Fosamax (Alendronate): What to Expect Week by Week in Your First Month

How alendronate works

Alendronate is an oral bisphosphonate that binds to bone hydroxyapatite and inhibits osteoclast activity, the cells that break bone down, without interfering with osteoclast recruitment or attachment [1]. Bone turnover falls, and bone formation exceeds resorption at remodeling sites, so bone mass rises [1]. Alendronate that has been built into bone matrix is not pharmacologically active; it is released slowly as bone remodels [1].

Week 1: how to take the dose

The Fosamax label's administration instructions are specific. It instructs patients to take alendronate at least one-half hour before the first food, beverage or medication of the day, with plain water only, and to take it upon arising for the day. The label says to swallow the tablet with a full glass of 6 to 8 ounces of water, not to lie down for at least 30 minutes and until after the first food of the day, and not to take it at bedtime or before arising [1].

Other beverages, including mineral water, food and some medications reduce absorption [1]. Taking alendronate with coffee or orange juice reduced bioavailability by about 60%, and absorption was negligible when it was taken with or up to 2 hours after a standardized breakfast [1]. Dosing 0.5 or 1 hour before breakfast reduced bioavailability by about 40% compared with dosing 2 hours before eating, yet alendronate was still effective in trials when taken at least 30 minutes before breakfast, tested in 49 postmenopausal women at a 10 mg dose [1]. Oral bioavailability is about 0.64% in women when taken after an overnight fast and 2 hours before a standardized breakfast [1].

One practical note on products: the label states that Fosamax is no longer marketed in the 5 mg, 10 mg, 35 mg and 40 mg strengths or as an oral solution, although generic versions of those may be available [1].

Side effects to watch for during the first month

The adverse reactions the label lists as most common, at 3% or more, are abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain and nausea [1]. In the two three-year US and multinational studies, drug-related reactions in the alendronate 10 mg daily group (196 patients) versus placebo (397 patients) were abdominal pain 6.6% versus 4.8%, nausea 3.6% versus 4.0%, dyspepsia 3.6% versus 3.5%, and esophageal ulcer 1.5% versus 0% [1]. In the four-year Fracture Intervention Trial cohort (3,236 on alendronate, 3,223 on placebo) the rates were similar to placebo: abdominal pain 1.5% versus 1.5% [1].

In a one-year trial, 70 mg once weekly (519 patients) and 10 mg daily (370 patients) had similar overall safety and tolerability [1].

What the label says to stop and report

The label instructs patients to discontinue alendronate and seek medical attention if they develop trouble swallowing, pain on swallowing, retrosternal pain, or new or worsening heartburn [1]. It also advises caution in people with active upper gastrointestinal problems such as Barrett's esophagus, dysphagia, gastritis, duodenitis or ulcers [1].

Gastric and duodenal ulcers have been reported after marketing, some severe, although no increased risk was seen in controlled trials [1].

Muscle, joint or bone pain has been reported from day one to several months in

Severe and occasionally incapacitating bone, joint or muscle pain has been reported after marketing, with onset from one day to several months after starting the drug [1]. Most patients had relief after stopping, and a subset had recurrence when rechallenged [1]. In the placebo-controlled studies, the percentages of patients with these symptoms were similar on alendronate and placebo [1]. The label says to discontinue use if severe symptoms develop [1].

Calcium, vitamin D and kidney function at the start

The label says low calcium (hypocalcemia) must be corrected before alendronate is started [1]. Small, asymptomatic decreases in serum calcium and phosphate can occur, seen in about 18% versus 12% on placebo for calcium and about 10% versus 3% for phosphate [1]. The label directs supplemental calcium when dietary intake is inadequate, and says patients at increased risk of vitamin D insufficiency, such as those over 70, nursing-home bound, or chronically ill, may need vitamin D supplementation [1].

The label says alendronate is not recommended for patients with a creatinine clearance below 35 mL/min; no dose adjustment is needed between 35 and 60 mL/min, and there is no adjustment for liver impairment [1].

What the label says about long-term use

The Fosamax label provides osteoporosis efficacy and safety data from four years of treatment, so a four-week bone-density result is not something it reports [1]. The label states that the optimal duration of use has not been determined, and that patients at low risk of fracture should be considered for drug discontinuation after 3 to 5 years, with the need for continued therapy re-evaluated periodically [1]. The American Society for Bone and Mineral Research suggests reassessing risk after 5 years of oral therapy, with a 2 to 3 year holiday an option for people not at high fracture risk. For women at high fracture risk, the task force says continuing oral bisphosphonate treatment for up to 10 years may be considered, with periodic evaluation [3].

Stopping does not end bone protection immediately. In FLEX, 1,099 women who had taken alendronate for a mean of 5 years were randomized to continue (662) or switch to placebo (437) for 5 more years; stopping lowered total hip bone density by 2.4% and spine density by 3.7% relative to continuing, while levels stayed at or above pretreatment values. Nonvertebral fractures were the same (19% versus 18.9%), and clinical vertebral fractures were lower with continuing (2.4% versus 5.3%); fracture was an exploratory outcome [4]. The terminal half-life in humans is estimated to exceed 10 years, reflecting slow release from the skeleton [1].

Missed doses and interactions that matter early

If a weekly dose is missed, the label says to take one dose the morning after remembering, never two doses on the same day, then return to the usual chosen day each week [1]. Calcium supplements, antacids and other oral products containing multivalent cations interfere with absorption, and the label directs waiting at least one-half hour after alendronate before any other oral medication [1]. Upper gastrointestinal adverse events were more frequent in patients taking daily alendronate doses above 10 mg together with aspirin-containing products [1]. NSAIDs may be taken with alendronate — in a three-year study of 2,027 patients, most on NSAIDs, upper gastrointestinal events were similar to placebo at 5 or 10 mg daily — but the label advises caution since NSAIDs irritate the gastrointestinal tract [1].

Rare but serious risks reported with bisphosphonates

Osteonecrosis of the jaw and atypical femur fractures are rare but serious reported risks [1][5]. An international consensus review estimated jaw osteonecrosis at 0.001% to 0.01% in osteoporosis patients, against 1% to 15% in cancer patients on high-dose parenteral therapy [5]. Atypical femur fractures run 3.2 to 50 cases per 100,000 person-years on bisphosphonates and rise with duration; in 196,129 women on bisphosphonates, 277 occurred, with a hazard ratio of 8.86 at 3 to under 5 years and 43.51 at 8 years or more, compared with under 3 months of use [6][7]. The label says any patient with bisphosphonate exposure who has thigh or groin pain should be evaluated for an incomplete femur fracture, noting that many patients had dull aching thigh pain for weeks to months beforehand [1].