Introduction
Osteoporosis is a chronic disorder that requires long-term treatment with pharmacologic therapy to ensure sustained anti-fracture benefit. Due to concerns about rare bone safety events, including atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ), questions have arisen regarding appropriate duration of treatment and whether efficacy, safety, and/or time-dependent thresholds should dictate when to discontinue therapy [
1,
2]. Bisphosphonates have a long terminal half-life in bone due to affinity to hydroxyapatite, and they are not metabolized. This has prompted the thinking that stopping therapy for an interval of time, commonly referred to as a “drug holiday,” could save medical costs while maintaining treatment benefits for at least some time, particularly in patients no longer at high risk of fracture [
3,
4]. Because of differences in mechanisms of action and metabolic clearance among different drug classes, the concept of a bisphosphonate drug holiday is not applicable to reversible, non-bisphosphonate treatments, including estrogen therapy, estrogen agonists/antagonists (raloxifene, bazedoxifene), parathyroid hormone analogues (teriparatide, abaloparatide), and the RANKL inhibitor denosumab. However, there are only limited data showing that treatment cessation with non-bisphosphonate bone active therapies may not be appropriate [
5‐
10].
Denosumab, a therapy for osteoporosis in men and postmenopausal women and for bone loss associated with hormone ablation therapy, is a fully human monoclonal antibody that binds to and inhibits RANKL. Treatment for up to 10 years results in continued gains in lumbar spine and total hip bone mineral density (BMD) without therapeutic plateau, with low fracture incidence, and a safety profile that remained consistent over time [
11‐
15]. Rare cases of femoral fractures with atypical features (
N = 2) and osteonecrosis of the jaw (
n = 8) have been observed with denosumab therapy up to 8 years [
14]. The original 4-year denosumab phase 2 dose-ranging trial was extended to 8 years to understand long-term effects of continued therapy [
16‐
20]. An additional 1-year observation study following the end of treatment was conducted to understand osteoporosis management strategies chosen by clinicians for patients with low bone mass who had received denosumab for up to 8 years. This report summarizes data from this final year.
Discussion
After completing the phase 2 clinical trial during which patients had received up to 8 years of denosumab treatment, most patients did not receive any medication for osteoporosis during the 1-year observation period. Most often, the patient’s physician had recommended that medication was no longer required. As is often the case, about half of the patients who began a prescription medication for osteoporosis after denosumab discontinuation stopped the therapy during the 1-year follow-up.
The decision by the patient and her personal physician not to continue therapy may have seemed reasonable since BMD on denosumab therapy had increased substantially, to average values well above the indications for treatment. However, unlike the skeletal effects of bisphosphonates which dissipate slowly, BMD decreases more quickly upon stopping more rapidly reversible agents such as estrogen, denosumab, and odanacatib [
18,
21‐
24]. Consistent with that knowledge, BMD decreased in our patients who stopped denosumab therapy and who did not take other osteoporosis medication. The rate of bone loss observed in those patients (6–7% in a year) was similar to that seen in earlier studies, although our patients had received therapy much longer. This suggests that long-term denosumab therapy, although resulting in large gains in BMD, does not protect patients from bone loss when therapy is discontinued. However, because the patients had experienced such large increases in BMD during the phase 2 trial, the lumbar spine BMD remained well above the phase 2 trial baseline 1 year after discontinuation, while the total hip BMD fell back to the average baseline value.
Taking an osteoporosis medication after stopping denosumab appeared to attenuate this decline in BMD. This is consistent with the observation that alendronate prevents bone loss upon stopping estrogen, parathyroid hormone, or denosumab therapy [
25‐
27]. In the latter study, postmenopausal women with low bone mass who had received denosumab for 1 year were switched to weekly alendronate therapy. The increase in BMD that had occurred with denosumab therapy was preserved during 1 year of alendronate therapy.
Eight of the 82 patients (9.8%) experienced one or more osteoporotic fractures during the 1-year observation study after stopping denosumab therapy. The incidence of osteoporotic fracture was 4.9% in patients who were receiving denosumab during years 5–8 of the phase 2 study [
20]. All patients in the observation study who experienced a fracture had at least one predisposing risk factor for fracture (e.g., prior fragility fracture, low BMD, advanced age). None of the patients with fractures had received osteoporosis treatment after stopping denosumab before their fractures occurred.
There is theoretical concern about a possible increased risk of fracture upon stopping estrogen or denosumab due to the rebound in bone turnover to values above pretreatment levels and the accompanying interval of rapid bone loss [
18,
28]. This concern is based on evidence that high bone turnover is a risk factor for fracture [
29]. Protection from fragility fractures appears to persist for at least several months after stopping teriparatide therapy [
9,
10]. However, in that setting, bone turnover decreases upon stopping therapy, in contrast to the large increase in turnover upon stopping estrogen or denosumab. Observational studies suggest that fracture risk increases upon stopping estrogen therapy, but whether there is an increase in risk above that seen in untreated women cannot be determined in those studies [
5‐
7]. A careful analysis of women in the Women’s Health Initiative (WHI) study demonstrated that hip and vertebral fracture risk after stopping estrogen therapy quickly returned to but did not rise above that observed in the group that had received placebo [
8].
Fracture incidence after denosumab therapy cessation has been evaluated in five clinical trials: an earlier part of this phase 2 dose-ranging study in postmenopausal women with low bone mass [
18], pivotal phase 3 fracture trial in postmenopausal women with osteoporosis (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months [FREEDOM] Study [
30]), phase 3 BMD study in postmenopausal women with low bone mass [
23], phase 3 prostate cancer study (Hormone Ablation Therapy [HALT] Study [
31]), and phase 3 breast cancer study (HALT; [data on file]). While these 5 studies in 2671 patients do not demonstrate an excess in fracture risk after discontinuation of denosumab, only the patients in the FREEDOM study had osteoporosis prior to treatment. In that study by Brown and colleagues [
30], the average duration of denosumab therapy was 3.4 doses (less than 2 years), and the median follow-up after stopping therapy was 0.8 years (maximum 24 months). In the 327 women who had discontinued denosumab, the incidence of both vertebral fracture and osteoporotic fracture was lower than that in the 470 women who had discontinued placebo therapy.
Multiple or severe vertebral fractures occurring soon after stopping denosumab therapy have recently been described in five patients, four of whom had osteoporosis before treatment, who had received five to six doses of denosumab [
32‐
34]. Like those patients, most of the vertebral fractures noted during the year of our observation study occurred within 3 to 4 months of treatment cessation, that is, 9 to 10 months after receiving their last dose of denosumab. The incidence of clinical vertebral fractures in our study (7/84 or 8% in 12 months) appears to be higher than was observed in women discontinuing estrogen therapy in the Women’s Health Initiative (WHI) study (<0.5%) [
8]. The women in our study were enrolled on the basis of low bone mass, which was not the case in the WHI. All of our patients who experienced vertebral fractures had a lumbar spine BMD T-score of −2.3 or lower at the beginning of the phase 2 study. Moreover, four of the seven patients in the observation study who experienced vertebral fracture, as well as both of the patients who were not in the observational study but who were known to have had a vertebral fracture after stopping denosumab, had a lumbar spine BMD T-score less than −2.5 at the phase 2 study baseline. Thus, it is possible that women in our study who had osteoporosis and the associated disruption of trabecular microarchitecture are more susceptible to vertebral fracture if high bone remodeling and rapid bone loss occurs upon stopping therapy than were patients in the WHI study who were generally younger, had higher bone density, and, probably, better trabecular structure.
Few studies have explored long-term management strategies in osteoporosis. This study is the first that involves a reversible treatment for osteoporosis. The emergence of rare bone safety concerns—ONJ and AFF—has prompted the thought that these events may be related to long treatment duration with bisphosphonates and denosumab. In many regions, health authorities have updated product labeling for bisphosphonates to encourage assessment of benefit/risk after 3–5 years of treatment before consideration of continuing treatment. The implication (to date unproven) is that a proposed “drug holiday or treatment cessation” will reduce the risks of ONJ and AFF. These and other potential rare risks of osteoporosis medication should not deter clinicians from treating patients with osteoporosis with an increased fracture risk. Indeed, in appropriately selected patients, the risk of fragility fracture is far higher than risk of ONJ or AFF, with the benefits of treatment far outweighing the risks [
35]. The results of this study make it clear that a “drug holiday” or “treatment cessation” is not appropriate for patients with osteoporosis who have been on long-term denosumab treatment.
We recognize that our study has many limitations, including its small size, observational design, the lack of spinal radiographs prior to and at the end of the study, and it not being planned to evaluate the effects of therapy on BMD or fracture risk during the observation study. The experience described here, however, reinforces our knowledge that, consistent with the drug’s mechanism of action, treatment cessation after long-term therapy is associated with reversibility of the treatment effect, including protection from vertebral fracture. The finding of an increase in fracture risk after stopping denosumab therapy is not surprising and may be similar to the loss of fracture protection observed upon stopping estrogen therapy. Given the small number of patients in our study and the lack of a control group, the question of whether an interval of excess risk occurs in women with osteoporosis when denosumab therapy is stopped cannot be answered. Our results do add to the evidence that transitioning to another osteoporosis therapy attenuates bone loss upon stopping denosumab.
Osteoporosis is a chronic condition requiring long-term if not indefinite treatment, especially in high-risk patients. While denosumab therapy increases BMD and reduces fracture risk, the disruption of trabecular architecture caused by osteoporosis is not reversed with treatment. The suggestion of a loss of fracture protection, which appears as an increase in fracture frequency after stopping denosumab therapy, is not surprising given its reversible mechanism and may be similar to the loss of fracture protection observed upon stopping estrogen therapy [
8]. There are few reasons to discontinue denosumab therapy. However, if denosumab treatment is discontinued for any reason, it seems very prudent that therapy with another anti-remodeling agent, such as a long-acting bisphosphonate, should be continued in patients at high risk for fracture unless there is a compelling reason not to do so.