Because osteoporosis is a multifactorial condition, its prevention and management are complex. From prevention to treatment of established disease, the goal is to intervene as early as possible to ensure retention of bone mass and to preserve structural integrity of the skeleton, thus preventing fragility fractures.
The results of large prospective RCTs, carried out over the last 10 years, have helped guide our therapeutic options, which include non-pharmacologic approaches that should be recommended for all patients. Currently available drug therapies are all anti-resorptive and focus on decreasing bone turnover. They have been shown to reduce fracture risk for some, although not necessarily all, fragility fractures. Newer therapies aimed at increased bone formation are being studied and are about to be released. It is difficult to assess the relative anti-fracture efficacy of the various therapies, as they have not been compared directly in trials.
Several anti-resorptive agents have been used successfully in the treatment of postmenopausal osteoporosis. However, recent trials of the bisphosphonates consistently provide the best evidence of efficacy in preventing both vertebral and non-vertebral fractures. Bisphosphonates are stable analogues of naturally occurring pyrophosphate. They contain 2 phosphonate groups attached to a single carbon atom to give a P-C-P structure. This structure renders them chemically stable and is responsible for the strong affinity of the bisphosphonates for bone.101
Bisphosphonates inhibit bone resorption through their effects on osteoclasts.102
They interfere with osteoclast recruitment, differentiation and action as well as enhancing osteoclast apoptosis.102
Bisphosphonates can be classified into 2 groups based on their mode of action102
: those that most closely resemble pyrophosphate (such as clodronate and etidronate) can be incorporated into cytotoxic adenosine triphosphate (ATP) analogues; the more potent nitrogen-containing bisphosphonates (alendronate and risedronate) induce apoptosis in osteoclasts by interfering with protein prenylation through their effects on the mevalonate pathway and, therefore, the intracellular trafficking of key regulatory proteins. These 2 mechanisms of action may help explain some of the pharmacologic differences between the 2 classes of bisphosphonates.
Currently the bisphosphonates approved for the treatment of osteoporosis in Canada are etidronate, alendronate and risedronate. Although all bisphosphonates, these drugs vary considerably in potency, their ability to inhibit bone resorption, toxicity and dosing regimens. Oral absorption of bisphosphonates is poor, at only 1–5%, even when the medication is taken on an empty stomach. The plasma half-life is 1 hour with 40–80% clearance by the kidneys. The remaining drug is taken up by the bone where it has a long half-life. The most common side effect of bisphosphonates is gastrointestinal upset, which is often dose-related.
Etidronate was the first bisphosphonate to show a benefit in the treatment of osteoporosis.103,104,105,106,107,108,109,110,111,112,113
It is generally well tolerated; reports of gastrointestinal upset are few, diarrhea being the most common complaint. When administered continuously for long periods, etidronate can cause impaired mineralization of bone with results similar to osteomalacia. As a result, etidronate is given in an intermittent fashion, typically 400 mg/day for 2 weeks every 3 months.
examined the anti-fracture efficacy of cyclical etidronate in postmenopausal women with prevalent vertebral fractures. In both, etidronate produced significant increases in lumbar spine BMD with variable reductions in vertebral fracture rates. These studies indicate that etidronate has some effect in preventing new vertebral fractures in postmenopausal women with severe osteoporosis. There is no evidence of a beneficial effect of etidronate on risk of hip or non-vertebral fracture.
Alendronate is a nitrogen-containing bisphosphonate, which is given continuously at a dose of 5 mg/day for the prevention of osteoporosis and 10 mg/day for the treatment of established osteoporosis. Recently, a weekly dose of alendronate (70 mg) was shown to have an effect on BMD that was comparable to that of a 10-mg daily dose regimen.114
Alendronate is generally well tolerated, although rare cases of esophagitis have been reported.115
Alendronate has been studied extensively for the treatment of osteoporosis.84,85,86,114,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132
In an initial 3-year study, alendronate significantly reduced the incidence of new fractures.85
Its efficacy has since been examined in two large populations of postmenopausal women, one with and one without pre-existing vertebral fractures.117
In the group with vertebral fractures, treatment with alendronate reduced the incidence of vertebral, hip and wrist fractures by about 50% over 3 years; the risk of multiple vertebral fractures was reduced by 90%. This was the first RCT to show hip fracture benefits in calcium- and vitamin D-replete osteoporotic women. In a post-hoc analysis,133
a reduction in the rate of clinical vertebral fractures was demonstrated as early as 1 year into the study.
The anti-fracture efficacy of alendronate has also been examined in postmenopausal women with no prior vertebral fractures.118
Alendronate increased BMD at all measured sites and significantly reduced (36%) the clinical vertebral fracture rate among women with initial T-scores below –2.5. The Fosamax International Trial Study Group (FOSIT)127
demonstrated a reduction in non-vertebral fracture incidence within 1 year in postmenopausal women with a T-score below –2.0. Alendronate prevents bone loss in normal postmenopausal women but anti-fracture efficacy in this context has not been demonstrated.
In summary, alendronate is beneficial in the prevention of vertebral, hip and non-vertebral fractures in postmenopausal women. It consistently increases bone mass at all measured sites. Alendronate has been used in patients who were also taking estrogen or raloxifene and had an additive effect in increasing BMD; however an additional anti-fracture benefit has not been demonstrated.124
Risedronate is generally well tolerated, with occasional reports of headache and diarrhea as side effects. Many studies have demonstrated risedronate efficacy, using both daily and once-weekly treatment regimens.38,83,134,135,136,137,138
Recently, 2 large, 3-year, multicentre RCTs136,137
evaluated the efficacy of risedronate in the treatment of postmenopausal osteoporosis. After 3 years of treatment at 5 mg/day, risedronate reduced the incidence of vertebral fractures by 41–49% and non-vertebral fractures by 39–33%. In a preplanned analysis, treatment with risedronate at 5 mg/day was shown to reduce the incidence of vertebral fractures within the first year of therapy by 61–65%. No significant differences in adverse events were seen between the risedronate and placebo groups.
In a large RCT38
designed to determine the efficacy of risedronate in the prevention of hip fractures, the drug was shown to reduce hip fracture rates in those with low femoral neck BMD by 40%. Among the latter women, risedronate reduced hip fracture by 60% in those with prior vertebral fracture. Risedronate did not significantly reduce the risk of hip fracture among elderly women selected primarily on the basis of risk factors other than low BMD.
In conclusion, risedronate at 5 mg/day, given over 3 years, is well tolerated and reduces the incidence of both vertebral and non-vertebral fractures in women with established postmenopausal osteoporosis. Furthermore, these studies were the first to show a significant reduction in the incidence of vertebral fractures (clinical and subclinical fractures) within 1 year of therapy.
A comprehensive evaluation of the evidence to date for the efficacy of these bisphosphonates is outlined in Hodsman et al.139
Cyclic etidronate has been used in combination with estrogen therapy in postmenopausal women.140,141
In a randomized study,141
at the end of 4 years, combination therapy produced a greater increase in BMD than either estrogen or etidronate alone; patients on estrogen or etidronate alone had lesser increases in spine and hip BMD.
The combined effect of alendronate and estrogen in postmenopausal women was studied in women who had been receiving estrogen replacement therapy for at least 1 year.124
They were randomly assigned to receive either 10 mg/day of alendronate or placebo. After 12 months, the patients taking alendronate in addition to estrogen showed significantly greater increases in BMD of the lumbar spine and trochanter; however, no conclusions about fracture rate reduction could be drawn. The results of this trial were supported by a 2-year trial of postmenopausal women who were randomly chosen to be treated with placebo, 10 mg/day of alendronate, conjugated estrogen or both treatments.121
Lumbar spine BMD in the placebo group remained stable over the 2 years. The alendronate and conjugated estrogen groups had similar gains in BMD, whereas the group given both treatments had a significantly greater gain than either of the single-treatment groups. These results suggest that, in those initiating therapy, the combination of alendronate and estrogen is more effective than either treatment alone. Although increases in BMD have been demonstrated with combination therapies, no direct evidence of fracture rate reduction has been shown.
Bisphosphonate treatment in men:
There is no RCT evidence of benefit from treatment with etidronate. Alendronate has been studied in the treatment of osteoporosis in men and has been shown to increase BMD significantly,142
while reducing vertebral fractures. One large study of risedronate in men on glucocorticoid therapy demonstrated a significant decrease in vertebral fractures after 1 year.143
Bisphosphonates and glucocorticoid-induced osteoporosis:
Studies of glucocorticoid-induced osteoporosis are directed at 2 groups: those starting preventive therapy at the time of glucocorticoid initiation and those on chronic long-term glucocorticoid therapy who require treatment for osteoporosis. There is ample evidence that etidronate therapy maintains BMD in patients taking glucocorticoids.144,145,146,147,148,149,150,151,152,153,154,155,156
Etidronate on initiation of glucocorticoid therapy has resulted in a slight increase in lumbar spine BMD, compared with bone loss with placebo.144,145,147,149,151
suggested that etidronate might be of benefit in preventing vertebral fractures. Two-year RCTs146,149
of etidronate in patients on long-term glucocorticoids demonstrated increases in BMD. These results suggest that etidronate is beneficial in the prevention and treatment of glucocorticoid-induced bone loss and may reduce the risk of fractures in glucocorticoid-treated postmenopausal women.
Alendronate has been studied in glucocorticoid-treated patients157,158,159
and in those with Cushing's syndrome.160
Statistically significant benefit has been shown in the spine, trochanter and femoral neck at doses of 5 and 10 mg/day. Alendronate benefitted all groups, including men, premenopausal and postmenopausal women; in postmenopausal women who were on HRT, alendronate therapy provided added benefit.158
Alendronate was effective in both the prevention and treatment of glucocorticoid-induced osteoporosis and reduced vertebral fracture risk.159
Risedronate has been studied in both the prevention and treatment of glucocorticoid-induced osteoporosis,161,162,163
and significant differences in lumbar spine and hip BMD have been observed compared with placebo. Analysis of pooled data from these studies revealed a significant reduction in the incidence of vertebral fractures among those taking 5 mg of risedronate daily.163
The newer nitrogen-containing bisphosphonates — alendronate and risedronate — should be considered first-line therapy for postmenopausal women with established osteoporosis who are at high risk for fracture. There is good evidence that they prevent both vertebral and non-vertebral fractures, including hip fractures. Bisphosphonates are the only therapy shown to be efficacious in reducing vertebral fracture in glucocorticoid-induced osteoporosis.
Bisphosphonates, particularly the more potent alendronate and risedronate, are effective in reducing risk of fracture in high-risk patients, with benefits seen as early as the first year of therapy.