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Objectives: Treatment discontinuation after long-term bisphosphonate (BP), termed a 'drug holiday', has been proposed to reduce the risk of BP-associated complications. The duration of treatment cessation remains unclear. Changes in bone mineral density (BMD), bone turnover markers (BTMs) and their relationship with FRAX were assessed to help determine the optimum length of a 'drug holiday'., Methods: A retrospective analysis of 134 patients (13M, 121F) aged [mean (SD)] 68·4 (8·2) years who discontinued BPs after treatment for 5·9 (3·0) years for osteoporosis was undertaken. BMD at the lumbar spine (LS), total hip (TH), and femoral neck (FN) and biochemical parameters including serum 25 (OH) vitamin D, bone turnover markers (plasma CTX, P1NP) and FRAX scores were determined at discontinuation, 12-18 months and 24-30 months off treatment., Results: BMD decreased significantly at the LS [% change mean (SD): -0·94 (3·6), P = 0·008], TH [-1·4 (2·4), P < 0·001] and FN [-1·8 (4·4), P < 0·001] after treatment discontinuation for 12-18 months. In the subgroup who remained off treatment for 24-30 months, a progressive decline in BMD was seen at the TH and FN with total % decrease of -2·52 (3·5) and -2·7 (4·76), P < 0·001, respectively. CTX and P1NP increased significantly at 12-18 months after discontinuation [% change CTX: 95 (88), P < 0·001, P1NP: 88 (73), P < 0·001]. FRAX scores were significant predictors of % change in BMD at the FN (P < 0·05), independently of bone turnover and vitamin D status. In summary, our data show that following a 'drug holiday', the use of DEXA scans, BTMs and FRAX may help guide when to resume treatment., (© 2015 John Wiley & Sons Ltd.)

Bisphosphonates (BPs) have been shown to influence angiogenesis. This may contribute to BP-associated side-effects such as osteonecrosis of the jaw (ONJ) or atypical femoral fractures (AFF). The effect of BPs on the production of angiogenic factors by osteoblasts is unclear. The aims were to investigate the effect of (1) alendronate on circulating angiogenic factors; vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) in vivo and (2) zoledronate and alendronate on the production of VEGF and ANG-1 by osteoblasts in vitro. We studied 18 post-menopausal women with T score⩽-2 randomized to calcium/vitamin D only (control arm, n=8) or calcium/vitamin D and alendronate 70mg weekly (treatment arm, n=10). Circulating concentrations of VEGF and ANG-1 were measured at baseline, 3, 6 and 12months. Two human osteoblastic cell lines (MG-63 and HCC1) and a murine osteocytic cell line (MLO-Y4) were treated with zoledronate or alendronate at concentrations of 10(-12)-10(-6)M. VEGF and ANG-1 were measured in the cell culture supernatant. We observed a trend towards a decline in VEGF and ANG-1 at 6 and 12months following treatment with alendronate (p=0.08). Production of VEGF and ANG-1 by the MG-63 and HCC1 cells decreased significantly by 34-39% (p<0.01) following treatment with zoledronate (10(-9)-10(-6)M). Treatment of the MG-63 cells with alendronate (10(-7) and 10(-6)) led to a smaller decrease (25-28%) in VEGF (p<0.05). Zoledronate (10(-10)-10(-)(6)M) suppressed the production of ANG-1 by MG-63 cells with a decrease of 43-49% (p<0.01). Co-treatment with calcitriol (10(-8)M) partially reversed this zoledronate-induced inhibition. BPs suppress osteoblastic production of angiogenic factors. This may explain, in part, the pathogenesis of the BP-associated side-effects., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Osteoporosis is a highly prevalent condition, characterized by compromised bone strength and fragility fractures and with an important associated socio-economic burden. Bisphosphonates are well established as the first line treatment for osteoporosis. However, while randomized control trials have in general demonstrated reasonable anti-fracture efficacy at the spine, they have shown moderate reduction in fracture incidence for non-vertebral sites. Furthermore, oral bisphosphonates are commonly associated with adverse gastrointestinal effects and both oral and parenteral bisphosphonates have been linked with osteonecrosis of the jaw and atypical femoral fracture, two rare but debilitating side effects. In addition, bisphosphonates are not recommended in patients with GFR <35 ml/min/1.73 m(2). Hence, there is a clear requirement for newer agents, which are able to reduce fracture risk further, whilst overcoming the limitations of bisphosphonates. Over the past 20 years, knowledge and a deeper understanding of the various signalling pathways involved in bone remodelling has increased, enabling identification of additional targets for therapy. This review focuses on these newer therapies and includes anti-resorptive agents such as raloxifene and other selective oestrogen receptor modulators, the monoclonal antibody denosumab (which inhibits the RANKL pathway), odanacatib, a cathepsin K inhibitor and the anabolic agents, PTH analogue; PTH (1-34) and anti-sclerostin antibodies (activator of the Wnt pathway). Strontium ranelate will not be reviewed as recent reports highlight concerns surrounding its cardiovascular safety and together with an apparent increased risk of thrombosis, its future use remains uncertain. Some of these agents such as raloxifene, denosumab and teriparatide are already in clinical use whilst others are at varying stages of development. This review will provide an overview of the mechanisms of action of these therapeutic agents on the skeleton and assess their efficacy in osteoporosis and fracture prevention.

Studies suggest that optimal vitamin D status is required for the maximal effect of antiresorptive agents. We investigated the relationship between vitamin D status, serum parathyroid hormone (PTH) concentrations, and change in bone mineral density (BMD) following iv zoledronate and denosumab. We carried out a retrospective analysis of 111 patients, mean age 70 (SD 13) years, 89 women and 22 men, prescribed zoledronate and 43 postmenopausal women treated with denosumab for osteoporosis. We measured BMD at the lumbar spine (LS) and total hip (TH), serum 25 (OH) vitamin D, PTH, and bone turnover markers (plasma CTX, P1NP) at 1 year. In patients on zoledronate, BMD increased at the LS and TH (mean LS change [SEM] = 2.6 % [0.5 %], mean TH change = 1.05 % [0.5 %], p < 0.05). A significant increase in BMD was seen at the LS only in the denosumab group (p = 0.001). Significant decreases in CTX and P1NP were observed at 12 months in both treatment groups. At baseline and at 12 months, 34 % and 23 % of the patients on zoledronate had a serum vitamin D of <50 nmol/L, respectively. The mean PTH concentration in patients with 25 (OH) vitamin D <50 nmol/L was 44 ng/L (SEM 16.6). Patients with PTH concentration <44 ng/L had significantly higher increases in TH BMD compared to those with PTH >44 ng/L (zoledronate 1.9 [0.83] vs. -0.43 [0.81], p = 0.04; denosumab 4.1 [0.054] vs. -1.7 [0.04], p = 0.004). Optimal vitamin D status and PTH concentrations improve the skeletal response to zoledronate and denosumab.

Quantitative bone scan imaging has a useful role in research for examining the pathophysiology of metabolic bone diseases and the response of patients to treatment. The advantage of nuclear medicine imaging as a way of measuring the rate of bone remodeling is that either the whole skeleton or discrete regions of interest (ROIs) may be studied depending on whether there is diffuse or localized disease. This article reviews methods of quantifying (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) kinetics based on a standard bone scan examination by measuring the plasma clearance of tracer to the whole skeleton and/or selected ROIs drawn on the bone scan image. Although the measurement of bone plasma clearance requires blood sampling to find the input curve for free (eg, nonprotein bound) (99m)Tc-MDP, we argue that plasma clearance studies give a more physiological approach in a better accord with the underlying changes in bone turnover than conventional measurements of whole-body retention or bone uptake. We describe 3 methods of measuring whole-skeleton (99m)Tc-MDP plasma clearance (K(bone)): (1) the area under the curve (AUC) method based on taking 6 blood samples at 5, 15, 60, 120, 180, and 240 minutes and measuring the plasma concentration of free (99m)Tc-MDP by ultrafiltration using a 30-kDa filter. The AUC method requires a simultaneous measurement of glomerular filtration rate using (51)Cr-EDTA as a cotracer; (2) the modified Brenner method, which measures K(bone) by drawing a soft-tissue ROI over the adductor muscles and plotting the soft tissue counts at 1, 2, 3, and 4 hours against the AUC values at the corresponding time points; (3) the Patlak method based on combining gamma camera measurements of whole-body retention with plasma data and measuring K(bone) from the slope of the Patlak plot fitted to the 2, 3, and 4 hours data points. Unlike the first 2 methods, the Patlak plot can also be used to measure regional values of K(bone) for any chosen ROI. Initial studies have shown good agreement between the 3 methods of measuring K(bone), and highly significant correlations between the change in K(bone) values during treatment and the corresponding changes in serum and urinary measurements of biochemical markers of bone formation and bone resorption.

Reports of osteonecrosis of the jaw (ONJ) in patients receiving long-term bisphosphonate therapy have appeared in the literature since 2003. This condition involves avascular necrotic bone in the area of maxilla or mandibula and there may be a secondary infection. Most cases of ONJ have been reported in cancer patients receiving the intravenous aminobisphosphonates zoledronic acid and pamidronate monthly or q 3 week; of note these are also the two most commonly used agents of this class. Risk factors for ONJ include a history of trauma, dental surgery or dental infection and intravenous bisphosphonate administration; in addition, the extent and duration of exposure to bisphosphonates also seem to correlate with the risk. Although a direct causal relationship with bisphosphonates cannot be assumed, these agents may possibly contribute to the development of ONJ by suppression of bone remodeling in the jaw which leads to increased rates of bone mineralisation and accumulation of microfractures. Clodronate, a non-aminobisphosphonate, appears to have a different mechanism of suppressing bone remodeling compared with aminobisphosphonates, and this may explain why few cases of ONJ have been reported with clodronate despite extensive use over the past 20 years; however, the potential of clodronate to reduce the risk of ONJ while providing equivalent clinical benefit to the aminobisphosphonates needs to be substantiated in controlled clinical trials. Use of bisphosphonate therapy should be carefully planned in patients with metastatic bone disease who have risk factors for ONJ, and appropriate preventive measures taken to avoid the development of this condition.

Background: It is still unclear whether addition of calcium/vitamin D supplements leads to an incremental benefit in patients taking bisphosphonates and whether achievement of serum level of 25 (OH) vitamin D of at least 70 nmol/L has an impact on the skeletal response to bisphosphonates. Moreover the maintenance of BMD after bisphosphonates withdrawal with the continuation of calcium/vitamin D supplements only, remains uncertain. The aims were to assess the impact of vitamin D status on changes in bone mineral density (BMD) in firstly patients with post-menopausal osteoporosis on bisphosphonates and secondly following discontinuation of bisphosphonates after long-term use., Methods: Two patient groups were recruited. The first study population comprised of 112 women treated with a bisphosphonate. The second study population consisted of 35 women who had been on bisphosphonates for > 5 years in whom the treatment agent was discontinued. Baseline BMD, changes in BMD following treatment, duration of treatment, serum 25 (OH) vitamin D, parathyroid hormone (PTH), urine C-terminal telopeptides of type 1 collagen (CTX) were obtained on the study participants., Results: In the first study group, subjects with serum vitamin D concentrations (> 70 nmol/L) had a significantly lower serum PTH level (mean [SEM] 41 2 ng/L). PTH concentrations of 41 ng/L or less was associated with a significantly higher increase in BMD at the hip following treatment with bisphosphonates compared to patients with PTH > 41 ng/L (2.5% [0.9] v/s -0.2% [0.9], P = 0.04). In the second study group, discontinuation of bisphosphonate for 15 months after long-term treatment did not result in significant bone loss at the lumbar spine and total hip, although a trend towards gradual decline in BMD at the femoral neck was observed., Conclusion: the data suggest that optimal serum 25 (OH) vitamin D concentration may lead to further reduction in bone loss at the hip in patients on bisphosphonates. A prospective controlled trial is needed to evaluate whether the response to bisphosphonates is influenced by vitamin D status. BMD is preserved at the lumbar spine and total hip following discontinuation of bisphosphonate for a short period following long-term treatment, although a gradual loss occurs at the femoral neck.

This article discusses methods for quantifying bone turnover based on tracer kinetic studies of the short-lived radiopharmaceuticals 99mTc-MDP and 18F-fluoride. Measurements of skeletal clearance obtained by using these tracers reflect the combined effects of skeletal blood flow and osteoblastic activity. The pharmacokinetics of each tracer is described, together with some of the quantitative tests of skeletal function that have been described in the literature. The physiologic interpretation of quantitative measurements of bone obtained with the use of short half-life radionuclides is discussed, and the advantages and limitations of 99mTc-MDP and 18F-fluoride are compared and contrasted. Currently, 18F-fluoride dynamic positron emission tomography (PET) is the technique of choice for physiologically precise quantitative studies of bone. However, comparable data could probably be obtained by using 99mTc-MDP if methods for single photon emission computed tomography (SPECT) quantitation were improved.

The effect of oral pamidronate on bone mineral density and its adverse effect profile was investigated by a double-masked placebo-controlled study of 122 patients aged 55-75 years with established vertebral osteoporosis. Patients on active therapy received disodium pamidronate 300 mg/day (group A) for 4 weeks every 16 weeks, 150 mg/day (group B) for 4 weeks every 8 weeks or placebo (group C). All patients additionally received 500 mg of calcium and 400 IU vitamin D daily. Dual-energy X-ray absorptiometry measurements of the spine, hip, forearm and total body were performed at baseline and 6-monthly for 2 years using a Hologic QDR 1000 device at two sites. Serum osteocalcin and urinary deoxypyridinoline were measured at the above visits and at 3 months. The percentage change (SEM) in spine bone mineral density (BMD) at 2 years based on intention-to-treat analysis was 4.64 (1.01) in group A, 6.10 (0.87) in group B and 1.13 (1.32) in group C. Analysis of variance showed significant increases in group A and B compared with placebo (p < 0.01). There were also significant rises in femoral neck BMD for group A (p = 0.005), trochanter BMD for groups A and B (p < 0.01) and total-body BMD for groups A and B (p < 0.001). There was a significant reduction in serum osteocalcin and urinary deoxypyridinoline for groups A and B (p < 0.01). There was an excess of gastrointestinal side-effects in the treated groups, particularly group A. We conclude that intermittent pamidronate therapy can prevent bone loss at both the lumbar spine and femoral neck in patients with established vertebral osteoporosis, although due to gastrointestinal side-effects the 300 mg dose in particular does not appear suitable for clinical usage.

Increased bone resorption following the menopause leads to accelerated bone loss and is a major contributory factor to subsequent osteoporosis. It is well recognised that an early menopause or prolonged amenorrhoea from whatever cause are also major risk factors for osteoporosis. The alterations in skeletal metabolism following oestrogen deficiency are inhibited by oestrogen replacement, and bone loss can be prevented. However, oestrogen therapy may often not be appropriate because of clinical contraindications, side effects or patient concerns regarding the risk of breast cancer. There is increasing evidence that bisphosphonates are effective in inhibiting bone resorption and these compounds are generally well tolerated. At the present time, for the prevention of bone loss related to hypo-oestrogenism, the main options for therapy are likely to be oestrogen replacement or treatment with bisphosphonates.

Pamidronate is one of several powerful bisphosphonates able to produce prolonged remissions of Paget's disease. This study examined to what extent bone scan changes parallel the clinical response and whether there is variability in the behavior of individual lesions. Twenty-five patients with pagetic bone pain for more than 2 yr were examined with bone scintigraphy before and on average 8 mo after six 30-mg infusions of pamidronate given weekly. Serum alkaline phosphatase and urinary hydroxyproline-to-creatinine ratios were measured before and 6 mo after treatment. A second course of pamidronate was given to 13 patients who had clinical or biochemical relapse. Of 136 pagetic lesions, 13 (10%) completely resolved, 90 (65%) improved and 33 (24%) remained unchanged. There was no significant difference in response between bony sites, although less active lesions were more likely to resolve completely. In conclusion pamidronate has a powerful effect on bone scan appearances in Paget's disease. Most lesions improve but complete resolution is uncommon. Less active lesions are more likely to resolve and are less likely to require further therapy.

Thirty patients with symptomatic Paget's disease of bone were treated with weekly infusions of 30 mg APD for 6 weeks and followed for up to 3 years (mean 2 years). Bone pain diminished or disappeared in 83%. Six months following treatment the serum alkaline phosphatase (sAP) had normalized in 53% and had fallen by an average of 68% in the remainder. The average fall in sAP was 65% at 6 months, 59% at 1 year and 51% at 2 years. Urine hydroxyproline/creatinine ratios (OHp/Cr) fell by an average of 72% over the 6 weeks of treatment whilst serum bone gla protein (BGP) showed no significant change. However, there was a significant fall in the mean BGP of 25% by 6 months following treatment. Radionuclide bone scan abnormalities improved in all patients and showed complete resolution in two. The same regimen was used to retreat eight patients with a persistence or recurrence of symptoms after 1 year. At 6 months following retreatment the sAP had fallen to normal in four and in the remainder by an average of 39%. Two patients had a third course after a further year and by 6 months the sAP had fallen by an average of 50%. Normalization of sAP occurred in 86% of patients with a pretreatment sAP less than 900 iu/l (normal less than 300) and 89% of patients with a sAP less than 600 iu/l immediately following the course of treatment. Therefore, knowledge of the pretreatment and post-treatment sAP should enable prediction of the need for further therapy in most cases. We confirm that APD is an effective and well tolerated treatment for the management of Paget's disease, giving long-term suppression.(ABSTRACT TRUNCATED AT 250 WORDS)

In two patients with metastatic disease more lesions were detected on scintigraphs obtained with the 'low uptake' bone-scanning agent dimethyl-amino-diphosphonate. The results in these two patients provide practical support for the suggestion that bone-scanning agents with low uptake in normal bone, but high tumour-to-normal bone ratios, will allow better delineation of focal bone abnormalities.

Bone scan imaging with the current bone-seeking radiopharmaceuticals, the technetium-99m labelled diphosphonates, provides a functional display of skeletal metabolism and has dramatically improved our ability to investigate skeletal pathology. While the role of bone scanning in metastatic disease was recognized early, and welcomed by oncologists and other specialists alike, in the field of metabolic bone disease the realization of its potential value has been slower, with perhaps more reluctant acceptance. Nevertheless, the skeleton remains an extremely difficult organ to investigate, and a familiarity with bone scanning should be an essential part of the investigational armamentarium for anyone with an interest in the metabolic bone disorders. The measurement of bone mineral by photon absorptiometry is a relatively new technique, which is rapidly gaining acceptance. The ability to accurately detect and quantify changes in bone mass is potentially of considerable value in the diagnosis and management of osteoporosis. The technique provides us with an extremely important and powerful research tool but, at the present time, its role in clinical practice has yet to be established.

The detection of focal pathology on a bone scan is dependent on the contrast between uptake in a lesion compared with the affinity of the scanning agent for the surrounding normal bone. Dimethyl-amino diphosphonate (DMAD) has a relatively low uptake in normal bone compared with methylene diphosphonate (MDP). We have compared the bone scan appearance with MDP and DMAD in 11 patients with multiple bone metastases from breast cancer. The median time between scans was 7 days (range 6 to 14). In two patients additional lesions were identified on the DMAD scan. No additional lesions were visible on the MDP scans. In five patients some lesions were visualized more clearly with DMAD and others with MDP. In six patients no differences were seen. Anatomical resolution was generally less clear with DMAD and precise anatomical localization was sometimes impossible. We have demonstrated superior lesion detection with DMAD. The clinical value of this for the detection of early relapse of disease in the skeleton requires further study.

The skeletal metabolism of patients with rheumatoid arthritis (RA) osteoarthritis (OA) and ankylosing spondylitis (AS) has been assessed by 24-h whole body retention of 99mTc diphosphonate (WBR). Values for RA and AS patients were significantly elevated but those of OA patients were not when compared to age and sex matched controls (27.0 +/- 8.6 vs 20.5 +/- 1.8%; 24.8 +/- 5.4 vs 19.4 +/- 1.5% greater than and 21.4 +/- 4.1 vs 21.2 +/- 1.4%, respectively). The WBR of patients taking steroids was greatly elevated and RA inpatients had higher values than outpatients, but the increased WBR could not be correlated with disease activity. The increased WBR in RA may represent an indirect effect possibly related to immobility.

Twenty normal volunteers had measurements of 24-hr whole-body retention (WBR) of three structurally related Tc-99m-labeled phosphonate skeletal imaging agents: (1-hydroxyethylidene) diphosphonate (HEDP), methylene diphosphonate (MDP), and hydroxymethylene diphosphonate (HMDP). The average WBR values, reflecting skeletal uptake, were 18.4, 30.3, and 36.6%, respectively. These results clearly illustrate that slight alterations in diphosphonate molecular structure have a significant effect upon specificity for osseous tissue, and thus may affect skeletal image quality and the usefulness of the WBR technique in diagnosing metabolic bone disease.

A new method for the sequential monitoring of skeletal uptake of 99mTc-diphosphonate over a 5-day period, utilising both a gamma camera and whole-body monitor, is presented. It has been found that diphosphonate continues to be removed from bone over this period. Normal subjects appear to lose skeletal activity initially at a more rapid rate than those with altered skeletal metabolism and it is suggested that differences in binding characteristics may exist.

The bone scan may be of value in the assessment of patients with metabolic bone disease. However the superiority of the bone scan when compared to radiology in conditions such as renal osteodystrophy, osteomalacia, primary hyperparathyroidism, and osteoporosis requires substantiation with the newer radiopharmaceuticals which have a higher affinity for bone. Two methods of quantitating skeletal uptake of tracer have been assessed to try to remove the subjective aspect of bone scan evaluation. Measurements of bone to soft tissue ratios have proved clinically disappointing, but 24 hour whole body retention of diphosphonate appears to provide a sensitive index of increased bone turnover.

The diphosphonates are currently the skeletal imaging agents of choice and while extremely sensitive for bony abnormality their mechanism of action remains poorly understood. The current concepts in bone uptake mechanisms are reviewed and it is concluded that diphosphonate uptake is most likely related to sites of newly forming bone with diphosphonate adsorbed onto the surface of hydroxyapatite crystals. In situations where there is markedly increased skeletal uptake of tracer, increased vascularity alone cannot account for changes in tracer uptake and changes in skeletal extraction, related to newly forming bone are more important.

24-h whole-body retention (WBR) of diphosphonate (a sensitive indicator of skeletal metabolism) was measured in 37 oophorectomised women. 14 women had been prescribed oestrogen supplements and 3 of these had defaulted from therapy. For the study group there was a significant correlation between WBR and both the rate of bone loss as measured by photonabsorptiometry (r = 0.7, p ¿ 0.001) and urinary hydroxyproline (r = 0.53, p < 0.001). The oestrogen-treated group had significantly lower values for WBR and rate of bone loss than the untreated group (p < 0.01, p < 0.01 respectively) indicating suppressed skeletal metabolism. However, the highest values were found in those who had defaulted from oestrogen therapy suggesting a rebound period of accelerated skeletal metabolism and bone loss. There was a significant negative correlation between WBR and oestrogen dosage (r = 0.75, p < 0.02) suggesting that it may be possible to adjust the dosage for optimal skeletal metabolic activity. WBR of diphosphonate provides a simple and sensitive measure of skeletal metabolism which correlates well with conventional measurements of bone loss. WBR may be useful in the screening and identification of women who have increased bone turnover just after the menopause and who may subsequently be at risk of osteoporosis developing.

The bone scan is generally recognized to be an extremely powerful investigational tool in the evaluation of patients with skeletal disease. Currently 99mTc-methylene diphosphonate is the most widely used bone scanning agent, but recently several new diphosphonate compounds have been introduced which appear to have relatively higher skeletal affinity, leading to greater absolute uptake of tracer by bone. While the resulting improved contrast between bone and background soft-tissue may provide more pleasing scan images, it is not clear that increased bone uptake of tracer is equally desirable for identification of disease. Nevertheless, to date, no significant difference in lesion detection has been found in any comparative study of diphosphonate compounds. In this review the clinical studies evaluating diphosphonate bone scanning agents are summarized and the properties required of an ideal bone scanning agent in both benign and malignant disease discussed.

Twenty-four-hour measurements of whole-body retention (WBR) of Tc-99m diphosphonate (a sensitive measure of skeletal metabolism) have been obtained in 250 healthy volunteer subjects. WBR values were found to fall from the age of 20 yr until 35 yr and then in men to rise linearly thereafter. Women showed a similar pattern initially but there was a marked rise in WBR corresponding to the menopausal years. Our results lend support to the belief that skeletal metabolism increases with age. It is suggested that some imbalance must always exist between resorption and formation in bone, with net loss of bone mineral, and increasing levels of skeletal metabolism will exaggerate this imbalance and accelerate the rate of bone loss.

The limited role of bone scanning in the diagnosis of metabolic bone disease might be considerably improved by accurate quantification of skeletal uptake of the radiopharmaceutical. Using a standard shadow-shield whole-body monitor, we have measured whole-body retention (WBR) of Tc-99m HEDP up to 24 hr in 11 patients with renal osteodystrophy (mean WBR 88.6% at 24 hr); in ten patients with Paget's disease (mean 56.9%); in seven patients with osteomalacia (mean 40.7%); in five patients with primary hyperparathyroidism (mean 50.7%); in four patients with osteoporosis (mean 21.2%); and in 12 normals (mean 19.2%). The osteoporotic group could not be differentiated from the normal group, but the other groups were significantly different from the normal group at 24 hr (p less than 0.002), and each individual rest for the 24-hr WBR of Tc-99m HEDP in these groups lay outside our normal range. This test may, therefore, provide a sensitive means of detecting conditions with increased bone turnover. We obtained measurements of plasma activity of Tc-99m HEDP in these patients up to 24 hr, and 4-hr bone to soft-tissue ratios from bonescan images, but little additional information resulted.

Summary: The aim of this study was to examine the effects of bisphosphonate discontinuation on bone metabolism at the spine and hip measured using F-fluoride PET. Bone metabolism at the spine remained stable following discontinuation of alendronate and risedronate at 1 year but increased in the hip in the alendronate group only. Introduction: Bisphosphonates such as alendronate (ALN) or risedronate (RIS) have persistent effects on spine BMD following discontinuation. Methods: Positron emission tomography (PET) was used to examine regional bone metabolism in 20 postmenopausal women treated with ALN ( n = 11) or RIS ( n = 9) for a minimum of 3 years at screening (range 3-9 years, mean 5 years for both groups). Subjects underwent a dynamic scan of the lumbar spine and a static scan of both hips at baseline and 6 and 12 months following treatment discontinuation. F-fluoride plasma clearance (K) at the spine was calculated using a three-compartment model. Standardised uptake values (SUV) were calculated for the spine, total hip, femoral neck and femoral shaft. Measurements of BMD and biochemical markers of bone turnover were also performed. Results: With the exception of a significant decrease in spine BMD in the ALN group, BMD remained stable. Bone turnover markers increased significantly from baseline by 12 months for both study groups. Measurements of K and SUV at the spine and femoral neck did not change significantly in either group. SUV at the femoral shaft and total hip increased significantly but in the ALN group only, increasing by 33.8% ( p = 0.028) and 24.0% ( p = 0.013), respectively. Conclusions: Bone metabolism at the spine remained suppressed following treatment discontinuation. A significant increase in SUV at the femoral shaft and total hip after 12 months was observed but for the ALN group only. This study was small, and further clinical studies are required to fully evaluate the persistence of BP treatment. [ABSTRACT FROM AUTHOR]

Genetic factors are important in the pathogenesis of osteoporosis but less is known about their possible role in predicting response to anti-osteoporotic therapy. Previous studies have shown that a polymorphic Sp1 binding site in the collagen type 1 alpha 1 gene (COLIA1) is associated with bone mineral density (BMD) and osteoporotic vertebral fracture. In this study we sought to determine if the COLIA1 Sp1 polymorphism might also act as a predictor of the response to treatment of osteoporosis with bisphosphonate therapy. The study group comprised 108 perimenopausal women with osteopenia who had been randomized to receive cyclical etidronate therapy for 2 years with a 1-year treatment-free follow-up as part of a randomized placebo controlled trial. Bone mineral density was measured at the lumbar spine and femoral neck by dual X-ray absorptiometry and genotyping performed on DNA extracted from peripheral blood leukocytes using standard techniques. The distribution of COLIA1 genotypes was similar to that previously reported in Caucasians with 69 (63.9%) "SS" homozygotes, 38 (35.2%) "Ss" heterozygotes, and 1 (0.9%) "ss" homozygote. There was no association between COLIA1 genotype and response of lumbar spine BMD during etidronate treatment or the follow-up phase. The response of femoral neck (FN) BMD, however, differed significantly between the genotype groups throughout the study period, such that FN BMD increased by 0.56%, 2.36%, 1.82%, and 1.32 % after 1, 2, 2.5, and 3 years, respectively in the "SS" genotype group, compared with ?1.56%, ?0.62%, ?0.37%, and ?0.66% in the "Ss/ss" genotype groups (P = 0.002). The data presented here show that site-specific heterogeneity exists in the response of BMD to cyclical etidronate therapy, which is related to COLIA1 genotype. Our data raise the possibility that COLIA1 genotyping could be used to target etidronate therapy to those most likely to respond in terms of FN BMD, with potential benefits in terms of economic cost and clinical outcome. [ABSTRACT FROM AUTHOR]

There is lack of consensus on whether quantitative ultrasound (QUS) measurements can be used to monitor response to therapy. The aim of this 2-year longitudinal study was to assess whether calcaneal QUS measurement variables respond to antiresorptive therapy and whether these measurements display adequate long-term precision to be useful for monitoring purposes. The study population consisted of 195 postmenopausal women divided into three groups: Group 1: 39 women treated with antiresorptive therapy who commenced treatment at baseline; Group 2: 25 women treated with antiresorptive therapy who had been on treatment for at least 2 years at baseline; Group 3: 131 women who did not taken estrogen, bisphosphonates, or calcium during the 2-year study period. Subjects had baseline and 12 and 24 months follow-up BMD measurements at the lumbar spine (LS), femoral neck (FN), and total hip (THIP) and calcaneal QUS measurements of broadband ultrasound attenuation (BUA) and speed of sound (SOS). BUA and SOS were combined to provide an estimate of heel BMD (Est heel BMD). For women in Group 1, all BMD and QUS measurement variables increased significantly from baseline after 2 years of treatment. For women in Group 2, only THIP BMD and BUA increased significantly after 2 years and the changes were less than those observed in Group 1 women. The overall treatment effect for each measurement variable, defined as the difference in the mean absolute changes between Groups 1 and 3 after 2 years, was 0.08, 0.03, and 0.04 g/cm2 for LS, FN, and THIP BMD, and for BUA, SOS, and Est heel BMD it was 5.8 dB/MHz, 13.1 m/sec, and 0.05 g/cm2, respectively. When the overall treatment effect was expressed in T-score units, the effect was greatest for LS BMD (0.65 T-score units) and lowest for FN BMD (0.31 T-score units). QUS measurement variables yielded intermediate values of 0.43 - 0.52 T-score units. The average least significant change (LSC) was 0.38 T-score units for BMD measurements, whereas the LSC for QUS measurements was three times greater at approximately 1.20 T-score units. Ninety-four percent of the women in Group 1 showed changes in LS BMD that exceeded the LSC after two years, while the percentage was lower for the other measurement variables ranging from approximately 6% for FN BMD, SOS and Est heel BMD to 50 % for THIP BMD. A lower percentage of women in Groups 2 and 3 displayed changes that exceeded the LSC for both BMD and QUS measurement variables. Changes in all QUS variables were significantly correlated with changes in LS BMD, with correlation coefficients ranging from 0.26 to 0.40. In conclusion, calcaneal QUS measurement variables were found to show a highly significant response to antiresorptive therapy. However, the precision of QUS measurements was not good enough to allow QUS to be used for monitoring response to treatment. Future improvements in the precision of calcaneal QUS measurements are required to increase the utility of QUS for monitoring purposes. [ABSTRACT FROM AUTHOR]