Mithramycin treatment of pacet's disease of bone exploration of combined mithramycin-ehdp therapy.код для вставкиСкачать
1155 MITHRAMYCIN TREATMENT OF PAGET’S DISEASE OF BONE Exploration of Combined Mithramycin-EHDP Therapy WILL G. RYAN and THEODORE B. SCHWARTZ MITHRAMYCIN TREATMENT Slightly over a decade has passed since we first reported the effects of mithramycin (Mithracin R) on Paget’s disease of bone (1). In that and a subsequent publication (2) we showed the rapid effects on the objective parameters of disease activity-the serum alkaline phosphatase and urinary hydroxyproline (Figure 1). Others have since provided more detailed information of the effects on hydroxyproline (3), calcium, phosphorous, and parathyroid hormone (4). Since our initial observations we have treated approximately 150 patients (some on multiple occasions) with this drug and have observed generally very favorable effects (relief of pain, return of function of lower extremities apparently secondary to relief of neural compression) in over 90% (5-8). The subjective observations have however been made without the benefit of placebo controls. Others have reported beneficial effects on the cardiovascular complications (9). Subsequent observations of ours have shown reversion of bone scans (“F and 99TcEHDP) and roentgenograms toward a more nearly normal appearance in those patients in whom disease remission was sustained for sufficient periods of time (5,6). Because of the generally tight coupling between osteoclastic and osteoblastic activity when normocalcemia is maintained, we have generally relied on the level of serum alkaline phosphatase as an indicator of disease activity since it is much less expensive and cumFrom the Department of Medicine, Section of Endocrinology and Metabolism, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois 60612. Address reprint requests to Will G. Ryan, MD, PresbyterianSt. Luke’s Hospital, Section of Endocrinology and Metabolism, 1753 West Congress Parkway, Chicago IL 60612. Arthritis and Rheumatism, Vol. 23, No. 10 (October 1980) bersome to measure. (However, this was after we had shown effects on hydroxyproline in what we considered a sufficient number (18) of patients ( 5 ) . During a 10-day course of mithramycin (15-25 pg/kg/day as 12-24 hour infusions) there is typically an approximately 60% reduction in serum alkaline phosphatase ( 5 ) and usually a subsequent decline in the following month or two to a level approximately 25% that of pretreatment. This reduction is maintained for variable periods of time ranging from several months to several years (5). The best effects observed were in the second patient we treated, who maintained a normal a l k a h e phosphatase for 4 years before relapse, and in one woman who was treated in 1972 and has shown no evidence of relapse to date (10). This one long-term remission suggests that it may be possible to totally eradicate the disease and effect a cure (Figure 2). Subsequent studies by others have generally been directed at achieving therapeutic effects with lessened toxicity by using smaller doses or less frequent administration ( 1 1- 14). Elias et a1 reported beneficial effects from the administration of 25pg/kg of mithramycin every 2 to 3 weeks for several months (13). Our own experience indicates that objective effects are reasonably closely related to dose used and frequency of administration (15). We have maintained a few patients on weekly outpatient bolus intravenous injections for up to 3 years without evidence of cumulative toxicity. This approach however did not lead to satisfactory biochemical control of the disease over the long term because of the nauseagenic side effect of mithramycin. Some patients actually developed a conditioned response and became nauseated on the day of administration before the drug was given. Recently Russell et a1 reported long-term effectiveness of low dose (10 pg/kg for 10 RYAN AND SCHWARTZ 1156 Mithramvcin Mithromycin Time (doys) Time (doys) Serum Colcium mg/lOO ml Serum Alkaline Phosphotose Bessey-Loury units Urine Hydro xyproline mg/24 hr Figure 1. Serum calcium, alkaline phosphatase, and urinary hydroxyproline responses to mithramycin infusions in 2 patients with disseminated Paget's disease of bone. Vertical shaded bar indicates periods of mithramycin administration (25 pg/kg/day) as 12-24 hour infusions. Bar lines at bottom of graphs indicate normal ranges. (JAMA 213: 1155, 1970. Copyright 1970, American Medical Association.) days) mithramycin for control of pain of Paget's disease (16). In their experience this works quickly with virtually complete pain relief by 4 to 5 days. Although biochemical variables and bone scan commonly return to their original, abnormal baselines by one year, this in itself is not associated with return of pain. In their opinion, including cost considerations, this represents the most rational approach to control of symptoms of the disease (17). Our limited experience with other cytotoxic drugs has not been salutory. Because of reports that actinomycin D inhibited effects of parathyroid and vitamin D activity on bone (18,19), we had originally administered actinomycin D in low dose (0.2 mg/day for 5 days) to 2 patients and observed transient hydroxyproline and alkaline phosphatase responses (unpublished observations, 1967). We did not think that pursuit of this agent would be fruitful. However, Fennelly et a1 (20-22) subsequently made extensive comparisons between mithramycin and actinomycin D and found their effects to be generally similar with a less profound hypocalcemic effect of actinomycin D. We administered actinomycin D in full chemotherapeutic dose (0.5 mg/ day for 5 days) to one patient who had previously received mithramycin. The effect on serum alkaline phosphatase was less pronounced or sustained, and transient leukopenia (2500 WBC/mm3) occurred. This effect was never observed with mithramycin. Mithramycin is an antibiotic which is cytotoxic apparently because of its ability to bind to DNA, thereby blocking RNA synthesis (23). Patients with neoplasms who are treated with mithramycin frequently develop significant hypocalcemia (24). In addition it has been effective in the treatment of hypercalcemia regardless of etiology (25). During treatment of Paget's disease with this drug the urinary hydroxyproline (an indicator primarily of osteoclastic activity), decreases much more rapidly (Figure 1) than does the alkaline phosphatase (an indicator primarily of osteoblastic activity), and hypocalcemia occurs often despite an increase in parathyroid hormone and 1,25 dihydroxy vitamin D levels (4,26). In vitro observations performed on fetal rat calvaria show that mithramycin inhibits release but not uptake of calcium (6). These observations suggest that mithramycin has somewhat selective and potent cytotoxic effects on osteoclasts. This suggestion is further substantiated by our observations that bone biopsies performed immediately after mithramycin administration for 10 days show a virtual disappearance of osteoclasts with apparent reduction in the number of osteoblasts as compared with biopsies obtained immediately before treatment. MITHRAMYCIN 1157 Because of other cytotoxic effects, mithramycin must be used like porcupines make love-very carefully. Its prime disadvantage has been its hepatic, nephritic, and platelet toxicity (23), and fatalities directly attributable to the drug have been observed in patients in whom it was being used for cancer (23). However we have seen no reports of serious toxicity in patients being treated for Paget’s disease in whom generally lower doses (10-25 pg/kg) are used in contrast to those in cancer chemotherapy (25-50 pg/kg). In our experience hepatotoxicity, as reflected in increases in serum enzymes (ICD, LDH, SGOT, SGPT), has been mild and transient (usually reversible within 48 hours) and without residue. (We have also wondered if some of the enzyme elevations seen may have been due to release from 2 vi 0 B %a TIME (wks) W.G. Ryan. M.D. Figure 3. Alkaline phosphatase time course in patient ER. Date in upper right hand corner indicates institution of EHDP treatment. Arrows indicate drug administration periods. A B Figure 2. Bone scans done in A, 1972 (before treatment with mithramycin) and B, 1979 (7 years after treatment) on patient HL. Note virtual obliteration of normal bone in scan on left secondary to attenuation necessary because of increased uptake in Paget’s bone in pelvis, and activity in pelvis on right not significantly different from normal bone. Deformity in right pelvis is secondary to old osteomyelitis complicating Paget’s disease. Amputation was done several years prior to our seeing patient. Increased uptake in shoulders, elbows, and wrists in scan on right is secondary to patients’ use of crutches. dying osteoclasts.) It has been our practice to let these enzyme levels reach at least ten times normal before interrupting therapy. Nephrotoxicity-blood urea nitrogen (BUN) increase to 40-60 mg/dl-has been somewhat more prolonged (approximately 7- 10 days), but infrequent (less than 5% of patients treated) and 3 patients have had BUN values remaining in a slightly elevated range (2028 mg/dl). Since we have begun monitoring nephrotoxicity by determination of daily serum creatinine level and interrupting therapy if it increased by more than 0.5 mg/dl, we have not observed significant prolonged renal toxicity. It is likely that an increase in BUN occurred relatively late during nephrotoxicity in that patients usually stopped eating much during therapy because of nausea or anorexia. Thus the prerenal azotemic component was significantly reduced, as reflected in a frequent decline in BUN to less than 10 mg/dl. Our only observation of significant thrombocytopenia (75,000 platelets/mm3) was when a patient received 50 pg/kg of mithramycin for 5 days through error. This too was transient and unaccompanied by other significant effects (the investigator was more affected than the patient). Daily platelet counts have been the only parameter measured routinely for hemostasis during therapy, and therapy is interrupted if platelets decrease to less than 150,000/mm3. We have never observed a bleeding episode secondary to mithramycin used for Paget’s disease. RYAN AND SCHWARTZ 1158 likely to effect a prolonged remission or cure of Paget’s disease. EXPLORATION OF COMBINED MITHRAMYCIN-EHDP THERAPY It is in the area of combined mithramycin-EHDP therapy that we have directed most of our investigative effort in the past 2 years (27). It seems likely to us that suppressive therapy alone might not be adequate for control in the 20 to 50 years’ duration commonly seen in this disease. As soon as EHDP (DidroneF) became available we began exploring various regimens of this drug combined with mithramycin in an effort to achieve more complete and sustained remissions, and our preliminary experience is quite encouraging. Figure 3 shows the alkaline phosphatase response of the first patient (ER, 54year-old white man) treated in this manner. This patient had been treated previously with both calcitonin and mithramycin (on separate occasions) and had relapsed after both. Although he obtained a very good response from EHDP alone, it was considered that subsequent mithramycin administration (15-20 pg/kg for 1 1 days) might provide the “coup de grice” for his disease. As indicated in the figure, the alkaline phosphatase became normal during mithramycin treatment, subsequently A B Figure 4. Bone scans in patient ER, A, after 6 months EHDP, B, 10 months after mithramycin. Note decrease in skull uptake of isotope despite enhanced normal bone uptake on right. Despite the lack of significant prolonged toxicity in our patients, we continue to monitor carefully for evidence of side effects (particularly serum creatinine) regardless of dose used and have thereby presumably kept adverse effects to a minimum. However, the development of relatively effective and less toxic agents (calcitonins and diphosphonates) has led us to believe that one or both of these agents should be used first for routine patient treatment, reserving mithramycin for failures of these agents or in patients in whom a very rapid reduction in disease activity might be desirable (e.g. patients with neural compression). However, we believe that mithramycin in combination with other agents is most Figure 5. Alkaline phosphatase course in patient IR. Lines with arrows indicate drug administration periods. See text for details. MITHRAMYCIN 1159 rose slightly but then returned to a low normal range (40 IU) where it has remained to date (17 months after treatment without subsequent administration). A recent urinary hydroxyproline determination was also normal. As indicated in Figure 4, there has been reversion toward normality of the bone scan (at 10 months). Another patient treated similarly who did not achieve as marked reduction in alkaline phosphatase with EHDP and did not achieve normal serum alkaline phosphatase during mithramycin administration showed signs of relapse during the subsequent months. He has recently been treated more vigorously but followup data are very preliminary. Figure 5 shows the alkaline phosphatase response of a patient (IR, 52-year-old white woman) similarly treated who also did not achieve normal alkaline phosphatase levels during the 10-day hospital course of mithramycin. She received subsequent weekly outpatient injections (1.2 mg) until the alkaline phosphatase became normal, and then biweekly injections for 6 weeks. As indicated, the alkaline phosphatase subsequently rose to slightly above normal but now has returned to almost normal (107 IU) 9 months after therapy. The dose of outpatient mithramycin was adjusted according to the degree of nausea experienced by the patients, and ranged from as low as 1.1 mg in one to 2.5 mg per week in another as a bolus intravenous injection. Toxicity was monitored by weekly serum creatinine determinations which did not change significantly during therapy . EHDP 400mglday 600 =! 500 Mithramycin approx IX/wk 8I 400 a ?i 300 2 200 I00 0 6 2/6/79 12 18 24 30 36 42 48 54 60 66 WEEKS Figure 7. Alkaline phosphatase course in patient HS. Figure 6 shows the alkaline phosphatase response of a patient (TK, 66-year-old white man) who received only weekly outpatient injections of mithramycin (1.5-2.0 mg) after 6 months of EHDP therapy. Findings indicate that the two agents are additive or synergistic in their effects. In this patient and 3 others (HS, 45-year-old white man; EK, 66-year-old white woman; IL, 63-year-old white woman) (Figure 7) it has been relatively easy to obtain alkaline phosphatase levels near normal but difficult to get them into the normal range. For this reason the EHDP dose was increased considerably for short periods of time. Both agents have been discontinued at present. It is too early to determine whether this approach will be significantly beneficial. EHDP 800 mgldoy I 1800 Yi Mithramycin IX/week approx. a 60 404 200 11/15/78 1/24/79 WEEKS Figure 6. Alkaline phosphatase course in patient TK. WEEKS Figure 8. Alkaline phosphatase course in patient LB. 1160 Figure 9. Alkaline phosphatase course in patient JS. Note increase in alkaline phosphatase despite continued administration of mithramycin when EHDP was discontinued temporarily. Figure 8 shows the alkaline phosphatase response (LB, 68-year-old white man) to concomitant administration of EHDP and mithramycin. The rate of response suggests that preloading with EHDP is probably desirable. This patient has shown evidence of subsequent partial relapse (most recent alkaline phosphatase 218 IU). Figure 9 shows the alkaline phosphatase response to EHDP and mithramycin (approximately 1.2 mg/wk) in a patient with disease very resistant to therapy. This 57-year-old judge (JS) had received several previous courses of mithramycin including outpatient therapy and had subsequently relapsed. He also had only transient alkaline phosphatase responses to both salmon and human calcitonin. During this period of study the EHDP was discontinued temporarily because of pain at the distal end of his tibia with Paget’s disease. Despite continued administration of mithramycin on a weekly basis, the alkaline phosphatase rose until the EHDP was resumed, indicating further the additive or synergistic effects of these agents. No significant adverse effects (other than nausea or vomiting) have been observed in any of these studies. These preliminary experiences are quite encouraging that combination therapy of this type may be capable of inducing long-term remissions of the disease. Although the mechanism of action of diphosphonates is unknown in this disorder, it seems likely that the high concentrations of these agents likely achieved in osteoclasts secondary to their preferential deposition in bone RYAN AND SCHWARTZ may exert toxic effects on them, and thus explain the apparent additive or synergistic effects with mithramycin. Although we have not tried a similar approach with calcitonins, it seems unlikely that such a combination would be as useful since calcitonins are probably primarily suppressive rather than toxic to the osteoclast. It also seems likely as a final point that combinations of the newer diphosphonates (C1,MDP and APD) with mithramycin may be even more effective than that with EHDP. Explorations of such combinations will probably appear in the near future. In summary, mithramycin, although a toxic agent, exerts potent suppressive beneficial effects on Paget’s disease of bone and is useful alone primarily when other agents have failed or when rapid effects are desirable. Experience of others indicates that in low dose, however, it may be the agent of choice for suppression of disease symptoms. Preliminary experience with combined mithramycin-EHDP suggests that this approach (or with other diphosphonates) may provide the means of consistently inducing long-term remissions. REFERENCES I . Ryan WG, Schwartz TB, Perlia CP: Effects of mithramycin on Paget’s disease of bone. Ann Intern Med 70:549557, 1969 2. Ryan WG, Schwartz TB, Northrop G: Experiences in the treatment of Paget’s disease of bone with mithramycin. JAMA 21311 153-1 157, 1970 3. Thiel GB, Ajlouni K: Effect of mithramycin on hydroxyproline metabolism in Paget’s disease. J Lab Clin Med 90803-809, 1977 4. Ajlouini K, Thiel GB: Mithramycin effects on calcium phosphorous and parathyroid hormone in osseous Paget’s disease. Am J Med Sci 269:13-18, 1975 5. Ryan WG, Schwartz TB, Northrop G: Treatment of Paget’s disease with mithramycin: further experiences. Sem Drug Tr 2:57-64, 1972 6. Ryan WG, Lebbin D, Northrop G, Schwartz TB: Treatment of Paget’s disease of bone with mithramycin. Clinical Aspects of Metabolic Bone Disease. Edited by B Frame, AM Parfitt, H Duncan, Amsterdam, 1973, pp 535-539 7. Ryan WG: Treatment of Paget’s disease of bone with mithramycin. Clin Orthop 127:106-110, 1977 8. Ryan WG: Paget’s disease of bone. Ann Rev Med 28:143152, 1977 9. Pembrook RC, Chung CH, Carvallo AP: Effects of mithramycin and calcitonin in cardiovascular complications of Paget’s disease of bone. Conn Med 39:209-214, 1975 MITHRAMYCIN 1161 10. Ryan WG, Schwartz TB, Fordham EW: Mithramycin and long remission of Paget’s disease of bone. Ann Intern Med 92: 129- 130, 1980 1 I. Condon JR, Reith SBM, Nassim JR, Millard, FJC, Hilb A: Treatment of Paget’s disease of bone with mithramycin. Br Med J 1.421423, 1971 12. Russell AS, Lentle BC: Mithramycin therapy in Paget’s disease. Can Med Assoc J 110:397400, 1974 13. Elias EG, Evans JT: Mithramycin in the treatment of Paget’s disease of bone. J Bone Joint Surg 54:1730-1736, I972 14. Aitken JM, Lindsay R: Mithramycin in Paget’s disease. Lancet 1:1177-1178, 1973 15. Lebbin D, Ryan WG: Outpatient treatment of Paget’s disease of bone with mithramycin. Ann Intern Med 8 1:635637, 1974 16. Russell AS, Chalmers IM, Percy JS, Lentle BC: Long term effectiveness of low dose mithramycin for Paget’s disease of bone. Arthritis Rheum 22:2 15-2 18, 1979 17. Russell AS: Calcitonin or mithramycin for Paget’s disease. Lancet 1:884, 1980 18. Eisenstein R, Passavoy M: Actinomycin D inhibits parathyroid hormone and vitamin D activity. Proc SOC Exp Biol 117:77, 1964 19. Rasmussen H, Arnaud C, Hawker C: Actinomycin D and 20. 21. 22. 23. 24. 25. 26. 27. the response to parathyroid hormone. Science 154:1019, 1964 Fennelly JJ, Groarke JF: Effect of actinomycin D on Paget’s disease of bone. Br Med J 1:423426, 1971 Fennelly JJ: Clinical and biochemical studies of Paget’s disease of bone with emphasis on the effects of RNA inhibitors actinomycin D and mithramycin. Ir J Med Sci 140:431 4 8 , 1971 Somerville PJ, Evans RA: Actinomycin D in the treatment of Paget’s disease of bone. Med J Aust 2: 13-16, 1975 Kennedy BJ: Metabolic and toxic effects of mithramycin during tumor therapy. Am J Med 48:494-503, 1970 Parsons V, Baum M, Self M: Effects of mithramycin on calcium and hydroxyproline metabolism in patients with malignant disease. Br Med J 1:474477, 1967 Perlia CP, Crem RL, Wolter J, Slayton RE, Taylor SG 111: Mithramycin treatment for hypercalcemia. Proceedings of International Cancer Congress, Houston, Texas, p 424, 1970 Bilezikian JP, Canfield RE, Jacobs TP, Polay JS, D’adamo AP, Eisman JA, DeLuca HF: Response of 1 alpha,25-dihydroxy vitamin D, to hypocalcemia in human subjects. N Engl J Med 299:43741, 1978 Ryan WG: Combined mithramycin-sodium etidronate treatment of Paget’s disease of bone. (abstract) Clin Res 27:660A, 1979 DISCUSSION Dr. Machtyre: Do you use chemical response rather than clinical response to determine therapy? Dr. Ryan: Mithramycin is not a first line therapy. Patients are referred to me because they are refractory to prior treatments. However, prolonged remission seems to be related to chemical response and not pain relief. Dr. MacIntyre: Does healing of lytic long bone lesions result from therapy with mithramycin? Dr. Ryan: A few patients have had lytic lesions fill in after 1-2 years but I have not reviewed the radiology carefully. Dr. Doyle: In our series we have noted that on bone scans the skull continues to remain “hot” after therapy. Can you comment? Dr. Ryan: I have seen considerable reduction in skull activity on bone scan, particularly with combined therapy of mithramycin and EHDP. Dr. Wallach What happens to serum alkaline phosphatase in your patients since mithramycin can affect the liver? Do you correct for liver alkaline phosphatase? Dr. Ryan: Serum alkaline phosphatase is followed during therapy. During intensive therapy the values may increase transiently, but other enzymes such as SGOT or LDH increase proportionately more. Dr. Russell: I have some concern about giving high doses of EHDP after mithramycin because the latter kills bone cells and the former impairs mineralization. Dr. Ryan: For that reason the high dose of EHDP is to be used only for short periods of time with careful monitoring. Dr. Meunier: What happens to parathyroid hormone blood levels during and after therapy? Dr. Ryan: Parathyroid hormone levels rise during mithramycin therapy, but levels have not been checked after therapy has been terminated. Dr. Wallach: Have you seen any changes in neurologic impingement with mithramycin treatment? Dr. Ryan: I have seen considerable return of function. Dr. Russell: Do you have any pathologic tissues? Dr. Ryan: We have five bone biopsies before and after 10 days of mithramycin treatment. Biopsies after therapy show reduction of osteoclasts and osteoblasts.