Velocity and BUA provide quantitative information on ultra­sound interaction with the medium; it is currently accepted that QUS parameters are not only influenced by bone density, but also by bone structure. Theory suggests that BUA is deter­mined by bone density and bone microarchitecture, while SOS is influenced by the elasticity of bone as well as by bone densi­ty. However, the exact mechanisms of ultrasound interaction with bone and the physical properties measured remain unde­termined. Considerable data exist showing the positive depen­dence of attenuation and velocity on bone mineral density. The relationship between QUS and BMD are higher in vitro than in vivo, probably also as a consequence of the presence of soft tissue and of anatomic discordance; otherwise this poor association with QUS and BMD has been often attributed to the fact that QUS may measure structure. In particular it has been shown that BUA depends on the trabecular orientation; moreover, Gluer et al. have suggested that SOS is relat­ed to trabecular separation and BUA either to trabecular sepa­ration or connectivity. Other Authors did not find any relation­ship between histomorphometry and QUS parameters after correction for BMD. Nicholson et al. have shown that the ability of QUS to reflect bone structure is also dependent on the direction of the measurement. Recently it has been demon­strated, in human calcaneal specimens, that QUS reflects es­pecially BMD and to a less extent, bone microarchitecture. It has been also shown that SOS, after correction for BMD, is the best predictor of Young modulus, indicating that this para­meter can give information on the mechanical architecture of trabecolar bone. In cadaver studies, calcaneal ultrasound correlates with femoral and vertebral strength, but the predic­tive ability is less than, and it is not independent, from BMD measurements. However, in contrast to these results, Lochmuller et al. found that calcaneal QUS correlates with failure load of the proximal femur similarly to femoral neck BMD.

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Introduction

The measurement of bone density has became an established method to determine the skeletal status for diagnosis and treat­ment of osteoporosis. Diagnosis of osteoporosis today is based mainly on this measurement since bone density at vari­ous anatomic sites has been found to be strongly associated with future fractures. However, both epidemiological and interventional investigations have identified risk factors for fracture other than bone mass. In particular it has been demonstrated that bone structure may play an important role in the determi­nation of fracture. Therefore the ideal diagnostic device should be able to measure bone fragility, whatever the cause is, and not just any decrease in bone mass. QUS seems to provide in­formation that is partly independent from bone density and is able to predict osteoporotic fractures. QUS offer the advantage of small size, relatively quick and simple measurements, no need of ionising radiation and low cost. For these characteris­tics, QUS has continued to be of interest in the last two decades; in 1999, the United States Food and Drug Adminis­tration approved five different ultrasound instruments for the routine diagnosis of osteoporosis, determination of fracture risk and monitoring bone changes.

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Alendronate. Alendronate is available for the treatment of Paget’s disease in most western countries (Fosamax 40). The recommended dose is 40 mg daily for 6 months to be taken with a large glass of water (>200 ml) on getting up in the morn­ing after an overnight fast. The patient is instructed not to take anything else orally (except more water) and not to lie down for at least 30 minutes after ingesting the dose. With this dosing schedule, a single course of alendronate was found to nor­malise bALP in over 63% of patients with biochemical remis­sion lasting for more than 12 months. Biopsy speci­mens from patients treated with alendronate revealed normal patterns of deposition of new bone and radiological improve­ment. The overall tolerability profile is good, although up­per gastrointestinal discomfort, nausea, or the less common but more serious complication of oesophageal ulceration, are not rare.

Risedronate. Risedronate 30 mg (Actonel 30) was approved by both FDA and EMEA in 1998 for the treatment of Paget’s dis­ease. Studies of risedronate have described the efficacy of a 30-mg dose given for 2 or 3 months to patients with moderately active disease. These short courses of therapy led to a nearly 80% reduction in bALP and normalisation of bone turnover markers in 50-70% of patients. The 30-mg risedronate dose is taken with 200 ml of water on getting up in the morning after an overnight fast, with no other oral intake (except water) and no lying down for 30 minutes after the dose. Gastrointesti­nal side effects of varying degrees of severity are expected in a minority of patients.

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Bisphosphonates are currently regarded as the treatment of choice and the only realistic therapeutic option, but in the near future other therapies (for example, anti-RANKL agents) may become available. Here we discuss the individual compounds, considering the evidence of their efficacy and the most com­monly used therapeutic regimens. With the sole exception of etidronate, the bisphosphonates appear to provide equivalent benefits. The degree of suppression of disease activity and the proportion of patients in whom the normalisation of bALP is achieved depends not on the potency of the individual com­pounds but rather on the dose administered and the duration of the treatment. Attempts to show that patients responding poor­ly to one compound can respond better to another have been unconvincing.

Etidronate. Etidronate was the first bisphosphonate used for the clinical treatment of Paget’s disease. It is still available in most countries, but is gradually being abandoned in favour of the new bisphosphonates. Etidronate is commer­cially available in a 200- or 400-mg tablet. The recommended regimen is 5 mg/kg/day (i.e., a daily dose of 400 mg in most patients, taken at any time of day on an empty stomach) for a period of 6 months. The main problem associated with etidronate therapy is the development of mineralisation de­fects. All bisphosphonates have the capacity, at high enough doses, to impair mineralisation of newly forming bone. In the case of etidronate, the doses that most effectively reduce the increased bone resorption can also impair mineralisation, thus making it necessary to administer the compound at sub- optimal doses, and for no longer than 6 months at a time. Thus, in the most severe cases, etidronate therapy is able neither to suppress disease activity adequately nor to relieve symptoms.

Tiludronate. Tiludronate is about 10 times more potent than etidronate, and its use at effective doses is not associated with mineralisation problems. In most countries it has been regis­tered for treatment of Paget’s disease as Skelid in a 200-mg tablet. The recommended dose is 400 mg daily for 3 months, followed by a 3-month post-treatment observation period, after which the bALP is likely to have reached its nadir. This ap­proach led to a normal serum bALP at the 6-month point in a quarter of moderately affected subjects. The drug should be taken with a large glass of water in fasting conditions (at least 4 h after food) and the patient should avoid lying down for 30 minutes after ingesting it.

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The primary objective of Paget’s disease treatment is the relief of symptoms, and the new bisphosphonates are the agents most likely to relieve the aches and pain, excessive warmth over affected bone, headache due to skull involvement, low- back pain secondary to pagetic vertebral changes, and effects of nerve compression associated with the condition. Even though filling in of osteolytic blade-of-grass lesions in weight- bearing bones has been reported in some treated cases, bone deformities and secondary osteoarthritic lesions usually remain unchanged, and loss of hearing is unlikely to improve. The question of whether or not to institute medical treatment to prevent the development of late complications in patients deemed to be at risk is still debated (8-10). In the past, medical intervention in patients with evidence of active disease (elevat­ed levels of bone turnover markers) but who were totally asymptomatic was not considered strictly necessary. This atti­tude is now changing, for three reasons:

1. Biopsy sample studies have reported restoration of normal patterns of new bone deposition following suppression of pagetic activity. This might imply that prolonged suppression of overactivity can allow full restoration of normal lamellar bone and eventually a partial resolution of the deformities.

2. Untreated disease, in which abnormal bone turnover persists for decades, may be associated with the appearance or worsening of irreversible bone deformities, and then sympto­matic disease. This has never been proven, although incom­plete suppression of elevated indices of bone turnover, on older therapies, has been associated with disease progres­sion. In this regard, it should be mentioned that pro­longed treatment with the new bisphosphonates is followed by a normalisation of indices in most patients.

3. The safety profile, the general acceptability, and the costs of treatment with the newer bisphosphonates, especially when administered intravenously are, in Europe at least, excellent. This very low cost/benefit ratio has encouraged a less con­servative attitude to definition of the treatment threshold.

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Introduction

The treatment of Paget’s disease of bone (Paget’s disease) is based on the use of agents capable of suppressing the abnor­mal activity of pagetic osteoclasts. Paget’s disease was an un- treatable condition until the mid-1970s when calcitonin became available and was registered in most countries for the treatment of the disease. Calcitonin was administered by subcutaneous injections at doses (100 IU/day) that were often poorly tolerated. The treatment proved able to alleviate bone pain within a few weeks, but the observed decreases in the activity of the dis­ease, as assessed by bone turnover markers, was often inade­quate. In the early ’80s the bisphosphonate etidronate was introduced. This had to be used at sub-optimal doses (10 mg/kg/day) because at higher doses etidronate therapy is asso­ciated with the development of osteomalacic features. Thus, in a large proportion of patients, neither calcitonin nor etidronate were able to suppress the disease activity completely.

These agents were replaced in the ’90s by the newer bisphos- phonates (clodronate, tiludronate, pamidronate, alendronate and risedronate), progressively more potent than etidronate, and potentially able to achieve greater disease suppression and frank remission (i.e., normalisation of pagetic indices) for prolonged periods. In addition to these bisphosphonates, oth­ers have been studied in some countries (olpadronate and ner- idronate) or are still awaiting final registration (ibandronate, zoledronate).

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