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Mithramycin treatment of pacet's disease of bone exploration of combined mithramycin-ehdp therapy.

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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.
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