This report provides a comprehensive summary of the systematic reviews and RCTs that evaluated the effect of various agents on fracture risk. Across these studies there is a high level of evidence that alendronate, risedronate, ibandronate, zoledronic acid, raloxifene, denosumab, and teriparatide each reduce the risk of vertebral fractures among postmenopausal women with osteoporosis. A high level of evidence shows that alendronate, risedronate, zoledronic acid, and denosumab each reduce the risk of nonvertebral fractures among postmenopausal women with osteoporosis. There is a high level of evidence that alendronate, risedronate, denosumab, and zoledronic acid each decrease the risk of hip fractures among postmenopausal women with osteoporosis. A high level of evidence supports the effectiveness of menopausal hormone therapy in decreasing vertebral fracture and hip fracture risk, and the effectiveness of teriparatide in reducing nonvertebral fracture risk. Accordingly, each of these agents is FDA-approved for therapy of osteoporosis. Studies directly comparing the antifracture effects among various bisphosphonates are few and do not provide conclusive evidence supporting the effectiveness of one bisphosphonate over another, despite some basic scientific evidence for why they might differ.⁴⁸¹ Neither is there evidence for statistically significant differences in the effects of bisphosphonates compared to raloxifene, teriparatide, or menopausal hormone therapy. Multiple RCTs do not demonstrate the effectiveness of calcium alone in reducing risk of vertebral, nonvertebral, or hip fractures. However it is critical to note that the currently approved prescription osteoporosis therapies are only proven efficacious in RCTs that administered concurrent calcium and vitamin D. A moderate level of evidence supports the effectiveness of vitamin D in combination with calcium in reducing hip fracture risk among institutionalized persons. No RCTs of exercise interventions have demonstrated a reduction in fracture risk.

This report reviewed evidence regarding whether the effectiveness of osteoporosis therapy may vary according to certain characteristics. Few data informed the question of whether antifracture effects varied by baseline FRAX score. In post hoc analyses of RCTs, the effectiveness of alendronate in decreasing vertebral fracture risk among postmenopausal women with T-score between -2 and -2.5 was confined to women with baseline vertebral fractures. Evidence was inconsistent regarding whether raloxifene's effectiveness against fracture risk was more pronounced among women with baseline vertebral fracture. Post hoc analyses suggest that age may modify the effect of risedronate or zoledronic acid on fracture, with a more pronounced effect among women less than 70 to 75 years-old. Few studies address relative effectiveness of osteoporosis pharmacotherapy according to race/ethnicity, age, or sex.

The data described in this report and the prior evidence review document variable and overall poor adherence and persistence with medications for osteoporosis. Any comprehensive evidence review of the factors affecting adherence and persistence with medications for osteoporosis is fraught with challenges, the most important of which is the tremendous heterogeneity in how adherence and persistence are defined and measured. This problem is not unique to the osteoporosis literature. Nonetheless, in the prior evidence review 25 studies were identified that discussed factors affecting adherence, and in the current review we identified 58 new studies describing the factors affecting adherence or persistence or associated with adherence or persistence. The factors discussed were numerous, and we describe in detail five of the most commonly studied (i.e., age, prior history of fracture, dosing frequency, polypharmacy, and adverse events). Of these five, the data support only dosing frequency and adverse events as independent factors related to adherence or persistence. Weekly dosing of bisphosphonates appears to improve adherence and persistence compared to daily dosing, although the evidence for any additional improvement in adherence using monthly or less frequently dosed bisphosphonates is scant. The role of once yearly bisphosphonates in improving adherence is unclear, and any potential improvement in adherence based on dosing frequency must be balanced by potential barriers to improved adherence such as cost and necessity of IV infusion. For all of these factors that potentially affect adherence and persistence, there is only very limited understanding of how the factors interact, and their relative influence on adherence and persistence when they coexist.

Despite the many barriers to adherence discussed in the literature, very few interventions to improve osteoporosis medication adherence have been successful. Gleeson performed a comprehensive systematic review of the topic²⁶³ identifying only 7 relevant randomized trials of adherence interventions, none of which were double blinded and only one of which included fracture outcomes. Of the three out of five successful adherence interventions, each included some version of enhanced communication between patient and healthcare provider, which may provide a clue for how to move forward on addressing the adherence problem. Gleeson comment on the necessity of standardizing the measurement of adherence in the literature, which is a conclusion we reach as well.

The data on the relationship between poor adherence and fracture risk are clear, and the inverse relationship between adherence and fracture risk persists, with worse adherence to bisphosphonates associated with increased risk of fracture. However, in the current review, these data all come from observational studies. The one randomized trial that assessed the role of adherence in fracture reduction studied raloxifene¹²⁰ and found no difference in antifracture effects between those who were at least 70 percent adherent and those who were not. Note that adherence in randomized trials of bisphosphonates is quite high (often >90%) (adherence being a frequent requirement for inclusion in the analyses), meaning that the power to detect small differences in fracture outcomes among those adherent versus not would be limited. Nevertheless, efforts could be made to report these subgroup differences in randomized trials if additional data on this topic were desired. The evidence for a “healthy adherer” effect in the two studies examined was not high, although subsequent observational studies should account for the possibility of this effect when studying the relationship between hip fractures and bisphosphonate adherence.

We reviewed evidence regarding adverse effects of osteoporosis pharmacotherapies. Zoledronic acid was associated with a statistically significantly increased risk of atrial fibrillation in a pooled analysis, but not in a meta-analysis. Thus, no association is yet proven, and further elucidation is required. Bisphosphonates are generally targeted to older individuals, so future studies will benefit from careful attention to the contribution of increasing age itself as a determinant of atrial fibrillation risk. Women taking raloxifene had higher odds of deep vein thrombosis, thromboembolic events, and vasomotor flushing. Compared to placebo, women taking estrogen or estrogen-progestin therapy had higher odds of stroke and thromboembolic events. Raloxifene increases the risk of myalgias, cramps, and limb pain. Several agents (alendronate, teriparatide, and denosumab) were associated with mild upper GI events (acid reflux, esophageal irritation, nausea, vomiting, and/or heartburn). We found low evidence that calcium therapy statistically significantly increased the risk of myocardial infarction, and that PTH increased risk of hypercalcemia. Compared to placebo, women taking menopausal estrogen therapy had lower odds, and women taking combined estrogen + progestin therapy had higher odds, of breast cancer. In a single study, estrogen + progestin therapy decreased the odds of colon cancer. The vast majority (89 percent) of cases of osteonecrosis of the jaw among users of bisphosphonates are related to treatment of malignancy, and 88 percent of cases occurred in people taking intravenous therapy. Limited inconsistent data support a possible association between bisphosphonate use and atypical subtrochanteric femur fracture. Moderate evidence suggests that teriparatide increases risk of headaches, and that denosumab increases risk of rash.

For clinicians, this report contributes information that may inform prescribing decisions. Bisphosphonates and denosumab are the only agents for which there is a high level of evidence for reduction in hip fracture risk. For reduction in vertebral fracture risk, there is a high level of evidence supporting the use of bisphosphonates, raloxifene, denosumab, and teriparatide. Raloxifene is not effective in reducing the risk of hip or nonvertebral fractures. Evidence for antifracture effects of currently available osteoporosis therapies is greatest among those with established osteoporosis, meaning with existing fracture, or with T-score less than -2.5. Because at least half of osteoporotic fractures occur in individuals with T scores between -1 and -2.5, clinicians require the ability to identify which individuals with T-scores between -1 and -2.5 are likely to experience fracture. Older individuals are as likely to benefit from treatment as younger individuals, in terms of reduced fracture risk. With the advent of tools such as the WHO FRAX, selection of treatment candidates will likely be refined. Emerging research is judging the antifracture effects of medications according to level of baseline FRAX score.

Post hoc analyses of open-label extension data support the thesis that certain features predict continued fracture reduction with a 10-year instead of 5-year duration of alendronate therapy: BMD T-score above -2 if women have baseline fractures, and BMD T-score <-2 if women do not have baseline fractures. It is unknown if these same precepts will hold with other osteoporosis pharmacotherapies. We cannot provide information regarding comparative effectiveness of various agents when used long-term, because studies have not directly compared the antifracture effects of longer durations of therapy among various therapies.

Clinicians should be aware that, among people taking FDA-approved osteoporosis pharmacotherapy, changes in BMD are poor predictors of antifracture effects. Serial BMD monitoring may be useful for other purposes, and this area of research is under active investigation.