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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.)

The functional imaging technique of dynamic fluorine-18 labeled sodium fluoride positron emission tomography ((18)F-NaF PET) allows the quantitative assessment of regional bone formation by measuring the plasma clearance of fluoride to bone at any site in the skeleton. (18)F-NaF PET provides a novel and noninvasive method of studying site-specific bone formation at the hip and spine, as well as areas of pure cortical or trabecular bone. The technique complements conventional measurements of bone turnover using biochemical markers and bone biopsy as a tool to investigate new treatments for osteoporosis, and holds promise of a future role as an early biomarker of treatment efficacy in clinical trials. This article reviews methods of acquiring and analyzing (18)F-NaF PET scan data, and outlines a simplified approach that uses 5-minute static PET scan images combined with venous blood samples to estimate (18)F-NaF plasma clearance at multiple sites in the skeleton with a single injection of tracer.

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.

The precision errors of dual-energy X-ray absorptiometry (DXA) measurements are important for monitoring osteoporosis. This study investigated the effect of body mass index (BMI) on precision errors for lumbar spine (LS), femoral neck (NOF), total hip (TH), and total body (TB) bone mineral density using the GE Lunar Prodigy. One hundred two women with BMIs ranging from 18.5 to 45.9 kg/m(2) were recruited. Participants had duplicate DXA scans of the LS, left hip, and TB with repositioning between scans. Participants were divided into 3 groups based on their BMI and the percentage coefficient of variation (%CV) calculated for each group. The %CVs for the normal (<25 kg/m(2)) (n=48), overweight (25-30 kg/m(2)) (n=26), and obese (>30 kg/m(2)) (n=28) BMI groups, respectively, were LS BMD: 0.99%, 1.30%, and 1.68%; NOF BMD: 1.32%, 1.37%, and 2.00%; TH BMD: 0.85%, 0.88%, and 1.06%; TB BMD: 0.66%, 0.73%, and 0.91%. Statistically significant differences in precision error between the normal and obese groups were found for LS (p=0.0006), NOF (p=0.005), and TB BMD (p=0.025). These results suggest that serial measurements in obese subjects should be treated with caution because the least significant change may be larger than anticipated., (Copyright © 2012 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Purpose: Visual changes on radionuclide bone scans have been reported with teriparatide treatment. To assess this, serial studies were evaluated and quantified in ten postmenopausal women with osteoporosis treated with teriparatide (20 μg/day subcutaneous) who had (99m)Tc-methylene diphosphonate (MDP) bone scans (baseline, 3 and 18 months, then after 6 months off therapy)., Methods: Women were injected with 600 MBq (99m)Tc-MDP, and diagnostic bone scan images were assessed at 3.5 h. Additional whole-body scans (10 min, 1, 2, 3 and 4 h) were analysed for (99m)Tc-MDP skeletal plasma clearance (K(bone)). Regional K(bone) differences were obtained for the whole skeleton and six regions (calvarium, mandible, spine, pelvis, upper and lower extremities). Bone turnover markers (BTM) were also measured., Results: Most subjects showed visual changes on 3- and 18-month bone scan images that disappeared after 6 months off therapy. Enhanced uptake was seen predominantly in the calvarium and lower extremities. Whole skeleton K(bone) displayed a median increase of 22% (3 months, p = 0.004) and 34% (18 months, p = 0.002) decreasing to 0.7% (6 months off therapy). Calvarium K(bone) changes were three times larger than other sites. After 6 months off therapy, all K(bone) and BTM values returned towards baseline., Conclusion: The increased (99m)Tc-MDP skeletal uptake with teriparatide indicated increased bone formation which was supported by BTM increases. After 6 months off therapy, metabolic activity diminished towards baseline. The modulation of (99m)Tc-MDP skeletal uptake during treatment was the result of teriparatide's metabolic activity. These findings may aid the radiological evaluation of similar teriparatide patients having radionuclide bone scans.

Studies of bone remodeling using bone biopsy and biochemical markers of bone turnover play an important role in research studies to investigate the effect of new osteoporosis treatments on bone quality. Quantitative radionuclide imaging using either positron emission tomography with fluorine-18 sodium fluoride or gamma camera studies with technetium-99m methylene diphosphonate provides a novel tool for studying bone metabolism that complements conventional methods, such as bone turnover markers (BTMs). Unlike BTMs, which measure the integrated response to treatment across the whole skeleton, radionuclide imaging can distinguish the changes occurring at sites of particular clinical interest, such as the spine or proximal femur. Radionuclide imaging can be used to measure either bone uptake or (if done in conjunction with blood sampling) bone plasma clearance. Although the latter is more complicated to perform, unlike bone uptake, it provides a measurement that is specific to the bone metabolic activity at the measurement site. Treatment with risedronate was found to cause a decrease in bone plasma clearance, whereas treatment with the bone anabolic agent teriparatide caused an increase. Studies of teriparatide are of particular interest because the treatment has different effects at different sites in the skeleton, with a substantially greater response in the flat bone of the skull and cortical bone in the femur compared with the lumbar spine. Future studies should include investigations of osteonecrosis of the jaw and atypical fractures of the femur to examine the associated regional changes in bone metabolism and to throw light on the underlying pathologies., (Copyright © 2011 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Unlabelled: In the United Kingdom (UK), T- and Z-scores are usually calculated using reference ranges derived from United States (US) populations. In the UK arm of a recent randomised trial (International Breast Cancer Intervention Study II (IBIS-II)), substantially, fewer women than expected were recruited into the osteopenic (-2.545 years with a typical body mass index of 28 kg m(-2) have spine and hip bone mineral density (BMD) 0.6 standard deviation higher than their US counterparts., Introduction: Dual energy X-ray absorptiometry (DXA) is widely used for the diagnosis of osteoporosis and to investigate the effect of pharmacological treatments on BMD. In both routine and research settings, it is important that DXA results are correctly interpreted., Methods: T- and Z-scores for the first 650 UK Caucasian women enrolled in the IBIS-II study were compared with data from two independent studies of unrelated, unselected UK Caucasian women: (1) 2,382 women aged 18 to 79 recruited to the Twins UK Adult Twin Registry; (2) 431 women aged 21 to 84 with no risk factors for osteoporosis recruited at Guy's Hospital. All DXA measurements were performed on Hologic densitometers. Subjects were divided into six age bands, and T- and Z-scores were calculated using the manufacturer's US reference range for the spine and the National Health and Nutrition Examination Survey III reference range for the femoral neck and total hip., Results: The overall mean Z-scores for the IBIS-II, Twin, and Guy's groups were: spine: +0.61, +0.29, +0.33; femoral neck: +0.42, +0.36, +0.45; total hip: +0.65, +0.38, +0.39 (all p<0.001 compared with the expected value of 0). The mean body weight of subjects in the three studies was 74.4, 65.5, and 65.4 kg, respectively. Analysis revealed a highly significant relationship between Z-score and weight at each BMD site with a slope of 0.03 kg(-1)., Conclusions: In general, US spine and hip reference ranges are not suitable for the calculation of Z-scores in UK women. For some research study designs, the differences may significantly influence the pattern of subject recruitment.

Dual energy X-ray absorptiometry (DXA) measurements of hip and spine bone mineral density (BMD) have an important role in the evaluation of individuals at risk of osteoporosis, and in helping clinicians advise patients about the appropriate use of anti-fracture treatment. Compared with alternative bone densitometry techniques, hip and spine DXA examinations have a number of advantages that include a consensus that BMD results can be interpreted using the World Health Organisation (WHO) T-score definition of osteoporosis, a proven ability to predict fracture risk, proven effectiveness at targeting anti-fracture therapies, and the ability to monitor response to treatment. This review discusses the evidence for these and other clinical aspects of DXA scanning, including its role in the new WHO algorithm for treating patients on the basis of their individual fracture risk.

Measurement of skin thickness has been proposed as a method of predicting low bone mineral density (BMD) and the consequent risk of osteoporotic fracture in postmenopausal women. The Episcan I-100 device is a new type of ultrasound device that uses high-frequency (20 MHz) ultrasound to measure skin thickness using a small probe placed on the skin. The aims of this study were to investigate whether there is any correlation between skin thickness as measured by ultrasound and BMD as measured by dual-energy X-ray absorptiometry, to establish whether patients with osteoporotic fractures have reduced skin thickness, and to investigate the relationship between skin thickness and clinical risk factors for osteoporosis. Short-term precision based on duplicate measurements on 132 patients gave a coefficient of variation of 3.2%. Small but statistically significant correlations between skin thickness measurements and BMD measurements at axial and peripheral sites were observed (r = 0.21-0.29, P < 0.0001). An odds ratio of 1.42 was found for identifying patients with a prevalent fracture at any skeletal site, suggesting that skin thickness measurements can discriminate patients with fractures. ROC analyses also demonstrated the ability of skin thickness measurements to discriminate fracture patients from controls. When measured by the decrease in Z-score, clinical risk factors for low BMD were found to affect skin thickness measurements to a similar extent as spine and hip BMD measurements. Skin thickness measurements have limited utility in identifying patients with low bone mass.

Dual energy x ray absorptiometry (DXA) scans to measure bone mineral density (BMD) at the spine and hip have an important role in the evaluation of individuals at risk of osteoporosis, and in helping clinicians advise patients about the appropriate use of antifracture treatment. Compared with alternative bone densitometry techniques, hip and spine DXA examinations have a number of advantages that include a consensus that BMD results can be interpreted using the World Health Organization T-score definition of osteoporosis, a proven ability to predict fracture risk, proven effectiveness at targeting antifracture therapies, and the ability to monitor response to treatment. This review discusses the evidence for these and other clinical aspects of DXA scanning, including its role in the new WHO algorithm for treating patients on the basis of their individual fracture risk.

Strontium ranelate (SR) is a new oral treatment for osteoporosis associated with large increases in bone mineral density (BMD) compared with alternative therapies such as bisphosphonates. Much of the BMD increase during SR treatment is a physical effect caused by the increased attenuation of X-rays due to the accumulation of strontium in bone tissue. The aim of this study was to assess the contribution made by bone strontium content (BSC) to the overall BMD increase by evaluating the percentage F of the BMD change explained by the physical presence of strontium in bone. A value of F less than 100% would provide evidence of the anabolic effect of SR as an additional factor contributing to the overall BMD increase. Studies of mixtures of strontium hydroxyapatite (SrHA) and calcium hydroxyapatite (CaHA) scanned on a variety of dual-energy X-ray absorptiometry (DXA) systems show that a 1% molar ratio of SrHA/(CaHA+SrHA) causes a 10% overestimation of BMD. The correction of spine BMD measurements for the physical effects of strontium depends on knowledge of 2 further factors: (1) bone biopsy measurements of iliac crest BSC and (2) the ratio R of BSC at the DXA site to BSC at the iliac crest measured in animal studies. We used clinical trial data and values of R(spine) measured in studies of monkeys and beagle dogs to determine values of F(spine) for 1, 2, and 3 yr treatment with SR. Based on the average value of R(spine) approximately 0.7 for male and female monkeys, we found values for F(spine) approximately 75-80% for 1, 2, and 3 yr of treatment. Using the value of R(spine) approximately 1.0 from the beagle study gave values of F(spine) approximately 100%. Although values of F(spine) as low as 40% are possible, we conclude that the most likely figure is 75% or greater. However, it is apparent that there are large uncertainties in the correction of BMD results for the effect of bone strontium and that the most important of these is the inference of BSC values at DXA scan sites from measurements of iliac crest bone biopsy specimens.

Dual energy X-ray absorptiometry (DXA) measurements of spine and hip bone mineral density (BMD) (referred to here as central DXA) have an important role as a clinical tool for the evaluation of individuals at risk of osteoporosis, and in helping clinicians give advice to patients about the appropriate use of antifracture treatment. Compared with alternative bone densitometry techniques such quantitative computed tomography (QCT), peripheral DXA (pDXA) and quantitative ultrasound (QUS), central DXA has a number of significant advantages that include a consensus that BMD results can be interpreted using the World Health Organization (WHO) T-score definition of osteoporosis, a proven ability to predict fracture risk, and proven effectiveness at targeting antifracture treatments. This review article discusses the evidence for these and other advantages of central DXA, including its role in the new WHO algorithm for treating patients on the basis of individual fracture risk.

Osteoporosis is a metabolic bone disorder, leading to bone fragility and fracture. Recent guidance from the National Institute for Clinical Excellence (NICE) emphasizes the importance of secondary prevention of fragility fractures in postmenopausal women. What impact can the expanding range of treatments make on the growing and costly burden of osteoporosis?

Unlabelled: Regional bone metabolism measured using 18F-fluoride PET was assessed in 72 postmenopausal women classified as normal, osteopenic, or osteoporotic. Lower values of regional bone formation activity at the lumbar spine were seen in osteoporotic women, whereas global markers of bone formation were significantly increased., Introduction: Evaluations of global bone remodeling have revealed that increased bone turnover is a feature of patients with osteoporosis. The noninvasive functional imaging technique of 18F-fluoride positron emission tomography (PET) allows the direct quantitative assessment of bone metabolism at specific sites in the skeleton, including the clinically important site of the lumbar spine., Materials and Methods: The aim of this study was to compare regional skeletal kinetics in 72 postmenopausal women (mean age, 61 years) classified as normal, osteopenic, or osteoporotic according to their BMD T score at the lumbar spine. Each woman had a dynamic PET scan of the lumbar spine after injection of 90 MBq 18F-fluoride ion and measurements of biochemical markers of bone formation and resorption. The arterial plasma input function was derived using aorta arterial activity from the PET image. Time-activity curves were obtained by placing regions of interest over the lumbar vertebrae. A three-compartmental model was used to calculate bone blood flow (K1) and the net plasma clearance of tracer to bone mineral (Ki), reflecting regional osteoblastic activity (ml/minutes/ml). Rate constants k2, k3, and k4, which describe transport between plasma, the extracellular fluid (ECF) compartment, and the bone mineral compartment, were also measured., Results: The net uptake of fluoride to the bone mineral compartment (Ki) was significantly lower in the osteoporotic group compared with both the osteopenic and normal groups, with a mean difference of 0.005 ml/minutes/ml (16.7%). The fraction of the tracer in the extravascular tissue space that underwent specific binding to bone mineral (k3/k2 + k3) was also significantly reduced in the women classified as osteoporotic. In contrast, levels of bone-specific alkaline phosphatase (BSALP) were significantly higher in the osteoporotic group compared with the normal and osteopenic groups by 35% and 27%, respectively. A significant negative correlation (r = -0.41) was observed between levels of BSALP and the fraction of the tracer that underwent specific binding to bone mineral., Conclusion: Lower values of Ki, a measurement of regional bone formation activity, were seen in women classified as osteoporotic, whereas levels of BSALP, a measure of global bone formation, were significantly increased. These findings are suggestive of increased global skeletal bone turnover in women with postmenopausal osteoporosis but with relatively reduced regional bone formation at the predominantly trabecular site of the lumbar spine.

Periprosthetic bone loss is a major cause of concern in patients undergoing total hip arthroplasty (THA). Further studies are required to identify the factors determining the pattern of bone remodelling following THA and obtain improvements in the design and durability of prostheses. In this study, we monitored periprosthetic bone loss around two different types of hydroxyapatite coated femoral implant over a 3-year period to evaluate their design and investigate the relationship with the preoperative bone mineral density (BMD) at the spine, hip and forearm. Sixty patients (35 F, 25 M, mean age 63 years, range 46-75 years) undergoing THA were randomised to either the Anatomic Benoist Girard (ABG) or Mallory-Head (MH) femoral stem. Preoperative dual-energy X-ray absorptiometry (DXA) scans were acquired of the posteroanterior (PA) and lateral lumbar spine, the contralateral hip and the non-dominant forearm. Postoperative DXA scans were performed to measure periprosthetic BMD at 10 days (treated as baseline), 6 weeks, and 3, 6, 12, 24 and 36 months after THA using a standard Gruen zone analysis. Results were expressed as the percentage change from baseline and the data examined for the differences in bone loss between the different Gruen zones, between the ABG and MH stems, and the relationship with preoperative BMD. A total of 50 patients (24 ABG, 26 MH) completed the study. Three months after THA there was a statistically significant BMD decrease in every Gruen zone that varied between 5.6% and 13.8% for the ABG prosthesis and between 3.8% and 8.7% for the MH prosthesis. Subsequently, in most zones BMD reached a plateau or showed a small recovery. However, BMD continued to fall in Gruen zones 1 and 7 in ABG patients and Gruen zone 1 in MH patients. Bone loss was less in every Gruen zone in MH patients compared with ABG with the largest difference (10%, P=0.018) in Gruen zone 7. Highly significant relationships were found between periprosthetic bone loss and preoperative BMD measured at the PA spine ( P<0.001), total hip ( P=0.004) and total distal radius ( P<0.001). This study showed differences between two different designs of hydroxyapatite-coated implant that confirmed that prosthesis design influences periprosthetic bone loss. The study also showed that patients' bone density measured at the spine, hip or forearm at the time of operation was a major factor influencing bone loss around the femoral stem.

The recent growth in the clinical use of bone densitometry began with the introduction of the first dual X-ray absorptiometry (DXA) scanning systems in the late 1980s. Today, scans to measure bone mineral density are seen as having an essential role in the evaluation of patients at risk of osteoporosis.

Purpose of Review: Scans to measure bone mineral density at the spine and hip have an important role in the evaluation of patients at risk of osteoporosis. Oral corticosteroid use is an important risk factor for a fragility fracture and the relative risk is particularly high for vertebral and hip fractures. In Europe and the USA, guidelines have been published for the investigation of patients at risk of corticosteroid-induced osteoporosis, with recommendations on the diagnostic use of bone mineral density scans and the initiation of treatment based on the findings., Recent Findings: Large trials of bisphosphonates, selective oestrogen receptor modulators and parathyroid hormone have addressed the issue of fracture prevention in women with postmenopausal osteoporosis and there is a growing consensus that the World Health Organization definition of osteoporosis of a -score=-2.5 is an appropriate threshold for preventive treatment in these patients. For most agents separate studies have been conducted of their use for the prevention and treatment of corticosteroid-induced osteoporosis., Summary: There is increased awareness of the importance of preventive treatment for osteoporosis in patients taking high doses of oral corticosteroids (daily dose of 7.5 mg prednisolone or greater). In view of evidence that corticosteroid use is an independent risk factor for fracture over and above bone mineral density, guidelines for intervention set a higher threshold than the World Health Organization figure ( -score=-1.5 rather than -2.5) for intervention with bone sparing treatment in these patients.

Reductions in circulating estradiol concentrations could be implicated in the pathogenesis of steroid-induced osteoporosis (SIOP) in men. We assessed serum estradiol and adrenal androgens (dehydroepiandrosterone sulfate [DHEAS] and androstenedione) in 77 men (group A: idiopathic osteoporosis [IOP], n = 38, aged [mean +/- SD] 57.7 +/- 12.1 years; group B: SIOP, n = 39, aged 55.3 +/- 13.1 years). We also studied the relationship between bone mineral density (BMD) and serum estradiol in the group of men with SIOP. In group B, we observed a higher prevalence of low serum testosterone concentrations (<9.0 nmol/L) (P =.0052), which was significantly correlated with steroid dosage (r = -0.42, P =.0089) and estradiol concentrations (r = 0.42, P =.012). There was a significant positive association between BMD at the lumbar spine and serum estradiol (P =.004) in the men with SIOP (group B). A high proportion of subjects had low serum estradiol concentrations (<48 pmol/L) in both groups (group A: 44.7 %, group B: 36 %). Serum adrenal androgens concentrations were also significantly suppressed in group B (serum androstenedione-group A: 4.99 +/- 1.8; Group B: 2.1 +/- 1.6 nmol/L; P =.0001). Serum DHEAS was undetectable in 59% of patients in group B versus 6% in group A (P =.001). Reductions in androstenedione also correlated with steroid dosage (r = -0.35, P =.01). In conclusion, the data show that adrenal androgens synthesis is markedly suppressed in men with SIOP. The clinical relevance of this finding remains to be determined. This study also shows a positive association between serum estradiol and BMD and a high prevalence of low serum estradiol in men with SIOP. Low serum estradiol may contribute to bone loss in men with SIOP., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Bone density scans using the technique of dual energy X-ray absorptiometry (DXA) are widely seen as having an essential role in the evaluation of patients at risk of osteoporosis. DXA scans of the spine and hip are the most useful because fractures at these sites result in the greatest impairment of quality of life. A hip DXA scan is the most reliable way of evaluating hip fracture risk, and the spine is the most sensitive site for monitoring response to treatment. Fundamental to the clinical role of DXA scanning are the findings of epidemiological studies that relate fracture risk to bone mineral density. The results of spine and hip DXA scans are interpreted using the World Health Organisation (WHO) definition of osteoporosis as a T-score less than -2.5. DXA scans are also used in longitudinal studies, both for research studies and for follow-up scans of individual patients. Although the former have an important role in the development of new treatments for osteoporosis, the latter are more controversial and are likely to be less important in the future. There is also interest in the use of smaller, less expensive DXA systems for scanning sites in the peripheral skeleton. However, in general, the results from these devices cannot be interpreted using the WHO definition of osteoporosis, and until there is a consensus over establishing an equivalent threshold, their use is premature.

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.

During the past ten years the range of treatments available for patients with osteoporosis has increased greatly. A decade ago the only proven therapy was oestrogen, while today the choice includes bisphosphonates, selective oestrogen receptor modulators, calcitonin, calcium and vitamin D supplementation and, in the near future, parathyroid hormone. Clinical trials involving bone mineral density (BMD) scans of the spine and femur have had an important role in the evaluation of these new therapies. Supplementary information about treatments has been provided by BMD scans of the total body and distal radius as well as by measurements of biochemical markers of bone turnover in serum and urine. Most important of all, the efficacy of treatments has been verified in large trials powered to show reductions in fracture risk. In routine clinical use, BMD scanning has an important role in identifying individual patients with osteoporosis and helping to make decisions about their treatment. However, in contrast to the use of BMD scans in clinical trials, their value for monitoring response to therapy in individual patients is less certain because in many cases the increases in BMD are too small to reliably distinguish between true changes and measurement error. However, experience with well established therapies such as oestrogen and bisphosphonates suggests that these treatments have a beneficial effect on bone in the large majority of patients and individual monitoring of BMD is probably not necessary.

We evaluated the role of bone scintigraphy in 60 osteoporotic patients with back pain. Thirty-four had scintigraphic evidence of vertebral fracture and were found to have a significantly lower bone density compared to those without fractures (p = 0.01). In only 14 patients was vertebral fracture considered to be the sole cause of pain with 38 having alternative abnormalities, the most common of which was facet joint disease (n = 30). Results of bone scintigraphy influenced a direct change in management in 18 patients and were able to exclude vertebral fracture as a cause of symptoms in 30. In symptomatic osteoporotic patients the bone scan may be helpful in elucidating the etiology of back pain and can impact on patient management.

The burden of non-vertebral fractures is enormous. Hip fractures account for nearly 10% of all fractures (and a much greater proportion in the elderly), while wrist fractures may account for up to 23% of all limb fractures. The best available predictors of non-vertebral fracture risk are low BMD and a tendency to fall. Hip, forearm, proximal humerus and rib fractures have all been associated with low BMD, though ankle fracture is not strongly related to osteoporosis. Although clinical risk factors identify only about one-third of postmenopausal women at increased risk of osteoporotic fracture, the occurrence of one fracture commonly predicts a second fracture. Guidelines are presented for identifying and treating patients at risk of non-vertebral osteoporotic fractures, especially those with a previous fracture, based on the algorithm recently published by the Royal College of Physicians and the Bone and Tooth Society. Prevention of falls and use of external hip protectors may reduce the occurrence of hip fracture. Treatment options for patients presenting with hip fracture include HRT, bisphosphonates, and calcium plus vitamin D, and for Colles' fracture include general measures, HRT, bisphosphonates, or calcitonin plus calcium.

Over the past decade, bone density scans have assumed an essential role in the diagnosis of osteoporosis. Although dual X-ray absorptiometry (DXA) scans of the central skeleton remain widely used, a variety of different types of equipment for measuring peripheral sites is now available. However, the poor correlation between different types of measurement and a lack of consensus on how results from peripheral sites should be interpreted have proved a barrier to the more widespread use of these devices. These issues prompt the following questions: Which technique best identifies patients at risk of fracture? What approaches to scan interpretation ensure the closest agreement among different methods? Does it matter if different patients are selected for treatment on the basis of different techniques? The relative risk (RR)of fracture derived from prospective studies is a key parameter for comparing the clinical value of different techniques. Recent reports confirm the advantages of hip bone mineral density compared with peripheral measurements for predicting hip fracture risk, although for fractures at other sites the differences are inconclusive. Using receiver operating characteristic curves, we show that the guidelines adopted for scan interpretation are of crucial importance for ensuring that the information provided is used effectively. The closest agreement among different techniques is achieved by setting thresholds for peripheral devices that target either the same percentage of the population or the same percentage of future fracture cases as femur DXA. Different methods select different groups of individuals from the total pool of patients who will later sustain a fracture, with the most successful technique being the one with the largest RR value. The emphasis placed by many studies on validating new techniques by studying their correlation with DXA may lead to the clinical value of peripheral devices being underestimated when the key datum is the RR value inferred from prospective fracture studies.

Because resources do not allow all women to be screened for osteoporosis, clinical risk factors are often used to identify those individuals at increased risk of fracture who are then assessed by bone densitometry. The aim of this study was to compare calcaneal quantitative ultrasound (QUS) and axial bone mineral density (BMD) T and Z scores in a large group of women, some with no clinical risk factors and others with one or more risk factors for osteoporosis. The study population consisted of 1115 pre- and postmenopausal women. A subgroup of 530 women was used to construct reference data for calculating T and Z scores. A total of 786 women was found to have one or more of the following risk factors: (i) atraumatic fracture since the age of 25 years, (ii) report of X-ray osteopenia, (iii) predisposing medical condition or use of therapy known to affect bone metabolism, (iv) premature menopause before the age of 45 years or a history of amenorrhea of longer than 6 months duration, (v) family history of osteoporosis, (vi) body mass index (BMI) <20 kg/m2, and (vii) current smoking habit. Calcaneal broadband ultrasound attenuation (BUA) and speed of sound (SOS) measurements were performed on a Hologic Sahara and a DTUone and BMD was measured at the spine and hip using dual-energy X-ray absorptiometry (DXA). The Z score decrements associated with the seven risk factors calculated using multivariate regression analysis were similar for QUS and BMD measurements. Z score decrements (mean of BMD and QUS measurements combined) associated with a history of atraumatic fracture (-0.67), X-ray osteopenia (-0.36), a family history of osteoporosis (-0.23), and a low BMI (-0.53) were all statistically significant compared with women with no risk factors. Z score decrements associated with a medical condition or use of therapy known to affect bone metabolism, a premature menopause or prolonged amenorrhea, or those who were current smokers were not significantly different from zero. As the number of risk factors present in each individual increased, the mean Z score decrements became more negative, increasing from -0.28 for women with one risk factor to -1.19 for those with four or more risk factors. QUS and BMD measurements yielded similar mean Z scores for women with one, two, three, or more than four risk factors. Using the World Health Organization (WHO) criteria to diagnose osteoporosis for BMD measurements and revised diagnostic criteria for QUS, approximately one-third of postmenopausal women aged 50+ years with clinical risk factors were classified as osteoporotic compared with only 12% of women without clinical risk factors. Over two-thirds of postmenopausal women with risk factors were classified as osteopenic or osteoporotic and approximately 28% were classified as normal. The proportion of women classified into each diagnostic category was similar for BMD and QUS. In conclusion, clinical risk factors for osteoporosis affected calcaneal BUA and SOS Z score measurements to the same extent as axial BMD Z score measurements. Provided revised diagnostic criteria are adopted for QUS, similar proportions of postmenopausal women are identified as osteopenic or osteoporotic as with BMD.

Over the past decade, bone density scanning has come to be seen as an essential part of the evaluation of patients at risk of osteoporosis. Although dual x-ray absorptiometry (DXA) is the technique most associated with the recent growth in bone densitometry, several innovative devices for performing measurements at sites in the peripheral skeleton are also available. This article examines the question of whether there is any one method or measurement site that performs better than all the others at identifying patients at risk of fracture. Given that it is essential to make greater use of the small, low-cost peripheral devices if the many millions of women most at risk are to be identified and treated, what approaches to the interpretation of bone density scans can be adopted to ensure the greatest degree of consistency among different methods? Finally, does it matter if the imperfect correlation among different types of measurement results in different patients being selected for treatment on the basis of different techniques?

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.

To investigate whether the therapeutic effect of etidronate is affected by the time of ingestion we have retrospectively studied 110 osteoporotic patients. They had been taking etidronate according to the manufacturer's instructions for a mean duration of 2.6 years either on waking (n=47), on retiring (n=47), or during the day (n= 16). No significant differences were found between the three groups with respect to percentage change in bone mineral density at all sites either for the first year of treatment or for the mean yearly percent change throughout the total course of treatment. These findings suggest that the time of ingestion of etidronate does not influence the therapeutic effect if a two hour fast before and after ingestion is adhered to.

In the UK, over 250 000 patients take continuous oral glucocorticoids (GCs), yet no more than 14% receive any therapy to prevent bone loss, a major complication of GC treatment. Bone loss is rapid, particularly in the first year, and fracture risk may double. This review, based wherever possible on clinical evidence, aims to provide easy-to-use guidance with wide applicability. A treatment algorithm is presented for adults receiving GC doses of 7.5 mg day(-1) or more for 6 months or more. General measures, e.g. alternative GCs and routes of administration, and therapeutic interventions, e.g. cyclical etidronate and hormone replacement, are recommended.

Over the past decade, growing awareness of the impact of osteoporosis on the elderly population and the availability of new treatments to prevent fractures have stimulated the rapid development of new radiologic techniques to assist in diagnosis. With the ability to perform high precision measurements of bone mineral density (BMD) in the spine and hip, dual X-ray absorptiometry (DXA) is well suited to meet this latter need. However, there is continuing interest in smaller, cheaper systems for assessing the peripheral skeleton that include DXA scanning of the distal forearm and a variety of devices for performing quantitative ultrasound (QUS) measurements on bone. Alongside the new equipment, new guidelines have been developed to assist in the interpretation of bone densitometry studies and, following a report by a World Health Organization working group, osteoporosis is increasingly diagnosed on the basis of the patient's T-score value (difference of BMD from young adult mean normalized to the population SD). For the future, wider provision of bone densitometry services is required to properly target the new treatments now becoming available. Since it is unlikely that conventional DXA can meet these needs, QUS is an attractive alternative, especially because this technique is now proven in its ability to predict fracture risk in the elderly and FDA approval is imminent.

Although osteoporosis is generally regarded as a disease of women, up to 30% of hip fractures and 20% of vertebral fractures occur in men. Risk factors for osteoporotic fractures in men include low body mass index, smoking, high alcohol consumption, corticosteroid therapy, physical inactivity, diseases that predispose to low bone mass, and conditions increasing the risk of falls. The key drugs and diseases that definitely produce a decrease in bone mineral density (BMD) and/or an increase in fracture rate in men are long-term corticosteroid use, hypogonadism, alcoholism and transplantation. Age-related bone loss may be a result of declining renal function, vitamin D deficiency, increased parathyroid hormone levels, low serum testosterone levels, low calcium intake and absorption. Osteoporosis can be diagnosed on the basis of radiological assessments of bone mass, or clinically when it becomes symptomatic. Various biochemical markers have been related to bone loss in healthy and osteoporotic men. Their use as diagnostic tools, however, needs further investigation. A practical approach would be to consider a bone density more than one SD below the age-matched mean value (Z < -1) as an indication for therapy. The treatment options for men with osteoporosis include agents to influence bone resorption or formation and specific therapy for any underlying pathological condition. Testosterone treatment increases BMD in hypogonadal men, and is most effective in those whose epiphyses have not closed completely. Bisphosphonates are the treatment of choice in idiopathic osteoporosis, with sodium fluoride and anabolic steroids to be used as alternatives.

Over the past decade, growing awareness of the impact of osteoporosis on the elderly population and the consequent costs of healthcare have stimulated development of new treatments to prevent fractures, together with new imaging technologies to assist in diagnosis. With its ability to perform high-precision measurements of bone mineral density (BMD) in the spine and hip, dual X-ray absorptiometry (DXA) is well suited to meet this latter need. However, there is continuing interest in smaller, less expensive, systems for assessing the peripheral skeleton. These include peripheral DXA scanning of the distal forearm and a variety of devices for performing quantitative ultrasound (QUS) measurements of broad-band ultrasonic attenuation (BUA) and speed of sound (SOS) in bone. Pivotal to all these developments is the demonstration in prospective studies that new technologies can reliably identify patients at risk of osteoporotic fractures. Whether DXA technology can meet the anticipated need for wider provision of diagnostic services is uncertain at present. The likely alternative is bone ultrasound. Although QUS technology is substantially cheaper than DXA and has proved its ability to predict fracture risk in the elderly, it is less precise, there is a lack of appropriate phantoms for quality control and there are doubts about how to interpret results in younger women.

Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mass and increased fracture risk. Current evidence suggests that the inheritance of bone mass is under polygenic control but the genes responsible are poorly defined. Type I collagen is the major protein of bone encoded by the COLIA1 and COLIA2 genes. While these are strong candidates for the genetic regulation of bone mass, no abnormality of either gene has so far been defined in osteoporosis. In this study, we describe a novel G-->T polymorphism in a regulatory region of COLIA1 at a recognition site for the transcription factor Sp1(7) that is significantly related to bone mass and osteoporotic fracture. G/T heterozygotes at the polymorphic Sp1 site (Ss) had significantly lower bone mineral density (BMD) than G/G homozygotes (SS) in two populations of British women and BMD was lower still in T/T homozygotes (ss). The unfavourable Ss and ss genotypes were over-represented in patients with severe osteoporosis and vertebral fractures (54%), as compared with controls (27%), equivalent to a relative risk of 2.97 (95% confidence interval 1.63-9.56) for vertebral fracture in individuals who carry the 's' allele. While the mechanisms that underlie this association remain to be defined, the COLIA1 Sp1 polymorphism appears to be an important marker for low bone mass and vertebral fracture, raising the possibility that genotyping at this site may be of value in identifying women who are at risk of osteoporosis.

Clinical experience with cyclical etidronate for the treatment of osteoporosis was reviewed in 69 consecutive patients. Six patients stopped treatment either due to adverse effects (5) or the decision to take hormone replacement therapy (HRT) (1). Bone mineral density (BMD) measurements using dual energy X-ray absorptiometry (DXA) were obtained in 63 patients (33 with spinal osteoporotic fractures and 30 with osteopenia) before and 1 year after treatment. BMD increased by an average of 4.50% (p < 0.001) in the lumbar spine (range +14% to -12%) and 5.5% (p < 0.01) at Ward's triangle (range +31% to -13%) while there was no significant change at the femoral neck (range +11% to -12%) and greater trochanter (range +12% to -15%). Significant rises in BMD were found at the lumbar spine and Ward's triangle in both osteoporotic and osteopenic groups. Of patients analysed after 1 year, 83% had an increased bone mass at the lumbar spine and 55% at the femoral neck. We conclude that there is a wide variation in the bone mass response to cyclical etidronate therapy, and in a minority of patients bone mass does not increase. For the majority of osteoporotic patients, however, we confirm the efficacy and tolerability of cyclical etidronate for the preservation of bone mass over 1 year in a clinical setting.

The significance of variability in bone mineral density (BMD) between lumbar vertebrae L1 to L4 in the same individual was investigated by dual-energy X-ray absorptiometry in 1000 normal women aged 40-60 years (average 52 years) and 145 women aged 45-80 years (average 65 years) with vertebral osteoporosis. The mean BMD increased from L1 to L4 in normal women from 0.841 g/cm2 to 1.017 g/cm2, and in osteoporotics from 0.562 g/cm2 to 0.709 g/cm2. Z scores for osteoporotic women (Z = osteoporotic BMD - age-normal BMD/normal SD) were significantly lower for individual vertebrae compared with L1-4 and at L4 compared with L1, L2 and L3 (p < 0.001). The mean difference between Z scores for the highest and lowest vertebrae in an individual was 0.70 for normals (SD = 0.40) and 0.64 for osteoporotics (SD = 0.36). The mean Z score difference between the L1-4 Z score and the lowest individual vertebral Z score was 0.36 for normals (SD = 0.23) and 0.06 for osteoporotics (SD = 0.31). However, receiver operating analysis (ROC) curves showed that the lowest Z score for any individual vertebra did not provide improved discrimination between normals and osteoporotics when compared with the L1-4 Z score. The area under the ROC curve for L1-4 was significantly greater than for individual vertebrae (p < 0.05) and that for L4 was significantly smaller than for L1, L2 or L3 (p < 0.001). In conclusion, L1-4 BMD gives greater diagnostic sensitivity for osteoporosis than individual vertebrae, and L1, L2 and L3 are better than L4.(ABSTRACT TRUNCATED AT 250 WORDS)

A group of 26 patients aged 47-81 years (average 67) with spinal osteoporosis and back pain for more than 6 months were investigated with planar and SPECT bone scintigraphy and anterior and lateral x-rays of the thoracolumbar spine. Abnormal activity on bone scintigraphy was found in all patients, of whom 22 had multiple lesions. A total of 17 (65%) patients had abnormal activity associated with collapsed vertebral bodies, 5 (19%) had degenerative disk disease, and 21 (81%) had facetal joint disease. Of 112 lesions identified by SPECT, 60 (54%) were localized to the apophyseal joints. Facetal lesions were commoner in those patients with more collapsed vertebrae, and 32 facetal lesions (54%) were associated with collapse of the vertebra immediately above or below. Bone scintigraphy findings suggest that in some individuals with osteoporosis and chronic back pain, collapse of the vertebral body or degenerative disk disease are causes of pain. However, the high frequency of increased apophyseal joint activity suggests that the facet joint may also be an important site of origin of pain in these individuals. Bone scintigraphy may identify a subgroup of osteoporotic patients with chronic back pain who would benefit from treatment to the facet joints.

Objective: To assess compliance with recommendations for hormone replacement therapy (HRT) in postmenopausal women following screening for osteoporosis., Design: A postal questionnaire sent to women an average of 8 months (range 6-12) following measurement of their bone mineral density (BMD), and recommendations regarding HRT given to the referring general practitioner., Setting: Referrals from local general practitioners. Mixed social class., Subjects: 400 postmenopausal women aged 40-69 years (average age 52)., Main Outcome Measures: Compliance with advice and if failing to comply, reasons for not doing so., Results: Replies were received from 352 women (88%) and 74% of respondents followed advice to start, continue, or refrain from starting or continuing HRT with regard to protecting their skeleton. Those who rejected advice to take HRT mostly had concern over side effects or the efficacy or safety of treatment. Of the women who started HRT 28% subsequently stopped, the principal reasons being withdrawal bleeding and weight gain. Of the women recommended to take HRT, 39% were not taking treatment by 8 months after referral, either because they ignored advice given (22%) or because of side effects (17%)., Conclusions: Screening leads to increased usage of HRT among women at most risk for osteoporosis. However, almost 40% of women with low bone mineral density were not taking HRT 8 months after referral, and therefore until improved compliance has been demonstrated screening cannot be widely recommended.

There is overwhelming evidence that oestrogen can prevent bone loss and there is less good but convincing evidence that oestrogen prevents fractures. Oestrogen use of between 5 and 10 years is associated with a 50% reduction in risk of fracture. There is good evidence that in established osteoporosis, oestrogen prevents further bone loss and reduces the incidence of fractures. Oestrogen use leads to lasting skeletal benefits and will prevent bone loss at whatever age it is started. Prior to fracture there are no symptoms associated with osteoporosis and few patients will be diagnosed at a time when effective treatment could be instigated. It is apparent that the risk of developing osteoporosis cannot be deduced from clinical data alone and bone mineral measurements provide the single best test for future risk. Bone mass can be measured directly and there is no need for guess work. The most important potential application for oestrogen is in preventive therapy, and the efficient use of oestrogen in this situation depends upon the diagnosis of low bone mass. Who to treat remains the issue. For any age group the median value of bone density and a range of percentiles can be generated, thus facilitating therapeutic decisions.

Dual photon absorptiometry enables measurement of bone mineral to be carried out at the clinically relevant sites of the spine and femur. Few would argue that it provides a powerful research tool, but defining its role in clinical practice has been somewhat more difficult. With the advent of X-ray based systems, studies can be rapidly carried out with improved precision, which has led to increased clinical interest. It is probable that this technology will be incorporated into routine use in the near future. In the present review we have addressed the role of dual photon absorptiometry in areas pertinent to osteoporosis and the direction in which recent developments are leading with regard to future research.

Two hundred and twenty-five premenopausal women were studied to evaluate age-related changes in trabecular bone mass. Measurements were made at the lumbar spine and femoral neck by dual photon absorptiometry. It was found that spinal bone density increased significantly from the 20s to reach a peak in the mid-30s. Identical trends were observed in total bone mass and bone mass normalized by length. Bone loss then proceeded at a rate of 1% per year, and by the early 50s, 10% of peak spinal density was lost. There was no peak in femoral neck density; loss commenced in the late 20s and continued at a rate of 0.4% per year. The cumulative premenopausal loss from the femur at 9% was comparable to that in the spine. It is concluded that significant amounts of trabecular bone are lost from both the spine and femoral neck before the menopause. The implications of these findings for the prevention of osteoporosis are discussed.

A comparison has been made between themetabolic consequences of daily administration for 6 weeks of 1.0 micrograms and 0.5 micrograms 1 alpha hydroxyvitamine D3 (1 alpha(OH)D3) in twenty patients with senile osteoporosis. There was no significant difference in the increase of calcium absorption which occurred in the two treatment groups between the beginning and end of the trial period. Serum and urinary calcium rose significantly in those receiving 1.0 micrograms 1 alpha(OH)D3 but not in the lower dosage group. Serum parathyroid hormone levels were suppressed in the higher dosage group only. There was a significantly greater rise of serum inorganic phosphate, and fall of serum magnesium, on the higher dosage, but no significant change in serum creatinine occurred in either group. It is, therefore, suggested that in long term therapy regimes for osteoporosis incorporating 1 alpha(OH)D3, 0.5 micrograms may be a more suitable daily dose than 1.0 micrograms 1 alpha(OH)D3.