Health Evidence Bulletins - Wales (logo)

Systematic literature search to December 2000 plus some key references from 2001

2: Screening and Diagnosis

This bulletin is a supplement to, not a substitute for, professional skills and experience. Users are advised to consult the supporting evidence for a consideration of all the implications of a recommendation

The Statements The Evidence
2a. The World Health Organisation criteria for classification/diagnosis of osteoporosis are as follows:
  • with osteopenia (a BMD of > 1SD below the young adult mean but <2.5 SD below this valuei); and
  • with osteoporosis (a BMD of 2.5 standard deviations or more below the young adult meani.ii) with or without pre-existing fragility fractures.
i. World Health Organisation. Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis. WHO Technical Report Series 843. Geneva: WHO, 1994
(Type V evidence – expert concensus opinion based on a review of the literature)
ii. Genant HK, Cooper C, Poor G. Interim report and recommendations of the World Health Organisation Task-Force for osteoporosis. Short report. Osteoporosis International 1999; 10(4): 259-264
(Type V evidence – expert opinion)
2b. The Royal College of Physicians agree with the recommendations of the Advisory Group on Osteoporosis and the NHS Executive letter (EL(96)110) that "Health Authorities should purchase bone density measurement by means of dual x-ray adsorptiometry (DXA)" i.

Measuring bone mineral density at various sites has the same predictive value of future fractures in forearm, hip or vertebrae, (relative risk 1.5; 95% CI: 1.4 - 1.6 for 1 standard deviation decrease below age-adjusted mean). Best predictors were Hip DXA for femoral neck fracture (relative risk 2.6; 95% CI: 2.0 - 3.5) and Spine DXA for vertebral fracture (relative risk 2.3; 95% CI: 1.9 - 2.8 ). These predictions are of the same order as blood pressure for stroke and smoking for coronary artery diseaseii.

Total hip BMD appears to be as effective as femoral neck BMD for detecting response to bisphosphonate treatment in the femur in the setting of a clinical trial or similar research settingiii.
(Health gain notation – 1 "beneficial")

Detailed recommendations for the use of biochemical markers of bone turnover in osteoporosis are availableiv.

i. Anonymous. Osteoporosis. Clinical Guidelines for Prevention and Treatment. London: Royal College of Physicians, 1999
[accessed 29.11.01]
(Type V evidence – expert opinion based on a systematic review of the literature)
ii. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. British Medical Journal 1996; 312: 1254-1259
[accessed 29.11.01]
(Type IV evidence - systematic review and meta-analysis of 11 cohort studies, 90,000 person years and 2000 fractures)
iii. Blake GM, Preston NG, Patel R, Herd JM, Fogelman I. Monitoring skeletal response to treatment: Which site to measure in the femur? Journal of Clinical Densitometry 2000; 3(2): 149-155
(Type IV evidence – comparison of BMD measurements of 152 postmenopausal women enrolled in a trial of bisphosphonate therapy. Measurements at 0, 1 and 2 years were compared at six sites in the hip and spine)
iv. Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan J, for the Committee of Scientific Advisors of the International Osteoporosis Foundation. The use of biochemical markers of bone turnover in osteoporosis. Osteoporosis International 2000; suppl.6: S2-S17
(Type V evidence – expert opinion based on a review of the literature)


2c. The use of the T-score requires a comparison of the measurement with measurements in a young reference population. Although fracture risk varies between populations there is insufficient knowledge at present to recommend that local reference ranges be usedi. It is recommended that the NHANES IIIii database be used as an international reference until further evidence changes this viewi. i. Kanis JA, Gluer CC. An update on the diagnosis and assessment of osteoporosis with densitometry. Osteoporosis International 2000; 11: 192-202
(Type V evidence – expert opinion based on a review of the literature)
ii. Chen Z, Maricic M, Lund P, Tesser J, Gluck O. How the new Hologic hip normal reference values affect the densitometric diagnosis of osteoporosis. Osteoporosis 1998; 8: 423-489
(Type V evidence – expert opinion)
2d. Prior to the publication of the Royal College of Physicians’ (RCP) guidelinesi, the major guidelines were produced by the European Foundation for Osteoporosis and Bone Disease (EFFO)ii and the National Osteoporosis Foundation of the USA (NOF) iii. All three guidelines recommend:
  • a case-finding strategy, rather than mass screening, for the diagnosis of osteoporosis.
  • the measurement of BMD, preferably at the hip, with defined intervention thresholds.

The RCP and the EFFO take a population wide approach to diagnosis and have provided a list of indicators for the diagnostic use of BMD. In contrast, the NOF takes an individual approach so that assessment thresholds vary from individual to individual based on planned treatment, risk factors and age.

i. Anonymous. Osteoporosis. Clinical Guidelines for Prevention and Treatment. London: Royal C
http://www.doh.gov.uk/osteorep.htm [accessed 29.11.01]
(Type V evidence – expert opinion based on a systematic review of the literature)
ii. Kanis JA, Delmas P, Buckhardt P, Cooper C, Torgerson D, on behalf of the European Foundation for Osteoporosis and Bone Disease. Guidelines for diagnosis and management of osteoporosis. Osteoporosis International 1997; 7: 390-406
(Type V evidence – consensus guidelines based on an extensive review of the literature)
iii. Eddy DM, Johnston CC, Cummings SR et al. Osteoporosis: Review of the evidence for prevention, disgnosis and treatment and cost-effectiveness analysis. Osteoporosis International 1998; 8(suppl.4): S1-S88
(Type V evidence – expert opinion based on an extensive review of the literature)


2e. On the basis of several cost-estimates, the use of bone densitometry for well defined clinical indications seem to be justifiable in terms of their cost utilityi.
Bone density measurements are recommended for the following indications where assessment would influence management i:
  • radiographic evidence of osteopenia and/or vertebral deformity
  • loss of height, thoracic kyphosis (after radiographic confirmation of vertebral deformity)
  • previous fragility fracture
  • prolonged corticosteroid therapy (prednisolone >7.5 mg daily for 6 months or more)
  • premature menopause (age <45 years)
  • prolonged secondary amenorrhaea (>1 year)
  • primary hypogonadism
  • chronic disorders associated with osteoporosis (eg Anorexia nervosa, malabsorption syndromes)
  • maternal history of hip fracture
  • low body mass index (<19 kg/m2)

Cost-utility studies indicate that the targeting of high-risk populations improves cost-effectiveness. In populations with a relative risk of 2 and intervention costs of £500 per year for 5 years, there are savings in women at the age of 80 years. For intervention costs of approximately £200 per year, cost-effectiveness can be demonstrated for 60 year olds.

i. Anonymous. Osteoporosis. Clinical Guidelines for Prevention and Treatment. London: Royal College of Physicians, 1999
http://www.doh.gov.uk/osteorep.htm [accessed 29.11.01]
(Type V evidence – expert opinion based on a systematic review of the literature. Cost-effectiveness information derived from:
Jonsson B, Kanis JA, Dawson A, Oden A, Johnell D. Effect and offset of effect of treatment for hip fracture on health outcomes. Osteoporosis International 1999; 10(3): 193-199; and
Eddy D, Lindsay R, Cummings SR, Dawson-Hughes B, Johnston C, Slemenda C. Analysis of the effectiveness and cost of screening and treatment strategies for osteoporosis: a basis for development of practice guidelines. Submitted in 1999 to Osteoporosis International, not yet published, May 2001)
2f. There is no scientific basis for recommending bone density measurement in mass screening, or as an extra component in health check-ups of asymptomatic individuals, with the aim of preventing fracturesi,ii.
(Health gain notation –5 "unlikely to be beneficial")
i. Ringertz H, Marshall D, Johannsson C et al. Bone Density Measurement - A Systematic Review. Journal of Internal Medicine 1997; 241(suppl 739): 1 - 60
(Type IV evidence - systematic review of observational studies)
ii. Anonymous. Osteoporosis. Clinical Guidelines for Prevention and Treatment. London: Royal College of Physicians, 1999
[accessed 29.11.01]
(Type V evidence – expert opinion based on a systematic review of the literature)


2g. In comparison to BMD measurements by DXA quantitative ultrasound (QUS) for bone measurement does not use ionising radiation, is cheaper, takes up less space and is easier to use than densitometry techniquesi. i. Prins SH, Jorgensen HL, Jorgensen LV, Hassager C. The role of quantitative ultrasound in the assessment of bone: a review. Clinical Physiology 1998; 18(1): 3-17
(Type V evidence – expert review of the literature)
2h. Ultrasound measurements can predict the risk of hip fracture in elderly peoplei,ii,iii.

Two large studies of elderly women found that low calcaneal ultrasonic variables (BUA and SOS) were able to predict increased hip fracture risk with similar accuracy to BMD measurement by DXAi,ii.

In one study, the relative risk of hip fracture for one SD reduction was 2.0 (95% CI 1.6-2.4) for ultrasound attenuation and 1.7 (1.4-2.1) for speed of sound, compared with 1.9 (1.6-2.4) for BMDi. In the second study each one SD reduction in calcaneal BUA was associated with a doubling of the relative risk for hip fracture (RR=2.0, 95% CI 1.5-2.7); a similar relationship was observed with bone mineral density of the calcaneus (RR=2.6, 95% CI 1.9-3.0) and femoral neck (RR=2.6, 95% CI 1.9-3.8)ii.

Using the results from a portable dry system, Cox regression analysis, adjusted for age and sex, showed that the relative risk (RR) of hip fracture for each standard deviation reduction was 2.3 (95% CI 1.4-3.7) for BUA and 1.6 (95% CI 1.1-2.3) for SOS. Slightly weaker relationships were found for any fracture. Multivariate analyses identified low BUA values and immobility as the strongest predictors for hip fractures and any fractureiii.
(Health gain notation – 4 "unknown")
Caveat: This was a small, low power study for fracture outcome; Only elderly people living in homes/sheltered housing were examined; fractures were self-reported.

i. Hans D, Dargent-Molina P, Schott AM et al. Ultrasonographic heel measurements to predict hip fracture in elderly women: the EPIDOS prospective study. Lancet 1996; 348: 511-514
(Type IV evidence – two year follow-up study of hip fractures in 5662 elderly women (aged 75 or more, mean age 80.4 years). Baseline BUA and SOS measures were carried out on a Lunar Achilles Ultrasound System. 115 hip fractures were recorded during the follow-up period (compliance, 97.7%))

ii. Bauer DC, Gluer CC, Cauley JA et al. Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women: a prospective study. Archives of Internal Medicine 1997; 157: 629-634
(Type IV evidence – Two year follow-up study of hip and other non-spinal fractures in 6189 women (older than 65 years). Baseline BUA measurements were carried out with the UBS 575 Walker-Sonix. 350 non-spine fractures, including 54 hip fractures, were documented during follow-up (compliance, 99%))

iii. Pluijm SMF, Graafmans WC, Bouter LM, Lips P. Ultrasound measurement for the prediction of osteoporotic fractures in elderly people. Osteoporosis International 1999; 9: 550-556
(Type IV evidence – prospective study of the relationship between QUS measurements and fracture risk in 710 elderly subjects (aged 70 or over) from seven homes and seven appartment homes in Amsterdam and vicinity. QUS measurements were obtained using a CUBA Clinical Instrument. During the study period, a median follow-up of 2.8 years (maximum 3.7 years), 30 participants had a first hip fracture and 54 suffered from a first other non spinal fracture).


2i. Linear regression coefficients between calcaneal QUS parameters and DXA were only modest in a group of 25-75 year-old Dutch women. In a subgroup of premenopausal women correlations between BUA and BMD at the hip and femoral neck were lower compared to those in postmenopausal women. The predictive value of QUS parameters for BMD is limited, therefore it is not appropriate to use QUS as a surrogate for DXAi.

There are significant differences in the classification of osteoporosis/osteopenia depending on the site measured and the technique used for bone mass measurement. For example, according to the proposed WHO guidelines, the percentage of women classified as osteopenic ranged from 25.9% by BUA at the heel, to 43% by BMD at the femoral neck. For men, the same range is from 20.5% by BUA to 44.1% by BMD at the femoral neck. For classification into the osteoporotic group, the range was from 2.5% by intertrochanteric BMD to 24.4% by BMD at Ward’s triangle for women and from 0% by SOS to 29.0% by BMD at Ward’s triangle for men. The development of technique and site specific cut-off values may increase the accuracy of the classification of osteoporosis and osteopenia in both men and womenii.

Although DXA and QUS parameters are significantly correlated, QUS parameters cannot predict osteopenia as defined by DXA, and sensitivities and specificities of QUS parameters were not sufficiently high for QUS to be used as an alternative to DXA. Further prospective studies with long follow-up periods are necessary to validate QUS measurements in subjects with low, normal or osteopenic valuesiii.
Caveat: The authors accept that QUS is an independent predictor of fracture risk and suggest, as other authors have suggested, that it measures not just BMD but other properties such as elasticity and trabecular architecture.

i. Dubois EF, van den Bergh JP, Smals AG et al. Comparison of quantitative ultrasound parameters with dual energy X-ray absorptiometry in pre- and postmenopausal women. Netherlands Journal of Medicine 2001; 58(2): 62-70
(Type IV evidence – Comparison of calcaneal QUS and DXA measurements, at spine, total hip and femoral neck, of 217 pre- and postmenopausal women (aged 25-75) referred for a BMD measurement because of osteoporosis in at least one family member either in the first or in the second degree)

ii. Jorgensen H, Warming L, Bjarnason NH, Andersen PB, Hassager C. How does quantitative ultrasound compare to dual X-ray absorptiometry at various skeletal sites in relation to the WHO diagnosis categories? Clinical Physiology 2001; 21(1): 51-59
(Type IV evidence – comparison by DXA at hip, spine and lower forearm and quantitative ultrasound (QUS), using the Osteometer DTUone, at the heel of 247 men, 209 postmenopausal women and 195 premenopausal women)

iii. Cetin A, Erturk H, Celiker R, Sivri A, Hascelik Z. The role of quantititive ultrasound in predicting osteoporosis defined by dual X-ray absorptiometry. Rheumatology International 2001; 20(2): 55-59
(Type IV evidence – BUA, SOS and BMD comparisons of 123 patients (39 male, 84 female) with osteoporosis and suspected of having osteoporosis)


2j. Clinical risk factors affect calcaneal BUA and SOS Z score measurements to the same extent as axial BMD Z score measurements. Provided revised diagnostic criteria are adopted, similar proportions of postmenopausal women are identified as osteopenic or osteoporotic as with BMDi.
(Health gain notation – 2 "likely to be beneficial")
Caveats: Calcaneal QUS appears to be responsive to the effect of antiresorptive therapies but these are often more pronounced re spinal BMD. The authors note that their revised criteria may be device specific (Hologic Sahara/Osteometer DTUone) and would need to be confirmed for other instruments. The reference group was selected from the study population (of referred and volunteer subjects) and may not be representative of the whole population.

The WHO threshold of T score = -2.5 for diagnosing osteoporosis requires modification when using QUS to assess skeletal status. For three QUS devices, a T-score threshold of –1.80 would result in the same percentage of postmenopausal women classified as osteoporotic as the WHO threshold for BMD measurements. Corresponding T-score thresholds for individual measurement parameters on the two commercially available ultrasound devices were –1.61, -1.94 and –1.90 for Sahara BUA, SOS and estimated BMD respectively, and –1.45 and –2.10 for DTU BUA and SOS respectively. Additional studies are needed to determine suitable T-score thresholds for other commercial QUS devicesii.

i. Frost ML, Blake GM, Fogelman I. Quantitative ultrasound and bone mineral density are equally strongly associated with risk factors for osteoporosis. Journal of Bone and Mineral Research 2001; 16(2): 406-416
(Type IV evidence – A QUS and BMD study of 1115 pre- and postmenopausal women. A subgroup of 530 women was used to construct reference data for calculating T and Z scores)

ii. Frost ML, Blake GM, Fogelman I. Can the WHO criteria for diagnosing osteoporosis be applied to calcaneal quantitative ultrasound? Osteoporosis International 2000; 11: 321-330
(Type IV evidence – comparison of DXA measurements at the spine and hip with QUS measurements (at the heel) on three calcaneal ultrasound devices (Hologic Sahara, Hologic UBA575+ and the Osteometer DTUone). The two groups of women studied were (i) 420 healthy women aged 20-79 years with no known risk factors for osteoporosis: (ii) 97 postmenopausal women with vertebral fractures)


2k. Using a CUBA Clinical II device, a BUA threshold of 60 dB/MHz was the most cost-effective threshold level as a DXA pre-screen. At this threshold, BUA had a sensitivity of 93% and a specificity of 84% in identifying those subjects who were subsequently identified as having osteoporosis. Based on local costs of £45 for DXA and £15 for QUS, QUS assessment does not appear cost-effective as a pre-screen for DXA, even in a high risk group of women with low trauma Colles’ fracture. A QUS pre-screen would only be cost-effective if the scan could be performed at a substantially lower costi. i. Sim MF, Stone M, Johansen A, Evans W. Cost effectiveness analysis of BMD referral for DXA using ultrasound as a selective pre-screen in a group of women with low trauma Colles’ fractures. Technology & Health Care 2000; 8(5): 277-284
(Type IV evidence – cost-effectiveness analysis based on UK prices)
2l. An evaluation of the Osteoporosis Risk Assessment Instrument (ORAI), a simple algorithm based on age, weight and current estrogen use, showed that the tool had a sensitivity of 93.3% (95%CI 86.3-97.0%) and a specificity of 46.4% (95%CI 41.0-51.8%) for selecting women with low bone mineral density. The sensitivity for selecting women with osteoporosis was 94.4% (95%CI 83.7-98.6%)i.

Both the ORAI and SCORE (Simple Calculated Osteoporosis Risk Estimation) decision rules are better that the National Osteoporosis Foundation guidelines at targeting BMD testing in high-risk patientsii.

Another assessment tool, based on the results of the Study of Osteoporotic Fractures (SOF), has recently been published – the FRACTURE Indexiii. In the model including BMD assessment, dichotomization of the Index at a cutpoint of 6/15 resulted in a sensitivity of 78.6% and a specificity of 61.7%iii. These results were validated with data for older women from the EPIDOS Studyiv.
(Health gain notation – 2 "likely to be beneficial")

i. Cadarette SM, Jaglal SB, Kreiger N, McIsaac WJ, Darlington GA, Tu JV. Development and validation of the Osteoporosis Risk Assessment Instrument to facilitate selection of women for bone densitometry. Canadian Medical Association Journal 2000; 162(9): 1289-1294
(Type IV evidence – observational study of 1376 cognitively normal women aged 45 years or more who had undergone x-ray absorptiometry testing for the Canadian Multicentre Osteoporosis Study. 926 were allocated to the development of the tool and 450 to its validation)

ii. Cadarette SM, Jaglal SB, Murray TM, Melsaac WJ, Joseph L, Brown JP; for the Canadian Multicentre Osteoporosis Study (CaMos). Evaluation of decision rules for referring women for bone densitometry by dual-energy x-ray absorptiometry. Journal of the American Medical Association 2001; 286(1): 57-63
Reviewed in: When to measure bone density. Bandolier August 2001: 90(7)
[accessed 29.11.01]
(Type IV evidence – observational study of a population-based community study of 2365 postmenopausal women, aged 45 or older, without bone disease)

iii. Black DM, Steinbuch M, Palermo L et al. An assessment tool for predicting fracture risk in postmenopausal women. Osteoporosis International 2001; 12: 519-528
(Type IV evidence – assessment tool using data from the five-year Study of Osteoporotic Fractures (SOF). 7782 women aged 65 or older (mean age 73.3 years) with BMD measurements and base-line risk factors included in the analysis)

iv. Dargent-Molina P, Favier F, Grandjean H et al. Fall-related factors and risk of hip fracture : the EPIDOS prospective study. Lancet 1996; 348: 145-149
(Type IV evidence – the FRACTURE Indexiii was validated with data from 6679 women (mean age 80.5 years) from this study, with similar results)


2m. Serum C-telopeptide of type I collagen (CTX) sampled under controlled conditions significantly predicts the subsequent risk of hip fracture in ambulatory elderly women, with the same magnitude as urinary markers of resorption. When restricted to samples taken in the early afternoon, serum CTX was significantly predictive with a relative hazard of 1.86 (95% CI 1.01-3.76) for values above the premenopausal range (mean + 2SD)i. i. Chapurlat RD, Garnero P, Breart G, Meunier PJ, Delmas PD. Serum type I collagen breakdown product (serum CTX) predicts hip fracture risk in elderly women: the EPIDOS study. Bone 2000; 27(2): 283-286
(Type IV evidence – case control study of baseline urinary and serum samples from 212 patients who subsequently had a hip fracture and from 642 controls within the EPIDOS prospective cohort. Mean follow-up was 3.3 years (maximum 4.9 years))
2n. A survey of General Practitioner (GP) activity in the UK suggested that GPs are increasingly pro-active in their management of osteoporosis. Awareness of the clinical factors that predispose individuals to osteoporosis was reasonably high, but in may cases active management did not occur until after a patient had had a fracture. One third of GPs were not satisfied with their access to DXA scans. Prescribing of therapeutic agents to reduce bone loss appeared to be increasing and a proportion of GPs were actively implementing guideline recommendations (ranging from 2% for the Royal College of Physicians guidelines (which had only just been published) to 29% for local guidelines). However, there was considerable variation in prescribing patterns and use of diagnostic facilitiesi.
Caveat: The generalisability of these results is seriously weakened by the very low response rate (20%) and lack of analysis of non-responders.
i. Rowe R. The management of osteoporosis in general practice: Results of a National Survey. Osteoporosis Review 1999; 7: 1-3
(Type IV evidence – telephone interview survey of data from 200 GPs who agreed to participate, a 20% response rate from a random sample of 1009 GPs, stratified by age and geographical location. GPs were contacted between April and May 1999)


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Health Evidence Bulletins: Wales, Duthie Library, UWCM, Cardiff CF14 4XN. e-mail: weightmanal@cardiff.ac.uk