Category: Disease - Part 2

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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The treatment of Paget's


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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An association between hypercalciuria and renal phosphate leak was first described by Bordier et al., who speculated that a primary defect of phosphate reabsorption at the proximal renal tubule could be responsible for hypophosphatemia, acti­vation of the renal 1 a-25(OH)2 vitamin D3 hydroxylase and par­tial inhibition of PTH secretion. The associated hypercalciuria would ensue from both increased intestinal absorption and de­creased tubular resorption of calcium. That this subtype of hy- percalciuria can be of clinical significance was confirmed by a recent report in which 19% of 207 stone formers had a TmPi of less than 0.63 mmol versus 5% of controls; daily calcium ex­cretion was higher in stone formers, more so if they had re­duced TmPi. It was also suggested that this hypothetical tubular defect could involve the type IIa Na+-phosphate co- transporter through mutations of the encoding gene Npt2. In fact, knock-out mice for the Npt2 gene [Npt2(-/-)] exhibited in­creased urinary Pi excretion, hypophosphatemia, elevation in 1,25-(OH)2 vitamin D, hypercalcemia, hypercalciuria and low PTH. Partially deficient mice [Npt2(+/-)] had similar though milder changes. It was suggested these features be typical of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH), and that patients with phosphate leak hypercalciuria could have heterozigous mutations of the Npt2 gene. canadian- online canadian pharmacy

However, others have denied that Npt2 mu­tations could be responsible for both diseases. Phosphate supplementation, as neutral slow-release potassi­um phosphate, was given to patients with absorptive hypercal­ciuria. In a short-term study daily dosages corresponding to 40 mmoles of phosphate and 63.5 mmoles of potassium de­creased 24-hr and fasting urinary calcium by 40% and 43%, re­spectively. These marked changes were not simply attrib­utable to a decrease in intestinal absorption of calcium, which only fell by 6%, but were associated to a clear-cut decrease in bone resorption, as suggested by the significant decline in markers of bone turn over. These effects are consistent with the aforementioned contribution of bone resorption to the phos­phate-depletion induced hypercalciuria. The efficacy of phosphate supplementation to restore mineral metabolism are still debatable since, in the presence of renal leak, an increase in phosphate disposal could result in phosphaturia. In mice Npt2 (-/-) phosphate supplementation did not prevent hyper­calciuria and renal calcification, unless associated to ^-hy­droxylase gene ablation. If this also applied to humans, treatment of phosphate leak should not only include phosphate supplies but also inhibition of calcitriol synthesis.

Treatment of primary hypercalciuria: Bisphosphonates

Bisphosphonates are widely used to prevent osteoporosis and, among these, alendronate and risedronate, exhibit a favourable efficacy/safety profile over long-term use. Theoretically, if increased bone resorption partly explained id- iopathic hypercalciuria, it follows that drugs capable of reduc­ing the rate of bone turnover should also have some effect on calcium excretion. Alendronate, 20 mg daily, had been shown to prevent hypercalciuria and the calcium-stone forming propensity induced by prolonged bed-rest. Independently of immobilization, genetic hypercalciuric rats reduced both cal­cium excretion and urine saturation with calcium salts upon al- endronate administration. The effects of bisphosphonates on calcium excretion was studied in the phosphate depletion induced hypercalciuria, which is referred to as being caused by increased efflux of calcium from bone. Phosphate depleted rats developed hypophosphatemia, hypercalcemia and hypercalci- uria, but failed to respond to pamidronate, despite an improved bone histology.  cheap generic drugs online

Recently we have reported similar results in patients with fast­ing hypercalciuria who had been given alendronate 10 mg/daily and re-studied after a three-month course. There was a signifi­cant decrease in both fasting and 24-hour calcium excretion and, consequently, a 43% reduction in urine saturation with calcium oxalate. These changes were obtained in the face of normal levels of plasma calcium and only minor and tran­sient increases in serum PTH, and maintained over a two-year follow-up (Figure 3). From these results bisphosphonates ap­pear as promising new tools in the management of hypercalci­uria, namely in the fasting hypercalciuria or in patients with bio­chemical (and clinical) evidence of increased bone resorption.

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Citrate supplementation, as alkaline potassium salt, was for­merly introduced in the treatment of distal renal tubular acido- sis and subsequently extended to idiopathic hypocitraturic calcium nephrolithiasis. Regardless of the accompanying cation (sodium, potassium, magnesium) citrate salts exhibit di­rect effects on calcium excretion, acting by two distinct mecha­nisms: first, citrate anion is a strong ligand of calcium, and this will result in a decrease in free ionised calcium concentration; second, alkalinisation is expected to reduce bone resorp­tion, thereby decreasing total calcium excretion. The principal effect of citrate on calcium excretion is due to its ability to bind calcium, so that the calcium-citrate soluble com­plex accounts for by about 10 to 40% of total urinary calcium (Figure 1). Therefore, an increase in urinary citrate will result in a decrease in the fraction of free-ionised calcium, which is the species thermodynamically important for the saturation of calci­um forming salts.

The effect of potassium citrate upon the skeleton is shared by other alkaline salts, such as potassium bicarbonate. In fact, in postmenopausal women, the oral administration of potassium bicarbonate, at a dose sufficient to neutralise endogenous acid, improved calcium balance, by reducing calcium excretion, through a reduction of bone resorption and an increase in the rate of bone formation. In a prospective short-term study, alkaline mineral water induced a significant reduction in the biochemical markers of bone resorption. There also are re­cent reports of a specific effect of potassium intake on calcium excretion, because it has been found that potassium deficiency increases, whereas potassium supplementation as either cit­rate or bicarbonate or chloride salts, decreases calcium excre­tion. Potassium citrate, given to healthy menopausal women decreased net acid excretion and concurrently de­creased markers of bone resorption (Figure 2). Percent varia­tions of urine citrate were inversely related to those of de- oxypyridinolines and hydroxyproline, whereas calcium excre­tion exhibited only minor decreases .

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The drugs of this class have been widely used in patients with calcium nephrolithiasis, more so in those presenting with idio­pathic hypercalciuria. Hydrochlorothiazide, chlortalidone or trichlormethiazide, alone or in association with amiloride, induce a significant reduction of calcium excretion, revert external balance of calcium to positive, and protect bone from demineralisation. Thiazides are able to reduce calcium excretion by acting at the cortical segment of the distal tubule, where they increase calcium reabsorption. This mecha­nism is thought to ensue from contraction of extra-cellular fluids induced by these drugs. Prostaglandin E2, which is likely involved in the pathogenesis of hypercalciuria, was suggested to be inhibited by thiazides. It has also been hypothesised that, over long-term therapy, they reduce both intestinal ab­sorption and bone resorption of calcium. Zerwekh et al. found that 50 mg of hydrochlorothiazide twice daily re­duced fractional intestinal absorption of calcium from 0.68 to 0.56 in patients with renal leak hypercalciuria, but not in those with absorptive hypercalciuria, and this effect was attributed to a reduction of serum levels of calcitriol. 1 Internet Online Drugstore 

Reduction of calci­um intestinal absorption was also observed by Coe et al. in 7 patients with severe hypercalciuria after 3 and 6 months of ei­ther chlortalidone or trichlormethiazide: despite this, calcium re­tention improved because calcium loss decreased even more. No changes were seen in calcitriol and parathormone serum concentrations. Favus et al. carried out an experimental study on rats in which secondary hyperparathyroidism was in­duced by a low-calcium diet. They found that thiazides prevented the increase in PTH induced by low-calcium diet but not the increase in calcitriol nor intestinal calcium transport, and the drug caused no change in rats fed normal chow. Fur­thermore, in rats given exogenous calcitriol to stimulate intesti­nal calcium absorption, thiazides greatly reduced urine calcium excretion but did not alter intestinal calcium absorption. The issue of calcium absorption and thiazides is important for the potential effect on intestinal absorption of oxalate, in that in­testinal transport of the former influences the latter. Earlier reports of the effects of thiazides found a decrease in oxalate excretion, whereas others failed to confirm it. This topic has not so far been studied in more depth.

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