Alendronate

INDICATIONS AND USAGE Alendronate sodium is a bisphosphonate indicated for: • Treatment and prevention of osteoporosis in postmenopausal women ( 1.1 , 1.2 ) • Treatment to increase bone mass in men with osteoporosis ( 1.3 ) • Treatment of glucocorticoid-induced osteoporosis ( 1.4 ) • Treatment of Paget's disease of bone ( 1.5 ) Limitations of use: Optimal duration of use has not been determined. For patients at low- risk for fracture, consider drug discontinuation after 3 to 5 years of use. ( 1.6 ) 1.1 Treatment of Osteoporosis in Postmenopausal Women Alendronate sodium tablets, USP are indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women, alendronate sodium tablets, USP increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures). [See Clinical Studies ( 14.1 ).] 1.2 Prevention of Osteoporosis in Postmenopausal Women Alendronate sodium tablets, USP are indicated for the prevention of postmenopausal osteoporosis [see Clinical Studies ( 14.2 )]. 1.3 Treatment to Increase Bone Mass in Men with Osteoporosis Alendronate sodium tablets, USP are indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies ( 14.3 )]. 1.4 Treatment of Glucocorticoid-Induced Osteoporosis Alendronate sodium tablets, USP are indicated for the treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have low bone mineral density [see Clinical Studies ( 14.4 )]. 1.5 Treatment of Paget's Disease of Bone Alendronate sodium tablets, USP are indicated for the treatment of Paget's disease of bone in men and women. Treatment is indicated in patients with Paget's disease of bone who have alkaline phosphatase at least two times the upper limit of normal, or those who are symptomatic, or those at risk for future complications from their disease. [See Clinical Studies ( 14.5 ).] 1.6 Important Limitations of Use The optimal duration of use has not been determined. The safety and effectiveness of alendronate sodium for the treatment of osteoporosis are based on clinical data of four years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

DOSAGE AND ADMINISTRATION Although alendronate tablets 5 mg, 10 mg, 35 mg, and 40 mg are available in the marketplace, FOSAMAX is no longer marketed in the 5 mg, 10 mg, 35 mg, and 40 mg strengths. Although an oral solution of alendronate may be available in the marketplace, FOSAMAX oral solution is no longer marketed. Treatment of osteoporosis in postmenopausal women and in men: 10 mg daily or 70 mg (tablet or oral solution) once weekly. ( 2.1 , 2.3 ) Prevention of osteoporosis in postmenopausal women: 5 mg daily or 35 mg once weekly. ( 2.2 ) Glucocorticoid-induced osteoporosis: 5 mg daily; or 10 mg daily in postmenopausal women not receiving estrogen. ( 2.4 ) Paget's disease: 40 mg daily for six months. ( 2.5 ) Instruct patients to: ( 2.6 ) Swallow tablets whole with 6-8 ounces plain water at least 30 minutes before the first food, drink, or medication of the day. Swallow oral solution followed by at least 2 ounces of water. Not lie down for at least 30 minutes after taking FOSAMAX and until after food. 2.1 Treatment of Osteoporosis in Postmenopausal Women The recommended dosage is: one 70 mg tablet once weekly or one bottle of 70 mg oral solution once weekly or one 10 mg tablet once daily 2.2 Prevention of Osteoporosis in Postmenopausal Women The recommended dosage is: one 35 mg tablet once weekly or one 5 mg tablet once daily 2.3 Treatment to Increase Bone Mass in Men with Osteoporosis The recommended dosage is: one 70 mg tablet once weekly or one bottle of 70 mg oral solution once weekly or one 10 mg tablet once daily 2.4 Treatment of Glucocorticoid-Induced Osteoporosis The recommended dosage is one 5 mg tablet once daily, except for postmenopausal women not receiving estrogen, for whom the recommended dosage is one 10 mg tablet once daily. 2.5 Treatment of Paget's Disease of Bone The recommended treatment regimen is 40 mg once a day for six months. Re-treatment of Paget's Disease Re-treatment with FOSAMAX may be considered, following a six-month post-treatment evaluation period in patients who have relapsed, based on increases in serum alkaline phosphatase, which should be measured periodically. Re-treatment may also be considered in those who failed to normalize their serum alkaline phosphatase. 2.6 Important Administration Instructions Instruct patients to do the following: Take FOSAMAX at least one-half hour before the first food, beverage, or medication of the day with plain water only [see Patient Counseling Information (17) ]. Other beverages (including mineral water), food, and some medications are likely to reduce the absorption of FOSAMAX [see Drug Interactions (7.1) ]. Waiting less than 30 minutes, or taking FOSAMAX with food, beverages (other than plain water) or other medications will lessen the effect of FOSAMAX by decreasing its absorption into the body. Take FOSAMAX upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, a FOSAMAX tablet should be swallowed with a full glass of water (6-8 ounces). To facilitate gastric emptying FOSAMAX oral solution should be followed by at least 2 ounces (a quarter of a cup) of water. Patients should not lie down for at least 30 minutes and until after their first food of the day. FOSAMAX should not be taken at bedtime or before arising for the day. Failure to follow these instructions may increase the risk of esophageal adverse experiences [see Warnings and Precautions (5.1) and Patient Counseling Information (17) ] . 2.7 Recommendations for Calcium and Vitamin D Supplementation Instruct patients to take supplemental calcium if dietary intake is inadequate [see Warnings and Precautions (5.2) ] . Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home-bound, or chronically ill) may need vitamin D supplementation. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D. 2.8 Administration Instructions for Missed Doses If a once-weekly dose of FOSAMAX is missed, instruct patients to take one dose on the morning after they remember. They should not take two doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day .

WARNINGS AND PRECAUTIONS Upper Gastrointestinal Adverse Reactions can occur. Instruct patients to follow dosing instructions. Discontinue if new or worsening symptoms occur. (5.1) Hypocalcemia can worsen and must be corrected prior to use. (5.2) Severe Bone, Joint, Muscle Pain may occur. Discontinue use if severe symptoms develop. (5.3) Osteonecrosis of the Jaw has been reported. (5.4) Atypical Fractures Including Femoral Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered (5.5) 5.1 Upper Gastrointestinal Adverse Reactions Alendronate sodium, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when alendronate sodium is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or ulcers). Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates including alendronate sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue alendronate sodium and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates including alendronate sodium and/or who fail to swallow oral bisphosphonates including alendronate sodium with the recommended full glass (6 to 8 ounces) of water, and/or who continue to take oral bisphosphonates including alendronate sodium after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient [see Dosage and Administration (2.6) ] . In patients who cannot comply with dosing instructions due to mental disability, therapy with alendronate sodium should be used under appropriate supervision. There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials [see Adverse Reactions (6.2) ] . 5.2 Mineral Metabolism Hypocalcemia must be corrected before initiating therapy with alendronate sodium [see Contraindications (4) ]. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with alendronate sodium. Presumably due to the effects of alendronate sodium on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients with Paget’s disease, in whom the pretreatment rate of bone turnover may be greatly elevated, and in patients receiving glucocorticoids, in whom calcium absorption may be decreased. Ensuring adequate calcium and vitamin D intake is especially important in patients with Paget’s disease of bone and in patients receiving glucocorticoids. 5.3 Musculoskeletal Pain In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the prevention and treatment of osteoporosis [see Adverse Reactions (6.2) ] . This category of drugs includes alendronate sodium. Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. In placebo-controlled clinical studies of alendronate sodium, the percentages of patients with these symptoms were similar in the alendronate sodium and placebo groups. 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including alendronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment. Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment. 5.5 Atypical Fractures Including Femoral Fractures Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported during treatment with bisphosphonates, including alendronate, in patients with osteoporosis. Atypical femur and other fractures most commonly occur with minimal or no trauma to the affected area. These fractures occurred anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical fractures of other bones have also been reported. They may be bilateral. There fractures can also occur in osteoporotic patients who have not been treated with bisphosphonates. Concomitant treatment with glucocorticoid may also induce these fractures. Prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs was reported by patients. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Bony pain in other locations should also be considered for evaluation of atypical fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered. 5.6 Renal Impairment Alendronate sodium is not recommended for patients with creatinine clearance less than 35 mL/min. 5.7 Glucocorticoid-Induced Osteoporosis The risk versus benefit of alendronate for treatment at daily dosages of glucocorticoids less than 7.5 mg of prednisone or equivalent has not been established [see Indications and Usage (1.4) ] . Before initiating treatment, the gonadal hormonal status of both men and women should be ascertained and appropriate replacement considered. A bone mineral density measur

CONTRAINDICATIONS FOSAMAX is contraindicated in patients with the following conditions: Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see Warnings and Precautions (5.1) ] Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration (2.6) ; Warnings and Precautions (5.1) ] Do not administer FOSAMAX oral solution to patients at increased risk of aspiration. Hypocalcemia [see Warnings and Precautions (5.2) ] Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and angioedema have been reported [see Adverse Reactions (6.2) ] . Abnormalities of the esophagus which delay emptying such as stricture or achalasia ( 4 , 5.1 ) Inability to stand/sit upright for at least 30 minutes ( 2.6 , 4 , 5.1 ) Do not administer FOSAMAX oral solution to patients at increased risk of aspiration ( 4 ) Hypocalcemia ( 4 , 5.2 ) Hypersensitivity to any component of this product ( 4 , 6.2 )

DRUG INTERACTIONS Calcium supplements, antacids or oral medications containing multivalent cations interfere with absorption of alendronate. ( 7.1 ) Use caution when co-prescribing aspirin/nonsteroidal anti- inflammatory drugs that may worsen gastrointestinal irritation. ( 7.2 , 7.3 ) 7.1 Calcium Supplements/Antacids Co-administration of BINOSTO and calcium, antacids, or oral medications containing multivalent cations will interfere with absorption of BINOSTO. Therefore, instruct patients to wait at least one-half hour after taking BINOSTO before taking any other oral medications. 7.2 Aspirin In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of alendronate sodium greater than 10 mg and aspirin-containing products. 7.3 Nonsteroidal Anti-inflammatory Drugs (NSAIDs) BINOSTO may be administered to patients taking NSAIDs. In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate sodium 5 or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with BINOSTO. 7.4 Levothyroxine The bioavailability of alendronate was slightly decreased when BINOSTO and levothyroxine were co-administered to healthy subjects [see Clinical Pharmacology (12.3) ] .

ADVERSE REACTIONS The following clinically significant adverse drug reactions are described elsewhere in the labeling: Upper Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1) ] Mineral Metabolism [see Warnings and Precautions (5.2) ] Musculoskeletal Pain [see Warnings and Precautions (5.3) ] Osteonecrosis of the Jaw [see Warnings and Precautions (5.4) ] Atypical Fractures Including Femoral Fractures [see Warnings and Precautions (5.5) ] Renal Impairment [see Warnings and Precautions (5.6) ] Patients sensitive to High Sodium Intake [see Warnings and Precautions (5.7) ] The most common adverse reactions (incidence greater than or equal to 3%) are abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Radius Health, Inc. at 1-855-672-3487 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of BINOSTO (alendronate sodium) effervescent tablet 70 mg is based on clinical trial data of alendronate sodium 10 mg daily and alendronate sodium 70 mg weekly. Treatment of Osteoporosis in Postmenopausal Women Daily Dosing The safety of alendronate sodium 10 mg daily in the treatment of postmenopausal osteoporosis was assessed in four clinical trials that enrolled 7453 women aged 44-84 years. Study 1 and Study 2 were identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational n=994); Study 3 was the three year vertebral fracture cohort of the Fracture Intervention Trial [FIT] (n=2027) and Study 4 was the four-year clinical fracture cohort of FIT (n=4432). Overall, 3620 patients were exposed to placebo and 3432 patients exposed to alendronate. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs were included in these clinical trials. In Study 1 and Study 2 all women received 500 mg elemental calcium as carbonate. In Study 3 and Study 4 all women with dietary calcium intake less than 1000 mg per day received 500 mg calcium and 250 IU Vitamin D per day. Among patients treated with alendronate 10 mg or placebo in Study 1 and Study 2, and all patients in Study 3 and Study 4, the incidence of all-cause mortality was 1.8% in the placebo group and 1.8% in the alendronate group. The incidence of serious adverse events was 30.7% in the placebo group and 30.9% in the alendronate group. The percentage of patients who discontinued the study due to any clinical adverse event was 9.5% in the placebo group and 8.9% in the alendronate group. Adverse reactions from these studies considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either alendronate or placebo are presented in Table 1. Table 1 Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients United States/Multinational Studies Fracture Intervention Trial Alendronate Sodium 10 mg/day for three years Placebo Alendronate Sodium 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years Placebo % (N = 196) % (N = 397) % (N = 3236) % (N = 3223) Gastrointestinal Abdominal pain 6.6 4.8 1.5 1.5 Nausea 3.6 4.0 1.1 1.5 Dyspepsia 3.6 3.5 1.1 1.2 Constipation 3.1 1.8 0.0 0.2 Diarrhea 3.1 1.8 0.6 0.3 Flatulence 2.6 0.5 0.2 0.3 Acid regurgitation 2.0 4.3 1.1 0.9 Esophageal ulcer 1.5 0.0 0.1 0.1 Vomiting 1.0 1.5 0.2 0.3 Dysphagia 1.0 0.0 0.1 0.1 Abdominal distention 1.0 0.8 0.0 0.0 Gastritis 0.5 1.3 0.6 0.7 Musculoskeletal Musculoskeletal (bone, muscle or joint) pain 4.1 2.5 0.4 0.3 Muscle cramp 0.0 1.0 0.2 0.1 Nervous system/psychiatric Headache 2.6 1.5 0.2 0.2 Dizziness 0.0 1.0 0.0 0.1 Special senses Taste perversion 0.5 1.0 0.1 0.0 Rarely, rash and erythema have occurred. Gastrointestinal Adverse Reactions: One patient treated with alendronate sodium (10 mg/day), who had a history of peptic ulcer disease and gastrectomy and who was taking concomitant aspirin developed an anastomotic ulcer with mild hemorrhage, which was considered drug related. Aspirin and alendronate sodium were discontinued and the patient recovered. In the Study 1 and Study 2 populations, 49-54% had a history of gastrointestinal disorders at baseline and 54-89% used nonsteroidal anti-inflammatory drugs or aspirin at some time during the studies [ see Warnings and Precautions (5.1) ]. Laboratory Test Findings: In double-blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum calcium and phosphate were observed in approximately 18% and 10%, respectively, of patients taking alendronate versus approximately 12% and 3% of those taking placebo. However, the incidences of decreases in serum calcium to less than 8.0 mg/dL (2.0 mM) and serum phosphate to less than or equal to 2.0 mg/dL (0.65 mM) were similar in both treatment groups. Weekly Dosing The safety of alendronate sodium 70 mg once weekly for the treatment of postmenopausal osteoporosis was assessed in a one-year, double-blind, multicenter study comparing alendronate 70 mg once weekly and alendronate 10 mg daily. The overall safety and tolerability profiles of once weekly alendronate 70 mg and alendronate 10 mg daily were similar. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients in either treatment group are presented in Table 2. Table 2 Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients Once Weekly Alendronate Sodium 70 mg % (N = 519) Once Daily Alendronate Sodium 10 mg % (N = 370) Gastrointestinal Abdominal pain 3.7 3.0 Dyspepsia 2.7 2.2 Acid regurgitation 1.9 2.4 Nausea 1.9 2.4 Abdominal distention 1.0 1.4 Constipation 0.8 1.6 Flatulence 0.4 1.6 Gastritis 0.2 1.1 Gastric ulcer 0.0 1.1 Musculoskeletal Musculoskeletal (bone, muscle, joint) pain 2.9 3.2 Muscle cramp 0.2 1.1 Osteoporosis in Men In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of alendronate sodium 10 mg/day and a one-year study of once weekly alendronate sodium 70 mg) the rates of discontinuation of therapy due to any clinical adverse event were 2.7% for alendronate 10 mg/day vs. 10.5% for placebo, and 6.4% for once weekly alendronate 70 mg vs. 8.6% for placebo. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 2% of patients treated with either alendronate or placebo are presented in the following table. Table 3 Osteoporosis Studies in Men Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 2% of Patients Two-Year Study One-Year Study Once Daily Alendronate Sodium Once Weekly Alendronate Sodium 10 mg % (N = 146) Placebo % (N = 95) 70 mg % (N = 109) Placebo % (N = 58) Gastrointestinal Acid regurgitation 4.1 3.2 0.0 0.0 Flatulence 4.1 1.1 0.0 0.0 Gastroesophageal reflux disease 0.7 3.2 2.8 0.0 Dyspepsia 3.4 0.0 2.8 1.7 Diarrhea 1.4 1.1 2.8 0.0 Abdominal pain 2.1 1.1 0.9 3.4 Nausea 2.1 0.0 0.0 0.0 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of alendronate sodium or bisphosphonate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably

Mechanism of Action Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [ 3 H] alendronate in bone showed about 10- fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [ 3 H] alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.