Osteoporosis

Dr Donna Cosgrove PhD MPSI provides an overview of osteoporosis, including symptom control and treatment opportunities

Introduction

Osteoporosis is a silent disease, until a bone fracture occurs. Once these fractures occur, they are associated with further health issues and increased mortality.¹ An international project, called Scorecard for Osteoporosis in Europe (SCOPE), aims to determine the burden of osteoporosis in 29 countries across Europe. SCOPE data has provided estimates of the total direct costs related to osteoporosis care (ie, fragility fracture treatment and pharmacological costs). These amounted to €37.4?billion in 2010, and increased in 2019  to a huge €56.9?billion.²

Past incidence estimates indicate that in Europe and the United States, 30 per cent of women have osteoporosis. In men, 30 per cent experience an osteoporotic fracture in their lives. Osteoporosis is more common in Caucasians, women and older people. There are multiple contributing factors to the disease, however, menopause and advancing age in particular cause an imbalance between bone resorption and formation rates, reducing bone resilience.¹

There are two main groups of osteoporosis, primary and secondary. Primary is caused either by oestrogen deficiency, mainly affecting the trabecular (‘spongy’) bone; or due to ageing of cortical (more compact) and trabecular bones. Secondary osteoporosis can be caused by lifestyle changes, medications, or other diseases.
Examples of these are shown in Table 1.

Osteoporosis Pharmacology

Our bones are constantly undergoing remodelling, which is a fundamental process for bone renewal. It allows bones to adapt to physical stress, and to repair damaged bone. About 5-10 per cent of the skeleton is replaced each year in this process.^3,4 The mechanism behind this involves osteoclasts and osteoblasts: Osteoclasts are responsible for bone resorption, removing bone mineral and organic matrix, while osteoblasts lay down new bone matrix. Hormones and growth factors have an important role in regulating bone function. Oestrogen and testosterone significantly affect bone remodelling, mostly through inhibition of bone breakdown. Cytokines also influence remodelling, ie, receptor activator of the nuclear factor kappa-B ligand (RANKL). RANKL is produced by osteoblasts that bind to RANK receptors on osteoclasts.
This results in the activation and maturation of osteoclasts, causing bone resorption. A potent protease named cathepsin K (CatK) has been identified in recent years. CatK is secreted by activated osteoclasts during bone resorption, resulting in the degradation of bone matrix and breakdown of mineral components of bone tissue. Parathyroid hormone (PTH) also plays an important role in bone formation. It indirectly increases the proliferation of osteoblasts through regulation of calcium homeostasis. The Wnt pathway is another central regulator of bone metabolism, and as a result its major inhibitors sclerostin and Dickkopf (DKK)-1 have become targets of great interest for the treatment of osteoporosis.²

Pharmacological Treatments

The strengthening and protective effect of the most anti-osteoporotic drugs, except for bisphosphonates (BPs), is not sustainable on bone metabolism.⁵ Antiresorptive drugs, especially BPs, are currently the treatment of choice in most countries. BPs inhibit osteoclast-mediated bone resorption due to inhibition of the enzyme farnesyl pyrophosphate synthase.⁶ The result improves bone mass and microarchitecture, reducing fracture risk as early as six months after therapy initiation.⁷ However, while BPs can increase bone mineral density (BMD), it has been suggested that they may decrease the flexibility of bone, increasing fracture risk.⁵  Anabolic agents in general (ie, romosozumab and teriparatide) are associated with a significant reduction of fracture risk, but their duration of use is restricted (two?years for teriparatide, one year for romosozumab), and their discontinuation is associated with a decrease in BMD levels.² Because of this, use of an antiresorptive therapy is recommended after discontinuation (ie, BPs or denosumab, a humanised monoclonal antibody against RANKL). Some evidence suggests that anabolic treatment should be given as the first-line treatment to patients most at risk of fracture. In certain patients, independently from BMD, anabolic treatment is cost-effective and should be encouraged.

Romosozumab, a sclerostin inhibitor, increases BMD rapidly and reduces the risk of fracture to a greater extent than BPs. One clinical trial has shown that people who took romosozumab before alendronic acid had a 50 per cent lower relative risk of vertebral fractures over 24 months than people taking alendronic acid alone. Risk of non-vertebral fractures was also 19 per cent lower.⁸ Romosozumab is licensed in Ireland but as of yet, is not reimbursable under any Government drug schemes.⁹ A rapid review process was commissioned by the HSE in April 2021. The National Centre for Pharmacoeconomics (NCPE) advised the HSE (May 2021) that a full Health Technology Assessment (HTA) was required to assess the clinical and cost-effectiveness of romosozumab compared with the current standard of care.¹⁰ This NCPE Assessment Process is still ongoing.¹¹

Other sclerostin inhibitors are well into development and will likely be available within the next decade, ie, blosozumab. DKK-1 inhibitors are also being studied. There is potential for the eventual use of dual inhibition (DKK-1 and sclerostin) in future osteoporosis treatment.²

Defining Osteoporosis in the Future

Current osteoporosis screening, using clinical risk factor and BMD scores, only identifies a subgroup of people who go on to experience fractures, which means many individuals at risk are not identified and offered preventive measures.¹² Half of all fragility fractures occur in patients with osteopenic or even normal T-scores. Although about 50 per cent of women will have at least one fracture after the age of 50, intervention is only recommended in about seven-to-25 per cent of women, depending on the clinical guideline being used for assessment. This is far from the 50 per cent actually experiencing fractures. Importantly, the traditional definition of osteoporosis, ie, in terms of BMD, only characterises about 20 per cent of older women who have had a bone fracture. It is suggested that a broader intervention protocol, with revised intervention thresholds, is required.

Access to alternative tools, or novel markers, that can indicate levels of bone fragility will help the early diagnosis of osteoporosis.² One example of this is the trabecular bone score (TBS), which uses information from DXA scans to estimate the quality of trabecular microarchitecture. This can be incorporated with the FRAX score calculation. The FRAX risk assessment tool allows an estimation of 10-year fracture risk for patients aged between 40 and 90 years. The score combines clinical risk factors for fracture with (or without) DXA information.¹³ FRAX is already included in DXA reports from some centres.

The measurement of volumetric BMD with quantitative computerised tomography (QCT) at the hip has also been shown to predict fracture risk. Additionally, bone microarchitecture can also be assessed at peripheral sites, ie, the distal radius and tibia, using high-resolution peripheral quantitative tomography (HRpQCT).

Machine learning approaches have also been shown to effectively predict fracture risk and BMD response following pharmacological treatment. Machine learning algorithms take into account a greater number of risk factors in risk estimation, but also include factors not traditionally thought to be associated with outcome. The major advantages of machine learning are that hundreds of clinical variables are considered, and this approach can be applied and automated to hospitals that use electronic medical records, reducing the burden on clinicians.

Local osteo-enhancement procedure (LOEP) is an emerging surgical procedure that has been shown to reduce the risk of re-fracture. LOEP involves the implantation of an osteoconductive, calcium-based material in the skeleton. This is incorporated, providing biomechanical benefits. The CONFIRM study is being conducted in order to evaluate further the safety and efficacy.²

Future Treatment Recommendations

Bisphosphonates still represent the most commonly used therapy for osteoporosis worldwide. The other most commonly mentioned drugs in the literature to incorporate in future therapeutic approaches include another potent antiresorptive (denosumab – Prolia), two bone anabolics (teriparatide – Forsteo; and abaloparatide – Eladynos), and a novel agent with a dual anabolic/antiresorptive mechanism of action (romosozumab – Evenity). However, the recommended duration of use for bone anabolics and romosozumab is restricted, despite the life-long pharmacologic treatment required in osteoporosis. It is now becoming clear that a planned approach to sequential pharmacological treatments should be considered, and should ideally be planned in advance. Specific guidelines for this have not yet been developed, but it is likely that future treatment discussions will focus more on the sequential approach to treatment as more scientific evidence accumulates. ?