Table 57Summary of evidence

Strength of EvidenceConclusion
Key Question 1. What are the comparative benefits in fracture risk reduction among the following treatments for low bone density:
a. BisphosphonatesHighVertebral fractures: alendronate, risedronate, ibandronate, and zoledronic acid reduce the risk of vertebral fractures among postmenopausal women with osteoporosis.
HighNon-vertebral fractures: alendronate, risedronate, and zoledronic acid reduce the risk of nonvertebral fractures among postmenopausal women with osteoporosis.
HighHip fractures: alendronate, risedronate and zoledronic acid reduce the risk of hip fractures among postmenopausal women with osteoporosis. The effect of ibandronate is unclear, since hip fracture risk reduction was not a separately reported outcome in trials reporting nonvertebral fractures.
LowWrist fractures: alendronate reduces the risk of wrist fractures among postmenopausal women with osteoporosis. Risedronate in a pooled analysis of two trials was associated with a lower risk of wrist fractures, but this did not quite reach the conventional level of statistical significance.
InsufficientData are insufficient from head-to-head trials of bisphosphonates to prove or disprove superiority for the prevention of fractures for any agent.
InsufficientData are insufficient from head-to-head trials of bisphosphonates compared to calcium, teriparatide, or raloxifene to prove or disprove superiority for the prevention of fractures.
ModerateBased on six RCTs, superiority for the prevention of fractures has not been demonstrated for bisphosphonates in comparison with menopausal hormone therapy.
b. CalciumModerateThe effect of calcium alone on fracture risk is uncertain. Several large, high quality RCTs were unable to demonstrate a reduction in fracture among postmenopausal women. However, a number of studies have demonstrated that compliance with calcium is low, and a subanalysis in one of the RCTs demonstrated a reduction in fracture risk with calcium relative to placebo among compliant subjects.
c. DenosumabHighDenosumab reduces the risk of vertebral, nonvertebral and hip fractures in postmenopausal women with osteoporosis.
d. Menopausal hormone therapyHighMenopausal hormone therapy reduces the risk of vertebral and hip fractures in postmenopausal women.
ModerateMenopausal hormone therapy does not reduce fracture risk significantly in postmenopausal women with established osteoporosis.
e. PTH (teriparatide)HighTeriparatide reduces the risk of vertebral fractures in postmenopausal women with osteoporosis.
ModerateTeriparatide reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis.
f. SERMs (raloxifene)HighRaloxifene reduces the risk of vertebral fractures among postmenopausal women with osteoporosis.
g. Vitamin DLow-ModerateThe effect of vitamin D on fracture risk is uncertain. Among a number of meta-analyses, some reported a reduced risk for vitamin D relative to placebo, some did not. There was no reduction in fracture risk for vitamin D relative to placebo in a large, high quality RCT published after the meta-analyses.
h. Exercise in comparison to above agentsInsufficientThere are no data from RCTs to inform this question. One RCT that assessed the effect of a brief exercise program on fracture risk found a small decrease in risk of fractures among exercisers but the study was not powered to detect differences in fracture risk.
Key Question 2. How does fracture risk reduction resulting from treatments vary between individuals with different risks for fracture as determined by bone mineral density (borderline/low/severe), risk assessment score, prior fractures (prevention vs. treatment),g age, sex, race/ethnicity, and glucocorticoid use?
HighAlendronate, ibandronate, risedronate, teriparatide, raloxifene, zoledronic acid, and denosumab reduce the risk of fractures among high risk groups including postmenopausal women with osteoporosis.
ModerateLow femoral neck BMD does not predict the effects of alendronate on clinical vertebral or nonvertebral fracture risk.
InsufficientPrevalent fracture predicted the effect of alendronate on fracture risk in one study but not another.
Low-moderateRisedronate reduces the risk of fragility fracture among postmenopausal women with osteopenia who do not have prevalent vertebral fractures.
InsufficientPrevalent fracture predicts the efficacy of raloxifene for fracture prevention in some studies but not others.
ModeratePrevalent fractures increase the relative efficacy of teriparatide in preventing fractures.
ModerateRaloxifene prevents fractures in postmenopausal women at low risk for fracture as assessed by FRAX.
InsufficientTeriparatide and risedronate but not calcium and vitamin D reduce risk of fracture among men.
HighIn general age does not predict the efficacy of bisphosphonates or teriparatide.
HighRaloxifene decreases the risk for vertebral fracture but not nonvertebral or hip fracture among postmenopausal Asian women, similar to other postmenopausal women.
Moderate-HighAmong subjects treated with glucocorticoids, fracture risk reduction was demonstrated for alendronate, risedronate, and teriparatide.
InsufficientThere are limited and inconclusive data on the effect of agents for the prevention and treatment of osteoporosis on transplant recipients and patients treated with chronic corticosteroids.
InsufficientEvidence is inconclusive on the effects of renal function on the efficacy of alendronate, raloxifene, and teriparatide in preventing fractures.
ModerateReduction in fracture risk for subjects treated with alendronate, risedronate, or vitamin D has been demonstrated in populations at increased risk for fracture due to conditions that increase the risk of falling including stroke with hemiplegia, Alzheimer's disease, and Parkinson's.
Key Question 3. What are the adherence and persistence with medications for the treatment and prevention of osteoporosis, the factors that affect adherence and persistence, and the effects of adherence and persistence on the risk of fractures?
ModerateEighteen RCTs reported rates of adherence to therapy. Twelve trials with bisphosphonates and two trials with denosumab reported high levels of adherence (majority with over 90% adherence). Two trials with raloxifene had adherence rates 65-70%.
HighThere is evidence from 58 observational studies, including 24 using U.S. data, that adherence and persistence with therapy with bisphosphonates, calcium, and vitamin D is poor in many patients with osteoporosis. One study described adherence with teriparatide. No studies describe primary nonadherence (i.e. nonfulfillment).
ModerateBased on evidence from 41 observational studies, many factors affect adherence and persistence with medications including, but not limited to, dosing frequency, side effects of medications, co-morbid conditions, knowledge about osteoporosis, and cost. Age, prior history of fracture, and concomitant medication use do not appear to have an independent association with adherence or persistence.
HighBased on 20 observational studies, dosing frequency appears to affect adherence/persistence: adherence is improved with weekly compared to daily regimens, but current evidence is lacking to show that monthly regimens improve adherence over that of weekly regimens.
ModerateEvidence from a systematic review and 15 out of 17 observational studies suggest that decreased adherence to bisphosphonates is associated with an increased risk of fracture (vertebral, nonvertebral or both).
LowThe evidence on adherence to raloxifene, teriparatide, and other drugs and its association with fracture risk is insufficient to make conclusions.
Key Question 4. What are the short- and long-term harms (adverse effects) of the above therapies, and do these vary by any specific subpopulations?
HighParticipants who took raloxifene showed higher odds for pulmonary embolism than did participants who took a placebo. Raloxifene participants also had greater odds of thromboembolic events.
HighEstrogen and estrogen-progestin combination participants had higher odds of cerebrovascular accident (CVA) and thromboembolic events than did placebo participants.
HighA pooled analysis of ten trials found an increased risk with raloxifene for myalgias, cramps, and limb pain.
HighWe categorized conditions such as acid reflux, esophageal irritation, nausea, vomiting, and heartburn as “mild upper GI events.” Our pooled analyses showed alendronate had a slightly increased risk of mild upper GI events. Alendronate participants also had higher odds of mild upper GI events in head-to-head trials vs. menopausal hormone therapy. Pooled analysis also showed alendronate users to be at an increased risk for mild GI events compared to denosumab. Denosumab was also associated with an increase in mild GI events.
LowA new systematic review of 15 placebo-controlled trials of calcium (administered for bone health in all trials but one) identified a statistically significant increase in the risk of myocardial infarction; however serious concerns have been expressed about possible bias.
ModerateTeriparatide-treated participants showed a significant increase in hypercalcemia.
InsufficientThe literature is equivocal on the potential association between bisphosphonates and the risk of atrial fibrillation.
HighOne trial, one post hoc analysis of three trials, two large observational studies, and a review of 2,408 cases of osteonecrosis of the jaw in patients taking bisphosphonates for osteoporosis prevention or treatment found that the incidence of osteonecrosis of the jaw in this group was small, ranging from less than one to 28 cases per 100,000 person-years of treatment.
HighOur pooled analysis of eight trials found an increased risk with raloxifene of hot flashes.
LowLimited data from clinical trials and observational studies support a possible association between bisphosphonate use and atypical subtrochanteric fractures of the femur. Data are not consistent, nevertheless these data were sufficient for FDA to issue a Warning regarding this possible adverse event.
ModerateA pooled analysis of three trials of teriparatide found an increased risk of headaches.
HighA pooled analysis of four trials of denosumab found an increased risk of rash but no increase in the risk for injection-site reactions.
ModerateA small number of clinical trials have reported an increased risk of hypocalcemia in patients treated with alendronate and zoledronic acid.
InsufficientFour observational studies that assessed whether the use of an oral bisphosphonate is associated with an increased risk of esophageal cancer had mixed findings.
HighA pooled analysis of four trials of denosumab found an increased risk for infection.
Key Question 5a. How often should patients be monitored (via measurement of bone mineral density) during therapy?
InsufficientThe role of BMD monitoring during therapy has not been explicitly studied; therefore any conclusions must be based on indirect evidence.
HighChanges in BMD during therapy account for only a small proportion of the decrease in fracture risk; while some studies suggest that greater change in BMD in active therapy groups predicts greater antifracture efficacy, these changes have not been demonstrated to apply to individuals. Even patients who continue to lose BMD during therapy have had statistically significant benefits in fracture reduction. Clinical guidance is lacking on appropriate responses to declines in BMD under active therapy, such as increasing medication dose, or the influence of discontinuing therapy among individuals who experience declines in BMD under active therapy but may nonetheless derive fracture protection.
Key Question 5b. How does the antifracture benefit vary with long-term continued use of pharmacotherapy?
ModerateOne large RCT showed that after 5 years of initial alendronate therapy, vertebral fracture risk and nonvertebral fracture risk were lower if alendronate was continued for an additional 5 years instead of discontinued.
LowA post hoc analysis of this same trial reported that there were statistically significant nonvertebral fracture risk reductions for women who at baseline had no vertebral fracture but had a BMD score of −2.5 or less.
g

Prevention vs. treatment: If a person begins pharmacotherapy after having sustained fractures (i.e., the person has prevalent fractures), the therapy is considered treatment because the person, by definition, has osteoporosis and the medication is being administered to treat the condition. When these medications are administered to individuals with no prior fractures, these are individuals who have been identified as being at risk for osteoporosis (due to low bone density), but who don't actually (yet) have osteoporosis. They are being given the medication to prevent the onset of osteoporosis (i.e., further lowering of bone density and/or a first fracture).

Prevention vs. treatment: If a person begins pharmacotherapy after having sustained fractures (i.e., the person has prevalent fractures), the therapy is considered treatment because the person, by definition, has osteoporosis and the medication is being administered to treat the condition. When these medications are administered to individuals with no prior fractures, these are individuals who have been identified as being at risk for osteoporosis (due to low bone density), but who don't actually (yet) have osteoporosis. They are being given the medication to prevent the onset of osteoporosis (i.e., further lowering of bone density and/or a first fracture).

From: Conclusions

Cover of Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: Update of a 2007 Report
Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: Update of a 2007 Report [Internet].
Comparative Effectiveness Reviews, No. 53.
Crandall CJ, Newberry SJ, Diamant A, et al.

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