The safety and effectiveness of Reclast for the treatment of osteoporosis is based on clinical data of three years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy reevaluated 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 reevaluated periodically.

Reclast injection must be administered as an intravenous infusion over no less than 15 minutes.

The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.

The recommended regimen is a 5 mg infusion given once every 2 years intravenously over no less than 15 minutes.

The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.

The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.

The recommended dose is a 5 mg infusion. The infusion time must not be less than 15 minutes given over a constant infusion rate.

After a single treatment with Reclast in Paget’s disease an extended remission period is observed. Specific re-treatment data are not available. However, re-treatment with Reclast may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, or in those patients who failed to achieve normalization of their serum alkaline phosphatase, or in those patients with symptoms, as dictated by medical practice.

The Reclast infusion time must not be less than 15 minutes given over a constant infusion rate.

The intravenous infusion should be followed by a 10 mL normal saline flush of the intravenous line.

Reclast solution for infusion must not be allowed to come in contact with any calcium or other divalent cation-containing solutions, and should be administered as a single intravenous solution through a separate vented infusion line.

Reclast contains the same active ingredient found in Zometa, used for oncology indications, and a patient being treated with Zometa should not be treated with Reclast.

Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates, including zoledronic acid. Most cases have been in cancer patients treated with intravenous bisphosphonates undergoing dental procedures. Some cases have occurred in patients with postmenopausal osteoporosis treated with either oral or intravenous bisphosphonates. A routine oral examination should be performed by the prescriber prior to initiation of bisphosphonate treatment. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with a history of concomitant risk factors (e.g., cancer, chemotherapy, angiogenesis inhibitors, radiotherapy, corticosteroids, poor oral hygiene, preexisting dental disease or infection, anemia, coagulopathy). The risk of ONJ may increase with duration of exposure to bisphosphonates. Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ.

Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur 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. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.

Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g., prednisone) at the time of fracture.

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. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.

While not observed in clinical trials with Reclast, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates. Use Reclast with caution in aspirin-sensitive patients.

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 practice.

The safety of Reclast in the treatment of postmenopausal osteoporosis was assessed in Study 1, a large, randomized, double-blind, placebo-controlled, multinational study of 7736 postmenopausal women aged 65 to 89 years with osteoporosis, diagnosed by BMD or the presence of a prevalent vertebral fracture. The duration of the trial was three years with 3862 patients exposed to Reclast and 3852 patients exposed to placebo administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes, for a total of three doses. All women received 1000 to 1500 mg of elemental calcium plus 400 to 1200 international units of vitamin D supplementation per day.

The incidence of all-cause mortality was similar between groups: 3.4% in the Reclast group and 2.9% in the placebo group. The incidence of serious adverse events was 29.2% in the Reclast group and 30.1% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 5.4% and 4.8% for the Reclast and placebo groups, respectively. 

The safety of Reclast in the treatment of osteoporosis patients with a recent (within 90 days) low-trauma hip fracture was assessed in Study 2, a randomized, double-blind, placebo-controlled, multinational endpoint-driven study of 2127 men and women aged 50 to 95 years; 1065 patients were randomized to Reclast and 1062 patients were randomized to placebo. Reclast was administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. The study continued until at least 211 patients had a confirmed clinical fracture in the study population who were followed for an average of approximately 2 years on study drug. Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 international units orally or IM) was given to patients and they were started on 1000 to 1500 mg of elemental calcium plus 800 to 1200 international units of vitamin D supplementation per day for at least 14 days prior to the study drug infusions.

The incidence of all-cause mortality was 9.6% in the Reclast group and 13.3% in the placebo group. The incidence of serious adverse events was 38.3% in the Reclast group and 41.3% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 5.3% and 4.7% for the Reclast and placebo groups, respectively.

Adverse reactions reported in at least 2% of patients with osteoporosis and more frequently in the Reclast-treated patients than placebo-treated patients in either osteoporosis trial are shown below in Table 1.

The signs and symptoms of acute phase reaction occurred in Study 1 following Reclast infusion, including fever (18%), myalgia (9%), flu-like symptoms (8%), headache (7%), and arthralgia (7%). The majority of these symptoms occurred within the first 3 days following the dose of Reclast and usually resolved within 3 days of onset but resolution could take up to 7-14 days. In Study 2, patients without a contraindication to acetaminophen were provided with a standard oral dose at the time of the IV infusion and instructed to use additional acetaminophen at home for the next 72 hours as needed. Reclast was associated with fewer signs and symptoms of a transient acute phase reaction in this trial: fever (7%) and arthralgia (3%). The incidence of these symptoms decreased with subsequent doses of Reclast.

In Study 1, in women with postmenopausal osteoporosis, approximately 0.2% of patients had notable declines of serum calcium levels (less than 7.5 mg/dL) following Reclast administration. No symptomatic cases of hypocalcemia were observed. In Study 2, following pre-treatment with vitamin D, no patients had treatment emergent serum calcium levels below 7.5 mg/dL.

In the osteoporosis trials, local reactions at the infusion site, such as itching, redness and/or pain have been reported in 0% to 0.7% of patients following the administration of Reclast and 0% to 0.5% of patients following administration of placebo.

In the postmenopausal osteoporosis trial, Study 1, adjudicated serious adverse events of atrial fibrillation in the zoledronic acid treatment group occurred in 1.3% of patients (50 out of 3862) compared to 0.4% (17 out of 3852) in the placebo group. The overall incidence of all atrial fibrillation adverse events in the zoledronic acid treatment group was reported in 2.5% of patients (96 out of 3862) in the Reclast group vs. 1.9% of patients (75 out of 3852) in the placebo group. Over 90% of these events in both treatment groups occurred more than a month after the infusion. In an ECG sub-study, ECG measurements were performed on a subset of 559 patients before and 9 to 11 days after treatment. There was no difference in the incidence of atrial fibrillation between treatment groups suggesting these events were not related to the acute infusions. In Study 2, adjudicated serious adverse events of atrial fibrillation in the zoledronic acid treatment group occurred in 1.0% of patients (11 out of 1054) compared to 1.2% (13 out of 1057) in the placebo group demonstrating no difference between treatment groups.

Cases of iritis/uveitis/episcleritis/conjunctivitis have been reported in patients treated with bisphosphonates, including zoledronic acid. In the osteoporosis trials, 1 (less than 0.1%) to 9 (0.2%) patients treated with Reclast and 0 (0%) to 1 (less than 0.1%) patient treated with placebo developed iritis/uveitis/episcleritis.

The safety of Reclast in postmenopausal women with osteopenia (low bone mass) was assessed in a 2-year randomized, multi-center, double-blind, placebo-controlled study of 581 postmenopausal women aged greater than or equal to 45 years. Patients were randomized to one of three treatment groups: (1) Reclast given at randomization and Month 12 (n=198); (2) Reclast given at randomization and placebo at Month 12 (n=181); and (3) placebo given at randomization and Month 12 (n=202). Reclast was administered as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. All women received 500 to 1200 mg elemental calcium plus 400 to 800 international units vitamin D supplementation per day.

The incidence of serious adverse events was similar for subjects given (1) Reclast at randomization and at Month 12 (10.6%), (2) Reclast at randomization and placebo given at Month 12 (9.4%), and (3) placebo at randomization and at Month 12 (11.4%). The percentages of patients who withdrew from the study due to adverse events were 7.1%, 7.2%, and 3.0% in the two Reclast groups and placebo group, respectively. Adverse reactions reported in at least 2% of patients with osteopenia and more frequently in the Reclast-treated patients than placebo-treated patients are shown in Table 2.

Cases of iritis/uveitis/episcleritis/conjunctivitis have been reported in patients treated with bisphosphonates, including zoledronic acid. In the osteoporosis prevention trial, 4 (1.1%) patients treated with Reclast and 0 (0%) patients treated with placebo developed iritis/uveitis.

In patients given Reclast at randomization and placebo at Month 12, Reclast was associated with signs and symptoms of an acute phase reaction: myalgia (20.4%), fever (19.3%), chills (18.2%), pain (13.8%), headache (13.3%), fatigue (8.3%), arthralgia (6.1%), pain in extremity (3.9%), influenza-like illness (3.3%), and back pain (1.7%), which occurred within the first 3 days following the dose of Reclast. The majority of these symptoms were mild to moderate and resolved within 3 days of the event onset but resolution could take up to 7-14 days.

The safety of Reclast in men with osteoporosis or osteoporosis secondary to hypogonadism was assessed in a two year randomized, multicenter, double-blind, active controlled group study of 302 men aged 25 to 86 years. One hundred fifty three (153) patients were exposed to Reclast administered once annually with a 5 mg dose in 100 mL infused over 15 minutes for up to a total of two doses, and 148 patients were exposed to a commercially-available oral weekly bisphosphonate (active control) for up to two years. All participants received 1000 mg of elemental calcium plus 800 to 1000 international units of vitamin D supplementation per day.

The incidence of all-cause mortality (one in each group) and serious adverse events were similar between the Reclast and active control treatment groups. The percentage of patients experiencing at least one adverse event was comparable between the Reclast and active control groups, with the exception of a higher incidence of post-dose symptoms in the Reclast group that occurred within 3 days after infusion. The overall safety and tolerability of Reclast was similar to the active control.

Adverse reactions reported in at least 2% of men with osteoporosis and more frequently in the Reclast-treated patients than the active control-treated patients and either (1) not reported in the postmenopausal osteoporosis treatment trial or (2) reported more frequently in the trial of osteoporosis in men are presented in Table 3. Therefore, Table 3 should be viewed in conjunction with Table 1.

Reclast was associated with signs and symptoms of an acute phase reaction: myalgia (17.1%), fever (15.7%), fatigue (12.4%), arthralgia (11.1%), pain (10.5%), chills (9.8%), headache (9.8%), influenza-like illness (8.5%), malaise (5.2%), and back pain (3.3%), which occurred within the first 3 days following the dose of Reclast. The majority of these symptoms were mild to moderate and resolved within 3 days of the event onset but resolution could take up to 7-14 days. The incidence of these symptoms decreased with subsequent doses of Reclast.

The incidence of all atrial fibrillation adverse events in the Reclast treatment group was 3.3% (5 out of 153) compared to 2.0% (3 out of 148) in the active control group. However, there were no patients with adjudicated serious adverse events of atrial fibrillation in the Reclast treatment group.

There were no patients who had treatment emergent serum calcium levels below 7.5 mg/dL.

There were 4 patients (2.6%) on Reclast vs. 2 patients (1.4%) on active control with local-site reactions.

The safety of Reclast in men and women in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in a randomized, multicenter, double-blind, active controlled, stratified study of 833 men, and women aged 18 to 85 years treated with greater than or equal to 7.5 mg/day oral prednisone (or equivalent). Patients were stratified according to the duration of their pre-study corticosteroid therapy: less than or equal to 3 months prior to randomization (prevention subpopulation), and greater than 3 months prior to randomization (treatment subpopulation).

The duration of the trial was one year with 416 patients exposed to Reclast administered once as a single 5 mg dose in 100 mL infused over 15 minutes, and 417 patients exposed to a commercially-available oral daily bisphosphonate (active control) for one year. All participants received 1000 mg of elemental calcium plus 400 to 1000 international units of vitamin D supplementation per day.

The incidence of all-cause mortality was similar between treatment groups: 0.9% in the Reclast group and 0.7% in the active control group. The incidence of serious adverse events was similar between the Reclast treatment and prevention groups, 18.4% and 18.1%, respectively, and the active control treatment and prevention groups, 19.8% and 16.0%, respectively. The percentage of subjects who withdrew from the study due to adverse events was 2.2% in the Reclast group vs. 1.4% in the active control group. The overall safety and tolerability were similar between Reclast and active control groups with the exception of a higher incidence of post-dose symptoms in the Reclast group that occurred within 3 days after infusion. The overall safety and tolerability profile of Reclast in glucocorticoid-induced osteoporosis was similar to the adverse events reported in the Reclast postmenopausal osteoporosis clinical trial.

Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis treatment trial or reported more frequently in the treatment and prevention of glucocorticoid-induced osteoporosis trial included the following: abdominal pain (Reclast 7.5%; active control 5.0%), and musculoskeletal pain (Reclast 3.1%; active control 1.7%). Other musculoskeletal events included back pain (Reclast 4.3%, active control 6.2%), bone pain (Reclast 3.1%, active control 2.2%), and pain in the extremity (Reclast 3.1%, active control 1.2%). In addition, the following adverse events occurred more frequently than in the postmenopausal osteoporosis trial: nausea (Reclast 9.6%; active control 8.4%), and dyspepsia (Reclast 5.5%; active control 4.3%).

Reclast was associated with signs and symptoms of a transient acute phase reaction that was similar to that seen in the Reclast postmenopausal osteoporosis clinical trial.

The incidence of atrial fibrillation adverse events was 0.7% (3 of 416) in the Reclast group compared to no adverse events in the active control group. All subjects had a prior history of atrial fibrillation and no cases were adjudicated as serious adverse events. One patient had atrial flutter in the active control group.

There were no patients who had treatment emergent serum calcium levels below 7.5 mg/dL.

There were no local reactions at the infusion site.

In the Paget’s disease trials, two 6-month, double-blind, comparative, multinational studies of 349 men, and women aged greater than 30 years with moderate to severe disease and with confirmed Paget’s disease of bone, 177 patients were exposed to Reclast and 172 patients exposed to risedronate. Reclast was administered once as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. Risedronate was given as an oral daily dose of 30 mg for 2 months.

The incidence of serious adverse events was 5.1% in the Reclast group and 6.4% in the risedronate group. The percentage of patients who withdrew from the study due to adverse events was 1.7% and 1.2% for the Reclast and risedronate groups, respectively.

Adverse reactions occurring in at least 2% of the Paget’s patients receiving Reclast (single 5 mg intravenous infusion) or risedronate (30 mg oral daily dose for 2 months) over a 6-month study period are listed by system organ class in Table 4.

In the Paget’s disease trials, early, transient decreases in serum calcium and phosphate levels were observed. Approximately 21% of patients had serum calcium levels less than 8.4 mg/dL 9-11 days following Reclast administration.

The signs and symptoms of acute phase reaction (influenza-like illness, pyrexia, myalgia, arthralgia, and bone pain) were reported in 25% of patients in the Reclast-treated group compared to 8% in the risedronate-treated group. Symptoms usually occur within the first 3 days following Reclast administration. The majority of these symptoms resolved within 4 days of onset.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified during post approval use of Reclast:

Fever, headache, flu-like symptoms, nausea, vomiting, diarrhea, arthralgia, and myalgia. Symptoms may be significant and lead to dehydration.

Acute renal failure requiring hospitalization and/or dialysis or with a fatal outcome have been rarely reported. Increased serum creatinine was reported in patients with 1) underlying renal disease, 2) dehydration secondary to fever, sepsis, gastrointestinal losses, or diuretic therapy, or 3) other risk factors, such as advanced age, or concomitant nephrotoxic drugs in the post-infusion period. Transient rise in serum creatinine can be correctable with intravenous fluids.

Allergic reactions with intravenous zoledronic acid, including anaphylactic reaction/shock, urticaria, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and bronchoconstriction have been reported.

Asthma exacerbations have been reported.

Hypocalcemia has been reported.

Hypophosphatemia has been reported.

Osteonecrosis of the jaw has been reported.

Cases of osteonecrosis of other bones (including femur, hip, knee, ankle, wrist and humerus) have been reported; causality has not been determined in the population treated with Reclast.

Cases of the following events have been reported: conjunctivitis, iritis, iridocyclitis, uveitis, episcleritis, scleritis, and orbital inflammation/edema.

Hypotension in patients with underlying risk factors has been reported.

Caution is advised when bisphosphonates, including zoledronic acid, are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in zoledronic acid clinical trials.

Caution should also be exercised when Reclast is used in combination with loop diuretics due to an increased risk of hypocalcemia.

Caution is indicated when Reclast is used with other potentially nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs).

Available data on the use of Reclast in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue Reclast when pregnancy is recognized.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use. Consequently, based on the mechanism of action of bisphosphonates, there is a potential risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables, such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

In pregnant rats given daily subcutaneous doses of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg during organogenesis, fetal skeletal, visceral, and external malformations, increases in pre-and post-implantation loss, and decreases in viable fetuses and fetal weight were observed at 0.2 and 0.4 mg/kg/day (equivalent to 2 and 4 times the human 5 mg intravenous dose, based on AUC). Adverse fetal skeletal effects at 0.4 mg/kg/day (4 times the human 5 mg dose) included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects at this dose included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were observed in all groups starting at 0.1 mg/kg/day (1.2 times the human 5 mg dose). Signs of maternal toxicity, including reduced body weight and food consumption were observed at 0.4 mg/kg/day (4 times the human 5 mg dose).

In female rats given daily subcutaneous doses of 0.01, 0.03, or 0.1 mg/kg, beginning 15 days before mating and continuing through gestation, parturition and lactation, dystocia and periparturient mortality were observed in pregnant rats allowed to deliver starting at 0.01 mg/kg/day (0.1 times the human 5 mg intravenous dose, based on AUC). Also, there was an increase in stillbirths and a decrease in neonate survival starting at 0.03 mg/kg/day (0.3 times the human 5 mg dose), while the number of viable newborns and pup body weight on postnatal Day 7 were decreased at 0.1 mg/kg/day (equivalent to the human 5 mg dose). Maternal and neonatal deaths were considered related to drug-induced periparturient hypocalcemia.

There are no data on the presence of zoledronic acid in human milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Reclast and any potential adverse effects on the breast-fed child from Reclast, or from the underlying maternal condition.

Reclast is not indicated for use in children.

The combined osteoporosis trials included 4863 Reclast-treated patients who were at least 65 years of age, while 2101 patients were at least 75 years old. No overall differences in efficacy or safety were observed between patients under 75 years of age with those at least 75 years of age, except that the acute phase reactions occurred less frequently in the older patients.

Of the patients receiving Reclast in the osteoporosis study in men, glucocorticoid-induced osteoporosis, and Paget’s disease studies, 83, 116, and 132 patients, respectively were 65 years of age or over, while 24, 29, and 68 patients, respectively were at least 75 years of age.

However, because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.

Reclast is not metabolized in the liver. No clinical data are available for use of Reclast in patients with hepatic impairment.

Reclast is a bisphosphonate and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption.

The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone. Intravenously administered zoledronic acid rapidly partitions to bone and localizes preferentially at sites of high bone turnover. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The relatively long duration of action of zoledronic acid is attributable to its high binding affinity to bone mineral.

In the osteoporosis treatment trial, the effect of Reclast treatment on markers of bone resorption (serum beta-C-telopeptides [b-CTx]) and bone formation (bone specific alkaline phosphatase [BSAP], serum N-terminal propeptide of type I collagen [P1NP]) was evaluated in patients (subsets ranging from 517 to 1246 patients) at periodic intervals. Treatment with a 5 mg annual dose of Reclast reduces bone turnover markers to the pre-menopausal range with an approximate 55% reduction in b-CTx, a 29% reduction in BSAP and a 52% reduction in P1NP over 36 months. There was no progressive reduction of bone turnover markers with repeated annual dosing.

Pharmacokinetic data in patients with osteoporosis and Paget's disease of bone are not available.

Zoledronic acid clearance was independent of dose but dependent upon the patient’s creatinine clearance. In a study in patients with cancer and bone metastases, increasing the infusion time of a 4 mg dose of zoledronic acid from 5 minutes (n=5) to 15 minutes (n=7) resulted in a 34% decrease in the zoledronic acid concentration at the end of the infusion ([mean ± SD] 403 ± 118 ng/mL vs. 264 ± 86 ng/mL) and a 10% increase in the total AUC (378 ± 116 ng x h/mL vs. 420 ± 218 ng x h/mL). The difference between the AUC means was not statistically significant.

Women enrolled in Stratum I (n=5661) were evaluated annually for incidence of vertebral fractures. All women (Strata I and II) were evaluated for the incidence of hip and other clinical fractures. Reclast was administered once a year for three consecutive years, as a single 5 mg dose in 100 mL solution infused over at least 15 minutes, for a total of three doses. All women received 1000 to 1500 mg of elemental calcium plus 400 to 1200 international units of vitamin D supplementation per day.

The two primary efficacy variables were the incidence of morphometric vertebral fractures at 3 years and the incidence of hip fractures over a median duration of 3 years. The diagnosis of an incident vertebral fracture was based on both qualitative diagnosis by the radiologist and quantitative morphometric criterion. The morphometric criterion required the dual occurrence of 2 events: a relative height ratio or relative height reduction in a vertebral body of at least 20%, together with at least a 4 mm absolute decrease in height.

Reclast significantly decreased the incidence of new vertebral fractures at one, two, and three years as shown in Table 5.

The reductions in vertebral fractures over three years were consistent (including new/worsening and multiple vertebral fractures) and significantly greater than placebo regardless of age, geographical region, baseline body mass index, number of baseline vertebral fractures, femoral neck BMD T-score, or prior bisphosphonate usage.

Reclast demonstrated a 1.1% absolute reduction and 41% relative reduction in the risk of hip fractures over a median duration of follow-up of 3 years. The hip fracture event rate was 1.4% for Reclast-treated patients compared to 2.5% for placebo-treated patients.

The reductions in hip fractures over three years were greater for Reclast than placebo regardless of femoral neck BMD T-score.

Reclast demonstrated superiority to placebo in reducing the incidence of all clinical fractures, clinical (symptomatic) vertebral and non-vertebral fractures (excluding finger, toe, facial, and clinical thoracic and lumbar vertebral fractures). All clinical fractures were verified based on the radiographic and/or clinical evidence. A summary of results is presented in Table 6.

Reclast significantly increased BMD at the lumbar spine, total hip and femoral neck, relative to treatment with placebo at time points 12, 24, and 36 months. Treatment with Reclast resulted in a 6.7% increase in BMD at the lumbar spine, 6.0% at the total hip, and 5.1% at the femoral neck, over 3 years as compared to placebo.

Bone biopsy specimens were obtained between Months 33 and 36 from 82 postmenopausal patients with osteoporosis treated with 3 annual doses of Reclast. Of the biopsies obtained, 81 were adequate for qualitative histomorphometry assessment, 59 were adequate for partial quantitative histomorphometry assessment, and 38 were adequate for full quantitative histomorphometry assessment. Micro CT analysis was performed on 76 specimens. Qualitative, quantitative and micro CT assessments showed bone of normal architecture and quality without mineralization defects.

In the 3-year osteoporosis study, standing height was measured annually using a stadiometer. The Reclast group revealed less height loss compared to placebo (4.2 mm vs. 7.0 mm, respectively [p < 0.001]).

Reclast significantly reduced the incidence of any clinical fracture by 35%. There was also a 46% reduction in the risk of a clinical vertebral fracture (Table 7).

Reclast significantly increased BMD relative to placebo at the hip and femoral neck at all timepoints (12, 24, and 36 months). Treatment with Reclast resulted in a 6.4% increase in BMD at the total hip and a 4.3% increase at the femoral neck over 36 months as compared to placebo.

The efficacy and safety of Reclast in postmenopausal women with osteopenia (low bone mass) was assessed in a 2-year randomized, multi-center, double-blind, placebo-controlled study of 581 postmenopausal women aged greater than or equal to 45 years, who were stratified by years since menopause: Stratum I women less than 5 years from menopause (n=224); Stratum II women greater than or equal to 5 years from menopause (n=357). Patients within Stratum I and II were randomized to one of three treatment groups: (1) Reclast given at randomization and at Month 12 (n=77) in Stratum I and (n=121) in Stratum II; (2) Reclast given at randomization and placebo at Month 12 (n=70) in Stratum I and (n=111) in Stratum II; and (3) Placebo given at randomization and Month 12 (n=202). Reclast was administered as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. All women received 500 to 1200 mg elemental calcium plus 400 to 800 international units vitamin D supplementation per day. The primary efficacy variable was the percent change of BMD at 24 Months relative to baseline.

Reclast significantly increased lumbar spine BMD relative to placebo at Month 24 across both strata. Reclast given once at randomization (and placebo given at Month 12) resulted in 4.0% increase in BMD in Stratum I patients and 4.8% increase in Stratum II patients over 24 months. Placebo given at randomization and at Month 12 resulted in 2.2% decrease in BMD in Stratum I patients and 0.7% decrease in BMD in Stratum II patients over 24 months. Therefore, Reclast given once at randomization (and placebo given at Month 12) resulted in a 6.3% increase in BMD in Stratum I patients and 5.4% increase in Stratum II patients over 24 months as compared to placebo (both p < 0.0001).

Reclast also significantly increased total hip BMD relative to placebo at Month 24 across both strata. Reclast given once at randomization (and placebo given at Month 12) resulted in 2.6% increase in BMD in Stratum I patients and 2.1% in Stratum II patients over 24 months. Placebo given at randomization and at Month 12 resulted in 2.1% decrease in BMD in Stratum I patients and 1.0% decrease in BMD in Stratum II patients over 24 months. Therefore, Reclast given once at randomization (and placebo given at Month 12) resulted in a 4.7% increase in BMD in Stratum I patients and 3.2% increase in Stratum II patients over 24 months as compared to placebo (both p < 0.0001).

The efficacy and safety of Reclast in men with osteoporosis or significant osteoporosis secondary to hypogonadism, was assessed in a randomized, multicenter, double-blind, active controlled, study of 302 men aged 25 to 86 years (mean age of 64). The duration of the trial was two years. Patients were randomized to either Reclast, which was administered once annually as a 5 mg dose in 100 mL infused over 15 minutes for a total of up to two doses, or to an oral weekly bisphosphonate (active control) for up to two years. All participants received 1000 mg of elemental calcium plus 800 to 1000 international units of vitamin D supplementation per day.

An annual infusion of Reclast was non-inferior to the oral weekly bisphosphonate active control based on the percentage change in lumbar spine BMD at Month 24 relative to baseline (Reclast: 6.1% increase; active control: 6.2% increase).

The efficacy and safety of Reclast to prevent and treat glucocorticoid-induced osteoporosis (GIO) was assessed in a randomized, multicenter, double-blind, stratified, active controlled study of 833 men and women aged 18 to 85 years (mean age of 54.4 years) treated with greater than or equal to 7.5 mg/day oral prednisone (or equivalent). Patients were stratified according to the duration of their pre-study corticosteroid therapy: less than or equal to 3 months prior to randomization (prevention subpopulation), and greater than 3 months prior to randomization (treatment subpopulation). The duration of the trial was one year. Patients were randomized to either Reclast, which was administered once as a 5 mg dose in 100 mL infused over 15 minutes, or to an oral daily bisphosphonate (active control) for one year. All participants received 1000 mg of elemental calcium plus 400 to 1000 international units of vitamin D supplementation per day.

In the GIO treatment subpopulation, Reclast demonstrated a significant mean increase in lumbar spine BMD compared to the active control at one year (Reclast 4.1%, active control 2.7%) with a treatment difference of 1.4% (p < 0.001). In the GIO prevention subpopulation, Reclast demonstrated a significant mean increase in lumbar spine BMD compared to active control at one year (Reclast 2.6%, active control 0.6%) with a treatment difference of 2.0% (p < 0.001).

Bone biopsy specimens were obtained from 23 patients (12 in the Reclast treatment group and 11 in the active control treatment group) at Month 12 treated with an annual dose of Reclast or daily oral active control. Qualitative assessments showed bone of normal architecture and quality without mineralization defects. Apparent reductions in activation frequency and remodeling rates were seen when compared with the histomorphometry results seen with Reclast in the postmenopausal osteoporosis population. The long-term consequences of this degree of suppression of bone remodeling in glucocorticoid-treated patients is unknown.

Reclast was studied in male and female patients with moderate to severe Paget’s disease of bone, defined as serum alkaline phosphatase level at least twice the upper limit of the age-specific normal reference range at the time of study entry. Diagnosis was confirmed by radiographic evidence.

The efficacy of one infusion of 5 mg Reclast vs. oral daily doses of 30 mg risedronate for 2 months was demonstrated in two identically designed 6-month randomized, double-blind trials. The mean age of patients in the two trials was 70. Ninety-three percent (93%) of patients were Caucasian. Therapeutic response was defined as either normalization of serum alkaline phosphatase (SAP) or a reduction of at least 75% from baseline in total SAP excess at the end of 6 months. SAP excess was defined as the difference between the measured level and midpoint of normal range.

In both trials, Reclast demonstrated a superior and more rapid therapeutic response compared with risedronate and returned more patients to normal levels of bone turnover, as evidenced by biochemical markers of formation (SAP, serum N-terminal propeptide of type I collagen [P1NP]) and resorption (serum CTx 1 [cross-linked C-telopeptides of type I collagen] and urine α-CTx).

The 6-month combined data from both trials showed that 96% (169/176) of Reclast-treated patients achieved a therapeutic response as compared with 74% (127/171) of patients treated with risedronate. Most Reclast patients achieved a therapeutic response by the Day 63 visit. In addition, at 6 months, 89% (156/176) of Reclast-treated patients achieved normalization of SAP levels, compared to 58% (99/171) of patients treated with risedronate (p < 0.0001) (see Figure 2).

The therapeutic response to Reclast was similar across demographic and disease-severity groups defined by gender, age, previous bisphosphonate use, and disease severity. At 6 months, the percentage of Reclast-treated patients who achieved therapeutic response was 97% and 95%, respectively, in each of the baseline disease severity subgroups (baseline SAP less than 3xULN, greater than or equal to 3xULN) compared to 75% and 74%, respectively, for the same disease severity subgroups of risedronate-treated patients.

In patients who had previously received treatment with oral bisphosphonates, therapeutic response rates were 96% and 55% for Reclast and risedronate, respectively. The comparatively low risedronate response was due to the low response rate (7/23, 30%) in patients previously treated with risedronate. In patients naïve to previous treatment, a greater therapeutic response was also observed with Reclast (98%) relative to risedronate (86%). In patients with symptomatic pain at screening, therapeutic response rates were 94% and 70% for Reclast and risedronate, respectively. For patients without pain at screening, therapeutic response rates were 100% and 82% for Reclast and risedronate, respectively.

Bone histology was evaluated in 7 patients with Paget’s disease 6 months after being treated with Reclast 5 mg. Bone biopsy results showed bone of normal quality with no evidence of impaired bone remodeling and no evidence of mineralization defect.