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Summary The annual number of patients treated for osteoporosis between 1998 and 2018 in Switzerland increased until 2008 and steadily decreased thereafter. With a continuously growing population at fracture risk exceeding an intervention threshold, the treatment gap has increased and the incidence of hip fractures has stopped declining in the past decade. Introduction The existence of an osteoporosis treatment gap, defined as the percentage of patients at risk for osteoporotic fractures exceeding an intervention threshold but remaining untreated, is widely acknowledged. Between 1998 and 2018, new bone active substances (BAS) indicated for the treatment of osteoporosis became available. Whether and if so to what extent these new introductions have altered the treatment gap is unknown. Methods The annual number of patients treated with a BAS was calculated starting from single-drug unit sales. The number of patients theoretically eligible for treatment with a BAS was estimated based on four scenarios corresponding to different intervention thresholds (one based solely on a bone mineral density T score threshold and three FRAX-based thresholds) and the resulting annual treatment gaps were calculated. Results In Switzerland, the estimated number of patients on treatment with a BAS increased from 35,901 in year 1998 to 233,381 in year 2018. However, this number grew regularly since 1998, peaked in 2008, and steadily decreased thereafter, in timely coincidence with the launch of intravenous bisphosphonates and the RANKL inhibitor denosumab. When expressed in numbers of untreated persons at risk for osteoporotic fractures exceeding a given intervention threshold, the treatment gaps were of similar magnitude in 1998 (when the first BSAs just had become available) and 2018. There was a strong association, which does not imply causation, between the proportion of patients treated and hip fracture incidence. Conclusion In Switzerland, the osteoporosis treatment gap has increased over the past decade. The availability of new BAS has not contributed to its decrease. Keywords Osteoporosis · Treatment gap · Hip fractures · FRAX · Bisphosphonates · Denosumab Introduction Osteoporosis is a crippling disease with alterations in bone quantity and quality leading to an increased risk of fragil- ity fractures most commonly located at the hip, spine, dis- tal radius, and/or proximal humerus, also known as major * Kurt Lippuner osteoporotic fractures (MOF). The operational definition of firstname.lastname@example.org osteoporosis proposed by the World Health Organization Bita Yousefi Moghadam relies on a T score at or below 2.5 measured by dual-energy email@example.com X-ray absorptiometry (DXA) at the femoral neck . Patrick Schwab In Switzerland, approximately 1 in 2 women and 1 in 5 firstname.lastname@example.org men will sustain a fragility fracture during their remain- ing lifetime after age 50 . While increasing in number, Department of Osteoporosis, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland the incidence and even more so the age-standardized inci- dence of hospitalizations for hip fractures have been shown Swiss Federal Statistical Office, Neuchâtel, Switzerland Vol.:(0123456789) 1 3 20 Page 2 of 11 Archives of Osteoporosis (2023) 18:20 to follow a long-lasting decreasing trend between 1998 and comparisons (EU27 + Switzerland + United Kingdom), fol- 2018 in both men and women . During these 21 years lowed a different methodology. SCOPE 2021 defined the of observation, the proportion of hospitalizations for hip patient population eligible for treatment as those with a fractures of all hospitalizations for MOF decreased from 10-year probability of MOF exceeding that of a woman with approximately 55% in both men and women to 44% and 42% a prior fragility fracture, estimated the number of patients in men and women, respectively. Among the most prescribed treated based the IQVIA drug sales database (whereby cal- osteoporosis drugs in Switzerland, the aminobisphospho- cium, vitamin D, and estrogens were not considered), and nates alendronate and zoledronate and the RANKL inhibi- adjusted for adherence by using a point estimate derived tor denosumab were shown to significantly reduce the risk from the Swedish Prescribed Drugs Register . Thus, of hip fractures in fracture endpoint trials [4–6] and their treatment gap studies and results should not be compared use may have contributed to the observed reduction in hip directly without the necessary caution with regard to the fracture incidence. methodology applied. Since the launch of the first oral bisphosphonate approved The aim of the present analyses was to determine the for the treatment of osteoporosis in Switzerland (alendronate number of patients treated with a pharmacologically active in 1996), an array of drug therapies aiming at reducing osteoporosis drug in Switzerland between 1998 and 2018, fracture risk in patients with osteoporosis has been made to evaluate the changes in treatment patterns following the readily available to physicians and patients, allowing for introduction of new substances, to identify and quantify a multiple therapeutic options based on different mechanisms potential osteoporosis treatment gap, and to explore the asso- of action, efficacy and safety profiles, and administration ciation between treated patients and changes in hip fracture routes and schemes. In Switzerland, approved and reim- incidence. bursed osteoporosis pharmacological treatments include bisphosphonates (as daily, weekly, or monthly tablets and as quarterly or yearly intravenous infusions), denosumab as Methods twice yearly subcutaneous injections, teriparatide as daily subcutaneous injections, and raloxifene as daily tablets. Of Yearly sales of counting units (i.e., the smallest available note, reimbursement restrictions generally based on a DXA single dosage of a preparation, e.g., a tablet or a vial) of T score threshold and/or the presence of one or more preva- all pharmacologically active osteoporosis drugs including lent fractures, apply to all except alendronate (Supplemental generics in all formulations, dosage strengths, and presen- table S1). Off-label prescriptions and prescriptions of non- tations available in Switzerland since 1998 and up to year reimbursed drugs are the exception rather than the rule and 2018, were obtained from IQVIA Switzerland (IQVIA RDS can be considered negligible. Switzerland Sàrl, Saint-Prex, Switzerland). Pharmacologi- In earlier publications, different groups have used differ - cally active osteoporosis drugs were defined as oral bispho- ent methodologies and definitions for estimating the osteo- sphonates (alendronate 10 mg daily or 70 mg weekly, rise- porosis treatment gap. While the common understanding is dronate 5 mg daily or 35 mg weekly, ibandronate 150 mg that treatment gap defines the proportion of patients who do QM, including generics), intravenous bisphosphonates not get treatment although eligible for therapy based on a (ibandronate 3 mg Q3M and zoledronate 5 mg Q12M), given intervention threshold, the source databases and the denosumab 60 mg Q6M, raloxifene 60 mg daily, and teri- inclusion criteria differed widely. Some authors estimated paratide 20 mcg daily. Not included were abaloparatide and the treatment gap based either on national health databases strontium ranelate (not available in Switzerland) and base- and database linkage such as the National Danish Health doxifene (available but not reimbursed). Early bisphospho- Registries  or the National Medicare Database in the US nates (including etidronate, clodronate, and pamidronate)  and others performed prospective studies such as the were neither available in Switzerland nor approved for the Austrian ICUROS  and the Belgian FRISBEE  stud- treatment of osteoporosis and thus not included in the analy- ies. Typically, all these studies included patients who had sis. Counting units were converted into treatment-years by experienced an index major osteoporotic fracture, either only applying the annualized recommended dose for the treatment women [8, 10] or both men and women [7, 9] with diverging of osteoporosis published in the Swiss prescribing infor- criteria regarding age at inclusion. The gap was then esti- mation (https:// compe ndium. ch). Of note, prescription data mated on these (sub-)populations with treatment generally were not available by sex, such that only the total number of defined as one of the bone active substances described above patients treated could be calculated. and generally excluding calcium, vitamin D, and estrogens, In the absence of Swiss data, persistence defined as the at the exception of the study by Malle et al. in which the duration of time from initiation to discontinuation of therapy latter were included . By contrast, the SCOPE 2021 pro- was calculated based on previously published findings in ject, aiming at standardizing the approach for cross-country women with US Medicare fee-for-service coverage . 1 3 Archives of Osteoporosis (2023) 18:20 Page 3 of 11 20 The annual persistence rates of women with records cov- osteoporosis treatment was cost-effective or cost-saving in ering three years or more were averaged leading to values the Swiss setting after the age of 55 years in men and 60 of 0.596, 0.476, and 0.312 for denosumab, intravenous bis- in women who had previously sustained a fragility fracture phosphonates, and oral bisphosphonates, respectively. The [14, 15]. For each FRAX-based scenario, the age-specific number of patients on treatment with a pharmacologically proportion of men and women qualifying for the predefined active osteoporosis drug in a given year was obtained by fracture risk categories was applied to the annual structure multiplying the number of treatment-days for each substance of the Swiss population from year 1998 through year 2018. with the corresponding persistence values. It was assumed The annual osteoporosis treatment gap was defined as the that persistence did not change between 1998 and 2018. absolute or relative difference between the patient potential The total number of patients eligible for treatment and the number of treated patients between 1998 and 2018. (patient potential) was estimated based on four scenarios. The number of hospitalizations for hip fractures in men For all, the annual Swiss population statistics by sex and and women aged 45 years and older were extracted for the 5-year age groups after age 45 published by the Swiss Fed- years 1998 through 2018 from the Swiss Federal Office of eral Office of Statistics were used as a starting point. The Statistics health database using the ICD-10 codes S72.0 most conservative scenario considered that the patient poten- Fracture of the femoral neck, S72.1 Pertrochanteric frac- tial was restricted to men and women with a T score at or ture, and S72.2 Subtrochanteric fracture) . The crude inci- below − 2.5 at the femoral neck or the lumbar spine. The dence of hip fractures in men and women pooled was calcu- latter was estimated based on the published US osteoporosis lated per 100,000 person-years. In the absence of available prevalence rates of 3.9% and 15.8% in non-Hispanic White covariates, the degree of association between the number of men and women . In this study, reference groups used patients treated by year and the earlier reported decrease in for the femoral neck and the lumbar spine were 20–29 year- hip fracture incidence  was explored by univariate regres- old non-Hispanic White females from NHANES III and sion analyses. It was considered that all hip fractures were 30-year old White females from the DXA manufacturer hospitalized. database, respectively . The three other scenarios for estimating the patient potential were defined based on FRAX risk thresholds by 5-year age groups for MOF in men and Results women. The FRAX algorithm allows for the country-spe- cific calculation of the individual 10-year absolute risk of Treatment‑years with pharmacologically active either hip fracture or MOF based on clinical risk factors osteoporosis drugs between 1998 and 2018 with or without BMD. For the purpose of this analysis, the number of men and women aged 45 years or older with a Figure 1 shows the treatment-years (assuming full persis- FRAX risk for MOF exceeding 15% or 20% or exceeding the tence and compliance) by pharmacologically active osteopo- risk of a Swiss woman with a prior fracture was calculated rosis drug and year since 1998. The cumulated total number based on previously published prevalence data used for the of patient-years of therapy in the IQVIA database was 1.894 Swiss-specific FRAX model (https:// www. she ffield. ac. uk/ Mio during 21 years of observation of which 914,979 with FRAX/) calibrated for Swiss-specific fracture risk and life oral bisphosphonates (48.3%), 547,600 with IV bisphospho- expectancy [2, 14, 15]. It was assumed that fracture risk in nates (28.9%), 359,814 with denosumab (19.0%), 56,333 the age group 45–49 years was identical with that in the age with raloxifene (3.0%), and 15,430 with teriparatide (0.8%). group 50–54 years. The thresholds of 15% and 20% were Thus, raloxifene and teriparatide were excluded from further chosen because osteoporosis treatment had previously been processing. shown to be cost-effective in the Swiss healthcare setting with a 10-year probability for a MOF at or above 15.1% Patients treated (range 9.9 to 19.9%) and 13.8% (range 10.8 to 15.0%) in men and women, respectively . The prior fracture risk After adjustment for persistence and as shown in Table 1, the equivalent threshold, i.e., the 10-year fracture probability estimated number of patients on treatment with a pharma- for MOF exceeding that of a woman with a prior fragil- cologically active osteoporosis drug increased from 35,901 ity fracture according to the FRAX algorithm calibrated for in year 1998, i.e., two years after the launch of alendronate, Switzerland, was chosen because of its general acceptance to 233,381 in year 2018. While in year 1998, all patients in the Swiss health economic context (almost all drugs are were treated with alendronate as the only available option, reimbursed in the presence of a positive fracture history) in year 2018, 35.7% were treated with denosumab, 34.3% and in the latest recommendations for osteoporosis treatment with an intravenous bisphosphonate (ibandronate 20.3%), from the Swiss Association Against Osteoporosis (SVGO/ and 30.0% with an oral bisphosphonate (alendronate 19.8%). ASCO) . Furthermore, earlier findings suggested that The number of patients treated grew regularly since 1998, 1 3 20 Page 4 of 11 Archives of Osteoporosis (2023) 18:20 Fig. 1 Treatment-years by pharmacologically active osteoporosis drug peaked in 2008, flattened in 2009, and steadily decreased definition of osteoporosis increased from 291,258 to 401,751 since then. Of note, the IV bisphosphonates were launched (+ 110,493) between 1998 and 2018. At the other extreme, in Switzerland in 2006 (ibandronate) and 2007 (zoledronate) the number of patients with a FRAX-based risk for MOF and denosumab in 2010. exceeding 15%, at which it still was cost-effective to treat osteoporosis in Switzerland, increased from 641,687 to Patient potential based on different scenarios 895,310 (+ 253,623). The DXA T score ≤ − 2.5 scenario based on NHANES data Treatment gap used the US prevalence rates of 3.9% and 15.8% in non-His- panic White men and women, respectively. For all scenar- The osteoporosis treatment gap, defined as the difference ios based on FRAX Switzerland, the proportion of patients between the potential of patients eligible for osteoporosis applied to the annual population structure is shown by 5-year treatment and the number of patients treated, varied based age groups and sex in Table 2. The aggregated numbers of on the intervention thresholds retained for the different patients eligible for osteoporosis treatment between 1998 scenarios (Table 3). The common pattern was a steadily and 2018 are shown by scenario in Fig. 2. In all scenarios, decreasing treatment gap between 1998 and 2008 followed the patient potential increased by 36.0 to 39.5% during the by a one-year plateau and a continuous increase up to 2018. 21-year observation period, mainly reflecting the fast aging As an example, Fig. 3 depicts the number of patients treated of the Swiss population. When considering patients with a with an oral bisphosphonate, an intravenous bisphosphonate, DXA T score at or below − 2.5 at either the hip or the lumbar or denosumab between 1998 and 2018 and the correspond- spine, the absolute number of patients (men and women) ing treatment gap for patients with a 10-year fracture prob- eligible for treatment based on the DXA-based operational ability for MOF exceeding that of a woman with a prior 1 3 Archives of Osteoporosis (2023) 18:20 Page 5 of 11 20 Table 1 Number of patients treated with a pharmacologically active osteoporosis drug per year Oral bisphosphonates Intravenous bisphosphonates Denosumab Total patients Alendronate Risedronate Ibandronate Ibandronate IV Zoledronate 1998 35,901 35,901 1999 48,076 48,076 2000 56,506 56,506 2001 76,893 1195 78,088 2002 114,470 4214 118,684 2003 145,868 12,258 158,127 2004 163,799 26,596 190,395 2005 170,610 36,649 2175 209,434 2006 165,127 38,132 31,736 1493 236,489 2007 156,833 37,675 49,503 12,488 452 256,952 2008 139,446 29,654 59,318 25,428 9779 263,625 2009 126,101 23,452 60,354 37,202 16,380 263,489 2010 112,210 18,600 57,757 49,558 20,176 1337 259,638 2011 93,771 13,697 51,147 57,106 21,021 12,469 249,210 2012 78,623 10,286 43,948 82,538 21,565 25,232 262,193 2013 65,659 8007 36,817 91,065 20,737 38,878 261,163 2014 53,768 6734 30,377 83,956 19,754 52,130 246,720 2015 49,461 5704 25,242 71,037 19,515 65,721 236,680 2016 43,942 5406 21,529 68,497 20,059 79,492 238,924 2017 41,980 4758 19,217 63,833 23,914 86,387 240,089 2018 46,201 4946 18,881 47,338 32,679 83,336 233,381 Values in bold indicate the line total Table 2 Proportion of men and Age group (years) FRAX risk for MOF > 15% FRAX risk for MOF > 20% FRAX risk for MOF women with a FRAX risk for above risk with prior MOF exceeding a predefined fracture threshold, by 5-year age groups Men (%) Women (%) Men (%) Women (%) Men (%) Women (%) 45–49 0.9 5.4 0.2 1.6 6.4 25.8 50–54 0.9 5.4 0.2 1.6 6.4 25.8 55–59 2.1 16.0 0.6 6.5 3.7 22.8 60–64 3.3 26.3 1.0 12.3 2.7 22.7 65–69 6.0 46.6 2.2 26.6 3.1 32.9 70–74 10.8 74.9 4.9 53.1 2.5 36.3 75–79 18.5 86.5 9.0 69.6 1.1 25.2 80–84 23.8 85.8 12.7 70.1 1.1 21.8 85 + 22.8 76.1 12.4 59.9 1.0 17.5 fragility fracture according to the FRAX algorithm cali- (treatment gap 61.8%). Thus, in terms of absolute numbers, brated for Switzerland. While the number of treated patients the treatment gap in 2018 can be considered as only margin- stopped increasing and even decreased after the introduc- ally different from that observed in 1998, i.e., in the very tion of the intravenous bisphosphonates and denosumab, early days of availability of osteoporosis drugs proven to the number of patients eligible for treatment continued to reduce fracture risk. increase steadily, resulting in a growing treatment gap since 2008. In this scenario, 449,328 men and women were at Association with changes in hip fracture incidence risk in 1998 of which 35,901 were treated leaving 413,427 patients untreated (treatment gap 92.0%). In 2018, 610,822 In Switzerland, the number of hospitalizations for hip frac- were at risk of which 233,381 treated and 377,501 untreated tures has continuously increased since 1998 in both men 1 3 20 Page 6 of 11 Archives of Osteoporosis (2023) 18:20 Fig. 2 Patient potential eligible for treatment according to different risk level-based intervention thresholds for osteoporotic fractures and women, mainly due to the rapid aging of the population for hip fractures stopped decreasing together with the stag- . The age-standardized and, to a lesser extent, the crude nation of and decrease in the proportion of patients treated incidence of hospitalizations for hip fractures have been for osteoporosis. regularly decreasing since 1998 in both men and women . The crude pooled incidence of hip fractures in men and women aged 45 years or older was 354 per 100,000 persons Discussion in 1998, 300 in 2008 (Fig. 4a), 297 in 2009, and 297 in 2018 (Fig. 4b.). The corresponding proportions of patients treated The present analysis represents a pragmatic and easily repro- for osteoporosis were 12.7, 81.9, 90.0, and 60.0 per 1000 ducible approach to the evaluation of the treatment gap. Key men and women aged 45 years or older. findings include the observation that the introduction of Between 1998 and 2018, the annual crude incidences of intravenous bisphosphonates (ibandronate and zoledronate) hip fractures in men and women aged 45 years or older (per and of the RANKL inhibitor denosumab has not resulted 100,000, pooled) was not significantly associated with the in a further increase of the total number of patients treated. proportion of these under treatment with a pharmacologi- Of mirrored concern, the treatment gap, which had been cally active osteoporosis drug (per 1000). However, when constantly decreasing since 1998, reached its nadir in 2008 considering specific time intervals, this association was sig- and steadily increased thereafter. Keeping in mind that the nificant between 1998 and 2008 ( r = − 0.89 (95%CI − 0.97 secular decrease in hip fracture incidence had already started to − 0.63), r = 0.80, two-sided p < 0.001) but not between in 1998 to 2001, i.e., at a time where the number of treated 2009 and 2018 (r = 0.54 (95%CI − 0.14 to 0.87), r = 0.29, patients was low, there was a strong association, which does two-sided p = 0.108). Thus, the incidence of hospitalizations not imply causation, between the decrease in hip fracture 1 3 Archives of Osteoporosis (2023) 18:20 Page 7 of 11 20 Table 3 Osteoporosis treatment Year Number of Treatment gap if the population at inacceptable fracture risk is defined as gap between 1998 and 2018 patients treated according to different thresholds DXA T FRAX risk for FRAX risk for MOF FRAX risk for of inacceptable fracture risk score ≤ − 2.5 MOF > 20% with prior fracture MOF > 15% justifying intervention 1998 35,901 87.7% 91.4% 92.0% 94.4% 1999 48,076 83.7% 88.6% 89.4% 92.6% 2000 56,506 80.9% 86.7% 87.6% 91.4% 2001 78,088 74.0% 81.9% 83.1% 88.2% 2002 118,684 61.1% 72.8% 74.6% 82.3% 2003 158,127 49.0% 64.5% 66.7% 76.9% 2004 190,395 39.5% 57.9% 60.4% 72.6% 2005 209,434 34.5% 54.3% 57.1% 70.3% 2006 236,489 27.3% 49.2% 52.4% 67.0% 2007 256,952 22.5% 45.7% 49.1% 64.7% 2008 263,625 22.0% 45.2% 48.9% 64.4% 2009 263,489 23.7% 46.1% 50.0% 65.1% 2010 259,638 26.8% 47.8% 52.1% 66.3% 2011 249,210 31.1% 50.8% 54.9% 68.2% 2012 262,193 28.8% 49.2% 53.4% 67.2% 2013 261,163 30.4% 50.4% 54.5% 67.9% 2014 246,720 36.3% 54.0% 57.7% 70.3% 2015 236,680 39.8% 56.7% 60.0% 72.0% 2016 238,924 39.2% 57.1% 60.2% 72.3% 2017 240,089 39.6% 57.7% 60.4% 72.7% 2018 233,381 41.9% 59.7% 61.8% 73.9% Values in bold indicate the peak year for the total number of patients treated incidence and the number of patients treated with a phar- not be granted reimbursed access to treatment. In terms of macologically active osteoporosis drug. total number of fractures, the end result would be that a large Using a more comprehensive and therefore complex number of fractures would still occur in unprotected patients modeling approach aimed at estimating the clinical and at risk and undermine achievable better public health results economic burden of osteoporotic fractures in year 2010, the at the global population level. This triggers and further sup- osteoporosis treatment gaps in men and women in Switzer- ports recent developments suggesting that a population- land were estimated at 36 and 58%, respectively . In the based screening for fracture risk in postmenopausal women present analysis, the calculated treatment gap for both sexes based on FRAX should be considered, in addition to the taken together varied from 27 to 66% in year 2010 depend- currently implemented high-risk case finding and treatment ing on the fracture risk threshold for intervention scenario approach, for incorporation in many healthcare systems to considered as acceptable. Importantly, while all of these sce- reduce the burden of fractures [18, 19]. narios were shown to be cost-effective or even cost-sparing The calculation of the number of patients on therapy in the Swiss setting , none exactly reflects the current should be considered with the caution relative to the under- requirements for reimbursement of osteoporosis drugs in lying assumptions. The drug-specific adjustments for per - Switzerland. The latter stipulate cum grano salis that reim- sistence were taken from a subset of Medicare patients with bursement is warranted in the presence of a T score at or fee for service coverage who had stayed on therapy for at below − 2.5 and/or a prevalent (fragility) fracture only. From least three years . Whether similar persistence rates a clinical perspective, treating patients having experienced apply to Switzerland is likely but not established. Whether one or more fragility fractures and thus all individuals with a these rates vary over time is also unknown. However, 10-year fracture probability exceeding that of a woman with considering that persistence is generally better in patients a prior fragility fracture may be more acceptable to physi- treated with denosumab than with IV bisphosphonates and cians than a cost-effective intervention threshold expressed worst with oral bisphosphonates has been repeatedly shown as percent risk [11, 16, 17]. However, such an approach may in the literature [20–23]. More important than the absolute lead to treating a minority of patients at highest risk, while values, the changes over time allow for internal consist- a majority of patients at lower but still increased risk may ency and acceptable comparability. It is remarkable that 1 3 20 Page 8 of 11 Archives of Osteoporosis (2023) 18:20 Fig. 3 Number of patients treated and number of individuals with a 10-year fracture probability for MOF exceeding that of a woman with a prior fragility fracture based on country-specific FRAX between 1998 and 2018 Fig. 4 Annual changes in the crude incidence of hip fractures (line) and the proportion of patients (men and women aged 45 years and older, pooled) treated with an osteoporosis drug (bisphosphonate or denosumab) in the time periods 1998–2008 (a) and 2009–2018 (b) the introduction of intravenous bisphosphonates and deno- patients has increased over time due to the rapid aging of sumab has not contributed to a market expansion in terms the population. A possible explanation is that at the time of number of patients treated, although the pool of eligible of launch of the early bisphosphonates all efforts were 1 3 Archives of Osteoporosis (2023) 18:20 Page 9 of 11 20 concentrated towards case finding, i.e., identifying new Overall, the present findings suggest that the key chal- patients eligible for treatment aimed at reducing fracture lenges for overcoming the treatment gap published in a 2017 risk within the boundaries set by reimbursement restric- narrative global perspective on strategies for the prevention tions. Ten years later, when ibandronate (oral in 2005, of fragility fractures need more urgent attention than ever intravenous in 2006), zoledronate (2007), and denosumab . Case finding and management of individuals at high (2010) were launched, an established market of almost risk of fracture should be revitalized, raising public awareness 250,000 patients, already identified and treated with an oral about osteoporosis and fragility fractures should be amplified bisphosphonate, existed. In such a situation, recommended or reinitiated, improving reimbursement and health system marketing strategies aim at “picking the low hanging fruits” policies should ensure access to the most appropriate treat- for fast market penetration, i.e., at switching patients on ments to those patients expected to benefit most, and optimiz- therapy to the new substance. Another explanation could ing our epidemiological understanding of osteoporosis and be that the market was already saturated, i.e., that all eligi- fractures should include tools for regular progress assessment. ble and accessible patients had already been treated which For that, the newly proposed scorecard within the SCOPE seems unlikely in the context of a growing patient potential. project should be considered as an excellent starting point to Finally, the number of newly identified patients starting on be tailored to individual countries’ specific needs . an osteoporosis drug and of those already diagnosed who Among the strengths of this study is the straightfor- resume treatment after an interruption may be equal to the ward and reproducible approach to the treatment gap cal- number of patients stopping treatment. The concept of drug culation ensuring internal data consistency and allowing holiday in low-risk patients treated during 3 to 5 years with for monitoring changes over time. It also overcomes the a bisphosphonate was introduced in 2011 based on a FDA challenges met when trying to estimate treated patient recommendation  triggered by considerations related to numbers based on DDDs (defined daily dosages). The bisphosphonate accumulation in bone , potentially suf- latter are mandated by the WHO in order to ensure ficient residual effects on fracture risk after treatment dis- worldwide data comparability but sometimes suffer from continuation in low risk patients [26–28], and safety con- important deviations when put into perspective with the cerns regarding rare reported of uncommon adverse events approved dosing schemes. Limitations include that the (osteonecrosis of the jaw and atypical femoral fractures) IQVIA drug sales database does not report drug use by . While holiday implies that treatment will be reiniti- indication. While some of the drugs used for the treatment ated and recommendations insisted on the importance of of osteoporosis have additional indications (such as the regular reassessments, many patients may have been lost prevention of bone loss under antihormonal treatments or to follow-up. Paget’s disease of bone), the impact on the number treated It was also intriguing to observe that the SERM raloxifene patients can be considered as limited. The latter is further (reimbursed in Switzerland if the T score is at or below − 1) warranted by the existence of specific formulations for and the bone anabolic substance teriparatide (reimbursed as additional indications unrelated to osteoporosis, such as a second-line therapy after a new fracture occurring under zoledronate 4 mg or denosumab 120 mg monthly, both treatment with a bisphosphonate or denosumab) were virtu- for oncological indications, which were excluded from ally inexistent in terms of patients treated, both representing the present analysis. The IQVIA database does not report less than 2% of the treatment-days in year 2018. According drug use by sex, such that an overall approach pooling to T score-based US prevalence data, 15.8% of all White men and women was chosen at the expense of a loss in non-Hispanic women should have a T score at or below − 2.5 data granularity. The IQVIA database does not either col- and 52.6% a T score at or below − 1 which corresponds to lect clinical characteristics which also preempted a more more than a tripling of the patient potential. Obviously, oste- detailed analysis by gradients of fracture risk. Assump- oporosis treatment is reserved to those at highest risk and lit- tions regarding persistence and DXA-based osteoporo- tle to no pharmacological intervention is the rule in patients sis prevalence where taken from US publications which with osteopenia. By contrast and consistent with the avail- may differ from the Swiss reality, highlighting the urgent able published evidence, many patients with highest fracture need for further epidemiological research at the individ- risk (e.g., patients with multiple vertebral fractures) should ual country level. In the absence of better data, it was have been eligible for treatment with the only bone anabolic assumed that persistence, which addresses the question substance available during the period of observation under of how long a patient stays on therapy after treatment ini- scrutiny, namely, teriparatide . Here again, available data tiation, did not change between 1998 and 2018. Whether suggest important underuse. Overall, these findings plead and to what extent prescription behavior and persistence in favor of an urgent need for drug prescription data with have been impacted by real or suspected emerging safety higher granularity which would allow evaluating the treat- concerns with antiresorptives, including the scientific dis- ment gap by risk categories and by sex. cussions around atypical femoral fractures, osteonecrosis 1 3 20 Page 10 of 11 Archives of Osteoporosis (2023) 18:20 Data Availability Source data are available from the corresponding of the jaw, and atrial fibrillation events, remains unknown author upon request. and deserves further research. On the other hand and com- plementary to that, adherence to the prescription, i.e., Declarations the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen, would Ethics approval This is not required by Swiss law for database analyses be important to know and adjust for, especially for oral without individual patient data drugs. Both adherence and persistence have been shown Consent to participate This is not applicable. important for optimizing fracture outcomes [32, 33]. Finally, we did not retain hormone replacement therapy Conflict of interest None was declared by BYM and PS. KL has served (HRT) in our selection of bone active substances, albeit as an expert in advisory board meetings of Amgen Switzerland AG and it was shown to significantly reduce hip fracture risk by UCB Pharma AG Switzerland. approximately one-third in the Women’s Health Initia- Open Access This article is licensed under a Creative Commons Attri- tive (WHI) trials [34, 35]. The WHI trials also showed a bution 4.0 International License, which permits use, sharing, adapta- significant increase in breast cancers, cardiovascular dis- tion, distribution and reproduction in any medium or format, as long eases, and all-cause mortality which led to drastic reduc- as you give appropriate credit to the original author(s) and the source, tions in systemic HRT use since 2002, now being mainly provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are reserved to younger postmenopausal women with vaso- included in the article's Creative Commons licence, unless indicated motor symptoms [36, 37]. As the effect of HRT on hip otherwise in a credit line to the material. If material is not included in fracture risk was shown having vanished three years after the article's Creative Commons licence and your intended use is not discontinuation , we consider that omitting HRT from permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a our analyses should not be expected to alter the present copy of this licence, visit http://cr eativ ecommons. or g/licen ses/ b y/4.0/ . observations and conclusions. 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Archives of Osteoporosis – Springer Journals
Published: Jan 18, 2023
Keywords: Osteoporosis; Treatment gap; Hip fractures; FRAX; Bisphosphonates; Denosumab
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