New in diagnostics and therapy

Since 2018, the update of the S3 guideline Prophylaxis, Diagnosis and Therapy of Osteoporosis (AWMF 183-001) took place after previous update of the underlying PICO questions (Population-Intervention-Comparison-Outcome questions) for systematic literature search. This was peer-reviewed and discussed in May/June 2023, and publication followed approval by the professional societies in September 2023. In addition to updating the evidence-based literature and recommendations, the focus of the guideline update was the development of a risk calculator for vertebral fractures and femoral neck fractures.

Since 2018, the update of the present S3 guideline Prophylaxis, Diagnosis and Therapy of Osteoporosis (AWMF 183-001) took place after previous update of the underlying PICO questions (Population-Intervention-Comparison-Outcome questions) for systematic literature search. This was peer-reviewed and discussed in a consultation version in May/June 2023, and publication followed approval by the professional societies in September 2023. In addition to updating the evidence-based literature and recommendations, the focus of the guideline update was the development of a risk calculator for vertebral fractures and femoral neck fractures. This is essential for managing risk assessment because of the multitude of risk factors that contribute to fracture risk. This paper considers the development of the guideline update in terms of content, this by reflecting on the core themes of the guideline update.

Introduction

Fracture risk cannot be predicted by determining bone density alone. It is important to ascertain and take into account risk factors that individually increase the risk of fracture when present. Risk calculators have been developed worldwide for the calculation of fracture risk and since 2006 the risk model of the German Osteological Association (DVO) has existed for the calculation of risk for vertebral and femoral neck fractures, which is used within the framework of the DVO guidelines for risk calculation. This distinguishes the goal of fracture prediction from the most widely used risk calculator in the world, FRAX. Because this aims to predict clinical vertebral fractures, femoral neck fractures, humerus fractures and distal radius fractures.

Risk factors for vertebral fractures and femoral neck fractures were comprehensively reviewed as part of the guideline development process. For this purpose, a risk calculator was developed, which is to be used web-based after validation and certification. Since this has not yet been completed due to the necessary validation and certification, a paper version of the risk calculator will be made available during the bridging period (see also Table 1 for an example).

The risk factors that increase the risk of vertebral and femoral neck fractures and that are considered in this risk calculator are diverse (101 candidates after literature search). For this reason, they were prioritized according to prevalence and extent of fracture risk increase, i.e. clinical relevance, 33 risk factors are thus considered in the risk calculation (Table 1). This is because not every fracture risk factor present increases the risk of vertebral or femoral neck fracture to the same degree, and because of existing or unknown interaction of risk factors, no more than two risk factors should be included in the calculation of absolute fracture risk in addition to age, sex, and bone densitometry score. Reaching the therapeutic thresholds defined by the guidelines is important for the assessment of risk.

Diagnostics and therapy thresholds in the new risk model of the 2023 guideline

Recommendation for osteoporosis diagnostics

Following the previous guideline versions, baseline diagnostics are recommended in women after the onset of menopause and in men from the age of 50 years, depending on the individual fracture risk factor profile. This recommendation is adapted from the SIGN recommendations (SIGN revised version Jan 202: 2.1 and 3.0-3.6), which states that baseline diagnostics should be recommended starting at age 50 years when a wide variety of risk factors are present. From this age onwards, it is useful to determine whether risk factors for an increased fracture risk are present. From the age of 70, the risk of fracture is so high that bone densitometry appears to make sense, as long as specific therapeutic consequences are to be derived from it, i.e. therapy is also considered. A constellation of risk factors deemed relevant by physicians is to be considered for the indication of osteoporosis diagnosis; in contrast to the previous version of the guideline, a specific fracture risk threshold is not maintained. This follows the idea of risk-adapted case finding. In addition to risk factors, risk indicators are considered for indication of baseline diagnostics. These are risk factors that are not included in the risk calculation but indicated the need for possible baseline osteoporosis diagnosis (Table 1).

Furthermore, as before, typical fragility fractures of the vertebral bodies or femur increase the fracture risk so substantially that therapy can be recommended even without the presence of a bone density result. In this case, bone densitometry is not mandatory before initiating therapy.

Further innovations in diagnostics

1. factors that imminently** increase the risk of fracture: The list of factors that individually increase fracture risk is long. The extent to which individual risk factors increase fracture risk varies. Thus, incisional vertebral or femoral neck fractures and glucocorticoid therapy >7.5 mg/d >3 months are risk factors that significantly increase fracture risk, especially in the first year after occurrence. This short-term emphasized immediate threatening increased risk of fracture, internationally called “imminent fracture risk,” has become increasingly prominent in recent years. Diagnostics initiated quickly after fracture occurrence as well as initiated osteoporosis drug therapy should effectively reduce the imminent fracture risk and thus prevent avoidable fractures.

** Definition Imminent fracture risk: very high risk of imminent fracture due to a sudden, very strong fracture risk factor that causes a short-term, significant increase in fracture risk.

2. risk calculation: Due to the increasing number of factors that change the individual fracture risk , but which do not influence the fracture risk completely independently of each other, the integration of a risk calculator for the assessment of the fracture risk is the goal in diagnostics. This is also intended to involve more disciplines in screening for osteoporosis.

3. bone density and differential laboratory in basic diagnostics: Based on the recommendations of the International Society for Clinical Densitometry (ISCD), a bilateral measurement at the hip is recommended in addition to the measurement of the spine. Here, the lowest of the two femoral neck and femoral total (total hip) values should be considered as the T-score, not the mean. The T-Score Total Hip is the value to be considered when using the tables for therapy threshold determination.

In the differential laboratory, serum protein electrophoresis is now mentioned as part of the basic laboratory, not optional; furthermore, CRP and ESR are recommended, since the former reacts predominantly to an increase in interleukins, while ESR reacts to a change in plasma proteins

4. diagnosis of vertebral fractures: the DVO algorithm calculates the fracture risk related to vertebral fractures and femoral neck fractures. That vertebral fractures are underdiagnosed is well known. One way to diagnose vertebral fractures is through the bone density procedure duale x-ray absorptiometry (DXA) with additional imaging of the lateral spine through the Vertebral Fracture Assessments (VFA). Also derivable from the DXA measurement is the Trabecular Bone Score (TBS), a parameter for the trabecular bone structure within the vertebral bodies, which influences fracture risk independently of bone density. Another development also offers the evaluation of conventional, e.g. CT abdomen images with programs developed with the help of artificial intelligence.

Therapy thresholds

In contrast to the previous guideline on the diagnosis and therapy of osteoporosis of the DVO (version 2017), not only one therapy threshold should be defined, but three. This is due to the knowledge of differential therapeutic approaches that reduce the existing fracture risk to different degrees and at different rates. Not every therapeutic approach is equally optimal for fracture risk reduction at all times. Recommendations for implementing the various therapeutic thresholds will be made in the soon-to-be-published guideline. For the definition of therapy thresholds, the prediction period was reduced from 10 years to three years, because this period can be more easily communicated in discussions with patients in the sense of a “shared decision process”, but above all because most studies allow a 10-year period to be covered only by extrapolation of the fracture data.

The following therapeutic thresholds were established:

• 3-<5%/3 years: Should drug therapy be considered.
• 5-<10%/3 years: Should drug therapy be recommended.
• from 10%/3 years: should osteoanabolic therapy be recommended, if necessary also as initial therapy

As an example, Table 2 shows the 5% fracture risk threshold for women.

Therapy

Recommendations for basic therapy

In patients without drug therapy, daily dietary calcium intake of at least 1000 mg is recommended. Supplementation is recommended only if 1000 mg calcium/day is not safely obtained from the diet. The maximum daily intake of calcium should not exceed 2000-2500 mg/day. In addition to calcium intake, 800-1000 international units (IU) of vitamin D3 are recommended daily. Here, 2000-4000 IU of cholecalciferol per day should not be exceeded and the weekly bolus dosage should not exceed 20 000 IU of cholecalciferol.

An adequate supply of vitamin K, vitamin B and folic acid is recommended as a general precaution. However, apart from compensating for vitamin K deficiency, which may occur, for example, in chronically ill patients, no further recommendation is made for vitamin K2 [1].

Especially in the elderly, a fall and fracture prevention program should be implemented as part of osteoporosis therapy, a fall risk assessment should be performed after a fall, and the cause of the fall should be investigated. This also includes a visual acuity check. Regular physical activity adapted to functional status should be encouraged. The recommended goal of physical activity is to improve muscle strength, sense of balance, reaction speed, and coordination. In addition, immobilization should be avoided [2].

Recommendations for drug therapy

Table 3 lists the drugs evaluated. Estrogens should only be used in postmenopausal women if gynecologists have indicated this on the basis of existing symptoms, or if there is a contraindication to all other therapeutic approaches in the case of a diagnosed increase in fracture risk in the sense of osteoporosis. If estrogens are taken, no further osteoporosis therapy is usually necessary in parallel, with the exception of high-risk patients with a fracture risk of 10%/3 years or more.

New and re-evaluated substances: In 2020, the sclerostin antibody romosozumab was launched in Germany and Switzerland for the treatment of manifest osteoporosis in postmenopausal women with a significantly increased risk of fracture. Romosozumab represents another osteoanabolic therapeutic option in addition to teriparatide. One cycle of romosozumab therapy is 12 months and reduces fracture risk more compared with the oral bisphosphonate alendronate [3]. Data on the osteoanabolic teriparatide are now available on the reduction of femoral neck fracture risk from meta-analyses [4].

Differential therapy: The indication for the use of osteoanabolic romosozumab is limited to postmenopausal women with a significantly increased risk of fracture. The indication of teriparatide is for postmenopausal women and men at high risk of fracture, including long-term glucocorticoid therapy-associated osteoporosis at high risk of fracture. What exactly is encompassed by the terms “significantly increased fracture risk” and “high fracture risk” is the subject of numerous publications. Reference may be made to the study inclusion criteria or the extent of fracture risk increase; discussion on this is ongoing. However, the important point is the resulting recommendation in the differential therapy. If there is an imminently increased risk of fracture, there is usually also a high-risk situation or a high risk of fracture.

With two statements published on the DVO website, a favoring of osteoanabolic therapy approaches after vertebral fractures and femoral neck fractures in comparison to oral bisphosphonates has already been formulated, statements whose message will be included in the chapter on differential therapy. In general, the more imminent and higher the immediate fracture risk, the faster and more effectively the fracture risk must be reduced. This is possible with osteoanabolic drugs that simultaneously counteract “skeletal insufficiency,” defined by decreased bone structure and quality, clinically resulting in advanced osteoporosis, and improve bone structure, strength, and quality [5]. The osteoanabolic therapy threshold is 10%/3 years. Rapid reduction of the imminently elevated fracture risk is also possible with potent, parenterally administered antiresorptives such as denosumab and zoledronate [6], but without altering the bone quality previously highlighted. Imminent fracture risk is also associated with increased long-term fracture risk, which must be considered in sequential therapy for a chronic disease such as osteoporosis.

And highlighted is what is important about the most commonly prescribed agent, bisphosphonates: In terms of the risk-benefit balance of therapy, taking into account the rare occurrence of osteonecrosis of the jaw (AR-ONJ) during antiresorptive therapy (0.7 per 100 000 years of life) [7], a dental presentation should no longer be recommended before starting therapy with bisphosphonates, denosumab, or romosozumab, but rather with the start of therapy. The initiation of osteoporosis therapy should not be delayed by dental ONJ prophylaxis because of the low AR-ONJ event rate.

5. follow-up diagnostics under drug therapy: Data are available for an additional benefit in the context of follow-up monitoring of bone density. On the one hand, with regard to improvement of therapy adherence [8], on the other hand, to predict the expected fracture risk reduction under drug therapy [9].

For bone remodeling parameters, data from a metaregression [10] show that these parameters can also be used to improve drug persistence, predict fracture risk reduction after initiation of specific osteoporosis therapy, and monitor pauses in specific osteoporosis therapy.

Take-Home Messages

• Osteoporosis diagnosis is recommended when there is a fracture risk constellation deemed relevant by a physician.
• In general, osteoporosis diagnostics should also be recommended from the age of 70 years in men and women due to the increasing risk of fractures with age.
• The therapy of osteoporosis should be based on the individual fracture risk and always be combined with the basic therapeutic measures.
• Three therapeutic thresholds have been established to optimize therapy. One threshold is for osteoanabolic therapy recommendation
  defined.
• Therapy with bisphosphonates, denosumab, romosozumab should not be delayed by dental necrosis of the jaw prophylaxis because of the low rate of occurrence of osteonecrosis of the jaw.

Literature:

1. Maus U, Kuehlein T, Jakob F, et al: Basic therapy: calcium, vitamin D and K, nutrition, physical training. Osteology 2023; 32(02): 110-114.
2. Thomasius F, Maus U, Niedhart C, et al: General fracture and osteoporosis prophylaxis: focus on falls. Osteology 2023; 32(02): 104-109.
3. Saag KG, Petersen J, Brandi ML, et al: Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. N Engl J Med 2017; 377(15): 1417-1427.
4. Simpson EL, Martyn-St James M, Hamilton J, et al: Clinical effectiveness of denosumab, raloxifene, romosozumab, and teriparatide for the prevention of osteoporotic fragility fractures: a systematic review and network meta-analysis. Bone 2020; 130: 115081.
5. Curtis EM, Reginster JY, Al-Daghri N, et al: Management of patients at very high risk of osteoporotic fractures through sequential treatments. Aging Clinical and Experimental Research 2022; 1-20.
6. Iconaru L, et al: Which treatment to prevent an imminent fracture? Bone reports 2021; 15: 101105.
7. Camacho PM, Petak SM, Binkley N, et al: American association of clinical endocrinologists and American college of endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract 2016; 22: 1-42; doi: 10.4158/EP161435.GL.
8. Leslie WD, Morin SN, Martineau P, et al: Association of Bone Density Monitoring in Routine Clinical Practice With Anti-Osteoporosis Medication Use and Incident Fractures: A Matched Cohort Study. J Bone Miner Res 2019; 34(10): 1808-1814; doi: 10.1002/jbmr.3813.
9. Bouxsein ML, Eastell R, Lui LY, et al: Change in Bone Density and Reduction in Fracture Risk: A Meta-Regression of Published Trials. J Bone Miner Res 2019; 34(4): 632-642; doi: 10.1002/jbmr.3641.
10. Bauer DC, Black DM, Bouxsein ML, et al: Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Anti-Resorptive Drugs: A Meta-Regression. J Bone Miner Res 2018; 33(4): 634-642; doi: 10.1002/jbmr.3355.
11. German Osteological Association (DVO): S3 Guideline Prophylaxis, Diagnosis and Therapy of Osteoporosis in Postmenopausal Women and in Men over the Age of 50, Version 2.0, dated 06.09.2023;
    https://register.awmf.org/de/leitlinien/detail/183-001; last accessed Sept. 18, 2023.

HAUSARZT PRAXIS 2023; 18(10): 16-21