Practical Therapeutics
Drugs 40 (6) 829-840, 1990 0012-6667/90/0012-0829/$06.00/0 © Adis International Limited All rights reserved. DRUG03410
Advances in the Management of Paget's Disease of Bone D.J. Hosking City Hospital, Nottingham, England
Contents
Summary .................................................................................................................................... 829 I. Assessment of Symptoms .......................................... ........................................................... 830 2. Monitoring the Response to Treatment ........................... ................................................... 831 2.1 Symptoms ........................................................................................................................ 831 2.2 Alkaline Phosphatase ................................................................. ..................................... 832 2.3 Hydroxyprol ine ................ .......................................................... ....... .............................. 832 2.4 Osteocalcin ...................................................................................................................... 832 2.5 Pyridinium Crosslinks .................................................................................................... 832 2.6 Radiographs ..................................................................................................................... 832 3. Treatment ............................;................................................................................. ................. 833 3.1 Calcitonin ........................ .................... ............................................................................ 833 3.1.1 Intramuscular or Subcutaneous Administration .................. .. ............................. 833 3.1.2 Intranasal Calcitoni,n ......... .................................................................................... 834 3.2 Bisphosphonates (Diphosphonates) ...............................................................................835 3.2.1 Etidronic Acid (Disodium Etidronate) ................................................................. 835 3.2.2 C1odronic Acid (Clodronate) ................................................................................. 835 3.2.3 Pamidronic Acid (Pamidronate, APD) ................................................................ 836 3.2.4 Newer Bisphosphonates .................................. ....................................................... 837 3.3 Sequential or Combined Use of Calcitonin and Bisphosphonate .............................. 837 4. Current Clinical Recommendations ....................................................................................838 4.1 Asymptomatic Patients ................................................................................................... 838 4.2 Symptomatic ,Patients ..................................................................................................... 838 4.3 Special Problems ............................................................................................................. 838 5. Conclusion ........'.. .... :.................................. .................... .......... .. ............................................ 838
Summary
The advent of potent new bisphosphonates (diphosphonates) now makes it possible to restore and maintain normal bone turnover in many patients with Paget's disease of bone (osteitis defor,mans). This has necessitated a reappraisal of the indications for treatment, the ways in which disease activity and response are assessed, as well as the place of existing therapies. Measurements of urinary hydroxyproline and serum alkaline phosphatase remain the most useful markers of disease activity. Pyridinium crosslinks may prove to be more specific than hydroxyproline ~ n the assessment of bone resorption but osteocalcin has been disappointing in monitoring the effect of treatment on bone formation. Etidronic acid (disodium citidronate), the first bisphosphonate introduced for clinical
Drugs 40 (6) 1990
830
use, is a potent inhibitor of osteoclastic bone resorption but its potential is limited by the development of defective mineralisation with high dosage (10 to 20 mg/kg/day). The newer bisphosphonates, c1odronic acid (c1odronate) and pamidronic acid (pamidronate, APD), are free from this problem and appear able to control a wide range of disease activity. A small number of patients appear resistant to the agents but the underlying mechanism is unclear. The efficacy and safety of these bisphosphonates makes it likely that the threshold for treating asymptomatic patients will fall in the hope of preventing long term complications. These developments will lead to a reappraisal of the role of calcitonin which can now be administered by both the parenteral and intranasal routes. One focus of interest will be on the quality of the bone laid down during treatment. Meticulous radiographic studies have shown that calcitonin improves bone architecture and this may have particular relevance to the treatment of lytic disease. The relative merits of the different forms of therapy for Paget's disease need further evaluation, particularly with respect to the identification of specific advantages of individual drugs.
Paget's disease of bone (osteitis deformans) is primarily a disorder of osteoclasts, characterised by increased bone resorption with a secondary stimulation of osteoblastic activity leading to the deposition of both lamellar and woven bone (Singer & Mills 1983). At a macroscopic level the trabecular architecture becomes distorted, with a loss of the definition between cortical and trabecular bone. Affected areas show mixed lysis and sclerosis, becoming painful, prone to deformity, fractures or neurological compression syndromes. Since this subject was last reviewed in the Journal (Hosking 1985) there have been a number of important advances in treatment which are considered in detail below. Citations to the literature are largely confined to the last 5 years. A more extensive bibliography can be found in several recent reviews (A violi 1987; Hamdy 1981 ; Hosking 1985; Kanis & Gray 1987; Singer & Mills 1983; Yates 1988).
1. Assessment of Symptoms Paget's disease predominantly affects the axial skeleton but virtually any bone can be involved, although the feet and hands are usually spared. The majority of affected individuals are probably asymptomatic (Collins 1956) and are often detected during radiographic or biochemical investigation of unrelated symptoms. Since therapy has become more effective, with fewer adverse effects,
the goal of long term control of abnormal bone turnover is within reach (Harinck et al. 1987a) so that the threshold for treating the asymptomatic patient is likely to fall. Bone pain is the most common indication for treatment and may arise from a number of different mechanisms in the same individual. I. Distinction of bone pain due to Paget's disease from that of associated degenerative joint dissease depends partly on the history but also on radiographs of the affected area. Pain, uncontrolled by simple analgesics, is an indication for a 2- to 3month therapeutic trial of either calcitonin or a bisphosphonate (Altman 1985). Failure of pain to improve suggests that degenerative joint disease is dominant. If the hip is involved, joint replacement using cemented components should give good results with only a slight increase in the risk of subsequent aseptic loosening (McDonald & Simm 1987). Plicamycin (mithramycin) [15 /otg/kg] has been used to obtain a more rapid control of bone turnover and so distinguish between joint and bone pain (Hadjipavlou et al. 1977). However, the risks associatyd with its use, such as marrow depression, are no longer justified now that bone turnover can be rapidly inhibited by intravenous bisphosphonates. 2. Fissure fractures ·in the convex cortex of a bowed long bone may extend and become complete,causing the acute onset of severe pain. The
831
Paget's Disease of Bone
patient must be immobilised immediately and if pain persists the limb must be externally splinted or the fracture fixed electively (Redden et al. 1981). The stability of this type of fracture depends upon active bone formation at the fracture site, and excessive inhibition of the reparative process may increase the risk of extension. If potent bisphosphonates are to be used in such patients they should be given in small, carefully monitored doses. 3. Coincidental bone pain not due to Paget's disease must be excluded by appropriate radiographs. Deformity may also involve the axial skeleton, producing a variety of neurological entrapment syndromes. These may be due to mechanical compression, a vascular steal syndrome in the absence of obstruction (Porrini et al. 1987) or, rarely, sarcomatous change (Gruszkiewicz et al. 1987; Sadar et al. 1972). Part of the rapid improvement following treatment with either calcitonin or bisphospho nates (diphosphonates) [Douglas et al. 1981; Porrini et al. 1987] may be due to a reduction in bone blood flow and a recovery in spinal circulation. These syndromes should be treated initially with calcitonin or bisphosphonates, not only because of their effectiveness and speed of onset but also because the results of laminectomy have been disappointing and attended by a high mortality and morbidity (Sadar et al. 1972). Deafness, which may have both conductive and sensorineural components, may be due to involvement of either the temporal bone or the ossicles. Early studies were conflicting as to whether calcitonin exerted a beneficial effect but occasional reports continue to appear documenting stabilisation of hearing loss with calcitonin either alone or in combination with etidronic acid (disodium etidronate) [EI Sammaa et al. 1986; Lando et al. 1988]. The remaining complications of Paget's disease - which include high output cardiac failure, immobilisation, hypercalcaemia and sarcomatous degeneration - are uncommon and little has changed in their management since the last review.
2. Monitoring the Response to Treatment (Table J) It is essential to monitor the response to treatment both to assess its efficacy in an individual and to make comparisons between different therapies. 2, I Symptoms Although symptom control is the reason for treatment its evaluation is clouded by a 30 to 40% placebo response (Bouvet 1977; Ibbertson et al. 1979). It is essential that objective ineasurements are made and those of serum alkaline phosphatase and urinary hydroxyproline excretion are convenient, reliable and generally available. Table I. Monitoring the response to treatment Symptoms 30-40% placebo response Qualitative, semiquantitative, subjective Alkaline phosphatase (ALP) Marker of osteoblastic activity Correlates with HYPRO and disease extent Levels stable (± 10%) over periods of months 50% extraskeletal origin; proportionately less in active disease Normal levels in active disease of limited extent Hydroxyproline (HYPRO) Marker of osteoclastic activity Only 1% of HYPRO in urine as free amino acid Tedious assay; less stable levels with time than ALP (± 20%) Rapid decline in concentration with osteoclast inhibition Extraskeletal sources: diet, nonskeletal collagen May be normal in some patients with active disease Osteocalcin Specific marker of osteoblastic activity Less sensitive than ALP in assessing disease activity .Correlates with ALP and HYPRO in untreated patients Discordant response during treatment Not a useful marker for monitoring the response to treatment Pyridinium crosslinks Specific for collagen degradation Deoxypyridinoline present only in bone collagen Bone radiol0!ly Meticulous attention to radiographic technique Assessment only of osteolytic lesions
832
2.2 Alkaline Phosphatase Alkaline phosphatase is a marker for bone formation but has a significant extraskeletal component in normal individuals. This becomes proportionately less in active Paget's disease, although distortions due to hepatic alkaline phosphatase become more significant as bone turnover approaches normal levels. Other liver function tests give some indication of the extent of possible interference but simultaneous measurements of urinary hydroxyproline excretion are essential for assessing bone turnover. Patients with localised Paget's disease may have insufficient activity to influence 'whole body' measurements. Changes within the normal range may then be useful in monitoring response but closely spaced measurements (together with urinary hydroxyproline excretion) are needed to avoid the risk of overtreatment. 2.3 Hydroxyproline Hydroxyproline is a marker for osteoclastic bone resorption and its measurement as a molar ratio to creatinine in a fasting urine sample is both convenient for the patient and avoids the interfering effects of dietary collagen. The disadvantage lies in its lack of sensitivity, since large amounts are broken down in the liver and because it is released at several stages of collagen biosynthesis and maturation. Moreover, only 1% of the hydroxyproline in urine is present as the free amino acid and most of the remainder is in the form of peptides. An important characteristic of hydroxyproline is that it declines rapidly over a few days at the start of treatment with potent osteoclast inhibitors, whereas alkaline phosphatase .changes more slowly over a period of weeks (Frijlink et al. 1979). Hydroxyproline also increases before alkaline phosphatase in a relapse and is therefore the best measure of the duration of remission. 2.4 Osteocalcin Osteocalcin is a vitamin-K- dependent protein which binds calcium and is synthesised exclusively by osteoblasts (Lian et al. 1978). Although osteo-
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calcin concentrations correlate with those of serum alkaline phosphatase and urinary hydroxyproline in untreated Paget's disease (Coulton et al. 1988; Papapoulos et al. 1987) it appears to be a less sensitive marker of disease activity. Osteocalcin and alkaline phosphatase may reflect different functions of the osteoblast but of much greater practical significance is the discordance between the measurements during treatment. For example, after inhibition of bone turnover with bisphosphonates, there is the expected rapid fall in hydroxyproline followed by a slower decrease in alkaline phosphatase, but either no change (Coulton et al. 1988) or an increase (Papapoulos et al. 1987) in osteocalcin. Where osteocalcin increases this seems to be causally related to increments in 1,25 dihydroxy vitamin D. This reflects the secondary hyperparathyroidism which follows the uncoupling between bone resorption and formation in the early phase of bisphosphonate therapy (Frijlink et al. 1979; Papapoulos et al. 1986). Thus, osteocalcin does not seem to be a useful marker of bone turnover during treatment but may be of value in studying other aspects of osteoblast function. 2.5 Pyridinium Crosslinks The problems associated with hydroxyproline measurements, described above, have prompted the search for other markers of bone resorption. One 'potential candidate is the urinary excretion of hydroxypyridinium crosslinks of collagen (Black et al. 1988). These are derived from the degradation of mature bone collagen (Ogawa et al. 1982) and may prove to be more specific markers of bone resorption than hydroxyproline (Black et al. 1989). 2.6 Radiographs Meticulous attention to radiographic technique and positioning of the patient make ·it possible to compare changes in trabecular architecture over prolonged periods. It is only possible to evaluate lytic lesions but several studies have shown important discrepancies between biochemical mark-
Paget's Disease of Bone
Table II. Standardisation of radiographic technique (reproduced with permission from Dodd et al. 1987) 1. Use of same x-ray unit for initial and follow-up studies 2. Accurate automatic exposure control 3. Records of Kv, filtration and screen-film combination for future duplication 4. Exposure consistency confirmed by aluminium step wedge and preliminary check radiograph 5. Assessmerit: Two independent observers; Change in bone texture on arbitrary scale of 1-4; Position of wedge resorption fronts assessed from fixed pOints; Progression measured in mm/month
ers of bone turnover and radiographic appearance. Improvements in bone texture, filling in of lytic lesions and decreased or reversed progression of lytic wedge lesions in the cortex oflong bones may be seen with both calcitonin (Nagant de Deuxchaisnes et al. 1977) and palmidronate (Dodd et al. 1987), despite failure to normalise either alkaline phosphatase or hydroxyproline in some patients. In contrast, deterioration in trabecular architecture may follow treatment with etidronic acid (Nagant de Deuxchaisnes et aL 1979) even though biochemical markers of bone turnover return to normal. Similar discrepancies may be seen where quantitative bone scans show improvement during etidronic acid treatment despite radiographic deterioration (Nagant de Deuxchaisnes et al. 1980). Although this degree of meticulous radiography can be achieved within a routine department (Dodd et al. 1987) the procedure must be standardised as far as possible and is best organised prospectively (table II).
3. Treatment The roles of the calcitonins and bisphosphonates in the treatment of Paget's disease have recently been reviewed (A violi 1987; Hosking 1985; Kanis & Gray 1987; Stumpf 1989). Only the essential features of their clinical effects are considered here, although more recent developments are reviewed in detail.
833
3.1 Calcitonin Calcitonin is a 32 amino acid peptide secreted by the parafollicular cells of the thyroid gland; it has been used clinically because of its inhibitory effect on osteoclastic bone resorption (Macintyre et al. 1987). A number of synthetic peptides are available for clinical use, although salmon calcitonin has been most widely used because of its enhanced potency in comparison with the human and porcine hormones. Since calcitonin is hydrolysed by gastric secretions it has to be given by injection, although preparations suitable fOf intranasal administration have recently become available (Buclin et al. 1987; Kurose et al. 1987; Reginster et al. 1987).
3.1.1 Intramuscular or Subcutaneous Administration Calcitonin treatment should be started with a single daily subcutaneous injection of 50 to 1000, which can be reduced to thrice weekly once symptoms have been relieved and providing that bone turnover continues to decline. Alkaline phosphatase and hydroxyproline decrease by about 50%, but responses show considerable interpatient and interstudy variation. Reductions in these markers usually reach their maximum level by 6 months, although bone turnover will increase once salmon calcitonin is stopped; this relapse is unaffected by the duration of treatment. Continuation beyond 6 months should be restricted to those with extensive osteolytic lesions in weight-bearing bones or those with neurological symptoms. Even when treatment is withdrawn control of bone pain may be more prolonged (A vramides et al. 1976), a factor that has been attributed to restoration of normal bone remodelling by calcitonin (Nagant de Deuxchaisnes et al. 1977). Therapy should be reinstituted at the previous dosage if symptoms recur. Adverse effects such as nausea, flushing or malaise are dose dependent and only rarely are they severe enough to warrant interruption or abandonment of treatment. If symptoms such as nausea and flushing are troublesome the hormone can be injected before bed and given with an antiemetic.
834
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Antibodies to the heterologous calcitonins develop in 30 to 60% of patients and tend to increase in concentration with time. Clinical resistance is unusual and tends to be associated with high titre antibodies which are more likely with prolonged treatment. The presence of antibody-mediated resistance can be confirmed by changing treatment to a calcitonin of a different species; human synthetic calcitonin is the logical choice, in a dose of 0.5 to I mg/day.
3.1.2 Intranasal Calcitonin A major development within the last few years has been the introduction of salmon calcitonin suitable for intranasal administration; this produces a maximum reduction in bone turnover of 30 to 40% (table III) after 4 to 6 months' treatment (D' Agostino et al. 1988; De Deuxchaisnes et al. 1987; Gagel et al. 1988; Reginsteret al. 1988b). These studies were small and the interpatient variability was large, which makes it impossible to assess dose-response relationships. A consistent finding has been that the intranasal route seems free of the side effects seen with calcitonin injections. This may be due to aitereq pharmacokinetics but is probably because of lower plasma calcitonin concentrations. Acute studies suggest that for a
given dose of calcitonin the intranasal route delivers 7.5 to 40% of the amount obtained from subcutaneous or intramuscular injections (De Deuxchaisnes et al. 1987; Gonzalez et al. 1987; O'Doherty et al. 1990; Reginster et al. 1987). Antibodies develop after intranasal salmon calcitonin just as they do after the parenterally administered hormone. Titrestend to rise more rapidly in those previously exposed to salmon calcitonin, and this may be accompanied by clinical resistance (Levy et al. 1988). For all these reasons calcitonin may be less effective when administered intranasally rather than parenterally, particularly in patients with very high rates of bone turnover. Local irritation of the nasal mucosa seems to be mild and transient. Coincidental allergic rhinitis seems to have a variable effect on absorption, some patients showing an enhancement while others experienced decreased absorption and calcitonin-related side effects. More Clinical studies are clearly needed to resolve this issue. Intranasal calcitonin is an advance in terms of patient acceptability, particularly in the elderly (Gagel et al. 1988). Salmon calcitonin can also be given as a 300U suppository (Buclin et al. 1987; De Deuxchaisnes et al. i 987) which reduced hydroxyproline to 67% and alkaline phosphatase to 83% of pretreatment
Table III. Response to intranasal ?alcitonin Reference
No. of pts a
Dose
Duration of
(U/day)
treatment (months)
Initial value b
ALP D'Agostino et al.
2
(1988)
3
Response: % of pretreatment value (time of assessment) [months] HYPRO
ALP
100 200
3
3.39
69.0 (3)
3
4.78
71.3 (3)
200 400
12 12
5.2
9
3.7
77.0 (4) 76.0 (6)
Gagel et al. (1988)
7
100-400
3
3.03
67 (3)
Reginster et al. (1988b)
8 9
200 400
12 12
4.08 2.48
De Deuxchaisnes et al. (1987)
13
a
Previously untreated with salmon cal.citonin .
b
Multiple of upper limit of normal range.
Abbreviations: ALP = alkaline phosphatase; HYPRO = hydroxyproline.
3.2 1.7
63.9 (6) 62.6 (6)
HYPRO
58 (6)
62 .3 (6) 84.9 (6)
Paget's Disease of Bone
levels. Local tolerance of the suppository was good, without significant adverse effects. Experience with eel calcitonin and its aminosuberic analogue, ASU 1,7-eel calcitonin, is still limited and although both preparations reduce bone turnover their place in current therapy in relation to other calcitonins is uncertain. 3.2 Bisphosphonates (Diphosphonates) Bisphosphonates are analogues of pyrophosphate characterised by a P-C-P bond. They bind strongly to hydroxyapatite crystals, inhibiting bone mineral deposition and dissolution. This effect appears to be independent of their clinically important action of inhibiting osteoclastic bone resorption (Fleisch 1987). The main emphasis of research in this field over recent years has been the development of compounds with larger margins between the dose-inhibiting resorption and that causing the unwanted inhibition of mineralisation. The first compound to be introduced into clinical use was etidronic acid (disodium etidronate) and, although the margin between its wanted and unwanted effects is narrow, a great deal of experience has been gained which has facilitated the introduction of more potent analogues. 3.2.1 Etidronic Acid (Disodium Etidronate) . Etidronic acid was the first compound to be introduced into clinical use and there is good evidence from double-blind placebo-controlled studies that it relieves pain and controls bone turnover in a dose-dependent fashion; The major problem with the drug occurs at doses of 10 to 20 mg/kg/ day, where between 10 and 20% of patients treated for 6 months develop severe incapacitating pain or long bone fractures · (not necessarily · in Pagetic bones), in association with histological evidence of defective mineralisation. Although the bones recover when the drug is withdrawn this has limited the dosage to 5 mg/kg/dayand the duration of treatment to 6 months. This dose and duration of therapy seems effective for most patients, 60% of whom will obtain significant clinical benefit which is not improved
835
upon by prolonging treatment. However, 1 month of treatment with etidronic acid 20 mg/kg/day may be as effective as 6 months at the same dose and significantly better than treatment with · 5· tng/kg! day, although there may be transient impairment of mineralisation (Preston et al. 1986). Since all bisphosphonatesare poorly absorbed.by theintestine and this is diminished by calcium .the drug should be given on an empty stomach and never taken with milk or milk products. The pretreatment level of bone turnover is the major determinant of whether etidronic acid will restore biochemical normality and ensure sustained remission (Altman 1985; Gray et al. 1987). Three-quarters of the patients with less than a doubling of bone turnover will achieve normal levels of alkaline phosphatase and hydroxyproline and may only need 6 months' treatment to remain in prolonged remission. Even those with more active disease may need less than one treatment course; year to stay in clinical remission, although the proportion with normal bone turnover will be le.ss. Patients \Vith very active disease (6- to lO-fold increments in bone turnover) present the major long term prqblem (Altman 1985). Although they may show a rapid initial response to etidronic acid they relapse quickly (often within 3 months) and tend to require . increasing doses to reduce bone turnover. Eventually they become refractory to highdose treatment, developing increasing bone pain, and the options are then to treat with one of the newerbisphosphonates (Delmas et al. 1987; Douglas et al. '1980) or to transfer to calcitonin (Altman & Collins-Yudiskas 1987; Perry et al. 1984). Serum alfacalcidollevels are normal in Paget's disease both before and after treatment with etidronic acid . (Foldes et al. 1989; Siris et al. 1989). Although vitamin D supplements reduce the prevalence Ot the mineralisation defect they also diminish the dinical and biochemical responses, suggesting that they may reduce etidronic acid absorptioll (Ralston et al. 1987). 3.2.2 Clodronic Acid (Clodronate) Clodronic acid is a more potent osteoclast inhibitor than etidronic acid (Fleisch 1987) and does not cause defective mineralisation even when given
836
in high doses (Delmas et al. 1982; Meunier et al. 1979). Optimal responses seem to be achieved with 6 months' treatment with 800mg daily, which reduces bone turnover by about 70% and achieves normal, or near normal, levels of alkaline phosphatase and hydroxyproline in most patients (Delmas et al. 1982; Douglas et al. 1980). Larger doses are neither more effective in reducing bone turnover nor in achieving a more prolonged remission. Bone turnover may remain controlled for up to 2 years in over 50% of patients without the need for further retreatment. Those who achieve normal levels of alkaline phosphatase remain in remission for longer than those with persistently elevated values (Gray et al. 1987). The uncoupling of bone resorption and formation during the early weeks of treatment leads to the development of secondary hyperparathyroidism, as seen with other potent bisphosphonates (Papapoulos et al. 1986; Siris et al. 1989). This can be minimised by using calcium and vitamin D supplements, which enhance the reduction in alkaline phosphatase but have no effect on hydroxyproline or pain relief (Delmas et al. 1982). Clodronic acid can also be given as a high-dose (1.6 g/day) short term (l month) regimen, which produces equivalent degrees of suppression of bone turnover compared to longer courses oflower-dose therapy (Chapuy et al. 1983). Intravenous clodronic acid avoids the problem of gastrointestinal side effects, and 300mg given daily for 5 days as a 3-hour infusion reduces bone turnover by 50% at 1 month, which is sustained for 6 months (Yates et al. 1985). Bisphosphonates must be infused slowly because of fears of renal toxicity (Boun~meaux et al. 1983), although this has not materialised in clinical practice except for transient proteinuria (Yates et al. 1985). The relationship between the pretreatment level of bone turnover and the ·frequency of clodronic acid infusions needed to predictably restore normal levels of alkaline phosphatase and hydroxyproline has yet to be defined. Despite initial impressions, retreatment does not seem to be associated with diminished effectiveness (Yates et al. 1985).
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3.2.3 Pamidronic Acid (Pamidronate, APD) Pamidronic acid is another second generation bisphosphonate with 10 times the potency of clodronic acid on a molar basis (Reitsma et al. 1982) which does not inhibit mineralisation (Harinck et al. 1987a). As with clodronic acid, the aim of treatment is to restore normal levels of bone turnover. Both oral and intravenous preparations are available and a number of different treatment protocols have been explored. Hydroxyproline falls rapidly after treatment with pamidronic acid, followed by a slower decline in alkaline phosphatase (Frijlink et al. 1979). Treatment can be withdrawn as soon as hydroxyproline becomes normal since alkaline phosphatase will invariably return: to normal in subsequent weeks (Harinck et al. 1987b). The proportion of patients who will achieve normal bone turnover depends on the initial disease activity and the administered dose. However, the duration of the subsequent remission, which may last for up to 2 years in 50% of patients, is mainly a function of the degree of suppression of bone turnover, although it is also influenced by pretreatment activity (Harinck et al. 1987a). A number of intravenous regimens have been studied in patients with modestly active Paget's disease (3-fold increments in alkaline phosphatase or hydroxyproline). 10 daily infusions of pamidronicacid 20mg restored normal levels of hydroxyproline, with a subsequent return of alkaline phosphatase to normal (Harinck et al. 1987b). A single infusion of 60mg given over 24 hours had a similar effect (Thiebaud et al. 1988)~ as did 5 daily 15mg infusion~ followed, if necess~ry, by weekly infusions for 3. months (Cantrill et al. 1986). More activ¢ disease failed to respond to 7 daily infusions of p~midronic acid 25mg, and the partially suppres~ed activity relapsed within 2 to 3 months (Vegaet al. 1987). However, intravenous treatment followed by long term oral therapy (600 mg/day) controlled 90% of patients, covering a wide spectrum of activity (Harinck et al. 1987b). Short (5-day) . courses of high-dose pamidronic acid (l200mg daily) are effective in modestly active disease but fail to control more severe cases (Thiebaud et al. 1987).
837
Paget's Disease of Bone
Direct comparisons between the clinical merits of pamidronic acid and clodronic acid are difficult at the present time. Both are capable of restoring normal bone turnover in a high proportion of patients. They have different modes of action, pamidronic acid inhibiting the accession of osteoclasts to the bone surface, while clodronic acid inhibits mature osteoclast function (Boonekamp et al. 1986). It is uncertain whether these differences have clinical implications. 3.2.4 Newer Bisphosphonates A number of other bisphophonates have been tested in Paget's disease but are not yet generally available. Aminohexane bisphosphonate, given either orally for 1 month (400 mg/day) or intravenously for 5 days (25 or 50mg), produced a 60% reduction in bone turnover which was sustained for 6 months after the withdrawal of treatment. A substantial proportion of the patients treated either orally or intravenously obtained normal levels of bone turnover, although there was little difference between the 2 intravenous doses (Atkins et al. 1987). The same compound has also been used to treat patients resistant to etidronic acid who had considerably increased bone turnover. Treatment with 400mg daily for 3 months produced a 60% reduction in alkaline phosphatase and a 46% reduction in hydroxyproline (Delmas et al. 1987). Aminobutylidene bisphosphonate also reduced bone turnover by 60% after 4 daily infusions of2.5 to 25 mg/day, and this effect was sustained for several months (Adami et al. 1986). Less impressive responses were obtained in previously treated patients, but this problem was also recognised with clodronic acid. The difficulties of interpreting changes in bone turnover in relapsing patients have been elegantly discussed by Yates et al. (1985). Thiomethylene bisphosphonate is the latest agent to be introduced, but in doses of 200 to 400 mg/ day given for 6 months seemed less effective than other bisphosphonates (Reginster et al. 1988a). This may be a function of dose because a short term study using 800 mg/day showed better responses,
although normal bone turnover was not obtained (Audranet al. 1989). 3.3 Sequential or Combined Use of Calcitonin and Bisphosphonate Since the calcitonins and the bisphosphonates have such different structures it is not unreasonable to suppose that their effects may be complementary. Various regimens have been explored where these 2 agents have been given either sequentially or in combination. In patients treated with etidronic acid in a dose of 400 mg/day (5 mg/kg bodyweight) for 6 months, further reductions in bone turnover can be achieved by a subsequent 6-month course of salmon calcitonin (Perry et al. 1984). Surprisingly, the reverse sequence had a disappointing effect, altho'ugh in this particular study the response to the initial treatment with salmon calcitonin was unusually poor. However, in another similar study (Adami et al. 1984) where human calcitonin had reduced bone turnover by 45% the elevated values were reduced by 60% following a 2-month course of clodronic acid. This suggests that bisphosphonates may also be useful where calcitonin fails to normalise bone turnover. The newer bisphosphonates do not seem to cause defective mineralisation and can be given long term, but where etidronic acid is the only available compound the sequential use of calcitonin is a reasonable option. This is particularly so with very active disease where it is well recognised that bone turnover will not be completely controlled by either etidronic acid or calcitonin alone (Altman et al. 1985). However, short courses of salmon calcitonin (10 days) interspersed with etidronic acid (20 days) and repeated over a 6-month period were slightly less effective than a to-day course of salmon calcitonin alone (Rico et al. 1988). Combinations of salmon calcitonin (100U 3 times/week) and etidronic acid (400 mg/day) given from the outset of treatment (Bijvoet et al. 1978; Hosking et al. 1976; O'Donaghue & Hosking 1987) are more effective than either agent given alone. Responses are generally at a maximum at 6 months; although further reductions can be achieved by
838
more prolonged treatment they are unpredictable and very active disease may not be completely controlled. However, the bisphosphonate component does ensure that once treatment is withdrawn, biochemical remission persists longer than it does after salmon calcitonin alone. Prolonged use of combined treatment does not seem to be complicated by the risk of defective mineralisation. Human calcitonin has been found to be of use in Paget's disease refractory to etidronic acid and salmon calcitonin (Altman & Collins-Yudiskas 1987). It is not clear to what extent the resistance to salmon calcitonin was antibody mediated but the observation that human calcitonin reduced bone turnover by 50% in patients resistant to etidronic acid is of considerable interest.
4. Current Clinical Recommendations
Drugs 40 (6) 1990
be achieved by either agent within 6 months, at which point treatment should be withdrawn but reintroduced at relapse. 'Clinical' relapse must be substantiated by measurements of bone turnover. Second generation bisphosphonates (if available) can be used for longer periods of time without the risk of defective mineralisation. 3. Very high bone turnover (> 3-fold increment): second generation bisphosphonates are the agents of choice but if they are unavailable a combination of calcitonin with etidronic acid is an alternative. Treatment should be continued until bone turnover is normal or at a stable minimum value. The risk of defective mineralisation with etidronic acid seems to be less if it is combined with calcitonin, but a bone biopsy to exclude defective mineralisation should be performed if treatment is continued for more than 12 months.
4.1 Asymptomatic Patients 4.3 Special Problems Asymptomatic · patients may be treated in the hope of avoiding long term complications. l. Normal bone turnover: no treatment. 2. Increased bone turnover: bisphosphonates are to be preferred to calcitonin because of more prolonged periods of remission without treatment. Second generation compounds (clodronic acid, pamidronic acid) are to be preferred to etidronic acid. Treatment should be continued until bone turnover reaches a minimum value and then withdrawn until disease relapses. There is a risk of defective mineralisation with long term etidronic acid therapy and a bone biopsy will be needed if treatment is continued beyond 6 months. 4.2 Symptomatic Patients
l. Normal bone turnover: treat first with analgesic agents. Consider the need for an orthopaedic opinion for associated degenerative joint disease or deformity. Use of calcitonin or bisphosphonates in such patients is of unproven value. 2. Moderately increased bone turnover (2- to 3fold increment): the choice lies between salmon calcitonin and bisphosphortates. The maximum response at this level of bone turnover will generally
I. Lytic disease or stress fractures in bowed bones: calcitonin is preferable to the bisphosphonates because over-treatment with the latter may impair fracture repair. Ifbisphosphonates are used they should be given only until hydroxyproline is normal and must be withdrawn if pain over the lytic/stress fracture site increases or if alkaline phosphatase falls below the upper limit of the normal range. 2. Spinal compression syndromes: medical therapy is preferable to surgery. Rapidity of effect is important and this seems to be achieved either with intravenous bisphosphonates or with calcitonin. A surgical opinion should be sought if neurological signs worsen or paraparesis develops. 3. Sarcomatous degeneration is extremely rare but treatment is only palliative.
5. Conclusion It is clear that with the introduction of potent second generation bisphosphonates the treatment of Paget's disease has entered a new and exciting phase. Further study is needed to evaluate the relative merits of the different bisphosphonates, their
839
Paget's Disease of Bone
routes of administration and the changing position of calcitonin.
References Adami S, Guarrera G, Salvagno G, Spiazzi G, Marini G, et at. Sequential treatment of Paget's disease with human calcitonin and dichloromethylene diphosphonate (CL2MDP). Metabolic Bone Disease and Related Research 5:. 265-267, 1984 Adami S, Salvagno G, Guarrera G, Montesanti F, Garavelli S, et at. Treatment of Paget's disease of .bone with intravenous 4 amino-I-hydroxybutylidene-I, 1-bisphosphonate. Calcified Tissue International 39: 226-229, 1986 Altman RD. Long term follow up of therapy with intermittent etidronate disodium in Paget's disease of bone. American Journal of Medicine 79: 583-590; 1985 Altman RD, Collins-Yudiskas B. Synthetic human calcitonin in refractory Paget's disease of bone. Archives of Internal Medicine 147: 1305-1308, 1987 Atkins RM, Yates AJP, Gray RES, Urwin GH, Hamdy NAT, et at. Aminohexane diphosphonate, in the treatment of Paget's disease of bone. Journal of Bone and Mineral Research 2: 273279, 1987 Audran M, Ciochon P, Etghen D, Mazieres B, Renier Jc. Treatment of Paget's disease of bone 'with .(4-chloro-phenyl) thiomethyline bisphosphonate. Clinidll Rheumatology 8: 71-79, 1989 Avioli LV. Paget's disease: state of the art. Clinical Therapeutics 9: 567-576, 1987 Avramides A, Flores A, De Rose J, Wallach S. Paget's disease of bone: observations after cessation of long term synthetic salmon calcitonin treatment. Journal of Clinical Endocrinology and Metabolism 42: 459-463, 1976 Bijvoet OLM, Hosking DJ, Frijlink WB, TeVelde J, Vellenga CJLR. Treatment of Paget's disel\se with combined calcitonin and diphosphonate (EHDP). Metab6lic Bone Disease and Related Research I: 251-256, 1978 ! . Black D, Duncan A, Robins SP. Quantitative analyses of the pyridinium crosslinks of collagen i? 'urine using iron-paired reversed-phase high-performance liquid chromatography. Analytical Biochemistry 169: 197-203, I ~88 Black D, Farquharson C, Robins SP. 'Exeretion of pyridinium cross links of collagen in ovariectomised rats as urinary markers for increased bone resorption. Calcifiecl Tissue International 44: 343-347, 1989 . .' Boonekamp PN, v.d. Wee-Pals U,:.., Wijk-v. Lennep MML, Thesingh CW, Bijvoet OLM. T,wo ,modes of action of bisphosphonates on osteoclastic resqrption of mineralised matrix. Bone and Mineral I: 27-39, 1986 Bounameaux HM, Schifferli J, Moritarii J-P, Jung A, Chatelanat F. Renal failure associated with ,intravenous diphosphonates. Lancet I: 471,1983 ., . Bouvet JP. Traitement de la maladie (Ie Paget par la thyrocalcitonine de saumon: etude cooperative en double insu. Nouvelle Presse Medicale 6: 1447-14~ O, ' 1977 Buclin T, Randin JP, Jacquet AF, A~ria )\1, Attinger M, et at. The effect of rectal and nasal administration of salmon calcitonin in normal subjects. Calcified Tissue Ihternational 41: 252-258, 1987 Cantrill JA, Buckler HM, Anderson ,Qe. Low dose intravenous 3-amino-I-hydroxypropylidine-l ; I-bi,sphosphonate (APD) for the treatment of Paget's disease 9f bcilne. Annals of the Rheumatic Diseases 45: 1012-1018, 1986 , Sustained biochemical Chapuy Me, Charhon SA, Meunier effects of short treatment of Paget's idisease of bone with dichloromethylene diphosphonate. Mei~bolic Bone Disease and Related Research 4: 325-328, 1983 ' Collins DH. Paget's disease of bo~e: incidence and subclinical forms. Lancet 2: 51-57, 1956 Coulton LA, Preston CJ, Cough M, Kanis JA. An evaluation of serum osteocalcin in Paget's disease 'o f bone and its response
v
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to diphosphonate treatment. Arthritis and Rheumatism 31: 1142-1147, 1988 D'Agostino HR, Barnett CA, Zielinski XJ, Gordan GS. Intranasal salmon calcitonin treatment of Paget's disease of bone. Clinical Orthopaedics and Related Research 230: 223-228, 1988 Delmas PD, Chapuy M-C, Edouard C, Meunier PJ. Beneficial effects of aminohexane diphosphonate in patients with Paget's disease of bone resistant to sodium etidronate. American Journal of Medicine 83: 276-282, 1987 Delmas PD, Chapuy MC, Vignon E, Charon S, Briancon D, et at. Long term effects of dichloromethylene diphosphonate in Paget's disease of bone. Journal of Clinical Endocrinology and Metabolism 54: 837-844, 1982 Dodd GW, Ibbertson HK, Fraser TRC, Holdaway 1M, Wattie D. Radiological assessment of Paget's disease of bone after treatment with the bisphosphonates EHDP and APD. British Jour. nal of Radiology 60: 849-860, 1987 Douglas DL, Duckworth T, Kanis JA, Preston D, Beard DJ, et at. Biochemical and clinical responses to dichloromethylene diphosphonate (CI2MDP) in Paget's disease of bone. Arthritis and Rheumatism 23: 1185-1192, 1980 Douglas DL, Kanis JA, Duckworth T, Beard DJ, Paterson AD, et at. Paget's disease. Improvement of spinal cord dysfunction with diphosphonates and calcitonin. Metabolic Bone Disease and Related Research 3: 327-335, 1981 EI Sammaa M, Linthicum FH, House HP, House JW. Calcitonin as treatment for hearing loss in Paget's disease. American Journal of Otology 7: 241-243, 1986 Fleisch H. Experimental basis for the use of bisphosphonates in Paget's disease of bone. Clinical Orthopaedics and Related Research 217: 72-78,1987 Foldes J, Shamir S, Kidroni G, Menczel J. Vitamin D in Paget's disease of bone. Clinical Orthopaedics and Related Research 243: 275-279, 1989 Frijlink WB, Bijvoet OLM, TeVelde J, Heynen G. Treatment of Paget's disease with (3-amino-I-hydroxypropylidene)-I, I-biphospho nate (APD). Lancet 1: 799-803, 1979 Gagel RF, Logan C, Mallette LE. Treatment of Paget's disease of bone with salmon calCitonin nasa1.spray. Journal of the American Geriatric Society 36: 10 11-1 0 14, 1988 Gonzalez D, Vega E, Ghiringhelli G, Mautalen C. Comparison of the acute effect of the intranasal and intramuscular administration of salmon calcitonin in Paget's disease. Calcified Tissue International 41: 313-315, 1987 Gray RES, Yates AJP, Preston CJ, Smith R, Russell RGG. Duration of effect of oral diphosphonate therapy in Paget's disease of bone. Quarterly Journal of Medicine 64: 755-767, 1987 Gruszkiewicz J, Doron Y, Borovich 'B, Zaaroor M. Spinal cord compression in Paget's disease of bone with reference to sarcomatous degeneration and calcitonin treatment. Surgical Neurology 27: 117-125, 1987 ' Hadjipavlou AG, Tsoukas GM, Siller TN, Danais S, Greenwood F. Combined drug therapy in treatment of Paget's disease of bone. Journal of Bone and Joint Surgery 59A: 1045-1051, 1977 Hamdy RC.Paget's disease of bone, pp. 1-3, Praeger Scientific, New York, 1981 Harinck ' HIJ, Bijvoet OLM, Blanksma HJ, Dahlinghaus-Nienhuys PJ. Efficacious management with aminobisphosphonate (APD) in Nget's disease of bOne. Clinical Orthopaedics and Related Research 217: 79-98, 1987a Harinck HIJ, Papapoulos SE, Blanksma HJ, Moolenaar AJ, Vermeij ·P, et at. Paget's disease of bone: early and late responses to three different modes of treatment with aminohydroxypropylidine bisphosphonate (APD). British Medical Journal 295: 1301-1305, 1987b Hosking DJ. Paget's disease of bone: an update on management. Drugs 30: 156~173, 1985 Hosking DJ, Bijvoet OLM, Van Aken J, Will EJ. Paget's disease of bone treated with diphosphonate and calcitonin. Lancet 1: 615-616, 1976 Ibbertson HK, Henley JW, Fraser TR, Tait B, Stevens EJ, et at. Paget's disease of bone: clinical evaluation and treatment with bisphosphonate. Australian and New Zealand Journal of Medicine 9: 31-35, 1979 Kanis JSA, Gray RES. Long term follow up observations on treat-
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ment in Paget's disease of bone. Clinical Orthopaedics and Related Research 217: 99-125,1987 Kurose H, Seino Y, Shima M, Tanaka H, Ishida M, et al. Intranasal absorption of salmon calcitonin. Calcified Tissue International 41: 249-251 , 1987 Lando M, Hoover LA, Finerman G. Stabilisation of hearing loss in Paget's disease with calcitonin and etidronate. Archives of Otolaryngology, Head and Neck Surgery 114: 891-894, 1988 Levy F, Muff R, Dotti-Sigrist S, Dambacher MA, Fischer JA. Formation of neutralizing antibodies during intranasal synthetic salmon calcitonin treatment of Paget's disease. Journal of Clinical Endocrinology and Metabolism 67: 541-545, 1988 Lian JB, Friedman PA. The vitamin K-dependent synthesis of carboxyglutamic acid by bone microsomes. Journal of Biological Chemistry 253: 6623-6626, 1978 MacIntyre I, Alevizaki M, Bevis PJR, Zaidi M. Calcitonin and the peptides from the calcitonin gene. Clinical Orthopaedics and Related Research 217: 45-55, 1987 McDonald DJ, Sim FH. Total hip arthropathy in Paget's disease. Journal of Bone and Joint Surgery 69A: 766-772, 1987 Meunier PJ, Chapuy MC, Alexandre C, Bressot C, Edouard C, et al. Effects of disodium dichloromethylene diphosphonate on Paget's disease of bone. Lancet 2: 489-492, 1979 Nagant De Deuxchaisnes C, Devogelaer JP, Huaux JP, Dufour JP, Esselinckx W, et al. New modes of administration of salmon calcitonin in Paget's disease. Clinical Orthopaedics and Related Research 217: 56-71, 1987 Nagant De Deuxchaisnes C, Rombouts-Lindemans C, Huaux JP, Devogelaer JP, Malghem J, et al. Roentenologic evaluation of the action of the diphosphonate EHDP and of combined therapy (EHDP and calcitonin) in Paget's disease of bone. In MacIntyre & Szelke (Eds) Molecular endocrinology, pp. 405-433, Elsevier/North Holland Biomedical Press, Amsterdam, 1979 Nagant De Deuxchaisnes C, Rombouts-Lindemans C, Huaux JP, Devogelaer JP, Malghem J, et al. Calcitonin or diphosphonates for osteolytic Paget's disease. Lancet I: 374, 1980 Nagant De Deuxchaisnes C , Rombouts-Lindemans C, Huaux JP, Malghem J, Maldague B. Roentgenologic evaluation of the efficacy of calcitonin in Paget's disease of bone. In Macintyre & Szelke (Eds) Molecular endocrinology, pp. 213-233, Elsevier/ North Holland Biomedical Press, Amsterdam, 1977 O' Doherty DP, Bickerstaff DR, McCloskeyEV,Atkins R, Hamdy NAT, et al. A comparison of the a9ute effects of subcutaneous and intranasal calcitonin. Clinical Science ~8: 215-219, 1990 O'Donoghue DJ, Hosking .DJ. Biochemical response to combination of disodium etidronate with calcitonin in Paget's disease. Bone 8: 219-225, 1987 Ogawa T, Ono T , Tsuda M, Kawanishi Y. A novel fluor in insoluble collagen: a cross linking moiety in collagen molecule. Biochemical and Biophysical Research Communications 107: 1252-1257, 1982 Papapoulos SE, Frolich M, Mudde AH, Harinck HIJ, v.d. Berg H, et al. Serum osteocalcin in Paget's disease of bone: basal concentrations and response to bisphosphonate treatment. Journal of Clinical Endocrinology and Metabolism 65: 89-94, 1987 Papapoulos SE, Harinck HIJ, Bijvoet OLM, Gleed JH, Fraher U, et al. Effects of decreasing serum calcium on circulating parathyroid hormone and vitamin metabolites in normocalcaemic and hypercalcaemic patients treated with APD. Bone and Mineral I: 69-78, 1986 Perry HM, Droke DM, Avioli LV. Alternate calcitonin and etidronate disodium therapy for Paget's bone disease. Archives of Internal Medicine 144: 929-933, 1984 Porrini AA, Maldonado Cocco JA, Garcia Morteo O. Spinal artery steal syndrome in Paget's disease of bone. Clinical and Experimental Rheumatology 5: 377-378, 1987
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Preston CJ, Yates AJP, Beneton MNC, Russell RGG, Gray RES, et al. Effective short term treatment of Paget's disease with oral etidronate. British Medical Journal 292: 79-80, 1986 Ralston SH, Boyce BF, Cowan RA, Fogelman I, Smith ML, et al. The effect of I-hydroxyvitamin D3 on the mineralisation defect in disodium etidronate treated Paget's disease - a double blind randomised clinical study. Journal of Bone and Mineral Research 2: 5-12, 1987 Redden JF, Dixon J, Vennart W, Hosking DJ. Management of fissure fractures in Paget's disease. International Orthopaedics 5: 103-106, 1981 Reginster JY, Denis D, Albert A, Franchimont P. Assessment of the biological effectiveness of nasal synthetic salmon calcitonin (SSCT) by comparison with intramuscular (1M) or placebo injection in normal subjects. Bone and Mineral 2: 133-140, 1987 Reginster JY, Jeugmans-Huynen AM , Albert A, Denis D, Deroisy R, et al. Biological and clinical assessment of a new bisphosphonate, (chloro-4-phenyl) thiornethylene bisphosphonate in the treatment of Paget's disease of bone. Bone 9: 349-354, 1988a Reginster JY, Jeugmans-Huynen AM, Albert A, Denis D, Franchimont P. One year's treatment of Paget's disease of bone by synthetic salmon calcitonin as a nasal spray. Journal of Bone and Mineral Research 3: 249-252, 1988b Reitsma PH , Teitelbaum SL, Bijvoet OLM, Kahn AJ . Differential action of the bisphosphonate (3 amino- I-hydroxypropylidene)I-I-bisphosphonate (APD) and disodium dichloromethylene bisphosphonate (CI2MDP) on rat macrophage-mediated bone resorption in vitro. Journal of Clinical Investigation 70: 927933, 1982 Rico H, Hernandez ER, Younes M, Hernandez D, Espinos D. Biochemical assessment of acute and chronic treatment of Paget's bone disease with calcitonin and calcium with and without bisphosphonate. Bone 9: 63-66, 1988 Sadar ES, Walton RT, Gossman HH. Neurological dysfunction in Paget's disease of the vertebral column. Journal of Neurosurgery 37: 661-665, 1972 Singer FR, Mills BG. Paget's disease of bone: etiologic and therapeutic aspects. In Peck WA (Ed.) Bone and mineral research annual 2, pp. 394-421 , Elsevier Science, Amsterdam , 1983 Siris ES, Clemens TP, McMahon D, Gordon A, Jacobs TP. Parathyroid function in Paget's disease of bone. Journal of Bone and Mineral Research 4: 75- 7 9, 1989 Stumpf JL. Pharmacologic management of Paget's disease. Clinical Pharmacy 8: 485-495, 1989 Thiebaud D, Jaeger P, Burckhardt P. Paget's disyase of bone treated in five d'lYs with AHPrBP (APD) per os. Journal of Bone and Mineral Research 2: 45-52, 1987 Thiebaud D, Jaeger P, Gobelet C, Jacquet AF, Burckhardt P. A single infusion of the bisphosphonate AHPrBP (APD) as treatment of Paget's disease of bone. American JC:lUrnal of Medicine 85: 207-212, 1988 Vega E, Gonzalez D, Ghiringhelli G, Mautalen C. Intravenous aminopropylidene bisphosphonate (APD) in the treatment of Paget's bone disease. Journal of Bone and Mineral Research 2: 267-2711, 1987 Yates AJP. Paget's disease of bone. Clinics in Endocrinology and Metabolism 2: 267-284, 1988 Yates AJP, GnlY RES, Urwin GH, Preston CJ, Russell RGG, et . al. Intravenous c1odronate in the treatment and retreatment of Paget's disease of bone. Lancet I: 1474-1477, 1985
Correspondence and reprints: Dr D.J. Hosking, Consulting Physician, City Hospital, Hucknall Road, Nottingham NG5 I PB, England.
Drugs 40 (6) 829-840, 1990 0012-6667/90/0012-0829/$06.00/0 © Adis International Limited All rights reserved. DRUG03410
Advances in the Management of Paget's Disease of Bone D.J. Hosking City Hospital, Nottingham, England
Contents
Summary .................................................................................................................................... 829 I. Assessment of Symptoms .......................................... ........................................................... 830 2. Monitoring the Response to Treatment ........................... ................................................... 831 2.1 Symptoms ........................................................................................................................ 831 2.2 Alkaline Phosphatase ................................................................. ..................................... 832 2.3 Hydroxyprol ine ................ .......................................................... ....... .............................. 832 2.4 Osteocalcin ...................................................................................................................... 832 2.5 Pyridinium Crosslinks .................................................................................................... 832 2.6 Radiographs ..................................................................................................................... 832 3. Treatment ............................;................................................................................. ................. 833 3.1 Calcitonin ........................ .................... ............................................................................ 833 3.1.1 Intramuscular or Subcutaneous Administration .................. .. ............................. 833 3.1.2 Intranasal Calcitoni,n ......... .................................................................................... 834 3.2 Bisphosphonates (Diphosphonates) ...............................................................................835 3.2.1 Etidronic Acid (Disodium Etidronate) ................................................................. 835 3.2.2 C1odronic Acid (Clodronate) ................................................................................. 835 3.2.3 Pamidronic Acid (Pamidronate, APD) ................................................................ 836 3.2.4 Newer Bisphosphonates .................................. ....................................................... 837 3.3 Sequential or Combined Use of Calcitonin and Bisphosphonate .............................. 837 4. Current Clinical Recommendations ....................................................................................838 4.1 Asymptomatic Patients ................................................................................................... 838 4.2 Symptomatic ,Patients ..................................................................................................... 838 4.3 Special Problems ............................................................................................................. 838 5. Conclusion ........'.. .... :.................................. .................... .......... .. ............................................ 838
Summary
The advent of potent new bisphosphonates (diphosphonates) now makes it possible to restore and maintain normal bone turnover in many patients with Paget's disease of bone (osteitis defor,mans). This has necessitated a reappraisal of the indications for treatment, the ways in which disease activity and response are assessed, as well as the place of existing therapies. Measurements of urinary hydroxyproline and serum alkaline phosphatase remain the most useful markers of disease activity. Pyridinium crosslinks may prove to be more specific than hydroxyproline ~ n the assessment of bone resorption but osteocalcin has been disappointing in monitoring the effect of treatment on bone formation. Etidronic acid (disodium citidronate), the first bisphosphonate introduced for clinical
Drugs 40 (6) 1990
830
use, is a potent inhibitor of osteoclastic bone resorption but its potential is limited by the development of defective mineralisation with high dosage (10 to 20 mg/kg/day). The newer bisphosphonates, c1odronic acid (c1odronate) and pamidronic acid (pamidronate, APD), are free from this problem and appear able to control a wide range of disease activity. A small number of patients appear resistant to the agents but the underlying mechanism is unclear. The efficacy and safety of these bisphosphonates makes it likely that the threshold for treating asymptomatic patients will fall in the hope of preventing long term complications. These developments will lead to a reappraisal of the role of calcitonin which can now be administered by both the parenteral and intranasal routes. One focus of interest will be on the quality of the bone laid down during treatment. Meticulous radiographic studies have shown that calcitonin improves bone architecture and this may have particular relevance to the treatment of lytic disease. The relative merits of the different forms of therapy for Paget's disease need further evaluation, particularly with respect to the identification of specific advantages of individual drugs.
Paget's disease of bone (osteitis deformans) is primarily a disorder of osteoclasts, characterised by increased bone resorption with a secondary stimulation of osteoblastic activity leading to the deposition of both lamellar and woven bone (Singer & Mills 1983). At a macroscopic level the trabecular architecture becomes distorted, with a loss of the definition between cortical and trabecular bone. Affected areas show mixed lysis and sclerosis, becoming painful, prone to deformity, fractures or neurological compression syndromes. Since this subject was last reviewed in the Journal (Hosking 1985) there have been a number of important advances in treatment which are considered in detail below. Citations to the literature are largely confined to the last 5 years. A more extensive bibliography can be found in several recent reviews (A violi 1987; Hamdy 1981 ; Hosking 1985; Kanis & Gray 1987; Singer & Mills 1983; Yates 1988).
1. Assessment of Symptoms Paget's disease predominantly affects the axial skeleton but virtually any bone can be involved, although the feet and hands are usually spared. The majority of affected individuals are probably asymptomatic (Collins 1956) and are often detected during radiographic or biochemical investigation of unrelated symptoms. Since therapy has become more effective, with fewer adverse effects,
the goal of long term control of abnormal bone turnover is within reach (Harinck et al. 1987a) so that the threshold for treating the asymptomatic patient is likely to fall. Bone pain is the most common indication for treatment and may arise from a number of different mechanisms in the same individual. I. Distinction of bone pain due to Paget's disease from that of associated degenerative joint dissease depends partly on the history but also on radiographs of the affected area. Pain, uncontrolled by simple analgesics, is an indication for a 2- to 3month therapeutic trial of either calcitonin or a bisphosphonate (Altman 1985). Failure of pain to improve suggests that degenerative joint disease is dominant. If the hip is involved, joint replacement using cemented components should give good results with only a slight increase in the risk of subsequent aseptic loosening (McDonald & Simm 1987). Plicamycin (mithramycin) [15 /otg/kg] has been used to obtain a more rapid control of bone turnover and so distinguish between joint and bone pain (Hadjipavlou et al. 1977). However, the risks associatyd with its use, such as marrow depression, are no longer justified now that bone turnover can be rapidly inhibited by intravenous bisphosphonates. 2. Fissure fractures ·in the convex cortex of a bowed long bone may extend and become complete,causing the acute onset of severe pain. The
831
Paget's Disease of Bone
patient must be immobilised immediately and if pain persists the limb must be externally splinted or the fracture fixed electively (Redden et al. 1981). The stability of this type of fracture depends upon active bone formation at the fracture site, and excessive inhibition of the reparative process may increase the risk of extension. If potent bisphosphonates are to be used in such patients they should be given in small, carefully monitored doses. 3. Coincidental bone pain not due to Paget's disease must be excluded by appropriate radiographs. Deformity may also involve the axial skeleton, producing a variety of neurological entrapment syndromes. These may be due to mechanical compression, a vascular steal syndrome in the absence of obstruction (Porrini et al. 1987) or, rarely, sarcomatous change (Gruszkiewicz et al. 1987; Sadar et al. 1972). Part of the rapid improvement following treatment with either calcitonin or bisphospho nates (diphosphonates) [Douglas et al. 1981; Porrini et al. 1987] may be due to a reduction in bone blood flow and a recovery in spinal circulation. These syndromes should be treated initially with calcitonin or bisphosphonates, not only because of their effectiveness and speed of onset but also because the results of laminectomy have been disappointing and attended by a high mortality and morbidity (Sadar et al. 1972). Deafness, which may have both conductive and sensorineural components, may be due to involvement of either the temporal bone or the ossicles. Early studies were conflicting as to whether calcitonin exerted a beneficial effect but occasional reports continue to appear documenting stabilisation of hearing loss with calcitonin either alone or in combination with etidronic acid (disodium etidronate) [EI Sammaa et al. 1986; Lando et al. 1988]. The remaining complications of Paget's disease - which include high output cardiac failure, immobilisation, hypercalcaemia and sarcomatous degeneration - are uncommon and little has changed in their management since the last review.
2. Monitoring the Response to Treatment (Table J) It is essential to monitor the response to treatment both to assess its efficacy in an individual and to make comparisons between different therapies. 2, I Symptoms Although symptom control is the reason for treatment its evaluation is clouded by a 30 to 40% placebo response (Bouvet 1977; Ibbertson et al. 1979). It is essential that objective ineasurements are made and those of serum alkaline phosphatase and urinary hydroxyproline excretion are convenient, reliable and generally available. Table I. Monitoring the response to treatment Symptoms 30-40% placebo response Qualitative, semiquantitative, subjective Alkaline phosphatase (ALP) Marker of osteoblastic activity Correlates with HYPRO and disease extent Levels stable (± 10%) over periods of months 50% extraskeletal origin; proportionately less in active disease Normal levels in active disease of limited extent Hydroxyproline (HYPRO) Marker of osteoclastic activity Only 1% of HYPRO in urine as free amino acid Tedious assay; less stable levels with time than ALP (± 20%) Rapid decline in concentration with osteoclast inhibition Extraskeletal sources: diet, nonskeletal collagen May be normal in some patients with active disease Osteocalcin Specific marker of osteoblastic activity Less sensitive than ALP in assessing disease activity .Correlates with ALP and HYPRO in untreated patients Discordant response during treatment Not a useful marker for monitoring the response to treatment Pyridinium crosslinks Specific for collagen degradation Deoxypyridinoline present only in bone collagen Bone radiol0!ly Meticulous attention to radiographic technique Assessment only of osteolytic lesions
832
2.2 Alkaline Phosphatase Alkaline phosphatase is a marker for bone formation but has a significant extraskeletal component in normal individuals. This becomes proportionately less in active Paget's disease, although distortions due to hepatic alkaline phosphatase become more significant as bone turnover approaches normal levels. Other liver function tests give some indication of the extent of possible interference but simultaneous measurements of urinary hydroxyproline excretion are essential for assessing bone turnover. Patients with localised Paget's disease may have insufficient activity to influence 'whole body' measurements. Changes within the normal range may then be useful in monitoring response but closely spaced measurements (together with urinary hydroxyproline excretion) are needed to avoid the risk of overtreatment. 2.3 Hydroxyproline Hydroxyproline is a marker for osteoclastic bone resorption and its measurement as a molar ratio to creatinine in a fasting urine sample is both convenient for the patient and avoids the interfering effects of dietary collagen. The disadvantage lies in its lack of sensitivity, since large amounts are broken down in the liver and because it is released at several stages of collagen biosynthesis and maturation. Moreover, only 1% of the hydroxyproline in urine is present as the free amino acid and most of the remainder is in the form of peptides. An important characteristic of hydroxyproline is that it declines rapidly over a few days at the start of treatment with potent osteoclast inhibitors, whereas alkaline phosphatase .changes more slowly over a period of weeks (Frijlink et al. 1979). Hydroxyproline also increases before alkaline phosphatase in a relapse and is therefore the best measure of the duration of remission. 2.4 Osteocalcin Osteocalcin is a vitamin-K- dependent protein which binds calcium and is synthesised exclusively by osteoblasts (Lian et al. 1978). Although osteo-
Drugs 40 (6) 1990
calcin concentrations correlate with those of serum alkaline phosphatase and urinary hydroxyproline in untreated Paget's disease (Coulton et al. 1988; Papapoulos et al. 1987) it appears to be a less sensitive marker of disease activity. Osteocalcin and alkaline phosphatase may reflect different functions of the osteoblast but of much greater practical significance is the discordance between the measurements during treatment. For example, after inhibition of bone turnover with bisphosphonates, there is the expected rapid fall in hydroxyproline followed by a slower decrease in alkaline phosphatase, but either no change (Coulton et al. 1988) or an increase (Papapoulos et al. 1987) in osteocalcin. Where osteocalcin increases this seems to be causally related to increments in 1,25 dihydroxy vitamin D. This reflects the secondary hyperparathyroidism which follows the uncoupling between bone resorption and formation in the early phase of bisphosphonate therapy (Frijlink et al. 1979; Papapoulos et al. 1986). Thus, osteocalcin does not seem to be a useful marker of bone turnover during treatment but may be of value in studying other aspects of osteoblast function. 2.5 Pyridinium Crosslinks The problems associated with hydroxyproline measurements, described above, have prompted the search for other markers of bone resorption. One 'potential candidate is the urinary excretion of hydroxypyridinium crosslinks of collagen (Black et al. 1988). These are derived from the degradation of mature bone collagen (Ogawa et al. 1982) and may prove to be more specific markers of bone resorption than hydroxyproline (Black et al. 1989). 2.6 Radiographs Meticulous attention to radiographic technique and positioning of the patient make ·it possible to compare changes in trabecular architecture over prolonged periods. It is only possible to evaluate lytic lesions but several studies have shown important discrepancies between biochemical mark-
Paget's Disease of Bone
Table II. Standardisation of radiographic technique (reproduced with permission from Dodd et al. 1987) 1. Use of same x-ray unit for initial and follow-up studies 2. Accurate automatic exposure control 3. Records of Kv, filtration and screen-film combination for future duplication 4. Exposure consistency confirmed by aluminium step wedge and preliminary check radiograph 5. Assessmerit: Two independent observers; Change in bone texture on arbitrary scale of 1-4; Position of wedge resorption fronts assessed from fixed pOints; Progression measured in mm/month
ers of bone turnover and radiographic appearance. Improvements in bone texture, filling in of lytic lesions and decreased or reversed progression of lytic wedge lesions in the cortex oflong bones may be seen with both calcitonin (Nagant de Deuxchaisnes et al. 1977) and palmidronate (Dodd et al. 1987), despite failure to normalise either alkaline phosphatase or hydroxyproline in some patients. In contrast, deterioration in trabecular architecture may follow treatment with etidronic acid (Nagant de Deuxchaisnes et aL 1979) even though biochemical markers of bone turnover return to normal. Similar discrepancies may be seen where quantitative bone scans show improvement during etidronic acid treatment despite radiographic deterioration (Nagant de Deuxchaisnes et al. 1980). Although this degree of meticulous radiography can be achieved within a routine department (Dodd et al. 1987) the procedure must be standardised as far as possible and is best organised prospectively (table II).
3. Treatment The roles of the calcitonins and bisphosphonates in the treatment of Paget's disease have recently been reviewed (A violi 1987; Hosking 1985; Kanis & Gray 1987; Stumpf 1989). Only the essential features of their clinical effects are considered here, although more recent developments are reviewed in detail.
833
3.1 Calcitonin Calcitonin is a 32 amino acid peptide secreted by the parafollicular cells of the thyroid gland; it has been used clinically because of its inhibitory effect on osteoclastic bone resorption (Macintyre et al. 1987). A number of synthetic peptides are available for clinical use, although salmon calcitonin has been most widely used because of its enhanced potency in comparison with the human and porcine hormones. Since calcitonin is hydrolysed by gastric secretions it has to be given by injection, although preparations suitable fOf intranasal administration have recently become available (Buclin et al. 1987; Kurose et al. 1987; Reginster et al. 1987).
3.1.1 Intramuscular or Subcutaneous Administration Calcitonin treatment should be started with a single daily subcutaneous injection of 50 to 1000, which can be reduced to thrice weekly once symptoms have been relieved and providing that bone turnover continues to decline. Alkaline phosphatase and hydroxyproline decrease by about 50%, but responses show considerable interpatient and interstudy variation. Reductions in these markers usually reach their maximum level by 6 months, although bone turnover will increase once salmon calcitonin is stopped; this relapse is unaffected by the duration of treatment. Continuation beyond 6 months should be restricted to those with extensive osteolytic lesions in weight-bearing bones or those with neurological symptoms. Even when treatment is withdrawn control of bone pain may be more prolonged (A vramides et al. 1976), a factor that has been attributed to restoration of normal bone remodelling by calcitonin (Nagant de Deuxchaisnes et al. 1977). Therapy should be reinstituted at the previous dosage if symptoms recur. Adverse effects such as nausea, flushing or malaise are dose dependent and only rarely are they severe enough to warrant interruption or abandonment of treatment. If symptoms such as nausea and flushing are troublesome the hormone can be injected before bed and given with an antiemetic.
834
Drugs 40 (6) 1990
Antibodies to the heterologous calcitonins develop in 30 to 60% of patients and tend to increase in concentration with time. Clinical resistance is unusual and tends to be associated with high titre antibodies which are more likely with prolonged treatment. The presence of antibody-mediated resistance can be confirmed by changing treatment to a calcitonin of a different species; human synthetic calcitonin is the logical choice, in a dose of 0.5 to I mg/day.
3.1.2 Intranasal Calcitonin A major development within the last few years has been the introduction of salmon calcitonin suitable for intranasal administration; this produces a maximum reduction in bone turnover of 30 to 40% (table III) after 4 to 6 months' treatment (D' Agostino et al. 1988; De Deuxchaisnes et al. 1987; Gagel et al. 1988; Reginsteret al. 1988b). These studies were small and the interpatient variability was large, which makes it impossible to assess dose-response relationships. A consistent finding has been that the intranasal route seems free of the side effects seen with calcitonin injections. This may be due to aitereq pharmacokinetics but is probably because of lower plasma calcitonin concentrations. Acute studies suggest that for a
given dose of calcitonin the intranasal route delivers 7.5 to 40% of the amount obtained from subcutaneous or intramuscular injections (De Deuxchaisnes et al. 1987; Gonzalez et al. 1987; O'Doherty et al. 1990; Reginster et al. 1987). Antibodies develop after intranasal salmon calcitonin just as they do after the parenterally administered hormone. Titrestend to rise more rapidly in those previously exposed to salmon calcitonin, and this may be accompanied by clinical resistance (Levy et al. 1988). For all these reasons calcitonin may be less effective when administered intranasally rather than parenterally, particularly in patients with very high rates of bone turnover. Local irritation of the nasal mucosa seems to be mild and transient. Coincidental allergic rhinitis seems to have a variable effect on absorption, some patients showing an enhancement while others experienced decreased absorption and calcitonin-related side effects. More Clinical studies are clearly needed to resolve this issue. Intranasal calcitonin is an advance in terms of patient acceptability, particularly in the elderly (Gagel et al. 1988). Salmon calcitonin can also be given as a 300U suppository (Buclin et al. 1987; De Deuxchaisnes et al. i 987) which reduced hydroxyproline to 67% and alkaline phosphatase to 83% of pretreatment
Table III. Response to intranasal ?alcitonin Reference
No. of pts a
Dose
Duration of
(U/day)
treatment (months)
Initial value b
ALP D'Agostino et al.
2
(1988)
3
Response: % of pretreatment value (time of assessment) [months] HYPRO
ALP
100 200
3
3.39
69.0 (3)
3
4.78
71.3 (3)
200 400
12 12
5.2
9
3.7
77.0 (4) 76.0 (6)
Gagel et al. (1988)
7
100-400
3
3.03
67 (3)
Reginster et al. (1988b)
8 9
200 400
12 12
4.08 2.48
De Deuxchaisnes et al. (1987)
13
a
Previously untreated with salmon cal.citonin .
b
Multiple of upper limit of normal range.
Abbreviations: ALP = alkaline phosphatase; HYPRO = hydroxyproline.
3.2 1.7
63.9 (6) 62.6 (6)
HYPRO
58 (6)
62 .3 (6) 84.9 (6)
Paget's Disease of Bone
levels. Local tolerance of the suppository was good, without significant adverse effects. Experience with eel calcitonin and its aminosuberic analogue, ASU 1,7-eel calcitonin, is still limited and although both preparations reduce bone turnover their place in current therapy in relation to other calcitonins is uncertain. 3.2 Bisphosphonates (Diphosphonates) Bisphosphonates are analogues of pyrophosphate characterised by a P-C-P bond. They bind strongly to hydroxyapatite crystals, inhibiting bone mineral deposition and dissolution. This effect appears to be independent of their clinically important action of inhibiting osteoclastic bone resorption (Fleisch 1987). The main emphasis of research in this field over recent years has been the development of compounds with larger margins between the dose-inhibiting resorption and that causing the unwanted inhibition of mineralisation. The first compound to be introduced into clinical use was etidronic acid (disodium etidronate) and, although the margin between its wanted and unwanted effects is narrow, a great deal of experience has been gained which has facilitated the introduction of more potent analogues. 3.2.1 Etidronic Acid (Disodium Etidronate) . Etidronic acid was the first compound to be introduced into clinical use and there is good evidence from double-blind placebo-controlled studies that it relieves pain and controls bone turnover in a dose-dependent fashion; The major problem with the drug occurs at doses of 10 to 20 mg/kg/ day, where between 10 and 20% of patients treated for 6 months develop severe incapacitating pain or long bone fractures · (not necessarily · in Pagetic bones), in association with histological evidence of defective mineralisation. Although the bones recover when the drug is withdrawn this has limited the dosage to 5 mg/kg/dayand the duration of treatment to 6 months. This dose and duration of therapy seems effective for most patients, 60% of whom will obtain significant clinical benefit which is not improved
835
upon by prolonging treatment. However, 1 month of treatment with etidronic acid 20 mg/kg/day may be as effective as 6 months at the same dose and significantly better than treatment with · 5· tng/kg! day, although there may be transient impairment of mineralisation (Preston et al. 1986). Since all bisphosphonatesare poorly absorbed.by theintestine and this is diminished by calcium .the drug should be given on an empty stomach and never taken with milk or milk products. The pretreatment level of bone turnover is the major determinant of whether etidronic acid will restore biochemical normality and ensure sustained remission (Altman 1985; Gray et al. 1987). Three-quarters of the patients with less than a doubling of bone turnover will achieve normal levels of alkaline phosphatase and hydroxyproline and may only need 6 months' treatment to remain in prolonged remission. Even those with more active disease may need less than one treatment course; year to stay in clinical remission, although the proportion with normal bone turnover will be le.ss. Patients \Vith very active disease (6- to lO-fold increments in bone turnover) present the major long term prqblem (Altman 1985). Although they may show a rapid initial response to etidronic acid they relapse quickly (often within 3 months) and tend to require . increasing doses to reduce bone turnover. Eventually they become refractory to highdose treatment, developing increasing bone pain, and the options are then to treat with one of the newerbisphosphonates (Delmas et al. 1987; Douglas et al. '1980) or to transfer to calcitonin (Altman & Collins-Yudiskas 1987; Perry et al. 1984). Serum alfacalcidollevels are normal in Paget's disease both before and after treatment with etidronic acid . (Foldes et al. 1989; Siris et al. 1989). Although vitamin D supplements reduce the prevalence Ot the mineralisation defect they also diminish the dinical and biochemical responses, suggesting that they may reduce etidronic acid absorptioll (Ralston et al. 1987). 3.2.2 Clodronic Acid (Clodronate) Clodronic acid is a more potent osteoclast inhibitor than etidronic acid (Fleisch 1987) and does not cause defective mineralisation even when given
836
in high doses (Delmas et al. 1982; Meunier et al. 1979). Optimal responses seem to be achieved with 6 months' treatment with 800mg daily, which reduces bone turnover by about 70% and achieves normal, or near normal, levels of alkaline phosphatase and hydroxyproline in most patients (Delmas et al. 1982; Douglas et al. 1980). Larger doses are neither more effective in reducing bone turnover nor in achieving a more prolonged remission. Bone turnover may remain controlled for up to 2 years in over 50% of patients without the need for further retreatment. Those who achieve normal levels of alkaline phosphatase remain in remission for longer than those with persistently elevated values (Gray et al. 1987). The uncoupling of bone resorption and formation during the early weeks of treatment leads to the development of secondary hyperparathyroidism, as seen with other potent bisphosphonates (Papapoulos et al. 1986; Siris et al. 1989). This can be minimised by using calcium and vitamin D supplements, which enhance the reduction in alkaline phosphatase but have no effect on hydroxyproline or pain relief (Delmas et al. 1982). Clodronic acid can also be given as a high-dose (1.6 g/day) short term (l month) regimen, which produces equivalent degrees of suppression of bone turnover compared to longer courses oflower-dose therapy (Chapuy et al. 1983). Intravenous clodronic acid avoids the problem of gastrointestinal side effects, and 300mg given daily for 5 days as a 3-hour infusion reduces bone turnover by 50% at 1 month, which is sustained for 6 months (Yates et al. 1985). Bisphosphonates must be infused slowly because of fears of renal toxicity (Boun~meaux et al. 1983), although this has not materialised in clinical practice except for transient proteinuria (Yates et al. 1985). The relationship between the pretreatment level of bone turnover and the ·frequency of clodronic acid infusions needed to predictably restore normal levels of alkaline phosphatase and hydroxyproline has yet to be defined. Despite initial impressions, retreatment does not seem to be associated with diminished effectiveness (Yates et al. 1985).
Drugs 40 (6) 1990
3.2.3 Pamidronic Acid (Pamidronate, APD) Pamidronic acid is another second generation bisphosphonate with 10 times the potency of clodronic acid on a molar basis (Reitsma et al. 1982) which does not inhibit mineralisation (Harinck et al. 1987a). As with clodronic acid, the aim of treatment is to restore normal levels of bone turnover. Both oral and intravenous preparations are available and a number of different treatment protocols have been explored. Hydroxyproline falls rapidly after treatment with pamidronic acid, followed by a slower decline in alkaline phosphatase (Frijlink et al. 1979). Treatment can be withdrawn as soon as hydroxyproline becomes normal since alkaline phosphatase will invariably return: to normal in subsequent weeks (Harinck et al. 1987b). The proportion of patients who will achieve normal bone turnover depends on the initial disease activity and the administered dose. However, the duration of the subsequent remission, which may last for up to 2 years in 50% of patients, is mainly a function of the degree of suppression of bone turnover, although it is also influenced by pretreatment activity (Harinck et al. 1987a). A number of intravenous regimens have been studied in patients with modestly active Paget's disease (3-fold increments in alkaline phosphatase or hydroxyproline). 10 daily infusions of pamidronicacid 20mg restored normal levels of hydroxyproline, with a subsequent return of alkaline phosphatase to normal (Harinck et al. 1987b). A single infusion of 60mg given over 24 hours had a similar effect (Thiebaud et al. 1988)~ as did 5 daily 15mg infusion~ followed, if necess~ry, by weekly infusions for 3. months (Cantrill et al. 1986). More activ¢ disease failed to respond to 7 daily infusions of p~midronic acid 25mg, and the partially suppres~ed activity relapsed within 2 to 3 months (Vegaet al. 1987). However, intravenous treatment followed by long term oral therapy (600 mg/day) controlled 90% of patients, covering a wide spectrum of activity (Harinck et al. 1987b). Short (5-day) . courses of high-dose pamidronic acid (l200mg daily) are effective in modestly active disease but fail to control more severe cases (Thiebaud et al. 1987).
837
Paget's Disease of Bone
Direct comparisons between the clinical merits of pamidronic acid and clodronic acid are difficult at the present time. Both are capable of restoring normal bone turnover in a high proportion of patients. They have different modes of action, pamidronic acid inhibiting the accession of osteoclasts to the bone surface, while clodronic acid inhibits mature osteoclast function (Boonekamp et al. 1986). It is uncertain whether these differences have clinical implications. 3.2.4 Newer Bisphosphonates A number of other bisphophonates have been tested in Paget's disease but are not yet generally available. Aminohexane bisphosphonate, given either orally for 1 month (400 mg/day) or intravenously for 5 days (25 or 50mg), produced a 60% reduction in bone turnover which was sustained for 6 months after the withdrawal of treatment. A substantial proportion of the patients treated either orally or intravenously obtained normal levels of bone turnover, although there was little difference between the 2 intravenous doses (Atkins et al. 1987). The same compound has also been used to treat patients resistant to etidronic acid who had considerably increased bone turnover. Treatment with 400mg daily for 3 months produced a 60% reduction in alkaline phosphatase and a 46% reduction in hydroxyproline (Delmas et al. 1987). Aminobutylidene bisphosphonate also reduced bone turnover by 60% after 4 daily infusions of2.5 to 25 mg/day, and this effect was sustained for several months (Adami et al. 1986). Less impressive responses were obtained in previously treated patients, but this problem was also recognised with clodronic acid. The difficulties of interpreting changes in bone turnover in relapsing patients have been elegantly discussed by Yates et al. (1985). Thiomethylene bisphosphonate is the latest agent to be introduced, but in doses of 200 to 400 mg/ day given for 6 months seemed less effective than other bisphosphonates (Reginster et al. 1988a). This may be a function of dose because a short term study using 800 mg/day showed better responses,
although normal bone turnover was not obtained (Audranet al. 1989). 3.3 Sequential or Combined Use of Calcitonin and Bisphosphonate Since the calcitonins and the bisphosphonates have such different structures it is not unreasonable to suppose that their effects may be complementary. Various regimens have been explored where these 2 agents have been given either sequentially or in combination. In patients treated with etidronic acid in a dose of 400 mg/day (5 mg/kg bodyweight) for 6 months, further reductions in bone turnover can be achieved by a subsequent 6-month course of salmon calcitonin (Perry et al. 1984). Surprisingly, the reverse sequence had a disappointing effect, altho'ugh in this particular study the response to the initial treatment with salmon calcitonin was unusually poor. However, in another similar study (Adami et al. 1984) where human calcitonin had reduced bone turnover by 45% the elevated values were reduced by 60% following a 2-month course of clodronic acid. This suggests that bisphosphonates may also be useful where calcitonin fails to normalise bone turnover. The newer bisphosphonates do not seem to cause defective mineralisation and can be given long term, but where etidronic acid is the only available compound the sequential use of calcitonin is a reasonable option. This is particularly so with very active disease where it is well recognised that bone turnover will not be completely controlled by either etidronic acid or calcitonin alone (Altman et al. 1985). However, short courses of salmon calcitonin (10 days) interspersed with etidronic acid (20 days) and repeated over a 6-month period were slightly less effective than a to-day course of salmon calcitonin alone (Rico et al. 1988). Combinations of salmon calcitonin (100U 3 times/week) and etidronic acid (400 mg/day) given from the outset of treatment (Bijvoet et al. 1978; Hosking et al. 1976; O'Donaghue & Hosking 1987) are more effective than either agent given alone. Responses are generally at a maximum at 6 months; although further reductions can be achieved by
838
more prolonged treatment they are unpredictable and very active disease may not be completely controlled. However, the bisphosphonate component does ensure that once treatment is withdrawn, biochemical remission persists longer than it does after salmon calcitonin alone. Prolonged use of combined treatment does not seem to be complicated by the risk of defective mineralisation. Human calcitonin has been found to be of use in Paget's disease refractory to etidronic acid and salmon calcitonin (Altman & Collins-Yudiskas 1987). It is not clear to what extent the resistance to salmon calcitonin was antibody mediated but the observation that human calcitonin reduced bone turnover by 50% in patients resistant to etidronic acid is of considerable interest.
4. Current Clinical Recommendations
Drugs 40 (6) 1990
be achieved by either agent within 6 months, at which point treatment should be withdrawn but reintroduced at relapse. 'Clinical' relapse must be substantiated by measurements of bone turnover. Second generation bisphosphonates (if available) can be used for longer periods of time without the risk of defective mineralisation. 3. Very high bone turnover (> 3-fold increment): second generation bisphosphonates are the agents of choice but if they are unavailable a combination of calcitonin with etidronic acid is an alternative. Treatment should be continued until bone turnover is normal or at a stable minimum value. The risk of defective mineralisation with etidronic acid seems to be less if it is combined with calcitonin, but a bone biopsy to exclude defective mineralisation should be performed if treatment is continued for more than 12 months.
4.1 Asymptomatic Patients 4.3 Special Problems Asymptomatic · patients may be treated in the hope of avoiding long term complications. l. Normal bone turnover: no treatment. 2. Increased bone turnover: bisphosphonates are to be preferred to calcitonin because of more prolonged periods of remission without treatment. Second generation compounds (clodronic acid, pamidronic acid) are to be preferred to etidronic acid. Treatment should be continued until bone turnover reaches a minimum value and then withdrawn until disease relapses. There is a risk of defective mineralisation with long term etidronic acid therapy and a bone biopsy will be needed if treatment is continued beyond 6 months. 4.2 Symptomatic Patients
l. Normal bone turnover: treat first with analgesic agents. Consider the need for an orthopaedic opinion for associated degenerative joint disease or deformity. Use of calcitonin or bisphosphonates in such patients is of unproven value. 2. Moderately increased bone turnover (2- to 3fold increment): the choice lies between salmon calcitonin and bisphosphortates. The maximum response at this level of bone turnover will generally
I. Lytic disease or stress fractures in bowed bones: calcitonin is preferable to the bisphosphonates because over-treatment with the latter may impair fracture repair. Ifbisphosphonates are used they should be given only until hydroxyproline is normal and must be withdrawn if pain over the lytic/stress fracture site increases or if alkaline phosphatase falls below the upper limit of the normal range. 2. Spinal compression syndromes: medical therapy is preferable to surgery. Rapidity of effect is important and this seems to be achieved either with intravenous bisphosphonates or with calcitonin. A surgical opinion should be sought if neurological signs worsen or paraparesis develops. 3. Sarcomatous degeneration is extremely rare but treatment is only palliative.
5. Conclusion It is clear that with the introduction of potent second generation bisphosphonates the treatment of Paget's disease has entered a new and exciting phase. Further study is needed to evaluate the relative merits of the different bisphosphonates, their
839
Paget's Disease of Bone
routes of administration and the changing position of calcitonin.
References Adami S, Guarrera G, Salvagno G, Spiazzi G, Marini G, et at. Sequential treatment of Paget's disease with human calcitonin and dichloromethylene diphosphonate (CL2MDP). Metabolic Bone Disease and Related Research 5:. 265-267, 1984 Adami S, Salvagno G, Guarrera G, Montesanti F, Garavelli S, et at. Treatment of Paget's disease of .bone with intravenous 4 amino-I-hydroxybutylidene-I, 1-bisphosphonate. Calcified Tissue International 39: 226-229, 1986 Altman RD. Long term follow up of therapy with intermittent etidronate disodium in Paget's disease of bone. American Journal of Medicine 79: 583-590; 1985 Altman RD, Collins-Yudiskas B. Synthetic human calcitonin in refractory Paget's disease of bone. Archives of Internal Medicine 147: 1305-1308, 1987 Atkins RM, Yates AJP, Gray RES, Urwin GH, Hamdy NAT, et at. Aminohexane diphosphonate, in the treatment of Paget's disease of bone. Journal of Bone and Mineral Research 2: 273279, 1987 Audran M, Ciochon P, Etghen D, Mazieres B, Renier Jc. Treatment of Paget's disease of bone 'with .(4-chloro-phenyl) thiomethyline bisphosphonate. Clinidll Rheumatology 8: 71-79, 1989 Avioli LV. Paget's disease: state of the art. Clinical Therapeutics 9: 567-576, 1987 Avramides A, Flores A, De Rose J, Wallach S. Paget's disease of bone: observations after cessation of long term synthetic salmon calcitonin treatment. Journal of Clinical Endocrinology and Metabolism 42: 459-463, 1976 Bijvoet OLM, Hosking DJ, Frijlink WB, TeVelde J, Vellenga CJLR. Treatment of Paget's disel\se with combined calcitonin and diphosphonate (EHDP). Metab6lic Bone Disease and Related Research I: 251-256, 1978 ! . Black D, Duncan A, Robins SP. Quantitative analyses of the pyridinium crosslinks of collagen i? 'urine using iron-paired reversed-phase high-performance liquid chromatography. Analytical Biochemistry 169: 197-203, I ~88 Black D, Farquharson C, Robins SP. 'Exeretion of pyridinium cross links of collagen in ovariectomised rats as urinary markers for increased bone resorption. Calcifiecl Tissue International 44: 343-347, 1989 . .' Boonekamp PN, v.d. Wee-Pals U,:.., Wijk-v. Lennep MML, Thesingh CW, Bijvoet OLM. T,wo ,modes of action of bisphosphonates on osteoclastic resqrption of mineralised matrix. Bone and Mineral I: 27-39, 1986 Bounameaux HM, Schifferli J, Moritarii J-P, Jung A, Chatelanat F. Renal failure associated with ,intravenous diphosphonates. Lancet I: 471,1983 ., . Bouvet JP. Traitement de la maladie (Ie Paget par la thyrocalcitonine de saumon: etude cooperative en double insu. Nouvelle Presse Medicale 6: 1447-14~ O, ' 1977 Buclin T, Randin JP, Jacquet AF, A~ria )\1, Attinger M, et at. The effect of rectal and nasal administration of salmon calcitonin in normal subjects. Calcified Tissue Ihternational 41: 252-258, 1987 Cantrill JA, Buckler HM, Anderson ,Qe. Low dose intravenous 3-amino-I-hydroxypropylidine-l ; I-bi,sphosphonate (APD) for the treatment of Paget's disease 9f bcilne. Annals of the Rheumatic Diseases 45: 1012-1018, 1986 , Sustained biochemical Chapuy Me, Charhon SA, Meunier effects of short treatment of Paget's idisease of bone with dichloromethylene diphosphonate. Mei~bolic Bone Disease and Related Research 4: 325-328, 1983 ' Collins DH. Paget's disease of bo~e: incidence and subclinical forms. Lancet 2: 51-57, 1956 Coulton LA, Preston CJ, Cough M, Kanis JA. An evaluation of serum osteocalcin in Paget's disease 'o f bone and its response
v
pr
to diphosphonate treatment. Arthritis and Rheumatism 31: 1142-1147, 1988 D'Agostino HR, Barnett CA, Zielinski XJ, Gordan GS. Intranasal salmon calcitonin treatment of Paget's disease of bone. Clinical Orthopaedics and Related Research 230: 223-228, 1988 Delmas PD, Chapuy M-C, Edouard C, Meunier PJ. Beneficial effects of aminohexane diphosphonate in patients with Paget's disease of bone resistant to sodium etidronate. American Journal of Medicine 83: 276-282, 1987 Delmas PD, Chapuy MC, Vignon E, Charon S, Briancon D, et at. Long term effects of dichloromethylene diphosphonate in Paget's disease of bone. Journal of Clinical Endocrinology and Metabolism 54: 837-844, 1982 Dodd GW, Ibbertson HK, Fraser TRC, Holdaway 1M, Wattie D. Radiological assessment of Paget's disease of bone after treatment with the bisphosphonates EHDP and APD. British Jour. nal of Radiology 60: 849-860, 1987 Douglas DL, Duckworth T, Kanis JA, Preston D, Beard DJ, et at. Biochemical and clinical responses to dichloromethylene diphosphonate (CI2MDP) in Paget's disease of bone. Arthritis and Rheumatism 23: 1185-1192, 1980 Douglas DL, Kanis JA, Duckworth T, Beard DJ, Paterson AD, et at. Paget's disease. Improvement of spinal cord dysfunction with diphosphonates and calcitonin. Metabolic Bone Disease and Related Research 3: 327-335, 1981 EI Sammaa M, Linthicum FH, House HP, House JW. Calcitonin as treatment for hearing loss in Paget's disease. American Journal of Otology 7: 241-243, 1986 Fleisch H. Experimental basis for the use of bisphosphonates in Paget's disease of bone. Clinical Orthopaedics and Related Research 217: 72-78,1987 Foldes J, Shamir S, Kidroni G, Menczel J. Vitamin D in Paget's disease of bone. Clinical Orthopaedics and Related Research 243: 275-279, 1989 Frijlink WB, Bijvoet OLM, TeVelde J, Heynen G. Treatment of Paget's disease with (3-amino-I-hydroxypropylidene)-I, I-biphospho nate (APD). Lancet 1: 799-803, 1979 Gagel RF, Logan C, Mallette LE. Treatment of Paget's disease of bone with salmon calCitonin nasa1.spray. Journal of the American Geriatric Society 36: 10 11-1 0 14, 1988 Gonzalez D, Vega E, Ghiringhelli G, Mautalen C. Comparison of the acute effect of the intranasal and intramuscular administration of salmon calcitonin in Paget's disease. Calcified Tissue International 41: 313-315, 1987 Gray RES, Yates AJP, Preston CJ, Smith R, Russell RGG. Duration of effect of oral diphosphonate therapy in Paget's disease of bone. Quarterly Journal of Medicine 64: 755-767, 1987 Gruszkiewicz J, Doron Y, Borovich 'B, Zaaroor M. Spinal cord compression in Paget's disease of bone with reference to sarcomatous degeneration and calcitonin treatment. Surgical Neurology 27: 117-125, 1987 ' Hadjipavlou AG, Tsoukas GM, Siller TN, Danais S, Greenwood F. Combined drug therapy in treatment of Paget's disease of bone. Journal of Bone and Joint Surgery 59A: 1045-1051, 1977 Hamdy RC.Paget's disease of bone, pp. 1-3, Praeger Scientific, New York, 1981 Harinck ' HIJ, Bijvoet OLM, Blanksma HJ, Dahlinghaus-Nienhuys PJ. Efficacious management with aminobisphosphonate (APD) in Nget's disease of bOne. Clinical Orthopaedics and Related Research 217: 79-98, 1987a Harinck HIJ, Papapoulos SE, Blanksma HJ, Moolenaar AJ, Vermeij ·P, et at. Paget's disease of bone: early and late responses to three different modes of treatment with aminohydroxypropylidine bisphosphonate (APD). British Medical Journal 295: 1301-1305, 1987b Hosking DJ. Paget's disease of bone: an update on management. Drugs 30: 156~173, 1985 Hosking DJ, Bijvoet OLM, Van Aken J, Will EJ. Paget's disease of bone treated with diphosphonate and calcitonin. Lancet 1: 615-616, 1976 Ibbertson HK, Henley JW, Fraser TR, Tait B, Stevens EJ, et at. Paget's disease of bone: clinical evaluation and treatment with bisphosphonate. Australian and New Zealand Journal of Medicine 9: 31-35, 1979 Kanis JSA, Gray RES. Long term follow up observations on treat-
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Correspondence and reprints: Dr D.J. Hosking, Consulting Physician, City Hospital, Hucknall Road, Nottingham NG5 I PB, England.
