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Osteo-489 390.406

Osteoporos Int (1997) 7:390–406 ß 1997 European Foundation for Osteoporosis and the National Osteoporosis Foundation Position Paper Guidelines for Diagnosis and Management of Osteoporosis
J. A. Kanis, P. Delmas, P. Burckhardt, C. Cooper and D. Torgerson on behalf of the European Foundation for Osteoporosis and Bone Disease Preamble. Significant developments have occurred in
The clinical significance of osteoporosis lies in the the field of osteoporosis over the past several years.
fractures that arise. Common fractures include vertebral There is now considerable information concerning its compression fractures, and fractures of the distal radius impact on general health and an international consensus and the proximal femur (hip fracture). In addition, when concerning the definition of osteoporosis. Conceptually, the skeleton is osteoporotic, fractures occur more this recognizes the multifactorial nature of the events commonly at many other sites including the pelvis, which give rise to the fractures, but operational proximal humerus, distal femur and ribs. Osteoporotic definitions have now been agreed and have gained a fractures occurring at the spine and the forearm are wide measure of acceptance. Accurate and precise associated with significant morbidity, but the most diagnostic tools are also available. Finally, there is serious consequences arise in patients with hip fracture, substantial evidence that the natural history of osteo- which is associated with a significant increase in porosis can be modulated by agents which in turn mortality (15–20%), particularly in elderly men and decrease the risk of fracture.
women. Hip fractures account for more than 20% of Despite an increasing professional and public aware- orthopaedic bed occupancy in the UK, in Scandinavia ness of osteoporosis, the management of osteoporosis and several other countries. After the age of 45 years, hip has been confined mainly to specialists. With the large fractures account for a higher proportion of hospital bed number of affected individuals and the wider availability occupancy than many other common disorders in of diagnostic aids and safe treatments, there is a need for women, including breast cancer and diabetes (Fig. 1).
osteoporosis to be managed predominantly by theprimary care physician. Against this background theEuropean Foundation for Osteoporosis and Bone Diseasethrough their Scientific Advisory Board has recognized aneed to develop practice guidelines for primary carephysicians which are summarized in this paper.
The internationally agreed definition of osteoporosis is:‘a progressive systemic skeletal disease characterized bylow bone mass and microarchitectural deterioration ofbone tissue, with a consequent increase in bone fragilityand susceptibility to fracture' [1].
———————Correspondence and offprint requests to: Professor John A. Kanis,WHO Collaborating Centre for Metabolic Bone Diseases, Department Fig. 1. Hospital bed occupancy in women aged 45 years or more
of Human Metabolism & Clinical Biochemistry, University of according to diagnostic category in the Trent Region of England (9% Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, of the UK population). COAD, chronic obstructive airways disease; UK. Tel: +44 (0)114 271 2649. Fax: +44 (0)114 273 9176.
MI, myocardial infarction. (Source: Trent Health.) Guidelines for Diagnosis and Management of Osteoporosis Table 1. Estimated remaining life-time fracture risk (%) with
measured as bone mineral that can presently be confidence intervals in women and men from Rochester, MN, USA measured with precision and accuracy, and its measure- at the age of 50 years ment forms the basis for the diagnosis of osteoporosis.
Techniques to Measure Bone Mineral There are two widely utilized techniques to assess bonemass. They variously assess mineral content of regional From Melton LJ, Atkinson EJ, O'Fallon WM, Wahner HW, Riggs BL.
sites, particularly those sites at risk of osteoporotic Long-term fracture risk prediction with bone mineral measurements fracture such as the wrist, spine and hip, but also the made at various skeletal sites. J Bone Miner Res 1991;6 (Suppl 1):S136.
whole skeleton.
aClinically diagnosed fractures.
Single-Energy Absorptiometry. The technique measuresbone mineral at peripheral (appendicular) sites such as The likelihood that any individual will suffer an the heel and the wrist. Single photon absorptiometry osteoporotic fracture is considerable. In many Western (SPA) utilizes a photon-emitting source such as iodine- countries the remaining life-time risk of a hip fracture in 125, and the amount of bone mineral in the tissue white women at the age of menopause lies between 15% traversed attenuates the photons from which the mineral and 17%. The risk for other common types of content is calculated. Single-energy X-ray absorptiome- osteoporotic fractures is nearly as high (Table 1), so try (SXA) has now supplanted SPA as the single-energy that the combined fracture risk is 30–40%. Thus, more technique for scanning the wrist. It is more precise and than one third of adult women will sustain one or more avoids the need for isotopes.
osteoporotic fractures in their life-time. This estimate isconservative since it does not include fractures at other Dual-Energy Absorptiometry. Sites such as the spine and sites and only takes into account those vertebral fractures hip cannot be measured accurately by SPA or SXA.
which come to clinical attention, so that the true risk of Dual-energy absorptiometry utilizing photons (DPA) or fracture is higher.
X-rays (DXA) permits bone mineral to be measured at These indices of fracture risk compare with a life-time these sites.
risk in women at the age of 50 years of 9–12% for breastcancer and 30–40% for cardiovascular disease. This The amount of bone mineral present at a specific site of a indicates the widespread prevalence of osteoporosis in scan is termed the bone mineral content. When the bone our society. In comparison, risks for men are about one- mineral content is divided by the area or volume third of those in women, and are even lower for forearm assessed (the region of interest), a value for bone fractures, but still represent a considerable burden.
mineral density is provided. With single- and dual- The increasing awareness of osteoporosis combined energy absorptiometry the bone mineral content is with the current availability and development of specific divided by the area assessed (because of the two- treatments is likely to increase the demand for manage- dimensional scan) and is not, therefore, a true volumetric ment of patients with osteoporosis. In the past the density but an areal density. A typical scan of the lumbar management has been largely confined to specialists, but spine is shown in Fig. 2 and an analysis in Table 2.
the increasing availability of diagnostic tools and well- Several other techniques have been developed to proven treatments, and the increasing numbers of measure bone mineral, but their use is less widespread patients identified, indicate that the burden of manag- and in some cases confined to clinical research. They ment will fall increasingly on the primary care physician.
include quantitative computed tomography, ultrasound The aim of this document is to provide a framework for evaluation of bone and several radiographic techniques the cost-effective diagnosis and management of osteo- including radiographic density measurements at the porosis. These guidelines do not consider the identifica- hand. Note that standard skeletal radiographs are a tion of patients at risk from osteoporosis and strategies very inaccurate method of assessing the amount of bone for prevention of the disease, though in many respects mineral, but apparent osteoporosis on X-rays is a the approaches are similar.
common reason for further assessment. The majorlimitations of computed tomography at the spine arethe expense, low precision and comparatively high Diagnosis of Osteoporosis
radiation dose. Computed tomography techniques toassess bone mineral density at appendicular sites are The definition of osteoporosis captures the notion that used in some countries with lower cost and radiation low bone mass is an important component of the risk of exposure and higher precision. Ultrasound attenuation fracture, but that other abnormalities occur in the and velocity measurements avoid exposure to radiation.
skeleton, and that non-skeletal factors such as falls are They may be useful as a diagnostic aid, but their value in also important. Nevertheless, it is only bone mass monitoring treatments is not yet established.

J. A. Kanis et al.
adults (‘peak bone mass') is approximately normalirrespective of the technique used. Because of thisnormal distribution, bone density values in individualsare often expressed in relation to a reference populationin standard deviation units. This reduces the problemsassociated with differences in calibration between someinstruments. When standard deviation units are used inrelation to the young healthy population, this is referredto as the T-score.
For diagnostic purposes two thresholds of bone mineral density have been proposed for Caucasianwomen based on the T-score [2]. The first defines themajority of individuals who will sustain a fracture in thefuture (osteoporosis) and the second a higher thresholdthat may identify those most likely to developosteoporosis and those women who might benefit mostby the prevention of bone loss at the time of themenopause (low bone mass or osteopenia). Osteoporosisdenotes a value for bone mineral density or bone mineralcontent that is two and a half standard deviations or morebelow the young adult mean value (T-score 4–2.5).
Osteopenia or low bone mass is a T-score that liesbetween –1 and –2.5.
Severe or ‘established' osteoporosis denotes osteo- porosis as defined above in the presence of one or moredocumented fragility fractures, usually of the wrist, spineor hip.
In the young healthy population, 15% of women will Fig. 2. Dual-energy X-ray absorptiometry scan of the lumbar spine in
have a T-score of less than –1, and thus have osteopenia.
a healthy, premenopausal woman aged 33 years. The computer hasselected the edge of the spine and the vertebrae have been Approximately half a per cent will already have distinguished by the operator to give the areas of interest to be osteoporosis (Fig. 3). Note that these thresholds apply to women only.
Suitable diagnostic cut-off values for men are less secure. It has been suggested that a similar absolute Table 2. Measurements made from an anteroposterior scan using
DXA at the lumbar spine in a 53-year-old woman at the menopause
value for bone mineral density as that used in womencan be taken as a cut-off point for the diagnosis of Note the increase in vertebral area, mineral content and density withthe more caudal direction. The results are compared either with thepremenopausal reference range (T-score) or with an age-matchedpopulation (Z-score). In this instance the bone mineral density is 6%below the average for peak bone density but 5% above average forage.
aStandard deviation units.
Bone Mineral and Osteoporosis Skeletal mass is relatively constant once growth has Fig. 3. Distribution of bone mineral density in young healthy women
aged 30–40 years. Because the distribution of bone density is normal,
ceased, until the age of 50 years or so. The distribution 15% of the population have a T-score of –1 or lower and less than of bone mineral content or density in young healthy 0.6% of the population have a T-score below –2.5.
Guidelines for Diagnosis and Management of Osteoporosis osteoporosis; namely a value for bone mineral 2.5 proportion of patients with osteoporosis increases standard deviations below the average for women.
exponentially with age because of the distribution ofbone mineral density in the population (Fig. 4). Boneloss occurs with age in men, but the rate of bone loss is Natural History of Bone Loss much slower so that the frequency of osteoporosis and offractures is less.
Bone mineral content and density are relatively constantin adult men and women under the age of 50 years. In What Does This Tell us About Fracture Risk? The women, loss of bone may occur before the age of average life-time risk of the common osteoporotic menopause at some sites, but losses are small compared fractures in white women and men is approximately with those in later life. Enhanced bone loss occurs 40% and 13% respectively at the age of 50 years (see thereafter, and coincides with ovarian failure shortly Table 1). The risk of fracture approximately doubles for before the menopause and continues throughout life. The each standard deviation decrease in bone mineraldensity. The risk is more than doubled in individualswith low bone mass and nearly 4-fold greater in womenwith osteoporosis (50% life-time risk at the age of 50years) compared with women with a normal bonemineral density (13% life-time risk at 50 years). Therisks can be doubled again when individuals have had afragility fracture beforehand (see below).
Estimating fracture risk by bone mineral measure- ments is comparable to the assessment of the risk ofstroke by blood pressure readings. Blood pressure valuesare continuously distributed in the population, as is bonemineral density. In the same way that a patient above acut-off level for blood pressure is diagnosed ashypertensive, the diagnosis of osteoporosis is based ona value for bone mineral below a cut-off threshold. As isthe case for blood pressure and stroke, there is noabsolute threshold for bone mineral that discriminatesabsolutely who will or will not fracture. The perfor-mance of bone mineral density in predicting fracture is,however, at least as good as that of blood pressure inpredicting stroke, and considerably better than the use ofserum cholesterol to predict coronary artery disease.
Nevertheless, it should be recognized that, just becausebone mineral density is normal, this is no guarantee thatfracture will not occur – only that the risk is decreased.
If, however, bone mineral density is in the osteoporoticrange, then fractures are likely.
Which Site Should be Measured? The site for assessmentdepends upon the reason for undertaking the scan andalso on the age of the patient. Osteoporosis is a systemicdisease and loss of bone occurs at all sites. For thisreason bone scans for diagnostic purposes shouldnormally be undertaken at any one site. There is only asmall advantage in the measurement of multiple sites.
Because, however, the correlation between bone mass atdifferent sites is less than perfect, osteoporosis at one siteis not invariably associated with osteoporosis at othersites, and therefore assessment of the relevant biologicalsite is preferable. For these reasons, measurements madeat the wrist, spine or hip may be appropriate in younger Fig. 4. Bone mineral density (BMD) in women at different ages and
individuals (to assess the risk of any fracture).
the prevalence of osteoporosis. Bone mineral density is normally In the elderly hip fractures are the major concern and distributed at all ages, but values decrease progressively with age. The carry the highest morbidity and mortality. If the clinician proportion of patients with osteoporosis (with a bone mineral density wishes to predict hip fracture risk with the greatest of 2.5 standard deviation units or less than the young adult mean) accuracy, then measurement at that site is more useful increases exponentially with age. (From Kanis JA, et al. OsteoporosInt 1994;4:368–81.) than elsewhere since measurements at the site of J. A. Kanis et al.
biological relevance predict fractures at that site most Table 4. Clinical risk factors providing indications for the diagnostic
accurately. In addition, osteoarthrosis is particularly use of bone densitometry common in the spine of men and in elderly women, and 1. Presence of strong risk factors.
in such cases this site is less suitable for the Oestrogen deficiency measurement of bone density in these age groups.
Premature menopause (<45 years) Changes in bone mineral density that occur in the Prolonged secondary amenorrhoea (>1 year) immediate postmenopausal period or as a result of Primary hypogonadism treatment are often more marked in the spine and can be Corticosteroid therapy (>7.5 mg/day for 1 year or more)Maternal family history of hip fracture detected earlier than at the hip or wrist.
Low body mass index (<19 kg/m2)Other disorders associated with osteoporosis Problems in the Assessment of Bone Mineral Primary hyperparathyroidismPost-transplantationChronic renal failure There are a number of problems and limitations in the assessment of bone mineral which should be recognized Prolonged immobilization in the interpretation of bone scans (Table 3). Bone Cushing's syndrome mineral density gives an estimate of bone mass based on 2. Radiographic evidence of osteopenia and/or vertebral deformity its mineral content. The presence of osteomalacia, a 3. Previous fragility fracture, particularly of the hip, spine or wrist disorder where mineralization of bone is defective thatmay occur in the elderly, will therefore, underestimate 4. Loss of height, thoracic kyphosis bone mass. Osteoarthrosis at both the spine and the hipare common in the elderly, and will contribute to thedensity measurement, partricularly at the spine, but not this ‘case-finding' approach. The use of risk factors to skeletal strength. Heterogeneity of density due to that add information on fracture risk independently of osteoarthrosis or previous fracture can often be detected bone mineral density improves the specificity of on the scan and in some cases be excluded from the analysis. In the case of the hip, smaller regions of There are relatively few clinical risk factors that can interest can be selected to exclude the joint.
be applied successfully to identify affected individuals(Table 4). Significant and useful factors include a Table 3. Problems in the interpretation of bone mineral measurements
corticosteroids and several diseases that adversely Osteoarthritis (especially the spine) affect bone metabolism. Very low body mass index Vascular calcification (especially the spine) (e.g. <19 kg/m2) and a maternal history of hip fracture Overlying metal objects are risk factors which are in part independent of bone Contrast media (spine)Previous gold therapy mineral density. So too is a history of fractures after the Previous fracture (spine, hip and wrist) age of 45 years, which is a strong risk factor for subsequent fractures at the spine and elsewhere. Loss of height may be estimated from the history or from the Vertebral deformities due to osteoarthrosis, Scheuermann's diseaseInadequate reference ranges difference between measured height and arm span, sincein health these measurements are usually nearly thesame. Combinations of relatively weak risk factors can It is important that an appropriate normal reference also be used. For example, the National Osteoporosis range is used to interpret bone density values. The ranges Foundation of the USA uses smoking, a parental history supplied by manufacturers may variously over- or of hip fracture and leanness (the lowest quartile of body underestimate the proportion of a tested population weight). Individuals with more than two of these risk categorized as having osteoporosis.
factors have a greater than 30% increase in fracture riskat any age.
Measurement of bone mass is indicated in individuals Identification of Patients with Osteoporosis
who have strong risk factors to optimize selection fortreatment (Table 4), provided that it will influence At present there is no universally accepted policy for management decisions for the patients. This is preferred screening to identify patients with osteoporosis. With the to blind treatment because not all patients with strong increasing development of effective agents specifically risk factors will have osteoporosis. This view does not affecting bone metabolism this view may change. In the preclude the usefulness of measurement of bone mineral absence of such policies patients are identified as having density in women without risk factors. In practice, osteoporosis largely because of a fragility fracture or physicians also have to manage patients without risk sometimes by the presence of strong risk factors. Bone factors who would take treatments if their bone mineral mineral density measurements can be used to enhance density were low. Although the use of bone density in Guidelines for Diagnosis and Management of Osteoporosis Table 5. Diagnostic categories based on bone mineral density and
individuals, but life expectancy is short. Up to the age of recommendations within each category 75 years the cut-off point of bone mineral density todiagnose osteoporosis is an appropriate treatment Diagnostic category threshold for several treatments. Hip fracture is a major problem in the elderly, but after the age of 75years the life-time risk of fracture for a given bone mineral measurement decreases (Fig. 5).
Consider prevention inperimenopausal women or In men and women over the age of 75 years, factors other than bone mineral density measurements may Consider treatment in more influence the decision to treat, such as likelihood of elderly with history of falling, the nutritional status for vitamin D, and life fragility fractures Exclude contributing causes,particularly if youngIntervention recommendedparticularly if less than Investigation of Patients with Osteoporosis
Established osteoporosis Very high Exclude contributing causes Intervention strongly indicated The same diagnostic approach should be undertaken inpatients with osteoporosis irrespective of the presence or From The Sheffield Protocol for the Management of the Menopause absence of fragility fractures. However, the range of Under the Prevention and Treatment of Osteoporosis. 4th edition.
clinical and biological tests will depend on the severity Osteoporosis 2000, PO Box 2000, Rotherham S61 2YU, UK.
of the disease, the age at presentation and the presence ofvertebral fractures. The aims of the clinical history, this way is a component of good clinical practice, the physical examination and biological tests (Table 6) are: cost-benefit of this approach is not yet established.
. To exclude a disease that can mimic osteoporosis Irrespective of the presence or absence of risk factors, . To elucidate causes of osteoporosis and contributory the assessment of bone mass is justified only in those cases in which the result obtained will influencedecisions about treatment. In some instances, treatment . To assess the severity of osteoporosis in order to will be justified without measurement of bone mineral determine the prognosis of the disease, i.e. the risk of density, for example in patients with fragility fractures subsequent fractures and other strong risk factors. In other instances, the low . To select the most appropriate form of treatment cost and absence of side effects justify the use of some . To perform baseline measurements for subsequent agents without bone mineral density measurements in monitoring of treatment populations at lower risk (e.g. vitamin D in the elderly).
Table 6. Diagnostic procedures in osteoporosis
Decisions about the need for treatment depend not only on establishing a diagnosis, but also on the age of the patient, as well as the efficacy, costs and side effects History and physical examination of treatment. The decision to treat osteoporosis will Blood cell count, sedimentation rate, serum calcium, albumin, differ between a 50-year-old and an 80-year-old patient phosphate, alkaline phosphatase, liver transaminases, serum proteinelectrophoresis, urinalysis (Table 5). Osteoporosis in the latter is found in 50% of Radiograph of lumbar and thoracic spinal columnBone mass measurement (DXA or SXA)Testosterone and gonadotrophins (in men) OptionalSerum and urine markers of bone turnoverSerum PTH, 25–OHD, TSH, cancer markersGonadotrophinsUrinary free cortisolBone marrow examinationIliac crest bone biopsy after tetracycline double labelling for histomorphometry and marrow analysis Differential Diagnosis of Osteoporosis Osteomalacia and malignancy commonly induce bone Fig. 5. Life-time risk (LTR%) for osteoporotic fractures shown by age
loss and fractures. Osteomalacia is characterized by a defect of mineralization of bone matrix most commonly J. A. Kanis et al.
due to impaired intake, production or metabolism ofvitamin D. Other causes include impaired phosphatetransport or the chronic use of some drugs such asaluminium salts (and other phosphate-binding antacids),high doses of fluoride or etidronate, and chronic use ofantacids and anticonvulsants. In most cases the diagnosisof osteomalacia is suspected by the clinical history andby abnormalities in biochemical tests such as low valuesof serum and urinary calcium, serum phosphate and 25-hydroxyvitamin D, and high values for alkaline phosphatase and parathyroid hormone. A transiliacbone necessary to demonstrate a defect in mineralizationunequivocally.
Diffuse osteoporosis with or without pathological fracture is common in patients with multiple myeloma, a Fig. 6. Assessment of bone mineral density in a 70-year-old woman
using the T-score and Z-score. The patient's value depicted by the
condition suspected by the severity of bone pain, filled square lies 1.2 standard deviations below the average expected increased sedimentation rate and Bence Jones proteinur- for her age (Z-score: –1.2). Bone density is lower than 3 standard ia and identified by marrow aspirate, serum and urine deviations below peak bone mass (T-score = –3.0), denoting the (immuno)electrophoresis of proteins. Similarly, patho- presence of osteoporosis.
logical fractures due to metastatic malignancies canmimic osteoporosis and can be excluded by clinical and radiological examination, biological tests and scintigra- Table 7. Factors contributing to osteoporosis
phy or other imaging techniques. Finally, vertebralfractures in osteoporosis should be differentiated from Genetic or constitutional vertebral deformities due to other disorders such as White or Asiatic ethnicity scoliosis, osteoarthrosis and Scheuermann's disease.
Family (maternal history of fractures)Small body frameLong hip axis lengthPremature menopause (<45 years) Causes of Osteoporosis and Contributing Factors Lifestyle and nutritional A variety of disorders is associated with an increased NulliparityProlonged secondary amenorrhoea risk of osteoporosis (Table 7). Many are evident from the history or physical examination. Unusual presentations Excessive alcohol intake of osteoporosis should alert the physician to search for such factors. Examples include osteoporosis before the Prolonged immobilization age of 50 years and osteoporosis in men. A low bone Prolonged parenteral nutritionLow body weight mineral density for the age of the patient may be used asa guide to search for secondary causes in both men and Medical disorders women. Bone mineral measurements in relation to the Malabsorption due to gastrointestinal and hepataobiliary diseases average value expected for that age can be expressed in age-specific standard deviation units, commonly referred to as the Z-score (Fig. 6). Individuals with a Z-score of Primary hypogonadism –1 will have approximately a 2-fold higher risk of fractures in their remaining life-time than those with an Osteogenesis imperfecta average value for bone mineral for their age. Those with Rheumatoid arthritis a Z-score of –2.5 will have a greater than 4-fold risk.
Chronic obstructive lung disease Such cases may require additional investigation and Chronic neurological disordersChronic renal failure referral to a specialist. Note, however, that some relatively common disorders such as thyrotoxicosis or vitamin D deficiency in the elderly may not be clinically obvious, and for this reason appropriate tests may be required (Table 6).
Chronic corticosteroid therapyExcessive thyroid therapyAnticoagulantsChemotherapy Assessment of Prognosis Gonadotropin-releasing hormone agonist or antagonistAnticonvulsant The assessment of the severity of osteoporosis is an Chronic phosphate-binding antacid use important step in the clinical investigation of the disease Guidelines for Diagnosis and Management of Osteoporosis to provide a prognosis and optimize therapeutic the known risk factors. Their identification is important, strategies. Four compontents can be identified: however, for evaluating the prognosis of osteoporosis and in some cases for its management.
Quantification of bone mass There are several different categories of risk factors.
. Identification of previous fractures (axial and appen- They may be related to the determinants of bone mineral density, capture the risk of falls, be related to skeletal . Identification of factors that influence the risk of fragility independently of bone mineral density or a fractures independently of bone mass combination of these. A risk factor for fragility fractures . Assessment of the rate of loss of bone independent of bone mineral is the length of the head ofthe femur (hip-axis length). In women, the longer thelength the higher the risk of hip fracture. Clinical and Quantification of Bone Mineral. The lower the bone environmental factors associated with an increased risk mass, the higher the risk of fracture. With DXA or SXA, of fracture are best documented in the elderly to assess the risk approximately doubles for each unit decrease in the risk of hip fracture. Excessive frailty, immobiliza- T-score. For example, a woman with a T-score of –3.5 tion, concurrent diseases or drugs which increase the has a 2-fold higher risk of fracture than a woman with a liability to falls are examples. Environmental factors T-score of –2.5, DXA and SXA are the preferred such as slippery surfaces and inadequate lighting techniques, but if they are not available, any estimate increase the risk of fractures independently of bone using a validated technique is better than none. Bone mass by causing falls or modifying the impact of the fall.
mass can be measured at the spine, hip, forearm or heel, Risk factors unrelated to bone mass have little impact in because osteoporosis is a systemic disease occurring the assessment of fracture risk in early postmenopausal throughout the skeleton. As mentioned, site-specific women, but in the elderly their presence appears to at least double the risk of hip fracture.
fracture risk is best assessed at the hip.
After the age of 65 years, the lumbar spine may not be Rates of Bone Loss. The loss of bone with age in women the site of choice because of the errors of accuracy and probably in men varies from patient to patient but associated with osteoarthritis, osteoarthrosis or lumbar continues throughout life. Where rates of bone loss are fractures. In the majority of cases, measurement at one high the risk of fractures is higher than where rates of site is sufficient, although in some cases measurement at loss are low. Direct measurement of the rate of bone loss two sites may be justified.
in an osteoporotic patient would require at least two The absolute risk of fracture depends not only upon measurements of bone mass over a 2–4 year interval, bone mineral density but also on life expectancy. Thus, given the precision errors of the technique and the for a given value of bone mineral density the remaining magnitude of change in bone mass that is expected. Such life-time risk in the absence of treatment for patients a strategy is not practical where it is necessary to decide aged 50 years is high compared with the same bone whether or not to treat at the time of initial assessment.
mineral density value in a patient of the same sex at 80 Because the rate of bone loss is proportional to the rate years. The conversion of relative risk to absolute risk is of bone turnover in postmenopausal women, it has been helpful information for the patient and physician and suggested that the rate of loss can be predicted by aids in management decisions.
assessing bone turnover with serum and/or urinarymarkers that are specific for bone formation and Previous Fractures. Patients who have suffered one or resorption. Serum osteocalcin and alkaline phosphatase, more fragility fracture at any site are at increased risk of in particular the bone-derived fraction, are validated having subsequent fracture for any given value of bone indices of bone formation. Urinary hydroxyproline and mineral. The earlier the age at fracture and the greater fasting urinary calcium/creatinine ratios are widely used the number of previous fractures, the greater the as indices of resorption. However, the pyridinoline subsequent risk. The risk of vertebral fractures is crosslinks and related peptides are more sensitive and particularly high in those with prevalent vertebral specific markers of bone resorption. The predictive value fractures and is increased at least 2-fold. A wrist fracture of future bone loss is improved by using a marker of doubles the risk of hip fracture and triples the risk of formation and a marker of resorption rather than one vertebral fracture. Thus, previous fractures should be marker alone. Although rates of loss assessed in this way documented. A lateral radiograph of the thoracic and are less accurate than rates of loss assessed over many lumbar spine is necessary to detect prevalent vertebral years by sequential bone mineral density measurements, a high rate of bone resorption (i.e. above the referencerange for premenopausal women) is associated with a 2- Additional Risk Factors. Although several clinical risk fold increase in the risk of vertebral and hip fracture factors are significantly associated with a low bone mass, independently of the prevailing bone mineral density.
their identification cannot be used in individuals as a Measurement of a bone marker at the time of the surrogate for bone mass measurement. For example, in initial investigation of osteoporosis also provides useful women 10 years after the menopause only 15–30% of baseline parameters for monitoring treatment using the total variance of bone mass can be accounted for by inhibitors of bone turnover (discussed below).
J. A. Kanis et al.
Non-drug Treatment of Osteoporosis
Table 8. Calcium content of some foods
Treatment of osteoporosis not only comprises the modification of bone mass, but in addition involves: . Maintenance or improvement of mobility Milk, semi-skimmed Nutritional advice . Treatment of associated disorders and risk factors Treatment of associated morbidity Maintenance of Mobility Canned sardines in oil Canned pilchards in oil Regular exercise is important for general health. Non- weight-bearing activities provided by physiotherapy, swimming or gymnastics variously improve well-being and increase confidence and coordination and may decrease the risk of falls. With respect to skeletal health, weight-bearing activity such as walking isbeneficial. The necessary intensity and frequency ofsuch exercise is unknown.
common foods is given in Table 8. Some mineral waters What is clear is that immobilization, even for a short are also rich in calcium. Where dietary manipulation is period, is deleterious. The gains from vigorous exercise not feasible, calcium may be given in the form of compared with everyday activities are probably small, supplements (see later). Higher intakes of calcium may and must be maintained to preserve any effect. Very be required where other treatments are given.
vigorous exercise can give rise to gonadal insufficiencyand aggravate osteoporosis. Planned exercise regimensare, however, important for the rehabilitation of Treatment of Associated Disorders and Risk Factors individuals with established osteoporosis.
Treatment of diseases associated with osteoporosis (seeTable 7) is unlikely to reverse osteoporosis except in children, but may prevent the progression of thedisorder. Examples include thyrotoxicosis, prolactinoma Vitamin D deficiency impairs the mineralization of bone and hypercortisolism. Thyroid replacement treatment and may also accelerate osteoporosis. The recommended should be carefully monitored and corticosteroids given dietary allowance for vitamin D is 400 IU daily in the lowest possible doses.
(approximately 10 mg) and, where necessary, the diet Many modifications to lifestyle which stand to may be modified or supplements given. The require- improve general health may also reduce the risk of ments for vitamin D in the elderly are not well fracture in patients with osteoporosis. Excessive use of established and may be as high as 800 IU daily. Intakes alcohol should be avoided. Smoking is probably a minor above this have no added benefits and expose patients to risk factor, but there are many other reasons to advise potential toxicity such as hypercalcaemia. The risks of patients to stop smoking. The risk of falls may be vitamin D deficiency are particularly high in institutio- reduced by treating underlying causes and revision of nalized individuals not exposed to sunlight.
concomitant drug treatment. Where possible, long-acting Normal protein intake is important in the elderly, and hypnotics and psychotropic drugs and overtreatment attention to dietary deficiencies at the time of hip with agents for hypertension should be avoided, since fracture decreases the morbidity and mortality.
these may increase the risk of falls. The provision of soft The intake of calcium that best advantages the floor coverings or the wearing of hip protectors decrease skeleton is controversial. The controversy surrounds the impact of falls and the risk of fractures. Such the requirements for peak skeletal mass rather than in measures are particularly useful in patients in institu- later life. In the young, the recommended dietary tional or sheltered accommodation. These approaches allowance (RDA) for calcium varies between countries.
should not be seen as substitutes for medical interven- In the United Kingdom, for example, the RDA is 400– tion, but as adjuncts to treatment.
500 mg daily, whereas in the United States it is 800 mg.
In contrast there is little disagreement that an adequate intake of calcium attenuates, though does not reverse, Treatment of Associated Morbidity bone losses in individuals with osteoporosis. It isimportant, therefore, that all patients with osteoporosis Early mobilization after fractures is a priority. In the are encouraged to take the RDA of calcium irrespective case of hip fracture, internal fixation or hemiarthroplasty of other treatments. The calcium composition of some is preferred to conservative management to avoid the Guidelines for Diagnosis and Management of Osteoporosis consequences of immobilization, particularly bone loss Because of the differences in the availability of which is not subsequently regained. In the elderly, specific agents directed at bone metabolism in different attention to post-operative nutrition, and particularly countries, approaches to treatment will vary. Never- protein intake, decreases morbidity and mortality.
theless, there are several general approaches that are Treatment of acute and chronic back pain related to vertebral fractures depends on general measures and noton anti-osteoporotic drugs. Acute pain due to a recentvertebral fracture responds to bed rest, analgesics, heatand gentle massage or transcutaneous electrical nerve 1. Inhibitors of Bone Turnover
stimulation (TENS) of paraspinal muscles to alleviatespasm. Total bed rest should not exceed a few days as The majority of agents used in osteoporosis inhibit bone prolonged immobilization may aggravate bone loss. The resorption and thereby the turnover of bone. In temporary use of a back support is often useful to help osteoporosis their administration causes a small incre- the patient to resume daily activities as soon as possible.
ment in bone mass (5–10% at the lumbar spine and less The long-term management of pain due to vertebral at other sites) over a period of up to 3 years. Thereafter, fractures include the use of analgesics, physiotherapy, bone mass is variously stabilized, decreases slowly or TENS and intermittent use of spinal supports for some increases slowly depending on the agent and dose activities. A supervised exercise programme to maintain selected. The increase in skeletal mass during the early strength and flexibility of the thoracic and lumbar spine years of treatment is not sufficient to restore skeletal is desirable. The lifting of heavy weights should be mass to normal in the osteoporotic patient. The oestrogens and bisphosphonates in sufficient dosesprevent bone loss. Less complete effects may be seenwith other agents.
Drug Treatment of Osteoporosis
The gains in bone mass or inhibition or attenuation of bone loss are associated with a decrease in the risk of A number of agents which favourably affect skeletal fractures. Observational and randomized controlled trials metabolism are available in different countries (Table 9).
indicate the gonadal hormones, bisphosphonates, calci- Several of these agents are utilized both in treatment and tonins and calcium decrease fracture risk, but the level of in prevention. The scope of these guidelines is very evidence for anti-fracture efficacy varies markedly much directed to the treatment of osteoporosis, but similar considerations apply to its prevention.
Table 10. Information on the anti-fracture effects of different
therapeutic agents commonly used in osteoporosis from randomized
Table 9. Some agents available for use in the treatment of
clinical trials (RCT) and observational studies.
RCT evidence RCT evidence Observational Inhibitors of bone turnover Oestrogens with and without progestogens Oestrogen derivatives and receptor agonists Calcitonins (salmon, eel, human, porcine) Pamidronate and others Vitamin D derivatives ± Anabolic steroids Stimulators of bone formation ++, consistent effects in several studies; +, consistent effects in a few Parathyroid hormone and other peptides studies; 0, not studied; ±, variable effects reported; –, negative effects Anabolic steroids Hormone Replacement Therapy Vitamin D and derivatives Calciferol and cholecalciferol (vitamins D2 and D3)Calcitriol In women with post menopausal osteoporosis, hormone replacement therapy (HRT) should be considered early in a management programme. HRT prevents further lossof bone at all skeletal sites, irrespective of the age of the J. A. Kanis et al.
individual, and the effects persist for the duration of Table 11. Potential, relative and absolute contraindications for
hormone replacement therapy The decision to utilize HRT will depend upon a number of factors, including: Active endometrial or breast cancer . Evidence of hypogonadal status PregnancyUndiagnosed abnormal vaginal bleeding . The absence of absolute contraindications to treatment Severe active liver disease . The risks and benefits of HRT for the individual Acute deep venous thrombosis and thromboembolic disease Recent hormone-dependent cancers The risks and benefits perceived by the patient Relative contraindications (specialist opinion may be sought) The acceptability of long-term HRT to the patient . Adequate treatment of any associated disorder, Previous spontaneous deep venous thrombosis or pulmonary particularly vitamin D deficiency Systemic lupus erythemotosus The assessment of hypogonadal status is not usually Endometriosis (unopposed oestrogens) problematic. The presence of postmenopausal symptoms FibroidsPrevious breast cancer or strong family history is presumptive evidence of hypogonadal status in Endometrial cancer (within 5 years) hysterectomized women. In some patients biochemical evaluation of gonadal status by the measurement of follicle stimulating hormone (FSH) is required.
Menopausal symptoms are a common reason why Pre-existing gall stones patients elect to take HRT. It should be explained, Mild liver disease however, that the duration of treatment required to control menopausal symptoms is relatively short (1–2 Parenteral route preferred.
years) compared with the duration of treatment that isappropriate for osteoporosis (5–10 years or even longer).
risks and benefits perceived by the patient. Despite an The risks and benefits of HRT should be explained to explanation of the risks and benefits, some women will patients. The side effects of HRT include menstrual or prefer to avoid HRT and alternative options should be breakthrough bleeding in non-hysterectomized women, breast tenderness, a bloated feeling and changes in There are few absolute contraindications to oestrogen weight. A number of apparent contraindications given in therapy (Table 11). Age is often cited as a contra- product information brochures in many countries are indication, but the risks and benefits do not change with misleading since they are derived from the pharmaco- age. There are, however, several disorders where a logical effects observed with high doses of synthetic careful assessment is appropriate and in some instances is an appropriate reason for referral (see Table 11).
cardiovascular disease is often cited as a relative Adequate treatment of any associated disorders should contraindication, but current evidence suggests that the in some cases precede or be given concurrently with converse is true. Indeed, the presence or risk of HRT. In the elderly it is particularly important to cardiovascular disease is a major reason why HRT is exclude vitamin D deficiency. For many disorders the preferred. Patients should also be counselled on the postmenopausal status will aggravate osteoporosis. Note potential adverse effects of HRT, including the risk of that HRT may be used with other treatment modalities, breast cancer and venous thromboembolism. An in- under specialist supervision. Examples include the use of creased risk of breast cancer is biologically plausible. It parathyroid hormone (PTH) and fluoride.
is known that endogenous hormonal factors play a part inthe aetiology of the disease throughout life (e.g. age at Types of Oestrogen Therapy. Hysterectomized women menarche, breast feeding and age at menopause). A can be given oestrogen preparations alone. Women with small increase in relative risk has been found by some, a uterus should be given both an oestrogen and a but not all studies with long-term use of HRT. If the risk progestogen intermittently or continously, which pre- is increased then the increase is small, and lower than the vents the occurrence of endometrial hyperplasia and any risks of breast cancer associated with obesity, regular risk of endometrial carcinoma. In most countries, so- alcohol intake or a family history of breast cancer. It called natural oestrogens such as 17b-oestradiol are should be explained that the reported increase in some preferred to synthetic oestrogens. Doses which prevent studies has not usually been associated with an increase bone loss (on average) of various preparations are shown in mortality and that the use of HRT implies regular in Table 12. In the elderly it is prudent to start with small surveillance. Women electing to take HRT should have doses and prescribe a bone-sparing dose after several Except in hysterectomized women and with some In many countries, combined continuous oestrogen HRT modalities (such as continuous combined regi- and progestogen regimes are available. They are mens), menstrual bleeding is an inevitable consequence.
particularly suitable for postmenopausal rather than Whereas most analyses indicate that benefits outweigh perimenopausal women in whom withdrawal bleeds the risks of HRT, counselling should also elucidate the are not tolerated. These regimens generally do not Guidelines for Diagnosis and Management of Osteoporosis Table 12. Bone-sparing doses of commonly used preparations
dose of 2.5 mg daily and there is usually no withdrawalbleed. The long-term effects of tibolone on cardiovas- Bone-sparing dose (mg) cular morbidity have not been evaluated, but it decreasesboth high density and low density lipoproteins (HDL and Oestradiol valerate Piperazine oestrone sulphate Conjugated equine oestrogens Oestradiol implants (6-monthly) Transdermal oestradiol women. Tamoxifen may accelerate skeletal losses Ethinyl oestradiol before the menopause and its prolonged use may Oestrone sulphate increase the risk of endometrial cancers. Tamoxifen is Other agents used in specialist centres, particularly in women with a history or family history of breast cancer. New modulators are currently being developed that may have agonist activity on the skeleton and cardiovascular system but not on the breast and endometrium.
Calcium. Calcium is widely available throughout theworld and is the major non-HRT intervention used in aGiven for 12–14 days out of 28 days with continuous oestrogen.
osteoporosis. Its principal effect is to decrease the rate of Commonly used in the United States.
bone loss rather than to prevent this loss entirely. It isless effective than many other treatments and is usually induce cyclical bleeding and suppress endometrial given as an adjunct to other treatments.
proliferation. In about a quarter of women, irregular The doses of calcium required to attenuate bone loss bleeding may occur, particularly in the first 6 months are pharmacological, and the diet should be supplemen- after the onset of treatment. This can be minimized by ted with an additional 1000–1500 mg daily. It is increasing the doses of progestogen where oestrogen and appropriate to offer calcium either as a supplement or progestogen are being used separately.
by dietary manipulation in all patients with osteoporosis Oestrogens and progestogens are usually given by in whom other treatment modalities are not prescribed.
mouth. Transdermal and subcutaneous delivery systems The major advantage of calcium is that it is easy to use, bypass the liver as do other parenteral routes. These requires little monitoring, and is acceptable to patients.
routes may be advantageous in patients with mild liver Compliance with treatment is high.
disease, previous thromboembolism or gall stones. Some A wide variety of calcium preparations is available in most countries. Many non-proprietary formulations are also available, but in many countries their calcium Implants of oestradiol are given as a pellet implanted content is small, so that more than 10 tablets need to be into subcutaneous fatty layers. They are most frequently taken daily in order to provide a dose of 1000 mg. It is used at the time of surgery in women undergoing important to recognize that the elemental content of oophorectomy or hysterectomy, but women with a uterus calcium varies with the product. For example, calcium should also take progestogens.
carbonate contains 40% of elemental calcium by weight Topical oestrogen vaginal creams, pessaries and whereas calcium gluconate contains only 9%.
tablets have a potent local action and effectively relieve There are small differences in the bioavailability of vaginal dryness and atrophic vaginitis. They relieve calcium between proprietary preparations, but these are urinary symptoms less consistently. They do not deliver unlikely to be of therapeutic significance. Acute adequate amounts to treat osteoporosis, but the rate ofabsorption of oestrogens from the vagina varies availability is greater with meals but is again of little considerably so that cyclical progestogens may be therapeutic significance. It may be more important to divide the daily dose so that each dose does not exceed500 mg, since the additional gains from larger does aretrivial.
Oestrogen Derivatives and Receptor Agonists The risks of supplemental calcium are negligible, but it is contraindicated in patients known to have increased Tibolone. Tibolone is a synthetic analogue of the intestinal absorption of calcium (e.g. due to hypercal- gonadal steroids with combined oestrogenic, progesto- ciuria nephrolithiasis or sarcoidosis) or hypercalcaemia.
genic and mild androgenic properties. It preventsoestrogen deficiency bone loss, is effective in controlling Calcitonins. Calcitonin in pharmacological amounts is hot flushes and sweats, and can also improve mood and an inhibitor of bone resorption, and this is a major reason libido. Its effects on fracture frequency have not been for its use in osteoporosis. It is given either as a nasal reported. It does not cause endometrial proliferation at a spray or as a parenteral injection.
J. A. Kanis et al.
In addition to preventing bone loss it also has analgesic 5–10% over 2 years and thereafter is stabilized.
effects and it is an attractive option for the acute Vertebral fracture risk is decreased. The effects on hip management of vertebral fracture, particularly where fracture are not known.
bed rest or other forms of immobilization are required.
Alendronate is given in a dose of 10 mg daily on a The effects of calcitonins on bone mass and fracture after continuous basis. Side effects are uncommon, but include many years of administration are not yet known. Short- upper intestinal and oesophageal irritation. Large term studies suggest a reduction in fracture rate and randomized controlled trials have clearly demonstrated fracture prevention studies are currently in progress.
a beneficial effect of oral alendronate on bone mineral Several different calcitonins are available for the density and the incidence of fractures among women with postmenopausal vertebral osteoporosis. In one such study calcitonin, salmon calcitonin (salcatonin), human calci- of women with low bone density in the lumbar spine or tonin and an analogue of eel calcitonin. Doses used vary femoral neck, who were treated with alendronate and from 50 to 100 International Units (IU) daily by calcium, patients showed progressive increases in bone parenteral injection. A commonly used regimen is 100 mineral density in the axial and appendicular skeleton IU three times per week. Higher doses (200 IU daily or over a 3-year period, as compared with a calcium-treated more) are required when salmon calcitonin is given by control group who lost bone. Mean differences in bone the nasal route.
mineral density between the treated and control groups There are no absolute contraindications to calcitonin after 3 years were 8.8% in the spine, 5.9% in the femoral with the exception of allergy, which is extremely rare.
neck and 2.5% in the total body. In this study treatment When given parenterally all the calcitonins induce was associated with a 48% reduction in the proportion of side effects which are inconvenient rather than serious.
women with new vertebral fractures, a decreased Their frequency and severity are dose-dependent. The progression of vertebral deformities, and a significant most frequent effect is nausea, which occurs shortly after reduction in height loss. In a second study, 6000 women injection in up to 30% of patients. It may be transient or aged 55–80 years, selected from the general population, persist for several hours. Occasionally it may persist underwent thoracolumbar radiography. The 2000 women until the next injection and 5–10% of patients cannot with vertebral deformities were randomized to receiving tolerate long-term treatment for this reason. Nausea can alendronate/calcium or calcium alone. The alendronate- be managed to some degree by the concurrent treated arm revealed a 57% reduction in painful spinal administration of anti-emetics. Both may be given at fractures, a 44% reduction in wrist fractures and a 50% reduction in hip fractures. All these differences were Other symptoms including flushing, vomiting, diar- rhoea and local pain at the site of injection. Systemic Much less data is available for clodronate and side effects are rarely, if ever, encountered with the use pamidronate. Clodronate is usually given as a daily of nasal calcitonin, but local nasal irritation occurs in dose of 800 mg but intermittent intravenous cyclical oral some patients.
regimens such as every other month are given in somecountries. The most frequently used oral dose of Bisphosphonates. Several bisphosphonates are available pamidronate is 150 mg daily. It may cause upper- in different countries for the management of osteoporo- intestinal intolerance and for this reason is not widely sis. At present etidronate and alendronate are the most utilized. Both these bisphosphonates induce progressive commonly used bisphosphonates, but clodronate and increments in spinal bone mineral density.
pamidronate are available for use in several countries.
The bisphosphonates are poorly absorbed from the gastrointestinal tract. Absorption is between 1% and 5% 2. Stimulators of Bone Formation
of the administered dose, but is reduced to nearly zero inthe presence of food or liquids containing calcium or Several agents are capable of inducing marked increases other divalent cation which chelate the bisphosphonate.
in skeletal mass in osteoporotic patients and indeed Thus, the bisphosphanates when given orally need to be skeletal mass may be restored to normal. Agents include taken away from food or calcium-containing liquids. A parathyroid hormone and its analogues, combination and proportion of the dose is bound to calcium in the sequential regimens using several interventions, and skeleton and the remainder excreted unchanged in the fluoride. With the exception of fluoride in some urine. At skeletal sites they inhibit bone resorption in a countries, they are used in specialist centres.
Etidronate is usually given in a dose of 400 mg daily for 2 weeks of a 13-week cycle. Usually, calcium is Fluoride Salts given continuously in the 11 weeks that the patient is nottaking etidronate. It is important that etidronate is not Fluoride salts are available in many countries but not given continuously since this may impair the miner- consistently, and where unavailable are utilized by alization of bone. Side effects are few and usually related specialist centres. Preparations of fluoride include sodium fluoride as a tablet and enteric coated or expected, bone mass increases at the lumbar spine by sustained release preparations. Disodium monofluoro- Guidelines for Diagnosis and Management of Osteoporosis phosphate is available in several European countries. A have been less well characterized than the inhibitors of dose of 100 mg is equivalent to 16.4 mg of fluoride ion bone turnover or stimulators of bone formation.
or 36 mg of sodium fluoride. Fluoride is one of the fewagents cancellous bone mass on a long-term basis, but its Anabolic Steroids effects on vertebral fracture are inconsistent. It must begiven with calcium to prevent secondary hyperparathy- Anabolic steorids can be broadly divided according to roidism and cortical bone porosity which may increase structural additions at the carbon 17 position. 17a- the risk of hip fracture. With the exception of calcium alkylated agents include stanozolol and oxymetholone.
monofluorophosphate and some soluble calcium salts, 17b-esterified derivatives include testosterone and calcium should be given away from fluoride since it nandrolone. The side effect profile is determined, in impairs its bioavailability. Appropriate doses of bio- part, by these different conformations.
available fluoride ion are 10–15 mg daily.
The anabolic steroids most commonly used in Side effects of fluoride therapy are common, but osteoporosis are stanozolol and nandrolone, but they mainly reversible when treatment is stopped. They are not universally approved for use; in countries where include gastrointestinal irritation (nausea, vomiting, their use is restricted they are commonly given in pain, diarrhoea and occasionally gastrointestinal bleed- specialist centres. Stanozolol is given by mouth 5 mg ing) and osteoarticular pain. Side effects are dose daily. The most common route for nandrolone is by dependent. Gastrointestinal side effects appear to be intramuscular injection of nandrolone decanoate (50 mg most troublesome with solutions, and are improved by i.m. every 2–4 weeks).
tablet formulations and when taken with food. Fewer The anabolic steroids prevent bone loss, probably by a gastrointestinal side effects are noted with sustained preferential effect on endocortical bone. In addition to release or enteric coated preparations.
their effects on skeletal metabolism, they have marked Osteoarticular pain is also dose dependent and anabolic effects on muscle mass and are commonly used commonly resolves after stopping treatment over 4–8 in the frail elderly population. They are also one of the weeks. It may be associated with the presence of few anti-osteoporotic agents which make patients feel microfractures visible on bone scans. These fractures better. A major difficulty with their use is side effects.
occur most commonly in patients with lower bone Agents given by mouth such as stanozolol increase mineral density. Treatment may be resumed at a lower hepatic transaminases in approximately 50% of patients.
dose when bone pain has ceased.
These changes are reversible when treatment is stopped.
A major problem in the management of osteoporosis Treatment is commonly continued unless liver enzyme with fluoride is that the response to treatment is activity exceeds 2 times the upper limit of the reference heterogeneous and up to 40% of patients show little or range. Another effect of stanozolol is the induction of an no anabolic effect of sodium fluoride. There is currently atherogenic lipid profile. This potential effect on no reliable way of assessing before treatment who will cardiovascular risk has to be weighed against the respond poorly or favourably. Effects on bone mass can potentially beneficial effects on coagulation, fibrinolysis be assessed either quantitatively by the assessment of and the skeleton. For this reason stanozolol and bone mineral density or qualitatively by radiographic oxandrolone may be more suitable for use in the elderly.
assessment of the spine.
Hoarseness and virilization are rare with the use of Fluoride should not be used in patients with renal stanozolol, but are major side effects of nandrolone. The failure, nor in patients in whom osteomalacia is most common side effect is hoarseness, and its suspected. The latter are likely to respond adversely to frequency is dose dependent. It is less frequent when fluoride unless vitamin D is also given. Indeed, nandrolone is given 4-weekly rather than 2-weekly.
physiological doses of vitamin D should be given Both agents may induce mild increases in sodium where the nutritional status of the patient is in doubt, retention. This is rarely a reason for stopping treatment, but pharmacological doses of vitamin D offer no but diuretics may be required. Many patients report an advantages over the use of fluoride and calcium alone.
improvement in general well-being. In a few, an increase It is unclear for how long treatment should be given, in libido is reported as an unwanted effect. Requirements but it should not be continued indefinitely. A common for anti-coagulants and oral hypoglycaemic agents may strategy is to treat for 2–3 years. In specialist centres decrease because of their effect on coagulation and longer treatments are sometimes given to restore skeletal glucose tolerance.
mass at cancellous skeletal sites to within the normalrange, which in most patients can be achieved within 5years.
Vitamin D and Derivatives Calcitriol and Alfacalcidol. Alfacalcidol is a synthetic 3. Other Agents with Heterogeneous Effects
analogue of the vitamin D metabolite calcitriol (1,25-dihydroxyvitamin D3) and it is metabolized to calcitriol Several other agents are available in different countries by 25-hydroxylation in the liver. It is somewhat less for the treatment of osteoporosis (see Table 9). They potent than calcitriol. Both agents are used in some J. A. Kanis et al.
countries for the treatment of osteoporosis. Several but it is extensively metabolized, so that no accumulation not all studies show decreases in vertebral fracture risk.
occurs in any body tissue. The most frequent side effects The effects on bone mineral density have been less No fracture data are available yet, but fracture The major problem with the use of the vitamin D prevention studies are currently in progress.
derivatives is hypercalcaemia and hypercalciuria. Ad-verse effects of prolonged hypercalcaemia include Thiazide Diuretics. Thiazide diuretics are not licensed for impairment of renal function and nephrocalcinosis. The use in osteoporosis, but one of their actions is to increase narrow therapeutic window demands that frequent renal tubular reabsorption of calcium and decrease bone surveillance of serum and possibly urine calcium turnover, thereby decreasing skeletal losses. Where should be undertaken in patients exposed to these diuretics are required there is clearly an advantage to agents. Calcium supplementation of the diet should be the use of thiazide diuretics, where appropriate.
avoided or used with care.
Vitamin D. Low values for calcidiol (25-hydroxyvitamin Monitoring of Treatment
D) are commonly found in the elderly, particularly thoseconfined to institutional care in whom the risk of hip and General Measures other fractures is much higher than in the generalcommunity. For this reason vitamin D may be used Physical examination should be repeated at intervals that routinely in institutionalized patients. In the elderly, will depend on the severity of the disease, and should privational deficiency is not always associated with include the assessment of weight, height (especially if florid osteomalacia, but a more common finding is vertebral fractures are present), clinical risk factors, secondary hyperparathyroidism. A parathyroid hormone recent drug intervention and peripheral fractures. In case value above normal using an intact assay or a calcidiol of episodes of acute back pain and/or of a significant loss value of <20 nmol/l are appropriate intervention thresh- of height (> 1 cm), lateral radiographs of the thoracic olds and treatment decreases fracture risk. Vitamin D2 or and lumbar spine should be performed. Detecting new vitamin D3 can be given alone or with calcium and other vertebral fractures requires a careful comparison of the supplements where other nutritional deficits are sus- previous and recent radiographs with adequate quality pected. In some countries combined formulations of control, particularly centering of films.
calcium and vitamin D are available and are useful in theelderly where multiple tablet types increase the risk ofnon-compliance or toxicity. It is important, however, to Repeated Bone Mass Measurement check that the dose of vitamin D and calcium isappropriate.
The goal of drug therapy in a patient with osteoporosis is Appropriate amounts of vitamin D are 400–800 IU to prevent further bone loss in order to decrease fracture daily. In patients who are unlikely to be compliant, risk. After 2 years of antiresorptive therapy there is intermittent intramuscular injection may be used. Annual usually a small increase in bone mass in the order of 5– injections of 150 000 or 300 000 units can be given in 10% at the lumbar spine and less than 5% at the femoral the autumn and levels of calcidiol remain increased neck and forearm. Gain at the spine is usually more throughout the year.
pronounced with agents that stimulate bone formation.
The risks of appropriate doses of vitamin D are very Fluoride induces a linear 4–8% per year increase of bone low in the absence of sarcoidosis and idiopathic mass at the spine and of smaller magnitude at the hip.
hypercalciuria where there is increased sensitivity to Although these differences in response between skeletal vitamin D. Although vitamin D status may also be sites with both types of therapy are not fully understood, improved by sunshine exposure and ultraviolet irradia- they are partly explained by a greater effect of anti- tion, radiation is less efficient in the elderly than in osteoporotic drugs on cancellous bone – which has a young adults. In addition, excessive sunshine exposure high turnover – than on cortical bone – which has a in the elderly increases the frequency of skin cancers.
lower turnover rate. Because the long-term precisionerror of the most precise techniques (DXA and SXA) isin the order of 1–2%, a change of 3–6% is required in a single patient to assess treatment effectiveness. Thus, inmost instances, repeating bone mass measurement at an Ipriflavone. Ipriflavone is a synthetic derivative of interval shorter than 2 years after intitiating therapy may naturally occurring isoflavones, and is available in not be helpful for the physician's decision-making about several countries for the management of osteoporosis.
treatment efficacy. It has been argued that repeating bone It may potentiate the effects of endogenous oestrogens or mass measurement during hormone replacement therapy directly inhibit bone resorption.
(HRT) is not useful, because treatment is effective in up Ipriflavone has been shown to prevent bone loss in to 90% of patients. This does not apply to daily practice, osteoporosis using a continuous treatment with a daily because variable doses are used and compliance is often oral dose of 600 mg. Its absorption is enchanced by food; low. In a patient with osteoporosis who has already lost a Guidelines for Diagnosis and Management of Osteoporosis significant amount of bone, monitoring treatment preventing hip fractures, for various agents in the efficacy appears to be necessary, even with HRT, and secondary prevention of vertebral fractures and for may improve compliance.
hypothetical interventions in the elderly.
Studies of postmenopausal oestrogen replacement that consider osteoporosis offer the following consistent The Use of Biochemical Markers of Bone Turnover to conclusions: (a) the cost per QALY saved when Monitor Drug Therapy oestrogen is used by hysterectomized women comparesfavourably with other healthcare interventions; (b) these Antiresorptive therapy in postmenopausal osteoporosis costs increase considerably when HRT is recommended induces a 30–60% decrease in specific markers of bone to all women; (c) targeting of HRT on the basis of turnover such as serum osteocalcin, bone alkaline fracture risk (using bone mineral density measurement) phosphatase and urinary pyridinoline crosslinks after is more cost-effective than treating all women; and (d) 3–6 months, followed by a plateau that is sustained as treatment in the elderly woman (around 65 years) is long as treatment is continued. Markers of bone more cost-effective than treatment at the menopause. In resorption decrease within 3 months and are followed one such analysis, for example, it was estimated that the by decreases in the indices of bone formation. The short- cost per QALY of treating all postmenopausal women term decrease in bone markers predicts the effects on with 15 years of oestrogen was US $204 000. If women bone mass over the subsequent 2 years, and a significant were screened to identify the lowest 16% of the decrease (30–60% or more depending on the marker) is a distribution by bone mineral density at the menopause, reliable predictor of treatment effect. Thus, repeating the cost per QALY saved would fall to US $14 620 [3].
baseline bone marker measurements after 3 months of therapy is likely to be helpful in the management of cardiovascular benefit of HRT. Epidemiological studies osteoporotic patients, since treatment effects can be consistently show a marked effect of HRT on morbidity detected before changes in bone mineral density. The and mortality and the inclusion of these effects into value of these markers other than in postmenopausal health economic models provides economic benefits osteoporosis has not been demonstrated.
greater than those derived from screening high-riskpopulations with bone mineral measurements. This isone of the reasons why the use of bone mineral density measurements is not recommended for widespreadscreening at the time of the menopause.
There is an increasing need for management strategies to Different considerations apply to non-HRT interven- be placed in an appropriate health economic perspective.
tions and to interventions in later life [4]. The cost- effectiveness studies of calcium and vitamin D focus on strategies may be performed in several ways. The cost- hip fracture prevention in the institutionalized elderly.
minimization technique involves the detailed costing of Treatment of this subgroup of the population with alternatives, and is dependent on the assumption that the parenteral vitamin D may lead to resource savings. The outcomes of different treatments are identical – an addition of oral calcium reduces the cost-effectiveness of assumption that is not true for medical interventions in such a strategy, but compares favourably with other osteoporosis. Cost-benefit analysis is a preferable form of economic evaluation, but this requires that all the The cost-effectiveness of a bone densitometry service effects produced by an intervention are translated into for clinical indications is less clear. The indications financial terms. The value of life saved, and pain which have been advocated by these guidelines include: avoided, is not easily categorized in this way. Cost- (a) subjects with vertebral fractures coming to clinical effectiveness analysis involves costing of the alternative attention, (b) subjects with forearm fractures or radio- interventions, and measuring the effectiveness in some graphic osteopenia, (c) the small subset of women who, simple, unitary measure (for example, the cost per year after counselling, predicate their decision on long-term of life saved or the cost per fracture saved). A problem oestrogen use on knowledge of low bone density, and (d) with this approach is that the effectiveness measure for patients commencing long-term high-dose therapy with different illnesses is likely to vary and comparison across corticosteroids or who have other rarer secondary causes diseases becomes difficult. To overcome this limitation a of osteoporosis (Table 4).
fourth technique of cost-utility analysis has been In the United Kingdom, with a population of 52 devised. This approach involves the expression of the million, it is estimated that 120 000 to 175 000 scans full social costs and effects of the alternative interven- would be required each year for these indications. The tions, using an outcome indicator (for example, the cost-effectiveness of the utilization of bone densitometry quality adjusted life year; QALY) which can be used in this way may be assessed using the following across therapeutic categories.
The majority of economic studies of prevention and treatment of osteoporosis focus upon the use of HRT at (a) the underlying annual incidence is 1% for the time of the menopause. However, analyses are also vertebral and forearm fracture, 0.3% for hip available for the use of calcium and/or vitamin D in J. A. Kanis et al.
(b) referred patients have an underlying risk 3 times using densitometry as compared with £1206 if all that of the general population, patients in the population were given treatment. The (c) the direct management costs for fractures are cost-effectiveness of a case finding strategy becomes £1000 for vertebral and forearm fracture, and more pronounced as the cost of treatment rises. Thus, for £4000 for hip fracture, a treatment that costs £350 per year, the cost per avertedfracture using bone density for clinical indications would (d) compliance with treatment is 50%, rise to £2887 in contrast with £8453 per averted fracture (e) bone densitometry predicts fracture with 50% if all eligible patients in the population were treated sensitivity and a 15% false positive rate, (Table 13). The marginal costs per averted fracture (the (f) the costs of a density assessment are £38, extra cost per fracture saved in not utilizing bone mineral (g) treatment costs and the effects of treatment are for density assessments) rise progressively with the cost of 5 years and cease when treatment is stopped.
treatment. Thus, the cost-effectiveness of bone mineraldensity measurements improves the more expensive the For a treatment that costs £50 a year and reduces therapy (and the longer the duration of treatment).
fractures by 50% skeletal assessment is of uncertain The cost-effectiveness of preventing vertebral frac- benefit. Whereas assessment saves resources compared tures among subjects with established vertebral osteo- with no assessment (Table 13), the amount is minimal.
porosis also produces estimates which are not dissimilar.
Thus, in this scenario, by treating all patients only an Assuming a 60% predicted reduction in various extra £1000 is spent, but about 8 more fractures are fractures, and annual (1994) costs of treatment, the costs per fracture averted are as follows: (a) Premarin£138, (b) Prempak C £277, (c) transdermal oestrogen Table 13. Estimates of cost-effectiveness of a treatment strategy with
£560, (d) Didronel PMO £1880, (e) intranasal calcitonin and without assessment of bone mineral density. For assumptions see On the basis of these estimates, the treatment of Cost of treatmenta established osteoporosis and the use of bone densito- (£/averted fracture) metry for well-defined clinical indications seem to bejustifiable in terms of their cost utility.
Acknowledgements. We are grateful to all the members of the Scientific Advisory Board and the Board of National Societies forhelpful comments and advice, and also to the following for their help in response to the early drafts: J. C. Branco, L. Bufalino, J. Compston, A. J. Dixon, P. Drake, R. Francis, M. Frazer, R. Lindsay, L. J. Melton, D. Purdie, D. M. Reid, E. Schacht, H. Schwietert and L. van Wersch.
aBoth costs and effects are discounted at 6%.
1. Consensus development conference. Diagnosis, prophylaxis and Saves £4187 per 1000 women treated.
treatment of osteoporosis. Am J Med 1991;90:170–210.
Saves £5023 per 1000 women treated.
2. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Techni- However, the cost-effectiveness of skeletal assessment cal report series 843. Geneva:WHO, 1994.
by densitometry is more favourable the greater the cost 3. Office of Technology Assessment. Effectiveness and costs of of treatment. For a treatment that costs £100 per patient osteoporosis screening and hormone replacement therapy. OTA-BP-H-160. 1995.
per year and reduces fracture rate by 50% over a 5-year 4. National Osteoporosis Foundation of the US. A cost-effective period, the cost per averted fracture would be £366 by analysis of diagnosis, prevention and treatment. 1997.
Received for publication 23 April 1997 Accepted on 16 May 1997


Microsoft word - renne elisha islam immunization paper fn3.doc

Islam and Immunization in Northern Nigeria Department of Anthropology and the Center for Afroamerican and African Studies University of Michigan 101 West Hall, 1085 S. University Ave. Ann Arbor, MI 48109-1107 Ph. (734) 647-9917; fax (734) 763-6077; email: Draft chapter from book, Protesting Polio and the Ethics of Eradication in Northern Nigeria. Please do not reproduce or circulate without permission of author.


Revista Brasileira de Farmacognosia Brazilian Journal of Pharmacognosy Anti-hyperlipidemic activity of oryzanol, isolated from crude rice bran oil, on Triton WR-1339-induced acute hyperlipidemia in Somsuvra B. Ghatak, Shital J. Panchal* Department of Pharmacology, Institute of Pharmacy, Nirma University, India.