These pyrophosphate analogues bind to hydroxyapatite crystals in the bone, are taken up by osteoclasts in the bone, and exert their action by inhibiting the mevalonate pathway, subsequently leading to inhibition of osteoclast
function and increase in rates of apoptosis. Oral bioavailability is generally low, only 1% to 3%, and is greatly inhibited by food, calcium, iron supplements, and drinks. Patients must be advised to take this medication in the morning, to withhold food and drinks to ensure good absorption, and to remain upright for at least 30 minutes.

Major side effects include erosions and ulcers in the upper gastrointestinal tract. Several studies have attempted to determine which agent is less erosive, but the results were not consistent. With the approval of once-monthly therapy with ibandronate, it remains to be determined whether less frequent exposure of the gut will lead to fewer gastrointestinal adverse events.

The Food and Drug Administration (FDA) has approved three oral bisphosphonates for the prevention and treatment of osteoporosis: alendronate (Fosamax), risedronate (Actonel), and ibandronate (Boniva), as well as an intravenous agent, ibandronate.

This drug is available in 5-, 10-, 35-, and 70-mg tablet forms. The 5-mg once daily or 35 mg once weekly is used for prevention, and 10-mg once daily or 70-mg once weekly for treatment of established osteoporosis. The pivotal study that established the efficacy of alendronate for the treatment of postmenopausal osteoporosis was the Fracture Intervention Trial (FIT) [1,2]. This was conducted on postmenopausal women, who were given alendronate
(daily) or placebo for 3 years. The study showed a 47% reduction in new radiographic vertebral fractures, a 55% reduction in clinical vertebral fractures, a 90% reduction in multiple vertebral fractures, and a 51% reduction in hip fractures among women without prior vertebral fractures [1]. Those with prior vertebral fractures experienced a 44% reduction in new radiographic vertebral fractures [2]. Mean increases in BMD were 6% to 8% for the lumbar spine (LS) and 4% to 5% for the hip [1,2]. A metaanalysis of alendronate trials showed similar fracture reduction and BMD benefits for postmenopausal osteoporosis [3,4].

In a follow-up study, postmenopausal osteoporotic women who took 10 mg alendronate daily for 10 years had a total increase of 13.7% in lumbar spine BMD, 10.3% in trochanter, and 5.4% in femoral neck BMD [5]. The BMD gradually declined after a number of years of discontinuation [5]. It appears that if used for only a year, discontinuation of alendronate led to a rate of bone loss that was similar to the group that did not receive the drug; however, at the end of 15 months, there was still a 3% difference in mean LS BMD between the groups, but the femoral neck BMD went back to baseline [6]. Whether fracture protection was indeed lost as bone mass declined is unknown.

The BMD efficacy of weekly alendronate dosing was studied in a 1-year trial that compared 70-mg weekly, 35-mg twice-weekly, and 10-mg daily doses of alendronate. At 1 year, similar increases in LS BMD (range, 5.1%–5.4%) in these three groups were seen, and there were no observed differences in the side effect profiles [7].

A head-to-head study comparing weekly 70 mg alendronate with 35 mg risedronate for 1 year revealed small but significantly greater increases in BMD at 6 and 12 months, and greater degrees of bone suppression in the alendronate group, with similar tolerability [8]. This study was not powered to detect differences in fracture rates.

Risedronate is approved in the 5-mg once-daily or a 35-mg once-weekly dose for prevention and treatment of osteoporosis. Two large randomized placebo-controlled studies of postmenopausal women showed a reduction in radiographic vertebral fractures by 41% to 49% after 3 years of daily risedronate therapy [9,10]. One of these trials was extended to 7 years, and the follow-up revealed persistence of BMD gains and fracture risk reductions through the seventh year of follow-up [11]. In another large study with hip fracture reduction as the primary endpoint [12], risedronate was found to significantly reduce fracture risk by 30%. In the subgroup of patients who entered into the study with BMD criteria for osteoporosis, a significant 40% risk reduction for fracture was seen, but no significant reduction was seen in the subgroup that entered into the study based on age alone. The exact reason why this subgroup did not experience a reduction in fracture risk is not known.

A metaanalysis on the use of risedronate for postmenopausal osteoporosis [13] showed a pooled risk reduction (RR) of 0.64 for vertebral and 0.73 for nonvertebral fractures. The pooled estimate of the differences in percentage of change in BMD between risedronate (5 mg) and placebo was 4.54% at the LS and 2.75% at the femoral neck.

The efficacy of once-weekly risedronate was shown in a randomized placebo-controlled study of 1,456 postmenopausal women with T-scores below -2.5 or below -2.0 with a prevalent vertebral fracture. Risedronate, at 5-mg daily, 35-mg weekly, or 50-mg weekly doses, was given for 1 year. Mean percentage changes in LS BMD after 12 months were similar, as were mean increases in femoral neck BMD in the three groups [14].

Ibandronate, FDA approved for the treatment and prevention of postmenopausal osteoporosis, is available in two oral forms, 2.5 mg daily and 150 mg monthly, as well as an intravenous form, 3 mg quarterly. The Monthly Oral Pilot Study was a 3-month, Phase 1 randomized, double-blind, multicenter, placebo-controlled study of 144 postmenopausal women who were given 50, 100, or 150 mg of ibandronate or placebo. The main endpoints were changes in serum and urine C-telopeptide (CTX), safety, and AUC. Ibandronate significantly decreased CTX in the 100- or 150-mg groups. No significant differences in adverse events compared with placebo were observed [15]. The MOBILE (Monthly Oral Ibandronate in Ladies) study was a 2-year, randomized, double-blind trial that searched for the appropriate ibandronate dose for the treatment of osteoporosis. The 1,609 women in the study were assigned to four groups: 2.5 mg daily, 50 mg once a month, 100 mg once a month, or 150 mg once a month. Those on monthly ibandronate experienced increases in LS (3.9%, 4.3%, 4.1%, and 4.9%, respectively) and hip (about 2%–3%) BMD. The 150-mg group had a small but significantly greater increase in LS BMD than the daily regimen. In addition, when the groups were evaluated for those who achieved BMD gains above baseline of more than 6% at the LS or 3% at the hip, the 150-mg and 100-mg groups had significantly more patients at these goals than the daily regimen (only 150 mg at the LS with respect to gains above baseline). The frequency of gastrointestinal symptoms with each dose was similar, but there was a small increase in flu-like symptoms with the monthly regimens [16].

In a noninferiority study [DIVA (Dosing Intravenous Administration)], two regimens—2 mg IV every 2 months and 3 mg IV every 3 months—were found to be similar in efficacy to daily ibandronate (2.5 mg) in terms of mean increases in lumbar spine and hip BMD at 1 and 2 years. Safety profiles were similar [17].

Raloxifene is a selective estrogen receptor modulator, with agonistic effects on bone. The major efficacy trial for raloxifene was the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial [25]. The LS BMD increase over the 3-year study period was 2% to 3%, and vertebral fracture reduction rates in women with and without preexisting fractures were 50% and 30%, respectively. No significant difference in nonvertebral and hip fracture reduction was observed, but the study was not powered to detect differences in such fractures. Efficacy of raloxifene was sustained through 4 years of treatment [26].

A metaanalysis of seven trials comparing raloxifene and placebo showed a similar BMD increase at the LS and a 2% increase at the hip [27]. This drug has other potential benefits, including reduction in breast cancer risk and improvement in lipids and markers of cardiovascular disease. In a large study of 10,101 postmenopausal women [Raloxifene Use for The Heart (RUTH) Trial], raloxifene did not show a significant reduction in primary coronary events but showed a reduction in invasive breast cancer [40 vs. 70 events; hazards ratio (HR), 0.56; 95% CI, 0.38–0.83; absolute RR, 1.2 invasive breast cancers per 1,000 women treated for 1 year]; increased risk of fatal stroke (59 vs. 39 events; HR, 1.49; 95% CI, 1.00–2.24; absolute risk increase, 0.7 per 1,000 woman-years) and venous thromboembolism (103 vs. 71 events; HR, 1.44; 95% CI, 1.06–1.95; absolute risk increase, 1.2 per 1,000 woman-years) [28]. Clinical vertebral fractures were reduced (64 vs. 97 events; HR, 0.65; 95% CI, 0.47–0.89) [28].

Because of its modest effect on BMD, and small fracture risk reduction, calcitonin is rarely used as first-line therapy; rather, owing to its mild analgesic effects, this drug is more commonly used now as an adjunctive therapy after an acute vertebral fracture, usually combined with a stronger antiresorptive. The major efficacy trial was the PROOF (Prevent Recurrence of Osteoporotic Fractures) study, which demonstrated a 1.2% increase in LS BMD and a 33% reduction in vertebral fractures with 200 IU of intranasal calcitonin [29]. No significant reduction was seen in the 100 or 400 international units groups. No significant reduction in nonvertebral and hip fractures was demonstrated in this trial. In a metaanalysis of 30 trials that compared calcitonin with placebo, the smaller studies were found to have more impressive results than the PROOF study [30]. The authors of that metaanalysis alluded to possible publication bias in the smaller studies.

Hormone replacement therapy (HRT) was the original antiresorptive therapy used for osteoporosis. However, current controversies centered on increased breast cancer, and cardiovascular risks have resulted in a marked decline in use for osteoporosis indications. A metaanalysis of 57 randomized studies, which compared at least 1 year of HRT with controls in postmenopausal women, showed a trend toward reduction of vertebral and nonvertebral fracture incidence. At 2 years, BMD increased by 6.76% in the LS and 4.12% in the femoral neck [31]. Perhaps the best prospective data to date that showed fracture reduction with combined HRT were those established in the Women’s Health Initiative study. The incidence of clinical vertebral fractures was reduced by 34%, hip fractures by 34%, and all fractures by 24%. Absolute excess risks per 10,000 person-years attributable to estrogen plus progestin were 8 more coronary heart disease events, 8 more strokes, 8 more pulmonary emboli, and 8 more invasive breast cancers, while absolute RRs per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures [32].

Synthetic human parathyroid hormone [PTH (1–34)], or teriparatide, is an anabolic agent that has been approved for postmenopausal and male osteoporosis treatment. The landmark trial in postmenopausal women was the Fracture Prevention Trial (FPT). In this study, 1,637 postmenopausal women received 20 or 40 mcg of teriparatide for a mean of 21 months. Vertebral fracture risk was decreased by 65% and 69%, respectively, and nonvertebral fracture risk by 53% and 54%. Mean increases in LS BMD of 9% and 13%, as well as 3% and 6% at the femoral neck, were seen. The most common side effects were nausea and headaches [33].

Teriparatide is approved for only 2 years of use because of a lack of studies that have gone beyond that time frame. Several studies have investigated what happens after the drug is discontinued. Extensions of the FPT have looked at changes in BMD and fracture risk after discontinuation of teriparatide. One study found that 30 months after discontinuation of teriparatide, the hazard ratio for nonvertebral fragility fractures was still significantly lower than placebo but only in the 40-μg group. BMD decreased over this time span in both groups, except in those who received bisphosphonates for at least 2 years during the trial [34]. Another study looked at vertebral BMD changes and fractures 1.5 years after discontinuing teriparatide. There continued to be a statistically significant increase in BMD and a decrease in fractures in those who had been on teriparatide. Those who used bisphosphonates for at least 1 year continued to gain BMD, whereas those who did not lost BMD [35].

The BMD effects of anabolic versus antiresorptive therapy have been compared in a randomized double-blind trial of teriparatide 40 μg versus alendronate 10 mg daily. By 3 months, and through the 14 months of the study, those in the teriparatide group experienced significantly greater increases in LS and hip BMD than those in the alendronate group. Nonvertebral fractures were significantly less in the teriparatide group [36].

What about administration of antiresorptive agents before anabolic therapy? The effects of teriparatide after administration of alendronate or raloxifene have been assessed. The prior raloxifene group had higher gains in BMD at the LS and the hip. The difference in LS BMD was largely due to an increase in the first 6 months [37]. Bone formation markers had a lesser and later peak in the alendronate group.