine vitamin D status and bone mineral density (BMD) in elderly, independent Scandinavians. A cross-sectional examination was conducted in a sample of 104 subjects (mean age 84.5 years), for possible correlations among anthropometric data, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, intact parathyroid hormone (PTH) and femoral neck BMD. Daily dietary calcium and vitamin D intakes were below the recommended levels. Five percent of the subjects were taking calcium, and 30% vitamin D supplements. Previous fragility fracture was reported in 30% of the men, and 55% of the women. Higher mean values of serum 25-hydroxyvitamin D (p = 0.03) and femoral neck BMD (p = 0.03) were recorded in subjects spending > or = 3 hours outdoors weekly. Independently of time spent outdoors, subjects taking daily supplements of vitamin D (on average 5 micrograms) had higher 25-hydroxyvitamin D (p < 0.001) levels, without significant changes in femoral neck BMD values. Serum levels of intact PTH (reference range 8-51 ng/L) were elevated in 41%, of which 5% had mild primary hyperparathyroidism. Serum levels of 25-hydroxyvitamin D (reference range 10-65 ng/mL) and 1,25-dihydroxyvitamin D (reference range 15-55 pg/mL) were below the reference ranges in 4% and 5% of the subjects, respectively. When serum levels of 25-hydroxyvitamin D were lower than approximately 30 ng/mL, the serum intact PTH values began to increase from a level of 43 pg/mL. This threshold most probably reflected a more relevant value of vitamin D insufficiency, indicating that 45% of our subjects rather than 4% actually had hypovitaminosis. Multiple regression analysis demonstrated femoral neck BMD to be significantly and positively associated with higher body mass index, male gender, no history of fragility fracture and 25-hydroxyvitamin D (R2 = 0.39). It is concluded that in this sample of healthy elderly people who regularly spend time outdoors, vitamin D levels leading to secondary hyperparathyroidism seem to be a major cause of osteoporosis. Correcting chronic dietary calcium deficiency is likely to eliminate another factor contributing to poor bone health.

Low IGF-I levels in hip fracture patients. A comparison of 20 coxarthrotic and 23 hip fracture patients.

We measured total body bone density and body composition with dual energy x-ray absorptiometry in 43 elderly patients, 23 with hip fracture and 20 with coxarthrosis, after surgery and after 6 months. Insulin-like growth factor-1 (IGF-I), a polypeptide known to affect bone metabolism, and two of its binding proteins (IGFBP-1, IGFBP-3) were measured preoperatively and after 6 months. Normal serum IGF-I levels are dependent on adequate nutrition and normal secretion of growth hormone (GH). We found consistently lower levels of IGF-I and IGFBP-3 and a tendency to higher levels of IGFBP-1 in the patients with hip fractures, who also had a lower total body mass, lower fat mass and bone mineral density than the coxarthrosis group, indicating a more catabolic state in the patients with hip fracture, even 6 months after the trauma.

Serum levels of insulin-like growth factor I in 152 patients with growth hormone deficiency, aged 19-82 years, in relation to those in healthy subjects.

Serum insulin-like growth factor I (IGF-I) levels within normal range for age have been reported to be common in adults with GH deficiency (GHD). Therefore, serum IGF-I levels were determined in 152 consecutive patients (71 women and 81 men) with evidence of hypothalamic-pituitary disorders or previous cranial radiation, who fulfilled the presently used criteria for GHD i.e. peak GH response below 3 microg/L at stimulation test. Patients treated for acromegaly were excluded. Forty-three patients, aged 19-63 yr, had childhood onset GHD, and 109, aged 23-82 yr, had adult-onset GHD. Their IGF-I levels were expressed in SD scores in relation to normal reference values based on 448 healthy subjects, aged 20-96 yr (247 women and 201 men). In healthy subjects a linear inverse correlation, without gender difference, was found between logarithmic transformed IGF-I levels and age (r = -0.774; P < 0.001). In contrast, no age dependency was found in GHD patients. All patients with childhood-onset GHD had IGF-I values below -2 SD, significantly lower than those in adult-onset GHD patients (-6.2 +/- 0.3 vs. -3.2 +/- 0.2 SD score; P < 0.001). In patients with adult-onset GHD, 34% of the IGF-I levels were within normal range, increasing to 40% in the subgroup above 60 yr of age, in whom 86% were diagnosed with hypothalamic-pituitary tumors. Normal IGF-I was more common in men than in women, but no difference was observed between patients with panhypopituitarism and those with partial pituitary insufficiency. High frequencies of IGF-I levels within the normal range were found in GHD patients with pituitary tumors (20 of 57 nonsecreting pituitary adenomas, 5 of 15 prolactinomas, 6 of 12 Cushing's disease, and 4 of 25 craniopharyngiomas), but in only 2 of 43 patients with GHD due to other causes. In conclusion, an IGF-I level below -2 SD seems to be of diagnostic value in GHD with onset in childhood or early adulthood, whereas values within normal range are common in patients over 60 yr of age, especially those with pituitary tumors. The outcome of GH replacement therapy may reveal whether the addition of IGF-I as a diagnostic criterion is of predictive value in older patients.

Growth hormone treatment of osteoporotic postmenopausal women - a one-year placebo-controlled study.

OBJECTIVES: To study the effect of 12 months of growth hormone (GH) treatment on bone markers, bone mineral density (BMD), lean body mass (LBM) and body fat mass (BF) in postmenopausal osteoporotic women. DESIGN: Sixteen patients were randomised to a double-blind randomised placebo-controlled one-year study with daily s.c. injections of GH or placebo. After the first year 14 patients (8 placebo treated, 6 GH treated) were recruited to GH treatment during the second year. All patients were also supplemented with 0.5 g calcium per oral. METHODS: Bone mineral density and body composition were assessed by dual energy X-ray absorptiometry. Biochemical bone markers were analysed by RIA or HPLC techniques. Diurnal GH profiles were performed with continuous venous blood sampling. RESULTS: Sixteen patients started in the placebo-controlled study. In all, twelve patients completed one year and only four patients completed two years of GH treatment. At baseline 3 patients had serum insulin-like growth factor-I (S-IGF-I) levels below -2 S.D. for age. Maximal diurnal GH levels tended to correlate negatively with S-IGF-I (P=0.076). S-IGF-I was unrelated to BMD. Serum IGF-binding protein-1 (S-IGFBP-1) correlated negatively with femoral neck BMD (r=-0.61, P=0.012). The intended GH dose of 0.05U/kg/day or a maximum of 3U/day s.c. was reduced to 0.024+/-0.004U/kg/day, equal to 0.5-2.7U/day due to frequent side effects, and four patients were excluded. After one year of GH treatment BF increased slightly, LBM and BMD in total body and lumbar spine were unchanged but femoral neck BMD had decreased 3.4+/-1.6% (P<0.05). The mean S-IGF-I increase was 32% (range -38-138%). Mean levels of the bone formation markers S-osteocalcin and S-procollagen type I propeptide increased maximally by 88 and 36% respectively after 9-12 months while the bone resorption markers were unchanged. In the placebo-treated group there were no significant alterations. CONCLUSIONS: The effects on S-IGF-I, bone markers and LBM were small although GH-related side effects were common. The reason for this apparent partial resistance to the anabolic effects of GH is not clear but nutritional deficits may be involved. Assessment of the effects of GH on bone mass and fracture rate requires longer study periods than one year.

Influence of the phosphate balance on the activity distribution of 99mTc-hydroxy-methylene diphosphonate. Experimental studies in the mouse.

OBJECTIVE: The purpose was to determine whether changes in the phosphate balance have an influence on the distribution of bone-seeking radiopharmaceuticals. MATERIAL AND METHODS: The biodistribution of 99mTc-HDP in mice, intravenously administered under varying conditions, was assessed by removing different organs and estimating their activity in a scintillation counter. Some experiments were also performed with 99mTc-MDP and 99mTc-DPD. RESULTS: After 1 h and 18 h on phosphate-enriched drinking water, the mice showed a strongly increased uptake in all organs/tissues representing background activity and a decrease in the bone uptake. This pattern changed with time. After 6-8 days of phosphate load, we saw a more favourable distribution with a reduction of the background and whole-body activity. Administration of hPTH 1-34 gave rise to an activity distribution similar to that after 6-8 days on phosphate-enriched water. Changing the phosphate balance had less obvious effects on the distribution of 99mTc-MDP and 99mTc-DPD. CONCLUSION: The activity distribution of bone-seeking radiopharmaceuticals in the mouse is affected by the phosphate balance. The mechanism behind this finding is unknown but it may be partially mediated by PTH. It is possible that changes in the phosphate balance, induced by pharmaceuticals or by dietary changes, may affect the image quality at bone scintigraphy.

Serum levels of insulin-like growth factor binding proteins (IGFBP)-4 and -5 correlate with bone mineral density in growth hormone (GH)-deficient adults and increase with GH replacement therapy.

Adults with growth hormone deficiency (GHD) exhibit low bone mineral density (BMD) which improves by growth hormone (GH) replacement therapy. The insulin-like growth factor (IGF) system has an established role in mediating the effects of GH on bone and IGF binding proteins (IGFBP)-4 and IGFBP-5 have been shown to modulate the effects of IGFs in bone. Therefore, we studied serum levels of IGFBP-4 and IGFBP-5 and their relationship to serum levels of bone biochemical markers and BMD in adults with GH deficiency (GHD) before and during GH therapy. Serum levels of IGFBP-5 and IGFBP-4 were measured on samples from 20 patients (11 males) 22-57 years of age. All had IGF-I serum values below -2 standard deviation score. The first 6 months were placebo controlled and all received 3 years of active treatment with the mean dose 0.23 +/- 0.01 IU/kg/week divided into daily subcutaneous injections. Serum IGFBP-5 levels in GHD adults were low at baseline and positively related to total body, femoral neck, trochanter, and Ward's triangle BMD (r = 0.471, 0.549, 0.462, and 0.470, respectively, p < 0.05). The mean serum IGFBP-5 level increased by about 2-fold within 3 months after the initiation of GH therapy and was correlated with serum IGF-I (r = 0.719, 0.801, and 0.722 before and after 18 and 36 months, respectively,p < 0.001). A positive correlation between serum IGFBP-5 levels and lumbar spine BMD was found during GH treatment but not before. The percentage increase of serum IGFBP-5 after GH therapy showed a positive correlation with the percentage increase of total alkaline phosphate activity (r = 0.347 p < 0.05). In contrast to IGFBP-5, serum IGFBP-4 levels were positively related to body mass index (r = 0.607, p < 0.01). Baseline serum IGFBP-4 levels also correlated with total body, femoral neck, trochanter, and Ward's triangle BMD (r = 0.502, 0.590, 0.612, and 0.471, respectively,p < 0.05). The mean serum IGFBP-4 level was increased by 25% within 3 months after initiation of GH therapy and did not correlate with serum IGF-I levels. Although the above findings are consistent with the idea that GH-induced changes in serum IGFBP-5 and IGFBP-4 levels may in part mediate the anabolic effects of GH on bone tissue in adults with GHD, further studies are needed to establish the cause and effect relationship.