82.1

Introduction

The primary goal of osteoporosis treatment is the prevention of fragility fractures, and several treatments have been shown to reduce this risk within 1 year for vertebral fractures, and within 18–36 months for nonvertebral fractures. As osteoporosis is a chronic condition, the optimal duration of treatment is an important decision that depends on individual risk, as well as the benefits and risks of long-term therapy all of which can vary at different ages due to changes in underlying risk of clinical events. Few guidelines have taken these factors into consideration in order to provide some help for clinicians to make decisions about when to stop, continue, or switch therapy . In addition, these guidelines have mostly considered treatment with bisphosphonates and have been rather conservative (i.e., 3–5 years of treatment in general and stopping when bone mineral density (BMD) greater than −2.5 T -score in the absence of recent fracture) and/or driven primarily by potential safety issues (such as increasing risk of atypical femur fracture after 5 years of bisphosphonates use). Stopping therapy prematurely however has consequences, particularly in subjects remaining at higher risk or when the benefits of therapy are quickly reversible, such as after denosumab . More recent data however provide evidence that achieving better BMD values on long-term denosumab further reduces fracture risk , whereas the use of bone-forming agents such as teriparatide, abaloparatide, and romosozumab before antiresorptives appears to provide faster and more thorough benefit for high-risk patients . These new data are leading us to reconsider the optimal duration and strategies of osteoporosis therapy, as driven by the goals to be achieved not only short-term but also long-term.

82.2

Hormone therapy and selective estrogen modulators

In patients who enter the menopause with low BMD (near or below osteoporosis range without fractures), medication should be used to prevent further deterioration of skeletal mass and structure and can include estrogen/hormone therapy (ET/HT), selective estrogen modulators (SERMs), and the combination of estrogen and bazedoxifene (CEE/BZA) . ET/HT and SERMs could be used in logical sequence from the 50s through the mid or late 60s, to help bridge the gap from menopause to older age when fracture risk is much higher, and more potent agents should be employed. It should be noted that the reduction of fracture risk observed while on HT seems to be maintained a few years upon cessation of therapy .

For patients with active hot flashes, low-dose ET/HT (as needed to treat the menopausal symptoms) or CEE/BZA is most appropriate . At some point after about 5 years, a tapering of the ET/HT dose might be warranted, particularly for those on HT (including progestins) where longer duration of treatment might increase risk of breast cancer . For women on ET only and those on CEE/BZA, the duration of therapy can be longer, because of fewer safety concerns, but attempts to wean women off these agents as they approach the decade of the 60s are still usually warranted.

For those who can successfully navigate off ET/HT, raloxifene or BZA is a reasonable second choice. SERMs are also a good first choice for women in the 50s–60s who do not have menopausal symptoms and therefore do not require an estrogenic agent. SERMs are also an excellent choice for women at mild–moderate risk of fracture who are at increased risk of breast cancer (such as history of proliferative breast lesions, family history, high breast density). Although there are no data confirming that raloxifene reduces risk of hip and all nonvertebral fractures, raloxifene preserves spine bone mass, reduces risk of vertebral fracture even when used for 5–8 years , and reduces risk of estrogen-positive breast cancer. However, due to their relatively weak antiresorptive effects, SERMs have a limited ability to prevent deterioration of cortical bone and will therefore not provide long-term protection against hip BMD loss , although hip fracture risk is exceedingly low in women in this age-group, so the lack of hip fracture efficacy is not a significant limitation for these patients. However, this limitation becomes more important as women enter their late 60s and early 70s. At this stage, for women who remain at risk, switching to an agent, which confers protection against hip fracture, becomes more critical.

82.3

Bisphosphonates

For patients with moderate osteoporosis (BMD T -score in the range of −2.9 to −2.5, without fractures) in their late 60s and beyond (or younger women who cannot take ET/HT/SERMs), bisphosphonates become an option to improve and/or maintain BMD and reduce risk of fracture throughout the skeleton . In these women, it is estimated that there is about a 50% probability that women will attain a T -score above the osteoporosis range with 3–5 years of bisphosphonate treatment . It is therefore reasonable to start with an oral bisphosphonate once monthly or once weekly and move to intravenous (IV) zoledronic acid (Zol) 5 mg once yearly or IV ibandronate 3 mg every 3 months if there are tolerability and/or compliance issues and/or contraindications to the oral regimen. IV zoledronic acid also has the best evidence for secondary fracture prevention in women at imminent risk, that is, those who have suffered a recent hip fracture.

After a 3- to 5-year course of bisphosphonate treatment, if treatment goals are met, that is, no on-treatment fractures and BMD above −2.5 at the main skeletal sites, a temporary withdrawal of treatment is reasonable . Because they bind to bone mineral, bisphosphonates will provide some residual protection from fractures even after discontinuation of the medication. Nevertheless, the extension phase of the HORIZON trial found that patients on Zol annually for up to 6 years had a 50% lower risk of new morphometric vertebral fractures versus those who discontinued after 3 years. In contrast, the rate of nonvertebral fractures remained constant past the first 3 years, whether or not Zol was discontinued. However, absolute risk of both vertebral and nonvertebral fractures was low in patients who had a hip T -score above −2.5 after 3 years of annual Zol treatment. This led to the conclusion that the potential benefit of continued Zol treatment would be minimal beyond 3 years in patients who had already achieved a nonosteoporotic T -score . Moreover, BMD at the hip plateaued at +4% above baseline and did not increase further with 3 more years of continued therapy .

The FLEX study also showed that alendronate (ALN) therapy progressively increased BMD for up to 5 years, but continuation from 5 to 10 years was associated with a plateauing of BMD at hip. Similar to Zol, ALN discontinuation increased (clinical) vertebral fracture risk by about twofold, but no differences in nonvertebral fractures were observed whether or not ALN was discontinued for 5 years. As seen in the HORIZON Extension with Zol, in those subjects with hip T -scores of −2.5 or lower, absolute fracture rates after discontinuing ALN were substantially higher than in those patients who had achieved a nonosteoporotic hip T -score on treatment. Continuing ALN in those patients was associated with reduced risk of fracture, whereas continuing ALN in patients above this T -score was not .

The observations have led to the first recommendations from the American Society of Bone and Mineral Research regarding the duration of use of bisphosphonates (BPs) depending on the individualized risk after 3–5 years of therapy: when no fractures have occurred, the hip T -score is above −2.5 and the fracture probability is below the intervention threshold (20% by FRAX in the United States), treatment could be suspended . More recently though, these recommendations have been revisited and a treatment goal of hip T -score above −2 recommended for subjects at much higher risk, such as those with a recent vertebral fracture and those above 70 years .

Hence, for subjects remaining at substantial fracture risk after 3–5 years of bisphosphonate use, it is mandatory to pursue therapy. At that stage, switching to denosumab will provide greater BMD gains than continuing on a bisphosphonate , whereas switching to or adding teriparatide or abaloparatide may be most effective in women with prevalent vertebral fractures and/or low spine BMD . Switching from a bisphosphonate to romosozumab has also been shown to be beneficial for both spine and hip BMD and estimated bone strength .

It is important to point out that patients interrupting bisphosphonate therapy must be monitored thereafter for clinical fracture occurrence, height loss (which might suggest an incident vertebral fracture), BMD loss, and biochemical turnover marker increase. Another short course (3 years) of bisphosphonate treatment might be warranted in those who begin to lose BMD with losses that exceed least significant change (3%–4% in the spine, 4%–6% in the hip and femoral neck). Biochemical marker increments above least significant change might also be a sign that bisphosphonates should be started again, but there are really no confirmatory data at this time. Certainly, if a fracture occurs on therapy, medication treatment must be intensified and anabolic therapy is most appropriate at this stage (see next).

82.4

Denosumab

In postmenopausal women at moderate fracture risk and without prior treatment, denosumab has been shown to reduce vertebral, nonvertebral, and hip fractures within 3 years of therapy . Depending on the country, denosumab can be used either as first-line or as second-line therapy. Typically though, due to its extreme potency as an antiresorptive agent, it is often considered for patients at higher fracture risk, particularly those with very low BMD and/or older age, the latter also because it does not affect renal function.

In the extension phase of the FREEDOM trial, BMD of the lumbar spine and hip continued to improve with continuous denosumab therapy up to 10 years and fracture incidence remained low . Of note, a further drop in the incidence of nonvertebral fractures at year 4 was noted with denosumab, which was maintained for 7 and 10 years, particularly among those individuals whose hip T -score remained below −1 after 3 years . Altogether these data suggest a new target for long-term therapy, namely, the absence of fragility fractures and a hip T -score as close as possible to normal (more than −1.5) in order to minimize fracture risk . In contrast, discontinuation of denosumab was associated with a rapid increase in vertebral fracture risk to placebo levels, with an excess (+1%) in multiple vertebral fractures, particularly in women with previous vertebral fractures . In such patients, denosumab should either be continued or transitioned to a 1- to 2-year course of bisphosphonates such as ALN or zoledronate ; however, there is little evidence so far to determine the optimal regimen to prevent vertebral fractures and bone loss after withdrawal.

82.5

Anabolic therapies

In patients at very high risk, particularly those with a history of vertebral fracture, whether clinical or radiographic, anabolic therapy should be considered first-line therapy (though there may be limitations regarding reimbursement). In order to determine risk comprehensively, vertebral imaging must be done to find vertebral fractures, which most often occur without acute localizing symptoms at the time of the event . We recommend that women at age 65 who have a spine, total hip, or femoral neck T -score −1.5 or lower have a vertebral imaging test [either lateral X-ray or vertebral fracture assessment by dual X-ray absorptiometry (DXA)] as well as a bone density test . Some would argue that anabolic therapy should be considered first line for patients with osteoporosis-related fractures at any skeletal site. This is particularly important in patients with recent fracture (within the preceding 2 years); absolute fracture risk is particularly high immediately after the first incident event, approaching 20% in the first 2 years . Patients who have had multiple fractures are also at particularly high risk of subsequent fracture .

In contrast to the antiresorptive agents, anabolic therapies, which stimulate bone formation (teriparatide, abaloparatide, and romosozumab), produce rapid reductions in risk of fracture, within 12–19 months for both vertebral and nonvertebral skeletal sites .

There are also several powerful head-to-head comparator studies indicating that anabolic agents are superior to antiresorptive agents against fracture over 1–2 years. In glucocorticoid-induced osteoporosis, teriparatide reduced vertebral fractures by 90% compared to ALN over 18 months . In patients with acute painful vertebral fractures, teriparatide reduced vertebral fractures by 50% compared to risedronate over 1 year . In patients with prevalent vertebral fracture, teriparatide significantly reduced vertebral fractures and produced a nearly significant reduction in incidence of nonvertebral fractures compared to risedronate over 2 years . Also in patients with prevalent vertebral fracture (or recent hip fracture), romosozumab produced a significant reduction in the incidence of vertebral, nonvertebral, and hip fractures compared with ALN over 2–3 years .

Although patients who present with very low BMD, in the absence of a prior fracture, may not be at such high imminent risk for fracture, remaining lifetime fracture probability is very high. Sequential therapy with anabolic followed by antiresorptive agents provides the greatest gain in BMD and will likely produce the greatest protection from long-term fracture risk. In contrast, switching from bisphosphonate or denosumab to teriparatide results in a decline in hip BMD for at least a year, most prominently for women previously on denosumab . Therefore, when possible, anabolic therapy should be initiated first. For patients who are currently on a bisphosphonate or denosumab who need teriparatide or abaloparatide because of a fracture or declining BMD, it might be best to continue an antiresorptive (but perhaps a switch to the most potent agent would be preferable) and then add the anabolic medication. This recommendation is based on extrapolation from data where teriparatide was added to ongoing ALN and data where teriparatide and denosumab were combined de novo in patients who were primarily treatment naïve .

Romosozumab also has great potential for patients on either bisphosphonates or denosumab who require anabolic therapy. Because of its intrinsic antiresorptive action, it might be preferable as a single agent to anabolic agents that stimulate bone remodeling in this setting. Effects of a switch from ALN to romosozumab are superior to those of switching from ALN to teriparatide on hip BMD and strength, as well as spine BMD . Patients who are switched from denosumab to romosozumab have an increase in spine BMD and stable hip BMD.

When a course of anabolic therapy is followed by antiresorptive treatment, continued fracture protection is seen in patients originally randomized to anabolic therapy during the subsequent antiresorptive period where all patients receive active therapy. For example, in the ACTIVE Extension trial, patients randomized to either abaloparatide or placebo for 18 months were then transitioned to ALN for 2 subsequent years. The cumulative incidence of vertebral and nonvertebral fractures remained lower in the group originally treated with abaloparatide after 6 months of ALN and throughout the 2-year ALN treatment period . Similarly, in patients randomized to treatment with romosozumab compared with placebo for 1 year, followed by 2 years of denosumab treatment in all patients, fracture risk reductions were maintained over 2 years and over a full 3 years of therapy in the group that originally received romosozumab, despite the fact that all patients received active denosumab for 2 years of the 3-year study .

Finally, even high-risk patients may achieve treatment goals (remaining free of fracture and reaching target BMD T -score levels above −2.5 or −2) after several years of a treatment sequence of anabolic therapy followed by denosumab and then a bisphosphonate or just followed directly by a bisphosphonate. In that case, long-term BMD could be further maintained by intermittent injections of zoledronic acid that could be given as infrequently as once every 5 years in some patients.

82.6

Summary of treatment strategies by level of risk

In early menopausal women with low BMD, ET/HT and SERMs prevent further skeletal deterioration and bridge the gap to older age when fracture risk increases. However, such treatments should rarely be prescribed for more than 5 years and SERMs will provide limited protection against hip BMD loss over time. For patients with moderate osteoporosis (BMD without fractures) in their late 60s and beyond (or younger women who cannot take ET/HT/SERMs), bisphosphonates for 3–5 years will improve and/or maintain BMD and reduce risk of fracture throughout the skeleton. Although denosumab is not anabolic, it does result in continued long-term BMD accrual. However, it needs to be continued indefinitely or if stopped, replaced with a different osteoporosis agent. Use of IV zoledronic acid and/or oral bisphosphonates might allow denosumab withdrawal, though optimal timing and dosing to maintain full skeletal integrity are not yet known.

Anabolic agents have the capability to fundamentally change skeletal integrity with improved skeletal mass and structure, but evidence shows that the best effects are attained when these agents are used as first-line treatment rather than after other therapies. Therefore, when possible, anabolic therapies should be considered first line for fracture patients, especially in those with recent fracture and those with multiple fractures. Anabolic agents reduce fracture risk quickly and to a greater extent than antiresorptive medications and provide the bone mass and architectural foundation for greater long-term strengthening of the skeleton. Anabolic agents should be followed by denosumab, for greatest continued BMD gain and fracture risk reduction, or bisphosphonates for those who appear to be already at minimized risk after a course of anabolic treatment or in whom denosumab is contraindicated or not tolerated.

In any case, bisphosphonates should be used for some time at the end of a treatment sequence with denosumab and/or anabolics to maintain skeletal benefits. It might be necessary to repeat a course of anabolic therapy in the future if a fracture occurs or if BMD falls substantially after the intermission of bisphosphonates therapy. Alternatively, if BMD starts to decrease or bone turnover markers start to increase, another 1–2 years of antiresorptive treatment might be enough to maintain skeletal integrity.

82.7

Conclusion: goal-directed therapy

The duration of osteoporosis therapy should be guided by a constant reevaluation of the individual fracture risk. For postmenopausal women who remain at high risk of fractures (prevalent major fracture; T -score less than −2.5 or less than −2 if 65 years of age and older; receiving aromatase inhibitors or glucocorticoids) after an initial course of 3–5 years with BPs, switching to denosumab or switching/adding teriparatide or abaloparatide may be considered; whereas therapy may be interrupted in those at lower risk, with continuous monitoring (bone turnover markers (BTMs), BMD). For those who have been on denosumab for 4–5 years and have achieved a lower risk, switching to BPs for 12–24 months might then allow suspending all treatment (at least temporarily). For women who remain at high fracture risk after 5 years of denosumab and have not reached their ideal BMD target, denosumab could be continued for up to 10 years at least. If the risk remains very high though, or there is fracture recurrence, adding teriparatide or abaloparatide to denosumab or perhaps switching to romosozumab could be considered . In women at very high/imminent fracture risk, anabolic agents should be considered first, followed by antiresorptives, in order to expedite the restoration of bone mass and strength and to minimize fracture risk more rapidly and durably.