Journal of Population Therapeutics & Clinical Pharmacology

Review Article DOI: 10.15586/jptcp.v26.i4.646

Pharmacological management of osteoporosis in postmenopausal women: The current state of the art Davide Gatti and Angelo Fassio Rheumatology Unit, University of Verona, Verona, Italy

Corresponding author: E-mail: [email protected]

Submitted: 3 October 2019. Accepted: 31 October 2019. Published: 20 November 2019.

ABSTRACT Osteoporosis is a common disease that increases fracture risk. Fragility fractures bring heavy consequences in terms of mortality and disability, with burdensome health and social costs. In subjects with clinical bone fragility, the first goal is to identify the secondary forms of osteoporosis, especially in young subjects, in males and in patients who recently experienced a fragility fracture. In addition, before considering any sort of treatment, it is fundamental to check for adequate calcium and vitamin D intake, since their deficiency is the most common reason for drug failure. In the last decade of the 20th century, several molecules have been developed and proved to be effective in achieving the true goal of any antiosteoporotic drug: fracture prevention. In this article, we considered the most commonly prescribed antiresorptive drugs (hormonal therapy, bisphosphonates, and denosumab), the anabolic agents (teriparatide), the dual-action drugs (romosozumab), and the drugs characterized by an unclear mechanism of action (strontium ranelate) to provide physicians with useful insights for their clinical practice. We discussed the main criteria for the appropriate choice selection and management of each treatment. Finally, we addressed the current con- troversies related to treatment discontinuation, sequential, and combination therapy. Keywords: osteoporosis; bone metabolism; bone mineral density; bisphosphonates; teriparatide; alendronate; zoledronate; risedronate; clodronate; hormonal therapy; TSEC; denosumab; romosozumab; strontium ranelate; combination therapy; sequential therapy

J Popul Ther Clin Pharmacol Vol 26(4):e1–e17; 20 November 2019. This article is distributed under the terms of the Creative Commons Attribution-Non Commercial 4.0 International License. ©2019 Davide Gatti and Angelo Fassio.

e1 Pharmacological management of osteoporosis in postmenopausal women

Osteoporosis is a chronic disease character- on postmenopausal osteoporosis, which currently ized by decreased bone mineral density (BMD) is the most studied and common form of bone and a deterioration of the bone micro-architec- fragility, with the aim of providing physicians ture that leads to an increased risk of fragility with useful insights for their clinical practice. fractures.1 This condition is mainly found in post- This article is a narrative overview on the menopausal women, but it can also affect men, pharmacological treatment of postmenopausal patients with other comorbidities or who are osteoporosis. When appropriated, the personal receiving treatment with drugs that affect bone opinions of the authors will be added in the text health (secondary osteoporosis). The definition and explicitly pointed out as such. of osteoporosis in clinical practice is based on We used as sources MEDLINE/PubMed, BMD measurement assessed by dual-energy EMBASE, and Cochrane Library, from incep- X-ray absorptiometry (DXA); the diagnosis is tion to 2019. made when the T-score at the femoral neck or In addition, we hand-searched references from spine is 2.5 standard deviations (SD) or more the retrieved articles and explored a number of below the young adults mean.2 related web sites. After discussion, we chose 68 In 2010, 22 million women and 5.5 million relevant papers. men were estimated to be affected by osteoporosis in Europe,3 with 3.5 million new fragility frac- REQUIREMENTS FOR THERAPY tures in the same year (610,000 hip fractures, A careful diagnosis of the nature of osteopo- 520,000 vertebral fractures, 560,000 forearm frac- rosis is fundamental for a correct treatment. A tures, and 1,800,000 other fractures). large and increasing number of diseases and Fragility fractures are associated with heavy drugs can contribute to bone fragility6 and these consequences in terms of mortality and disabil- conditions often require specific treatment. For ity, with burdensome health and social costs.4 these reasons, the first goal of the physician Their recovery is usually slow and often incom- should always be to identify the secondary forms plete.5 For these reasons, a large proportion of of osteoporosis, especially in young subjects, in fractured individuals is destined to lose function males and in people with recent fractures. Referral and independence and to suffer from persistent to a qualified specialist might be needed as well. pain and decreased quality of life.5 Another key requirement for therapy is an ade- Due to the progressive aging of the general quate vitamin D status. Recently, some large trials population, the annual incidence of fragility frac- and meta-analyses concluded that vitamin D sup- tures is expected to rise from 3.5 million in 2010 plementation has no beneficial effects neither on to 4.5 million in 2025.2 bone health, fracture risk nor falls,7 but these In the last three decades, pharmacological treat- statements require a critical analysis that cannot ments of osteoporosis have shown to be effective be limited to the raw results. As a matter of fact, and able to reduce the fracture risk by about 50%, most of these studies investigated the effects of with consequent benefits on the patients’ health sta- vitamin D supplementation in healthy (nonosteo- tus.4 Unfortunately, only a small proportion of porotic) subjects, not at significant risk for falling them is presently receiving adequate treatment.4 and, overall, without any vitamin D deficiency. In In this article, we summarized the most rele- such a scenario, data suggesting positive results vant data regarding the requirements for treat- would be indeed unexpected. In any case, these ment, different drug options, and the rationale of recent papers criticized the usefulness of vitamin sequential and combination therapy. We focused D supplementation with the goal to maintain or

e2 Pharmacological management of osteoporosis in postmenopausal women improve musculoskeletal health in the general the quick rise in the rate of bone resorption and population, but its role in patients receiving treat- therefore of bone loss, with an increase of the risk ment for osteoporosis is an entirely different topic. of osteoporosis.13 In young women in whom pre- It is well-known that, in these patients, adequate mature menopause is induced by surgery or cancer calcium and vitamin D intake are essential, and treatments, the estrogen drop can be particularly their deficiency represents the most common rea- marked and its adverse effects (AEs) on bone loss son for lack of response to any treatment,5,8,9 This and fracture risk are therefore greater.14,15 observation has been confirmed also in a recent Estrogens are key determinants of skeletal large retrospective study based on Italian admin- health due to their specific effects on bone metab- istrative databases.4 The study showed once again olism. For instance, they inhibit bone resorption that pharmacological treatments for osteoporosis by decreasing the signaling of the receptor activa- are associated with a lower risk for both refracture tor of nuclear factor-κB (RANKL), they induce and all-cause mortality to a greater extent when gene expression and synthesis of osteoprotegerin they are administered in combination with cal- (OPG), and they block osteoclastogenesis and cium and vitamin D.4 promote osteoclasts’ apoptosis.15 In addition, DRUGS FOR THE TREATMENT OF estrogens inhibit bone remodeling and decrease OSTEOPOROSIS the development of new basic multicellular units, probably by limiting osteocytes’ apoptosis and The main goal of the treatment for osteoporo- their production of sclerostin,15 a key inhibitor of sis is to decrease fracture risk. This often implies the Wnt pathway that is involved in the pathogen- the reduction of systemic bone loss and the stabi- esis of osteoporosis.16 lization or the increase of BMD. Hormone replacement therapy (HRT) was From the last decade of the last century, several routinely prescribed for primary prevention of molecules have been developed and proved effec- osteoporosis (independently of the presence of 10,11 tive in achieving these goals. The mechanism of menopausal symptoms) before the publication of action of the various drugs is defined by their rela- the Women’s Health Initiative (WHI)17 and of the tion to the bone cells on which they act (Table 1). epidemiological UK-based Million Women Hormonal Therapy Study.18 The results of these studies reported an The physiologic decline of estrogens in women association between HRT and an increased risk begins from 1 to 2 years before menopause and of breast and ovarian cancer. However, recent reaches its plateau about 1 to 2 years after the evidence showed that estrogen-alone therapy was menses cessation.12 The drop in estrogens explains not associated with any increase in mortality19 or

TABLE 1. Drugs Available for the Treatment of Osteoporosis Classified by Mechanism of Action Antiresorptive drugs: reducing the osteoclastic bone resorption • Estrogens and selective estrogen receptor modulators (SERMs) • Bisphosphonates • Denosumab Anabolic drugs: increasing the osteoblastic bone formation activity • Teriparatide Dual-action drugs: increasing the osteoblastic bone formation activity and reducing the osteoclastic bone resorption • Romosozumab Drugs with unclear mechanism of action • Strontium ranelate

e3 Pharmacological management of osteoporosis in postmenopausal women in the risk of breast cancer, even in the women Tibolone, after oral ingestion, is metabolized who carry the BRCA1 gene mutation.20 into three active molecules: two with estrogenic We need to remember that, in females who action and one with androgen and progestin carry the BRCA1 mutation, the cumulative risk of activities.25 Tibolone was shown to be as effective ovarian and breast cancer by age 80 is over 40 and as an estrogen–progestin combination treatment 70%, respectively.21 Prophylactic salpingo-oopho- in preventing postmenopausal bone loss and it rectomy is currently the only strategy able to can also increase muscle strength and lean body reduce the risk of both cancers. Unfortunately, the mass due to its androgen action.15 Similar to premature withdrawal of ovarian hormones HRT, tibolone is recommended only in subjects induced by this surgery causes long-term AEs that under 60 years of age, because the study that can be avoided, or at least limited, with HRT with- involved older women (age range 60–80 years) out a significant increase in cancer incidence.14,20 was prematurely stopped due to the evidence of For this reason, there is now a large scientific con- an increased risk of stroke in the treated arm.26 sensus that hormonal therapy at menopause rep- Selective estrogen receptor modulators resents an effective prevention strategy for (SERMs) are compounds with estrogen agonistic osteoporosis and fragility fractures, with an over- activities on some tissues (i.e., on bone) and antag- all favorable benefit to risk ratio when it is started onistic actions on other tissues (i.e., on breast and before 60 years of age and within 10 years from uterus), based on their different effects over differ- the last menses.15 ent estrogen receptors subtypes whose distribu- The hormonal options available for the treat- tion is specific for each target tissue.27 At present, ment and prevention of postmenopausal bone raloxifene (RLX), bazedoxifene (BZA) and laso- loss are HRT, tibolone, and SERMs. foxifene (LSX) are the SERMs with documented The efficacy of HRT in reducing the inci- evidence of efficacy for postmenopausal osteopo- dence of both vertebral and nonvertebral frac- rosis.15,28 They prevent bone loss and reduce the tures has been confirmed for almost 20 years.22 incidence of vertebral osteoporotic fractures in The analysis of the intervention and postinter- postmenopausal women.15,28 vention phases of large clinical trials showed a To date, RLX has not been demonstrated to different benefit to risk profile when we compare reduce the risk of hip fractures at currently the data of estrogen plus progestin to estro- approved doses, while BZA (20 mg/die), in a post gen-alone treated subjects.23,24 These two hor- hoc analysis on a subgroup at high fracture risk, monal treatments granted similar protection succeeded in reducing the risk of nonvertebral from fractures and similar improvement in BMD fracture both versus placebo and versus RLX (60 between them when compared to placebo, with a mg/die).29 The post hoc nature of this analysis better safety profile in women with prior hyster- called for caution in the interpretation of the ectomy receiving the estrogen-alone treatment results until the publication of the 2-years exten- both during the pharmacological intervention sion of the same study.30 At its conclusion, the and in the posttreatment follow-up period. trial confirmed the protective effect of BZA on Furthermore, the breast cancer and cardiovas- new vertebral fractures in postmenopausal cular (CV) disease findings tended to be worse in women with osteoporosis and on nonvertebral the arm treated with the estrogen-progestin fractures in the high-risk subgroup.30 In addition, combination, while no difference was found two meta-analyses performed an indirect com- between the placebo arm and the patients treated parison of the protective effect of BZA versus with estrogen alone.24 oral bisphosphonates (BPs) and estimated a

e4 Pharmacological management of osteoporosis in postmenopausal women similar efficacy on vertebral fractures and, in the symptoms: the SERM-estrogen combination, now subgroup at higher fracture risk, also on nonver- defined “tissue selective estrogen complex” tebral events.31,32 (TSEC).15,28 This strategy is noteworthy because LSX has been approved in Europe for the the addition of SERMs makes the progestin treatment of postmenopausal osteoporosis after unnecessary. Therefore, TSEC merges the positive a 5-year placebo-controlled randomized clinical clinical effects of estrogens alone (as already seen, trial (RCT) showed its efficacy in decreasing the they do not increase the risk of breast cancer), risk of both new vertebral and nonvertebral frac- with the efficacy and improved tolerability of tures (but not hip fractures).33 SERMs that antagonize their endometrial effects. Similar to HRT, SERMs can increase the risk Presently, the combination of BZA (20 mg/day) of venous thromboembolism (primarily deep with conjugated estrogens (0.45 mg/day) is the vein thromboses), but, differently from HRT, due only one approved in the class of TSEC. The posi- to their antagonist activity on the breast, SERMs tive clinical outcomes of large RCTs support the may decrease the risk of breast cancer.28 This was use of this combination therapy that can decrease shown to be true particularly for RLX, which in the frequency and severity of hot flushes, improve the United States is also approved for the preven- symptoms of vulvar and vaginal atrophy and pre- tion of breast cancer.28,34 No effect on endome- vent bone mass loss, independently of the number trial proliferation is reported with RLX and BZA, of years from menopause.15,34 whereas an increase of endometrial thickness, although without a real clinical significance, is Bisphosphonates associated with LSX.33 BPs are the most widely used drugs for the pre- In our opinion, SERMs are preferable to HRT vention and treatment of all kinds of osteoporo- due to their better safety profile in the long-term sis. They are approved, in both males and females, and can be considered a viable second-line treat- also for the treatment of glucocorticoid-induced ment for patients AEs related to oral BPs, particu- osteoporosis (GIOP) and of antihormonal thera- larly for women under 65 years of age at risk for py-associated bone disease (i.e., androgen depri- vertebral fractures and at some risk for breast vation therapy and treatment with aromatase cancer. inhibitors).33,35 These compounds have been used SERMs represent also a possible first-line for more than 25 years and several millions of therapy after menopause for younger subjects patients have been treated with BPs, and their who are expected to receive treatment for many excellent safety profile is now well established.2,33,36 years. Unfortunately, this opportunity is often It is therefore quite unlikely that new unexpected difficult to seize, because hot flushes are a com- side effects may be discovered in the future. mon AE of these drugs, especially in younger BPs are a large family of stable analogs of postmenopausal women within the first year of pyrophosphate with a strong affinity for bone treatment.34 For this reason, SERMs are not rec- apatite. BPs reduce the recruitment and activity ommended in women with vasomotor symptoms of mature osteoclasts and increase their apopto- and HRT is preferable instead. sis. Consequently, they act as potent inhibitors of The observation that SERMs (particularly bone resorption and this is the rationale of their BZA) inhibit the effects of conjugated estrogens in use in postmenopausal osteoporosis.2,33,36 the uterus and mammary glands has opened the Several BPs have been approved for the treat- way to a new strategy for the prevention of sys- ment of osteoporosis, such as alendronate (ALN), temic bone loss and the treatment of climacteric risedronate (RIS), ibandronate (IBA), and

e5 Pharmacological management of osteoporosis in postmenopausal women zoledronate (ZOL). All these drugs have shown not (<85%).36 Despite these data, oral ALN and oral only to increase BMD and bone strength but also RIS are still the most commonly prescribed BPs.2 to be effective on a hard endpoint such as the reduc- A large case-control analysis that involved more tion in the fracture incidence; indeed, their registra- than 90,000 patients, older than 80 years and with tion process was based on RCTs powered to detect previous history of fragility fractures, showed an effect on new vertebral fractures in patients with that ALN significantly reduces not only the hip moderate-to-severe osteoporosis.2,33,36 fracture risk (−34%) but also mortality (−12%). Oral formulations are available for daily (ALN, Unfortunately, this treatment was also associ- RIS), weekly (ALN, RIS), and monthly (IBA, ated with a 58% increase in the risk of mild upper RIS) administration. Oral bioavailability of BPs is gastrointestinal (GI) symptoms.37 The GI side very low, roughly 1% of the ingested dose, and it is effects are the most typical AEs associated with reduced by food (especially if rich in calcium). For oral BPs and may involve a large number of users this reason, they must be ingested with plain water (about 25%).6 However, of this 25%, less than 1% on an empty stomach and after an overnight fast, require hospitalization due to GI bleeding.6 with a postdose fast of 30 to 60 minutes.36 A more Treatment with i.v. ZOL has also shown to recent (but still not widely available) delayed-re- decrease mortality when given shortly after the lease formulation of 35 mg risedronate (weekly first hip fracture38 and, as expected, without GI administration) can be taken before or immedi- side effects. On the other hand, i.v. aminobis- ately following breakfast, with a potential improve- phosphonates (such as ZOL), in about 30% of ment in adherence and persistence.2 patients, can induce a transient acute phase reac- Two intravenous BPs have been licensed by the tion characterized by flulike symptoms (fever, European Medicines Agency for the treatment of myalgia, arthralgias, bone pain, headache, and osteoporosis: IBA (administered every 3 months) nausea). Usually, this undesired event occurs and ZOL (administered yearly). These options within 24 hours after the first drug administra- are particularly interesting in subjects with AEs tion and can be controlled by paracetamol or related to oral BPs and in whom adherence to nonsteroidal anti-inflammatory and improves or chronic treatment might be an issue. To date, disappears within 3 days.2,6 comparative head-to-head RCTs with fracture Major severe AEs with BPs are extremely rare. incidence as endpoint are not available, but if we Osteonecrosis of the jaw (ONJ) is a condition compare the results from each RCTs that investi- characterized by long-lasting (>8 weeks) necrotic gated each molecule, all compounds showed to exposed bone in the maxillofacial region associ- approximately halve the incidence of vertebral ated with the use of antiresorptive drugs such as fractures in patients affected by postmenopausal BPs and denosumab (DMAb). ONJ has been osteoporosis.36 described in cancer patients receiving doses of On the contrary, the efficacy on nonvertebral BPs (and DMAb) 10 times higher than subjects fractures, and particularly at the hip, differs con- with postmenopausal osteoporosis. Indeed, in siderably across the various BPs.36 However, this this latter scenario, ONJ is extremely rare (one observation can be largely explained from the dif- case every 100,000 patients/year) and its incidence ferent statistical power of the studies.36 seems to be only slightly higher than the general Regarding the better results obtained with i.v. population.2,6 ZOL once yearly, they have been attributed to the BPs and DMAb have been associated also with complete adherence of i.v. ZOL during the first an increased risk of atypical femoral fractures. year of treatment (100%) versus oral BPs Atypical femoral fractures are transverse or short

e6 Pharmacological management of osteoporosis in postmenopausal women cortical oblique fractures, occasionally associated Clodronate is a relatively weak BP, widely avail- with periosteal thickening. However, this particu- able for the treatment of neoplastic bone disease lar kind of fractures may also occur in treat- and licensed for the use in osteoporosis in only a few ment-naïve subjects. The risk seems to rise with countries.2 The data about osteoporosis are not the increase in the exposure to BPs (or DMAb) conclusive, and the evidence of its efficacy is weaker and to decrease rapidly after its cessation.2,6,33 than the other BPs previously discussed.33 Two In addition, atypical femoral fractures are RCTs showed the efficacy of 800 mg daily oral clo- indistinguishable from those observed in patients dronate in both increasing BMD and reducing the with other bone diseases characterized by bone incidence of vertebral fractures in women with fragility, such as hypophosphatasia, osteopetro- senile, postmenopausal, or secondary osteoporosis, or osteogenesis imperfect.39,40 All these sis.44,45 In Italy, intramuscular clodronate is regis- remarks emphasize the key role of a correct diag- tered for postmenopausal osteoporosis and GIOP nosis in each patient with bone fragility before on the basis of few low-quality studies.46–48 prescribing any pharmacological treatment and Clodronate is usually prescribed in subjects at they also suggest caution before considering a low fracture risk or when all the other treatments longstanding antiresorptive treatment in patients cannot be used. In conclusion, clodronate, espe- with baseline low-bone turnover states.41 cially when administered intramuscularly, should In any case, the incidence of atypical fractures not be currently considered a real option for oste- is extremely low (about 3–50 cases every 100,000 oporosis treatment. patients/year), and the excellent risk to benefit ratio of this drug class is out of the question. Denosumab Indeed, we need to consider the benefit of the Like BPs, DMAb belongs to the antiresorptive treatment on the much more common typical hip drugs class (Table 1). DMAb is a fully humanized fractures:42 for every 100 atypical fractures pre- monoclonal antibody that neutralizes RANKL sig- vented by BPs, an increase of one single atypical naling by interfering with its interaction with its fracture has been calculated.43 receptor located on the membrane of preosteoclasts Caution is advised also with patients at risk of and mature osteoclasts (RANK). In this way, it kidney impairment, given that high doses of BPs impairs the recruitment, maturation, and survival administered over a short period of time could of osteoclasts and leads to a stronger inhibition of induce or worsen renal failure. Because of the bone resorption than BPs.49 Its potency and activity very low bioavailability of oral BPs (less than at the cortical bone explain why DMAb is able to 1%), the serum concentration is so low that renal induce greater increases in BMD than BPs both at damage is an issue only for the i.v. formulation.6 trabecular sites (i.e., at lumbar spine) and at cortical For this reason, i.v. BPs are contraindicated in ones (i.e., hip and radius).49 The drug is adminis- patients with creatinine clearance lower than 60 tered subcutaneously every 6 months at a dose of 60 ml/min.6 For safety concerns, however, in this mg. DMAb is not cleared by kidneys and therefore kind of patients also the oral formulations should it can be used also in patients with renal failure.33 be prescribed very carefully. DMAb is also approved for treatment in males, in A possible association between BPs therapy GIOP and antihormonal therapy-associated bone (especially i.v. ZOL) and atrial fibrillation has been disease.33,35 reported, but subsequent studies have produced Long-term treatment determines sustained conflicting results. Presently, the possibility of this increases in BMD (both at the spine and at association cannot be completely excluded.2 the hip), without any plateauing after 4 years of

e7 Pharmacological management of osteoporosis in postmenopausal women treatment, as commonly seen with BPs. This fea- in Europe. TPD is the active 1–34 N-terminal frag- ture could be a consequence of a greater activity ment of parathyroid hormone (PTH) and its daily on cortical bone and/or of its unique effects on subcutaneous administration produces anabolic Wnt inhibitors and in particular on Dkk-1.16 effects on the bone tissue. This occurs in contrast In postmenopausal osteoporosis, over 3 years of with the well-known bone catabolic consequences therapy, DMAb reduced the incidence of vertebral of chronic overproduction of PTH. As known, pri- fractures (−68%), hip fractures (−40%), and non- mary hyperparathyroidism is characterized predom- vertebral fractures (−20%), without significant inantly by the overstimulation of osteoclast’s adverse events.2,33 The yearly incidence of new frac- activity, while daily (pulsatile) pharmacological tures (both vertebral and nonvertebral) remained PTH administration determines the predominance low also during the long extension trial that involved of bone formation over bone resorption due to a a subgroup of women treated for further 7 years.2 direct action on osteoblasts.51 Treatment with TPD Due to its mechanism of action, discontinua- has been shown to reduce significantly the risk of tion of DMAb therapy is associated with a rapid vertebral and nonvertebral fractures and its use is offset of action as soon as the drug is cleared strongly recommended in high-risk subjects and in from the plasma.2 For this reason, the positive patients with previous history of vertebral fractures.2 effects of DMAb on BMD are quickly reversible The data concerning TPD and GIOP are par- after its discontinuation, with a return to pre- ticularly intriguing. One clinical trial versus ALN treatment values within 12 to 18 months, inde- in patients treated with glucocorticoids showed pendently of the treatment duration, while bone that TPD is more effective not only in improving turnover markers increase above pretreatment BMD but also in reducing the incidence of verte- levels and then return to baseline values within 1 bral fractures.52 These results support the prefer- to 2 years after its discontinuation.2 ential use of an anabolic agent over a traditional Recently, RANKL serum levels have been shown antiresorptive drug in patients with GIOP. The to progressively increase after suspension of long- mechanistic explanation of the clinical evidence term DMAb treatment, and this observation may may rely on the inhibitory effect of glucocorti- support the hypothesis of a sudden loss-of-inhibition coids on osteoblasts, a mechanism that, together of the resting osteoclast line after DMAb clearance.50 with the increase in bone resorption, explains their This rebound effect is associated with an increase in severe negative effects on the quantity and quality fracture risk of vertebral fractures, while no increase of bone.53 In this setting, TPD should be consid- in nonvertebral fracture has been reported to date.2 ered the first-line option for patients on long-term Therefore, in case of DMAb discontinuation, the glucocorticoid treatment with low BMD or with initiation of a different antiresorptive treatment previous history of osteoporotic fractures. (such as BPs) should be considered to prevent, or at The duration of treatment with TDP is limited least limit, this rapid bone loss.2 to a maximum of 2 years and the decline of its DMAb is well tolerated. Few cases of ONJ positive effects on bone formation (seen after 12 and atypical femoral fractures have been reported to 24 months) seems to be dependent on the reg- to date and the same considerations already dis- ulation of the Wnt pathway and the overproduc- cussed for BPs apply. tion of its inhibitor Dkk-1.54 The most commonly reported AEs of TPD are Teriparatide nausea, pain in limbs, dizziness, and headache.6 In Currently, teriparatide (TPD) is the sole anabolic addition, cases of moderate hypercalcemia and drug available for the treatment of osteoporosis hypercalciuria have been reported but they are

e8 Pharmacological management of osteoporosis in postmenopausal women usually asymptomatic and only rarely request the For all these reasons, RMZ represents the first cessation of the treatment.6 true dual-action agent: it increases osteoblastic Besides TPD, other peptides of the PTH family bone formation by enhancing Wnt canonical sig- are abaloparatide (currently still in development) naling and reduces osteoclastic bone resorption and the 1 to 84 intact molecule (whose marketing by unbalancing the OPG/RANKL ratio (in favor authorization has not been confirmed).2 of OPG).49 Overall, all these agents are contraindicated in The dual action of RMZ was already remark- severe kidney impairment and in all diseases able in the phase I study, in which it showed an characterized by increased bone turnover and/or impressive (dose-dependent) increase in the hypercalcemia, such as primary hyperparathy- markers of bone formation (+70 to 140%), roidism, Paget’s disease of bone, malignancies, or simultaneous with a less considerable, but statis- bone metastasis.2 tically significant, dose-dependent decrease in Studies on rats chronically exposed to very the markers of bone resorption (−15 to −50%).56 high doses of TPD have reported an increased This interesting dual activity can explain the incidence of osteosarcoma. However, the analysis extraordinary effects on BMD that overtake of the pivotal clinical trial and the postmarketing what seen with any other osteoporosis treat- surveillance did not show any increased risk of ment, TPD included.49 osteosarcoma with the doses of TPD presently The unique metabolic effect of long-term RMZ used in humans (which are much smaller by rela- treatment is limited to the first 12 months of tive comparison).2,6 Unfortunately, despite these therapy. Markers of bone formation increase safety data, the TPD Summary of Product still immediately after the first RMZ injection and includes a warning for physicians and patients reach their peak after the first month. Thereafter, about this unproven complication. they decrease and return to baseline within 9 months and they eventually reach values signifi- Romosozumab cantly lower than baseline after the 12th month.57 Romosozumab (RMZ) is a humanized mono- Interestingly, during the second year of RMZ, clonal antibody that acts by blocking sclerostin, a the serum levels of both bone formation and molecule almost exclusively expressed by osteo- bone resorption markers remained below their cytes and one of the main inhibitors of the Wnt baseline.57 This may suggest that, within the first canonical pathway.16 year of treatment, RMZ acts as a true dual-action As known, this pathway plays a key role in drug, but later on it probably works just as a bone bone metabolism. On one hand, it promotes turnover inhibitor, without any further anabolic osteoblastogenesis and directly contributes to the action. differentiation, proliferation, and survival of Notably, the BMD gain, which is outstanding osteoblasts.55 On the other, it enhances the expres- in the first year of treatment, is less relevant sion of OPG by indirectly inhibiting osteo- during the second year of RMZ. An increase in clast-mediated bone resorption.55 Therefore, BMD similar to the first year of treatment has sclerostin is an important negative regulator of been shown only in the subgroup of women who bone formation with a potential key role in the were then randomized to receive DMAb for an pathogenesis of disuse osteoporosis.16 In addition additional year.57 to its antianabolic role, it enhances the catabolic For these reasons, the phase III trial (FRAME activity on the bone tissue through the up-regula- trial) investigated the effects of subcutaneous tion of RANKL expression.55 monthly injections of RMZ for 12 months versus

e9 Pharmacological management of osteoporosis in postmenopausal women placebo, followed by treatment with DMAb myocardial infarction was confirmed and thus, in (administered in both arms).58 The effects on 2014, the EMA restricted its use to patients fracture incidence within these 12 months were affected by severe osteoporosis who cannot be remarkable: the incidence of vertebral fractures treated with different medications and in whom was reduced by 73% and of clinical fractures by the risk of fracture overwhelmingly exceeds the 36%. At 24 months, after the switch to DMAb, CV risk.6 the incidence of new vertebral fractures remained significantly lower in the RMZ group (−75%). Treatment discontinuation AEs incidence was balanced between the BPs, in particular ALN and ZOL, are the drugs groups. In the RMZ group, a single atypical fem- with the most persistent “tail effect” concerning oral fracture and two cases of ONJ were reported bone turnover after their discontinuation.36 Their among the 3,500 treated subjects.58 antifracture efficacy is only partially lost after After the publication of the results of the RCT treatment discontinuation for several months.36 comparing RMZ and ALN (ARCH trial), con- Unfortunately, the impact of the discontinuation cerns were raised about a possible increased CV of the other drug classes is very different. risk associated with the use of RMZ.59 The inci- After suspension of hormonal therapy, bone dence of severe CV events resulted higher in the turnover and bone loss return to pretreatment RMZ group versus the ALN group, despite a levels within few weeks. Therefore, reassessment similar CV risk at baseline.59 It should be noted, of fracture risk and of the opportunity of resum- however, that RMZ was not associated with any ing treatment itself is strongly warranted.63 increase of the CV risk in the previous and larger TPD is strongly recommended in severe osteo- FRAME trial,58 in which RMZ was compared porosis, but the regulatory authorities limited the with placebo. Indeed, the increase in CV events in treatment duration to a maximum of 2 years. the RMZ group might be explained by the pro- There is now a very large agreement about the tective CV effects of ALN (and of amino-BPs in absolute need for the start of an antiresorptive general), as already reported several times.60–62 agent soon after the conclusion of the TPD treatment cycle to avoid the quick rebound on BMD.63 Strontium ranelate Sequential administration of ALN, ZOL, or Strontium ranelate (SrR) is an oral medication DMAb after TPD have been associated to further that has been approved in Europe for the treatment BMD gains; however, the effects on fracture risk of postmenopausal osteoporotic women.33 Its reduction are to date still speculative.33 mechanism of action is still not completely under- In patients treated with DMAb, its discontinu- stood, but the RCTs showed its efficacy in reducing ation is followed by an overshoot in bone turn- the risk of vertebral and nonvertebral fractures over, with accelerated bone loss and increased respectively after 3 and 5 years of treatment.33 fracture risk.2 The best exit strategy to adopt after A consistent increase in the risk of venous DMAb discontinuation is still unclear and large thromboembolism has been documented in the randomized and active-controlled trials are war- registration trials and, during the postmarketing ranted to investigate this key topic. Presently, BPs surveillance, rare but severe dermatological reac- are recommended by most experts as the prefera- tions were also reported, with consequent limita- ble choice to prevent or at least limit the rebound tions to its clinical use.6 During the long-term effects of DMAb discontinuation. postapproval surveillance safety analyses, the As already discussed, RMZ has a peculiar mech- increased risk of pulmonary embolism and anism of action and combines the stimulation of

e10 Pharmacological management of osteoporosis in postmenopausal women bone formation with the inhibition of bone resorp- Injectable treatments such as DMAb and tion. Unfortunately, the benefits in terms of BMD ZOL may solve GI issues associated with oral are lost after its discontinuation.64 Hence, sequential BPs and may also improve the adherence to the treatment with antiresorptives is required, as it was treatment with their more deferred administra- scheduled in its RCTs.58,59 tion schedule. In the case of new fractures occurring during Sequential Therapy treatment with oral BPs, ZOL might represent a In these last decades, the number of drugs possible choice, given its 100% adherence on the available for the treatment of osteoporosis has first year of therapy. DMAb might be considered grown exponentially. The development of novel as well due to its stronger inhibition of bone turn- and more potent antiresorptives (such as DMAb over and the greater BMD increases at all skeletal and ZOL), bone anabolic agents (such as TPD), sites, even when compared to ZOL.2 and antisclerostin antibody (such as RMZ) deter- mined a substantial growth in the field. As already Antiresorptive agents after agents with discussed, the discontinuation of many of these anabolic effects therapies (DMAb, TPD, and RMZ) requires the In patients with high fracture risk, the use of initiation of another treatment in order to avoid anabolic drugs seems the most appropriate for its the loss of the BMD gains. Furthermore, a treat- quick reduction. ment switch might need to be recommended also As already discussed, treatment with drugs in patients who experience a new fragility fracture characterized by anabolic effects is limited to 12 despite already being on osteoporosis medica- (RMZ) or 24 months (TPD), and their benefits tions, or in case of tolerability or adherence issues. can be preserved only through the initiation The different mechanisms of action of osteo- antiresorptive agents as soon as possible after porosis drugs strongly influence the cumulative their discontinuation.2 Therefore, prompt treat- effects of the possible sequential and/or combina- ment with antiresorptives after bone anabolic tion approaches and should guide the physician agents is recommended. to the choice of the correct treatment. Hereby we will briefly discuss the different Anabolic agents after antiresorptive agents The choice of an anabolic agent as the first-line opportunities presently available for sequential therapy is not often possible due to its high cost, but therapy: it is recommended in patients who experience a new Antiresorptive agents after antiresorptive agents fragility fracture despite BPs therapy. Unfortunately, Sequential treatment with different antire- there is some evidence suggesting that the effective- sorptive agents might be required when: ness of anabolic medications might be impaired when started after prolonged exposure to antire- • a patient discontinues DMAb and there is the sorptive drugs.65 Indeed, when patients on long- necessity to limit the rebound effect term potent antiresorptive treatments are switched • poor compliance with ongoing oral BP therapy to TPD, hip BMD tends to decline for at least 12 • occurrence of a new fragility fracture during months, especially when the antiresorptive is treatment with oral BPs. DMAb.66 Therefore, the switch from antiresorptive drugs to an anabolic agent, a quite common sce- As already mentioned, to prevent or at least nario in clinical practice, is not currently supported limit the rebound effect of DMAb discontinua- by much evidence. How can we manage these tion, BPs are presently considered the best choice. patients? Combination therapy might be an answer.

e11 Pharmacological management of osteoporosis in postmenopausal women

Combination Therapy hip, the combination arm showed the greatest The dual action of RMZ demonstrates the benefits overall. effectiveness of the association of strong stimula- Obviously, these results regard only BMD tion on bone formation with powerful inhibition measurements and currently there is no data on on bone resorption. Currently, no other drug fracture incidence. However, it is noteworthy that administered alone can act in this manner, but a maximum BMD effects can be reached with an similar therapeutic framework could be obtained anabolic agent (such as TPD or RMZ) followed by combining two different treatments and there is by an antiresorptive and that the combined evidence to support this possibility. An interesting DMAb plus TPD regimen seems to provide the comparison between patents who switched from greatest skeletal benefits to patients with estab- ALN to TPD versus those who added TPD to lished osteoporosis.65 Like RMZ, combination ongoing ALN, showed a greater benefit of combi- therapy of DMAb plus TPD should be consid- nation therapy on BMD and strength at the hip.65 ered for patients with severe osteoporosis who are Another small study compared the changes of at the highest risk of imminent fragility fracture. bone turnover markers in patients treated with DMAb versus TPD versus a third therapeutic NEW DIRECTIONS FOR FUTURE STUDIES scheme: TPD added to ongoing DMAb (TPD Our recent improvements in the knowledge of was started 3 months after DMAb).67 The results the RANK/RANKL/OPG and the Wnt/beta-cat- showed that the effects of TPD on bone turnover enin pathways have led us to the development of markers were not blunted by prior and concur- DMAb and RMZ. rent DMAb administration. In the combination In our opinion, RMZ represents a new era arm of the study, the increase in markers of bone and, as previously discussed, it is likely to open a formation was observed quite earlier than the new scenario in the management of the imminent increase in the ones of bone resorption.67 This fracture risk, a concept that could be considered remark supported the hypothesis of a consequent born and raised with RMZ itself. It cannot be wider anabolic window of the concurrent treat- excluded that further biotechnological agents ment than TPD alone.67 interfering with the inhibitors of the Wnt/ The favorable metabolic profile of the combi- beta-catenin pathway (i.e., Dkk-1) will be devel- nation therapy (DMAb plus TPD) found confir- oped in the future. However, preclinical studies mation in the DATA-Switch study.68 This study evaluating the effects of monoclonal antibodies compared the effects on BMD of three different to Dkk-1 as potential treatment for osteoporosis therapeutic schemes: DMAb administered after have not shown encouraging results to date.69 TPD, TPD after DMAb, and the combination Other possible approaches in the future might of the two medications given concurrently for include stem cells transplantation, antisenescence 2 years, followed by DMAb alone.68 The results agents, and drugs that target specific osteoblast confirmed that TPD to DMAb sequential ther- pathway but, unfortunately, the relating research apy is significantly superior than DMAb to TPD. is still in its very early stages.9 At the end of the study, the TPD to DMAb arm In our opinion, the low costs and the good achieved similar BMD benefits at the lumbar effectiveness of many currently available thera- spine compared to TPD plus DMAb combina- pies (i.e., BPs) will not encourage large investment tion therapy, but the latter reached the BMD in the field of osteoporosis. For this reason, the peak 12 months earlier than sequential treatment. drugs that are going to be developed in the future Besides, if we consider the BMD gains at total will be likely limited to a small proportion of

J Popul Ther Clin PharmacolVol 26(4):e1–e17; 20 November 2019. This article is distributed under the terms of the Creative Commons Attribution-Non Commercial 4.0 International License. ©2019 Davide Gatti and Angelo Fassio.

e12 Pharmacological management of osteoporosis in postmenopausal women patients affected by the most severe form of etc.), HRT and TSEC are preferable. For protec- osteoporosis. tion from breast cancer risk, SERMs (RLX in On the contrary, we hope that the reduction in particular) are more indicated. the costs of TPD (due to the expiration of its pat- Bisphosphonates (BPs). Oral BPs are widely ent) is going to encourage clinicians to prescribe available and should be considered the first-line both the sequential and the combined approach. treatment for most patients with mild to moderate osteoporosis. ZOL is the first choice in CONCLUSION patients with intolerance to oral formulations or Several pharmacological treatments are avail- when they are contraindicated. ZOL, due to its able for osteoporosis. The challenge is to identify yearly regimen and the long-tail effect can be the optimal treatment for each patient. Indeed, also useful in patients with adherence issues. all the different drugs have specific features that ZOL is contraindicated in patients with impaired make them more or less preferable for each kidney function. patient. A possible flowchart based on the opin- Denosumab (DMAb) is preferable in patients ion of the authors is presented in Table 2. who do not tolerate oral BPs or when they are Hormonal therapy is particularly indicated in contraindicated. As a side note, DMAb is not women younger than 60 years old, within 10 years contraindicated in the presence impaired kidney from their last menses, at risk for osteoporosis function. DMAb can be also considered in and without known risk factors for thromboem- patients incurring a new fragility fracture while bolism. In the presence of symptoms of meno- already on treatment with BPs due to its stronger pause (hot flushes, vulvar and vaginal atrophy, inhibition of bone turnover.

TABLE 2 Proposed Flowchart for Treatment Selection in Postmenopausal Osteoporosis 1. Primary prevention of fractures in osteoporotic postmenopausal women • Women, 50–60 years old, without risk factors for thromboembolism  First choice: hormonal therapy  Second choice: oral bisphosphonates • Women over 60 years old, or with risk factors for thromboembolism, or unwilling to begin hormonal treatment  First choice: oral bisphosphonates  Second choice: (i.e., in case of low compliance or tolerability of oral bisphosphonates) intravenous bisphosphonates or denosumab 2. Secondary prevention of fractures in postmenopausal women • Women with a single osteoporotic vertebral or nonhip fracture  First choice: oral bisphosphonates  Second choice: (i.e., in case of low compliance or tolerability of oral bisphosphonates) intravenous bisphosphonates or denosumab • Women with a more than one osteoporotic vertebral or previous hip fracture  First choice: teriparatide  Second choice: denosumab or bisphosphonates 3. Patients with severe osteoporosis who experienced a new vertebral fracture during treatment with bisphosphonates • First choice: add a treatment with teriparatide or start romosozumab  Second choice: denosumab or intravenous bisphosphonates (in patients previously treated with oral bisphosphonates)

e13 Pharmacological management of osteoporosis in postmenopausal women

Teriparatide (TPD) is strongly recommended Society for Clinical and Economic Aspects of in severe osteoporosis, especially in the presence Osteoporosis (ESCEO) and the Committees of of history of vertebral fractures and for the man- Scientific Advisors and National Societies of agement of GIOP. Its use is limited to 24 months the International Osteoporosis Foundation of therapy and its benefits are maintained only if (IOF). European guidance for the diagnosis followed by an antiresorptive agent. Therefore, and management of osteoporosis in postmenopausal women. Osteoporos Int 2019;30 prompt treatment with these agents is recom- (1):3–44. mended after TPD discontinuation. 3. Hernlund E, Svedbom A, Ivergård M, et al. Romosozumab (RMZ) represents the first true Osteoporosis in the European Union: Medical dual-action drug. Its unique metabolic effect is management, epidemiology and economic bur- limited to the first 12 months of therapy and after den. A report prepared in collaboration with the that a sequential treatment with antiresorptive International Osteoporosis Foundation (IOF) agents is needed. The BMD effects of RMZ are and the European Federation of Pharmaceutical superior to any other osteoporosis treatment Industry Associations (EFPIA). Arch Osteoporos already in the first few months of therapy, with an 2013;8:136. impressive effect on fracture risk in the first year. 4. Degli Esposti L, Girardi A, Saragoni S, et al. Use For these reasons, it is recommended in patients of antiosteoporotic drugs and calcium/vitamin D with severe osteoporosis at high risk for imminent in patients with fragility fractures: Impact on fragility fracture. re-fracture and mortality risk. Endocrine 2019; 64(2):367–77. COMPLIANCE WITH ETHICAL STANDARDS 5. Prieto-Alhambra D, Moral-Cuesta D, Palmer A, CONFLICT OF INTEREST et al. The impact of hip fracture on health-related quality of life and activities of daily living: The Davide Gatti reports personal fees from SPARE-HIP prospective cohort study. Arch Abiogen, Celgene, Eli-Lilly, Janssen, Pfizer, UCB, Osteoporos 2019;14(1):56. and BMS, outside the submitted work. 6. Rossini M, Adami S, Bertoldo F, et al. Guidelines Angelo Fassio reports personal fees from for the diagnosis, prevention and management of Abiogen and Novartis, outside the submitted work. osteoporosis. Reumatismo 2016;68(1):1–39. 7. Fassio A, Rossini M, Gatti D. Vitamin D: No effi- ETHICAL APPROVAL cacy without deficiency. What’s new? Reumatismo This article does not contain any studies with 2019;71(2):57–61. 8. Adami S, Viapiana O, Gatti D, Idolazzi L, Rossini human participants or animals performed by M. Relationship between serum parathyroid hor- any of the authors. mone, vitamin D sufficiency, age, and calcium INFORMED CONSENT intake. Bone 2008;42(2):267–70. 9. Adami S, Romagnoli E, Carnevale V, et al. For this type of study, formal consent is not Guidelines on prevention and treatment of vitamin required. D deficiency. Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS). REFERENCES Reumatismo 2011;63(3):129–47. 1. Consensus development conference: Diagnosis, 10. Murad MH, Drake MT, Mullan RJ, et al. Clinical prophylaxis, and treatment of osteoporosis. Am J review. Comparative effectiveness of drug treat- Med 1993;94(6):646–50. ments to prevent fragility fractures: A systematic 2. Kanis JA, Cooper C, Rizzoli R, Reginster J-Y, review and network meta-analysis. J Clin Scientific Advisory Board of the European Endocrinol Metab 2012;97(6):1871–80.

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