Alendronate (Fosamax)
This was the first US FDA bisphosphonate drug approved for the prevention and treatment of osteoporosis. It has revolutionized the management of this disease and has been a boon to people with this disease and to those at high risk for getting it, like those on glucocorticoids (cortisone). In randomized clinical trials, it was shown to significantly reduce the risk of spine, hip, and wrist fracture. Alendronate’s only statistically significant side effect is gastritis.

Indications and Usage for Fosamax from the Label
Treatment of Osteoporosis in Postmenopausal Women
Fosamax® is indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women, Fosamax increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures).

Prevention of Osteoporosis in Postmenopausal Women
Fosamax is indicated for the prevention of postmenopausal osteoporosis

Treatment to Increase Bone Mass in Men with Osteoporosis
Fosamax is indicated for treatment to increase bone mass in men with osteoporosis

Treatment of Glucocorticoid-Induced Osteoporosis
Fosamax is 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.

Treatment of Paget’s Disease of Bone
Fosamax is 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.

Treatment of Osteoporosis in Postmenopausal Women
Fosamax was studied in the early 1990s in 4 separate trials that enrolled 7452 postmenopausal women some with and some without osteoporosis. They ranged in age from 44 to 84 years. The studies lasted for 3 to 4 years, were structured similarly so the results could be combined and analyzed as one. All the patients took calcium and vitamin D.

The results of a US study (Lieberman) that enrolled 478 women lasting 3 years and a Multinational study that enrolled 516 women and lasted 3 years were combined. In those 994 patients, the Fosamax treated group had a 48% relative risk reduction in new vertebral fractures.

Only 1 in 3 of the subjects with new fractures confirmed on X-ray had any pain. This was an important observation because it was the first time we became aware that most spine fractures experienced in women with osteoporosis were silent occurring without symptoms.

The 3-year FIT I study had 2027 postmenopausal women with a T-score < -2.5 in the spine or hip and at least 1 pre-existing vertebral fracture. These characteristics defined them as high fracture risk patients. All subjects received calcium and vitamin D.

The FIT I placebo subjects had a hip fracture rate of 22 per 1,000 vs. 11 per 1,000 in the Fosamax group for a statistically significant 51% relative risk reduction meaning that 91 women like those in the study would need to be treated for 3 years with Fosamax to prevent one fracture.

The wrist fracture rate in the FIT I study in the placebo group was 41 per 1,000 vs. 22 per 1,000 for a statistically significant 48% relative risk reduction and an absolute risk reduction of 1.9%. To prevent 1 fracture in women like those in the study requires treatment of 53 women for 3 years.

The only study Fosamax demonstrated hip fracture prevention in FIT I the result was just barely statistically significant with the P value being P = 0.05. The meager 1.1% absolute risk reduction highlights the importance of assessing all the statistical evidence available before making deciding whether or not to use a drug. A 51% relative risk reduction for hip fracture sounds great but in absolute terms a 1.1% reduction in the rate of hip fractures with Fosamax treatment that is not nearly as compelling.

The FIT II study cohort enrolled 3066 osteoporotic and osteopenic postmenopausal women in a 4-year trial. All subjects had a T-score of at least < -2.0 at the beginning of the trial. One third were osteopenic and two thirds were osteoporotic. All patients received calcium and vitamin D.

The FIT I placebo subjects had a hip fracture rate of 22 per 1,000 vs. 11 per 1,000 in the Fosamax group for a statistically significant 51% relative risk reduction meaning that 91 women like those in the study would need to be treated for 3 years with Fosamax to prevent one fracture.

The wrist fracture rate in the FIT I study in the placebo group was 41 per 1,000 vs. 22 per 1,000 for a statistically significant 48% relative risk reduction and an absolute risk reduction of 1.9%. To prevent 1 fracture in women like those in the study requires treatment of 53 women for 3 years,

The only study Fosamax demonstrated hip fracture prevention in FIT I the result was just barely statistically significant with the P value being P = 0.05. The meager 1.1% absolute risk reduction highlights the importance of assessing all the statistical evidence available before making deciding whether or not to use a drug. A 51% relative risk reduction for hip fracture sounds great but in absolute terms a 1.1% reduction in the rate of hip fractures with Fosamax treatment that is not nearly as compelling.

The FIT II study cohort enrolled 3066 osteoporotic and osteopenic postmenopausal women in a 4-year trial. All subjects had a T-score of at least < -2.0 at the beginning of the trial. One third were osteopenic and two thirds were osteoporotic. All patients received calcium and vitamin D.

After 4 years of therapy, the fracture rate for new vertebral fractures in the placebo group was 48 per 1,000 vs. 25 per 1,000 in the Fosamax subjects for a statistically significant relative risk reduction of 48%. The absolute risk reduction was 2.3%. This means 43 women like those in the study need to be treated for 4 years to prevent one new vertebral fracture.

Hip and wrist fractures were not reduced significantly in the FIT II study.

Fosamax Label

Fosamax for Prevention of Osteoporosis
In 1997, the US FDA registered Fosamax for prevention of osteoporosis based upon bone density studies that showed it increased bone density. Merck obtained the indication for prevention of osteoporosis by simply showing that Fosamax increased DXA bone density significantly more that placebo. In 2008, the agency decided to stop approving drugs for prevention of osteoporosis

Treatment to Increase Bone Mass in Men with Osteoporosis
The efficacy of Fosamax in men with hypogonadal or idiopathic osteoporosis was demonstrated in two clinical studies. To receive this indication, Fosamax had to show it increased bone density statistically significantly in men, which it did. There was no requirement for fracture rate reduction because that had been shown conclusively in women. At two years, the mean increases relative to placebo in BMD in men receiving Fosamax 10 mg/day were significant at the following sites: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%.

Treatment of Glucocorticoid-Induced Osteoporosis
The efficacy of Fosamax in men and women receiving glucocorticoids 7.5 mg/day of prednisone or equivalent was demonstrated in two one-year studies that included 560 patients. All patients received calcium and vitamin D. After one year, significant increases relative to placebo in BMD were seen in the combined studies at each of the sites tested in the Fosamax treated patients. The US FDA only required Fosamax show that it significantly increased DXA bone density. It did not need to show fracture rate reduction in the treatment group.

Studies in Glucocorticoid-Induced Osteoporosis

Warning, Limitations, Contraindications, Cautions and Side Effects with Fosamax

Important Limitations of Use from the Fosamax Label
The optimal duration of use has not been determined. The safety and effectiveness of Fosamax 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.

Contraindications from the Fosamax Label
Fosamax is contraindicated in patients with the following conditions:

  • Abnormalities of the esophagus, which delay esophageal emptying such as stricture or achalasia.
  • Inability to stand or sit upright for at least 30 minutes.
  • Do not administer Fosamax oral solution to patients at increased risk of aspiration.
    Hypocalcemia
  • Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and angioedema have been reported

Musculoskeletal Pain from the Fosamax Label
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. This category of drugs includes Fosamax (alendronate). 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 Fosamax, the percentages of patients with these symptoms were similar in the Fosamax and placebo groups.

Warnings
Upper Gastrointestinal Adverse Reactions

  • Actonel, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Actonel should be avoided in 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.

Everybody knows Fosamax causes an upset stomach or a worsening of GERD right? In the research studies with about 7,000+ patients, they saw no significant GI side effects with Fosamax. My experience with the drug is that about 10% of people who use it have gastritis or GERD from it. Taking omiprazole (Prilosec) 20 mg the night before the patient takes Fosamax has helped my patients with this side effect.

Glucocorticoid-Induced Osteoporosis from the Fosamax Label
The risk versus benefit of Fosamax for treatment at daily dosages of glucocorticoids less than 7.5 mg of prednisone or equivalent has not been established. Before initiating treatment, the gonadal hormonal status of both men and women should be ascertained and appropriate replacement considered. A DXA measurement should be made at the initiation of therapy and repeated after 6 to 12 months of combined Fosamax and glucocorticoid treatment.

Mineral Metabolism from the Fosamax Label
Hypocalcemia must be corrected before initiating therapy with Fosamax. 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 Fosamax. Presumably due to the effects of Fosamax 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.

Osteonecrosis of the Jaw from the Fosamax Label
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 Fosamax.

Alendronate causes osteonecrosis of the jaw in >1:1000 people who use it. The longer it is taken the higher the likelihood. This side effect is rare in osteoporosis patients. I have only seen it one time and the patient has a tiny ulcer in her mouth. It did not need treatment and healed on its own.

Renal Impairment from the Fosamax Label
Fosamax is not recommended for patients with creatinine clearance less than 35 mL/min

I agree with this for all bisphosphonates because they are not metabolized in the body but slowly excreted by the kidney unchanged over many years. The excretion of this class of drugs is therefore entirely dependent on how good your kidney function is. In CKD, the drug builds up. Normal people do not have a problem with this but those with what is now called Class IV Chronic Kidney Disease by my colleagues should not take any bisphosphonate drug.

Atypical Subtrochanteric and Diaphyseal Femoral Fractures from the Fosamax Label
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 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.

Alendronate causes atypical fracture of the femur. How often this serious adverse event occurs with alendronate is not known. A study of people with atypical fractures hospitalized in Scandinavia published in 2016 found that that out of 20,000 cases identify over a 10-year period, most were seen in women treated with alendronate. That study suggests the incidence of atypical fractures in people on alendronate may be  1 per 1,000. That compares with the expert panel opinion of 1 per 20,000. The difference between these two estimates is very important because the expert opinion estimate represents an acceptable risk while the Scandinavian estimate is an unacceptable risk. My clinical experience suggests that alendronate causes more atypical fractures than any other drug and more often, in my opinion than estimated by the expert panel. I still prescribe it but it is not my first choice.