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.

Rapid suppression of bone resorption and parathyroid hormone secretion by acute oral administration of calcium in healthy adult men.

Acute effects of oral calcium supplementation have been studied mainly in pre- and post-menopausal women, whereas very few data concerning men are available. We investigated the effects of 1.2 g of oral calcium administered for 4 days in 18 healthy young men. The day before the first calcium dosing (day -1) and the day of the last calcium dosing (day 4) total and ionized serum calcium and intact PTH were measured at multiple time-points up to 24 h; calcium, C-terminal telopeptide (CTX), pyridinoline (PYD) and deoxypyridinoline (DPD) were measured in urine collected every six h. On day 4, total and ionized serum calcium increased during the 6 h following oral calcium: the maximum increase over baseline was 5.04 and 7.4% respectively, occurring after 2.9 +/- 1.9 h (mean +/- SD) and 2.6 +/- 0.9 h. The AUC was significantly higher on day 4 than on day -1 for both total serum calcium (+4.6%, p<0.02) and ionized serum calcium (+9.2%, p<0.0001). Twenty-four h urinary excretion of total calcium increased significantly on day 4 (+15.1%, p<0.02), mainly as a consequence of increased excretion during the first 6 h. Serum PTH was suppressed by oral calcium, with a significant reduction of AUC on day 4 (-15.1%, p<0.05). Serum concentrations of intact PTH dropped from 26.4 +/- 9.8 pg/ml at time zero to a minimum mean value of 14.9 +/- 7.6 pg/ml at time +2 h. Bone resorption markers significantly decreased on day 4 (CTX -33.2%, p<0.001; PYD -28.5%, p<0.05; DPD -35.8%, p<0.02). Most of the effect was seen in the first 6 h after oral calcium load. These data support the concept that acute suppression of PTH and bone resorption induced by calcium administration is not gender specific and provide the rationale to further assess also in men the long-term effects of oral calcium in the prevention and treatment of osteoporosis.

Short-term intravenous therapy with Neridronate in Paget's disease.

AIMS: To describe the effects of two consecutive intravenous infusions of aminohexane bisphosphonate (Neridronate) in patients with active Paget's disease of bone. METHODS: The study population included 83 patients, aged 41 to 85 years, randomized to 4 cumulative doses of Neridronate (25, 50, 100, 200 mg) given over 2 days, with a follow up of 180 days. The baseline serum alkaline phosphatase activity was at least 10% above the upper limit of the laboratory range. The response to treatment was assessed by changes in the serum total alkaline phosphatase (primary end point of the study), bone alkaline phosphatase and N-telopeptide urinary excretion. RESULTS: All Neridronate doses significantly suppressed the biochemical indices of disease activity. The nadir of total alkaline phosphatase levels ranged from -16 % to -57.5% of pretreatment values in the four groups, with a dose-response relationship that was apparent even between the two highest doses. The proportion of patients still maintaining a partial response (decreases in serum total alkaline phosphatase >25%) at the 6 month follow-up was also related to the dose: 98%, 67%, 57%, 21% in the patients given 200, 100, 50, 25 mg respectively. The proportion of responders in terms of bone alkaline phosphatase and N-telopeptide excretion changes was similar. Bone pain attributed to Paget's disease was significantly reduced. A typical acute phase reaction (fever and/or arthromyalgia) occurred in 16 out of 83 patients. CONCLUSIONS: We conclude that all of the Neridronate doses tested here were well tolerated and effective in decreasing, in a dose-related manner the bone turnover parameters of Paget's disease. The highest dose (200 mg) resulted in the normalization of the markers of disease activity in more than 60% of the patients.

Effects of 12-month GH treatment on bone metabolism and bone mineral density in adults with adult-onset GH deficiency.

Serum bone-Gla protein (BGP), bone alkaline phosphatase (B-AP), and C-terminal cross-linked telopeptide of type I collagen (ICTP) levels were evaluated in 18 adults with acquired GH deficiency (GHD, 14 males and 4 females, age range: 25-59 yr) before, at 3, 6, 9 and 12 months of rec-GH treatment (0.125 IU/kg/week for the first month, followed by 0.25 IU/kg/week for 11 months) and 6 months after the withdrawal of therapy. Total body bone mineral density (BMD, g/cm2) was measured with dual energy X-ray absorptiometry (Hologic QDR 1000/W) before, at 12 months of GH treatment and 6 months after its withdrawal. Before treatment, BGP (mean+/-SE: 5.1+/-0.4 ng/ml), B-AP (59.4+/-6.5 IU/l), ICTP (3.1+/-0.3 ng/ml) levels of patients were similar to in healthy controls (BGP: 5.4+/-0.1 ng/ml; B-AP: 58.2+/-2.0 IU/l; ICTP: 4.1+/-0.3 ng/ml). GH treatment caused a significant increase of BGP, B-AP, ICTP levels, the maximal stimulation of bone resorption, occurring after 3 months of GH treatment, while the maximal effect on bone formation being evident later (at 6th month). A slight decline in BGP, B-AP, T-AP and ICTP levels occurred at 9-12 months of therapy, although the values remained significantly higher than in basal conditions and with respect to healthy controls. Before treatment, mean total body BMD of patients (1.110+/-0.027 g/cm2, range: 0.944-1.350 g/cm2) was not significantly different (z-score: +0.47+/-0.31, NS) from that observed in healthy controls (1.065+/-0.008 g/cm2, range: 1.008-1.121 g/cm2). GH therapy was associated with a significant reduction of mean total body BMD values (6th month: -1.8+/-0.5%, p<0.01; 12th month: -2.1+/-1.0%, p<0.05 vs baseline), particularly evident in the first six months of treatment. Six months after the withdrawal of GH therapy, BGP (5.9+/-0.5 ng/ml), B-AP (57.3+/-7.0 IU/l) and ICTP (3.2+/-0.1 ng/ml) levels returned similar to those recorded before treatment, while total BMD increased (+1.5+/-0.7, p<0.05), remaining however slightly lower than in basal conditions (-0.6+/-1.2, NS). In conclusion, our study shows that: a) acquired GHD in adulthood is associated with both normal bone formation/resorption indexes and normal total body BMD; b) GH therapy causes a significant rise of bone formation/resorption markers (earlier and greater for bone resorption); c) one-year GH therapy is associated with a reduction of total body BMD values, particularly evident in the first 6 months of treatment; d) the effects of GH therapy on bone turnover are transient, being completely reverted six months after the withdrawal of GH therapy; e) the increase of total body BMD (up to baseline values) after GH withdrawal might be explained as consequence of persisting effects of previous GH stimulation on bone remodeling.

Periprosthetic bone density around fully hydroxyapatite coated femoral stem.

In this study, periprosthetic bone mineral density was measured at scheduled time intervals after surgery by dual energy x-ray absorptiometry in 21 patients to assess the history of bone density redistribution after femoral stem insertion. Measurements of changes in bone density with time were obtained for the regions of the greater trochanter, the lateral cortex, the tip, the medial cortex, and the calcar. In all regions, bone density decreased during the first 3 months after surgery; this was followed by a prolonged period of 18 to 30 months of bone gain, a subsequent period of steady state, and the final resumption of bone aging processes after the third postoperative year. The greatest loss was observed in the calcar region after 6 months (greater than 50%). The characteristic pattern of time related bone density changes obtained in this study may make it possible to compare other pathologic, design, or stiffness related patterns. This could have clinical relevance in the early diagnosis of pathologic processes and as a means of evaluating prosthetic designs.

Effects on bone mineral density of 12-month goserelin treatment in over 40-year-old women with uterine myomas.

We evaluated the effects on bone mineral density (BMD) of a 12-month treatment with goserelin depot, a gonadotropin-releasing hormone agonist, in a group of women with symptomatic uterine myomas requiring hysterectomy. Sixteen women, mean age 45.6 +/- 5.0, reporting menorrhagia associated with uterine myomas, candidates for hysterectomy, were scheduled to be treated with goserelin depot for 12 months. BMD was measured at the vertebral (L2-L4) and proximal femur level (femoral neck and trochanter) at the start of therapy and 6, 12, and 18 months later using dual energy X-ray absorptiometry (Hologic QDR 1000/W). The patients were followed for a minimum of 6 months after the end of treatment. Thirteen of the 16 women enrolled completed the treatment and three suspended it after 5, 6, and 7 months, respectively, because of side effects (hot flashes, insomnia, depression). Of the 13 women who completed the treatment, three underwent hysterectomy because of myoma regrowth and the recurrence of symptoms 3-18 months later; four reached the menopause 5-16 months later, and six were all menstruating normally with a follow-up varying from 6 to 18 months. After 12 months of therapy we observed a bone loss at vertebral, femoral neck, and trochanter of 4.4% (P < 0.05 versus baseline; P = not significant versus 6 months), 7.5% (P < 0.01 versus baseline, P < 0.01 versus 6 months), and 7.6% (P < 0.001 versus baseline, P < 0.05 versus 6 months), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Rationale for the use of alendronate in osteoporosis.

Bisphosphonates are being used in disorders associated with accelerated resorption of bone, particularly Paget's disease of bone and the bone disease of malignancy. Their undoubted biological efficacy and relatively low apparent toxicity make them attractive candidates for the management of osteoporosis. The bisphosphonate alendronate has many characteristics which suggest that it is suitable for use in osteoporosis. It is a potent inhibitor of osteoclast-mediated bone resorption with no adverse effect on the mineralization of bone. Earlier studies have shown it to be one of the most active bisphosphonates in Paget's disease and the hypercalcemia of malignancy. In common with other bisphosphonates tested thus far, alendronate appears to inhibit bone loss in a variety of experimental models of osteoporosis. Long-term studies are needed to determine its steady-state effects on bone mass in man. Most data indicate that alendronate is capable at least of decreasing the rate of bone loss, and might even induce increments in bone mass for many years. Since the experimental studies show that the increase in bone mass observed with alendronate is associated with an increase in bone strength, its use is likely to decrease the frequency of fractures. However, direct clinical evidence for this requires the outcome of well-designed long-term prospective studies.

Gonadotropin releasing hormone agonist therapy and its effect on bone mass.

The effects on bone mass of a 6 month therapeutic cycle with a gonadotropin releasing hormone agonist (GnRHa) were studied in 22 patients, ten affected by pelvic endometriosis and 12 by uterine fibroids. All patients were subjected to preliminary full examinations to confirm their diagnosis (laparoscopy for the endometriosis group and precise ultrasound volume measurements for uterine fibroids group). Before the beginning of treatment, bone mineral density (BMD) was measured in each patient both on the distal third of the forearm, with single-photon absorptiometry, and on the lumbar spine (L1-L4), with dual photon absorptiometry. The gonadotropin releasing hormone agonist used was buserelin. In the first week of therapy 0.5 mg of the drug was administered subcutaneously thrice daily. In the following 25 weeks the same drug was given intranasally, at a dosage of 300 micrograms again three times a day. Bone mass measurements, both at the peripheral and at the axial site, were repeated at the end of the 26-week therapeutic cycle and then again 6 months later. At the 26th week, a significant decrease of BMD was observed at both sites. The loss was 1.5% (p less than 0.05) on the lumbar spine, and 2.1% (p less than 0.05) on the radius. No bone mass restoration took place in the following 6 months. On the contrary, a less significant but discernible trend towards a further bone loss was apparent in the BMD values measured 6 months after the end of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclic hormonal replacement therapy after the menopause: transdermal versus oral treatment.

In an open, randomized, comparative, between-patient trial, 45 postmenopausal women were treated for 4 months with cyclical transdermal oestradiol 0.05 mg per day or oral conjugated equine oestrogens 0.625 mg per day, in both cases, plus, medroxyprogesterone acetate 10 mg per day on the last 8 days of each cycle. Similar relief from postmenopausal symptoms was obtained with both treatments. Post-treatment histological evaluation of the endometrium did not reveal neoplastic or hyperplastic change in any patient. Early follicular-phase plasma oestradiol levels were observed only after transdermal oestradiol. There was a significant reduction in serum total cholesterol and LDL cholesterol in both treatment groups, with no difference between treatments, whereas serum triglyceride levels were decreased only by transdermal oestradiol. Plasma calcium and phosphorus fell significantly and serum intact parathyroid hormone rose significantly, with no difference between the therapies. No significant changes were observed in clotting factors. Transdermal oestradiol appears to be an effective and safe hormonal replacement therapy, and this route of administration may be responsible for the more useful action of the drug on serum lipids and plasma oestradiol levels.

1,25-Dihydroxyvitamin D3 in the treatment of idiopathic thrombocythemia and myelofibrosis.

The effect of treatment with 1,25-dihydroxyvitamin D3 administered at the dose of 1.50-3.00 ug/day for at least 12 months was evaluated in three patients with idiopathic myelofibrosis and in five patients with idiopathic thrombocythemia. This treatment did not cause any significant change in the hematological values or the clinical course of the myeloproliferative diseases in any of the patients. Based on these data, treatment with 1,25-dihydroxyvitamin D3 in non toxic doses seems to be of doubtful benefit in patients with these disorders.

Immunoreactive calcitonin: a tumor marker for myelogenous leukemias.

In a series of 59 patients with chronic or acute myelogenous leukemia (CML, AML) we investigated whether circulating immunoreactive human calcitonin (i-hCT) levels correlate with diagnosis, response to therapy and clinical course. I-hCT was detectable in plasma samples of 88% of patients with CML in the chronic phase and in 100% of patients with CML in blastic transformation. In the AML patients, a significant relation was observed between the cytological subtype and i-hCT levels at diagnosis. In sequentially studied patients the i-hCT plasma concentration was related to the overall mass of leukemic cells, being lower when complete remission was achieved than at diagnosis and increasing at time of recurrence. These data suggest that circulating i-hCT levels can serve as a "tumor marker" in human myelogenous leukemias.

Bone involvement in primary hemochromatosis and alcoholic cirrhosis.

Biochemical indexes of bone metabolism, bone mineral density, and histomorphometry were evaluated in 14 male patients with noncholestatic cirrhosis due to primary hemochromatosis (six cases) or to chronic alcohol abuse (eight cases), and in 30 male controls of similar age. Alkaline phosphatase in alcoholic patients was significantly higher than in controls (mean +/- SD 50.4 +/- 33.7 vs 33.0 +/- 7.1 U/L, p less than 0.01), as was urinary hydroxyproline in both hemochromatotics and alcoholics (mean +/- SD, 44.3 +/- 8.4 and 40.4 +/- 16.8, respectively, vs 30.1 +/- 4.5 mg/g, p less than 0.001 and p less than 0.005). Bone mineral density was significantly lower in hemochromatotics than in alcoholics and controls (mean +/- SD, 591 +/- 90 vs 765 +/- 87 and 759 +/- 34 mg/cm2, respectively, p less than 0.005 and p less than 0.001). At bone biopsy, trabecular osteoporosis was observed in two hemochromatotics and four alcoholics, and osteomalacia was seen in another alcoholic. Overall densitometric and histomorphometric findings indicate a derangement of trabecular bone in both alcoholic and hemochromatotic cirrhosis, whereas cortical osteoporosis seems limited to hemochromatotic patients.

Vitamin D concentrations in women of postmenopausal age with fractures of the femoral neck.

Thirty-eight women of postmenopausal age, suffering from fractures of the femoral neck or vertebral bodies were studied in relation to differences in bone metabolism. The blood and urinary changes concerned in mineral and bone metabolism were recorded within 10 days of trauma, and in some femoral neck fractures, a histological study of the femoral heads removed in the course of prosthetic substitution was carried out. The patients with femoral neck fractures were older than those with vertebral fractures and had metabolic and histological findings suggestive of osteomalacia. A particularly significant difference between the two groups was the plasma level of 25 hydroxycholecalciferol, which was lower in femoral neck fractures, and the urinary excretion of calcium, which was also more reduced in femoral neck fractures. A deficit of vitamin D hepatic metabolite thus appears to be a risk factor for femoral neck fractures in old patients.

Plasma immunoreactive N-terminal parathyroid hormone and cyclic AMP and cyclic GMP urinary levels in man after I. M. administration of two different doses of porcine calcitonin.

The effects of acute porcine calcitonin (pCT) administration were studied in 11 healthy volunteers with no metabolic disease. Each subject was given, intramuscularly, 1 MRC unit of pCT in glycine vehicle, 160 units of pCT in gelatine vehicle, and placebo, according to a crossover design. The following parameters were studied: blood calcium, phosphorus and immunoreactive parathyroid hormone (iPTH); urine calcium, phosphorus, cyclic AMP and GMP. Both the pCT preparations produced, at the same time after administration, a hypocalcemic effect (P less than 0.01) which was not dose related, without any modification of urinary calcium excretion, implying that both doses are able to inhibit completely bone destruction. Despite the blood calcium decrease, no significant modifications in plasma iPTH levels were observed. pCT administration did not modify the urinary excretion of cyclic AMP, while it increased the urinary levels of cyclic GMP, particularly at the higher dose employed. Blood phosphorus decrease and urinary phosphate excretion increase were observed only after the administration of 160 MRC units of pCT. These observations suggest that the effects on urinary cyclic GMP and on blood and urine phosphorus are not mediated by PTH but could be the result of a direct action of calcitonin seen only when high doses are employed. In conclusion, one MRC unit of pCT is sufficient to inhibit bone resorption.