What’s new in osteoporosis care?

Osteoporosis is a disease characterised by low bone mineral density (BMD), deterioration of bone tissue, disrupted bone microarchitecture, compromised bone strength, and resulting fracture. According to the World Health Organization (WHO) diagnostic classification, osteoporosis is defined by BMD at the hip or lumbar spine that is less than or equal to 2.5 standard deviations below the mean BMD of a young adult reference population (T-score).¹

Women are more at risk of developing osteoporosis than men because the hormone changes that happen at the menopause directly affect bone density. Increased bone loss after menopause and age-related bone loss means the prevalence of osteoporosis increases markedly with age, from 2% at 50 years to more than 25% at 80 years in women.
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Osteoporosis is a risk factor for fracture. Among Caucasian adults aged 50 years and older, about 50% of women and 20% of men will experience an osteoporotic fracture in their remaining lifetime. Broken bones caused by osteoporosis are not only extremely painful, they can affect person’s independence and could lead to life-changing disability. A quarter of people die within a year of suffering a hip fracture, the most serious osteoporosis-related injury.

Many people with osteoporosis show no symptoms, but they may be at increased risk of fracture. Osteoporosis leads to nearly 9 million fractures around the world each year, and over 300,000 people per year attend hospitals in the UK with fractures caused by osteoporosis.²

Key learning points Osteoporosis remains an underdiagnosed and undertreated long-term condition. There is no national systematic approach to screening for osteoporosis in UK. FRAX assessment should be used to identify 10-year probability of major osteoporotic fracture and for intervention thresholds. Start treatment promptly following a fracture due to imminent refracture risk. Consider referral of very high risk patients to secondary specialist service for possible ‘anabolic first’ approach. Treatment with teriparatide or romosozumab, which are anabolic skeletal agents, result in rapid and greater fracture risk reductions than some antiresorptive treatments. Denosumab cessation can lead to ‘rebound’ vertebral fractures.

Screening of osteoporosis lags behind other diseases

Over the past 30 years, there has been tremendous progress in the ability to diagnose osteoporosis. Unfortunately, despite that progress, the use of dual-energy X-ray absorptiometry (DXA) and fracture risk assessments—tests that can accurately diagnose osteoporosis and determine the likelihood of having a hip or other bone fracture—have been on the decline.

A recent article³ highlighted that screening and treatment of osteoporosis lags behind other diseases, resulting in significant morbidity, mortality, and economic costs. The use of DXA in women 65 years and older has dropped to 11.3%, down from 13.2% from five years earlier. Moreover, many at-risk patients are not advised to take preventive medications, and may be unduly frightened to take them.

Failures in primary prevention of osteoporosis are compounded by inadequate post-fracture follow-up care. In a comparative analysis, 96% patients with acute myocardial infarction received standard-of-care medication, while only 30% of women 66 years or older received standard-of-care medication to treat osteoporosis in the 12 months after their fracture.³

Failings in osteoporosis care in the UK

Findings from a national inquiry published in November 2022 by the All Party Parliamentary Group (APPG) on Osteoporosis and Bone Health show major shortcomings in osteoporosis identification, treatment and care. It called on the government and the NHS to make urgent changes.⁴

• 74% of respondents weren’t aware what proportion of GP practices had a process for systematically identifying patients at high risk of fracture
• 90%of respondents weren’t aware if there is an identified clinician with a special interest in osteoporosis in any of their practices
• 97% of respondents did not hold information about five yearly reviews of osteoporosis treatment.
• Only 48% of people were confident they were on the right medication.

Simple, cheap risk assessment tools can be used in five minutes in any GP surgery and are proven to prevent hip fractures. GPs are well placed to identify people at high risk of fractures before they happen, based upon information about risk factors for poor bone health. But opportunities for diagnosis are being routinely missed, thereby putting people at risk of life-changing fractures.⁴

GPs are well placed to identify people at high risk of fractures before they happen

Screening programmes in primary care have already been successfully implemented around other health conditions, such as bowel, breast and cervical cancer and routine tests for those at risk of diabetes, COPD, or asthma. Currently in the UK, there is no systematic national approach to screening for osteoporosis.

Osteoporosis is not included in the NHS Health Check, or any other mandated GP checks. Evidence shows a programme of targeted screening for 1,000 women aged between 70 and 85 years saved nine hip fractures and 20 non-hip fractures over the remaining lifetime (mean 14 years) compared with usual management.⁵

In total, the screening arm saved costs (£286) and gained 0.015 QALYs/patient in comparison with usual management arm. (SCOOP randomised trial).⁵  Systematic, community-based screening programme of fracture risk in older women in the UK is feasible, and could be effective in reducing hip fractures.

Diabetes and osteoporosis

Researchers from China conducted a systematic literature review and meta-analysis to estimate the prevalence of osteoporosis in patients with diabetes. A total of 21 studies through July 2022, without country and language restrictions, were included. In a pooled analysis, the researchers found that among 11,603 people with type 2 diabetes, there was a high prevalence of osteoporosis (27.67%) – nearly one fourth worldwide.

The implications from this study suggest that strong measures to prevent and treat osteoporosis in diabetic patients are required.⁶

DXA scan

BMD as determined by DXA remains the gold standard in the diagnosis of osteoporosis and for deciding the most appropriate care pathway and management. In a matched cohort study⁷ utilising the BMD Database (completeness and accuracy in excess of 99%) the authors identified 4,559 women who were above 40 years of age and were receiving anti-osteoporotic therapy with serial bone densities for a mean interval of 3.2 years and 4,559  score matched women who did not have BMD monitoring.

The monitored women had significantly better survival free from a major osteoporotic fracture (p = 0.04) and better hip fracture rate (p = 0.001).⁷ The medication persistence ratio, days of medication use, and treatment switching were greater in the monitored women.

Hence periodic evaluation reinforces the need for continued treatment for both the patient and the physician.

Artificial intelligence and osteoporosis screening

A Chinese study showed that the attenuation values of thoracic and lumbar vertebrae on chest CT could be used for opportunistic screening of osteopenia or osteoporosis. This will be beneficial to improve the detection rate of osteoporosis and reduce the incidence of adverse events caused by osteoporosis.⁸

FRAX

Fracture risk assessment of individuals without fracture was previously based on the individual assessment of known risk factors. Now the FRAX algorithm has facilitated the assessment of fracture risk on the basis of fracture probability over the next 10 years, using an internet tool that integrates validated risk factors for fracture with or without the use of BMD.⁹

Thresholds have been devised in many countries to advise clinicians on when to prescribe antiosteoporosis treatment (intervention thresholds). Country-specific FRAX models are now available for 73 countries based on national epidemiology of hip fracture and mortality rates.⁹ FRAX has some limitations and adjustments have been proposed.

Calcium plus Vitamin D both are important

In a systemic review and meta-analysis of databases utilising an additional analysis of six randomised controlled trials with 49,282 participants, 5,449 fractures, and 730 hip fractures, supplementation with both vitamin D (400 to 800 IU) and calcium (1,000 to 1,200 mg/day) resulted in an increase of 9.2ng/mL in 25(OH)D concentration, a 6% reduced risk of any fracture, and a 16% reduced risk of a hip fracture.¹⁰

This study¹⁰ reinforces the concept that vitamin D treatment alone is not beneficial but, when combined with calcium, it significantly lowers the risk of fragility fractures, most notably those of the hip.

Teriparatide

Teriparatide is a parathyroid hormone (PTH) analogue and anabolic agent in use since 2002 for osteoporosis. It is given as a subcutaneous injection daily patient self administered for two years.

The VERO study¹¹ of teriparatide versus risedronate in osteoporosis demonstrated the superiority of the anabolic over the antiresorptive agent in preventing fragility fractures. This trial¹¹ of postmenopausal women with vertebral fracture showed that at 24 months, there was a significant reduction of new vertebral fractures and clinical fractures in the teriparatide group. Based on this study, clinicians should consider teriparatide for optimal management of patients with prevalent vertebral fractures—a well-defined high fracture risk group.

The recent results from the 13 years of data collected by the Osteosarcoma Surveillance Study¹² showed that the incidence of osteogenic sarcoma in patients treated with teriparatide was no different from the background incidence rate. Since 2021, the FDA no longer has a black box warning on the drug Forteo (teriparatide).

Abaloparatide

The US Food and Drug Administration (FDA) approved abaloparatide, a parathyroid hormone-related peptide analogue, in 2022 to increase bone mineral density among men with osteoporosis at high risk for fracture. Thirty percent of all hip fractures occur in men. Abaloparatide is already approved in USA and Europe for postmenopausal women with osteoporosis at high risk for fracture since 2017 after findings from the ACTIVE trial¹³ revealed the agent reduced the relative risks for new vertebral fractures in women by 86% and for nonvertebral fractures by 43% compared with placebo.

This drug is still not available in the UK.

Denosumab (Prolia)

Denosumab is a monoclonal antibody that binds to the receptor activator of nuclear factor kappa-B ligand (RANKL), thereby inhibiting osteoclast function and is in use since 2010. It is given as injection subcutaneously twice a year.

Denosumab treatment for up to 10 years in the FREEDOM EXTENSION TRIAL¹⁴ was associated with low rates of adverse events, low fracture incidence compared with that observed during the original FREEDOM trial, and demonstrated continued increases in BMD without plateau. .

Recently, there has been concern about what are termed “rebound fractures.” If a dose is missed or a patient discontinues the medication without starting another treatment, cases of vertebral compression fractures have been reported. A literature review¹⁵ reported the rates of rebound fractures at the end of denosumab treatment to be between 1% and 10% with a median of five vertebral fractures at a median time of 11 months following the last denosumab injection.

When patients are unable to receive a dose of denosumab or plan to discontinue treatment, starting a bisphosphonate medication is recommended to prevent the rebound phenomenon. At present, the exact timing, duration, and treatment option are unclear. Most recommend the use of a potent oral bisphosphonate or intravenous zoledronic acid for one year starting at six months from the last denosumab dose.

Romosozumab

A clinical trial ARCH (Active-contRolled FraCture Study in Postmenopausal Women with Osteoporosis at High Risk of Fracture)¹⁶ showed that patients who took romosozumab before alendronic acid had a 50% lower relative risk of vertebral fractures  and 19% lower for nonvertebral fractures over 24 months than patients having alendronic acid alone. The drug is given as a subcutaneous injection once every month for one year and should be avoided for patients with cardiovascular disease.

NICE recommended romosozumab (Evenity) in April 2022 for high risk female osteoporosis patients after menopause. It has already been in use in USA and Europe. Over 20,000 people could be eligible for the treatment in the UK. It is the first new treatment for osteoporosis for several years.

It is of interest that the effects of romosozumab are greater the higher the fracture probability at baseline, a phenomenon which is not seen with teriparatide.¹⁷ This makes romosozumab of particular relevance in patients at very high fracture risk.

Sequential therapy- anabolic agents first in high risk patients

Anti-resorptive drugs, especially, bisphosphonates, are currently the treatment of choice in most developing countries. However, they do have limitations and adverse effects, which, to some extent, helped the development of anabolic drugs such as teriparatide and romosozumab. Anabolic agents can improve the structure of bone, making them an especially attractive choice for treatment of patients at very high risk of fracture, when degradation of bone structure is often advanced.

In patients with high or very high risk for fracture, sequential or combined therapies may be considered with the initial drugs being anabolic agents. Starting with bone-forming treatment (teriparatide or romosozumab) and then continuing with an antiresorptive – anabolic first approach – is the best treatment sequence, so it should be the preferred option in patients with a very high risk of fracture.

The BMD gain achieved with teriparatide can be increased if, after its discontinuation, a bisphosphonate is administered, also maintaining the anti-fracture efficacy. But the teriparatide-denosumab sequence is probably the one that provides the highest BMD gain (18% in the lumbar spine and 8% in the femoral neck after two years of treatment with teriparatide followed by another two years of treatment with denosumab.¹⁸

The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the National Osteoporosis Guideline Group (NOGG)  has strong evidential support from recent studies comparing anabolic with antiresorptive medications, demonstrating a more rapid and greater fracture risk reduction with the former, compared with antiresorptive treatments alone.¹⁹

A good example of the benefit of anabolic followed by antiresorptive therapy is the “foundation effect” described in a report showing that treatment with romosozumab for one year followed by denosumab for one year increases BMD to a level comparable to about seven years of treatment with denosumab alone²⁰.

Fracture liaison services

A recent systematic analysis²¹ examined the impact on subsequent fractures and mortality before and after a fracture liaison service implemention. Fracture liaison service intervention led to lower subsequent fractures (odds ratio, 0.70 [95% CI, 0.52 to 0.93]; p = 0.01). The significant difference was only evident in studies with  more than two years of follow-up. There was no significant difference in mortality. This metaanalysis²¹ reinforces the proven benefits of a fracture liaison service in preventing subsequent low-energy fractures.

The results of this study should be seriously considered by orthopaedic professionals who treat geriatric patients with fracture, as orthopaedic surgeons are the clinicians who care for patients immediately following a fracture. Patients can benefit from  nurse practitioners who can specifically diagnose and treat osteoporosis in order to optimise patient care.

NOGG guidance in the UK recommends that patients who sustain a fragility fracture should have access to a multidisciplinary, coordinator-based fracture liaison service that enables timely fracture and falls risk assessment, investigation, treatment, and monitoring.²²

Other key updates to the NOGG guidance²² include: a greater emphasis on vertebral fracture detection; the new concept of ‘very high fracture risk’ which should prompt consideration of the use of parenteral anti-osteoporosis therapy; new guidance regarding anabolic treatment options; the urgent need to get patients with a fragility fracture onto treatment to reduce re-fracture risk with follow-up to check tolerance and ensure adherence; the use of intravenous zoledronate as a first-line anti-osteoporosis therapy; concerns regarding denosumab cessation; and intervention thresholds for patients too frail to undergo bone density scanning.

It also recommends which high-risk patients should be referred to secondary care (Table 1). 

Table 1

Criteria for referral for specialist advice (NOGG)22

Vertebral fracture within last two years Multiple vertebral fractures BMD T-Score ≤-3.5 Treatment with high dose glucocorticoids [≥7.5 mg/day of prednisolone or equivalent over 3 months Presence of multiple clinical risk factors, particularly with a recent fragility fracture indicating high imminent risk of re-fracture Other indicators of very high fracture risk.

 Figure 1 Reproduced with permission from NOGG

Osteosarcopenia

Increasing evidence shows that muscle strength and function may be as important a risk factor and, conversely, a protector when one looks at fragility fractures. Sarcopenia is defined as a syndrome characterised by progressive and generalised  loss of muscle mass and strength²³.

Sarcopenia is evident in around 20% of over 70-year-olds; the figure rises to 50% for those over the age of 80,²³ Fracture risk is increased 3.5-fold in male osteosarcopenia patients and herewith significantly higher than in sarcopenia and osteopenia alone. Therapeutic interventions (nutrition, exercise, vitamin D) should be started early and confer benefits on both bones and muscles.

Conclusions

Osteoporosis, osteopenia and minimal trauma fractures are becoming increasingly common in the ageing population. Fractures lead to significant morbidity and mortality and serious financial impact on the healthcare systems and society.

Addressing risk factors for osteoporosis early can prevent or delay the onset of fractures. Calcium and vitamin D supplementation is beneficial for people with a high risk of deficiency (e.g. institutionalised older people). Impact and resistance exercises and physical activity can increase bone density and prevent falls.

Antiresorptive drugs such as bisphosphonates remain first-line treatment options for many patients with osteoporosis with urgent need for treatment soon after fracture.  The ongoing need for bisphosphonates should be assessed after five years and treatment may then be interrupted in some patients. Denosumab therapy should not be interrupted without switching to another therapy, as post-treatment bone loss can progress rapidly. All osteoporosis patients will need ongoing monitoring and most will require some long-term therapy once started.

Raloxifene may be considered in women who do not tolerate first-line antiresorptive drugs. Romosozumab is a new anabolic treatment for osteoporosis and, together with teriparatide, should be considered as first-line sequential therapy for individuals with severe disease and multiple fractures for rapid and potent efficacy.

Specialist referral should be considered for very high risk patients and patients who sustain fractures while undergoing osteoporosis therapy. Organised fracture liaison services is the best model of care for fracture identification and intervention. Falls, fractures, frailty, sarcopenia coexist and need to be addressed together in the ageing population.

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Dr Abhaya Gupta, Consultant Physician, Glangwili hospital, Carmarthen

[email protected]

Conflict of interest: none

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References

1. Kanis JA, Melton U. Christiansen C, et al. The diagnosis of osteoporosis. J Bone Miner Res 1994; 9:1137-1141
2.  van Staa TP, Dennison EM, Leufkens HG, Cooper C. Epidemiology of fractures in England and Wales. Bone. 2001;29:517–22
3. Khosla S, Wright N, Elderkin AL et al, Osteoporosis in the USA: prevention and unmet needs, The Lancet Diabetes & Endocrinology (2022). DOI: 10.1016/S2213-8587(22)00322-9.
4.  www.thros.org.uk.
5. Lee Shepstone, Elizabeth Lenaghan, Cyrus Cooper,et al Screening in the community to reduce fractures in older women (SCOOP): a randomised controlled trial.; for the SCOOP Study Team Lancet 2018 Feb 24;391(10122):741-747. doi: 10.1016/S0140-6736(17)32640-5. Epub 2017 Dec 16
6.  Xueying L,F Chen,Lei Liu, et al. Prevalence of osteoporosis in patients with diabetes mellitus: a systematic review and meta-analysis of observational studies. BMC Endocrine Disorders. 2023.23.1
7. Leslie WD, Morin SN, Martineau Pet 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 Oct;34(10): 1808-14
8.  Yang J, Liao M, Wang Y. et al. Opportunistic osteoporosis screening using chest CT with artificial intelligence Osteoporosis International  2022. volume 33, pages2547–2561.
9.  McCloskey EV, Harvey NC, Johansson H, et al. Fracture risk assessment by the FRAX model. Climacteric. 2022;25(1):22–28.
10.  Yao P, Bennett D, Mafham M, Lin X, Chen Z, Armitage J, Clarke R. Vitamin D and calcium for the prevention of fracture: a systematic review and meta-analysis. JAMA Netw Open. 2019 Dec 2;2(12):e1917789.
11.  Kendler DL, Marin F, Zerbini CAF et al . Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet 2018. 391:230–240.
12.  Gilsenan A, Midkiff K, Harris D, Kellier-Steele N, McSorley D, Andrews EB. Teriparatide did not increase adult osteosarcoma incidence in a 15-year US Postmarketing Surveillance Study. J Bone Miner Res. 2021 Feb;36(2):244-51.
13. Miller P, Hattersley G, Riis BJ et al. ACTIVE Study Investigators Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With OsteoporosisA Randomized Clinical Trial. JAMA.  2016;316(7):722-733. doi:10.1001/jama.2016.11136
14. Henry G Bone , Rachel B Wagman ^, Maria L Brandi et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension  Lancet Diabetes Endocrinol. 2017 Jul;5(7):513-523. doi: 10.1016/S2213-8587(17)30138-9. Epub 2017 May 22
15. Tsourdi E, Zillikens MC, Meier C, et al. Fracture risk and management of discontinuation of denosumab therapy: a systematic review and position statement by ECTS. J Clin Endocrinol Metab. 2020 Oct 26:dgaa756.
16. Saag KG, Peterson J, Brandi ML et al. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis.N Engl J Med 2017; 377:1417-1427DOI: 10.1056/NEJMoa1708322
17. McCloskey EV, Johansson H, Harvey NC et al . Romosozumab efficacy on fracture outcomes is greater in patients at high baseline fracture risk: a post hoc analysis of the first year of the frame study. Osteoporos Int 2021.32:1601–1608
18. Leder BZ, Tsai JN, Uihlein AV, et al. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial. Lancet. 2015; 386(9999): 1147-55.
19. Curtis EM, Reginster JY, Daghri NA et al. Management of patients at very high risk of osteoporotic fractures through sequential treatments. Aging Clinical and Experimental Research.2022. volume 34, pages695–714.
20. Cosman F, Crittenden DB, Ferrari S, et al. FRAME Study: The Foundation Effect of Building Bone With 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab. J Bone Miner Res 2018;33:1219-26. 10.1002/jbmr.3427

21. Li N, Hiligsmann M, Boonen A, etal. The impact of fracture liaison services on subsequent fractures and mortality: a systematic literature review and metaanalysis. Osteoporos Int. 2021 Aug;32(8):1517-30.
22. Gregson CL, Armstrong DJ, Bowden J et al. UK clinical guideline for the prevention and treatment of osteoporosis. Archives of Osteoporosisvolume17, Article number: 58.
23. Polito A, Barnaba L, Ciarapica D. Osteosarcopenia: A Narrative Review on Clinical Studies. J. Mol. Sci.2022, 23(10), 5591;  https://doi.org/10.3390/ijms23105591