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Long-term therapy of paget's disease of bone with ehdp.

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Forty patients with Paget’s disease of bone were
treated with intermittent courses of the diphosphonate,
EHDP. Seven individuals had prolonged remissions after their initial course of therapy, nineteen responded to
retreatment with 5 mg/kg of EHDP for 6 months of
each year, while 14 patients required cycles of 20 mg/kg
for 1 month of every 4. Improvement was indicated by
alleviation of symptoms and reduction in serum alkaline
phosphatase and urinary hydroxyproline. Data suggesting a possible role for parathyroid hormone in the expression of Paget’s disease are also discussed.
During the past decade clinical studies of the effects of ethane- 1-hydroxy-1, 1-diphosphonate (EHDP)
on patients with Paget’s disease of bone have generally
reported results describing the use of this agent for a period of only 6-12 months (1-9) with one study reporting
up to 2 years of followup data, with or without retreatment (9). Hence there is a paucity of information available in the literature concerning the long-term effects of
treatment with respect to the doses of EHDP required to
suppress the activity of this disease. In this progress report we have made an effort to address this issue, based
upon data obtained from 40 patients with Paget’s disease whom we have observed and retreated with various
doses of EHDP for up to 6 years.
While we have been pursuing these studies of patients with Paget’s disease of bone, several lines of eviFrom the Department of Medicine, Columbia University
College of Physicians and Surgeons, New York, NY 10032.
Supported by National Institutes of Health Grants AM
09579 and RR 00645.
Address reprint requests to Robert E. Canfield, MD, Department of Medicine, College of Physicians and Surgeons, 630 West
168th Street, New York NY 10032.
Arthritis and Rheumatism, Vol. 23, No. 10 (October 1980)
dence have emerged from our data and those of others
(10,ll) to suggest that parathyroid hormone may play a
role in the exaggeration of the expression of this disease.
The evidence and our thesis regarding this process are
also discussed.
Forty patients with Paget’s disease of bone (17
women, 23 men) have been observed for a period of time
ranging from 36 to 75 months (mean = 52 months). All have
received intermittent therapy with one or more treatment
schedules using EHDP for a total duration of therapy between
6 and 30 months. At the time of initial treatment with EHDP,
the patients ranged from 46 to 79 years in age (mean = 63
years). In most cases EHDP was administered initially at a
dose of 5, 10, or 20 mg/kg/day for 6 months, in a doubleblind, placebo-controlled trial. Data from some of these subjects have been reported previously (8). Seven of the patients
had been treated with calcitonin or mithramycin prior to receiving their first course of EHDP. At the time this long-term
study was initiated it included 3 additional patients: two subsequently died and one moved away from the New York area.
It should be noted that the initial report contained patients
from four hospitals; only those from the Columbia Presbyterian Medical Center were included in the present study. All
patients provided written informed consent prior to institution
of this study.
For most of the patients their first treatment consisted
of 6 months of EHDP that coincided with the study noted previously (8) in which they were treated with 5, 10, or 20 mg/kg.
Additional patients were added to this group, commencing
therapy at 5 mg/kg/day. After the completion of the first 6
months of therapy, we retreated each patient on an individual
basis (usually with 5 mg/kg/day) as it seemed indicated based
upon changes in symptoms or rising levels of urinary hydroxyproline excretion or serum alkaline phosphatase. For the
purposes of this report we will refer to this as the initial followup phase. During the 18 to 57 months comprising the
phase in which we managed patients in this way, it became
apparent that there was a wide variation in responses. Within
the last 2 years, therefore, we have applied a more systematic
approach to therapy, and we will refer to this second component as the systematic study.
Accordingly, after the initial followup phase, the data
that had been acquired were analyzed and the patients assigned to one of three groups, based upon their prior response
to EHDP, for the systematic study that followed. Seven patients (5 women, 2 men) had remained in a prolonged biochemical remission after their initial 6-month course of therapy, and they have required no additional treatment.
Nineteen (6 women, 13 men) were considered to have
been adequate responders to cycles of low dose EHDP (i.e., 5
mg/kg/day)* and were continued on a program of EHDP at
this dose for 6-month periods followed by 6 months of no
medication, in repeated cycles. This was designated as the low
dose group.
The third group of 14 patients (6 women, 8 men) were
considered to have shown inadequate responses to low doses
of EHDP and they were placed on a regimen consisting of repeated cycles of 1 month of EHDP at 20 mg/kg/day* followed by 3 months of no therapy. These patients were designated the high dose group. Observations of the responses to
repeated courses given on this schedule have been made for at
least 12 months for each subject and up to 36 months for
some. The patients were selected to participate in the high
dose treatment program because they continued to have
marked elevations of urinary hydroxyproline and serum alkaline phosphatase despite 18 to 57 months of continued observation with intermittent treatment consisting of EHDP at
doses of 5 mg/kg for 6-month periods.
The biochemical indices monitored in all of the patients were 24-hour total urinary hydroxyproline excretion analyzed by the method of Kivirikko et al (12) with the upper
limit of normal being less than 45 mg/24 hours, and serum alkaline phosphatase determined as previously described ( 13).
Over the course of the 6 years during which alkaline phosphatase determinations have been made, the methodology has
been modified and the units have been changed. For this reason the serum alkaline phosphatase levels are expressed as the
ratio of the observed value divided by the upper limit of normal for the assay; the normal range is, therefore, up to 1. Each
of these tests was obtained at 3-month intervals in patients receiving 6-month cycles of EHDP, and determinations were
made at least before and after the month of EHDP therapy in
the patients on the high dose regimen.
In one instance a patient on the high dose regimen
was hospitalized for the initial month of therapy and daily 24hour urine collections were obtained to determine the time of
onset and rate of decline of urinary hydroxyproline. This patient also provided weekly to bimonthly 24-hour urine samples for the next 36 months during which repeated treatment
courses of the high dose regimen were administered.
Skeletal radiographs were obtained in all patients at
the time of initial therapy with EHDP and a skeletal survey
was repeated in 32 of the subjects between 24 and 60 months
after their first exposure to EHDP. Although wholly objective
radiographic data regarding progression or improvement in
*This medication is available as Didronel (Proctor and
Gamble Company) in 200 mg tablets. A dose of 400 mg is equivalent
to 5 mg/kg, and 1600 mg is equivalent to 20 mg/kg for most individuals.
pagetic sites in response to therapy require highly standardized techniques and, ideally, the same radiologist reviewing
all films on a single patient (14-16), we attempted to achieve
at least a qualitative estimate of change by careful review of
radiographs obtained in our clinical diagnostic unit. All radiographic data reported here were obtained in the Radiology
Department at the Columbia Presbyterian Medical Center,
and all pretreatment and post-treatment radiographs were
carefully compared by radiologists who were cognizant of our
study design but unaware of patient treatment regimens.
Skeletal symptoms were recorded at least every 3
months throughout the period of observation in all patients.
Any fractures were noted with respect to their occurrence in
pagetic versus nonpagetic sites, association with trauma, and
occurrence during periods when EHDP was administered;
some of these data from the earlier phases of the study on
EHDP have been reported previously (8).
Statistical analyses of data were performed using a
two-tailed Student’s t-test.
Changes in biochemical indices: urinary hydroxyproline and serum alkaline phosphatase. In 7 patients
urinary hydroxyproline excretion and serum alkaline
phosphatase decreased after a single 6-month course of
EHDP at either 5 mg/kg (in 4 patients) or 20 mg/kg (in
3 patients), and the improvement was sustained without
further therapy. Mean urinary hydroxyproline was 104
k 25(SE) before therapy and 26 f 3 immediately after
therapy; mean serum alkaline phosphatase was 3.3
0.7 before therapy and 0.8 & 0.1 after therapy in this
group. None of these patients required retreatment for a
period between 36 and 58 months (mean = 45 months)
after the first course of therapy, since the patients continued to feel improvement and biochemical indices remained at or near normal.
Changes in urinary hydroxyproline excretion in
response to EHDP therapy in the remaining 33 patients
are shown in Figure 1.
Nineteen of the patients (the low dose group, depicted in the left half of the figure) had highly significant decreases in urinary hydroxyproline after 18 to 57
months of intermittent treatment cycles (i.e., the period
shown as the initial followup phase in Figure l), with a
decline from a pretreatment mean of 191 k 32 mg/24
hours to 56 f 6 by the end of the initial followup phase
(P<O.OOl). During the subsequent 18 months, when
every patient in the group received 5 mg/kg/day alternating with 6-month cycles of no therapy (systematic
study), urinary hydroxyproline declined further into the
normal range (mean = 42 f 12). This further decrease,
though significantly lower than the initial pretreatment
value of 191 k 32 (P<O.OOl), was not significantly
lower than the mean at the initiation of the systematic
19 Polienls
5 rng/kq EHDP
6 of eoch 12 months
2 0 m g / k g EHDP
I of every 4 months
alkaline phosphatase was 18.8 4.6 pretreatment, 13.5
f 2.2 at the end of the initial followup phase, and 14.8
f 2.8 at the end of 12 months on high dose.
Data depicting the response to high dose therapy
for one patient during the first month of 20 mg/kg/day
are shown in Figure 2. Urinary hydroxyproline was
clearly declining after 2 weeks of treatment and was
nearly normal by the end of 4 weeks, after having been
markedly elevated initially. In this patient, serum alkaline phosphatase also declined from 6000 units/liter
(upper limit of normal = 100 units/liter) or 60 times
normal to 10 times normal by the end of the month. As
shown in Figure 3, observations in this patient over 36
months of followup on the high dose regimen show a
fall in urinary hydroxyproline in response to each
month-long course of therapy. Serum alkaline phosphatase has ranged between 1000 and 2000 during this period (10 to 20 times normal). This patient has had a decrease in symptoms of back pain and a marked increase
in mobility during the 36-month period.
Radiographic changes. Initial skeletal radiographs in all 40 patients revealed polyostotic disease in
37 and monostotic in 3. Skeletal radiographs taken in 32
of the patients after 2 to 5 years of intermittent EHDP
therapy revealed no changes in 25 patients (78%), apparent improvement in 1 patient, and apparent progression of disease in 6 patients (19%), all of whom had
polyostotic disease. Among these six, two had increased
areas of osteoporosis circumscripta in previously affected skulls, two had increased sclerosis in the skull
: :
Syslemallc Study
Syslernolic Sludy
Figure 1. Mean total urinary hydroxyproline data from 2 groups of
patients, collected during 2 periods of observation and treatment. See
text for details.
study. In this group of 19 subjects, serum alkaline phosphatase declined significantly from a pretreatment
mean of 7.1 f 1.0 (upper limit of normal = 1, see Materials and Methods) to 2.7 f 0.3 (Pc0.001) during the
initial followup phase and then rose slightly but significantly (R0.02) to 3.4 f 0.5 during the systematic study.
In essence these are patients who exhibited a good response to intermittent therapy with low doses of EHDP
in both components of the followup studies.
As a result of the initial followup phase we identified 14 patients who did not have a satisfactory response to cycles of low doses of EHDP. They were then
placed in the systematic study on the high dose program. Data for those patients who received repeated cycles of 20 mg/kg/day for 1 month of every 4 are shown
on the right side of Figure 1. Prior to any EHDP therapy the mean hydroxyproline for this group was 323 f
63, and after an 18- to 57-month period of intermittent
EHDP (initial followup phase) at low doses, the mean
hydroxyproline was reduced to 223 47. This decrease
was not statistically significant. This mean post-therapy
value for hydroxyproline was in fact higher than the
mean pretreatment level observed in the low dose group
of 19 patients, a finding that suggests a correlation between initial urinary hydroxyproline excretion and response to therapy. However, by the end of 12 months on
the high dose regimen (systematic study) the patients
showed a statistically significant fall in mean hydroxyproline to 155 f 35 (PcO.02) as compared with the
mean pretreatment value. Serum alkaline phosphatase
for this group did not change significantly. Mean serum
t , k I
EHDPI 2 0I rng/kqldoy
Figure 2. Twenty-four hour urinary hydroxyproline excretion and
serum alkaline phosphatase in a 62-year-old woman with severe and
extensive polyostotic Paget's disease. This patient was treated with I
month of EHDP at a dose of 20 mg/kg/day. Urinary hydroxyproline
excretion fell rapidly and was nearly normal at the end of 2 weeks. By
the end of 1 month, serum alkaline phosphatase had decreased from
60 times normal to 10 times normal.
El 2 0 m q / k g / d a y EHDP
for I m o n t h
Figure 3. The effects of 36 months of repeated treatment cycles of
EHDP at a dose of 20 mg/kg/day for 1 month of every 4 in the patients described in Figure 2. Both urinary hydroxyproiine and serum
alkaline phosphatase levels decreased markedly in response to this
regimen, with maintenance of the lower levels throughout the duration of therapy. During this period the patient has had a sustained improvement in overall mobility and a striking decrease in bone pain.
and in thoracic vertebral bodies, respectively, and one
had an increased area of disease in two previously affected sites (humerus and ilium). One patient had evidence of pagetic changes in two new sites.
Clinical effects: symptoms of bone pain. Thirtyseven of the patients had symptoms of pain attributable
to Paget's disease prior to EHDP therapy. After the
long-term period of observation and treatment, 19 of
these subjects have reported improvement with a subjective decrease in skeletal symptoms. However, this
group includes 3 patients whose improvement is attributable at least in part to successful low friction arthroplasties for painful hip dysfunction from Paget's disease
involving the hip joint. Sixteen patients continue to
have symptoms similar to those they experienced initially, but are apparently no worse. Only one individual
has had a slowly progressive and marked increase in
symptoms despite 4 years of intermittent therapy.
Fractures. Since the initiation of the systematic
study depicted in Figure 1, we have accumulated approximately 100 patient years of followup. During this
time no patient has sustained a fracture through pagetic
bone. Two individuals have experienced fractures
through nonpagetic bone, both involving the distal
radius and both the result of trauma. Two other individuals had sustained fractures through pagetic bone in the
first months of our initial study and were reported as
cases #506 and #767 in the earlier report (8).
Adverse effects of EHDP. Generally, EHDP has
been well tolerated. The patients treated with EHDP at
a dose of 5 mg/kg/day had no side effects from its administration. Four of the 14 high dose patients have ex-
perienced episodes of diarrhea during the period of
EHDP administration. This symptom was controlled
with antidiarrheal agents as needed, and generally these
patients did not have to discontinue EHDP.
Since these patients began treatment with low
dose or high dose therapy in the systematic study described earlier, there has been no incidence of new bone
pain that we attributed to EHDP. However, since all of
these individuals had received EHDP prior to this phase
of the study, these results do not reflect the possibility of
new bone pain arising coincident with first treatment
with EHDP.
The early studies of the effects of EHDP on patients with Paget's disease of bone led to the conclusion
that this compound was efficacious, based upon the decrease in the concentrations of the abnormal biochemical indices for the disease, evidence of symptomatic improvement, and evidence from bone biopsies that the
disease process was altered toward normal (1-9). However, other data suggested that prolonged use of EHDP,
especially at the dose of 20 mg/kg/day, could be deleterious. The findings that patients treated with higher
doses had widened osteoid seams on bone biopsy (3)
and occasionally developed symptoms of new bone pain
after 4 to 6 months of therapy (8,17), as well as the apparent increase in fracture rate with prolonged treatment (8,17), were the major factors that led us to a treatment philosophy designed to seek the minimum dose
for a desired effect. We have also chosen to alternate
treatment periods with drug-free intervals to allow for
repair of any defects in mineralization that might have
resulted from excessive diphosphonate action. Even at
low doses, which have relatively mild effects on the normal skeleton, a large proportion of the absorbed EHDP
is delivered to the highly vascular pagetic lesions, as exemplified by the distribution of isotope in Tc-diphosphonate bone scans of patients with this disorder.
In the series reported here, a few patients exhibited prolonged suppression of their disease after the first
course of treatment. The majority appeared to benefit
from a program consisting of 6 months of therapy at 5
mg/kg/day alternating with 6-month drug-free intervals. For those patients who did not respond adequately
to the low dose therapy, we took note of the fact that in
earlier studies the major effects of high dose EHDP in
suppressing bone resorption occurred during the first
month of treatment (2,8), and as a consequence, we embarked upon a treatment program alternating one
month at 20 mg/kg/day with a 3-month drug-free inter-
Val. The latter period was chosen because it approximates the estimated lifetime of a bone remodeling unit
in pagetic bone (18).
Two years ago we began in a systematic fashion
to apply this approach to therapy in a population of patients who had previously been treated with EHDP for 2
to 4 years. Thus we are reporting data relating to prolonged therapy of a group of patients and also have indicated how our observations during this time led us to
focus on two alternative chronic treatment regimens.
One note of caution is that our patient population may
not be entirely representative since individuals who are
more severely afflicted are more likely to be referred for
care at a university center.
Biochemical changes. As the results indicate, we
found that approximately 15% of our patients responded to 6 months of EHDP therapy with a sustained
suppression of serum alkaline phosphatase and urinary
hydroxyproline excretion to near normal levels and
maintained that state for periods of up to 5 years. Of
those individuals who required retreatment, the majority showed an adequate response to cycles of low dose
EHDP (5 mg/kg/day) for 6 months of each year. Disease in the remainder of individuals (approximately
30% of our total patient population) was not adequately
suppressed by the low dose therapy, and this group of
patients was distinguished on the average by higher pretreatment values of urinary hydroxyproline and alkaline
phosphatase (see Figure 1). For this latter group we
chose to utilize the high dose of EHDP (20 mg/kg/day),
but each treatment period was limited to 1 month. The
results to date have been promising for this group of patients, but further data will be required. Although the
high dose drug regimen is within the guidelines for the
approved use of EHDP, we wish to emphasize that we
still consider this approach experimental.
It is noteworthy that despite the sustained suppression of hydroxyproline excretion in the two groups
of patients who continued to receive intermittent EHDP
therapy, serum alkaline phosphatase generally fell less
dramatically and appears on the average to be rising
again with time after reaching a nadir following earlier
phases of treatment. There is a significant correlation
between urinary hydroxyproline and serum alkaline
phosphatase in patients who have not received specific
therapy for Paget’s disease (8), but this correlation appears to diminish after EHDP administration, particularly when higher doses are used. The reason for this divergence is unclear. In a practical sense, it suggests that
serum alkaline phosphatase may not be as reliable an
index of response to treatment with EHDP as is a pre-
cise and accurate determination of total urinary hydroxyproline excretion+specially when treating with
the high dose of EHDP.
Symptoms. The early placebo-controlled,
double-blind studies permitted an objective evaluation
of symptomatic response to EHDP, and our results were
consistent with benefit to the group treated with low
doses of EHDP even though these results had to be analyzed on a high background placebo response rate (8).
The open type of clinical trial described in this report
does not permit controlled observations, so only a subjective estimate is possible. Overall, the patients have
reported that they feel improved with respect to symptoms attributable to Paget’s disease. In a number of individuals this assessment is based upon the apparent arrest or slowing of the rate of progression of their disease.
Nevertheless, the basic physical disabilities that
the patients had at entry into the study, such as bowing
of limbs, remain, so the expectations for therapy must
be tempered with a realistic appraisal of which components of the patient’s discomfort drug therapy can
reasonably be expected to reverse. In our patient population, bone pain, uncomfortable warmth over pagetic
lesions, and some elements of joint pain have been the
most common symptoms relieved by therapy. Salicylate-containing analgesics and the newer nonsalicylate
antiinflammatory agents have been valuable additions
to the EHDP regimen, offering added benefit to many
patients with bone pain and joint symptoms.
Fractures. The data vary considerably on the incidence of fractures to be anticipated in a patient population with Paget’s disease (19,20). We reported earlier
on the fractures that occurred in patients treated with
high doses of EHDP for prolonged periods of time (8).
Since initiating the present long-term followup study of
this group of patients, with the systematic use of either
the low or high dose regimens described earlier, we have
accumulated data for 100 additional patient years of exposure, and no fracture has occurred through pagetic
bone during this time. The two fractures in normal bone
were both traumatic fractures of the radius and both
healed uneventfully. They occurred in individuals in the
low dose program; the drug was discontinued while the
fractures healed. Although these results are too preliminary to permit firm conclusions, we are hopeful that the
approach to treatment we are following currently is decreasing the risk of fracture.
Radiographic changes. The usual procedures employed for diagnostic radiographs do not permit precise
comparisons of bone lesions of Paget’s disease studied
at different time intervals (14-16), so that our radio-
graphic data cannot be subjected to rigorous analysis.
However, based upon our experience, we can conclude
that physicians need not subject patients to frequent
skeletal radiographs to assess the progress of EHDP
therapy, because evidence of improvement does not
emerge with up to 6 years of treatment. Therapy with
EHDP itself may arrest the processes that would be necessary to remodel pagetic bone toward normal architecture, as assessed by radiologic diagnostic procedures.
New bone pain has been, in our opinion, a reason to repeat radiographic studies to evaluate the possibility of
fractures or rarely of osteosarcoma.
We have not seen the kind of acutely increased
lytic disease described by Nagant de Deuxchaisnes (15),
except for the progression of osteoporosis circumscripta
in 2 patients. In these two instances it was not possible
to determine whether the changes reflected EHDP therapy or were an expression of the natural history of this
disease. Also, we have not had a single case of osteosarcoma in our population of EHDP-treated pagetic patients.
Objectives of therapy. At present the most meaningful reflection of the effectiveness of therapy of Paget’s disease is the relief of symptoms. As noted earlier,
however, many of the symptoms are caused by skeletal
deformities that cannot be readily reversed by any drug
therapy. Prevention of progression of those changes in
bone architecture which lead to deformity might be another goal of therapy, but in the absence of sound data
from a control population this is difficult to measure.
Hence, the physician is frequently left to examine
changes in urinary hydroxyproline excretion or serum
alkaline phosphatase as the indices of therapeutic efficacy; here we would like to express a note of caution.
Urinary hydroxyproline excretion probably best reflects
the pagetic process, since elevations are interpreted in
this situation as an index of increased bone resorption.
However, accurate assays are not widely available.
Serum alkaline phosphatase, thought to reflect new
bone formation and regarded as an indirect measure of
pagetic activity, may not always fall commensurate with
urinary hydroxyproline, especially when high doses are
Role of parathyroid hormone. Although it is generally accepted that serum parathyroid hormone levels
are normal in patients with Paget’s disease (21), several
observations have led us to postulate that the secretion
of parathyroid hormone may play a role in the expression of Paget’s disease in individual patients. We, as
well as others (lo), have noted a high incidence of para-
thyroid adenomas in patients with Paget’s disease,
which probably represents the independent coexistence
of two common disorders. Particularly noteworthy is the
decline in activity of Paget’s disease that occurs after
surgery for hyperparathyroidism, which testifies to the
effect that excess parathyroid hormone secretion can
have on the pagetic process.
Recently we studied 8 patients with severe Paget’s disease of bone after the infusion of mithramycin
and reported data concerning studies of vitamin D in
these individuals (22). A particularly noteworthy feature of that population was the average pretreatment
value for serum parathyroid hormone, urinary cyclic
AMP excretion, and 1 a,25 dihydroxyvitamin D3 levels
in serum. All three were at the upper limits of or slightly
above normal, consistent with a state of excess parathyroid hormone secretion. Since it is unlikely that all
of these patients had parathyroid adenomas, the question arises whether patients with severe Paget’s disease
of bone may have some reason to have secondary hyperparathyroidism. At approximately the same time
that these observations were made, Evans published results suggesting that therapy which produced a slight
elevation in serum calcium in patients with Paget’s disease (and presumably suppressed endogenous parathyroid hormone secretion) led to a fall in serum alkaline phosphatase comparable to that seen with either
diphosphonate or calcitonin therapy (1 1).
Taken together, these data suggest to us that
parathyroid hormone secretion may affect the expression of Paget’s disease in some patients. The enlarged, multinucleated pagetic osteoclast probably remains responsive to parathyroid hormone (23) and
could conceivably be more responsive than osteoclasts
in other parts of the skeleton. If so, patients with different endogenous rates of secretion of parathyroid hormone, even those who exhibit serum hormone levels
within normal limits, may have different degrees of expression of Paget’s disease as a result of the relative responsiveness of their normal and pagetic osteoclasts to
parathyroid hormone. Additionally, in those individuals
with widespread Paget’s disease that goes through
phases of lytic and blastic activity, the blastic phases
may represent a prolonged period of calcium demand
leading to chronic stimulation of the parathyroid
glands. Based upon what is known about the pathophysiology of chronic renal insufficiency, the chronic
stimulation hypothesized to occur in the blastic phase of
the pagetic state may produce a secondary hyperparathyroidism that is not readily reversed. In either
event, during such periods of excess parathyroid hormone secretion, the hormone may help to drive the disease to greater levels of activity.
We wish to suggest, therefore, that patients with
severe Paget’s disease of bone with biochemical indices
many times normal may have several possible mechanisms by which parathyroid hormone could play a role
in the exaggeration of the disease. We recommend that
all such patients be studied closely for evidence of primary or secondary hyperparathyroidism.
We are grateful to Dr. E. Glenn Armstrong and Mr.
John P. Schlatterer for their assistance in performing the hydroxyproline analyses, and to the Procter and Gamble Company for providing the EHDP and also for their assistance in
meeting other costs of the study.
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Dr. Krane: We have had 2 patients in my group with severe disease on 5 mg/kg EHDP who had bone pain
syndrome about 4 to 6 weeks into therapy. Dr. Kantrowitz has also had 3 similar cases.
Dr. Wallach I have treated 15 patients with 5 mg/kg
EHDP. Five of these patients had increased bone
pain so that medication had to be discontinued.
Dr. Canfield I have definitely seen increased bone pain
in patients on 20 mg/kg EHDP. For 2 people with
sustained or increasing pain who were taking 5 mg/
kg, we have changed therapy. The prejudice of the
physician may have some effect. We have had more
problems and side effects from calcitonin than from
Dr. MacIntyre: What is the total accumulated dose of
EHDP? Do you know what the total body burden is?
Dr. Altman: The absorption of EHDP increases proportionally with higher doses, and this drug is excreted
from the body slowly, but the accumulated dose has
not been calculated.
Dr. Russell: EHDP remains in body for a long time.
Levels can still be found in urine 1 month after a
course of therapy.
Dr. Singer: Since absorption is variable, it is possible
that people with the bone pain syndrome on 5 mg/kg
EHDP absorb as much as some people on 20 mg/kg
EHDP. Absorption should be studied further.
Dr. Fleisch Should orthopedic surgery be undertaken
while the patient is taking EHDP?
Dr. Canfield Some of my patients on EHDP sustained
traumatic fractures of the femur and had surgical repair. Several recovered uneventfully although one
exception had nonunion. When someone has a fracture, I usually stop EHDP therapy for 12-18 months.
Dr. Johnston: Irrespective of EHDP therapy, are primary or secondary hyperparathyroidism and parathyroid adenomas occurring in patients with Paget’s
disease and does this make the Paget’s disease worse?
Dr. Canfield Yes.
Dr. Avioli: Could elevated parathyroid hormone values
be an age-related phenomenon independent of Paget’s disease?
Dr. Canfield I don’t think so. There is so much suggested evidence from separate studies, e.g. bone
biopsy, parathyroid hormone levels, that happens to
fit. This question needs further study.
Dr. Meunier: In my data, which takes age into consideration, the higher values are still statistically significant.
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