Introduction

Osteoporosis is a skeletal disorder of low bone mass and microarchitectural deterioration of bone, leading to bone fragility and increased risk of fracture.¹ Osteoporosis affects more than 10 million U.S. adults aged 50 years or older.² About two million U.S. adults experience an osteoporotic or other low- or no-trauma fracture each year.³ These fractures frequently cause pain, disability, and impaired quality of life;^{4, 5} and hip and clinical vertebral fractures, specifically, are associated with increased mortality.^{5, 6} Because risk of most fractures rises steeply with age, and the population is aging, fracture burden is projected to increase in coming decades.

In short-term (18 to 36 months) randomized controlled trials (RCTs) for osteoporosis treatment, bisphosphonates (alendronate, zoledronate, risedronate, ibandronate), denosumab, teriparatide, and abaloparatide lower risk of nonvertebral fractures, clinical vertebral fractures (usually diagnosed in the community because of back pain, with study comparison of study and community radiographs), and radiographic vertebral fractures (identified in studies by comparing vertebral heights on scheduled serial vertebral radiographs; mostly unrecognized in the community).^{7, 8} Several bisphosphonates (alendronate, zoledronate, risedronate) and denosumab also lower risk of hip fractures.⁷

Despite the evidence on the efficacy of short-term osteoporosis drug treatment for reducing fracture risk in appropriate patients, there is uncertainty about the balance of benefits and harms of long-term or continued treatment. A recent American College of Physicians clinical practice guideline recommended treatment of osteoporotic women with a bisphosphonate or denosumab for 5 years to reduce risk of hip and vertebral fractures, and suggested that high-risk patients may benefit from more than 5 years of treatment.⁸

However, concerns that long-term bisphosphonate persistence in bone might increase fracture risk by inhibiting normal repair of bone microdamage^{9, 10} have led to the suggestion that bisphosphonate treatment be discontinued periodically.⁹ Several groups advocate bisphosphonate “drug holidays” to minimize harms while preserving as much fracture benefit as possible. But, there is no consensus about who should get them, when they should start, how long they should last, and the criteria for restarting treatment.^{9, 11, 12} By contrast, drug holidays are not recommended after denosumab, because bone loss increases rapidly after discontinuation, possibly increasing risk of radiographic vertebral fractures.¹³

Uncertainties about the most appropriate use of long-term osteoporosis drug treatment and of osteoporosis drug holidays led to scheduling a National Institutes of Health (NIH) Office of Disease Prevention (ODP) Pathways to Prevention (P2P) workshop. The goals of the workshop were to present an evidence-based synthesis of the pertinent research base, and to suggest future research to assist patients, clinicians, and other healthcare decision makers.

To further these aims, we conducted this systematic review to address the following questions: (1) What are the effects of long-term (>3 years) osteoporosis drug treatment versus control on risks of incident fractures and harms; (2) Do effects of long-term osteoporosis drug treatment vary as a function of patient, bone, or osteoporosis drug characteristics; (3) Among individuals receiving osteoporosis drug treatment to prevent fracture, what are the effects of continuing versus discontinuing treatment (i.e., osteoporosis drug holiday) on risks of incident fractures and harms; and (4) Do these outcomes of drug holidays vary as a function of patient, bone, or osteoporosis drug characteristics?

Methods

The review was conducted following the Agency for Healthcare Research and Quality (AHRQ) methods guidance. The protocol is available at https://effectivehealthcare.ahrq.gov/topics/osteoporosis-fracture-prevention/research-protocol and is registered in PROSPERO. We detail our literature search strategy, study selection criteria, and data extraction and synthesis methods in the full report.

Results

We identified 8,356 unique publications through October 2018, of which 61 met eligibility criteria and were included in the review. Of 48 publications with low or medium risk of bias (ROB), there were 35 randomized or controlled clinical trials (9 unique studies) and 13 controlled observational studies (11 unique studies) (Appendix C of the full report). Most publications were based on three RCTs of alendronate, zoledronic acid, and raloxifene, respectively, and their extension studies.

All trials enrolled only postmenopausal women, with most limited to women with osteoporosis as defined by bone mineral density (BMD) and vertebral fracture history, and some including women with osteopenia. Observational studies included 84 to 100 percent women. Mean participant age was 72 years, with all but two studies reporting mean age <80 years. Most observational studies presumed participants had osteoporosis because of past fracture or use of osteoporosis drugs, but none reported BMD status.

Long-Term Osteoporosis Drug Treatment

Variation in Efficacy as a Function of Patient, Bone, or Osteoporosis Drug Characteristics

Efficacy of long-term alendronate appears to vary as a function of baseline BMD.¹⁴ Relative risk of incident clinical fractures was significantly reduced in women with osteoporotic BMD (femoral neck BMD ≤-2.5 (moderate SOE), but not in women with osteopenic BMD (femoral neck BMD −1.6 to >-2.5) (low SOE) (Table A; Appendix Table D8). In women with osteoporosis, relative risk of incident radiographic vertebral fracture with long-term alendronate was halved versus placebo (HR 0.50 [95% CI 0.31, 0.82]) (moderate SOE). Although women with femoral neck BMD −2.5 to −2 had a similar relative reduction in these fractures versus placebo (HR 0.54 [95% CI 0.28, 1.04]) (low SOE), a lower proportion of women with osteopenia had incident radiographic vertebral fractures, and results were not statistically significant. No tests of interaction were reported for these BMD stratified results.

In a post hoc analysis, women with osteoporosis had a reduced risk of incident hip fracture with long-term alendronate versus placebo, but women with osteopenia had no reduced risk (p-value for interaction not reported).¹⁴ In additional post hoc analyses, some conducted in women with osteopenia,^{22, 23} neither past nonvertebral fracture,²³ 10-year major osteoporotic fracture probability calculated with femoral neck BMD,²⁴ nor pretreatment levels of bone turnover markers²⁵ significantly modified the effect of long-term alendronate versus placebo on risk of any incident fracture outcome.

Neither age,¹⁷ baseline BMD,¹⁷ nor baseline radiographic vertebral fracture^{16, 17, 26, 27} modified the effect of long-term raloxifene versus placebo on risk of incident fractures. Two large trials of oral hormone therapy versus placebo in women with unknown osteoporosis or osteopenia status reported inconsistent findings about whether treatment effect on risk of incident hip and clinical fractures differed as a function of age or time since menopause.^{19, 28} However, authors minimized their one significant interaction for age because of the many interactions examined.¹⁹

Table A

Evidence on efficacy of long-term (>3 years) osteoporosis drug treatment.

Variation in Harms as a Function of Patient, Bone, or Osteoporosis Drug Characteristics

We found little evidence about factors that modify risk of harms with long-term osteoporosis drug treatment. One study was inconclusive about whether relative risk for AFF associated with bisphosphonate use increased with age.³⁸ Three controlled observational studies reported that >5 years of bisphosphonate use increased risk of subtrochanteric or femoral shaft fractures (ST/FSF) or radiologically confirmed AFF more than did 3–5 years of use.^{38, 48, 49} However, none of these studies reported tests for interaction by treatment duration. For long-term raloxifene versus placebo, one study reported that risk of deep venous thrombosis and pulmonary embolism did not vary as a function of baseline cardiovascular risk,³² and another that risk of incident stroke was lower with raloxifene versus placebo in women with increased cardiovascular risk.³¹ Trials of long-term oral hormone therapy evaluated whether risk of harms varied by a long list of patient characteristics.^44–47 Though results suggested that risk of breast cancer with estrogen/progestin compared to placebo may be greater with increased duration of prior postmenopausal hormone use, this was the only significant result out of many examined, and may have been due to chance. Strength of evidence was not assessed for effect modifiers.

Table B

Evidence on harms of long-term (>3 years) osteoporosis drug treatment.

Osteoporosis Drug Holidays

Variation in Harms as a Function of Patient, Bone, or Osteoporosis Drug Characteristics

We found no evidence about whether the risk of harms between continuation of any osteoporosis drug treatment and discontinuation varied as a function of patient, bone or drug characteristics.

Table C

Evidence on effects of osteoporosis drug continuation versus discontinuation on incident fractures.

Table D

Evidence on harms of osteoporosis drug continuation versus discontinuation.

Discussion

In long-term placebo-controlled trials, alendronate for 4 years reduced incident radiographic vertebral and nonvertebral fractures in women with osteoporosis, and zoledronate for 6 years reduced vertebral and nonvertebral fractures in women with osteopenia or osteoporosis. Observational studies suggested that long-term treatment with bisphosphonates as a class increased risk of AFF, ST/FSF, and ONJ, though these adverse events were rare. In women with osteoporosis, long-term raloxifene for 4 years reduced incident vertebral fractures, but not hip or nonvertebral fractures; long-term raloxifene also increased risk of deep vein thrombosis and pulmonary embolism. In women with unknown osteoporosis or osteopenia status, oral hormone therapy for 5–7 years reduced incident clinical and hip fractures compared with placebo, but increased risk of cardiovascular disease and cognitive impairment. Trials also showed that continuation of zoledronate or alendronate after 3–5 years of prior treatment versus discontinuation reduced some vertebral fracture outcomes but not others, did not reduce nonvertebral fractures, and observational data suggested that continuation of bisphosphonates as a class may increase risk of ST/FSF compared with discontinuation.

Whereas long-term treatment with alendronate reduced risk of incident clinical fractures compared with placebo in women with osteoporosis, it did not reduce fracture risk in women with osteopenia. Otherwise, risk of fracture with long-term alendronate versus placebo did not vary by history of prior fracture, World Health Organization Fracture Risk Assessment Tool (FRAX®) score, or pretreatment levels of bone turnover markers. Risk of incident fracture between long-term raloxifene and placebo did not vary as a function of age, baseline BMD, or history of prior fracture. Reduction in incident clinical fracture with oral hormone therapy compared with placebo appeared possibly greater in women aged 60–79 years than in younger women, though similar results were not found for hip fracture, suggesting possible chance findings. We found no information about possible modifiers of fracture risk with long-term zoledronate treatment.

Our findings have several clinical implications. In women with osteoporosis, indications for long-term raloxifene may be limited, because it only reduces vertebral fractures, while both long-term alendronate and zoledronate also reduced nonvertebral fractures. While the effects of long-term alendronate and zoledronate appear roughly similar in older women with osteoporosis, only long-term zoledronate also reduced nonvertebral fractures in women with osteopenia. It is unclear if these possibly discrepant findings are explained in part by differences in study populations (e.g., the zoledronate population was older). Unfortunately, there are no eligible long-term trials that directly compare alendronate and zoledronate in older women with osteopenia. While oral hormone therapies for 5–7 years lowered both clinical and hip fractures in women not selected to be at high fracture risk, and might be expected to have larger effects in those with osteoporosis, because fracture benefits were offset by risk of serious harms, these agents are not likely to be a viable option for long-term osteoporosis treatment. However, it is unknown whether a lower dose or different route of administration of hormone therapy would have a more favorable balance of fracture benefits to harms. In patients who have completed 3–5 years of bisphosphonate treatment, continued alendronate or zoledronate versus discontinuation each reduced one of two measures of incident vertebral fracture, but did not reduce nonvertebral fractures. Observational data suggested that long-term bisphosphonates increase risk of AFF, that risk likely increases with longer duration of treatment, and that these events are rare. Estimating the relative balance between benefits and harms, for every 1,000 women with osteoporosis treated with alendronate for 4 years or with osteopenia or osteoporosis treated with zoledronate for 6 years compared with placebo, approximately 50 to 70 more will avoid an incident clinical fracture, while an additional 2 will experience a ST/FSF. Since only a minority of ST/FSF meet AFF criteria, the absolute number of additional AFF would be expected to be smaller. Analogously, for every 1,000 women previously treated for osteopenia or osteoporosis with 3 to 5 years of alendronate or zoledronate who continue bisphosphonate treatment another 3 to 5 years, compared with discontinuation, approximately 30 more will avoid an incident vertebral fracture, while an additional 1 will experience a ST/FSF. However, the inconsistency of the vertebral fracture results, the uncertainty around the outcome risk estimates, and the fact that relatively few ST/FSF meet AFF criteria, suggest that the ratio of these fracture benefits to AFF harms with bisphosphonate continuation could be either substantially larger or smaller. Evidence appeared less robust for ONJ, but suggested long-term bisphosphonate treatment also may increase risk of this outcome. Data from eligible studies did not identify clear patient, bone or drug characteristics that modify likelihood of fracture benefits or harms with long-term or continuing osteoporosis drug treatment.

Limitations

The available data limit this review in several ways. First, there were few unique trials of long-term osteoporosis drug treatment or of drug discontinuation, and only one trial that included a treatment arm involving osteoporosis drug discontinuation and subsequent osteoporosis drug resumption. We often identified only one trial for a given treatment comparison. Second, only two trials were designed with incident fracture as the primary outcome. Consequently, many studies had few incident clinical fractures, especially for hip fractures, and statistical power often was low to precisely estimate differences in their risk between treatment interventions. Third, all trials were conducted in generally health, usually white, postmenopausal women, limiting their generalizability. Further, most of the trials were conducted in populations selected for osteoporosis or osteopenia by BMD or radiographic vertebral fracture criteria. Generalizability of results to populations who have other reasons for heightened fracture risk is unknown. Fourth, observational studies investigating the association between treatment and risk of AFF or ONJ had marked methodologic differences that likely affected the specificity of these outcomes and the associated risk estimates. Major differences included the definitions of the cases (e.g., whether or not fractures were defined using American Society for Bone and Mineral Research [ASBMR] radiographic AFF features) and noncase controls, drug therapy exposure and control groups, and adjustment for possible confounding. Fifth, reporting on harms was sparse and inconsistent between studies, limiting confidence around harms risk estimates, and raising concerns about possible reporting bias. Sixth, few studies reported information about possible effect modifiers of drug treatment outcomes. These analyses were almost entirely post hoc, often did not test for interactions between potential effect modifiers, treatment assignment, and treatment outcomes, and did not test for multiple testing, raising the likelihood of type 1 errors. Seventh, there were no eligible long-term fracture trials for several U.S. Food and Drug Administration (FDA) approved osteoporosis drugs, including risedronate, ibandronate, teriparatide, and abaloparatide; long-term fracture data for denosumab came from only one small trial in which the pooling of fracture data from different intervention groups made interpretation impossible. There also were no eligible trials of sequential treatment, such as with an anabolic followed by an anti-resorptive, or denosumab followed by bisphosphonate. Finally, there were no usable data comparing different durations of osteoporosis drug holidays.

Research Needs

Future trials of long-term osteoporosis drug treatment and osteoporosis drug continuation versus discontinuation should be designed with adequate statistical power to assess risks of clinical fracture endpoints, including hip fractures, the fracture type with the greatest risk of morbidity and mortality. Broader trial samples that include men, nonwhite women, more adults with comorbidities, and adults aged 80 years and older are needed to improve generalizability. Future long-term trials should evaluate sequential osteoporosis drug treatment, including comparisons of anabolic therapy followed by antiresorptive therapy, and denosumab followed by bisphosphonate therapy, with both compared with continuous long-term antiresorptive therapy. Trials should compare continuous long-term osteoporosis drug treatment to different osteoporosis drug holiday durations, with or without restarting osteoporosis drug therapy, and possibly with repeating cycles of osteoporosis drug therapy alternating with drug holidays. Future studies should systematically collect, analyze and report harms data. Randomized trials will continue to have limited statistical power to estimate the risk of rare treatment harms such as AFF and ONJ, so observational studies will be essential for examining these outcomes. These observational studies should use consensus case definitions,^{64, 65} standard non-case and exposure controls, cohort designs to estimate incidence rates, and adequate statistical adjustment to reduce the effects of confounding by indication and selection bias. Observational studies may provide insights about the benefits and harms of drug holidays of different durations and about patient and treatment characteristics that predict which patients are likely to benefit or be harmed by treatment continuation versus discontinuation.^{66, 67} Future trials and observational studies should pre-specify analyses to investigate possible effect modifiers of benefits and harms of long-term osteoporosis drug treatment and drug holiday outcomes. Among other factors, these should include age, and BMD and bone markers before and during long-term treatment or drug holidays. Patient-level data from osteoporosis drug trials on the associations of early treatment changes in BMD and bone turnover markers with risk of incident fractures may improve understanding of the potential use and limitations of these measures as surrogates for incident fracture.^68–70

Conclusions

Only alendronate, zoledronate, and oral hormone therapy reduced nonvertebral fractures with long-term treatment. However, for all these agents, these fracture benefits were limited to mostly older, postmenopausal women. They were further limited to women with osteopenia or osteoporosis for zoledronate, and to women with osteoporosis for alendronate. Absolute reductions in clinical fractures with long-term bisphosphonates appeared far greater than absolute increases in risk of AFF and ONJ with these treatments. However, reductions in hip fracture with long-term oral hormone therapy appear offset by risk of serious harms. In patients with prior osteoporosis drug treatment, continued treatment appeared to reduce vertebral fractures but not nonvertebral fractures, and may increase risk of AFF. While fracture benefits of continued osteoporosis drug treatment versus drug holiday numerically appeared to outweigh these risks, the more limited morbidity prevented and greater uncertainty about the outcome measures and risk estimates require further investigation to better inform clinical decisions about continuing treatment. This research should include examination of how these benefits and risks vary as a function of patient, bone, and drug treatment characteristics (e.g., age, sex, comorbidity, pre-drug holiday BMD, duration of prior osteoporosis drug treatment). Future modeling studies also may incorporate probabilities of experiencing fracture-related morbidity to help patients weigh trade-offs of treatment more easily.

References

1.

Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 1993 Jun;94(6):646–50. PMID: 8506892. [PubMed: 8506892]

2.

Wright NC, Looker AC, Saag KG, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014 Nov;29(11):2520–6. doi: 10.1002/jbmr.2269. PMID: 24771492. [PMC free article: PMC4757905] [PubMed: 24771492] [CrossRef]

3.

Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007 Mar;22(3):465–75. doi: 10.1359/jbmr.061113. PMID: 17144789. [PubMed: 17144789] [CrossRef]

4.

Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. 2006 Dec;17(12):1726–33. doi: 10.1007/s00198-006-0172-4. PMID: 16983459. [PubMed: 16983459] [CrossRef]

5.

Schousboe JT. Epidemiology of Vertebral Fractures. J Clin Densitom. 2016 Jan-Mar;19(1):8–22. doi: 10.1016/j.jocd.2015.08.004. PMID: 26349789. [PubMed: 26349789] [CrossRef]

6.

Katsoulis M, Benetou V, Karapetyan T, et al. Excess mortality after hip fracture in elderly persons from Europe and the USA: the CHANCES project. J Intern Med. 2017 Mar;281(3):300–10. doi: 10.1111/joim.12586. PMID: 28093824. [PubMed: 28093824] [CrossRef]

7.

Miller PD, Hattersley G, Riis BJ, et al. Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis: A Randomized Clinical Trial. JAMA. 2016 Aug 16;316(7):722–33. doi: 10.1001/jama.2016.11136. PMID: 27533157. [PubMed: 27533157] [CrossRef]

8.

Qaseem A, Forciea MA, McLean RM, et al. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Ann Intern Med. 2017 Jun 6;166(11):818–39. doi: 10.7326/M15-1361. PMID: 28492856. [PubMed: 28492856] [CrossRef]

9.

Adler RA, El-Hajj Fuleihan G, Bauer DC, et al. Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016 Jan;31(1):16–35. doi: 10.1002/jbmr.2708. PMID: 26350171. [PMC free article: PMC4906542] [PubMed: 26350171] [CrossRef]

10.

Sellmeyer DE. Atypical fractures as a potential complication of long-term bisphosphonate therapy. JAMA. 2010 Oct 6;304(13):1480–4. doi: 10.1001/jama.2010.1360. PMID: 20924014. [PubMed: 20924014] [CrossRef]

11.

Compston J, Bowring C, Cooper A, et al. Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013. Maturitas. 2013 Aug;75(4):392–6. doi: 10.1016/j.maturitas.2013.05.013. PMID: 23810490. [PubMed: 23810490] [CrossRef]

12.

Watts NB, Bilezikian JP, Camacho PM, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis: executive summary of recommendations. Endocr Pract. 2010 Nov-Dec;16(6):1016–9. PMID: 21216723. [PMC free article: PMC4890158] [PubMed: 21216723]

13.

Cummings SR, Ferrari S, Eastell R, et al. Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res. 2018 Feb;33(2):190–8. doi: 10.1002/jbmr.3337. PMID: 29105841. [PubMed: 29105841] [CrossRef]

14.

Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998 Dec 23–30;280(24):2077–82. PMID: 9875874. [PubMed: 9875874]

15.

Reid IR, Horne AM, Mihov B, et al. Fracture prevention with zoledronate in older women with osteopenia. New England Journal of Medicine. 2018. 379(25):2407–2416. [PubMed: 30575489]

16.

Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab. 2002 Aug;87(8):3609–17. doi: 10.1210/jcem.87.8.8750. PMID: 12161484. [PubMed: 12161484] [CrossRef]

17.

Siris ES, Harris ST, Eastell R, et al. Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study. J Bone Miner Res. 2005 Sep;20(9):1514–24. doi: 10.1359/JBMR.050509. PMID: 16059623. [PubMed: 16059623] [CrossRef]

18.

Miller PD, Bolognese MA, Lewiecki EM, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008 Aug;43(2):222–9. doi: 10.1016/j.bone.2008.04.007. PMID: 18539106. [PubMed: 18539106] [CrossRef]

19.

Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the women’s health initiative randomized trial. J Bone Miner Res. 2006 Jun;21(6):817–28. doi: 10.1359/jbmr.060312. PMID: 16753012. [PubMed: 16753012] [CrossRef]

20.

Wimalawansa S, J. A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. American Journal of Medicine. 1998 Mar;104(3):219–26. PMID: 9552083. [PubMed: 9552083]

21.

Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA. 2003 Oct 1;290(13):1729–38. doi: 10.1001/jama.290.13.1729. PMID: 14519707. [PubMed: 14519707] [CrossRef]

22.

Quandt SA, Thompson DE, Schneider DL, et al. Effect of alendronate on vertebral fracture risk in women with bone mineral density T scores of-1.6 to −2.5 at the femoral neck: the Fracture Intervention Trial. Mayo Clin Proc. 2005 Mar;80(3):343–9. PMID: 15757015. [PubMed: 15757015]

23.

Ryder KM, Cummings SR, Palermo L, et al. Does a history of non-vertebral fracture identify women without osteoporosis for treatment? J Gen Intern Med. 2008 Aug;23(8):1177–81. doi: 10.1007/s11606-008-0622-0. PMID: 18459010. [PMC free article: PMC2517956] [PubMed: 18459010] [CrossRef]

24.

Donaldson MG, Palermo L, Ensrud KE, et al. Effect of alendronate for reducing fracture by FRAX score and femoral neck bone mineral density: the Fracture Intervention Trial. J Bone Miner Res. 2012 Aug;27(8):1804–10. doi: 10.1002/jbmr.1625. PMID: 22492479. [PubMed: 22492479] [CrossRef]

25.

Bauer DC, Garnero P, Hochberg MC, et al. Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res. 2006 Feb;21(2):292–9. doi: 10.1359/JBMR.051018. PMID: 16418785. [PubMed: 16418785] [CrossRef]

26.

Johnell O, Cauley JA, Kulkarni PM, et al. Raloxifene reduces risk of vertebral fractures [corrected] in postmenopausal women regardless of prior hormone therapy. J Fam Pract. 2004 Oct;53(10):789–96. PMID: 15469774. [PubMed: 15469774]

27.

Sontag A, Wan X, Krege JH. Benefits and risks of raloxifene by vertebral fracture status. Curr Med Res Opin. 2010 Jan;26(1):71–6. doi: 10.1185/03007990903427082. PMID: 19908937. [PubMed: 19908937] [CrossRef]

28.

Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat. 2001 Jan;65(2):125–34. PMID: 11261828. [PubMed: 11261828]

29.

Barrett-Connor E, Cauley JA, Kulkarni PM, et al. Risk-benefit profile for raloxifene: 4-year data From the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. J Bone Miner Res. 2004 Aug;19(8):1270–5. doi: 10.1359/JBMR.040406. PMID: 15231013. [PubMed: 15231013] [CrossRef]

30.

Barrett-Connor E, Cox DA, Song J, et al. Raloxifene and risk for stroke based on the framingham stroke risk score. Am J Med. 2009 Aug;122(8):754–61. doi: 10.1016/j.amjmed.2009.01.033. PMID: 19540454. [PubMed: 19540454] [CrossRef]

31.

Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA. 2002 Feb 20;287(7):847–57. PMID: 11851576. [PubMed: 11851576]

32.

Duvernoy CS, Kulkarni PM, Dowsett SA, et al. Vascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial: incidence, patient characteristics, and effect of raloxifene. Menopause. 2005 Jul-Aug;12(4):444–52. doi: 10.1097/01.GME.0000151653.02620.89. PMID: 16037760. [PubMed: 16037760] [CrossRef]

33.

Ensrud K, Genazzani AR, Geiger MJ, et al. Effect of raloxifene on cardiovascular adverse events in postmenopausal women with osteoporosis. Am J Cardiol. 2006 Feb 15;97(4):520–7. doi: 10.1016/j.amjcard.2005.09.083. PMID: 16461049. [PubMed: 16461049] [CrossRef]

34.

Grady D, Cauley JA, Stock JL, et al. Effect of Raloxifene on all-cause mortality. Am J Med. 2010 May;123(5):469 e1–7. doi: 10.1016/j.amjmed.2009.12.018. PMID: 20399327. [PubMed: 20399327] [CrossRef]

35.

Grady D, Ettinger B, Moscarelli E, et al. Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol. 2004 Oct;104(4):837–44. doi: 10.1097/01.AOG.0000137349.79204.b8. PMID: 15458908. [PubMed: 15458908] [CrossRef]

36.

Martino S, Cauley JA, Barrett-Connor E, et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst. 2004 Dec 1;96(23):1751–61. doi: 10.1093/jnci/djh319. PMID: 15572757. [PubMed: 15572757] [CrossRef]

37.

Martino S, Disch D, Dowsett SA, et al. Safety assessment of raloxifene over eight years in a clinical trial setting. Curr Med Res Opin. 2005 Sep;21(9):1441–52. doi: 10.1185/030079905X61839. PMID: 16197663. [PubMed: 16197663] [CrossRef]

38.

Schilcher J, Koeppen V, Aspenberg P, et al. Risk of atypical femoral fracture during and after bisphosphonate use. Acta Orthop. 2015 Feb;86(1):100–7. doi: 10.3109/17453674.2015.1004149. PMID: 25582459. [PMC free article: PMC4366670] [PubMed: 25582459] [CrossRef]

39.

Lim SJ, Yeo I, Yoon PW, et al. Incidence, risk factors, and fracture healing of atypical femoral fractures: a multicenter case-control study. Osteoporosis International. 2018. doi: 10.1007/s00198-018-4640-4. PMID: 623239244. [PubMed: 30039251] [CrossRef]

40.

Black DM, Abrahamsen B, Bouxsein ML, et al. Atypical Femur Fractures–Review of epidemiology, relationship to bisphosphonates, prevention and clinical management. 2018. [PubMed: 30169557]

41.

Vestergaard P, Schwartz K, Rejnmark L, et al. Oral bisphosphonate use increases the risk for inflammatory jaw disease: a cohort study. J Oral Maxillofac Surg. 2012 Apr;70(4):821–9. doi: 10.1016/j.joms.2011.02.093. PMID: 21764202. [PubMed: 21764202] [CrossRef]

42.

Lin TC, Yang CY, Kao Yang YH, et al. Incidence and risk of osteonecrosis of the jaw among the Taiwan osteoporosis population. Osteoporos Int. 2014 May;25(5):1503–11. doi: 10.1007/s00198-014-2624-6. PMID: 24515577. [PubMed: 24515577] [CrossRef]

43.

Chiu WY, Chien JY, Yang WS, et al. The risk of osteonecrosis of the jaws in Taiwanese osteoporotic patients treated with oral alendronate or raloxifene. J Clin Endocrinol Metab. 2014 Aug;99(8):2729–35. doi: 10.1210/jc.2013-4119. PMID: 24758181. [PubMed: 24758181] [CrossRef]

44.

Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003 May 28;289(20):2651–62. doi: 10.1001/jama.289.20.2651. PMID: 12771112. [PubMed: 12771112] [CrossRef]

45.

Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2947–58. doi: 10.1001/jama.291.24.2947. PMID: 15213206. [PubMed: 15213206] [CrossRef]

46.

Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321–33. PMID: 12117397. [PubMed: 12117397]

47.

Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004 Apr 14;291(14):1701–12. doi: 10.1001/jama.291.14.1701. PMID: 15082697. [PubMed: 15082697] [CrossRef]

48.

Park-Wyllie LY, Mamdani MM, Juurlink DN, et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA. 2011 Feb 23;305(8):783–9. doi: 10.1001/jama.2011.190. PMID: 21343577. [PubMed: 21343577] [CrossRef]

49.

Kim SY, Schneeweiss S, Katz JN, et al. Oral bisphosphonates and risk of subtrochanteric or diaphyseal femur fractures in a population-based cohort. J Bone Miner Res. 2011 May;26(5):993–1001. doi: 10.1002/jbmr.288. PMID: 21542002. [PMC free article: PMC3179299] [PubMed: 21542002] [CrossRef]

50.

Black D, M. Kelly, M, P. Genant, H, K. Palermo, L, Eastell, R, Bucci, Rechtweg C, Cauley, J, Leung, P, C. Boonen, S, Santora, A, de, Papp A, Bauer, D, C. Fracture Intervention Trial, Steering Committee, Horizon Pivotal Fracture Trial Steering, Committee. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. New England Journal of Medicine. 2010 May 13;362(19):1761–71. PMID: 20335571. [PubMed: 20335571]

51.

Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res. 2009 Jun;24(6):1095–102. doi: 10.1359/jbmr.081247. PMID: 19113931. [PubMed: 19113931] [CrossRef]

52.

Vestergaard P, Schwartz F, Rejnmark L, et al. Risk of femoral shaft and subtrochanteric fractures among users of bisphosphonates and raloxifene. Osteoporos Int. 2011 Mar;22(3):993–1001. doi: 10.1007/s00198-010-1512-y. PMID: 21165600. [PubMed: 21165600] [CrossRef]

53.

Erviti J, Alonso A, Oliva B, et al. Oral bisphosphonates are associated with increased risk of subtrochanteric and diaphyseal fractures in elderly women: a nested case-control study. BMJ Open. 2013 Jan 30;3(1)doi: 10.1136/bmjopen-2012-002091. PMID: 23370011. [PMC free article: PMC3563115] [PubMed: 23370011] [CrossRef]

54.

Koh J, H., Myong J, P., Yoo J, et al. Predisposing factors associated with atypical femur fracture among postmenopausal Korean women receiving bisphosphonate therapy: 8 years’ experience in a single center. Osteoporosis International. 2017 01 Nov;28(11):3251–9. PMID: 617716961. [PubMed: 28748389]

55.

Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006 Dec 27;296(24):2927–38. doi: 10.1001/jama.296.24.2927. PMID: 17190893. [PubMed: 17190893] [CrossRef]

56.

Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004 Mar 18;350(12):1189–99. doi: 10.1056/NEJMoa030897. PMID: 15028823. [PubMed: 15028823] [CrossRef]

57.

Tonino RP, Meunier PJ, Emkey R, et al. Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. Phase III Osteoporosis Treatment Study Group. J Clin Endocrinol Metab. 2000 Sep;85(9):3109–15. doi: 10.1210/jcem.85.9.6777. PMID: 10999794. [PubMed: 10999794] [CrossRef]

58.

Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012 Feb;27(2):243–54. doi: 10.1002/jbmr.1494. PMID: 22161728. [PMC free article: PMC3427916] [PubMed: 22161728] [CrossRef]

59.

Black DM, Reid IR, Cauley JA, et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2015 May;30(5):934–44. doi: 10.1002/jbmr.2442. PMID: 25545380. [PubMed: 25545380] [CrossRef]

60.

Schwartz AV, Bauer DC, Cummings SR, et al. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res. 2010 May;25(5):976–82. doi: 10.1002/jbmr.11. PMID: 20200926. [PubMed: 20200926] [CrossRef]

61.

McClung M, Miller P, Recknor C, et al. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstetrics & Gynecology. 2009;114(5):999–1007. [PubMed: 20168099]

62.

Ensrud KE, Barrett-Connor EL, Schwartz A, et al. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension. J Bone Miner Res. 2004 Aug;19(8):1259–69. doi: 10.1359/JBMR.040326. PMID: 15231012. [PubMed: 15231012] [CrossRef]

63.

Adams AL, Adams JL, Raebel MA, et al. Bisphosphonate Drug Holiday and Fracture Risk: A Population-Based Cohort Study. Journal of Bone and Mineral Research. 2018 PMID: 622353500. [PubMed: 29529334]

64.

Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015 Jan;30(1):3–23. doi: 10.1002/jbmr.2405. PMID: 25414052. [PubMed: 25414052] [CrossRef]

65.

Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014 Jan;29(1):1–23. doi: 10.1002/jbmr.1998. PMID: 23712442. [PubMed: 23712442] [CrossRef]

66.

Adams AL LB, Ryan DS, Geiger EJ, Dell RM, Black DM. Do Drug Holidays Reduce Atypical Femur Fracture Risk?: Results from the Southern California Osteoporosis Cohort Study (SOCS). American Society for Bone and Mineral Research Annual Meeting, September 28-October 1, Montréal, Québec, Canada. 2018.

67.

Curtis J CR, Li Z, Arora T, Saag K, Wright N, Daigle S, Kilgore M, Delzell E. The Impact of Bisphosphonate Drug Holidays on Fracture Rates. American Society for Bone and Mineral Research Annual Meeting, September 28-October 1, Montréal, Québec, Canada. 2018.

68.

Bauer DC. Change in Bone Turnover as a Surrogate for Fracture Outcomes: A Novel Individual-level Analysis of Pooled Anti-resorptive Trials from the FNIH Bone Quality Study [abstract]. American Society for Bone and Mineral Research Annual Meeting, September 28-October 1, Montréal, Québec, Canada. 2018.

69.

Bauer DC, Black DM, Bouxsein ML, et al. Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Anti-Resorptive Drugs: A Meta-Regression. Journal of Bone and Mineral Research. 2018;33(4):634–42. [PubMed: 29318649]

70.

Black D. Change in BMD as a Surrogate for Fracture Risk Reduction in Osteoporosis Trials: Results from Pooled, Individual-level Patient Data from the FNIH Bone Quality Project [abstract]. American Society for Bone and Mineral Research Annual Meeting, September 28-October 1, Montréal, Québec, Canada. 2018.