Is it time to consider population screening for fracture risk in postmenopausal women? A position paper from the International Osteoporosis Foundation Epidemiology/Quality of Life Working Group.

The IOF Epidemiology and Quality of Life Working Group has reviewed the potential role of population screening for high hip fracture risk against well-established criteria. The report concludes that such an approach should strongly be considered in many health care systems to reduce the burden of hip fractures. INTRODUCTION: The burden of long-term osteoporosis management falls on primary care in most healthcare systems. However, a wide and stable treatment gap exists in many such settings; most of which appears to be secondary to a lack of awareness of fracture risk. Screening is a public health measure for the purpose of identifying individuals who are likely to benefit from further investigations and/or treatment to reduce the risk of a disease or its complications. The purpose of this report was to review the evidence for a potential screening programme to identify postmenopausal women at increased risk of hip fracture. METHODS: The approach took well-established criteria for the development of a screening program, adapted by the UK National Screening Committee, and sought the opinion of 20 members of the International Osteoporosis Foundation's Working Group on Epidemiology and Quality of Life as to whether each criterion was met (yes, partial or no). For each criterion, the evidence base was then reviewed and summarized. RESULTS AND CONCLUSION: The report concludes that evidence supports the proposal that screening for high fracture risk in primary care should strongly be considered for incorporation into many health care systems to reduce the burden of fractures, particularly hip fractures. The key remaining hurdles to overcome are engagement with primary care healthcare professionals, and the implementation of systems that facilitate and maintain the screening program.

[Position paper on medication-related osteonecrosis of the jaw (MRONJ)]. / Positionspapier zur medikamentenassoziierten Osteonekrose des Kiefers (MRONJ).

It is now 12 years since the first article on medication-related osteonecrosis of the jaw (MRONJ) was reported in 2003. The recognition of MRONJ is still inconsistent between physicians and dentists but it is without doubt a severe disease with impairment of oral health-related quality of life. This position paper was developed by three Austrian societies for dentists, oral surgeons and osteologists involved in this topic. This update contains amendments on the incidence, pathophysiology, diagnosis, staging and treatment and provides recommendations for management based on a multidisciplinary international consensus. The MRONJ can be a medication-related side effect of treatment of malignant and benign bone diseases with bisphosphonates (Bp), bevacizumab and denosumab (Dmab) as antiresorptive therapy. The incidence of MRONJ is highest in the oncology patient population (range 1-15 %), where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of MRONJ is estimated to be 0.001-0.01 %, marginally higher than the incidence in the general population (< 0.001 %). Other risk factors for MRONJ include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, ill-fitting dentures as well as other drugs, including antiangiogenic agents. Prevention strategies for MRONJ include elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for the development of MRONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage. Management of MRONJ is based on the stage of the disease, extent of the lesions and the presence of contributing drug therapy and comorbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Early data have suggested enhanced osseous wound healing with teriparatide in those patients without contraindications for its use. The MRONJ related to denosumab may resolve more quickly with a drug holiday than MRONJ related to bisphosphonates. Localized surgical debridement is indicated in advanced nonresponsive disease and has proven successful. More invasive surgical techniques are becoming increasingly more important. Prevention is the key for the management of MRONJ. This requires a close teamwork for the treating physician and the dentist. It is necessary that this information is disseminated to other relevant health care professionals and organizations.

[Direct and indirect costs of fractures due to osteoporosis in Austria]. / Direkte und indirekte Kosten von osteoporotisch bedingten Frakturen in Österreich.

OBJECTIVES: We examined the financial burden of osteoporosis in Austria. METHODS: We took both direct and indirect costs into consideration. Direct costs encompass medical costs such as expenses for pharmaceuticals, inpatient and outpatient medical care costs, as well as other medical services (e.g., occupational therapies). Non-medical direct costs include transportation costs and medical devices (e.g., wheel chairs or crutches). Indirect costs refer to costs of productivity losses due to absence of work. Moreover, we included costs for early retirement and opportunity costs of informal care provided by family members. While there exist similar studies for other countries, this is the first comprehensive study for Austria. For our analysis, we combined data of official statistics, expert estimates as well as unique patient surveys that are currently conducted in the course of an international osteoporotic fracture study in Austria. RESULTS: Our estimation of the total annual costs in the year 2008 imposed by osteoporosis in Austria is 707.4 million €. The largest fraction of this amount is incurred by acute hospital treatment. Another significant figure, accounting for 29% of total costs, is the opportunity cost of informal care. CONCLUSIONS: The financial burden of osteoporosis in Austria is substantial. Economic evaluations of preventive and therapeutic interventions for the specific context of Austria are needed to inform health policy decision makers.

Low bone turnover and increase of bone mineral density in a premenopausal woman with postoperative hypoparathyroidism and thyroxine suppressive therapy.

We report the case of a 36-year-old woman who developed permanent hypoparathyroidism after thyroidectomy for differentiated thyroid carcinoma. A 6-year follow-up showed an increase of 11% in absolute bone mineral density at the spine and 6% at the hip accompanied by low bone turnover despite thyroid-stimulating hormone suppressive thyroxine therapy.

The effect of RANKL and OPG on bone mineral density in pre-dialysis chronic renal failure.

AIMS: The influence of pre-dialysis chronic kidney disease (CKD) on bone is ill defined. Isolation of specific pathogenic mechanisms would improve the understanding and therapeutic options. We therefore investigated whether parathyroid dysfunction, altered vitamin D and hormonal status, or RANKL and OPG have an influence on bone mineral density (BMD) in patients with pre-dialysis renal failure. MATERIAL: 132 patients with chronic renal failure stage 1 - 5 (not yet on dialysis) were investigated in a cross sectional study. Osteoprotegerin (OPG), receptor activator of nuclear factor kB ligand (RANKL), parathyroid hormone (whole, intact and 7-84 fragment), bone markers, sex hormones, and vitamin D status were assessed together with femoral neck and trochanter z-score. Correlation and multivariate analyses were performed between the different parameters and BMD. RESULTS: In the multivariate analysis a significant association was found between the femoral neck z-score and sRANKL (B = -0.45; p < 0.001), and OPG (B = 0.20; p < 0.05). A significant negative association was also found between the trochanter z-score and sRANKL (B = -0.32; p < 0.001). No associations were found between the trochanter z-score and OPG or the sRANKL/OPG ratio. The body mass index was the only additional marker associated with both FN z-score (B = 0.20, p < 0.05) and TR z-score (B = 0.20, p < 0.05). Neither markers of osteoblast nor osteoclast activity, or intact PTH, whole PTH, the PTH 7-84 fragment or vitamin D status were related to bone mineral density. CONCLUSION: Our results demonstrate that the RANKL/RANK/OPG system is associated with bone mineral density in pre-dialysis chronic renal failure.

Successful antibiotic treatment of Borreliosis associated pseudolymphomatous systemic infiltrates.

The clinical management of late stage Borreliosis can be difficult due to various associated symptoms and signs and cumbersome microbiological tests. We report a case of successful antibiotic treatment of Borreliosis-associated pseudolymphomatous infiltrates in bone marrow and lymph nodes, which were diagnosed by bone marrow trephine biopsy and positron emission tomography.

Early onset and effective inhibition of bone resorption in patients with rheumatoid arthritis treated with the tumour necrosis factor alpha antibody infliximab.

OBJECTIVE: To investigate the effect of the tumour necrosis factor alpha antibody infliximab on bone metabolism in patients with rheumatoid arthritis (RA). METHODS: Twelve RA patients with active disease on a constant dose of methotrexate were treated with a single infusion of infliximab (10 mg/kg BW). Serum beta-CrossLaps and serum osteocalcin as markers of bone resorption and formation were measured two days and one day before and one and 14 days after infliximab infusion with an electrochemiluminiscence immunoassay. RA disease activity was determined using the Disease Activity Score (DAS) and the ACR-response criteria. RESULTS: Infliximab treatment significantly reduced serum beta-CrossLaps levels from 0.29 +/- 0.13 (mean +/- SD) ng/ml at study entry to 0.17 +/- 0.09 pg/ml one day after infusion (p < 0.005). At day 14 serum beta-CrossLaps levels were still significantly lower compared to pre-treatment levels (0.24 +/- 0.13 pg/ml, p < 0.05). In contrast, serum osteocalcin levels remained unchanged during the observation period (17.8 +/- 9.8 vs 18.2 +/- 9.9 vs 18.6 +/- 12.1 ng/ml, respectively). All but one patient improved clinically after infliximab infusion and the DAS dropped significantly from 6.5 +/- 0.9 prior to treatment to 5.8 +/- 1.3 and 5.0 +/- 1.3 at Day one and 14 days after treatment, respectively. Four patients showed an ACR 20-response one day after therapy and 10 patients 14 days after therapy. CONCLUSION: Infliximab might have potential to inhibit generalised bone loss in patients with RA in addition to its clinical efficacy in reducing disease activity and inhibiting joint destruction.

[Guidelines for drug therapy of postmenopausal osteoporosis]. / Leitfaden zur medikamentösen Therapie der postmenopausalen Osteoporose.

Osteoporosis is known as a condition characterized by low bone mass and microarchitectural deterioration of bone tissue leading to bone fragility and a consequent susceptibility to fracture. Osteoporosis has its highest rate of occurrence in postmenopausal women, and in Western countries it has been estimated that for white women aged fifty, the life-time risk of developing an osteoporotic fracture is nearly 40%. Given the consequences of osteoporosis, the most important goal of therapy is to prevent fractures. In Austria, several pharmacologic options for treatment of osteoporosis are available, including bisphosphonates (alendronate, etidronate, risedronate), selective estrogen receptor modulators (raloxifene), calcitonins (salm-calcitonin, elcatonin), fluorides (sodium-fluoride, monofluorophosphate), anabolic steroids (nandrolone-decanoate), steroid derivates (tibolone), estrogen and hormone replacement therapy. An evidence-based evaluation of these treatment options clearly indicates that alendronate, risedronate and raloxifene sufficiently reduce the risk of vertebral fractures. There is less evidence for reduction of vertebral fracture risk for etidronate, calcitonin, estrogen replacement therapy or hormone replacement therapy. Only alendronate and risedronate have been shown to reduce the risk of hip fractures. Calcium and vitamin D are useful adjuncts to any specific treatment for osteoporosis, particularly when Calcium and vitamin D deficiencies have been diagnosed. Also, there is good evidence that in women with Calcium and vitamin D deficiency, a combination of Calcium and vitamin D may reduce the risk of non-vertebral fractures. There is no evidence so far that a combination therapy of antiresorptive drugs would result in reduced fracture risk.

Bone loss in patients with untreated chronic obstructive pulmonary disease is mediated by an increase in bone resorption associated with hypercapnia.

This study sought to determine whether the bone loss in untreated chronic obstructive pulmonary disease (COPD) is associated with hypercapnia and/or respiratory acidosis. Bone mineral density (BMD) measured at the distal forearm of the nondominant arm (with peripheral quantitative computed tomography [pQCT]) and serum markers of bone turnover were determined in 71 male patients with untreated COPD and 40 healthy male subjects who matched the patients in age, weight, and body mass index (BMI). The COPD patients, compared with controls, had reduced pulmonary functions, lower arterial pH, and elevated arterial partial pressure of CO2 (PCO2) The BMD (in T score) was significantly lower in COPD patients than that in control subjects (-1.628 +/- 0.168 vs. -0.058 +/- 0.157; p < 0.001). The BMD of COPD patients correlated positively with arterial pH (r = 0.582; p < 0.001), negatively with PCO2 (r = -0.442; p < 0.001), and negatively with serum cross-linked telopeptide of type I collagen (ICTP), a bone resorption marker (r = -0.444; p < 0.001) but not with serum osteocalcin, a bone formation marker. Serum ICTP, but not osteocalcin, correlated with PCO2 (r = 0.593; p < 0.001) and arterial pH (r = -0.415; p < 0.001). To assess the role of hypercapnia, COPD patients were divided into the hypercapnic (PCO2 > 45 mm Hg; n = 35) and eucapnic (PCO2 = 35-45 mm Hg) group (n = 36). Patients with hypercapnia had lower BMD, lower arterial pH, and higher serum ICTP than did patients with eucapnia. Arterial pH and serum ICTP of eucapnic patients were not different from those of controls. To evaluate the role of uncompensated respiratory acidosis, COPD patients with hypercapnia were subdivided into those with compensatory respiratory acidosis (pH > or = 7.35; n = 20) and those with uncompensated respiratory acidosis (pH < 7.35; n = 15). The BMD and serum ICTP were not different among the two subgroups. In conclusion, this study presents the first associative evidence that the bone loss in COPD is at least in part attributed to an increased bone resorption that is associated primarily with hypercapnia rather than uncompensated respiratory acidosis.

Calcitonin increases the concentration of insulin-like growth factors in serum-free cultures of human osteoblast-line cells.

The current studies were intended to determine whether the anabolic effects of calcitonin (CT) on human osteoblast-line cells were (1) unique to osteosarcoma cells or also evident in osteoblast-line cells derived from normal human bone; and/or (2) associated with effects on several insulin-like growth factor (IGF) system components. Preliminary studies identified several osteoblastic cell lines, derived from normal human bone, which showed calcitonindependent increases in cell proliferation, alkaline phosphatase activity, and/or (45)Ca uptake (P < 0.05-P < 0.001). Two of these cell lines-(human vertebrae) HBV-155 and HBV-163-were included with the human osteosarcoma cell line, SaOS-2, in most of our subsequent studies of calcitonin effects on selected IGF system components: IGF-II, IGF-I, and IGF binding proteins -3, -4, and -5. The results of those studies revealed that a 48 hour exposure to salmon CT caused a dose-dependent (0.03-3 mU/ml) increase in the net extracellular level of IGF-II (r = 0.96, P < 0.01) in serum-free cultures of SaOS-2 cells, with a maximal 60% increase at the highest tested dose (P < 0.02). Similar effects were seen with HBV-163 cells (r = 0.90, P < 0.01) and HBV-155 cells (r = 0.55, P < 0.02). The effect of calcitonin on the extracellular level of IGF-II was biphasic with respect to time: it decreased at 6 hours (P < 0.005 and P < 0.001, for SaOS-2 cells and HBV-163 cells, respectively) and increased at 24 hours (P < 0.02 and P < 0.05). These calcitonin-dependent increases in the extracellular level of IGF-II were associated with parallel increases in IGF-I (P < 0.005 for SaOS-2 cells and P < 0.03 for HBV-163 cells), but calcitonin did not affect the extracellular level of transforming growth factor (TGF)-beta. The calcitonin-dependent changes in IGF-II were not associated with changes in the extracellular levels of IGF binding proteins -3, -4, or -5. Finally, our studies showed that two other members of the CT superfamily-CT gene-related peptide and amylin-did not mimic the effect of CT to increase the extracellular level of IGF-II. Together, these data demonstrate that human osteoblast-line cells derived from normal human bone can respond to CT, and that those responses can include CT dose- and time-dependent increases in the extracellular levels of IGF-I and IGF-II.

Variable bone mass recovery in hyperthyroid bone disease after radioiodine therapy in postmenopausal patients.

OBJECTIVES: Long-term follow-up of postmenopausal hyperthyroid females after radioiodine therapy, since hyperthyroidism is known to cause impressive bone loss which may increase the risk of bone fractures. METHODS: Bone mineral density (BMD) and biochemical parameters of bone metabolism in hyperthyroid postmenopausal patients were investigated before and 2 years after radioiodine therapy and compared with euthyroid age-matched controls. RESULTS: At baseline, the incidence of low BMD with t-scores more than 2.5 S.D. below normal was significantly higher in hyperthyroid patients (54%) than in controls (20%, P<0.001). Regardless of initial BMD values, osteocalcin (OC) was also higher in all hyperthyroid patients (P<0.0001). After 2 years, all treated patients were euthyroid and OC levels were in the upper normal range. In hyperthyroid patients with initially low BMD, bone density values had increased significantly by +6.5% (P<0.008) as compared with baseline values. In contrast, hyperthyroid patients with initially normal BMD showed a further decrease in lumbar BMD values of -4.3% despite radioiodine treatment. BMD in euthyroid controls decreased by -6.5% within 2 years. CONCLUSIONS: We conclude that hyperthyroid postmenopausal patients with generally increased bone turnover may show individual differences in bone loss and BMD recovery after radioiodine treatment. The mechanisms for this variable manifestation of osteoporosis have still to be elucidated, since this has implications for prophylactic and therapeutic strategies in these elderly patients.

[Altitude hypoxia: effects on selected endocrinological parameters]. / Höhenbedingte Hypoxie: Effekte auf ausgewählte endokrinologische Parameter.

During the past few years, the investigation of altitude hypoxia and its effect on metabolic functions in humans has increasingly attracted the attention of endocrinologists. Most of the studies have been performed as field studies at moderate or high altitude, but with conflicting results. One of the possible reasons certainly is the fact that standardisation of field studies is almost impossible. Furthermore, many factors such as wind, temperature, radiation and others, may affect certain endocrine parameters, but they cannot be individually quantified. Hence, their inclusion into statistical analyses of the obtained data is not useful. Nevertheless, several endocrine parameters were shown to be affected by altitude hypoxia. Among them, there is erythropoietin, a hormone which is well known to stimulate erythropoiesis. This hormone shows a rapid increase after ascent to moderate or high altitude. There is also evidence that urinary and serum noradrenalin levels increase significantly, whereas adrenalin seems to be less affected. Another "stress-hormone", cortisol, also shows a significant increase. Furthermore, the biologically active fraction of the thyroidal hormones thyroxine and triiodothyronine increases significantly. And last but not least, one of the most important proinflammatory cytokines, interleukin-6, shows a manyfold increase compared to the basal level. However, the clinical significance of most of these studies is not yet clear. Hence, from an endocrinological point of view, no specific recommendations may be given to people staying at moderate or high altitude.

Hyperthyroidism of Graves' disease: evidence for only unilateral involvement of the thyroid gland in a 31-year-old female patient.

Hyperthyroidism of Graves' disease (Morbus Basedow) is known to involve the thyroid gland in toto, unlike Graves' ophthalmopathy which clinically may either be unilateral or bilateral. We report a 31-year-old Caucasian female patient who presented with unilateral goiter and clinical and laboratory evidence for hyperthyroidism. High-resolution ultrasonography of the thyroid gland revealed a morphology indicative of an autoimmune thyroid disease strictly limited only to the right lobe. 123I-scintiscanning showed a homogenous but several fold increased uptake of the radionuclide in the right lobe of the thyroid gland, whereas the uptake in the left lobe did not differ from the uptake in normal controls. Cytology of the fine needle aspirate of the right lobe revealed a remarkable inflammatory background mainly by presence of lymphocytes, a finding which was not seen in the cytology of the left lobe. Furthermore, both serum antibodies to TSH-receptors and thyroid peroxidase were significantly increased. Consequently, hyperthyroidism of Graves' disease with the involvement of only one lobe of the thyroid gland was diagnosed.

Osteoclast formation in bone marrow cultures from two inbred strains of mice with different bone densities.

For the purpose of identifying genes that affect bone volume, we previously identified two inbred mouse strains (C57BL/6J and C3H/HeJ) with large differences in femoral bone density and medullary cavity volume. The lower density and larger medullary cavity volume in C57BL/6J mice could result from either decreased formation or increased resorption or both. We recently reported evidence suggesting that bone formation was increased in vivo and that osteoblast progenitor cells are more numerous in the bone marrow of C3H/HeJ compared with C57BL/6J mice. In the present study, we determined whether osteoclast numbers in vivo and osteoclast formation from bone marrow cells in vitro might also differ between the two mouse strains. We have found that the number of osteoclasts on bone surfaces of distal humerus secondary spongiosa was 2-fold higher in 5.5-week-old C57BL/6J mice than in C3H/HeJ mice of the same age (p < 0.001). Bone marrow cells of C57BL/6J mice cocultured with Swiss/Webster mouse osteoblasts consistently produced more osteoclasts than did C3H/HeJ bone marrow cells at all ages tested from 3.5-14 weeks of age (p < 0.001). Osteoclast formation was also greater from spleen cells of 3.5-week-old C57BL/6J mice than C3H/HeJ mice. The distribution of nuclei per osteoclast and the 1, 25-dihydroxyvitamin D3 dose dependence of osteoclast production from bone marrow cells were similar. Osteoclasts that developed from both C57BL/6J and C3H/HeJ marrow cells formed pits in dentin slices. Cultures from C57BL/6J marrow cells formed 2.5-fold more pits than cultures from C3H/HeJ marrow cells (p < 0.02). We compared the abilities of C57BL/6J and C3H/HeJ osteoblasts to support osteoclast formation. When bone marrow cells from either C57BL/6J or C3H/HeJ mice were cocultured with osteoblasts from either C57BL/6J or C3H/HeJ newborn calvaria, the strain from which osteoblasts were derived did not affect the number of osteoclasts formed from marrow cells of either strain. Together, these observations suggest that genes affecting the bone marrow osteoclast precursor population may contribute to the relative differences in bone density that occur between C3H/HeJ and C57BL/6J mouse strains.

Effects of zinc on human skeletal alkaline phosphatase activity in vitro.

Inorganic phosphate (Pi) can regulate the level of skeletal alkaline phosphatase (ALP) activity in human osteoblast-like cells by stabilizing the enzyme (without affecting transcription, ALP release from the cell surface, or the amount of ALP protein). These observations suggest that Pi determines the level of ALP activity by modulating a process of irreversible inactivation. The current studies were intended to examine the hypothesis that this inactivation of ALP activity is caused by the dissociation of an active center Zn and that Pi inhibits that dissociation. Initial studies showed that Zn, like Pi, could increase ALP specific activity in human osteosarcoma SaOS-2 cells in a time- and dose-dependent manner (e.g., a 50% increase at 0.2 micromol/liter Zn, P < 0.005). This effect was specific for Zn (i.e., no similar effect was seen with Ca, Fe, Co, Mg, Mn, or Cu), but not for SaOS-2 cells. Zn also increased ALP specific activity in (human osteosarcoma) MG-63 cells and in cells derived from normal human vertebrae (P < 0.001 for each). The effect of Zn to increase ALP activity was not associated with parallel increases in total protein synthesis, collagen production, or tartrate-resistant acid phosphatase activity (no change in any of these indices), net IGF-2 synthesis (a Zn-dependent decrease, P < 0.005), or PTH-dependent synthesis of cAMP (a biphasic increase, P < 0.02). Kinetic studies of Pi and Zn as co-effectors of ALP activity showed that Zn was a mixed-type effector with respect to Pi, whereas Pi was competitive with respect to Zn. Mechanistic studies showed that (1) Zn reversed the effect of Pi withdrawal to decrease ALP activity, but not by reactivating inactive ALP protein (the process required protein synthesis, without increases in ALP mRNA or the level of ALP immunoreactive protein); (2) Zn increased the half-life of ALP activity in intact cells and after a partial purification; and (3) Pi inhibited the process of ALP inactivation by EDTA (which chelates active center Zn). All these findings are consistent with the general hypothesis that Pi increases the half-life of skeletal ALP by preventing the dissociation of active center Zn and with a mechanistic model of skeletal ALP activity in which active center Zn participates in Pi-ester binding and/or hydrolysis.

Post-transplantation lymphoproliferative disorder of the T-cell/B-cell type: an unusual manifestation in a renal allograft.

Marked impairment of the cellular immune system predisposes renal transplant recipients to Epstein-Barr virus (EBV) associated clinical syndromes. This can culminate in post-transplantation lymphoproliferative disorders (PTLD) and malignant lymphomas. An unusual PTLD in a 59-year-old renal transplant recipient is reported here. Sonography and CT scan revealed a hypovascular infiltrating tumor mass in the lower pole of the graft which on histopathologic examination revealed a monotonous lymphoid proliferation. T-cell receptor and immunoglobulin heavy chain gene rearrangement as well as immunohistochemical analyses demonstrated a polyclonal origin of atypical lymphatic T- and B-cells. The Epstein-Barr viral genome was detected in the mass by Southern blot analysis, and a primary EBV infection was confirmed by serologic studies. Clinical follow-up showed a tumor-free course till the patient's sudden cardiac death 14 months after the operation.

Daily oral magnesium supplementation suppresses bone turnover in young adult males.

This study examined the effects of daily oral magnesium (Mg) supplementation on bone turnover in 12 young (27-36 yr old) healthy men. Twelve healthy men of matching age, height, and weight were recruited as the control group. The study group received orally 15 mmol Mg (Magnosolv powder, Asta Medica) daily in the early afternoon with 2-h fasting before and after Mg intake. Fasting blood and second void urine samples were collected in the early morning on days 0, 1, 5, 10, 20, and 30, respectively. Total and ionized Mg2+ and calcium (Ca2+), and intact PTH (iPTH) levels were determined in blood samples. Serum biochemical markers of bone formation (i.e. C-terminus of type I procollagen peptide and osteocalcin) and resorption (i.e. type I collagen telopeptide) and urinary Mg level adjusted for creatinine were measured. In these young males, 30 consecutive days of oral Mg supplementation had no significant effect on total circulating Mg level, but caused a significant reduction in the serum ionized Mg+ level after 5 days of intake. The Mg supplementation also significantly reduced the serum iPTH level, which did not appear to be related to changes in serum Ca2+ because the Mg intake had no significant effect on serum levels of either total or ionized Ca2+. There was a strong positive correlation between serum iPTH and ionized Mg2+ (r = 0.699; P < 0.001), supporting the contention that decreased serum iPTH may be associated with the reduction in serum ionized Mg2+. Mg supplementation also reduced levels of both serum bone formation and resorption biochemical markers after 1-5 days, consistent with the premise that Mg supplementation may have a suppressive effect on bone turnover rate. Covariance analyses revealed that serum bone formation markers correlated negatively with ionized Mg2+ (r = -0.274 for type I procollagen peptide and -0.315 for osteocalcin), but not with iPTH or ionized Ca2+. Thus, the suppressive effect on bone formation may be mediated by the reduction in serum ionized Mg2+ level (and not iPTH or ionized Ca2+). In summary, this study has demonstrated for the first time that oral Mg supplementation in normal young adults caused reductions in serum levels of iPTH, ionized Mg2+, and biochemical markers of bone turnover. In conclusion, oral Mg supplementation may suppress bone turnover in young adults. Because increased bone turnover has been implicated as a significant etiological factor for bone loss, these findings raise the interesting possibility that oral Mg supplementation may have beneficial effects in reducing bone loss associated with high bone turnover, such as age-related osteoporosis.

Relapse of pulmonary Mycobacterium kansasii disease associated with large-cell cancer of the lung: a case report.

A 43-year-old caucasian male diabetic presented with purulent cough and a history of weight-loss, elevated temperature, night-sweat and dyspnea. Four years previously, the patient had undergone a 12-month antimycobacterial regimen because of pulmonary mycobacterium kansasii (MK) disease of the left upper lobe (LUL). Treatment had led to complete recovery with the exception of minor fibrous residuals in the involved pulmonary segments. Chest radiograph and computed tomography (CT), performed on recent admission, revealed a dense infiltration of these residual-containing segments. Microbiological evaluation of bronchial brushings, aspirates and histology of the transbronchial biopsies indicated a relapse of pulmonary MK disease. Although antimycobacterial treatment was started immediately, therapeutic effects were only minimal and remained to be limited to the initial phase of the treatment. After four weeks of treatment, the patient's general condition worsened again. Follow-up CT of the lung showed a marked increase of the infiltration in the left apicoposterior lobe and re-bronchoscopy showed a tumorous protrusion of the bronchial wall involving the apicoposterior segment ostium, a finding which was not seen in the previous bronchoscopy. Histology of the transbronchial biopsies revealed a carcinoma mainly from large-cell type.

Skeletal alkaline phosphatase activity is primarily released from human osteoblasts in an insoluble form, and the net release is inhibited by calcium and skeletal growth factors.

Skeletal alkaline phosphatase (ALP) is anchored to membrane inositol-phosphate on the outer surface of osteoblasts. Although skeletal ALP activity in serum is, essentially, all in an anchorless (soluble) form, in vitro studies indicate that ALP can be released in either an anchorless, soluble form (e.g., by a phospholipase) or an anchor-intact, insoluble form (e.g., by vesicle exocytosis). The current studies were intended to define the contributions of each of these putative processes of ALP release and to assess the significance of regulation by calcium (Ca) and skeletal effectors. ALP activity was measured in serum-free medium from replicate cultures of human osteosarcoma (SaOS-2) cells and normal human bone cells. Temperature-sensitive phase distribution (in Triton X-114) allowed separation of soluble from insoluble ALP activity. Our studies revealed that most of the ALP activity released from SaOS-2 cells was in an insoluble form (78% +/- 8%), a percentage that was constant between 2 and 96 hours. A similar result was seen for normal human bone cells. Calcium had a negative, biphasic dose-dependent effect on net release of ALP activity: r = -0.85, P < 0.001 at 24 hours, with KIapparent values for biphasic inhibition of 20 and 300 mumol/l Ca. Of the skeletal effectors tested, insulin-like growth factor-II (IGF-II) had the greatest effect, decreasing the net release of ALP activity in a dose-dependent manner (r = -0.82, P < 0.005). Neither Ca nor IGF-II affected the distribution of soluble/insoluble ALP activity by more than 9%. IGF-II had no effect on extracellular ALP stability, but the addition of Ca to Ca-free cultures resulted in parallel losses of extracellular ALP activity and ALP immunoreactive protein (P < 0.001 for each). A similar effect was seen when Ca was added to Ca-free, cell-free, conditioned medium, but not when Ca was added to purified ALP, which is consistent with the general hypothesis that a Ca-dependent protease might be present in the cell-conditioned medium. Together, these data suggest that most of the ALP activity released from osteoblasts is insoluble (and, presumably, anchorless), net release of ALP activity is negatively regulated by Ca and skeletal growth factors, the effect of Ca may reflect Ca-dependent protease activity, and an exogenous (e.g., serum) phospholipase may be responsible for releasing ALP from its insoluble anchor.

Alkaline phosphatase levels and osteoprogenitor cell numbers suggest bone formation may contribute to peak bone density differences between two inbred strains of mice.

Previous studies have shown that C3H/HeJ (C3H) mice have higher peak bone density than C57BL/6J (B6) mice, at least in part because of differences in rates of bone resorption. The current studies were intended to examine the alternative, additional hypothesis that the greater bone density in C3H mice might also be a consequence of increased bone formation. To that end, we measured two presumptive, indirect indices of bone formation and osteoblast number in these inbred strains of mice: alkaline phosphatase (ALP) activity in serum, bones, and bone cells; and the number of ALP-positive colony-forming units (CFU) in bone marrow stromal cell cultures. We found that C3H mice had higher serum levels of ALP activity than B6 mice at 6 (118 vs. 100 U/L, p < 0.03) and 32 weeks of age (22.2 vs. 17.2 U/L, p < 0.001). Tibiae from C3H mice also contained higher levels of ALP activity than tibiae from B6 mice at 6 (417 vs. 254 mU/mg protein, p < 0.02) and 14 weeks of age (132 vs. 79 mU/mg protein, p < 0.001), as did monolayer cultures of bone-derived cells from explants of 7.5-week-old C3H calvariae and femora (8.2 times more, p < 0.02, and 4.6 times more, p < 0.001, respectively). Monolayer cell cultures prepared by collagenase digestion of calvariae from newborn and 6-week-old mice also showed similar strain-dependent differences in ALP-specific activity (p < 0.001 for each). Our studies also showed more ALP-positive CFU in bone marrow stromal cell cultures from 8-week-old C3H mice, compared with B6 mice (72.3 vs. 26.1 ALP-positive CFU/culture dish, p < 0.001). A similar result was seen for ALP-positive CFU production at 6 and 14 weeks of age, and the difference was greatest for the CFU that contained the greatest numbers of ALP-positive cells. Because skeletal ALP activity is a product of osteoblasts and has been shown to correlate with rates of bone formation, and because the number of ALP-positive CFU is believed to reflect the number of osteoprogenitor cells, the current data are consistent with the general hypothesis that bone formation may be greater in C3H than B6 mice because of a difference in osteoblast number. Our data further suggest that peak bone density may be greater in C3H mice than B6 mice due to a combination of decreased bone resorption and increased bone formation.