Spontaneous fractures of uninvolved bones in patients with Paget's disease during unduly prolonged treatment with disodium etidronate (EHDP)

Three patients with Paget's disease of bone were treated by disodium etidronate (EHDP) without interruption during periods of 18 to 30 months. In one case the daily dose was also unduly high (approximately equal to 18 mg/kg/day). A moderate to conspicuous diminution of the renal function was observed in all cases. The three patients developed skeletal pain in a gradual but progressively severe pattern. Seven nontraumatic fractures in nonpagetic bones were encountered. EHDP produces blockage of bone mineralization and excessive suppression of bone remodeling, therefore increasing the risks of fracture. EHDP affects not only pagetic bones but normal skeleton. A baseline evaluation of the renal function might help to identify those patients with greater risk to develop skeletal side effects during EHDP treatment.     

The effect of 1 alpha-hydroxyvitamin D3 on the mineralization defect in disodium etidronate-treated Paget's disease--a double-blind randomized clinical study

A double-blind randomized study of 29 patients with symptomatic Paget's disease was conducted comparing the clinical, biochemical, and histomorphometric responses to 3-month treatment with placebo (10 patients), low-dose disodium etidronate (EHDP) (5-7 mg/kg/day) (10 patients), and low-dose EHDP plus 1 alpha-hydroxyvitamin D3 (1 alpha D3) 0.5 mcg daily (9 patients). In placebo-treated patients no significant changes were observed in symptoms, biochemistry, or bone histomorphometry. Histologically apparent mineralization defects developed after 3 months of therapy in 90% of patients in the EHDP group, compared with 45% of patients in the EHDP/1 alpha D3 group. In 19% of the patients treated with active medication, the mineralization defects in pagetic bone were accompanied by histological evidence of continued osteoclastic resorption. The development of mineralization defects was not related to serum levels of vitamin D metabolites, alkaline phosphatase, or intestinal calcium absorption but did correlate with the occurrence of hyperphosphatemia during treatment, which was most marked in patients treated with EHDP alone. Although mineralization defects were less frequent in the EHDP/1 alpha D3 group, these patients also responded less well symptomatically, thus limiting the potential usefulness of this drug combination in Paget's disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biochemical assessment of acute and chronic treatment of Paget's bone disease with calcitonin and calcium with and without biphosphonate

Response to acute and chronic administration of calcitonin and calcium and of biphosphonates (EHDP) was evaluated in 14 patients with Paget's bone disease who were grouped on the basis of homogeneous disease activity, as appraised by bone involvement and alkaline phosphatase and hydroxyproline levels. At first, 100 MRC U of calcitonin followed 4 hours later by 500 mg of elemental calcium were given for 10 days; a significant (p less than 0.001; paired and unpaired Student t test) reduction in alkaline phosphatase (-25%) and hydroproline (-55%) was observed. Subsequently, 5 mg/kg/day of EHDP was given for 20 days. Both parameters increased to levels similar to basal values. These increases were significant (p less than 0.001 for the paired and unpaired Student test) compared with those obtained after calcitonin administration; alkaline phosphatase rose +27% and hydroxproline +135%. After this, patients were divided into 2 groups (A and B). Group A was treated with calcitonin and calcium, at the dosage indicated above, for 10 days a month during 6 months. Group B continued with the same protocol with the addition of EHDP for the 20 days during which calcitonin and calcium were not given. The results of 6 months of treatment showed that calcitonin was more active and suggested that EHDP diminishes hormonal effects. These results also demonstrate a short-term absence of EHDP activity.     

Focal mineralization defect during disodium etidronate treatment of calcinosis

Summary The use of disodium etidronate (EHDP) for the treatment of calcinosis is complicated by the threat of drug-induced inhibition of skeletal mineralization. Adults with Paget's disease of bone treated for 6 months with 10–20 mg/kg/day of EHDP have been reported to show both a marked delay in mineralization and a diffuse excess of unmineralized bone matrix. Drug-induced bone disease is, however, a function of growth as well as of the dose and duration of therapy. Therefore, children treated with EHDP may respond differently to the drug-induced mineralization defect. A 10-year-old girl with dermatomyositis developed incapacitating ectopic calcification. After 9 months of therapy with 12 mg/kg/Day of EHDP, a small decrease in the calcinosis was accompanied by a dramatic increase in joint mobility. Bone mineral content of the radial diaphysis showed a failure to gain mineral density as expected with prepubertal growth (8 cm/year). Bone biopsy revealed a patchy excess of osteoid. Although the percentage of osteoid surface labeled by tetracycline was reduced, normal mineralization was evident in the double-labeled areas. In children, the mineralization defect occurring with EHDP treatment may be focal.     

Biochemical response to combination of disodium etidronate with calcitonin in Paget's disease

The biochemical responses to salmon calcitonin (SCT: 100 MRC units thrice weekly) and disodium etidronate (EHDP: 400 mg daily) alone and in combination for 6 months were compared in 72 patients with symptomatic Paget's disease of bone unresponsive to simple analgesic agents. SCT produced a 53% reduction in alkaline phosphatase (AP) and a 38% reduction in 24 h urinary hydroxyproline excretion (HYPRO). The response to EHDP was not significantly different--56% reduction in AP and 48% reduction in HYPRO. Their use in combination produced a significantly greater reduction of 71% in AP (P less than 0.002) and 69% reduction in HYPRO (P less than 0.0001). In those that remained symptomatic with increased disease activity treatment for longer than 6 months had a unpredictable effect and normal bone turnover was rarely achieved. Once therapy was withdrawn AP and HYPRO increased rapidly in those given SCT alone, returning to initial levels within 6 months. More sustained control of disease activity was achieved in those given EHDP either alone or with SCT but the combination retained the advantage obtained during treatment. Combinations of SCT + EHDP may find a place in the treatment of very active Paget's disease.     

Ethane-1-hydroxy-1, 1-diphosphonate (EHDP) effects on growth and modeling of the rat tibia

One hundred gram male Sprague-Dawley rats were divided into groups which were injected daily for 10 or 30 days with vehicle (control group), 0.2, 0.4, 2.0, or 10.0 mg ethane-1-hydroxy-1,1-diphosphonate (EHDP)/kg/day. The proximal tibial metaphysis and epiphysis were assayed for changes in percentage of hard tissue and bone formation factors. Knowing these, information about hard tissue resorption was deduced. After ten or thirty days treatment with 2.0 or 10.0 mg EHDP/kg/day, there was an increase in percentage of hard tissue. This was due to a decrease in bone formation with a greater decrease in hard tissue resorption. Furthermore, after thirty days treatment with 0.2 and 0.4 mg EHDP/kg/day, there was an increase in percentage of hard tissue, which was due to a decrease in resorption with no change in formation. Ultrastructural studies on osteoclasts from EHDP-treated rats showed a general decrease in their vacuolization and amount of organelles as dosage of EHDP increased. Histologic findings suggest that EHDP is similar to fluoride in the way in which it depresses hard tissue resorption.     

The effects of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) on bone and serum chemistry in rabbits

The effects of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) on bone and serum chemistry were investigated in adult rabbits. EHDP was administered by subcutaneous injection at doses of 0.25, 2.5 and 10 mg/kg body weight/day for of 28 days. Blood samples were obtained weekly from each rabbit and serum levels of total calcium, ionized calcium, inorganic phosphate and alkaline phosphatase were determined. At the end of the treatment period all rabbits were sacrificed and the tibiae removed for chemical analysis and histological evaluation. The effect of EHDP administration on serum chemistry was both dose- and time-related. The highest of the three doses, 10 mg/kg/day, resulted in a time-related decrease in total serum calcium. This dose also caused a rapid but transient reduction in serum ionized calcium. The effect of EHDP on serum inorganic phosphate was biphasic. Administration of 2.5 mg/kg/day resulted in a time-related elevation in this parameter, whereas the 10 mg/kg/day dose resulted in a time-related hypophosphatemic response. There were no significant drug-related changes in tibial fat-free dry weight, ash weight, total calcium or total phosphorus values. However, administration of 2.5 and 10 mg/kg/day EHDP resulted in increased osteoid tissue as measured histologically. These results are compared with data from other EHDP studies, and discussed in relation to the maturity and growth-state of the experimental animals.     

Low back pain in Paget's disease of bone

Clinical and laboratory evaluation with bone scan, radiography, and computed tomography were performed on 25 patients with severe Paget's disease of bone and low back pain. Back pain was classified as caused by Paget's disease in only three patients. The remaining 22 patients had coexistent Paget's disease and osteoarthritis. There was difficulty separating the cause of back pain in those patients with coexistent Paget's disease and osteoarthritis, even when the diseases were present at different levels of the spine. The pathogenesis of Paget's disease appears to precipitate osteoarthritis and several low back syndromes. Suppressive therapy with disodium etidronate (EHDP) for Paget's disease was of benefit in eight of 22 patients (36%) with identifiable osteoarthritis. It is suggested that EHDP and perhaps other suppressive agents for Paget's disease receive limited use in patients with back pain unless a defined pagetic lesion appears related to the clinical syndrome in the absence of identifiable osteoarthritis.     

Treatment of ectopic calcification in uremia.

Nine uremic patients on maintenance hemodialysis who showed wide arterial and/or stable periarticular calcifications in spite of a well controlled hyperphosphatemia were treated with the diphosphonate disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) in doses of 7.5 to 10 mg/kg of body wt/per day for 5 to 9 months. No clinical or biochemical side-effects were noted. A significant reduction of the extent of periarticular calcifications was observed in five patients: two of them had a complete regression of soft-tissue calcifications, and one patient showed a reduction of arterial calcification. EHDP (7.5 to 10 mg/kg of body wt/per day) induced a significant increase of the osteoid volume and osteoid surface without significant modification of the calcification front. No evident effect on bone resorption and on the mineral content of the radius has been observed.     

Efficacy of the bisphosphonate APD in the control of Paget''s bone disease

Fifty-four patients with Paget's bone disease have been treated with the bisphosphonate APD. Twenty-six patients had not previously received treatment for Paget's disease; and 28 had been treated before with EHDP alone or in combination with calcitonin. APD was given orally in a mean dose of 500 mg daily ( 6.8 mg/kg of body weight) for 4 to 12 months. Bone pain diminished or disappeared in 34 of 39 patients with symptoms. A very significant diminution of the biochemical indices of bone turnover was observed in all patients, but the responses were faster in patients who had not previously received treatment for Paget's disease. After 4 months of treatment the serum levels of alkaline phosphatase of previously untreated patients diminished from 58.8 ± 8.0 to 20.0 ± 3.9 KA units (P 0.001) and urinary excretion of hydroxyproline diminished from 108.6 ± 16.9 to 42.4 ± 8.3 mg/24 h (P 0.001). In 23 of 26 previously untreated patients the biochemical indices decreased to the normal range (complete response). A reduction of 50% or more without reaching the normal range was observed in the other 3 patients (partial response). Actuarial analysis of the duration of the effect 12 months after stopping APD disclosed that 63% of patients who had achieved a complete response but only 23% of those with a partial response were in biochemical remission. A second course of APD was administered to 11 patients. The results were as effective during the second as the first course in 9 patients, whereas 2 patients had no response to retreatment. It was found that the nonresponders had a shorter therapy-free interval as compared with the good responders. These observations indicate that APD is an effective agent in the long-term control of the activity of Paget's bone disease. No significant side effects have been observed in this group of patients.     

Ethane-1-hydroxy-1,1-diphosphonate (EHDP) effects on incorporation and accumulation of osteoclast nuclei

Male rats weighing 100 g were injected with vehicle (control group), 0.4 or 4.0 mg/kg/day of ethane-1-hydroxy-1,1-diphosphonate (EHDP). Beginning after 6 days of EHDP treatment all rats received six subcutaneous injections of³H-thymidine at 8 h intervals. The multiple labeling index of autoradiographically defined labeled cells was determined for the osteoprogenitor cells of the primary spongiosa of the proximal tibial metaphysis. The osteoclasts in the proximal tibial metaphysis were assayed for population parameters and incorporation of labeled nuclei at sequential intervals after the administration of³H-thymidine.After 6 days of EHDP pre-treatment the multiple labeling index of the osteoprogenitor cells was reduced with 4.0 mg/kg/day dose of EHDP. At the beginning of the experimental kinetic sampling period, after the 6 days of EHDP pre-treatment, EHDP treatment resulted in significant increases in the numbers of osteoclasts, nuclei per osteoclast profile, and total osteoclast nuclei. During the sampling period, the 4.0 mg/kg/day dose of EHDP caused further increases in the number of total osteoclasts.EHDP treatment caused a marked increase in the rate of incorporation and accumulation of³H-thymidine-labeled nuclei in osteoclasts. Thus, EHDP causes an accelerated rate of osteoclast production from precursor cells in spite of its ability to slow bone resorption.Although the origin of osteoclast nuclei is not clear, the kinetic data from this study suggests that osteoclast nuclei are not arising from osteoprogenitor cells or osteocytes in the EHDP-treated animals.     

Treatment of Paget's disease with combined calcitonin and diphosphonate (EHDP)

Thirty patients with Paget's disease were treated with a combination of EHDP and calcitonin. EHDP was given orally (7.5 mg/kg body weight/day) and calcitonin, either as synthetic human calcitonin 0.5 mg or as salmon calcitonin 50 or 100 MRC units day, by self-administered subcutaneous injection. All patients noted subjective improvement, being able to walk further or work longer before pain developed. Twenty five obtained complete biochemical remission in six to twelve months, while five obtained near to normal values for alkaline phosphatase and hydroxyproline. Iliac crest biopsies showed a decrease in the volume percentage of osteoid and in numbers of asteoclasts, and bone scans improved. At six months calcium balances had become more positive, consistent with continued mineralization of earlier formed bone. Seven patients suffered recurrence within three months of withdrawal of therapy. Maintained remission has been observed in six patients followed for more than half a year, in six followed for more than a year and in six followed for more than two years.     

Myositis Ossificans Progressiva:: Clinical and Metabolical Observations in a Case Treated with a Diphosphonate (EHDP) and Surgical Removal of Ectopic Bone

A 20-year-old woman with a severely crippling myositis ossificans progressiva was treated with a diphosphonate (EHDP), 10-20 mg/kg/day. While being treated with this drug, surgical removal of ectopic bone was performed. Although ectopic calcification recurred postoperatively, considerable functional improvement was achieved. At the highest dosage of EHDP, hypercalcaemia gradually appeared, but was reversible upon cessation of drug treatment. It is probably related to a direct effect of EHDP on the bone.     

Myositis ossificans progressiva. Clinical and metabolical observations in a case treated with a diphosphonate (EHDP) and surgical removal of ectopic bone.

A 20-year-old woman with a severely crippling myositis ossificans progressiva was treated with a diphosphonate (EHDP), 10-20 mg/kg/day. While being treated with this drug, surgical removal of ectopic bone was performed. Although ectopic calcification recurred postoperatively, considerable functional improvement was achieved. At the highest dosage of EHDP, hypercalcaemia gradually appeared, but was reversible upon cessation of drug treatment. It is probably related to a direct effect of EHDP on the bone.     

The effects of EHDP on regenerating trabecular bone usingin vivo microscopic,light and electron microscopic,and electron microprobe techniques

Metallic chambers were implanted into the proximal tibiae of rabbits to permit microscopic examination of living bonein situ. The bone repair process secondary to the injury produced during installation of the chamber, was visualized. Six to 8 weeks after implantation, osteoid and/or bone could be seen. The effects of various doses of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) on the repair and regeneration processes following chamber implantation were studied. Data from various techniques indicated that: (1) following low dose EHDP (0.25 mg/kg/day) chambers contained bone tissue morphologically and ultrastructurally indistinguishable from controls; and (2) with higher doses of EHDP (2.5 or 10 mg/kg/day) chamber contained spicules of normal osteoid, osteoblasts and osteocytes, but were devoid of osteoclasts. The effects of the various regimes of EHDP also were assessed on regenerated, trabecular bone contained within the tibia chambers three months after implantation of the chambers. Data from various methods of analysis supported the following conclusions: (1) the low dose of EHDP (0.25 mg/kg/day) had no toxic effects on the trabecular bone within the chambers but there appeared to be an increase in bone formation as compared to saline control; (2) higher doses of EHDP (2.5 or 10 mg/kg/day) were not toxic to bone cells but thick osteoid seams formed on the trabecular bone within the chambers. No osteoclasts were found associated with the bone apparently due to the coverage of bone surfaces by osteoid seams; and (3) osteoid which accumulated after EHDP treatment of 2.5 mg/kg/day for 2 months remained uncalcified for as long as 2 months following withdrawal of EHDP administration. The results showed the value of tibial chamber for examining microscopically living bonein situ and demonstrated the inhibitory effect of EHDP on mineralization of newly formed osteoid and a lack of effect on bone cells.     

Effect of ethane-1-hydroxy-1,1-diphosphonate on ectopic bone formation induced by murine osteosarcoma-derived bone-inducing substance

The effects of ethane-1-hydroxy-1,1-diphosphonate (EHDP) on ectopic bone formation were studied qualitatively and quantitatively in an experimental system for ectopic bone formation induced by murine osteosarcoma-derived bone-inducing substance. At a low dose of EHDP (3 mg/kg per day i.p.), histologic sequelae of ectopic bone formation were normal, and the size of the induced bone mass was unaffected. At a high dose of EHDP (30 mg/kg per day i.p.), an unmineralized bone matrix with hematopoietic bone marrow was formed without evidence of retardation. This osteoid tissue showed no radiologic and histologic evidence of mineralization during the period of EHDP administration. When EHDP was withdrawn, its inhibitory effect on mineralization was reversed. The induced bone mass was almost the same size as that in controls. These results suggest that EHDP might not prevent ectopic bone matrix formation, but its mineralization and withdrawal of EHDP might lead to the formation of a normal bone similar in size to that formed without EHDP treatment.     

Prevention of ectopic bone formation by local application of ethane-1-hydroxy-1,1-diphosphonate (EHDP): an experimental study in rabbits

This report shows that ectopic bone formation, a serious problem in orthopedic surgery, can be controlled in an animal model by local application of EHDP (disodium-ethane-1-hydroxy-1,1-diphosphonate). The results might be particularly pertinent to the clinical problem of preventing the recurrence of ectopic bone after surgical excision. Male New Zealand white rabbits were treated with immobilization and intermittent passive manipulation of the right knee. The treatment caused bone formation in the quadriceps muscle, which was visible on radiographs after 3 weeks. In this model, the effect of methacrylate implants containing EHDP was studied. A concentration of 16 g EHDP/100 g methacrylate inhibited bone formation in experimental cortical defects. Release of radiolabeled EHDP was studied in an in vitro system. The release of the drug was approximately 20 mg/day and implant initially, decreasing to about 0.1 mg/day/implant after 30 days. Standardized implants containing 16 g EHDP/100 g were then surgically attached to the femur, and the ectopic bone formation created by immobilization and intermittent manipulation was compared with that in rabbits treated with implants but without EHDP. The ectopic bone was measured from lateral and frontal radiograms and from radiograms of serial transverse sections of the thigh. We found that the EHDP implants were capable of preventing major ectopic bone formation in all cases, whereas all rabbits with an implant containing no EHDP had substantial ectopic bone formation at the end of the experiment. There was no difference between groups in the relative amount of cartilage, connective tissue, and normal bone. We conclude that local administration of EHDP may be a useful method for prevention of ectopic bone formation under the conditions and time employed.     

The comparative effects of dichloromethylene diphosphonate (Cl2MDP) and ethane-1-hydroxy-1,1-diphosphonate (EHDP) on growth and modeling of the rat tibia

Summary Male rats weighing 100 g were assigned to groups and injected daily for 10 days with vehicle (control), 0.4, 2.0, 4.0, 10.0, or 20.0 mg/kg/day of ethane-1-hydroxy-1,1-diphosphonate (EHDP) or dichloromethylene diphosphonate (Cl₂MDP). The proximal tibial metaphysis and epiphysis were assayed for changes in percentage of hard tissue and bone formation parameters. From the data, information about hard tissue resorption was deduced.All doses of Cl₂MDP and doses of 2.0 mg EHDP/kg/day and greater caused significant increases in percentage of hard tissues with Cl₂MDP being more effective than similar doses of EHDP in decreasing bone resorption.Osteoclast population parameters were increased with all doses of both Cl₂MDP and EHDP with Cl₂MDP having a greater effect than similar doses of EHDP. Decreases in the proliferation of the osteoprogenitor pool parallel the decreases in osteoblasts and bone formation parameters. These decreases in osteoprogenitor pool proliferation do not account for the increases with diphosphonates in osteoclast population parameters.     

The effects of disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDP) on mineral and organic components of rat bone

The purpose of this study was to determine the short-term effects of various systemic doses of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) on bone organic matrix and to relate these effects to the corresponding dose-related changes in bone mineral. EHDP was administered daily by subcutaneous injection at doses of 0.25, 2.5 and 40 mg/kg body weight for periods of one and two weeks. At both time intervals, rat tibiae were quantitatively analyzed for mineral content (ash, calcium and phosphorus) and for organic matrix content (matrix weight, nitrogen and certain amino acids). The latter data were correlated with semiquantitative histological analyses of the tibiae. Results of this study demonstrate that the short term effects of EHDP on bone chemistry and histology are variable and depend on the systemic dose and the duration of treatment. Systemic doses of 0.25 and 2.5 mg/kg EHDP following daily administration for one week resulted in transitory decreases in bone mineral content compared to controls. Following two weeks of treatment, both of these dose levels resulted in increased bone mineral content and, in addition, the 2.5 mg/kg dose resulted in tibiae which contained more organic matrix compared to control bones. In contrast to the low dose effects, a high systemic dose of EHDP—e.g. 40 mg/kg administered daily for 1 or 2 weeks—appears to act solely by inhibiting mineralization of newly-formed matrix.     

Influence of disodium etidronate on Paget's disease of bone

The use of agents that decrease bone resorption, notably the calcitonins, diphosphonates and mithramycin, has been shown to result in symptomatic and/or biochemical improvement in patients with Paget's disease of bone (osteitis deformans). The effects of short-term (6 months), low-dose (5 mg/kg body mass/d) etidronate disodium, a diphosphonate compound at present subject to registration in this country, on the clinical and laboratory manifestations of this disorder were examined. Marked symptomatic improvement was noted in 70% of patients, while biochemical parameters of bone turnover, namely serum alkaline phosphatase level (44%) and urine hydroxyproline excretion (56%), decreased significantly (P less than 0.001). A technetium-99m bone scan revealed an impressive reduction in uptake of isotope in 50% of patients. The drug was well tolerated and no adverse reactions (clinical, biochemical or haematological) were evident. It is concluded that short-term low-dose etidronate disodium affords a convenient and effective therapeutic alternative in patients with symptomatic Paget's disease.