The treatment of Paget’s: Available specific therapies
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.
Pamidronate. Pamidronate has been available in the Netherlands for several decades and worldwide (in an i.v. formulation) only since the early ’90s. The greater potency of pamidronate provided a number of advantages over etidronate and tilu- dronate, which are shared by all the newer, amino-bisphospho- nates:
a. it allows a majority of patients to obtain normalisation of pagetic indices rather than the partial suppression that is seen with calcitonin, etidronate, and (in most cases) tilu- dronate;
b. the effects may be longer lasting. In some cases with monostotic disease a single treatment course is followed by an apparent permanent remission and, in most cases, up to a year or more of disease suppression;
c. with pamidronate, as with all the newer, more potent bispho- sphonates, the inhibition of mineralisation occurs at doses several times greater than those recommended for the treatment of Paget’s disease, thus the risk of focal osteomalacia is markedly reduced;
d. although the oral formulation was investigated in earlier studies carried out in Leiden by Bijvoet, the drug was eventually developed for the treatment of malignant hyper- calcaemia, for which the i.v. formulation is considered more appropriate. Thus, the i.v. formulation remained the preferred – and indeed the only available – formulation in most European countries. Don’t blow your budget on pharmacy items buy asthma inhalers online
Pamidronate has a long history as a treatment for Paget’s disease and in some countries, where it has been registered only for the treatment of malignant hypercalcemia, it is still used off-label in pagetic patients. For these reasons several dosing regimens have been proposed in the literature. Where available with the indication for Paget’s disease, the package insert for pamidronate, marketed as Aredia, recommends three daily 4-hour infusions, each of 30 mg in 500 ml of normal saline or 5% dextrose in water. However, in clinical practice, on the basis of accumulated experience of malignant conditions, the most common treatment is a single 60-90 mg infusion in 300-500 ml of 5% dextrose in water given over a 2-h period. In some patients with more severe disease (e.g., serum bALP levels 3-10 times normal), multiple infusions may be required. If the bALP levels are still above the normal range six months after the initial course of treatment, further infusions may be required in order to achieve complete biochemical suppression of disease activity. The most common side effect is the appearance, 24-36 hours after the first infusion, of a typical acute phase reaction with low-grade fever and flu-like symptoms. The likelihood and severity of the acute phase reaction decreases progressively with repeated dosing. Transient hypocalcaemia and hypophosphataemia with secondary hyperparathyroidism may result from the intense positive skeletal calcium and phosphate balance, in relation to the uncoupling between bone resorption and bone formation. This is proportional to the Paget’s disease activity and tends to occur with any bis- phosphonate therapy but it is more evident when bisphosphonates are administered intravenously. Hypocalcaemia is almost invariably asymptomatic if patients are normally vitamin D repleted. In any case, it is desirable to give oral calcium supplements at a dose of 500 mg, two or three times daily, and vitamin D, 400 to 800 U daily, to prevent or counter a reduction in serum calcium and concomitant rise in PTH. There has been one report of asymptomatic mineralisation abnormalities with dosing in the usual clinical range, but this is not the general experience. Venous irritation may arise, especially if an insufficient volume of fluid is used or if the fluid extravasates. The rate of infusion should also be kept low in order to avoid overconcentration of the drug in the renal tubuli and renal failure, observed after i.v. infusion of clodronate and etidronate.