Osteoporosis is a systemic skeletal disease characterized by low bone mineral density (BMD) and deterioration of bone architecture, resulting in reduced bone strength and, consequently, increased susceptibility to fractures [1]. The clinical manifestation of osteoporosis is a fragility fracture, and about 80% of all fractures are osteoporosis-related [2]. As fractures are associated with a decrease in quality of life and an increase in premature mortality, disability, and financial burden [3–6], it is important to identify individuals at high and very high risk of fracture and to provide them with adequate therapeutic options.

A large gap currently exists in the primary prevention of fracture, and studies show that an estimated 80% to 90% of adults do not receive appropriate osteoporosis management even in the secondary prevention setting [2,7]. In contrast, approximately 90% of patients with cardiovascular disease are provided appropriate secondary preventive care [8]. System-level and country-level healthcare initiatives have been implemented worldwide to focus on addressing the secondary fracture prevention gap [9,10], with several reports showing these initiatives being effective in reducing not only subsequent fragility fracture rates, but also associated mortality [11–13]. Considering these data and the current fracture prevention gap, it is important to further improve knowledge on the optimal osteoporosis treatment regimen in the secondary prevention setting [14].

This publication addresses how best to use the pharmacological options available for postmenopausal osteoporosis to provide lifelong fracture protection in patients at high and very high risk of fracture. Managing patients with moderate fracture risk and drug holidays will not be addressed.

The Endocrine Society has recently published a clinical practice guideline update on Pharmacological Management of Osteoporosis in Postmenopausal Women [28], in which they proposed the following recommendations:

Head-to-head trials have documented the superiority of bone-forming agents (teriparatide [TPTD] or romosozumab) over antiresorptives (risedronate or alendronate) for reducing fractures in postmenopausal women at very high risk of fracture [29,30]. In these patients, the optimal sequence should be to initiate treatment with a bone-forming agent first followed by an antiresorptive, and not the reverse [31]. TPTD and romosozumab treatment should always be followed by an antiresorptive drug to prevent the rapid loss of BMD that occurs when treatment is stopped [32].

The mechanism of action of osteoporosis therapies is summarized in Fig. 1. Nitrogen-containing (amino-) bisphosphonates (BPs) impair osteoclast function by inhibiting farnesyl pyrophosphate synthase (FPPS), thereby preventing the prenylation of small GTPase proteins [32,33]. This results in disruption of cytoskeletal organization [34], loss of the ruffled membrane border [34], and altered vesicular trafficking [35]. In addition, while osteoclasts naturally undergo apoptosis, this process is accelerated in osteoclasts exposed to BPs [36]. BPs bind to bone mineral and are taken up by mature osteoclasts at sites of bone resorption [37]. BPs can remain bound to bone mineral for many years; those with greater binding affinities (zoledronic acid > alendronate > ibandronate > risedronate) possess longer skeletal residency [38]. Consequently, after BP discontinuation, bound BP provides residual pharmacological action for many years [38,39], in contrast to other anti-resorptive therapies in which activity is quickly lost after discontinuation (e.g., denosumab [DMAb], estrogen, raloxifene, and calcitonin) [40–42].

Although osteoblasts are not generally considered to be a target for BP inhibition, in vitro experiments provided direct evidence that inhibition of FPPS in osteoblasts may explain the blunting of the bone anabolic response to parathyroid hormone (PTH) observed after chronic exposure to BPs in rats [43]. BPs reduce prenylation of Rap1A, a small G protein participating in cytoskeletal reorganization in osteoblasts and allowing PTH to activate flat bone lining cells into cuboid, collagen-synthesizing osteoblasts [43]. Due to the inefficient uptake of BPs into osteoblasts by fluid-phase endocytosis [44], this mechanism is only observed after chronic treatment in vivo [43].

DMAb is a fully human monoclonal antibody that inhibits bone resorption by neutralizing with high affinity and specificity the receptor activator of nuclear factor-κB ligand (RANKL), a key mediator of osteoclast differentiation, function, and survival [45,46]. Unlike BPs, DMAb inhibits osteoclast activity at all developmental stages (prefusion, multinucleated, and resorbing mature osteoclasts) [37], leading to easier access to bone remodeling compartments in cortical bone than BPs [47]. DMAb is not incorporated into bone; therefore, its effect on bone resorption stops rapidly after treatment discontinuation [40].

TPTD, a recombinant human PTH, given subcutaneously once daily produces intermittent pulses of exogenous PTH, which stimulates bone remodeling (osteoblastic activity over osteoclastic activity). It also regulates reabsorption of calcium and phosphate in the kidney, and absorption of calcium in the intestine. Romosozumab inhibits sclerostin, a glycoprotein secreted by osteocytes. It acts as a modeling-based bone-forming agent with a dual effect on stimulating bone formation and, to a lesser extent, inhibiting bone resorption.

We will focus on long-term antiresorptive therapies because bone-forming therapies have a defined treatment duration (1 or 2 years). Once patients are diagnosed with osteoporosis, they will be at an increased risk for fracture for the rest of their lives. Even when patients’ BMD improves because of treatment, they will still be at increased risk for fracture and their risk for fracture will eventually return to baseline if they stop treatment. This is similar to what occurs in patients with controlled diabetes or hypertension.

The appropriate duration of antiresorptive therapy (BPs or DMAb) has become a topic of discussion, due to concern about the possible treatment interruption risk of osteonecrosis of the jaw (ONJ) and atypical femur fracture (AFF), and “drug holidays” (treatment interruption), particularly from BPs, have become common practice.

The safety concerns of antiresorptives have been recently reviewed [33]. Observational register-based studies and post-marketing reports based upon millions of patient-years and long-term (>5 years) clinical administration, have associated some previously-unknown, rare adverse events with antiresorptive use, including ONJ and subtrochanteric/diaphyseal AFFs [34–36]. These rare risks should always be integrated in a global perspective taking into account the benefit of long-term pharmacological therapy of postmenopausal osteoporosis (Fig. 2) [48].

The International Task Force on Osteonecrosis of the Jaw defined ONJ as: (1) exposed bone in the maxillofacial region that does not heal within 8 weeks after identification by a health care provider; (2) exposure to an antiresorptive agent; and (3) no history of radiation therapy to the craniofacial region” [34]. In the osteoporosis patient population, who receive much lower doses of antiresorptives (BPs or DMAb), the incidence of ONJ is very low, ranging from 0.15% (150 in 100,000) to less than 0.001% (1 in 100,000 person-years of exposure), which appears to be only slightly higher than that seen in the general population [34]. In the Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension (DMAb 60 mg subcutaneously every 6 months for up to 7 or 10 years in postmenopausal women with osteoporosis), 13 adjudicated cases of ONJ were reported, leading to an incidence of 0.05% (52 in 100,000 person-years of exposure) [37]. ONJ was slightly more common in women who had invasive oral procedures or events (0.68% vs. 0.05%); however, the overall rate remained low [38]. All cases of ONJ with complete follow-up resolved with treatment [38].

Factors associated with the development of ONJ include poor oral hygiene, glucocorticoid use, and invasive dental procedures such as dental extraction [34]. Therefore, it is suggested that patients should complete any invasive dental procedures before initiating an antiresorptive (BP or DMAb) to minimize the already small risk; however, those on treatment should not delay emergency dental procedures nor discount dental implants [34].

AFFs are insufficiency or fissure transverse fractures [39] originating on the lateral cortex of the subtrochanteric or diaphyseal (shaft) region of the femur and becoming oblique as they progress medially (medial spike) when complete [35,36].

Concern has arisen that long-term BP use may increase the risk of these fractures through a number of putative mechanisms including a prolonged reduction of bone remodeling. Incidence rates of AFF range from 1.8 per 100,000 cases per year with a 2-year BP exposure to 113.1 per 100,000 cases per year with BP exposure from 8 to 9.9 years [36]. However, only 2 AFFs (8 per 100,000 person-years) were reported with the prolonged use of DMAb (up to 7 or 10 years), a more potent antiresorptive, in treatment-naïve postmenopausal women with osteoporosis: one in the long-term group during year 4 of the extension (year 7 of DMAb treatment) and one in the crossover group during year 3 of the extension (year 3 of DMAb treatment) [37]. In postmenopausal women with osteoporosis previously treated with oral BPs (alendronate for a mean duration of 6.2 to 6.4 years), AFF was adjudicated in one of 321 patients transitioning to zoledronic acid (5 mg, intravenous) and in two of 322 patients transitioning to DMAb over 1 year [40]. Transition to a more potent antiresorptive in patients previously treated with long-term BPs could prevent the clearance of accumulated BPs from the bone matrix and increase the risk of AFF. This possibility would have to be assessed in a much larger population transitioning from oral BPs to intravenous zoledronic acid or DMAb.

Experts have proposed a “treat-to-target” strategy, in which a specific goal is set in order to achieve long-term fracture prevention (e.g., a total hip T-score between −2 and −1.5) [41] and therapy is individualized and periodically reassessed based on this goal [42]. Historically, BPs were the first-line treatment for osteoporosis, and physicians would consider another treatment after years of use or after a failure to respond. With treat-to-target, physicians select the drug or sequence of drugs most likely to achieve the target over a given period, which could be short (1 to 2 years for imminent risk of fracture) or long (10 years for high risk of fracture) [43]. It is important to note that achieving this goal does not mean patients can stop therapy.

Through a meta-regression analysis of clinical trials of all pharmacological therapies commercially available, Bouxsein et al. [44] demonstrated that improvements in BMD were strongly associated with reductions in hip and vertebral fractures. This suggests that BMD can be used as a target and as a surrogate endpoint for fracture risk.

The Endocrine Society guidelines recommend postmenopausal women at high risk for fracture continue BP therapy without interruption, if they remain at high risk after 3 to 5 years of therapy, but also state that there is little evidence to support any recommendation regarding duration of therapy [28]. In a systematic literature review of patients who discontinued BPs, the risk of new clinical fracture was 20% to 40% higher and the risk of vertebral fracture was almost double compared to the period on BPs [45], indicating that “drug holidays” may not be safe in all patients on BPs. Despite a lack of long-term evidence, we should approach osteoporosis similarly to chronic conditions like hypertension and diabetes, which we are confident in treating long-term.

Antiresorptive drugs, such as amino-BPs and more recently, DMAb, have dominated the landscape of osteoporosis therapies for the last three decades. Since osteoporosis is a chronic disease, anti-fracture therapy could conceivably continue for the rest of a patient’s life. We discussed how best to use the pharmacological options available for postmenopausal osteoporosis to provide lifelong fracture protection in patients at high and very high risk of fracture. The benefit of osteoporosis therapies far outweighs the rare risks.