PRODUCT MONOGRAPH

GEN-ETIDRONATE

(Etidronate Disodium Tablets, USP)

mg Tablets

Bone Metabolism Regulator, Anti-Pagetic Agent Anti-Hypercalcemic Agent

Genpharm Inc. Date of Preparation:

Advance Road May 26, 2003

Etobicoke, Ontario M8Z 2S9

Ctrl# 079323

PRODUCT MONOGRAPH

NAME OF DRUG

GEN-ETIDRONATE

(Etidronate Disodium Tablets, USP) 200 mg Tablets

CLINICAL PHARMACOLOGY

Etidronate disodium acts primarily on bone. It can inhibit the formation, growth and dissolution of hydroxyapatite crystals and their amorphous precursors by chemisorption to calcium phosphate surfaces. Inhibition of crystal resorption occurs at lower doses than are required to inhibit crystal growth. Both effects increase as the dose increases.

General

The gastrointestinal absorption of etidronate disodium is approximately 3.5%. The plasma half life (t1/2) is between 1-6 hours. The drug is not metabolized. It is either rapidly excreted unchanged in the urine or is taken up by bone. About half the dose is deposited in the skeleton, with the subsequent elimination controlled by bone turnover rate, which in turn is influenced by the metabolic conditions and specific bone type.

Paget *s Disease

Etidronate disodium acts on bones by slowing the rate of turnover (resorption and accretion) both in Pagetic lesions and to a lesser extent in the normal bone remodeling process. During treatment with etidronate disodium histologic examination of bone from Pagetic lesions shows a decrease in the excessive cellular activity accompanied by a suppression of bone turnover, an improved histologic pattern including lamellar bone formation, a decrease in fibrotic marrow pattern, a decrease in vascularity and an increase in normal hematopoietic marrow elements. Etidronate disodium therapy, in patients with Paget *s disease, results in lowering of urinary hydroxyproline as well as serum alkaline phosphatase and radionuclide uptake by Pagetic bone is reduced in many patients. The associated pathophysiological manifestations of increased bone vascularity, increased skin temperature and increased cardiac output are also improved. These actions are generally accompanied by symptomatic improvement, including reduction of bone pain. At a dose of 20 mg/kg/day in excess of three months and after six or more months of therapy at doses of 10 mg/kg/day, unmineralized osteoid can accumulate. (See PRECAUTIONS).

Hypercalcemia of Malignancy

Hypercalcemia of malignancy is usually related to increased bone resorption associated with the presence of neoplastic tissue. It occurs in 8 to 20% of patients with malignant disease. Whereas hypercalcemia is more often seen in patients with demonstrable osteolytic, osteoblastic, or mixed metastatic tumors in bone, discrete skeletal lesions cannot be demonstrated in at least 30% of patients. Etidronate disodium *s reduction of abnormal bone resorption is responsible for its therapeutic benefit in hypercalcemia. Following successful treatment with etidronate disodium IV infusion, which effectively reduces total and ionized serum calcium, etidronate disodium tablets help maintain clinically acceptable serum calcium levels.

Pharmacokinetics

A comparative, randomized, two-way, single-dose, fasting bioavailability study was performed in normal healthy male volunteers using GEN- ETIDRONATE TABLETS 200 mg and DIDRONEL(r) (etidronate disodium tablet) 200 mg. The pharmacokinetic data for both formulations is presented below:

Table 1: Summary Table of Comparative Bioavailability Data

(from measured data) fasting conditions

(etidronate disodium 4 x 200 mg)

* expressed as arithmetic mean (CV%) only

* *

Didronel(r) Tablets 200 mg manufactured by Procter & Gamble Pharmaceuticals was purchased in Canada.

* * * 90% Confidence Intervals for the ratio of geometric means N/AP - Not Applicable

CONTRAINDICATIONS

Gen-Etidronate (etidronate disodium) is contraindicated for patients with known hypersensitivity to the drug. Gen-Etidronate is also contraindicated for patients with clinically overt osteomalacia; appropriate treatment to resolve their osteomalacia should be initiated before prescribing Gen-Etidronate.

WARNINGS

General

Since absorbed Gen-Etidronate (etidronate disodium) is excreted through the kidneys, periodic renal function assessment should be carried out in patients whose renal function may be deteriorating. While there is no experience to specifically guide treatment in patients with impaired renal function, in such cases renal function should be monitored carefully.

Paget *s Disease

The physician should adhere to the recommended dose regimen in order to avoid unnecessary overtreatment with Gen-Etidronate (See PRECAUTIONS and ADVERSE REACTIONS). The response to therapy may be slow onset and may continue even for months after treatment when the drug has been discontinued. Dosage should not be increased prematurely nor should treatment be resumed before there is clear evidence of reactivation of the disease process. Retreatment should not be initiated until the patient has had at least a three-month drug-free interval to determine whether remission has occurred and to promote mineralization of any unmineralized osteoid which may have developed. The incidence of osteogenic sarcoma is known to be increased in Paget *s disease. Pagetic lesions, with or without therapy, may appear by x-ray to progress markedly, possibly with some loss of definition of periosteal margins. Such lesions should be evaluated carefully to differentiate these from osteogenic sarcoma. Although there is no evidence of impaired fracture healing with Gen- Etidronate, in case of spontaneous or pathological fractures occurring during Gen-Etidronate therapy the drug should be discontinued until complete healing of the fracture takes place. (See ADVERSE REACTIONS)

PRECAUTIONS

General

Etidronate disodium 200 mg as a single ingredient, indicated for the treatment of Paget's disease and Hypercalcemia of Malignancy, should not be used for the management of osteoporosis. To assure optimal absorption of Gen-Etidronate (etidronate disodium), the drug should be taken on an empty stomach as a single oral daily dose at least two hours before or after meals with a full glass of water. It should not be taken with milk. Gen-Etidronate therapy should be approached with caution in patients with gastrointestinal disease, because Gen-Etidronate may cause diarrhea in some patients at doses above 5 mg/kg/day.

Paget *s Disease

Patient Monitoring:

During therapy, periodic monitoring of urinary hydroxyproline excretion and/or serum alkaline phosphatase levels to assess disease activity is desirable. Additionally, monitoring of serum phosphate levels may provide indications of patient compliance. A failure of serum phosphate levels to increase at Gen-Etidronate dose levels of 10 mg/kg/day or above may be suggestive of non-compliance.

Osteoid Mineralization: (See CONTRAINDICATIONS - osteomalacia)

: Gen-Etidronate may retard mineralization of osteoid laid down during the bone accretion process. This effect is dose and time-dependent. There may be an overlap of beneficial and mineralization inhibition effects in

some patients at higher doses. Extended periods of continuous medication should be approached cautiously. When administered at doses of 20 mg/kg/day, Gen-Etidronate suppresses bone turnover and essentially stops mineralization of new bone in Pagetic lesions and, to a lesser extent, in the uninvolved skeleton. Mineralization of Pagetic lesions has been demonstrated to occur normally after discontinuation of the drug.

Nutrition

: Patients with Paget *s disease of bone should maintain an adequate nutritional status, and particularly, an adequate intake of calcium and vitamin D. Patients with restricted vitamin D and calcium intake may be particularly sensitive to drugs that affect calcium homeostasis and should be closely followed while under treatment with Gen-Etidronate.

Hyperphosphatemia

: Gen-Etidronate therapy at daily doses of 10 mg/kg/day and above, and occasionally at doses of 5 mg/kg/day, is associated with serum phosphate elevations, probably due to increased renal tubular reabsorption of phosphate. Serum values of up to 2.26 mmol/L (7 mg%) are seen at the highest doses. The usual increments are approximately 0.32 mmol/L (1 mg%) over the pretreatment levels. Serum phosphate returns to normal within two to four weeks after the drug is discontinued.

Therapy with etidronate disodium alone is not accompanied by clinically, significant changes in serum parathyroid hormone or serum calcium levels.

Bone Pain

: Bone pain at the Pagetic site may increase or recur during

Gen-Etidronate therapy even in patients who are experiencing relief of their original symptoms. Continuance of therapy will usually result in resolution of pain. However, on occasion, therapy may have to be discontinued (see ADVERSE REACTIONS).

Hypercalcemia of Malignancy

Patient Monitoring

: Serum calcium levels should be monitored in patients receiving etidronate disodium IV infusion therapy and/or oral Gen- Etidronate maintenance therapy for hypercalcemia of malignancy. The physiologically important component of serum calcium is the ionized portion. In most institutions, this cannot be measured directly. It is important to recognize that factors influencing the ratio of free and bound calcium such as serum proteins, particularly albumin, may complicate the interpretation of total serum calcium measurements. If indicated, a corrected (adjusted) serum calcium value should be calculated using an established algorithm, such as

Caadj = CaT-0.71(A-Am) where, Caadj = adjusted calcium concentration (mg/100 mL)

Serum creatinine and blood urea nitrogen should be monitored in patients with known or suspected renal insufficiency.

Drug Interactions

The concurrent use of Gen-Etidronate with corticosteroid, phosphate, calcitonin, furosemide or mithramycin therapies may result in additive effects. The concurrent use of etidronate disodium with warfarin has been associated with isolated reports of patients experiencing increases in their prothrombin time. The majority of these reports concerned variable elevations in prothrombin times without clinically significant sequelae. Although the relevance of these reports and any mechanism of coagulation alterations is unclear, patients on warfarin should have their prothrombin time more closely monitored.

Laboratory Tests

Depending on the time elapsed since the last dose of etidronate, the Gen-Etidronate therapy may prevent bone-imaging diagnostic agents (e.g.. technetium-99m-methylene diphosphonate) used in bone scans, from adhering to bone and thus affect the interpretation of imaging results.

Use in Children

The safety and effectiveness of Gen-Etidronate in children has not been established.

Use in the Elderly

Special precautions related to the use of Gen-Etidronate in geriatric patients have not been identified. However, serum creatinine levels should be closely monitored in patients with renal impairment.

Use in Pregnancy

Studies performed in rats and rabbits using orally administered etidronate disodium at doses up to five times the maximum human dose have revealed no evidence of impaired fertility or harm to the fetus. At doses of twenty-two times the maximum human dose, a decrease in live fetuses was observed in rats. Malformations occurred only in rats at exaggerated doses following parenteral administration and were skeletal in nature. These malformations were deemed to be the result of the pharmacologic action of the drug. The relationship of oral and intravenous routes of administration in reproduction/teratology studies is unknown. There are no adequate, well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Use in Nursing Mothers

Gen-Etidronate is not intended for administration during lactation. It is not known whether etidronate is excreted in human milk; it is excreted in the milk of rats. Because many drugs are excreted in human milk and because of the potential for adverse effects on the skeletons of infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Clinical experience with etidronate disodium overdosage is extremely limited. Decreases in serum calcium following substantial overdosage may be expected in some patients. Signs and symptoms of hypocalcemia also may occur in some of these patients. In one event, an 18-year old female who ingested an estimated single dose of 4,000- 6,000 mg (67-100 mg/kg) of etidronate disodium was reported to be mildly hypocalcemic (1.88 mmol/L or 7.52 mg/dL) and experienced paresthesia of the fingers. Hypocalcemia resolved 6 hours after lavage and treatment with intravenous calcium gluconate. A 92-year old female who accidentally received 1,600 mg of etidronate disodium per day for 3.5 days experienced marked diarrhea and required treatment for electrolyte imbalance. Some patients may develop vomiting and expel the drug. Gastric lavage may remove unabsorbed drug. Standard procedures for treating hypocalcemia, including the intravenous administration of ionizable calcium salts, would be expected to restore physiologic amounts of ionized calcium and relieve signs and symptoms of hypocalcemia. Such treatment has been effective.

DOSAGE AND ADMINISTRATION

General

Gen-Etidronate (etidronate disodium) should be taken on an empty stomach as a single, oral daily dose at least two hours before or after meals with a full glass of water. However, should gastrointestinal discomfort occur, the dose may be divided. To maximize absorption, patients should avoid taking the following items within two hours of dosing:

• Food, especially those high in calcium, such as milk or milk products.

• Vitamins with mineral supplements or antacids which are high in metals such as calcium, iron, magnesium or aluminum.

Paget's Disease

Initial Treatment Guidelines:

The recommended initial dose of Gen- Etidronate for most patients is 5 mg/kg body weight/day, not to exceed a period of six months. Doses above 10 mg/kg/day should be reserved for use when there is an overriding requirement for suppression of increased bone turnover associated with Paget *s disease or when the patient requires more prompt reduction of elevated cardiac output. Treatment with doses above 10 mg/kg/day should be approached cautiously and should not exceed three months duration. Doses in excess of 20 mg/kg/day are not recommended.

Urine hydroxyproline excretion and/or serum alkaline phosphatase levels should be monitored periodically during the course of Gen-Etidronate therapy.

Retreatment Guidelines:

Retreatment should be initiated only after:

1. An etidronate disodium-free period of at least 90 days and,

2. There is biochemical, symptomatic or other evidence of active disease process.

patients may go drug-free for extended periods. Retreatment regimens are the same as for initial treatment. For most patients the original dose will be adequate for retreatment. If not, consideration should be given to increasing the dose within the recommended guidelines.

Hypercalcemia of Malignancy

Gen-Etidronate tablets may be started on the day following the last dose of etidronate disodium IV infusion. The recommended oral dose of Gen- Etidronate for patients who have hypercalcemia is 20 mg/kg body weight/day for 30 days. If serum calcium levels remain normal or at clinically acceptable levels, treatment may be extended. Treatment for more than 90 days has not been adequately studied and is not recommended.

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Etidronate Disodium Chemical Name: disodium salt of (1-hydroxyethylidene) bisphosphonic acid. Structural Formula:

NaO

O

H ONa

O P P O

HO CH3 OH Molecular Formula: C2H6P2Na2O7 Molecular Weight: 249.99 Description: Etidronate disodium is a white or almost white crystalline powder, odourless or almost odourless. Solubility: Soluble in water (0.2857 g/ml) and insoluble in acetone, 2-propanol, methanol and ethanol.

Composition

Each 200 mg Gen-Etidronate tablet contains 200 mg etidronate disodium USP as active ingredient. Each tablet contains the following inactive ingredients: corn starch, microcrystalline cellulose, magnesium stearate and pregelatinized starch. Gen-Etidronate tablets do not contain lactose.

Storage Recommendation

Store at controlled room temperature (15 - 30degC)

DOSAGE FORMS AND AVAILABILITY

Gen-Etidronate (etidronate disodium) Tablet 200 mg is supplied as a white, rectangular-shaped biconvex tablet with "ED 200" on one side and "G" on the other available in HDPE bottles of 60's.

PHARMACOLOGY

Etidronate disodium chemisorbs onto hydroxyapatite (a calcium phosphate hydroxide) at physiological pH. This may be responsible for etidronate disodium *s activity in vivo - at low doses, reduction of bone turnover (resorption and formation) and at high doses, inhibition of mineral accretion. Following oral administration to animals the absorption of etidronate disodium varies from 3% in rats and rabbits to 5 to 21% in young dogs. In humans the absorption is 3 to 4% of the oral dose. The non-absorbed fraction of orally administered etidronate disodium is excreted unchanged in the feces; of the absorbed fraction, about half is deposited in the skeleton, while the remainder is rapidly excreted without metabolism in the urine. The elimination of etidronate disodium from bone is slow (the half-life is approximately 120 days) and is controlled by the bone turnover rate, which in turn is influenced by metabolic conditions and specific bone types. The pharmacologic conclusion from animal studies is that etidronate disodium significantly reduces the rate of bone turnover. The data supports a conclusion that the level response to etidronate disodium can be controlled by modifying either the dose or the duration of dosing, or both. The effect of etidronate disodium on inhibition of mineralization is reversible when medication is stopped.

CLINICAL EXPERIENCE

Paget *s Disease

Etidronate disodium acts primarily on bone. It can modify the crystal growth of calcium hydroxyapatite by chemisorption onto the crystal surface. Depending on concentration, the drug may either inhibit crystal resorption or crystal growth. Etidronate disodium slows the rate of bone turnover (bone resorption and new bone accretion) in Pagetic bone lesions and in the normal remodeling process. Paget *s disease is an idiopathic bone disorder characterized by abnormal and accelerated bone resorption and formation in one or more bones. The extent and severity of the disease is highly variable. Characteristic symptoms may be bone pain, varying degrees of bone deformity, and vascular disorders, including abnormally elevated cardiac output secondary to the increased vascularity associated with Paget *s disease. Serum phosphate elevations have been observed when etidronate disodium is administered at daily doses of 10 mg/kg body weight/day or above and occasionally at 5 mg/kg/day. This has not been found to be an indication for discontinuing therapy. This drug-related elevation appears to be the result of increased tubular reabsorption of phosphate by the kidney, and serum values in excess of 2.3 mmol/L (7 mg/l00 mL) have been observed with high doses. No adverse effects of Gen-Etidronate- induced hyperphosphatemia have been found. Serum phosphate levels generally return to normal 2-4 weeks after stopping medication. To elicit the bone effects of the drug, patients with Paget *s disease of bone, myositis ossificans progressiva, as well as normal volunteers on prolonged bed rest, were studied. In general etidronate disodium, at a dose of 20 mg/kg/day, produced a reduction of approximately 50% in both mineral accretion rate and mineral resorption rate as measured by 47Calcium kinetics methods. Patients generally showed an increased intestinal calcium absorption (and urinary calcium excretion) and a more positive calcium balance on the drug, but only a slight, clinically insignificant increase in serum calcium levels. The first evidence of therapeutic response to etidronate disodium in Paget *s patients, reduction of urinary hydroxyproline excretion, usually occurs after one to three months of medication. Average percent reductions of elevated hydroxyproline and alkaline phosphatase during etidronate disodium therapy at the recommended dose of 5 mg/kg/day for 6 months are shown in Figure 1. Etidronate disodium's effectiveness has been demonstrated primarily in patients with polyostotic Paget *s disease with symptoms of pain and with clinically significant elevations of urinary hydroxyproline and serum alkaline phosphatase. In patients treated with etidronate disodium at the dose of 5 mg/kg/day, the elevated urinary hydroxyproline and serum phosphatase decreased by 30% or more in about 80% of patients. Hydroxyproline and alkaline phosphatase either returned to normal or were decreased by at least half in about 60% and 50% of patients respectively. Figure 1 Percentage Change in Elevated Biochemical Parameters (Patients Treated with Etidronate at 5 mg/kg/day in Double-Blind, Placebo-Controlled Studies) In controlled studies of Paget *s patients, approximately 60% of the patients experienced decreased pain and/or improved mobility. About 40% of the patients in the placebo group showed similar subjective improvement. Objective measurements in etidronate disodium-treated patients have shown reductions of elevated cardiac output in about 65% of the patients. Reductions in elevated skin temperature over Pagetic lesions have also been measured. The number of treated patients in these categories is still too small to predict with certainty how likely such a result will be in any given patient. Objective evidence of hearing improvement has not been demonstrated. Histologic examination of Pagetic bone from patients treated with etidronate disodium shows a reduction in the excessive cellular activity, accompanied by a suppression of abnormal bone resorption and accretion. Marrow spaces become less vascular and normal fat and hematopoietic cellular elements replace the fibrous Pagetic marrow. Accumulation of unmineralized osteoid was frequently observed in patients treated with 20 mg etidronate disodium/kg/day for six months, and in some patients after longer periods of therapy at lower doses. This accumulation of osteoid is more marked in Pagetic bone than in the uninvolved portion of the skeleton. Withdrawal of the drug permits the osteoid to mineralize normally. Impaired vitamin D metabolism could be associated with decreased calcium absorption. At a clinical dose of 20 mg/kg/day. Etidronate disodium has been observed to increase intestinal calcium absorption. In addition, administration of vitamin D3 or its active metabolite does not reverse etidronate disodium induced inhibition of mineralization. This would seem to rule out any important effect of the drug on vitamin D metabolism at clinically employed doses.

Hypercalcemia of Malignancy

In a multicentre, randomized, double-blind study, patients with hypercalcemia due to malignant disease or with hypercalcemia due to primary hyperparathyroidism disease were treated with daily intravenous infusions of etidronate disodium plus saline or saline alone. All patients were eligible to receive up to 3 liters of additional saline and 80 mg furosemide daily during the IV treatment period. Patients in this study could participate in one or more of four treatment periods, which, in themselves, constituted individual studies. Three of the periods involved evaluating a response to IV infusion therapy; the other involved evaluating a response to maintenance therapy with oral etidronate disodium (blinded oral etidronate disodium or oral placebo). In this trial, patients who had reductions in serum calcium to the normal range after the etidronate disodium IV therapy were randomized to receive either oral etidronate disodium at a dose of 20 mg/kg/day for 90 days, or a similar placebo regimen. Eighty-one of the original 233 patients continued to the oral treatment period of the study, 63 of whom could be analyzed. Of these analyzable patients, about half were treated with oral etidronate disodium. A comparison of the duration of response between the two groups, using a lifetable analysis method, demonstrated a statistically significantly longer (p<0.01) median time of noromocalcemia for patients treated with oral etidronate disodium (29 days) versus placebo-treated patients (11 days) (Figure 2). The success rates were 35% for oral etidronate disodium and 6% for placebo when total serum calcium was analyzed. The difference between the groups was statistically significant (p<0.01). Twenty patients were available for analysis of albumin adjusted serum calcium levels. The success rates were 38% and 0% respectively.

TOXICOLOGY

The acute oral toxicity of etidronate disodium is low relative to the clinical dosage. The oral LD50 is about 1300 mg/kg in rats and the emetic dose in dogs is approximately 85 mg/kg. No significant adverse effects were seen in rats and dogs fed diets containing up to 1% etidronate disodium for two years other than a spontaneously remitting microcytic, hypochromic anemia in dogs during the first 6 months of the study. In rats treated by oral gavage for 1 year at dosages up to 216 mg/kg the primary effect was an extension of the pharmacology on the skeleton from long term continuous administration with subsequent secondary effects on organ systems. Spontaneous fractures have occurred in dogs receiving etidronate disodium at doses of 2 mg/kg subcutaneously for 1 year and orally at 100 mg/day for 2 years. Higher doses completely inhibited bone mineral accretion and turnover, resulting in susceptibility to fractures after 9-12 months of continuous treatment. The spontaneous fractures healed normally when the drug was discontinued and at lower parenteral doses occurred and healed normally while etidronate disodium treatment continued. Subsequent studies of fracture healing in dogs and rats have demonstrated that when etidronate disodium is administered at low but not at high doses, the bone heals normally following fracture. In order to study the effects of intravenous infusion followed by oral administration for the indication of hypercalcemia, etidronate disodium was administered intravenously to dogs at doses of 0, 10, or 20 mg/kg for 5 days (2 hr/day) followed by oral administration, 0 or 300 mg (ca.20 mg/kg), for either 7 (short cycle) or 21 (long cycle) days. This regimen was repeated three times. No compound related changes in the clinical chemistry, hematologic, or histologic parameters were observed in the 10 mg/kg IV/300mg PO long cycle group, or in those groups dosed with 0 mg/kg IV/300mg PO at both the long and short cycles. Chronic interstitial nephritis was observed in those long cycle groups dosed with 20 mg/kg IV/300mg PO, and in the short cycle groups dosed with either 10 or 20 mg/kg IV/0 or 300 mg PO.

Mutagenesis, Carcinogenesis, Impairment of Fertility

A two year feeding study in rats and five mutagenicity assays (dominant lethal assay in mice, two Salmonella microsomal point mutation assays, a micronucleus test in the bone marrow of the Chinese hamster, and an in vitro Saccharomyces cerevisiae MP-1 point mutation assay) indicate that etidronate disodium is not carcinogenic or mutagenic.

BIBLIOGRAPHY

General

1. Didronel Product Monograph. Procter and Gamble Pharmaceuticals. (February 1998)

Reviews

1. Fleisch, H.: Bisphosphonates. Pharmacology and Use in the Treatment of Tumour-Induced Hypercalcemia and Metastatic Bone Disease. Drugs, 42:919-944, 1991.

2. Ibbertson, H.K., Fraser, T.RC., Scott, D.J., Cullen, J.C., Henley, J.W., Stephens, ES., Tait, B., and Wattie, D.J. : Paget *s Disease of Bone: Assessment and Management. Drugs, 18:33-47 (1979).

3. Russell, R.G.G. : Diphosphonates and Polyphosphates in Medicine, Br.J. Hosp. Med.. 274-314(1975).

4. Russell, R.G.G., and Fleisch, H.: Pyrophosphate and Diphosphonates in Skeletal Metabolism. Physiological, Clinical and Therapeutic Aspects, Clin. Orthoped.,

108,241-263(1975). Russell, R.G.G., and Fleisch, H.: Biochemistry and Physiology of Bone, Vol. III. Calcification and Physiology, G.H. Bourne, Academic Press, Inc., New York, Chapter 2,61-104.

Paget *s Disease

1. Altman, R.D., Johnston, C. Conrad, Khairi, M.R.A., Wellman, H., Serafini, A.N., and Sankey, R.R. : Influence of Disodium Etidronate on Clinical and Laboratory Manifestations of Paget *s Disease of Bone (Osteitis Deformans), N. Engl.J.Med. 289:1379(1973).

2. Canfield, R., Rosner, W., Skinner, J., McWhorter, I., Resnick, L., Feldman, F., Kammerman, S., Ryan, K., Kunigonis, M., and Bohne, W.: Diphosphonate Therapy of Paget *s Disease of Bone, J. Chin, Endocrinol. Metab. 44(1):96(1977).

3. Guncago, J., Lauffenburger, T., Lentner, C., Dambacher, MA., Haas, G.H., Fleisch, H. and Olah, A.J. Diphosphonate Treatment of Paget *s Disease of Bone: A Correlated Metabolic, Calcium Kinetic and Morphometric Study, Horm. Metab. Res. 6:62(1974).

4. Johnston, C.C., Khairi, M.R.A., and Meunier, P.J. : Use of Etidronate (EHDP) in Paget *s Disease of Bone. Arthritis and Rheumatism, 23:1172-1176(1980).

5. Khairi, M.RA., Altman, R.D., DeRosa, G.P., Zimmerman, J., Schenk, R.K., and Johnston, C.C. : Sodium Etidronate in the Treatment of Paget *s Disease of Bone: A study of Long-Term Results, Ann. Intern. Med. 87(6):656(1977).

6. Russell, R.G.G., Smith, R., Preston, C., Walton, R.J., and Woods, C.G. : Diphosphonates in Paget *s Disease. Lancet. 1:894(1974).

7. Siris, E.S., Canfield, R.E., Jacobs, T.P., and Baquiran, D.C.: Long- Term Therapy of Paget *s Disease of Bone with EHDP, Arthritis and Rheumatism, 23:1177-1184(1980).

8. Stein, I., Shapiro, B., Ostnun, B., and Beller, M.L. : Evaluation of Sodium Etidronate in the Treatment of Paget *s Disease of Bone. Clin. Orthop. Related Res. 122:347(1977).

Hypercalcemia of Malignancy

1. Ringenberg, Q.S., Ritch, P.S. Efficacy of Oral Administration of Etidronate Disodium in Maintaining Normal Serum Calcium Levels in Previously Hypercalcemic Cancer Patients. Clin. Thera. 1987; 9(3) 318-325.

2. Shevrin. D.H., Bressler, L.R., McGuire, W.P., Kukreja, S.C., Kulka, L.J., and Lad, T.E. Treatment of Cancer-Associated Hypercalcemia with Mithramycin and Oral Etidronate Disodium. Clin. Pharm. 1985; 4(2):204-205.